Sensitive measures of nutritional status in children in hospital and in the field.
Protein-energy malnutrition and obesity are the most common nutritional disorders that complicate the clinical course of children with neoplastic diseases. Sensitive measures of nutritional status should be used to detect these problems in children with cancer. Height and weight measurements are the mainstay of the nutritional assessment of the child. These measurements can be converted to growth velocities or to height-for-age and weight-for-height Z-scores or percent of expected values to provide a measure of the degree of under- or over-nutrition in the child. Skinfold thickness and circumference measurements of the arms, legs and/or trunk may be useful to characterize the changes in peripheral fat depots and muscle mass, respectively. However, the assessments of body composition using these measurements are subject to methodological error because selected skinfold sites are excluded. Whole-body potassium, measured by 40K counting, and total body water, measured by deuterium or 18O dilution, serve as "gold standards" to determine the lean body mass and body fat status of the child, but these techniques may not be practical in all settings. The assessment of the nutritional status of the child serves as a guide to early nutritional intervention. Indicators for early nutritional intervention include: (1) height-for-age and weight-for-height or -age Z-scores more than 2 SD below the mean for age, (2) height-for-age measurements less than 95% of expected, (3) weight-for-height measurements less than 90% or greater than 120% of expected and (4) height velocities less than 5 cm/year after 2 years of age. Early nutritional intervention is essential to restore normal body composition, reverse linear growth arrest, promote tolerance to chemotherapeutic and radiation regimens and improve the quality of life in children with cancer.


Association of Arterial Blood pH at Cannulation With 1 Year Survival Among Veno-Arterial Extracorporeal Membrane Oxygenation Recipients: The Three Seven Rule.
We aimed to describe the clinical outcomes of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy in our institution considering clinical context and pH at cannulation. All patients treated by VA-ECMO during the 2005-2020 period with 1 year complete follow-up were included. Our cohort was divided in three groups according to the pH level at cannulation: pH <7 (group 1), pH 7-7.2 (group 2), and pH>7.2 (group 3). Survival was analyzed using Kaplan-Meier method. Association between pH group and survival was estimated using a Cox model. A total of 572 patients were included: 60 patients in group 1, 115 in group 2, and 397 in group 3. Refractory cardiogenic shock (36%) was the main indication. One year survival rates were 13%, 36%, and 43% in groups 1, 2, and 3, respectively ( p < 0.001). Death mainly occurred within the first month. The strong correlation between pH and lactates led to propose a simple "three seven rule": pH <7 and lactate >7 was associated with <7% survival. Veno-arterial extracorporeal membrane oxygenation should be considered with caution in patients with pH <7. Lactates and pH might be important parameters to elaborate a new score to predict survival in this population. The "three seven rule" can be very relevant when facing emergency situations.


Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants.
Zinc ions have an insulin-like (insulinomimetic) effect. A particularly sensitive target of zinc ions is protein tyrosine phosphatase 1B (PTP 1B), a key regulator of the phosphorylation state of the insulin receptor. Modulation of insulin signaling by zinc chelating agents and the recognition of temporal and spatial fluctuations of zinc suggest a physiological role of zinc in insulin signal transduction. Tyrosine phosphatases seem to be regulated jointly by insulin-induced redox (hydrogen peroxide) signaling, which results in their oxidative inactivation, and by their zinc inhibition after oxidative zinc release from other proteins. In diabetes, the significant oxidative stress and associated changes in zinc metabolism modify the cell's response and sensitivity to insulin. Zinc deficiency activates stress pathways and may result in a loss of tyrosine phosphatase control, thereby causing insulin resistance.


Cell Membrane Transport Mechanisms: Ion Channels and Electrical Properties of Cell Membranes.
Cellular life strongly depends on the membrane ability to precisely control exchange of solutes between the internal and external (environmental) compartments. This barrier regulates which types of solutes can enter and leave the cell. Transmembrane transport involves complex mechanisms responsible for passive and active carriage of ions and small- and medium-size molecules. Transport mechanisms existing in the biological membranes highly determine proper cellular functions and contribute to drug transport. The present chapter deals with features and electrical properties of the cell membrane and addresses the questions how the cell membrane accomplishes transport functions and how transmembrane transport can be affected. Since dysfunctions of plasma membrane transporters very often are the cause of human diseases, we also report how specific transport mechanisms can be modulated or inhibited in order to enhance the therapeutic effect.


Evaluation of the water-equivalence of plastic materials in low- and high-energy clinical proton beams.
The aim of this work was to evaluate the water-equivalence of new trial plastics designed specifically for light-ion beam dosimetry as well as commercially available plastics in clinical proton beams. The water-equivalence of materials was tested by computing a plastic-to-water conversion factor, [Formula: see text]. Trial materials were characterized experimentally in 60 MeV and 226 MeV un-modulated proton beams and the results were compared with Monte Carlo simulations using the FLUKA code. For the high-energy beam, a comparison between the trial plastics and various commercial plastics was also performed using FLUKA and Geant4 Monte Carlo codes. Experimental information was obtained from laterally integrated depth-dose ionization chamber measurements in water, with and without plastic slabs with variable thicknesses in front of the water phantom. Fluence correction factors, [Formula: see text], between water and various materials were also derived using the Monte Carlo method. For the 60 MeV proton beam, [Formula: see text] and [Formula: see text] factors were within 1% from unity for all trial plastics. For the 226 MeV proton beam, experimental [Formula: see text] values deviated from unity by a maximum of about 1% for the three trial plastics and experimental results showed no advantage regarding which of the plastics was the most equivalent to water. Different magnitudes of corrections were found between Geant4 and FLUKA for the various materials due mainly to the use of different nonelastic nuclear data. Nevertheless, for the 226 MeV proton beam, [Formula: see text] correction factors were within 2% from unity for all the materials. Considering the results from the two Monte Carlo codes, PMMA and trial plastic #3 had the smallest [Formula: see text] values, where maximum deviations from unity were 1%, however, PMMA range differed by 16% from that of water. Overall, [Formula: see text] factors were deviating more from unity than [Formula: see text] factors and could amount to a few percent for some materials.


Novel muscle patterns for reaching after cervical spinal cord injury: a case for motor redundancy.
A fundamental issue in the neuromotor control of arm movements is whether the nervous system can use distinctly different muscle activity patterns to obtain similar kinematic outcomes. Although computer simulations have demonstrated several possible mechanical and torque solutions, there is little empirical evidence that the nervous system actually employs fundamentally different muscle patterns for the same movement, such as activating a muscle one time and not the next, or switching from a flexor to an extensor. Under typical conditions, subjects choose the same muscles for any given movement, which suggests that in order to see the capacity of the nervous system to make a different choice of muscles, the nervous system must be pushed beyond the normal circumstances. The purpose of this study, then, was to examine an atypical condition, reaching of cervical spinal cord injured (SCI) subjects who have a reduced repertoire of available distal arm muscles but otherwise a normal nervous system above the level of lesion. Electromyography and kinematics of the shoulder and elbow were examined in the SCI subjects performing a center-out task and then compared to neurologically normal control subjects. The findings showed that the SCI-injured subjects produced reaches with typical global kinematic features, such as straight finger paths, bell-shaped velocities, and joint excursions similar to control subjects. The SCI subjects, however, activated only the shoulder agonist muscle for all directions, unlike the control pattern that involved a reciprocal pattern at each joint (shoulder, elbow, and wrist). Nonetheless, the SCI subjects could activate their shoulder antagonist muscles, elbow flexors, and wrist extensor (extensor carpi radialis) for isometric tasks, but did not activate them during the reaching movements. These results demonstrate that for reaching movements, the SCI subjects used a strikingly different pattern of intact muscle activities than control subjects. Hence, the findings imply that the nervous system is capable of choosing either the control pattern or the SCI pattern. We would speculate that control subjects do not select the SCI pattern because the different choice of muscles results in kinematic features (reduced fingertip speed, multiple shoulder accelerations) other than the global features that are somehow less advantageous or efficient.


