Is cardiopulmonary exercise testing a useful test before esophagectomy?
Cardiopulmonary exercise (CPX) testing may identify patients at high risk of postoperative cardiopulmonary morbidity and mortality. This study aims to assess the utility of CPX testing before esophagectomy. Between January 2004 and October 2006, 78 consecutive patients (64 men) with a median age of 65 years (range, 40 to 81 years) underwent CPX testing before esophagectomy (50% transhiatal; 50% transthoracic). Measured variables included anaerobic threshold (AT) and maximum oxygen uptake at peak exercise (VO2peak). Outcome measures were postoperative morbidity and mortality, length of hospital stay, and unplanned intensive therapy unit admission. Cardiopulmonary complications occurred in 33 (42%) patients and noncardiopulmonary complications in 19 (24%). One in-hospital death (1.3%) occurred, and 13 patients (17%) required an unplanned intensive therapy unit admission. The level of VO2peak was significantly lower in patients with postoperative cardiopulmonary morbidity (p = 0.04). The area under a receiver operating characteristic curve was 0.63 (95% confidence interval [CI], 0.50 to 0.76) for the VO2peak and 0.62 (95% CI, 0.49 to 0.75) for AT. An AT cutoff of 11 mL/kg/min was a poor predictor of postoperative cardiopulmonary morbidity. Although the VO2peak was significantly lower in those patients who developed cardiopulmonary complications, CPX testing is of limited value in predicting postoperative cardiopulmonary morbidity in patients undergoing esophagectomy.


Association of Relative Telomere Length and LINE-1 Methylation with Autism but not with Severity.
Autism is associated with genomic instability, which is regulated by telomere length (TL) and index of global methylation (LINE-1). This study will determine relative TL (RTL) and LINE-1 methylation percentage for 69 patients and 33 control subjects to evaluate their potential role as biomarkers for autism. The results displayed a significant decrease of both RTL and LINE-1 methylation in autistic cases relative to controls (P < 0.001). Analysis of receiver operating characteristics curve revealed that both of RTL and LINE-1 methylation percentage have the ability to serve as autism biomarkers (area under the curve = 0.817 and 0.889, respectively). The statistical analysis revealed positive correlation between the two biomarkers (correlation coefficient = 0.439 and P < 0.001).


Characterization of the novel HLA-DRB1*11:01:20 allele.
The HLA- DRB1*11:01:20 allele differs from DRB1*11:01:01:01 by 1 nucleotide substitution at position 219.


Multiple steroid metabolic pathways in ZR-75-1 human breast cancer cells.
In order to characterize the main enzymatic systems involved in androgen and estrogen formation as well as metabolism in ZR-75-1 human breast cancer cells, incubation of intact cells was performed for 12 or 24 h at 37 degrees C with tritiated estradiol (E2), estrone (E1), androst-5-ene-3 beta, 17 beta-diol (5-ene-diol), dehydroepiandrosterone (DHEA), testosterone (T), androstenedione (4-ene-dione), dihydrotestosterone (DHT) or androsterone (ADT). The extra- and intracellular steroids were extracted, separated into free steroids, sulfates and non-polar derivatives (FAE) and identified by HPLC coupled to a Berthold radioactivity monitor. Following incubation with E2, 5-ene-diol or T, E1, DHEA and 4-ene-dione were the main products, respectively, thus indicating high levels of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD). When 4-ene-dione was used, on the other hand, a high level of transformation into 5 alpha-androstane-3,17-dione (A-dione), Epi-ADT and ADT was found, thus indicating the presence of high levels of 5 alpha-reductase as well as 3 alpha- and 3 beta-hydroxysteroid dehydrogenase. Moreover, some T was formed, due to oxidation by 17 beta-HSD. No estrogen was detected with the androgen precursors T or 4-ene-dione, thus indicating the absence of significant aromatase activity. Moreover, significant amounts of sulfates and non-polar derivatives were found with all the above-mentioned substrates. The present study shows that ZR-75-1 human breast cancer cells possess most of the enzymatic systems involved in androgen and estrogen formation and metabolism, thus offering an excellent model for studies of the control of sex steroid formation and action in breast cancer tissue.


Theory-based interventions for contraception.
The explicit use of theory in research helps expand the knowledge base. Theories and models have been used extensively in HIV-prevention research and in interventions for preventing sexually transmitted infections (STIs). The health behavior field uses many theories or models of change. However, educational interventions addressing contraception often have no stated theoretical base. Review randomized controlled trials (RCTs) that tested a theoretical approach to inform contraceptive choice; encourage contraceptive use; or promote adherence to, or continuation of, a contraceptive regimen. We searched computerized databases for trials that tested a theory-based intervention for improving contraceptive use (MEDLINE, POPLINE, CENTRAL, PsycINFO, EMBASE, ClinicalTrials.gov, and ICTRP). We also wrote to researchers to find other trials. Trials tested a theory-based intervention for improving contraceptive use. We excluded trials focused on high-risk groups and preventing sexually transmitted infections or HIV. Interventions addressed the use of one or more contraceptive methods for contraception. The reports provided evidence that the intervention was based on a specific theory or model. The primary outcomes were pregnancy, contraceptive choice, initiating or changing contraceptive use, contraceptive regimen adherence, and contraception continuation. The primary author evaluated abstracts for eligibility. Two authors extracted data from included studies. We calculated the odds ratio for dichotomous outcomes. No meta-analysis was conducted due to intervention differences. Fourteen RCTs met our inclusion criteria. In 2 of 10 trials with pregnancy or birth data, a theory-based group showed better results. Four of 10 trials with contraceptive use data (other than condoms) showed better outcomes in an experimental group. For condom use, a theory-based group had favorable results in three of eight trials. Social Cognitive Theory was the main theoretical basis for five trials, of which three showed positive results. Two based on other social cognition models had favorable results, as did two of four focused on motivational interviewing. Thirteen trials provided multiple sessions or contacts. Of seven effective interventions, five targeted adolescents, including four with group sessions. Three effective trials had individual sessions. Seven trials were rated as having high or moderate quality; three of those had favorable results. Family planning researchers and practitioners could adapt the effective interventions. Reproductive health needs high-quality research on behavior change, especially for clinical and low-resource settings. More thorough use of single theories would help, as would better reporting on research design and intervention implementation.


Babesia argentina: observations on the immunogenicity of the cryofibrinogen complex.
Rabbit antisera were prepared against the soluble and insoluble fractions of a cryofibrinogen complex that formed in plasma of cattle acutely infected with Babesia argentina. Analyses of the rabbit antisera indicated that the cryofibrinogen complex contained proteins from erythrocytes and parasites as well as fibrinogen and related proteins.


C.T. aided stereotaxy for depth electrode implantation and biopsy.
We describe a computer program which facilitates the analysis of a series of C.T. scans made while a stereotaxic frame is fixed to the patient. The program has 2 modes of operation: a) The operator may select a region and determine the three-dimensional frame coordinate. b) The operator may select a set of frame coordinates and have the computer program display these at the appropriate sites on the C.T. scans. It these sites are the positions of depth electrodes, then a recording of the epileptic spike activity may be displayed at the appropriate sites on the scans.


Placenta praevia: perinatal outcomes in the experience of a third level medical unit.
To describe the perinatal results of patients who underwent complicated pregnancy with anomalous insertion of the placenta. We reviewed the clinical records with diagnosis of anomalous placental insertion after 34 weeks of gestation from January 2012 to January 2015. 200 cases were included. Diagnosis was made by endovaginal ultrasound, and 52.5% of the cases corresponded to total central placenta, 19.5% to placenta with low insertion, 18.5% to marginal placenta, and 9.5% to partial placental insertion. 24% of the pregnancies were resolved between weeks 34 and 35.6, and 76% in week 36 or more. All patients underwent cesarean: 77% were scheduled surgeries and 23% emergency surgeries. 77 patients required obstetric hysterectomy. In 58 patients, confirmed accretism by pathology. There were no maternal deaths. The most frequent complications in neonates were respiratory distress (18.5%) and newborn transitory tachypnea (5%). There was one neonatal death. Surgical treatment of anomalous placement of the placenta in third-level hospitals can prevent adverse perinatal outcomes. Expectant management is possible in selected patients.


Exodontia associated bacteremia in horses characterized by next generation sequencing.
Bacteremia resulting from dental surgery is increasingly recognized as a health risk, especially in older and immunocompromised patients. Dentistry-associated bacteremia can lead to remote infections, as exemplified by valvular endocarditis. Emerging evidence points to a novel role played by oral cavity commensals in the pathogenesis of diabetes, respiratory disease, cardiovascular disease, and adverse pregnancy outcomes. Whether dental extraction, a commonly undertaken procedure in old horses, causes bacteremia has not been reported extensively. In a prospective clinical study using next generation sequencing (based on bacterial 16S rRNA), the circulating blood microbiome was characterized before and at 1 h following extraction of incisor, canine or cheek teeth from 29 adult horses with dental disease. 16S rRNA gene sequencing results from the blood microbiome were compared with those from gingival swab samples obtained prior to extraction at the location of the diseased tooth. Bacteremia associated with translocated gingival commensals was demonstrated in horses undergoing exodontia and was, in some cases, still evident one hour post-operatively.


The Raystation conversation: Multidisciplinary perceptions about training, leadership, and communication during implementation of new technology.
There is very little information guiding cancer centres as they plan for costly and time consuming implementation programs for new technology. The purpose of this research was to explore the perspectives of multiple professional groups directly involved in the implementation of a next generation treatment planning system at a large academic cancer centre . This research was a single centre, prospective study using a qualitative design and three-phased approach (interviews, questionnaire, and focus groups). The target population included radiation therapists, oncologists, and physicists that received Raystation training during initial clinical implementation. Training was received positively by most respondents, but the lengthy lead-up time between training and clinical use led to decreased confidence with the software across all professional groups. Multidisciplinary training was not considered useful when learning tool function, but would have been helpful when practicing on clinically relevant cases. Respondents appreciated the proactive communication, as well as the multidisciplinary leadership implementation strategy. Therapist 'Super Users' emerged as a pivotal leadership and communication role in the successful implementation of Raystation. This research provided valuable multidisciplinary insight into the implementation of Raystation. The multidisciplinary leadership team and proactive communication strategy were considered vital to the success of the implementation. Learner suggestions - such as increasing the number of Therapist 'Super Users', minimizing training-to-clinical lead time, and the creation of practice cases that are more relevant to daily clinical duties - should be incorporated into future training programs for similar new technology.


Correlation analysis of national elite Chinese male table tennis players' shoulder proprioception and muscle strength.
Shoulder is the most injured part in table tennis players, and it takes multiple roles in transmitting power and striking the center of the ball during the stroke. Proprioception is strongly correlated with high level of athletic performance. It is customary to assume that there is a correlation between proprioception and muscle strength and therefore proprioceptive assessment and rehabilitation is often neglected. To investigate the correlation between isokinetic muscle strength and proprioception in the internal and external rotation muscle groups of elite Chinese male table tennis players, to provide reference for physical training and rehabilitation of elite table tennis players. A total of 19 national elite table tennis players from the Chinese National Table Tennis Team were recruited in this research. All of them had more than 10 years training experience and had participated major competitions such as the National Games and World Youth Championships. IsoMed 2000 was used to test the peak torque of internal and external rotation isokinetic concentric contraction of the athletes' bilateral shoulder joints at low speed (60°/s) and high speed (180°/s) respectively; IsoMed 2000 was used to conduct the Joint Position Reproduction test to evaluate the athletes' proprioceptive ability capacity at low speed (60°/s) and high speed (180°/s) respectively. If the data satisfied the normal distribution, the correlation between the differences in peak torque s and angles in different directions was analyzed using a Pearson simple linear model; otherwise, Spearman correlation analysis was used. The comparison of proprioceptive ability between the table tennis racket-holding hand and non-racket-holding hands was performed using independent samples t-test if the data satisfied a normal distribution; otherwise, the Mann-Whitney U test was used. There was no direct linear correlation between the strength and proprioceptive correlation analysis at slow speed (60°/s) and fast speed (180°/s) in the racket-holding hand; At the slow speed (60°/s) and fast speed (180°/s), there was no correlation between muscle strength and proprioception in the non-racket-holding hand except for the internal rotation variable error (VE) and external rotation relative peak torque, which showed a moderate positive correlation (r = 0.477, P < 0.05), (r = 0.554, P < 0.05). The internal rotation's constant error (CE) and VE were 1.06 ± 3.99 and 2.94 ± 2.16, respectively, for the racket-holding hand, and -3.36 ± 2.39 and 1.22 ± 0.93, respectively, for the non-racket-holding hand; the internal rotation's CE, VE of the racket-holding hand was lower than that of the non-racket-holding hand, and there was a highly significant difference (P < 0.01). There was no correlation between muscle strength and proprioceptive function in the internal and external rotation of the racket-holding hand's shoulder in elite Chinese male table tennis players. These results may be useful for interventions for shoulder injuries and for the inclusion of proprioceptive training in rehabilitation programs.


National Trends, Risk Factors, and Outcomes of Acute In-Hospital Stroke Following Lung Transplantation in the United States: Analysis of the United Network for Organ Sharing Registry.
Lung transplantation (LTx) is the definitive treatment for end-stage lung failure. However, there have been no large, long-term studies on the impact of acute in-hospital stroke in this population. What are the trends, risk factors, and outcomes of acute stroke in patients undergoing LTx in the United States? We identified adult first-time isolated LTx recipients from the United Network for Organ Sharing database, which comprehensively captures every transplant in the United States, between May 2005 and December 2020. Stroke was defined as occurring at any time after LTx but prior to discharge. Multivariable logistic regression with stepwise feature elimination was used to identify risk factors for stroke. Freedom from death in patients with a stroke vs those without a stroke was evaluated with Kaplan-Meier analysis. Cox proportional hazards analysis was used to identify predictors of death at 24 months. Of 28,564 patients (median age, 60 years; 60% male), 653 (2.3%) experienced an acute in-hospital stroke after LTx. Median follow-up was 1.2 (stroke) and 3.0 (non-stroke) years. Annual incidence of stroke increased (1.5% in 2005 to 2.4% in 2020; P for trend = .007), as did lung allocation score and utilization of post-LTx extracorporeal membrane oxygenation (P = .01 and P < .001, respectively). Compared with those without stroke, patients with stroke had lower survival at 1 month (84% vs 98%), 12 months (61% vs 88%), and 24 months (52% vs 80%) (log-rank test, P < .001 for all). In Cox analysis, acute stroke conferred a high hazard of mortality (hazard ratio, 3.01; 95% CI, 2.67-3.41). Post-LTx extracorporeal membrane oxygenation was the strongest risk factor for stroke (adjusted OR, 2.98; 95% CI, 2.19-4.06). Acute in-hospital stroke post-LTx has been increasing over time and is associated with markedly worse short- and long-term survival. As increasingly sicker patients undergo LTx as well as experience stroke, further research on stroke characteristics, prevention, and management strategies is warranted.


A metagenomic-based study of two sites from the Barbadian reef system.
We study the microbiome of sea water collected from two locations of the Barbadian coral reefs. The two sites differ in several environmental and ecological variables including their endogenous benthic community and their proximity to urban development and runoffs from inland watersheds. The composition of the microbial communities was estimated using whole genome DNA shotgun sequencing with adjuvant measurements of chemical and environmental qualities. Although both sites exhibit a similar degree of richness, the less urbanized site (Maycocks reef at Hangman's Bay) has a strong concentration of phototrophs whereas the more urbanized location (Bellairs reef at Folkstone) is enriched for copiotrophs, macroalgal symbionts and marine-related disease-bearing organisms from taxa scattered across the tree of life. Our results are concordant with previous profiles of warm ocean surface waters, suggesting our approach captures the state of each coral reef site, setting the stage for longitudinal studies of marine microbiome dynamics in Barbados. The online version contains supplementary material available at 10.1007/s00338-022-02330-y.


Prevalence of temporomandibular disorders in the Brazilian population: A systematic review and meta-analysis.
This systematic review aimed to assess the prevalence of temporomandibular disorders (TMD) in the Brazilian population, with studies that used the RDC/TMD or DC/TMD as diagnostic tools. A total of 6365 people from 11 studies were included. Sample mean age ranged from 12 to 69.5 years. The pooled prevalence of TMD was 33.6% (95% CI 31.5-35.8; I2 = 37.2). Prevalence of TMD was higher in females (37.0%) than in males (29.3%). Our results indicate that TMD is a prevalent condition across Brazil's territories. The results from this meta-analysis can help calculate more accurate sample sizes for future studies.


Survey of the frequency of olfactory dysfunction in Taiwan.
Olfactory function is related to the scrutiny of environmental dangers and the tasting of food. However, olfactory dysfunction is not as distinctive as visual loss and may go unnoticed, especially when olfactory function deteriorates slowly. Most studies have used either questionnaires or relatively insensitive tests to assess olfactory dysfunction. Therefore, the objective of this study was to evaluate the frequency of olfactory dysfunction in Taiwan. A total of 211 participants were recruited randomly from the community, factories or offices in Taichung City, Taiwan from April 2005 to March 2006. Age ranged from 19 to 89 years (mean age, 43.3 +/- 12.7 years). All participants filled in questionnaires about sociodemographic data, self-rated olfactory function and impact on quality of life. The olfactory test was performed with identification task of the "Sniffin' Sticks" olfactory function test. The frequency of olfactory dysfunction in our series was 12.3%. There was a statistically significant difference in the ages of the normal and olfactory dysfunction groups (t test, p < 0.0001). The incidences of parosmia and phantosmia in the 211 participants were 10% and 30.8%, respectively. Most subjects did not rate their olfactory function well. There was no correlation between olfactory function and self-ratings of impact of olfactory function on quality of life. Our present results provide preliminary data and clinical experience regarding the frequency of olfactory dysfunction in Taiwan. Future modifications and suggestions for the study of the prevalence of olfactory dysfunction are also mentioned.


Surgical Ventricular Reconstruction Eligible for Late Assist Device Implantation.
In patients with ischemic cardiomyopathy and left ventricular aneurysm formation who are symptomatic despite optimal medical therapy, it is challenging to determine whether surgical ventricular reconstruction, heart transplantation, or left ventricular assist device (LVAD) implantation is the treatment of choice. This report describes the concept of surgical ventricular reconstruction with a specially prepared LVAD fixation ring to facilitate subsequent LVAD implantation if required. In the patient reported in this case, endoventricular circular LVAD ring plasty sufficiently reduced the ventricular volume, normalized the left ventricular geometry, and subsequently led to an improvement of left ventricular ejection fraction.


Content analysis of health-related subjects in the K12 school curricula of Japan, Indonesia, Philippines, Guam, Micronesia, Marshall Islands, Palau, and Fiji.
As a component of health promoting school, a school curriculum for health education was considered a fundamental. This survey aimed to identify the components of health-related topics and in which subjects were they taught. Four topics were chosen: (i) hygiene, (ii) mental health, (iii) nutrition-oral Health, and (iv) environmental education related to global warming in Education for Sustainable Development (ESD). Before gathering the curricula from partner countries, school health specialists were gathered to discuss the appropriate components of a curriculum that required evaluation. The survey sheet was distributed to and answered by our partner in each country. About hygiene, individual practices or items that improve health-related were widely covered. However, items that imparted health-related education from an environmental perspective were not widely covered. About mental health, two types of country groups were identified. The first group included countries that taught mental health topics mainly as part of morals or religion; the second group included countries that imparted mental health topics mainly as part of health. The first group focused mainly on communication skills or coping methods. The second group focused not only on communication and coping skill but also on basic knowledge of mental health. About nutrition-oral education, three types of country groups were identified. One group imparted nutrition-oral education mainly in terms of health or nutrition. Another group imparted this topic mainly in terms of morals, home economics, and social science. The third group was the intermediate group. About ESD, a solid structure for this topic was not identified in any country. Many items were taught as part of science, while some were taught as part of social studies. Climate change was the most commonly taught item across all countries. The items related to environment were relatively limited compared to those related to natural disasters. Overall, two different approaches were identified: the cultural-based approach, which promotes healthy behaviors as moral codes or community-friendly behaviors and the science-based approach, which promotes children's health through scientific perspectives. Policymakers should initially consider the findings of this study while making decisions on which approach should be taken.


Isolation, Culture, Cryopreservation, and Preparation of Skin-Derived Fibroblasts as a Final Cellular Product Under Good Manufacturing Practice-Compliant Conditions.
Cell-based therapies have become a popular approach in the field of regenerative medicine. Human fibroblast cells, one of the cell types widely used in clinical applications, have been used for skin regeneration and wound healing procedures. Furthermore, they are utilized for aesthetic purposes since fibroblasts lose their abilities such as collagen synthesis with age. Here, we describe detailed procedures for isolation, culture, cryopreservation, and preparation of fibroblasts derived from adult human skin as a final product under good manufacturing practice-compliant conditions.