Isolation and screening of bioactive principle from Chaetomorpha antennina against certain bacterial strains.
Microbial pathogens develop resistance to a particular antibiotic after repeated administration during the treatment of infectious diseases. Moreover, multiple drug resistance is a very common problem especially in hospital acquired infections. Therefore, it is necessary to find out alternative antibacterial drugs and the present trend is focused on seaweeds. This preliminary research work was carried out to find out the antibacterial activity of petroleum ether extract of Chaetomorpha antennina. The extracts were tested against Staphylococcus aureus MTCC 121, Bacillus cereus MTCC 492, Bacillus subtilis MTCC 441, Klebsiella pneumoniae MTCC 530, Escherichia coli MTCC 443 and Pseudomonas aeruginosa MTCC 779 by agar well diffusion technique. It was observed that petroleum ether extract showed prominent zone of inhibition against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus even at 50 μg/ml concentration. The maximum spectrum of activity was observed against Staphylococcus aureus ranged from 7.3 ± 0.8 to 18 ± 2.4 mm at the concentration 50 to 500 μg/ml, respectively. Hence the most susceptible bacterium was Staphylococcus aureus among the tested organisms. However, Escherichia coli and Pseudomonas aeruginosa are also susceptible. But the Bacillus cereus and Klebsiella pneumoniae are resistant against the tested extract.


Gender analysis of musculoskeletal disorders and emotional exhaustion: interactive effects from physical and psychosocial work exposures and engagement in domestic work.
The objective of this study was to assess the relationships between physical and psychosocial work exposures, engagement in domestic work and work-home imbalance in relation to symptoms of musculoskeletal disorders and emotional exhaustion in white- and blue-collar men and women. Three thousand employees from 21 companies were asked to answer a questionnaire on family structure, household and child care tasks, work exposure, work-home imbalance and symptoms of neck/shoulder disorders, low back disorders and emotional exhaustion. Women reported more musculoskeletal disorders and engagement in domestic work. Adverse at-work exposures were highest in blue-collar women. High engagement in domestic work was not separately associated with symptoms but paid work exposure factors were associated. High engagement in domestic work interacted with adverse work exposure and increased risk estimates for low back disorders and emotional exhaustion. Reported work-home imbalance was associated with neck/shoulder disorders in women and with emotional exhaustion in both women and men. The current article adds to earlier research by showing that high engagement in domestic work is not separately associated with increased symptoms, but interacts with psychosocial work exposure variables to produce emotional exhaustion in both women and men and low back disorders in women.


External muscle heating during warm-up does not provide added performance benefit above external heating in the recovery period alone.
Having previously shown the use of passive external heating between warm-up completion and sprint cycling to have had a positive effect on muscle temperature (T m) and maximal sprint performance, we sought to determine whether adding passive heating during active warm up was of further benefit. Ten trained male cyclists completed a standardised 15 min sprint based warm-up on a cycle ergometer, followed by 30 min passive recovery before completing a 30 s maximal sprint test. Warm up was completed either with or without additional external passive heating. During recovery, external passive leg heating was used in both standard warm-up (CONHOT) and heated warm-up (HOTHOT) conditions, for control, a standard tracksuit was worn (CON). T m declined exponentially during CON, CONHOT and HOTHOT reduced the exponential decline during recovery. Peak (11.1 %, 1561 ± 258 W and 1542 ± 223 W), relative (10.6 % 21.0 ± 2.2 W kg(-1) and 20.9 ± 1.8 W kg(-1)) and mean (4.1 %, 734 ± 126 W and 729 ± 125 W) power were all improved with CONHOT and HOTHOT, respectively compared to CON (1,397 ± 239 W; 18.9 ± 3.0 W kg(-1) and 701 ± 109 W). There was no additional benefit of HOTHOT on T m or sprint performance compared to CONHOT. External heating during an active warm up does not provide additional physiological or performance benefit. As noted previously, external heating is capable of reducing the rate of decline in T m after an active warm-up, improving subsequent sprint cycling performance.


Changes in pre- and in-hospital management and outcomes among children with out-of-hospital cardiac arrest between 2012 and 2017 in Kanto, Japan.
Previously, the SOS-KANTO 2012 studies, conducted in the Kanto area of Japan, reported a summary of outcomes in patients with out-of-hospital cardiac arrest (OHCA). This sub-analysis of the SOS-KANTO study 2017 aimed to evaluate the neurological outcomes of paediatric OHCA patients, by comparing the SOS-KANTO 2012 and 2017 studies. All OHCA patients, aged < 18 years, who were transported to the participating hospitals by EMS personnel were included in both SOS-KANTO studies (2012 and 2017). The number of survival patients with favourable neurological outcomes (paediatric cerebral performance category 1 or 2) at 1 month did not improve between 2012 and 2017. There was no significant difference in achievement of pre-hospital return of spontaneous circulation (ROSC) [odds ratio (OR): 2.00, 95% confidence interval (95% CI): 0.50-7.99, p = 0.50] and favourable outcome at 1 month [OR: 0.67, 95% CI: 0.11-3.99, p = 1] between the two studies, matched by age, witnessed arrest, bystander CPR, aetiology of OHCA, and time from call to EMS arrival. Multivariable logistic regression showed no significant difference in the achievement of pre-hospital ROSC and favourable outcomes at 1 month between the two studies.


The relationship between parental bonding and mood, anxiety and related disorders in adulthood: A systematic review and meta-analysis.
A strong bond between parents and their children is essential in promoting healthy psychological development. Poor quality parent-child relationships can render children vulnerable to various adverse outcomes. Although extensive research has highlighted the association between abnormal parent-child bonding and mood and anxiety-related psychopathology in offspring, no systematic review or meta-analysis has assessed this relationship in adults. A literature search was conducted in five databases (MEDLINE, Embase, PsycINFO, CINAHL, Web of Science) on January 4th, 2021. Studies that assessed the relationship between parental bonding and the presence of a mood or anxiety disorder in adults were eligible for inclusion. Fifty-seven studies were included in the systematic review (n = 44 in the meta-analysis). Quantitative results indicated that individuals with major depression, panic disorder, or persistent depressive disorder reported lower parental care and higher overprotection compared to individuals without psychiatric diagnoses. Qualitative results indicated that individuals with diagnoses of mood or anxiety disorders tended to report higher parental abuse than controls. The measures of parental bonding used by the included studies are retrospective and subject to biases. All studies had a case-control design and thus, causal-relationships cannot be drawn from the results. Our findings suggest that poor-quality parental bonding early in life may place offspring at greater risk for mood and anxiety disorders during adulthood. Future research should extend these results by confirming the relationship between parental bonding and other psychiatric disorders, as well as identifying which factors mediate the relationship between abnormal parental bonding and psychiatric disorders.


Dendritic spine density in the lobus parolfactorius of the domestic chick is increased 24 h after one-trial passive avoidance training.
One to three day old chicks spontaneously peck at small objects. When presented with a chrome bead coated with the bitter tasting substance methyl anthranilate (MeA), chicks peck once, display a characteristic disgust response and subsequently avoid a similar bead. Chicks that are trained on a water coated bead continue to peck a similar bead on retrial. Twenty four hours after training on this one-trial passive avoidance paradigm, chicks were tested for retention. The brains of chicks displaying the correct behavioural response (> 90%) were removed and the lobus parolfactorius from each hemisphere was dissected from the brain and impregnated using a rapid Golgi technique. Analysis of large multipolar neurones by centrifugal dendritic branch order showed that there were significantly more spines on all orders examined in the left hemispheres of MeA-trained chicks compared to water-trained control chicks. Significantly higher spine densities were also found on 4th and 5th order branches of neurones in the right lobus parolfactorius of MeA-trained chicks compared to water-trained chicks. No significant difference in dendritic length was observed. These results suggest that substantial plasticity occurs in post-synaptic structures in the lobus parolfactorius following passive avoidance training. It is suggested that this plasticity is related to processes involved in long term information storage.


PEA I and PEA II based implantable haemodynamic monitor: pre clinical studies in sheep.
The aims of this study were first, to demonstrate that Peak Endocardial Acceleration during isovolumic systole (PEA I) is related to positive peak LVdP/dt, while Peak Endocardial Acceleration during isovolumic relaxation time (PEA II) is related to aortic diastolic pressure (ADP) and to negative peak LVdP/dt; and second, to test if the simultaneous recording of PEA I and PEA II offers a new chance to monitor indexes of LV systolic and diastolic function. An implantable haemodynamic monitor, based on PEA I and PEA II measurements via a microaccelerometer sensor located in the tip of a pacing lead, screwed into the right ventricle, was tested in nine sheep at baseline and during acute haemodynamic interventions: nitrate (0.1 mg/ kg), metaraminol (0.15 mg/kg), dobutamine (5 microg/kg) infusion. ADP, positive and negative peak LVdP/dt were simultaneously recorded by an aortic and left ventricular Millar catheter. PEA I changes were significantly related to positive peak LVdP/dt changes during dobutamine induced inotropic changes (r = 0.83, P < 0.001). PEA II changes were significantly related to both ADP (r = 0.91, P < 0.001) and negative peak LVdP/dt changes (r = 0.92, P < 0.001) during nitrate induced hypotension and metaraminol induced hypertension. The simultaneous recording of PEA I and PEA II with an implantable system offers a new chance to monitor indexes of LV systolic and diastolic function.


Serotonergic activity contributes to analgesic overuse in chronic tension-type headache.
To evaluate the possible existence of a genetically determined innate factor that could exert a profound influence on the development of analgesic overuse in chronic tension-type headache (CTTH). Many patients with CTTHs report the regular use of analgesics. Continuous use of analgesics results in the ultimate worsening of headaches. The factors related to development of analgesic overuse, however, remain poorly understood. The genetic factors for serotonin metabolism and the harm avoidance (HA) personality dimension are known to be associated with various substance abuse patterns. We performed serotonin transporter protein (5-HTT) gene-linked polymorphic region (5-HTTLPR) genotype polymorphism analyses, and investigated serotonin-related personality traits by assessing the HA dimension using tridimensional personality questionnaire, given to 48 patients with CTTHs and reported analgesic overuse (CTTH-AO), in 50 patients with CTTHs without analgesic overuse (CTTH-NO), and in 100 healthy controls. We compared their headache characteristics using standardized questionnaires. We discovered an excess frequency of 5-HTTLPR short allele and a different genotypic distribution in patients with CTTH-AO. The S/S genotype frequency was significantly higher in patients with CTTH-AO (83%) than in CTTH-NO (72%) and control (59%; P= .010) groups. Patients with CTTH-AO exhibited the highest HA scores (23.3 +/- 5.4), as compared to CTTH-NO (19.9 +/- 6.7) and control (16.3 +/- 6.1) groups. Individuals with the S/S genotype showed a greater tendency toward analgesic overuse (13.3 +/- 11.3 days per month) than did those with the non-S/S genotype (7.0 +/- 8.6 days per month: P= .02). Our data suggest that serotonergic activity may be involved in the development of analgesic overuse in CTTH and that 5-HTTLPR might be one of the genetically contributing factors.


Diagnostic testing of cervical vertebral maturation staging: An independent assessment.
The reliability of the cervical vertebral maturation (CVM) method has been questioned. The objective of this research was to evaluate the diagnostic reliability of the CVM method to diagnose the mandibular growth spurt using longitudinal records from an alternative database (Iowa Facial Growth Study [IFGS]) using established diagnostic testing methods. Cephalometric films from 43 subjects (males = 20, females = 23) with Class I or Class II skeletal pattern from the IFGS were scanned, digitized, and adjusted for magnification. At least 5 consecutive, annual films were digitized. For each subject, mandibular length (Co-Gn) was measured for each film, and the growth increment between films was calculated. The largest growth increment was the growth spurt. For each subject, the film displaying CVM stage 3 was identified by a blinded examiner viewing the films in random order. Interrater and intrarater repeatability for Co-Gn (intraclass correlation) and CVM staging (weighted kappa) were calculated. Diagnostic tests, including sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were carried out. The present data were compared with data previously derived from samples of the University of Michigan, Oregon, and Burlington Growth studies (UMGS, OGS, and BGS, respectively). A multilevel logistic regression analysis was also run with the mandibular growth peak as the response variable. Interrater repeatability for mandibular measurements (intraclass correlation coefficient [ICC] = 0.91) and CVM staging (k = 0.88) were excellent. Intrarater repeatability for mandibular measurements (ICC = 0.98) and CVM staging (kw = 0.55) were excellent to moderate. The UMGS data demonstrated higher sensitivity with comparable specificity. Accuracy was largely similar. Their PPV and NPV had larger ranges. The OGS and BGS data, compared with the IFGS data, showed that our sensitivity and PPVs were higher, that their specificity was higher, and that the NPV and accuracy were very similar. The regression analysis was applied to age groups 10-11 years through 13-14 years. Only chronological age was significant (P = 0.04). Agreement between CVM stage 3 and the maximum mandibular growth spurt is inconsistent. The diagnostic capability of CVM for the mandibular growth spurt is questionable.


Healthcare Costs and Resource Utilization Associated with the Use of Empagliflozin Versus Other Antihyperglycemic Agents Among Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease: A Real-World Retrospective Cohort Analysis.
Empagliflozin has demonstrated lower rates of cardiovascular outcomes vs. standard of care among patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). However, the impact of empagliflozin compared to other branded antihyperglycemic agents (AHAs) on total cost of care has yet to be quantified. This retrospective cohort study evaluated the impact of empagliflozin (n = 441) on costs and healthcare resource utilization (HCRU) vs. other branded AHAs (n = 13,122) among patients with T2DM and CVD, using the IQVIA PharMetrics® Plus Claims Database (1 August 2013-31 December 2017). Date of the first prescription (index date) for empagliflozin or other branded AHAs was used to classify patients into study cohorts. All-cause costs and HCRU were computed on a per patient per month (PPPM) basis and compared across study cohorts using outcome-appropriate statistical models. Overall, the empagliflozin cohort was younger and had a lower comorbidity burden. After covariate adjustment, the total all-cause costs (mean difference - $412 PPPM; 95% CI - $593, - $214) were significantly lower for the empagliflozin cohort. These cost differences were mainly driven by lower all-cause medical costs (mean difference - $400 PPPM; 95% CI - $577, - $196). For HCRU, the mean adjusted all-cause visits in the physician office and other outpatient settings were lower with empagliflozin vs. other branded AHAs (p < 0.001). This study demonstrated that the all-cause healthcare costs and HCRU were significantly lower for patients with T2DM and CVD who initiated empagliflozin vs. other branded AHAs. Along with the positive clinical evidence base of empagliflozin, these results can guide healthcare decision makers during therapy selection.


The forgotten art of cold therapeutic properties in cancer: A comprehensive historical guide.
Cold therapy has been used for centuries, from Julius Caesar to Mohandas Gandhi, as a potent therapeutic approach. However, it has been largely forgotten in modern medicine. This review explores the history of cold therapy and its potential application as a therapeutic strategy against various diseases, including cancer. We examine the different techniques of cold exposure and the use of other therapeutical approaches, such as cryoablation, cryotherapy, cryoimmunotherapy, cryothalectomy, and delivery of cryogen agents. While clinical trials using cold therapy for cancer treatment are still limited, recent research shows promising results in experimental animal cancer models. This area of research is becoming increasingly significant and warrants further investigation.


Hepatocyte NLRP3 interacts with PKCε to drive hepatic insulin resistance and steatosis.
Hepatic insulin resistance (IR), as a downstream sequela of nonalcoholic fatty liver disease (NAFLD), is strongly associated with liver steatosis. Despite numerous mechanism advancements, the molecular underpinnings and pathogenesis of hepatic IR, especially regarding the pattern recognition receptors in hepatocytes, remain elusive. Here, we identified hepatocyte NLRP3 as a direct and previously-unresolved driver of hepatic IR to promote steatosis response. Under the model of NAFLD, we identified hepatocyte NLRP3 as a crucial inducer of hepatic IR by undertaking multilayer transcriptomic searches and further confirmed that its expression was increased in the liver tissues from NAFLD patients and mouse models (high-fat diet (HFD), leptin-receptor-deficient (db/db) mice), and in palmitic acid (PA)-induced hepatocytes. Loss- or gain-of-function of hepatocyte-specific NLRP3 in HFD-induced mice ameliorated or exacerbated hepatic IR and steatosis, respectively. Mechanistically, NLRP3 directly bound to and promoted protein kinase C epsilon (PKCε) activation to impair insulin signaling and increase liver steatosis, while inhibition of PKCε activation dampened the beneficial effects seen in HFD-induced NLRP3-deficient mice. Moreover, we performed screening and discovered that the transcription factor Yin Yang 1 (YY1) positively controlled NLRP3 expression. In translational potential, adeno-associated virus serotype 8 (AAV8)-mediated NLRP3 knockdown in the liver alleviated hepatic IR and steatosis in db/db mice, and pharmacological inhibition of NLRP3 markedly alleviated diet-induced metabolic disorders. This finding reveals a previously-unexpected regulatory axis from YY1 to PKCε via NLRP3 induction for metabolic diseases and establishes the YY1-NLRP3-PKCε axis as a potential therapeutic target for NAFLD.