Prophylactic antibiotics for preventing genital tract infection in women undergoing surgical procedures for incomplete abortion: a systematic review and meta-analysis of randomised controlled trials.
Findings about the effect of prophylactic antibiotics in preventing genital tract infection (GTI) associated with surgical procedures used for incomplete abortions are conflicting. Some reported a decrease in infection associated with the use of antibiotic prophylaxis, whereas others found no significant reduction in GTI. To synthesise systematically the evidence on the effect of prophylactic antibiotics compared with placebo in women undergoing surgical procedures for incomplete abortion. In February 2020, PubMed, Embase and Cochrane Central for Register of Controlled Trials were searched for relevant published randomised controlled trials. Randomised controlled trials reporting GTI following surgical procedures for incomplete abortion and comparing antibiotic prophylaxis with placebo. Meta-analysis using inverse variance heterogeneity model included subgroup and sensitivity analyses determined a priori were conducted. The quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). A total of 16 178 women who participated in 24 eligible randomised controlled trials published between 1975 and 2019 were included. Pooled estimates showed the risk of GTI following surgical procedures after incomplete abortion was significantly lower among those who had prophylactic antibiotics (relative risk [RR] = 0.72; 95% CI 0.58-0.90; I2 = 49%). There was no significant effect of antibiotics in women in low- and middle-income countries (three studies, 3579 participants, RR = 0.90; 95% CI 0.50-1.62; I2 = 63%), but it was clinically and statistically significant among women high-income countries (21 studies, 12 599 participants, RR = 0.67; 95% CI 0.53-0.84; I2 = 44%), with a strong level of evidence as assessed by GRADE. This study provides evidence that antibiotic prophylaxis is beneficial in reducing post-abortion GTI among women undergoing surgical procedures for incomplete abortion. More studies are needed from low- and middle-income countries. Prophylactic antibiotics after incomplete abortion are effective in reducing GTI. More studies are needed from low- and middle-income countries.


Crossing the blood-brain barrier: A review on drug delivery strategies using colloidal carrier systems.
The blood-brain barrier represents the major challenge for delivering drugs to the central nervous system (CNS). It separates the blood circulation from the brain tissue, thereby protecting the CNS and maintaining its ion homeostasis. Unfortunately, most drugs are not able to cross this barrier in vivo despite promising in vitro results. One approach to solve this problem is the delivery of drugs via surface modified nanocarrier systems. This review will give an overview on currently tested systems, mainly liposomes and solid nanoparticles and inform about new developments.


A single dose of aminophylline administration during therapeutic hypothermia; does it make a difference in glomerular filtration rate?
Aminophylline has been demonstrated to be effective in improving renal functions of the infants suffering from acute kidney injury (AKI) due to perinatal asphyxia. We aimed to evaluate the effect of a single-dose aminophylline on estimated glomerular filtration rate (eGFR), urine output (UO), and incidence and severity of AKI according to the pediatric-modified RIFLE and neonatal RIFLE criteria in newborns with perinatal asphyxia under therapeutic hypothermia. This was a single-center, retrospective cohort study including newborns (gestational age ≥36 weeks) who underwent therapeutic hypothermia due to hypoxic ischemic encephalopathy between 2016 and 2019. Demographic and clinical data were obtained from electronic medical records and patient files. Two patient groups were established: aminophylline group and control group which were only under therapeutic hypothermia. Twenty-one newborns were in the aminophylline group and 13 newborns were in the control group. Our study revealed that on the third day of life (DOL), eGFR was significantly higher in the control group (p=0.025), but UO was significantly higher in the aminophylline group (p=0.021). In the aminophylline group, eGFR on the first DOL was higher than the value on the second DOL (p=0.017) while UO was higher on the second and third DOL compared to the first DOL (1-2 DOL p=0.006, and 1-3 DOL p=0.004). However, in the control group, there was no statistically significant difference in UO over the four DOL. Both groups were similar in the presence, severity, and outcome of AKI.Conclusion: This study demonstrated that aminophylline increases UO even in the infants under therapeutic hypothermia. However, the eGFR did not significantly increase in the aminophylline group. Understanding how therapeutic hypothermia affects pharmacokinetics may help us improve our results in future studies. What is known: • Therapeutic hypothermia (TH) reduces the incidence of acute kidney injury in asphyxiated newborns. • Aminophylline is effective in improving renal functions in asphyxiated newborns. What is new: • This is the first study evaluating the effect of a single dose of aminophylline on renal functions in newborns under TH. • A single dose of aminophylline administration in newborns under TH was associated with increased urine output especially on the third day of life. However, no significant increase was detected in glomerular filtration rate associated with aminophylline administration.


Effect of phosphonate functional group on corrosion inhibition of imidazoline derivatives in acidic environment.
In the present study, ({2-[2-(7-Isopropyl-1,4-dimethyl-9,10-octahydro-phenanthren-1-yl)-4,5-dihydro-1-yl]-ethylamino}-methyl)-phosphonicimidazole (GSIM) was synthesized by introducing phosphonate (-PH2O3) group into imidazoline derivatives and its corrosion inhibition performance was studied for Q345 steel in acidic medium along with SIM using potentiodynamic polarization, EIS and SECM analysis. Surface analysis of steel samples was also performed by optical microscopy and SEM-EDS analysis after polarization tests. XPS was used to detect chemical composition of the surface passive films. It was observed that introducing -PH2O3 group not only improved the adsorption capacity on the metal surface by coordinating with iron ions, but also inhibited the interference of hydrogen bond formed by -NH2 group and water molecules on the adsorption. GSIM not only inhibited intercrystalline corrosion and pitting corrosion, but also reduced uniform corrosion. Thermodynamics studies demonstrated that GSIM followed the Langmuir adsorption isotherm and had a larger adsorption equilibrium constant than SIM, which indicated that it had a stronger adsorption capacity. XPS and UV confirmed that the coordination between GSIM and Fe3+ and hydrogen bonding between SIM and water molecules. The quantum chemical study further clarified that the site and strength of hydrogen bond between SIM and H2O and the dominant configuration and coordination stability of GSIM with Fe3+.


Unexpected complication of intra-aortic balloon counterpulsation via the ascending aorta: balloon migration.
A case of intraaortic balloon pump catheter migration after an ascending aortic insertion, occurring 16 h postoperatively in a 48 year old man after myocardial revascularization, is presented. The prevention and management of this rare but serious complication of intraaortic balloon pumping is reviewed.


Effect of Dietary Microalgae on Growth Performance, Profiles of Amino and Fatty Acids, Antioxidant Status, and Meat Quality of Broiler Chickens.
The study used 96 broiler chickens to evaluate the impact of three species of microalgae on performance, profiles of fatty and amino acids, antioxidants, and meat quality of breast muscles. Birds were divided into four groups (24 birds/each) with 4 replicates (6 birds each). Birds in the first group were fed basal diet and served as a control (C). Birds of 2-4 groups were fed basal diet mixed with same dose (1 g/kg diet) of Chlorella vulgaris (CV), Spirulina platensis (SP), and Amphora coffeaformis (AC). At the age of 36 days, performance parameters were reported, and breast muscle samples were collected and stored frozen at -80 °C. AC shared CV in the superiority of increasing final body weight and body weight gain compared to SP and control. AC shared SP in the superiority of increasing the level of essential fatty and amino acids and decreasing the microbial growth in breast muscle compared to CV and control. All studied microalgae reduced malondialdehyde (MDA) and protein carbonyl (PC) levels, cooking loss, and aerobic plate count (APC) and increased the superoxide dismutase (SOD) activities in breast muscle compared to control. The current study indicated that studied microalgae, notably AC, can be used to enhance performance and meat quality in broilers chickens.


Cytotoxicity of dental disclosing solution on gingival epithelial cells in vitro.
Coloring dental biofilm and plaque with a dental disclosing solution is visually effective in dental treatment and oral hygiene education. Despite continuous reports of the risk of the product ingredients, dental disclosing solution are widely used in dentistry. However, the cytotoxic mechanism of dental disclosing solution is not known. Here we elucidated the tissue dyeing range and investigated the cytotoxic mechanism of dental disclosing solution. Gingival epithelial cells and mouse head and neck tissue were stained with dental disclosing solution. Changes in the cell cycle distribution by the dental disclosing solution treatment were analyzed. A deoxynucleotidyl transferase dUTP nick and labeling (TUNEL) assay was performed to examine the apoptotic features of the gingival epithelial cells. Dental disclosing solution stained the chromosome strongly, as well as both the hard and soft tissue of the mouse head and neck. The results of flow cytometric analysis and TUNEL analyses revealed that the cytotoxicity associated with dental disclosing solution was related to the induction of apoptosis. However, the staining of porcine skin by dental disclosing solution was not easily removed, even with a wide range of pH solutions. These results suggest that dental disclosing solution had strong cytotoxicity and safer alternatives are needed.


Actionable Genetic Screens Unveil Targeting of AURKA, MEK, and Fatty Acid Metabolism as an Alternative Therapeutic Approach for Advanced Melanoma.
Despite the remarkable improvements achieved in the management of metastatic melanoma, there are still unmet clinical needs. A considerable fraction of patients does not respond to immune and/or targeted therapies owing to primary and acquired resistance, high-grade immune-related adverse events, and a lack of alternative treatment options. To design effective combination therapies, we set up a functional ex vivo preclinical assay on the basis of a drop-out genetic screen in metastatic melanoma patient-derived xenografts. We showed that this approach can be used to isolate actionable vulnerabilities predictive of drug efficacy. In particular, we highlighted that the dual targeting of AURKA and MAPK/extracellular signal-regulated kinase kinase employing the combination of alisertib and trametinib is highly effective in a cohort of metastatic melanoma patient-derived xenografts, both ex vivo and in vivo. Alisertib and trametinib combination therapy outperforms standard-of-care therapy in both BRAF-mutant patient-derived xenografts and targeted therapy-resistant models. Furthermore, alisertib and trametinib treatment modulates several critical cancer pathways, including an early metabolic reprogramming that leads to the transcriptional upregulation of the fatty acid oxidation pathway. This acquired trait unveiled an additional point of intervention for pharmacological targeting, and indeed, the triple combination of alisertib and trametinib with the fatty acid oxidation inhibitor etomoxir proved to be further beneficial, inducing tumor regression and remarkably prolonging the overall survival of the mice.


Histologic classification of pure primary epithelial breast cancer.
Current classifications of breast cancer are based on either morphologic descriptive or histogenetic criteria. The positive features and shortcomings of the most commonly used systems are presented. Our knowledge of breast cancer leads validity to a histogenetic topographic classification, a modification of which is suggested.