SCUBE1 is associated with thrombotic complications, disease severity, and in-hospital mortality in COVID-19 patients.
COVID-19 disease, which has recently become an important cause of mortality and morbidity all over the world, is remarkably associated with thrombotic complications. Although many factors are responsible for these increased thrombotic complications in COVID-19 disease, its relationship with a marker that increases the risk of thrombosis such as Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1) has not yet been clarified. This is the first study to examine the potential diagnostic and prognostic value of SCUBE1 levels in patients with COVID-19. In this study, we aimed to clarify the relationship between the increased risk of thrombosis and SCUBE1 in the course of COVID-19 disease. 553 patients with COVID-19 and 553 healthy controls were compared in terms of SCUBE1 levels. Additionally, patients with COVID-19 were divided into two groups according to their SCUBE1 levels and compared in terms of severity of disease, thrombotic complications and ın-hospital mortality. SCUBE1 levels were significantly higher in patients with COVID-19 compared to the control group (p < 0.001). Plasma SCUBE1 levels were significantly higher in patients with severe disease and thrombotic complications, those with mild to moderate disease, and those without thrombotic complications (p < 0.001, for both). In addition, SCUBE1 was found to be an independent predictor of in-hospital mortality (p < 0.001). SCUBE1 may be one of the major determinants of thrombotic complications, which is an increased cause of mortality and morbidity in COVID-19 patients so inhibition of this peptide may be among the therapeutic targets in patients with COVID-19.


Comparison between superficial and solid-state cultures of Isaria fumosorosea: conidial yields, quality and sensitivity to oxidant conditions.
Conidia production and quality from mycoinsecticides in solid-state cultures (SSC) are frequently inferred from superficial culture (SC) results. Both parameters were evaluated for two Isaria fumosorosea strains (ARSEF 3302 and CNRCB1), in SC and SSC, using culture media with the same chemical composition. For both strains, conidia production was higher in SC than SSC in terms of conidia per gram of dry substrate. Germination in both strains did not show significant differences between SC and SSC (>90 %). Similarly, conidia viability in ARSEF 3302 strain did not show differences at early stages between SC and SSC, but was higher in SC compared to SSC in the late stage of culture; in contrast, conidia from CNRCB1 strain did not differ between both culture systems. Some infectivity parameters improved in conidia from SSC, compared to SC at the early stages, but these differences disappeared at the final stage, independently of the strain. Both strains showed decreased conidia production when 26 % O2 pulses were applied; nevertheless, conidiation in SSC was two orders of magnitude more sensitive to oxidant pulses. In SC with 26 % O2 pulses, conidia viability for both strains at early stages, was higher than in normal atmospheric conditions. Infectivity towards Galleria mellonella larvae was similar between conidia from normal atmosphere and oxidant conditions; notably, for the strain ARSEF 3302 infectivity decreased at the final stage. This study shows the intrinsic differences between SC and SSC, which should be considered when using SC as a model to design production processes in SSC.


Ultracytochemical localization of aldehyde dehydrogenase in Acinetobacter calcoaceticus.
A membrane-bound aldehyde dehydrogenase is induced in Acinetobacter calcoaceticus grown on aliphatic hydrocarbons as sole carbon source. This enzyme is NADP-dependent and is able to oxidize medium- and long-chain aliphatic aldehydes to their corresponding fatty acids. Electron micrographs of sectioned alkane-adapted bacteria showed hydrocarbon inclusions in the cytoplasmic matrix. The cytochemical phenazine methosulphate-tetranitro tetrazolium blue capture reaction allowed to localize the activity of the aldehyde dehydrogenase near the surface of these inclusions. At the same location we also found a NADPH tetrazolium-reducing activity.


Ximenia caffra Sond. (Ximeniaceae) in sub-Saharan Africa: A synthesis and review of its medicinal potential.
Ximenia caffra Sond. (Ximeniaceae), commonly known as "sour plum" is traditionally used, both topically and orally to treat a wide range of human diseases and ailments such as wounds, sexually transmitted infections (STIs), infertility, stomach ache, fever, eye problems, diarrhoea, bilharzia, menorrhagia, malaria, intestinal worms, impotence and coughs. The bark and fruits are used by small-scale farmers as ethnoveterinary medicine to treat dermatophilosis, foot rot, saddle sores and control ectoparasites. Oil from X. caffra seed is traditionally used as a moisturiser, soap and shampoo for dry, fragile and damaged hair. The aim of this study was to comprehensively summarize the research that has been done on the botany, ethnomedicinal uses, phytochemistry and biological activities of X. caffra in different locations throughout its geographical range in the sub-Saharan African region so as to understand its importance and potential in primary healthcare systems. This study was carried out using a comprehensive and systematic literature search on the ethnomedicinal uses, phytochemistry and biological activities of the species throughout its distributional range. Literature sources included papers published in international journals, reports from international, regional and national organizations, conference papers, books and theses. PubMed and Scopus, search engines such as Google Scholar and online collection ScienceDirect were used. This study showed that X. caffra is used as traditional medicine in 83.3% of the countries in tropical Africa where it is indigenous. A total of 65 human and animal ailments and diseases are recorded for X. caffra, with a high degree of consensus for wounds, sexually transmitted infections (STIs), infertility, stomach ache, fever, eye problems, diarrhoea, bilharzia, menorrhagia, malaria, intestinal worms and coughs. Phytochemical investigation of X. caffra revealed that the species has various compounds including flavonoids, phenols, phytosterols, tannins and fatty acids. Different plant parts, aqueous and organic extracts exhibited anti-amoebic, antibacterial, antifungal, anti-inflammatory, antioxidant, antiparasitic, antiproliferative, HIV-1 reverse transcriptase (RT) inhibitory, insecticidal, non-mutagenic and toxicity activities. In this review, the ethnomedicinal uses, phytochemistry, biological activities and toxicity of different extracts and compounds of X. caffra have been summarized. Although many of the ethnomedicinal uses of X. caffra have been validated by phytochemical and pharmacological studies, there are still some gaps where current knowledge could be improved. There are very few to nil experimental animal studies, randomized clinical trials and target-organ toxicity studies involving X. caffra and its derivatives that have been carried out so far. At the present moment, there is not sufficient evidence to interpret the specific chemical mechanisms associated with some of the documented biological activities of the species. Therefore, future studies should identify the bioactive components, details of the molecular modes or mechanisms of action, pharmacokinetics and physiological pathways for specific bioactives of X. caffra.


Are interventions delivered by healthcare professionals effective for weight management? A systematic review of systematic reviews.
There are many systematic reviews of weight management interventions delivered by healthcare professionals (HCP), but it is not clear under what circumstances interventions are effective due to differences in review methodology. This review of systematic reviews synthesises the evidence about: (a) the effectiveness of HCP-delivered weight management interventions and (b) intervention and sample characteristics related to their effectiveness. The review of reviews involved searching six databases (inception - October 2020). Reviews were included if they were (a) systematic, (b) weight management interventions delivered, at least partially, by HCP, (c) of randomised controlled trials and (d) written in English. Data regarding weight management outcomes (e.g. weight) and moderating factors were extracted. Secondary analyses were conducted using study-level data reported in each of the reviews. The review included studies that were delivered by HCP in any clinical or non-clinical setting. Not applicable. Six systematic reviews were included (forty-six unique studies). First-level synthesis showed that weight management interventions delivered by HCP are effective. The second-level synthesis found that interventions are only successful for up to 6 months, are most effective for women, non-Caucasians and adults and are most effective if they have at least six sessions. As interventions are only successful for up to 6 months, they are not sufficient for achieving and maintaining a healthy weight.


Development of new IgE specificities to allergenic components in birch pollen extract during specific immunotherapy studied with immunoblotting and Pharmacia CAP System.
New IgE sensitizations to proteins in allergen extracts have been shown to occur during allergen-specific immunotherapy (IT). However little is known about the kinetics of the changes in antibody reactivities. Twenty-four allergic children and adults were treated with birch pollen rush IT (RIT). Fifteen matched patients served as allergic controls. Sera were obtained at regular intervals for up to three years and analyzed with immunoblotting and Pharmacia CAP System with recombinant (r) birch pollen allergens (rBet v 1, rBet v 2, and rBet v 4). All birch-allergic patients had specific IgE to the major birch pollen allergen Bet v 1, but only three had IgE to rBet v 2 and/or rBet v 4 at the beginning of the study. New IgE sensitizations developed in 65% of the birch RIT-treated patients when studied by immunoblotting. Twenty-nine percent of the patients developed new sensitizations to rBet v 2 and/or rBet v 4 during RIT as measured by Pharmacia CAP System. Generally, new specific IgE reactivities occurred after at least one year of RIT, and only at low levels (< 1 kUA/l). Sensitization to additional allergenic pollen components frequently occurs during prolonged birch RIT. However, the IgE levels are low and the clinical relevance is not known.


Role of trospium chloride in brachytherapy-related detrusor overactivity.
After prostate brachytherapy, pronounced urinary irritative symptomatology occurs in a substantial minority of patients. In this study, we evaluated the impact of trospium chloride in prostate brachytherapy patients with symptoms consistent with an overactive bladder (OAB). From January 1999 through December 2005, 69 permanent prostate brachytherapy patients were identified who received trospium as first-line treatment for OAB. The median interval from implant to initiation of trospium was 23.4 months. Before trospium, we obtained a postvoid residual urine assessment (PVR) and International Prostate Symptom Score (IPSS) for all patients. IPSS resolution was defined as a return to within 2 points of the pre-brachytherapy value and individual IPSS question resolution was defined by a decrease of at least 1 point. The mean patient age was 66.0 years, with a pre-brachytherapy prostate volume of 31.0 cm(3) and a mean preimplant IPSS of 6.5. At trospium initiation, the mean IPSS was 9.6 with a mean PVR of 12.3 mL. IPSS normalization was documented in 55 (79.7%) patients. Twelve months after trospium initiation, the IPSS had decreased by a mean of 4.3 points with the improvement most pronounced for urgency. After trospium, no clinically significant differences were noted in the mean PVR. Twenty-two patients discontinued trospium as a result of the absence of a clinical response or pharmacologic side effects, or after complete resolution of symptoms. Nearly 80% of patients with brachytherapy-related detrusor overactivity responded favorably to trospium with improvements in IPSS (especially urgency). This was accomplished with an acceptable morbidity profile.


Effect of extracorporeal shock wave lithotripsy on bacterial viability. Relationship to the treatment of struvite stones.
The aim of this study was to determine whether extracorporeal shock wave lithotripsy (ESWL) affected the viability of the infecting bacteria within a simulated struvite stone matrix. A strain, Proteus mirabilis 28cii, was prepared in three forms: (1) suspended in saline and urine, (2) artificially encapsulated by suspending in agar beads and (3) artificially encapsulated and mineralised by suspending in agar beads with calcium carbonate crystals. The preparations were placed in capped vials partially immersed in degassed water and held in the focal point of the Siemens Lithostar and given 1,000 shocks. Subsequent viability testing showed that bacteria suspended in urine were greatly affected by shock treatments (55% loss in viability), but incorporation into agar beads negated this effect (even if the cells were exposed to 2000 shocks). Mineralisation of the beads with calcium carbonate crystals caused a decrease in viability of 82% that was significantly different from controls. However, this still left 2.3 X 10(8) viable organisms (82% of 2.8 X 10(8], easily enough to form the focus for further infections. A series of control experiments carried out using an ultrasonic cell sonicator probe gave comparable results to those obtained with ESWL. These results demonstrate the ESWL treatment of infected stones must be accompanied by antimicrobial coverage.


JNK inhibitor SP600125 is a partial agonist of human aryl hydrocarbon receptor and induces CYP1A1 and CYP1A2 genes in primary human hepatocytes.
SP600125, a specific inhibitor of c-Jun-N-Terminal kinase (JNK), was reported as a ligand and antagonist of aryl hydrocarbon receptor (AhR) [Joiakim A, Mathieu PA, Palermo C, Gasiewicz TA, Reiners Jr JJ. The Jun N terminal kinase inhibitor SP600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug Metab Dispos 2003;31(11):1279-82]. Here we show that SP600125 is not an antagonist but a partial agonist of human AhR. SP600125 significantly induced CYP1A1 and CYP1A2 mRNAs in primary human hepatocytes and CYP1A1 mRNA in human hepatoma cells HepG2. This effect was abolished by resveratrol, an antagonist of AhR. Consistent with the recent report, SP600125 dose-dependently inhibited CYP1A1 and CYP1A2 genes induction by a prototype AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in human hepatocytes. Moreover, SP600125 displayed typical behavior of a partial agonist in HepG2 cells transiently transfected with a reporter plasmid containing two inverted repeats of the dioxin responsive element or with a plasmid containing 5'-flanking region of human CYP1A1 gene. SP600125 transactivated the reporter plasmids with EC(50) of 0.005 and 1.89 microM, respectively. On the other hand, TCDD-dependent transactivation of the reporter plasmids was inhibited by SP600125 with IC(50) values of 1.54 and 2.63 microM, respectively. We also tested, whether the effects of SP600125 are due to metabolism. Using liquid chromatography/mass spectrometry approach, we observed formation of two minor monohydroxylated metabolites of SP600125 in human hepatocytes, human liver microsomes but not in HepG2 cells. These data imply that biotransformation is not responsible for the effects of SP600125 on AhR signaling. In conclusion, we demonstrate that SP600125 is a partial agonist of human AhR, which induces CYP1A genes.


Late-presenting acute acetaminophen toxicity and the role of N-acetylcysteine.
NAC is an effective antidote for APAP toxicity. NAC has been shown to be effective for early toxicity and is gaining acceptance for late toxicity. As the knowledge of APAP toxicity advances, the duration and route of NAC administration may be clarified.


Meta-analysis of the prognostic significance of perinodal spread in head and neck squamous cell carcinomas (HNSCC) patients.
To assess the risk factor of capsular rupture for individual prognosis and potential therapeutic decision making, the present meta-analysis elaborated the prognostic significance of perinodal spread in a large group of patients suffering from head and neck squamous cell carcinomas (HNSCC). A review of the published literature was conducted, and fixed and random effects models were applied for estimation of the summarised odds ratio and 95% confidence intervals, including a test for homogeneity of the odds ratios. Study methodology allowed the enrollment of only nine studies of 115 published papers. Excluded studies lacked regarding primary tumour location, number and location of lymph node metastases, values on five-year survival, or adequate follow-up data. A summarised odds ratio of 2.7 leads to the conclusion that perinodal spread negatively impacts the five-year survival. The lower confidence limit of more than 2 also supports the concept that perinodal spread significantly reduces (doubled risk) the five-year-survival. These results support the conclusion that perinodal spread is a significant adverse risk factor for survival in patients with HNSCC.


[Severe fetal growth retardation by maternal heroin addiction. A casuistic report (author's transl)].
A case of poor intrauterine fetal growth is reported, observed during the pregnancy of a 16 years old heroin addicted primigravida. Near on term she was delivered of an almost mature male liveborn of only 37 cm and 1300 g. Our results of placental function-tests with reference to otherwise reported effects of maternal heroin addiction are discussed.


The Zoom Wigner transform and its application to the analysis of blood velocity waveforms.
The analysis of blood velocity using noninvasive Doppler ultrasound is now an important clinical technique. The paper discusses the application of the Wigner transform to the estimation of blood velocity from the Doppler signal. A new type of Wigner transform, the Zoom Wigner Transform or ZWT is developed. The ZWT has certain advantages over the standard Wigner transform, particularly in relation to the frequency resolution of specific components, these are discussed. The final section of the paper considers practical aspects of blood velocity estimation and illustrates the use of the WZT in relation to other methods.


Requirements for medical writing.
Scientific communication is a responsibility and obligation of the surgeon to enrich and advance knowledge. Reporting in journals is a means of achieving this interaction, which is particularly important in the developing field of bariatric surgery.


Safety and Effectiveness of Multiple Switching Between Originators and Biosimilars: Literature Review and Status Report on Interchangeability.
To date, numerous biosimilars are available in Europe and the practice of switching between originator and biosimilar or between two different biosimilars has become very widespread. However, multiple switching has not been adequately studied. The aim of this study is to conduct a literature review to assess the effectiveness and safety of multiple switches. All PubMed articles involving multiple switches from originator to biosimilars or between different biosimilars were considered. The relevant data on effectiveness and safety were extracted from these studies and the results were reported through descriptive analysis. Fifteen studies were considered, of which 11 were observational and 4 clinical trials. Inflammatory bowel disease and psoriasis were the most studied diseases. All studies reported that the effectiveness and safety in patients whose treatment involved multiple switches, was comparable to patients whose treatment involved a single or no switch at all. Some therapeutic fields such as oncology and renal insufficiency were not represented at all in the multiple switch studies. New evidence is desperately needed and should be made available to the scientific community and decision-makers.