Background-suppressed tumor-targeted photoacoustic imaging using bacterial carriers.
Photoacoustic (PA) imaging offers promise for biomedical applications due to its ability to image deep within biological tissues while providing detailed molecular information; however, its detection sensitivity is limited by high background signals that arise from endogenous chromophores. Genetic reporter proteins with photoswitchable properties enable the removal of background signals through the subtraction of PA images for each light-absorbing form. Unfortunately, the application of photoswitchable chromoproteins for tumor-targeted imaging has been hampered by the lack of an effective targeted delivery scheme; that is, photoswitchable probes must be delivered in vivo with high targeting efficiency and specificity. To overcome this limitation, we have developed a tumor-targeting delivery system in which tumor-homing bacteria (Escherichia coli) are exploited as carriers to affect the point-specific delivery of genetically encoded photochromic probes to the tumor area. To improve the efficiency of the desired background suppression, we engineered a phytochrome-based reporter protein (mDrBphP-PCMm/F469W) that displays higher photoswitching contrast than those in the current state of the art. Photoacoustic computed tomography was applied to achieve good depth and resolution in the context of in vivo (mice) imaging. The present system effectively integrates a genetically encoded phytochrome-based reporter protein, PA imaging, and synthetic biology (GPS), to achieve essentially background-suppressed tumor-targeted PA monitoring in deep-seated tissues. The ability to image tumors at substantial depths may enable target-specific cancer diagnoses to be made with greater sensitivity, fidelity, and specificity.


Effects of regular consumption of different forms of almonds and hazelnuts on acceptance and blood lipids.
Regular nut consumption is inversely associated with cardiovascular disease risk. No study has compared the effects of regular consumption of different types and forms of nuts on acceptance, which is a crucial determinant of long-term compliance to consume nuts regularly. This study examined the effects of different types and forms of raw, unpeeled nuts on acceptance and the effects of nut consumption on blood lipids through a randomised crossover study with six dietary phases: 30 g/day of ground, sliced, or whole almonds or hazelnuts for 5 days each (n = 74). Acceptance ('desire' and 'liking') for nuts was measured daily using visual analogue scales. Blood lipids were measured at baseline and week 6. Acceptance was stable over all conditions, but there were differences between nut forms (ground < sliced < whole, P < 0.001 for both 'desire' and 'liking') with some nut type-nut form interactions. Compared with baseline, week 6 HDL-C was higher (0.06 mmol/L, 95% CI 0.02-0.10, P = 0.002) while LDL-C and total-C:HDL-C ratio were lower (0.15 mmol/L, 95% CI 0.06-0.25, P = 0.002 and 0.25, 95% CI 0.07-0.43, P = 0.006). In conclusion, acceptance was stable for all combinations but was highest for whole nuts. Six weeks of nut consumption improved blood lipids.


Expansion of the Conceptual Model for the Accumulation of Selenium in Lentic Food Chains to Include Redox-Controlled Generation and Diffusion of Selenite and Dissolved Organo-Selenium Compounds.
The controls governing the availability of reduced selenium (Se) species, namely selenite (Se[IV]) and dissolved organo-Se (DOSe), to primary producers at the sediment-water interface in depositional environments (i.e., lentic systems) were assessed through consideration of theoretical principles and field data. Selenite is generated in suboxic sediment porewater via the microbially mediated reduction of selenate (Se[IV]) and/or reductive dissolution of Se-bearing iron oxides. Field data for lentic environments demonstrate that the production of DOSe in sediment porewaters can also be redox- and depth-dependent. In this manner, the remobilization depths of Se(IV) and DOSe in depositional environments are dependent on the vertical redox gradient (dEh/dz), where deeper depths of remobilization are observed in less reducing sedimentary environments (lower dEh/dz). In turn, remobilization depth has a direct bearing on the concentration of dissolved Se(IV) and DOSe that may be realized at the sediment-water interface because the depth of reaction governs the diffusive path length, concentration gradient, and rate of diffusional transport toward the sediment-water interface. The principles that link sediment redox gradients, depth of remobilization, diffusive transport processes, and concentration of reduced Se species at the sediment-water interface have a direct bearing on the potential for Se uptake by primary producers in lentic food chains (e.g., phytoplankton, biofilms, bacteria). Overall, these processes complement the current conceptual "benthic detrital food chain" model that describes the accumulation of Se in lentic systems. Environ Toxicol Chem 2022;41:2859-2869. © 2022 SETAC.


The nucleotide sequence of cysteine transfer ribonucleic acid from baker's yeast. Identification of the products from partial degradation of the molecule and derivation of the complete sequence.
1. A series of large oligonucleotide fragments derived from tRNA Cys, were separated chromatographically and the sequence of each was deduced by examination of the products of digestion with pancreatic and T1 ribonucleases. 2. The location of the specific cleavage points in the nucleotide chain was similar to that produced by brief treatment with pancreatic ribonuclease. 3. The fragments could be arranged into two alternative sequences. The correct sequence was deduced by the sequential removal and identification of the first nine nucleotides from the 3'-end of the terminal half of the molecules.


Secretory carcinoma of the salivary gland: a multi-institutional clinicopathologic study of 90 cases with emphasis on grading and prognostic factors.
Secretory carcinoma (SC) is a rare form of salivary carcinoma that was first described in 2010 and is characterized by ETV6::NTRK3 fusion in most cases. In this large retrospective study, we aimed to identify adverse clinicopathologic factors and propose a prognostically relevant grading scheme for SC. A detailed clinicopathologic review was conducted on 90 SCs from the major and minor salivary glands. The median age at presentation was 50 years (range: 7-93). Sixty-nine (77%) tumours originated from major salivary glands, whereas the remaining 21 involved minor salivary glands.Six cases (7%) had cervical nodal metastasis. Only lymphovascular invasion (LVI) was associated with a risk of nodal metastasis (P < 0.05). The 5-year disease-specific survival and disease-free survival (DFS) were 98% and 87%, respectively. On univariate survival analysis, adverse prognostic factors associated with decreased DFS included minor salivary gland origin, atypical mitosis, high mitotic index, high-grade transformation (HGT), necrosis, nuclear pleomorphism, infiltrative tumour border, fibrosis at the invasive front, LVI, positive margin, and advanced pT stage (P < 0.05). When adjusted for pT stage and margin status, mitotic index, LVI, nuclear pleomorphism, and HGT remained as independent prognostic factors. We therefore propose a two-tiered grading system for SC. The low-grade SC is defined as those with <5 mitoses /10 high-power fields and no tumour necrosis, and high-grade SC as those with ≥5 mitoses /10 high-power fields and/or necrosis. This proposed grading system can be useful to risk stratify patients with SC for appropriate clinical management.


Detecting Redox Potentials Using Porous Boron Nitride/ATP-DNA Aptamer/Methylene Blue Biosensor to Monitor Microbial Activities.
Microbial activity has gained attention because of its impact on the environment and the quality of people's lives. Most of today's methods, which include genome sequencing and electrochemistry, are costly and difficult to manage. Our group proposed a method using the redox potential change to detect microbial activity, which is rooted in the concept that metabolic activity can change the redox potential of a microbial community. The redox potential change was captured by a biosensor consisting of porous boron nitride, ATP-DNA aptamer, and methylene blue as the fluorophore. This assembly can switch on or off when there is a redox potential change, and this change leads to a fluorescence change that can be examined using a multipurpose microplate reader. The results show that this biosensor can detect microbial community changes when its composition is changed or toxic metals are ingested.


The Bone Marrow Microenvironment in Immune-Mediated Inflammatory Diseases: Implications for Mesenchymal Stromal Cell-Based Therapies.
Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) are promising candidates for cell-based therapy for several immune-mediated inflammatory diseases (IMIDs) due to their multiplicity of immunomodulatory and reparative properties and favorable safety profile. However, although preclinical data were encouraging, the clinical benefit demonstrated in clinical trials of autologous MSC transplantation in a number of conditions has been less robust. This may be explained by the growing body of evidence pointing to abnormalities of the bone marrow microenvironment in IMIDs, including impaired MSC function. However, it is not currently known whether these abnormalities arise as a cause or consequence of disease, the role they play in disease initiation and/or progression, or whether they themselves are targets for disease modification. Here, we review current knowledge about the function of the BM microenvironment in IMIDs including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and type I diabetes, focusing on MSCs in particular. We predict that an improved understanding of disease-related changes in the bone marrow microenvironment including the role of MSCs in vivo, will yield new insights into pathophysiology and aid identification of new drug targets and optimization of cell-based therapy in IMIDs.


The importance of ergonovine maleate provocation in the diagnosis of coronary artery spasm. A case report.
Ergonovine maleate produced transient vasospastic occlusion of the entire left anterior descending coronary artery in a young woman with atypical angina pectoris and normal coronary arteries. Electrocardiographic evidence of extensive anterior subendocardial ischaemia persisted for days after an episode of spontaneous pain, suggesting that the patient was at risk of developing completed infarction due to coronary spasm.


Optimization of antioxidant, anti-diabetic, and anti-inflammatory activities and ganoderic acid content of differentially dried Ganoderma lucidum using response surface methodology.
The dried Ganoderma lucidum (GL) has been widely used for its pharmacological properties and bioactive ganoderic acids (GAs). Herein, extraction procedures combining ultra-sonication and heating were optimized using response surface methodology based on four variables (antioxidant activity, anti-diabetic activity, total GAs content, and total polysaccharide content) and principal component analysis. The extraction of freeze-dried GL at temperatures between 64.2 and 70 °C for 1.2 h maximized the antioxidant activity and GA content, whereas the polysaccharide content and anti-diabetic activity were maximized by extraction between 66.8 and 70 °C for more than 2.8 h. Heat-dried GL extracted at 50 °C for 3 h provided the greatest anti-inflammatory activity against HaCaT cells by suppressing the response to inflammation related cytokines at mRNA levels. These results suggest that extraction conditions might be a limiting factor for target-oriented investigations, and optimized extraction methods may improve the potential effect and quality of harvested GL products.


The risk of intradural spinal metastases in patients with brain metastases from bronchogenic carcinomas.
Intradural spinal metastases can develop following dissemination via the cerebrospinal fluid from various primary or secondary brain tumors. Since the risk of intradural spinal metastases has never been formally studied in patients with brain metastases, we reviewed patients with brain metastases from bronchogenic carcinomas and looked for the subsequent development of intradural spinal metastases. Of 160 consecutive patients, only 6 presented intradural spinal metastases, however none were among the 105 patients who had exclusively supratentorial metastases and all intradural spinal metastases were in patients who had lesions in the posterior fossa. In this group, the 1-year actuarial risk of having intradural spinal metastases was 21% (p less than .01 compared with patients who had supratentorial metastases). We could not find any other risk factor for intradural spinal metastases. Recommendations for the group of patients with increased risk of intradural spinal metastases are made.