A nomogram based on multi-modal ultrasound for prediction of microvascular invasion and recurrence of hepatocellular carcinoma.
To establish and validate a nomogram based on multi-modal ultrasound for preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC), and to assess the ability thereof to stratify recurrence-free survival (RFS). A total of 287 HCC patients undergoing surgical resection were prospectively enrolled, including 210 patients in the training cohort and 77 patients in the test cohort. All patients underwent conventional ultrasound, contrast-enhanced ultrasonography, and shear wave elastography examinations within one week before surgery. Taking histopathological examination result as the reference standard, independent factors associated with MVI in HCC were determined by logistic regression and a nomogram was established and further evaluated. The Kaplan-Meier method was used to analyze the prognostic value of histologic MVI status and nomogram-predicted MVI status. Multivariate analysis showed that tumor diameter, echogenicity, tumor shape, arterial phase peritumoral enhancement and enhancement level in portal venous phase were independent predictors of MVI (all p < 0.05). The nomogram based on these variables showed good discrimination and calibration with the areas under the receiver operating characteristic curve (AUC) of 0.821 (0.762-0.870) and 0.789 (0.681-0.874) in the training and test cohorts. There was a significant difference in RFS between the nomogram-predicted MVI positive and the nomogram-predicted MVI negative groups in training and test cohorts (p < 0.001 and p = 0.004 respectively). The multimodal ultrasound features were effective imaging markers for preoperative prediction of MVI of HCC and the nomogram might be an effective tool to stratify the risk of recurrence and guide the individualized treatment of HCC.


Characterization of two negative regulators of the Toll-like receptor pathway in Apostichopus japonicus: inhibitor of NF-κB and Toll-interacting protein.
The Toll-like receptor (TLR) signaling cascade plays a central role in host cell recognition and responses to microbial pathogens via the specific recognition of distinct pathogen-associated molecular patterns (PAMPs). However, no negative regulators of the TLR-signaling cascade have been described in sea cucumber (Apostichopus japonicus). In the present study, two negative regulators known as the inhibitor of NF-κB (IκB) and Toll-interacting protein (Tollip) have been identified in coelomocytes of this species using transcriptome sequencing and RACE (denoted as AjIκB and AjTollip, respectively). Both of these factors share a remarkably high degree of structural conservation with their mammalian orthologs, such as a central ankyrin repeat domain (ARD) for the deduced amino acids of AjIκB and the C2 and CUE domains for AjTollip. Constitutive expression patterns with differential expression levels were observed for these two genes. Moreover, mRNA transcript expression for AjIκB and AjTollip was highest in the tentacle and abundant in the muscle, respectively. Vibrio splendidus challenge study revealed that the expression level of these two genes was decreased within the first 48 h with 0.53-fold and 0.61-fold decrease compared with that in the control group for AjIκB and AjTollip, respectively. Taken together, these results indicated that AjIκB and AjTollip functioned as negative regulators in the TLR cascade in response to a V. splendidus challenge.


The life-cycle of the avian haemosporidian parasite Haemoproteus majoris, with emphasis on the exoerythrocytic and sporogonic development.
Haemoproteus parasites (Haemosporida, Haemoproteidae) are cosmopolitan in birds and recent molecular studies indicate enormous genetic diversity of these pathogens, which cause diseases in non-adapted avian hosts. However, life-cycles remain unknown for the majority of Haemoproteus species. Information on their exoerythrocytic development is particularly fragmental and controversial. This study aimed to gain new knowledge on life-cycle of the widespread blood parasite Haemoproteus majoris. Turdus pilaris and Parus major naturally infected with lineages hPHYBOR04 and hPARUS1 of H. majoris, respectively, were wild-caught and the parasites were identified using microscopic examination of gametocytes and PCR-based testing. Bayesian phylogeny was used to determine relationships between H. majoris lineages. Exoerythrocytic stages (megalomeronts) were reported using histological examination and laser microdissection was applied to isolate single megalomeronts for genetic analysis. Culicoides impunctatus biting midges were experimentally exposed in order to follow sporogonic development of the lineage hPHYBOR04. Gametocytes of the lineage hPHYBOR04 are indistinguishable from those of the widespread lineage hPARUS1 of H. majoris, indicating that both of these lineages belong to the H. majoris group. Phylogenetic analysis supported this conclusion. Sporogony of the lineage hPHYBOR04 was completed in C. impunctatus biting midges. Morphologically similar megalomeronts were reported in internal organs of both avian hosts. These were big roundish bodies (up to 360 μm in diameter) surrounded by a thick capsule-like wall and containing irregularly shaped cytomeres, in which numerous merozoites developed. DNA sequences obtained from single isolated megalomeronts confirmed the identification of H. majoris. Phylogenetic analysis identified a group of closely related H. majoris lineages, two of which are characterized not only by morphologically identical blood stages, but also complete sporogonic development in C. impunctatus and development of morphologically similar megalomeronts. It is probable that other lineages belonging to the same group would bear the same characters and phylogenies based on partial cytb gene could be used to predict life-cycle features in avian haemoproteids including vector identity and patterns of exoerythrocytic merogony. This study reports morphologically unique megalomeronts in naturally infected birds and calls for research on exoerythrocytic development of haemoproteids to better understand pathologies caused in avian hosts.


Nanomedicines for developing cancer nanotherapeutics: from benchtop to bedside and beyond.
Cancer is a devastating disease and remains a significant cause of mortality and morbidity in both developed and developing countries. Although there are large number of drugs that can be used for the treatment of cancer, the problem is selective and specific killing of cancerous cells without harming the normal cells. There are some biological barriers to potential drug delivery in cancer cells like hepatic, renal, abnormal vasculature, dense extracellular matrix, and high interstitial fluid pressure. The physicochemical characteristics of nanoparticles (NPs) such as size, shape, and surface charge may also have significant effects on tumor penetration. NPs coated with drug can be used to overcome these biological barriers to enhance targeted delivery. This literature survey encompasses the biological barriers to potential drug delivery in cancer cells, elaborate on designing strategies to enhance NPs penetration and distribution inside the tumor interstitium. Scientists are now doing great efforts to design next-generation of nanomedicines (NMs) that need to be better targeted with high specificity and efficacy to kill cancer cells. These challenges need to be overcome through collaborations among academia, pharmaceutical industries, and regulatory agencies to eradicate this global menace. Furthermore, this review article has critically discussed the recent developments, controversies, challenges, emerging concepts, and future perspectives in cancer NMs.


Estimation of the intrinsic dimensionality of fMRI data.
A new method based on an autoregressive noise model of order 1 is introduced to the problem of detecting the number of components in fMRI data. Unlike current information-theoretic criteria like AIC, MDL, and related PPCA, which do not incorporate autocorrelations in the noise, the new method leads to more consistent estimates of the model order, as illustrated in simulated and real fMRI resting-state data.


[The effect of chloramphenicol on sleep in cat -- comparison with thiamphenicol, erythromycine, and oxytetracycline (author's transl)].
The effects of various antibiotics, which inhibit protein synthesis, has been studied on the sleep-waking cycle of cats. Chloramphenicol (CAP) selectively inhibits paradoxical sleep (SP). Thiamphenicol (TAP) and oxytetracycline however are ineffective; erythromycine induces only a small decrease of SP. When CAP is injected after TAP, the SP inhibition is longer than after CAP alone. Combining erythromycine and CAP produces the same effect as one or other of the antibiotic alone, depending only on the interval between administration of the two drugs. Slow wave sleep is decreased only with high doses of CAP and is unaffected by TAP, oxytetracycline or erythromycine. These results suggest that CAP may inhibit a peptide or protein synthesis involved in the mechanisms of SP.


Phase II evaluation of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) in patients with gastric adenocarcinoma.
A phase II study of m-AMSA in patients with gastric adenocarcinoma was conducted. Twenty-three patients received m-AMSA, 90-120 mg/m2, every 3 weeks. There were no major responses among 20 evaluable patients, although one patient experienced a minor response. Depression of the white blood count was the most prominent toxicity. m-AMSA has little activity in patients with gastric adenocarcinoma.


Using the Bayesian detection of potential risk using inference on blinded safety data (BDRIBS) method to support the decision to refer an event for unblinded evaluation.
In the Sponsor Responsibilities-Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies: Draft Guidance for Industry (June 2021) the Food and Drug Administration recommends that sponsors develop a Safety Surveillance Plan as a key element of a systematic approach to safety surveillance and describes two possible approaches to assess the aggregate safety data. One approach regularly analyzes unblinded serious adverse events (SAEs) by treatment group. The alternative approach prespecifies estimated background rates for anticipated SAEs in the study population (e.g., myocardial infarctions in an older adult population). If the event rate in the blinded data from the study population exceeds a "trigger rate," then an unblinded analysis by treatment group is conducted. The Bayesian detection of potential risk using inference on blinded safety data (BDRIBS) method has been previously described and offers a quantitative approach for assessing blinded events. In this article we provide a procedural workflow for blinded review of safety data that is consistent with the unblinding "trigger approach" for aggregate safety review. In addition, this publication contextualizes the use of BDRIBS within the broader safety surveillance framework, extends the method to allow for multiple studies, and offers examples of its use in various settings via an R-Shiny application that allows for dynamic visualization and assessment.