Self-rated health trajectory and frailty among community-dwelling older adults: evidence from the Taiwan Longitudinal Study on Aging (TLSA).
Self-rated health (SRH) is an assessment and predictor of health based on an individual's general condition; however, evidence of the value of SRH for predicting frailty remains scarce for older Asian adults. This study aimed to evaluate the relationship between SRH score trajectory and frailty among older individuals in Taiwan. An 8-year retrospective cohort study. Data were retrieved from the Taiwan Longitudinal Study on Aging from 1999 to 2007. Respondents aged 53-69 years old who were not frail or disabled in 1999 (n=1956). Frailty was defined using the Fried criteria. The group-based trajectory modelling technique was used to estimate SRH trajectories. Logistic regression analysis was used to examine the associations between changes in SRH and frailty. Four SRH trajectory classes were identified across the 8-year follow-up: 232 participants (11.9%) were classified into the constantly poor SRH group, 1123 (57.4%) into the constantly fair SRH group, 335 (17.1%) into the constantly good SRH group and 266 (13.6%) into the good-to-fair SRH group. After adjusting for gender, age, level of education, income, social participation, health behaviours and major comorbidities, it was found that age, poor income satisfaction, without job and constantly poor SRH were associated with increased risk of frailty, while constantly good SRH (OR 0.04, 95% CI (0.01 to 0.32)) and good-to-fair SRH (OR 0.19, 95% CI (0.06 to 0.63)) were associated with reduced risks of frailty. Constantly poor SRH was associated with an increased risk of frailty in older age. SRH in older adults should be recognised as a predictive tool for future frailty. Diet and exercise interventions may help to prevent frailty among high-risk older individuals with constantly low SRH.


Differences in the prevalence of a TaqI RFLP in the 3' flanking region of the alpha 1-proteinase inhibitor gene between asthmatic and non-asthmatic black and white South Africans.
The prevalence of the Taq I(-) allele in variants of alpha 1-proteinase inhibitor (alpha 1PI) was investigated in a group of 28 black asthmatic patients and 32 black control individuals, and was compared to 43 white asthmatic patients and 32 white control individuals. The plasma concentration of alpha 1PI was determined in eight black and 14 white asthmatics without the Taq I(-) allele, and compared to seven black and three white asthmatics with the Taq I(-) allele. Alpha-1-PI concentration was also determined in 10 black and 29 white control individuals without the Taq I(-) allele and compared to seven black and three white controls with the Taq I(-) allele. There was a highly significant difference in the frequency of the Taq I(-) allele between black South Africans (24.1%) and white South Africans (6%) (p < 0.00001) and a significant difference in the frequency of the Taq I(-) allele between black asthmatics and white asthmatics (p = 0.0004) and between black controls and white controls (p = 0.011). The Taq I(-) allele was significantly associated with the M1 (Val213) variant as compared to the M1 (Ala213) of alpha 1PI (p = 0.0042). There was no difference in the concentration of alpha 1PI between the asthmatics (black and white) lacking the Taq I(-) allele and the asthmatics (black and white) with the allele. However, a significant increase in plasma alpha 1PI concentration was found in the asthmatics compared to the controls (p = 0.011). The Taq I(-) allele did not seem to interfere with the basal expression of alpha 1PI in the groups of asthmatic patients in this study.


A simplified alternative diagnostic algorithm for SARS-CoV-2 suspected symptomatic patients and confirmed close contacts (asymptomatic): A consensus of Latin American experts.
Latin America accounts for one-quarter of global COVID-19 cases and one-third of deaths. Inequalities in the region lead to barriers to the best use of diagnostic tests during the pandemic. There is a need for simplified guidelines that consider the region's limited health resources, international guidelines, medical literature, and local expertise. Using a modified Delphi method, 9 experts from Latin American countries developed a simplified algorithm for COVID-19 diagnosis on the basis of their answers to 24 questions related to diagnostic settings, and discussion of the literature and their experiences. The algorithm considers 3 timeframes (≤7 days, 8-13 days, and ≥14 days) and presents diagnostic options for each. SARS-CoV-2 real- time reverse transcription-polymerase chain reaction is the test of choice from day 1 to 14 after symptom onset or close contact, although antigen testing may be used in specific circumstances, from day 5 to 7. Antibody assays may be used for confirmation, usually after day 14; however, if clinical suspicion is very high, but other tests are negative, these assays may be used as an adjunct to decision-making from day 8 to 13. The proposed algorithm aims to support COVID-19 diagnosis decision-making in Latin America.


Ultrasound and microbubble-induced local delivery of MicroRNA-based therapeutics.
MicroRNAs are involved in many pathologic processes and are a promising target for therapeutic intervention. However, successful, localized delivery of microRNA-based therapeutics is lacking. In this study, cationic ultrasound-responsive microbubbles (MBs) were used to deliver microRNA blockers and mimics in vitro and in vivo. Cationic MBs successfully delivered microRNA blockers to human endothelial cells on ultrasound (US) exposure in vitro. This in vitro US protocol did not successfully deliver microRNA mimics to skeletal muscle of mice, whereas an US protocol that is routinely used for contrast imaging did. Additionally, we used cationic MBs and US to locally deliver antimiR and antagomiR molecules with US causing inertial cavitation. Delivery of antimiR to the extracellular compartments of the muscle was only slightly increased, whereas delivery of antagomiR to the capillaries, myocytes and extracellular space was significantly increased. AntagomiR seems to be a more suitable microRNA blocker than antimiR for use in combination with MBs and US for local delivery.


Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer.
MicroRNAs (miRNAs) represent a new class of small non-coding RNAs regulating gene expression by inducing RNA degradation or interfering with translation. Aberrant miRNA expression has been described for several human malignancies and tumour suppressor functions have been ascribed to this new class of small regulatory RNAs. Accordingly, inactivation due to deletion or mutation has been found in human malignancies. Here, we describe the role of aberrant hypermethylation as an additional mechanism for miRNA gene inactivation in human breast cancer. Aberrant hypermethylation was shown for mir-9-1, mir-124a3, mir-148, mir-152, and mir-663 in 34-86% of cases in a series of 71 primary human breast cancer specimens. For comprehensive methylation analysis, combined bisulphite restriction analysis, bisulphite sequencing, and Pyrosequencing were employed. miRNA gene hypermethylation correlated strongly with methylation of known tumour suppressor genes (p = 0.003). After treatment of various breast cancer cell lines with the demethylating agent 5-aza-2'-deoxycytidine, reduction of mir-9-1 gene methylation and concomitant reactivation of expression could be observed. For the mir-9-1 gene, which is already hypermethylated in pre-invasive intraductal lesions, a good correlation between quantitative methylation level and reduction of expression could be demonstrated in a subset of primary human breast cancer specimen (r = 0.8). In conclusion, this study demonstrates that various microRNA genes are also affected by epigenetic inactivation due to aberrant hypermethylation and that this is an early and frequent event in breast cancer development.


FGF receptor inhibitor BGJ398 partially rescues osteoarthritis-like phenotype in older high molecular weight FGF2 transgenic mice via multiple mechanisms.
We have used Basic Fibroblast Growth Factor (FGF2) transgenic mice as experimental models for human X-linked hypophosphatemia (XLH)-related degenerative osteoarthritis (OA) to investigate the pathogenesis of the disease and to test potential pharmacotherapies for treatment. This study tested the efficacy of BJG398, a small molecule fibroblast growth factor receptor tyrosine kinase (FGFRTK) inhibitor, to rescue the knee joint osteoarthritis phenotype in High Molecular Weight fibroblast growth factor 2 transgenic (HMWTgFGF2) mice. BJG398 was administered in vivo to 8-month-old female HMWTgFGF2 mice for six weeks. Histomorphometry, immunohistochemistry and micro-CT were used to examine the knee joints in BGJ398-treated and control mice. We assessed: Fibroblast Growth Factor 23 (FGF23) expression and FGFR1 activity; Matrix metalloproteinase 13 (MMP13) and Aggrecanase2 (ADAMTS5) expression; then signaling by SMAD1/5/8-pSMAD6, pERK1/2 and Runt-related transcription factor 2 (RUNX2). Using PrimePCR arrays, we identified a contributing role for major target genes in the TGFB/BMP2 signaling pathway that were regulated by BGJ398. BGJ398 inhibited HMWFGF2/FGF23-induced increase in bone morphogenic protein receptor-1, bone morphogenic protein-2 and 4 and Serine peptidase inhibitor, clade E, member 1. The results from Micro-CT and histology show BGJ398 treatment rescued the OA changes in subchondral bone and knee articular cartilage of HMWTgFGF2 mice. The gene expression and signal transduction results provide convincing evidence that HMWFGF2 generates OA through FGFRTK with characteristic downstream signaling that defines OA, namely: increased FGF23-FGFR1 activity with BMP-BMPR, activation of pSMAD1/5/8-RUNX2 and pERK signaling pathways, then upregulation of MMP13 and ADAMTS5 to degrade matrix. BGJ398 treatment effectively reversed these OA molecular phenotypes, providing further evidence that the OA generated by HMWFGF2 in the transgenic mice is FGFR-mediated and phenocopies the OA found in the Hyp mouse homolog of XLH with a spontaneous mutation in the Phex (phosphate regulating endopeptidase on the X chromosome) gene and human XLH-OA. Overall, the results obtained here explain how the pleotropic effects of FGF2 emanate from the different functions of HMW protein isoforms for cartilage and bone homeostasis, and the pathogenesis of XLH-degenerative osteoarthropathy. BGJ398 inhibits HMWFGF2-induced osteoarthritis via multiple mechanisms. These results provided important scientific evidence for the potential application of BGJ398 as a therapeutic agent for osteoarthritis in XLH.


PTEN Regulates Mitochondrial Biogenesis via the AKT/GSK-3β/PGC-1α Pathway in Autism.
Autism spectrum disorder (ASD) is a widespread, complex and serious neurodevelopmental disorder. Complex genetic and environmental factors are thought to contribute to the development of ASD. Genome-wide association analysis has identified multiple autism-related genes. Mutation of the phosphatase and tensin homolog (Pten) is closely related to autism and accounts for 5-17% of cases of autism. However, the detailed mechanism is still unclear. Recently, mitochondrial dysfunction was tightly associated with ASD pathogenesis, such as developmental degeneration, learning and various behavioral disorders. The mitochondrial DNA (mtDNA) copy number in children with autism is also significantly increased. The correlation between Pten and mitochondrial dysfunction in autism is still unknown. In this study, we examined how Pten regulates mitochondrial biogenesis through the AKT/GSK-3β/PGC-1α signaling pathways. We found that PTEN could dephosphorylate AKT to inhibit its activity, leading to decreased GSK3β phosphorylation. This decrease in GSK3β phosphorylation, which could activate itself, increased PGC-1α phosphorylation to promote its degradation and then regulated mitochondrial biogenesis by NRF-1 and TFAM downstream of PGC-1α. In the Valproic acid (VPA) induced autism mouse model, the PTEN protein level was significantly decreased while PGC-1α and COX IV levels were increased in the hippocampus and cortex. Our data suggest that there is a correlation between PTEN and mitochondrial dysfunction and this correlation may be a potential mechanism of ASD.


Viral kinetics in genotype 1 chronic hepatitis C patients during therapy with 2 different doses of peginterferon alfa-2b plus ribavirin.
Pegylated interferon (peginterferon) alfa-2b plus ribavirin achieves a higher sustained response rate in patients with genotype 1 chronic hepatitis C virus (HCV) than standard combination therapy. This study evaluated HCV kinetics throughout therapy with 2 doses of peginterferon alfa-2b and ribavirin in 55 patients. Twenty-eight patients were randomized to receive a high once-weekly dose of peginterferon alfa-2b (3 microg/kg for 1 week, 1.5 microg/kg for 3 weeks, and 1.0 microg/kg for 44 weeks), and 27 patients were randomized to receive a low dose (0.5 microg/kg) for 48 weeks. Both groups also received 800 mg ribavirin daily. Mean baseline HCV RNA load, measured by reverse-transcription polymerase chain reaction, was similar in both groups (5.32 +/- 0.86 log vs. 5.15 +/- 1.04 log). The 3-microg/kg dose of peginterferon alfa-2b inhibited HCV RNA more significantly than the 0.5-microg/kg dose during the first 48 hours (2.08 +/- 0.93 log vs. 1.09 +/- 0.80 log; P <.001) and both increased at 72 hours (0.54 +/- 0.73 log vs. 0.03 +/- 0.36 log; P = not significant [NS]), but the high dose showed a greater reduction at the end of the week (1.07 +/- 0.99 log vs. 0.72 +/- 0.73 log). Both doses showed a progressive, slower viral decrease throughout therapy; however, HCV RNA became undetectable faster and in more patients with the high dose (22% vs. 7% at week 4, 56% vs. 44% at week 12, 69% vs. 63% at week 24, and 71% vs. 61.5% at the end of therapy). In conclusion, peginterferon alfa-2b/ribavirin produces an initial rapid decline in HCV RNA levels, followed by a slower, progressive decrease, similar to the biphasic kinetic profile of standard combination therapy. Higher doses of peginterferon alfa-2b also accelerate viral clearance.


Structural studies of the Hsp70/Hsp90 organizing protein of Plasmodium falciparum and its modulation of Hsp70 and Hsp90 ATPase activities.
HOP is a cochaperone belonging to the foldosome, a system formed by the cytoplasmic Hsp70 and Hsp90 chaperones. HOP acts as an adapter protein capable of transferring client proteins from the first to the second molecular chaperone. HOP is a modular protein that regulates the ATPase activity of Hsp70 and Hsp90 to perform its function. To obtain more detailed information on the structure and function of this protein, we produced the recombinant HOP of Plasmodium falciparum (PfHOP). The protein was obtained in a folded form, with a high content of α-helix secondary structure. Unfolding experiments showed that PfHOP unfolds through two transitions, suggesting the presence of at least two domains with different stabilities. In addition, PfHOP primarily behaved as an elongated dimer in equilibrium with the monomer. Small-angle X-ray scattering data corroborated this interpretation and led to the reconstruction of a PfHOP ab initio model as a dimer. Finally, the PfHOP protein was able to inhibit and to stimulate the ATPase activity of the recombinant Hsp90 and Hsp70-1, respectively, of P. falciparum. Our results deepened the knowledge of the structure and function of PfHOP and further clarified its participation in the P. falciparum foldosome.


Association of PRLR, IGF1, and LEP genes polymorphism with milk production and litter size in Egyptian Zaraibi goat.
Studying variation in genes responsible for physiological characters is important to enhance goat productive and reproductive efficiency. This study aimed to detect specific nucleotide polymorphisms in prolactin receptor (PRLR), insulin-like growth factor (IGF1), and leptin (LEP) genes and their correlation with milk production (MP) and litter size (LS) traits in Zaraibi goat. PCR-SSCP products of different patterns of each gene were sequenced and aligned to reveal two mutations (T > C) and (G > A) in 3'UTR of PRLR gene and registered on NCBI with accession numbers OM418863 for TT and OM418864 for CT, while (G > A) variation was registered as OM418861 for GG and OM418862 for AG in exon 10. TT, CT, AG, and GG genotypes were distributed in the studied animals with frequencies 0.43, 0.57, 0.65, and 0.35, respectively. While alleles C, T, A, and G frequencies were 0.28, 0.72, 0.32, and 0.68, respectively. CT and AG genotypes associated significantly (P < 0.05) with higher MP and LS, respectively. By studying the haplotypes of PRLR, C-A and T-A were associated with the highest and the lowest level of MP, respectively. For LS, T-A and C-G showed significant correlation with the highest and the lowest rate, respectively. Regarding IGF1 gene, two polymorphisms were detected; T74C at exon 4 which registered on NCBI as OM418860, and combined mutations as ins. G470, A531G, and T534C (PP genotype) at 5' flanking region that registered as OM418859. For LEP, only one polymorphism was found in intron 2 (G281A) which submitted to NCBI as OM418855. All detected polymorphisms have shown to be involved in regulating the MP or LS as reproductive traits in goat.


Strategies for elimination of cyanogens from cassava for reducing toxicity and improving food safety.
Toxicity of cassava arises due to the presence of the cyanoglucosides linamarin and lotaustralin which are hydrolysed by endogenous enzyme linamarase to acetonecyanohydrin (ACN) and cyanide (CN) which are toxic. Major research efforts to eliminate/reduce cyanoglucosides have focused on (i) development of acyanogenic cassava varieties by breeding; (ii) controlling its metabolism; and (iii) processing to remove cyanogens. The cyanoglucoside (CNG) content in cassava is genetically controlled and cultivars may be classified as low (<50 μg/g), medium (50-100 μg/g) and high CN (>100 μg CN eq./g) varieties. Molecular techniques for reducing tuber CNG have focused on development of transgenic plants with reduced expression of cyt P 450 in leaves, or increased expression of hydroxynitrilelyase in tuber. For immediate solution, CNG content can be reduced using several processing methods. Traditional methods used for processing include boiling, drying, parboiling and drying, baking, steaming, frying and preparation of flour. These processes result in CN losses ranging from 25% to 98%. The cyanogen level in the final product is influenced both by the tuber CNG and the method of processing. In order to achieve safe levels of 10 μg/g in cassava products, new methods of processing, especially for cassava containing more than 250 μg CN eq./g, remains a challenging problem.


Computed tomography versus fluoroscopic guided-sacroiliac joint injection: a prospective comparative study.
There are limited data discussing long-term pain relief and comparability of different image-guided sacroiliac joint (SIJ) injection. This study compared CT and fluoroscopic-guided SIJ injections regarding statistically and clinically significant differences in numeric pain reduction, radiation doses, and patient's satisfaction. A prospective study conducted on 52 patients who met specific inclusion criteria of SIJ pain. A mixture of 1 ml of 40 mg methylprednisolone acetate diluted in 2 ml of lidocaine 2% was injected under either CT or fluoroscopic guidance. Numeric rating score (NRS) and Oswestry disability index (ODI) were assessed and recorded for each patient before procedure and one-week, and one-, three-, six-, and 12-months after procedure. The results were compared between both groups. Analysis of NRS one-month post-procedure showed a significant decrease from baseline in both groups: 12.5% in CT group (p = 0.002) and 9.5% in fluoroscopic group (p = 0.006). No significant difference in NRS between two groups at one- and three-months post-procedure (p = 0.11 and 0.1, respectively). There was a significant difference in NRS between two groups at six- and 12-months post-procedure (p = 0.001 and < 0.0001, respectively). Comparison of ODI at six-month post-procedure revealed that both groups had a statistically significant improvement (p < 0.0001). There was a significant difference in ODI between two groups at six-months post-procedure (p = 0.01). CT-guided SIJ injection compares favorably with fluoroscopic guidance and offers statistically and clinically significant long-term pain relief. The use of dose reduction protocol in CT is important for decreasing the radiation dose.


Competitive ELISA method for novel estrogen-negative breast cancer biomarker quantitation.
Estrogen-negative (ER-) breast cancer, is recognized as an aggressive subtype, more difficult to treat, with poor survival and prognosis. They are hormonally unresponsive, with no readily effective and specific target therapy. We have previously identified Nw-hydroxy L-Arginine (NOHA) as a blood-based biomarker to distinguish between ER- and ER+ breast cancer tumors based upon disease burden, progression and molecular phenotype (U.S. Utility Patent 10,073,099). In this study we have demonstrated a competitive ELISA based assay for NOHA measurement using a proprietary monoclonal antibody (mAb) specific for NOHA (U.S. provisional patent 62/754,053). The ELISA assay was evaluated on sensitivity, selectivity, precision, dilution linearity and percent recovery parameters. The assay showed sensitivity at ≥60 pg/ml NOHA antigen with 1 ng/ml NOHA mAb, and maintained NOHA antigen specificity even in the presence of other closely related cationic amino acids (i.e. L-Arginine, D-Arginine, l-Lysine, d-Lysine, L-Ornithine, and L-Citrulline). The reliability of the ELISA protocol was confirmed with the low percent-covariance, for all tested parameters of sensitivity (≤8.2%), selectivity (≤8.6%), precision (≤12.6%), dilution linearity (≤11.2%) and recovery (≤6.7%). Additionally, we can demonstrate NOHA quantification by this ELISA assay to complement the sensitivity achievable with LC-MS (in both assay buffer and with patient plasma samples), thus suggesting it's utility as a simple yet sensitive methodology that might help in ER- breast cancer prognosis, and disease progression monitoring without the need for expensive analytical equipment (such as LC-MS), large lab space, or specialized technical training.