The contribution of electrostatic factors to the stabilization of the conformation of cytochrome c. Studies on the maleylated protein.
All the lysines of horse heart cytochrome c were maleylated yielding a low spin product. At room temperature and low salt concentration, this product lacked the 695 nm absorption band and showed tryptophan fluorescence and circular dichroic spectra typical of denatured cytochrome c. The 695 nm band and the native tryptophan fluorescence and circular dichroic spectra were restored by addition of salts, their effectiveness being dependent on the charge of the cation. On low salt concentration, the 695 nm band was also restored by lowering the temperature. Studies of the temperature dependence of the 695 nm band indicate that the thermal denaturation of maleylated cytochrome c occurs at temperatures 60-70 degrees C lower than in the native protein. This implies a destabilization of the native conformation by 5.6 kcal/mol; a similar value is evidenced by comparative urea denaturation studies on the native and modified proteins. The results confirm the assumption that the native conformation of cytochrome c is mostly determined by interactions involving internal residues.


The relationships between streptococcal species and periodontopathic bacteria in human dental plaque.
The existence of antagonistic and commensal relationships between microorganisms was investigated. The predominant cultivable flora in 172 plaque samples from active and non-active sites in 32 human subjects with destructive periodontitis was determined. The presence of putative periodontopathic organisms (Bacteroides gingivalis, Bacteroides intermedius, Bacteroides forsythus, Wolinella recta, Actinobacillus actinomycetemcomitans, and Eikenella corrodens) in a site was correlated with the absence of certain viridans streptococci (Streptococcus sanguis, Streptococcus uberis and Streptococcus intermedius), and vice versa. A strong commensal relationship was found between B. gingivalis and Strep. intermedius. The second study involved 3 subjects with intractable periodontitis whose plaque harboured large numbers of one or more of these periodontopathic organisms. This plaque contained fewer organisms capable of inhibiting the growth of the periodontopathic strains in vitro when compared with a clinically-healthy control subject. Intermediate levels of inhibitors were found in plaque taken from non-active lesions. The majority of inhibitors in plaque from the healthy control were viridans streptococci. Hydrogen-peroxide production by these organisms appears to be the principal mechanism of growth inhibition for periodontopathic organisms. Bacterial interactions may thus be causally related to both periodontal health and disease.


The effect of acetazolamide on myocardial carbon dioxide space.
Carbon dioxide, water and vascular space were measured in the heart muscle of the dog before and after the administration of acetazolamide. In contrast to the skeletal muscle whose CO2 space was markedly reduced by acetazolamide, cardiac muscle CO2 space was only minimally reduced. This suggests that cardiac muscle does not have extravascular carbonic anhydrase. Its presence in skeletal muscle and absence in cardiac muscle probably relates to the differences in cell size between the two types of muscle and their differing degree of vascularity.


Expression of toll-like receptors on B lymphocytes.
Toll-like receptors (TLRs) are a family of trans-membrane receptors that play an important role in the innate immune system. Most studies examining the cellular expression of TLRs on immune cells have focussed on neutrophils, monocytes and dendritic cells, but there is little evidence of TLRs being expressed on lymphocytes. Using 3-colour flow cytometry, expression of TLR-1, TLR-2, TLR-3, TLR-4, and TLR-9 on peripheral blood lymphocyte populations was determined. Further examination of TLRs on CD5- and CD5+ CD19+ B cell subsets was performed. The binding of TLR1 and TLR9 antibodies was detected on 15-90% of resting B cells, but not on resting T-cells. The higher expression of TLR1 and TLR9 on CD5+ B cells compared to CD5- B cells may reflect the role of B1 cells in more primitive, less specific antibody responses.


Cataract formation after posterior chamber phakic intraocular lens implantation.
Posterior chamber phakic intraocular lens (PCP IOL) implantation is an emerging refractive procedure. We report a case of cataract formation 6 months after uneventful implantation of a Staar PCP IOL to correct high myopia. Visual recovery was achieved after explantation of the phakic IOL and phacoemulsification with implantation of a foldable IOL through the same unenlarged self-sealing corneal incision.


On the role of volume transmission and receptor-receptor interactions in social behaviour: focus on central catecholamine and oxytocin neurons.
This article is focused on understanding the mechanisms for the interactions between the central catecholamine (CA) and oxytocin (OXY) neurons and their relevance for brain function especially social behaviour in the field of pair bonding. Such a topic is analysed under two perspectives namely the intercellular communication modes between CA and OXT neurons and the molecular integrative mechanisms at the plasma membrane level between their respective decoding systems. As a matter of fact, recent observations strongly indicate a major role of volume transmission and receptor-receptor interactions in the CA/OXT neuron interplay in the brain control of social behaviour and pair bonding. This article is part of a Special Issue entitled: Brain Integration.


Can We Predict the Lateral Compartment Lymph Node Involvement in RET-Negative Patients with Medullary Thyroid Carcinoma?
Lateral lymph node dissection (LND) in the absence of macroscopic nodal metastasis remains controversial in sporadic medullary thyroid carcinoma (MTC). The aims of our study were to determine the risk of lateral lymph node (LN) metastases with a focus on lateral contralateral N1, and to define a risk-adapted surgical treatment for these patients. All patients who underwent surgery from 1980 to 2012 for previously untreated RET-negative MTC were reviewed. We focused on the lateral compartments of LN metastases and identified three groups: no lateral LN metastases, ipsilateral lateral (ILL)-LN metastases with no contralateral LN involvement, and contralateral lateral (CLL)-LN metastases. Overall, 131 patients underwent surgery for RET-negative MTC. A total thyroidectomy with LND was performed in 112 patients (85 %), including 97 patients who had an ILL-LND and 92 patients who had a CLL-LND. Lateral LN metastases (N1) occurred in 40 patients (37 %): 31 patients (32 %) had ILL-LN metastases with no contralateral LN involvement, and 9 patients (10 %) had CLL-LN metastases. The preoperative cut-offs for LN metastases in the ILL compartment were very low, with a smallest tumor size of 5 mm, and lowest serum calcitonin level of 38 pg/ml. Disease-free survival rates decreased from 92 % for patients with no lateral LN metastases to 41 % for patients with ILL-LN metastases and 0 % for patients with CLL-LN metastases. ILL-LND should be performed in every patient and only a minority of MTC patients with small micro-MTC, and low serum calcitonin levels should not have a CLL-LND.


Long-Term Survival and Reintervention After the Ross Procedure Across the Pediatric Age Spectrum.
There are limited data regarding long-term outcomes after the Ross procedure in children. We evaluated mortality and reintervention in a large pediatric cohort. A retrospective analysis of all patients aged younger than 18 years who underwent the Ross procedure at our institution (1991 to 2013) was conducted. Kaplan-Meier curves and Cox proportion hazard models were used to evaluate long-term outcomes and associated risk factors. Included were 240 consecutive patients undergoing a Ross/Ross-Konno procedure: 18% infants, 48% children, and 33% adolescents. Infants were more likely to have complex left heart disease (p = 0.005). Overall survival to hospital discharge was 96%; infants had the highest mortality (18%). Long-term survival status was known for 99.6% (median follow-up, 10.7 years). Overall 15-year survival was 87% (lowest in infants, 72%; p = 0.003). Reintervention status was known in 87%. Overall 15-year freedom from any left ventricular outflow tract reintervention was 59%; 85% still had their autograft valve at the latest follow-up. Left ventricular outflow tract reintervention was uncommon in infants (n = 2). Overall 15-year freedom from right ventricular outflow tract reintervention was 53%, and was lower in infants (19%) than in children (51%) and adolescents (76%; p < 0.0001). Outcomes after the Ross procedure in children vary by age. Infants more commonly have complex left heart disease and experience higher mortality but have excellent long-term autograft durability. Children and adolescents have higher rates of left ventricular outflow tract reintervention, whereas infants are at highest risk of right ventricular outflow tract reintervention.