Oral metastasis of lung cancer. A challenge for the clinician.
Bone metastases are a major cause of morbidity in cancer patients. Jawbone metastasis from lung cancer is a rare condition that may occur in the late state of the disease. We report the case of a 74-year-old male presenting with an oral asymptomatic swelling that had grown substantially over the last 2 months. Biopsy and histological examination revealed the presence of a metastatic lung cell adenocarcinoma. Although metastases to the oral cavity are uncommon, clinicians may play a crucial role also in the diagnosis of primary tumors.


Patterns of Glucose Metabolism in [ 18 F]FDG PET Indicate Regional Variability and Neurodegeneration in the Progression of Alzheimer's Dementia.
In disorders of cognitive impairment, such as Alzheimer's disease, neurodegeneration is the final common pathway of disease progression. Modulating, reversing, or preventing disease progression is a clinical imperative most likely to succeed following accurate and explanatory understanding of neurodegeneration, requiring enhanced consistency with quantitative measurements and expanded interpretability of complex data. The on-going study of neurodegeneration has robustly demonstrated the advantages of accumulating large amounts of clinical data that include neuroimaging, motiving multi-center studies such as the Alzheimer's Disease Neuroimaging Initiative (ADNI). Demonstrative advantages also arise from highly multivariate analysis methods, and this work reports advances provided by non-negative matrix factorization (NMF). NMF revealed patterns of covariance for glucose metabolism, estimated by positron emission tomography of [ 18 F]fluorodeoxyglucose, in 243 healthy normal participants of ADNI. Patterns for glucose metabolism provided cross-sectional inferences for 860 total participants of ADNI with and without cerebral amyloidosis and clinical dementia ratings (CDR) ranging 0-3. Patterns for glucose metabolism were distinct in number and topography from patterns identified in previous studies of structural MRI. They were also distinct from well-establish topographies of resting-state neuronal networks mapped by functional magnetic resonance imaging. Patterns for glucose metabolism identified significant topographical landmarks relating age, sex, APOE ε4 alleles, amyloidosis, CDR, and neurodegeneration. Patterns involving insular and orbitofrontal cortices, as well as midline regions of frontal and parietal lobes demonstrated the greatest neurodegeneration with progressive Alzheimer's dementia. A single pattern for the lateral parietal and posterior superior temporal cortices demonstrated preserved glucose metabolism for all diagnostic groups, including Alzheimer's dementia. Patterns correlated significantly with topical terms from the Neurosynth platform, thereby providing semantic representations for patterns such as attention, memory, language, fear/reward, movement and motor planning. In summary, NMF is a data-driven, principled, supervised statistical learning method that provides interpretable patterns of neurodegeneration. These patterns can help inform the understanding and treatment of Alzheimer's disease. ▪ Data-driven non-negative matrix factorization (NMF) identified 24 canonical patterns of spatial covariance of cerebral glucose metabolism. The training data comprised healthy older participants (CDR = 0 without amyloidosis) cross-sectionally drawn from ADNI. ▪ In healthy participants, mean SUVRs for specific patterns in precuneus, lateral parietal cortex, and subcortical areas including superficial white matter and striatum, demonstrated increasing glucose metabolism with advancing age. ▪ In asymptomatic participants with amyloidosis , glucose metabolism increased compared to those who were asymptomatic without amyloid , particularly in medial prefrontal cortex, frontoparietal cortex, occipital white, and posterior cerebellar regions. ▪ In symptomatic participants with amyloidosis , insular cortex, medial frontal cortex, and prefrontal cortex demonstrated the most severe losses of glucose metabolism with increasing CDR. Lateral parietal and posterior superior temporal cortices retained glucose metabolism even for CDR > 0.5. ▪ NMF models of glucose metabolism are consistent with models arising from principal components, or eigenbrains, while adding additional regional interpretability. ▪ NMF patterns correlated with regions catalogued in Neurosynth. Following corrections for spatial autocorrelations, NMF patterns revealed meta-analytic identifications of patterns with Neurosynth topics of fear/reward, attention, memory, language, and movement with motor planning. Patterns varied with degrees of cognitive impairment.


[Studies on as-triazine derivatives. XIX. Synthesis of 2,3-diarylpyrazine 2,3-diarylpyridine derivatives as blood platelet aggregation inhibitors].
4,5-Diphenyl-2-ethoxypyrimidine (1), 3,4-diphenyl-6-ethoxypyridazine (2) and 2,3-diphenyl-5-ethoxypyrazine (3) were evaluated for inhibitory activity towards arachidonic acid-induced aggregation of rabbit blood platelet in vitro. 2,3-Diphenyl-5-ethoxypyrazine (3) exhibited significant inhibitory activity. Thus, various 5-substituted 2,3-bis(4-methoxyphenyl)pyrazines were synthesized by the nucleophilic substitution reaction of 5-chloro-2,3-bis(4-methoxyphenyl)pyrazine (9). In a similar manner, substituted 2,3-bis(4-methoxyphenyl)pyridines were prepared from 2,3-bis(4-methoxyphenyl)-6-methylsulfonylpyridine (17), which was synthesized by the cycloaddition retro Diels-Alder reaction of 5,6-bis(4-methoxyphenyl)-3-methylsulfonyl-1,2,4-triazine (16) with norbornadiene. Among the compounds prepared, 6-isopropoxy-2,3-bis(4-methoxyphenyl)-pyrazine (10f) showed the most potent inhibitory activity, which was more than the activity of anitrazafen[5,6-bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine.


Effectiveness and Safety of Trabectedin and Radiotherapy for Patients With Myxoid Liposarcoma: A Nonrandomized Clinical Trial.
Preclinical data about the synergistic activity of radiotherapy (RT) and trabectedin have been reported. The combination of trabectedin and RT in treating myxoid liposarcomas appears worth exploring. To explore the effectiveness and safety of trabectedin combined with RT. This international, open-label, phase 2 nonrandomized clinical trial including 46 patients with myxoid liposarcoma was conducted in 4 centers in Spain, 1 in Italy, and 2 in France from July 1, 2016, to September 30, 2019. Eligible patients had to have a histologic, centrally reviewed diagnosis of localized resectable myxoid liposarcoma arising from an extremity or the trunk wall. Trabectedin was administered at the recommended dose stemming from the phase 1 trial (1.5 mg/m2), with intravenous infusion during 24 hours every 21 days for a total of 3 cycles. Radiotherapy was started after completion of the first trabectedin infusion (cycle 1, day 2). Patients received 25 fractions of radiation for a total of 45 Gy. Surgery was planned 3 to 4 weeks after the administration of the last preoperative cycle and not until 4 weeks after the end of preoperative RT. Pathologic specimens were mapped in tumor sections to estimate the histologic changes and the percentage of viable tumor after neoadjuvant treatment. The primary objective of the phase 2 part of the study was overall response. Secondary objectives were effectiveness measured by relapse-free survival and activity measured by functional imaging and pathologic response. A total of 46 patients were enrolled. Four patients were not evaluable. The median age was 43 years (range, 18-77 years), and 31 patients were male (67%). Overall, 9 of 41 patients (22%) achieved a partial response with neoadjuvant treatment with trabectedin and RT, with 5 of 39 patients (13%) achieving a complete pathologic response and 20 of 39 patients (51%) having 10% or less of a viable remaining tumor. Partial responses according to Choi criteria were observed in 24 of 29 evaluable patients (83%), and no patient had disease progression. Treatment was well tolerated. Although the primary end point of this phase 2 nonrandomized clinical trial was not met (Response Evaluation Criteria in Solid Tumors response in ≥70% of patients), results suggest this combination was well tolerated and effective in terms of pathologic response. Thus, trabectedin plus RT might be a treatment option regarding tolerability; further evidence should be generated in this setting.


Use of directed acyclic graphs (DAGs) to identify confounders in applied health research: review and recommendations.
Directed acyclic graphs (DAGs) are an increasingly popular approach for identifying confounding variables that require conditioning when estimating causal effects. This review examined the use of DAGs in applied health research to inform recommendations for improving their transparency and utility in future research. Original health research articles published during 1999-2017 mentioning 'directed acyclic graphs' (or similar) or citing DAGitty were identified from Scopus, Web of Science, Medline and Embase. Data were extracted on the reporting of: estimands, DAGs and adjustment sets, alongside the characteristics of each article's largest DAG. A total of 234 articles were identified that reported using DAGs. A fifth (n = 48, 21%) reported their target estimand(s) and half (n = 115, 48%) reported the adjustment set(s) implied by their DAG(s). Two-thirds of the articles (n = 144, 62%) made at least one DAG available. DAGs varied in size but averaged 12 nodes [interquartile range (IQR): 9-16, range: 3-28] and 29 arcs (IQR: 19-42, range: 3-99). The median saturation (i.e. percentage of total possible arcs) was 46% (IQR: 31-67, range: 12-100). 37% (n = 53) of the DAGs included unobserved variables, 17% (n = 25) included 'super-nodes' (i.e. nodes containing more than one variable) and 34% (n = 49) were visually arranged so that the constituent arcs flowed in the same direction (e.g. top-to-bottom). There is substantial variation in the use and reporting of DAGs in applied health research. Although this partly reflects their flexibility, it also highlights some potential areas for improvement. This review hence offers several recommendations to improve the reporting and use of DAGs in future research.


Health occupations salary outcomes: intersections of student race, gender, and first-generation status.
Greater diversity in the healthcare workforce has been identified as a critical need in serving an increasingly diverse population. Higher education institutions have been tasked with increasing the number of underrepresented students in the health occupations pipeline to better align with the demographics of the general population and meet the need for a diverse health occupations workforce. This study used the National Science Foundation's National Survey of College Graduates dataset to capture data across time, examining the intersectionality of race, gender, and first-generation status on the salary outcomes of students who earn degrees related to health occupations. Results indicate that the intersecting identities of students who earn a bachelor's degree or higher in the health professions impact salary outcomes. Results of this study have implications for higher education policies that can impact increased diversity in the health occupations workforce pipeline.


Contribution of an affect-associated gene to human longevity: prevalence of the long-allele genotype of the serotonin transporter-linked gene in Japanese centenarians.
Negative affect such as depression and anxiety has been reported to be associated with morbidity and mortality, and polymorphisms of the serotonin transporter (5HTT) gene may be associated with such affect disorders. Hypothesizing that 5HTT gene polymorphisms could influence human longevity via negative affect; we compared the polymorphic variation of the 5HTT gene between 265 Japanese centenarians and control subjects. In addition, we evaluated the relationships between the 5HTT genotype and the physical, cognitive, and biologic status of centenarians, as indicated by the Barthel Index, the Mini-Mental State Examination, and serum albumin concentration, respectively. The frequency of the l/l genotype and the l allele was significantly greater in centenarians than in younger control subjects, particularly women. A significant effect of the 5HTT genotype on serum albumin concentration was observed in both sexes. Although, there was sex optionality, the l allele may carry a longevity advantage possibly through behavioral mechanisms.


Population Pharmacokinetics and Pharmacodynamics of Burosumab in Adult and Pediatric Patients With X-linked Hypophosphatemia.
Burosumab is a fully human monoclonal antibody against fibroblast growth factor 23, which has been approved to treat X-linked hypophosphatemia (XLH) in adult and pediatric patients. The present work describes the pharmacokinetics (PK) of burosumab and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between burosumab and serum phosphorus in adult and pediatric patients with XLH. A total of 2844 measurable serum concentrations of burosumab and 6047 measurable serum concentrations of phosphorus in 277 subjects from 9 clinical studies were included in the population PK and PK-PD modeling. The serum concentration of burosumab following a subcutaneous administration was well described by a population PK model comprising a first-order absorption, 1-compartmental distribution, and a linear elimination. The relationship between serum burosumab and serum phosphorus was adequately described by a sigmoid maximal efficacy model. Body weight was the only covariate associated with PK and PK-PD parameters. No other intrinsic factors affected PK or PK-PD relationship in adult and pediatric patients with XLH. Further simulations helped to guide the dosing regimen of burosumab in adult and pediatric patients with XLH including age groups with no clinical data.


Dopamine D(2) receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse.
Previous research suggests that brain oxidative stress and altered rodent locomotor behavior are linked. We observed bio-behavioral changes in methionine sulfoxide reductase A knockout mice associated with abnormal dopamine signaling. Compromised ability of these knockout mice to reduce methionine sulfoxide enhances accumulation of sulfoxides in proteins. We examined the dopamine D(2)-receptor function and expression, which has an atypical arrangement and quantity of methionine residues. Indeed, protein expression levels of dopamine D(2)-receptor were higher in knockout mice compared with wild-type. However, the binding of dopamine D(2)-receptor agonist was compromised in the same fractions of knockout mice. Coupling efficiency of dopamine D(2)-receptors to G-proteins was also significantly reduced in knockout mice, supporting the compromised agonist binding. Furthermore, pre-synaptic dopamine release in knockout striatal sections was less responsive than control sections to dopamine D(2)-receptor ligands. Behaviorally, the locomotor activity of knockout mice was less responsive to the inhibitory effect of quinpirole than wild-type mice. Involvement of specific methionine residue oxidation in the dopamine D(2)-receptor third intracellular loop is suggested by in vitro studies. We conclude that ablation of methionine sulfoxide reductase can affect dopamine signaling through altering dopamine D(2)-receptor physiology and may be related to symptoms associated with neurological disorders and diseases.


The effect of heart rate and pulse pressure on mean arterial pressure: the combined formula for calculation of mean arterial pressure.
We demonstrate a new formula to predict mean arterial pressure (MAP) using corrections of the key factors associated with the inaccuracy of the standard formula: heart rate (HR) and pulse pressure (PP). A total of 99 patients (50 men, 49 women; mean age 52.5 ± 10.3 years), who underwent elective coronary angiography, were enrolled in our study. The arterial pressure was measured in the aortic root. MAP was measured digitally by the area-under-the-pressure-time curve method. We evaluated the accuracy of four different formulas: the standard formula, the formula of Razminia et al., the formula of Meaney et al. and the combined formula. PP coefficient deviation of the standard formula was negatively correlated with PP (R = -0,561, P < 0.001), and positively correlated with HR (R = 0,298, P = 0.003). Both R and R2 values of the combined formula were higher than previous formulas. Accuracy parameters of the combined formula [root mean square error (RMSE): 1.801 mmHg, mean square residuals (MSR): 3.244 mmHg2, Akaike information criterion (AIC): 401.4] were superior to the standard formula (RMSE: 1.902 mmHg, MSR: 3.620 mmHg2, AIC: 412.3), the formula of Razminia et al. (RMSE: 2.022 mmHg, MSR: 4.089 mmHg2, AIC: 424.3) and the formula of Meaney et al. (RMSE: 2.137 mmHg, MSR: 4.568 mmHg2, AIC: 435.3). In the multivariate linear regression analysis, the combined formula was the only method that independently predicts the measured MAP (beta = 0,990, P < 0.001). The combined formula is superior to previous formulas for accurately predicting MAP.


The radical chemistry of milk xanthine oxidase as studied by radiation chemistry techniques.
The kinetics of electron transfer within the molybdoflavoenzyme xanthine oxidase has been investigated using the technique of pulse radiolysis. Subsequent to one-electron reduction of native enzyme at 20 degrees C in 20 mM pyrophosphate buffer, pH 8.5, using the CO-.2 species as reductant, a spectral change is observed having a rate constant of approximately 290 s-1. From its wavelength dependence, this spectral change is assigned to the transfer of an electron from flavin semiquinone (formed on reaction with the CO2-. species) to one of the iron-sulfur centers of the enzyme in an intramolecular equilibration process. The value for this rate constant agrees well with the 330 s-1 observed in previous stopped-flow pH-jump experiments carried out at 25 degrees C (Hille, R., and Massey, V. (1986) J. Biol. Chem. 261, 1241-1247). Experimental results with fully reduced enzyme reacting with the radiolytically generated N.3 species also support the conclusion that the equilibration of reducing equivalents among the oxidation-reduction centers of xanthine oxidase is a rapid process. Evidence is also found that xanthine oxidase possesses an unusually reactive disulfide bond that is reduced rapidly by radiolytically generated radicals. The ramifications of the present results with regard to the interpretation of experiments involving chemically reactive radical species, generated either by photolysis or radiolysis, are discussed.


Optimal timing of joint replacement using mathematical programming and stochastic programming models.
The optimal timing for performing radical medical procedures as joint (e.g., hip) replacement must be seriously considered. In this paper we show that under deterministic assumptions the optimal timing for joint replacement is a solution of a mathematical programming problem, and under stochastic assumptions the optimal timing can be formulated as a stochastic programming problem. We formulate deterministic and stochastic models that can serve as decision support tools. The results show that the benefit from joint replacement surgery is heavily dependent on timing. Moreover, for a special case where the patient's remaining life is normally distributed along with a normally distributed survival of the new joint, the expected benefit function from surgery is completely solved. This enables practitioners to draw the expected benefit graph, to find the optimal timing, to evaluate the benefit for each patient, to set priorities among patients and to decide if joint replacement should be performed and when.


Cigarette Use and Vaping Among Sexual and Gender Minority (SGM) Adolescents Assigned Male at Birth: Patterns of Use and Associations with Demographic and Psychosocial Factors.
This study described cigarette and electronic nicotine delivery systems (ENDs) use and their demographic and psychosocial correlates in a sample of sexual and gender minority (SGM) adolescents assigned male at birth. One-way ANOVA, multivariate linear regression, and correlation analyses were conducted to examine correlates of cigarettes/ENDs use on 159 SGM adolescent users, ages 15-18. Fifty-three percent of the sample used cigarettes/ENDs, with differences based on sexual orientation: bisexual, pansexual, and queer adolescents used ENDs more than gay adolescents. White adolescents smoked more cigarettes than adolescents of color, independent of ENDs use. Regarding psychosocial correlates, alcohol use and depression were associated with greater daily cigarette use, while sexual orientation identity was associated with greater daily ENDs use. This study characterized frequency and psychosocial correlates of cigarettes/ENDs use among SGM adolescents. Findings highlighted several risk factors for tobacco use and will inform future interventions for SGM adolescents.


Optimal stereotactic body radiotherapy dosage for hepatocellular carcinoma: a multicenter study.
The optimal dose and fractionation scheme of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) remains unclear due to different tolerated liver volumes and degrees of cirrhosis. In this study, we aimed to verify the dose-survival relationship to optimize dose selection for treatment of HCC. This multicenter retrospective study included 602 patients with HCC, treated with SBRT between January 2011 and March 2017. The SBRT dosage was classified into high dose, moderate dose, and low dose levels: SaRT (BED10 ≥ 100 Gy), SbRT (EQD2 > 74 Gy to BED10 < 100 Gy), and ScRT (EQD2 < 74 Gy). Overall survival (OS), progression-free survival (PFS), local control (LC), and intrahepatic control (IC) were evaluated in univariable and multivariable analyses. The median tumor size was 5.6 cm (interquartile range [IQR] 1.1-21.0 cm). The median follow-up time was 50.0 months (IQR 6-100 months). High radiotherapy dose correlated with better outcomes. After classifying into the SaRT, SbRT, and ScRT groups, three notably different curves were obtained for long-term post-SBRT survival and intrahepatic control. On multivariate analysis, higher radiation dose was associated with improved OS, PFS, and intrahepatic control. If tolerated by normal tissue, we recommend SaRT (BED10 ≥ 100 Gy) as a first-line ablative dose or SbRT (EQD2 ≥ 74 Gy) as a second-line radical dose. Otherwise, ScRT (EQD2 < 74 Gy) is recommended as palliative irradiation.


Surgical correction of childhood intermittent exotropia and the risk of developing mental illness.
To assess whether successful surgical intervention for intermittent exotropia, or the timing of intervention, has any effect on the development of mental illness. Retrospective, observational case series. All patients (<19 years of age) diagnosed with intermittent exotropia in Olmsted County, Minnesota, from January 1, 1975, through December 31, 1994, were reviewed retrospectively. Potential cases were identified using the resources of the Rochester Epidemiology Project, a medical records database designed to capture data on any patient-physician encounter in Olmsted County, Minnesota. The main outcome measures were the occurrence and severity of mental illness among those who underwent strabismus surgery compared with those who did not. Ninety-six (52%) of the 184 children identified were diagnosed with a mental illness at a mean age of 23.3 years (range, 6 to 41 years). Thirty-five (36%) of the 96 children in whom mental illness developed underwent strabismus surgery. Success at surgery (<10 prism diopters) was not associated with a decreased occurrence of mental illness (P = .30). Of the 88 patients in whom mental illness did not develop, strabismus surgery was not more commonly performed (P = .54), nor was it performed at a younger age (P = 1.0), when compared with the 96 patients in whom mental illness developed later. Strabismus surgery for children with intermittent exotropia, regardless of success or age at surgery, did not alter the development of mental illness by early adulthood.