Performance of Interleukin-6 and Interleukin-8 serum levels in pediatric oncology patients with neutropenia and fever for the assessment of low-risk.
Patients with chemotherapy-related neutropenia and fever are usually hospitalized and treated on empirical intravenous broad-spectrum antibiotic regimens. Early diagnosis of sepsis in children with febrile neutropenia remains difficult due to non-specific clinical and laboratory signs of infection. We aimed to analyze whether IL-6 and IL-8 could define a group of patients at low risk of septicemia. A prospective study was performed to assess the potential value of IL-6, IL-8 and C-reactive protein serum levels to predict severe bacterial infection or bacteremia in febrile neutropenic children with cancer during chemotherapy. Statistical test used: Friedman test, Wilcoxon-Test, Kruskal-Wallis H test, Mann-Whitney U-Test and Receiver Operating Characteristics. The analysis of cytokine levels measured at the onset of fever indicated that IL-6 and IL-8 are useful to define a possible group of patients with low risk of sepsis. In predicting bacteremia or severe bacterial infection, IL-6 was the best predictor with the optimum IL-6 cut-off level of 42 pg/ml showing a high sensitivity (90%) and specificity (85%). These findings may have clinical implications for risk-based antimicrobial treatment strategies.


Maximal oxygen uptake during cycling is reduced in moving environments; consequences for motion-induced fatigue.
In previous studies on physical fatigue during simulated ship movements, the apparent exhaustion of subjects after experimentation suggested that the traditional index of physical workload, oxygen consumption expressed as the percentage of peak oxygen consumption (VO2-peak) measured in a separate graded exercise test (GXT), underestimates workload in a moving environment. In these studies, the GXT was carried out in a stationary environment, as is standard practice. To explain the underestimation, it was hypothesized that VO2-peak might have been less if the GXT had been carried out in the moving environment. This paper reports on three experimental tests of this hypothesis, performed with a ship motion simulator and aboard a ship at sea. In all three experiments, VO2-peak was indeed significantly reduced when the GXT was carried out in the moving environment. Theoretical reasons for this phenomenon are discussed and investigated, but a clear explanation is still lacking.


Soundscapes and Larval Settlement: Larval Bivalve Responses to Habitat-Associated Underwater Sounds.
We quantified the effects of habitat-associated sounds on the settlement response of two species of bivalves with contrasting habitat preferences: (1) Crassostrea virginicia (oyster), which prefers to settle on other oysters, and (2) Mercenaria mercenaria (clam), which settles on unstructured habitats. Oyster larval settlement in the laboratory was significantly higher when exposed to oyster reef sound compared with either off-reef or no-sound treatments. Clam larval settlement did not vary according to sound treatments. Similar to laboratory results, field experiments showed that oyster larval settlement in "larval housings" suspended above oyster reefs was significantly higher compared with off-reef sites.


Comparative evaluation of static and dynamic simulated digestion models.
The digestion behavior of lipids plays a crucial role in their nutritional values. Currently, the complex dynamic variations of human gastrointestinal conditions are considered in simulated digestion models. The present study compared the digestion behavior of glycerol trilaurate (GTL), glycerol tripalmitate (GTP) and glycerol tristearate (GTS) in a static in vitro digestion model and a dynamic in vitro digestion model. In the dynamic digestion model, the parameters of gastric juice secretion, the rate of gastric emptying, the secretion of intestinal juice and the pH variations were estimated. The dynamic digestion model showed a certain extent of gastric lipase hydrolysis, while almost no lipolysis happened in the gastric phase of the static digestion model. A smoother digestive behavior was observed in the dynamic model than that in the static model. In the static model, the particle size distribution in gastric and intestinal phase changed rapidly in all triacylglycerol (TAG) groups. The change of particle size during the whole digestion period in GTL is more moderate than GTP and GTS. In addition, the final free fatty acids release degree was 58.558%, 54.36%, and 52.97% for GTL, GTP, and GTS, respectively. This study illustrated the different digestion profiles of TAGs in two digestion models and the results will contribute to a better understanding of different in vitro digestion models in lipid digestion. © 2023 Society of Chemical Industry.


Pax6 controls radial glia differentiation in the cerebral cortex.
Radial glia cells perform a dual function in the developing nervous system as precursor cells and guides for migrating neurons. We show here that during forebrain neurogenesis, the transcription factor Pax6 is specifically localized in radial glia cells of the cortex but not of the basal telencephalon. In Pax6-deficient mice, cortical radial glia cells were altered in their morphology, number, tenascin-C (TN-C) expression, and cell cycle. We show that some of these alterations are cell-autonomous, whereas others were rescued by coculturing with wild-type cortical cells. Our results suggest that Pax6 plays an essential role in the differentiation of cortical radial glia. Thus, despite their widespread distribution, radial glia cells are regionally specified in the developing CNS.


A Survey of prevalence of serum antibodies to human immunodeficiency deficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) among blood donors.
It is a well known fact that HIV, HBV and HCV are global infectious pathogens contributing to mortality and morbidity in all ages thereby making them infections of grievous public health importance. As donor's potend a possible risk of transfusing these infections of global importance, it makes it imperative for the screening of blood and blood products for these pathogens. This study aims at determining the seroprevalence of HIV, HBV and HCV among intending blood donors. A retrospective data analysis for seroprevalence of antibodies to HIV, HBV and HCV was carried out between the 2(nd) of January and 15(th) of June 2010 among intending blood donors aged 18-45 and the association of these infections with age group and blood group were analyzed. Sterile venous anticoagulated blood was collected from each of the donors and analyzed for HIV, HBV and HCV using highly sensitive and specific kits. All the positive samples for HIV- 1/2 were sent for reconfirmation using polymerase chain reaction. Of the 427 samples analyzed, 203 were positive for HIV, 200 for HBV and 24 for HCV, representing a prevalence of 47.54%, 46.83% and 5.71% respectively among intending blood donors. Among them, blood group O "positive" was the most common blood group with 59.25% followed by blood group B "positive", A "positive" and O "negative" respectively (p<0.001). The analysis of relationship showed a tendency of high association of these infections in subjects with O "positive" blood group. This study emphasizes the need for proper screening of blood donors for HIV, HBV and HCV.


Phyto Synthesis of Manganese-Doped Zinc Nanoparticles Using Carica papaya Leaves: Structural Properties and Its Evaluation for Catalytic, Antibacterial and Antioxidant Activities.
The current study aims to synthesize bimetal oxide nanoparticles (zinc and manganese ions) using the carica papaya leaf extract. The crystallite size of the nanoparticle from X-ray diffraction method was found to be 19.23 nm. The nanosheet morphology was established from Scanning Electron Microscopy. Energy-dispersive X-ray diffraction was used to determine the elemental content of the synthesized material. The atomic percentage of Mn and Zn was found to be 15.13 and 26.63. The weight percentage of Mn and Zn was found to be 7.08 and 10.40. From dynamic light scattering analysis, the hydrodynamic diameter and zeta potential was found to be 135.1 nm and -33.36 eV. The 1,1-diphenyl-2-picryl hydroxyl radical, hydroxyl radical, FRAP, and hydrogen peroxide scavenging tests were used to investigate the antioxidant activity of Mn-Zn NPs. Mn-Zn NPs have substantial antioxidant properties. The photocatalytic activity of the Mn-Zn NPs was assessed by their ability to degrade Erichrome black T (87.67%), methyl red dye (78.54%), and methyl orange dye (69.79%). Additionally, it had significant antimicrobial action S. typhi showed a higher zone of inhibition 14.3 ± 0.64 mm. Mn-Zn nanoparticles were utilized as a catalyst for p-nitrophenol reduction. The bimetal oxide Mn-Zn NPs synthesized using C. papaya leaf extract exhibited promising dye degradation activity in wastewater treatment. Thus, the aforementioned approach will be a novel, low cost and ecofriendly approach.


Cooperative cyclic interactions involved in metal binding to pairs of sites in EF-hand proteins.
This study focuses on a closed net of electron-pair donor-acceptor interactions, present in the core of all metal-bound EF-hand pairs, that link both metal ions across a short two-stranded beta-sheet. A molecular model based on the above cycle of interactions was studied using semi-empirical molecular orbital quantum mechanical methods. The calculations indicate that the interactions in the model cycle are cooperative, that is, that the interaction energy of the cyclic structure is greater than that of the sum of isolated interactions between its components. The cooperativity in this cycle can be attributed to an increase in the stability of the interactions resulting from a mutual polarisation of the associated groups. The predicted polarisation of the amide groups in the cycle is in agreement with experimental NMR 15N deshielding observed for these amide groups upon metal binding. Experimental observations of strengthening of the beta-sheet hydrogen bonds are also consistent with the model calculations. By this mechanism, the binding of the first metal ion would enhance the binding of the second metal ion, and thus, the intradomain cooperativity in cation binding of calmodulin and related EF-hand proteins can be ascribed, at least partly, to this short-range molecular mechanism.


Utilizing bio-affinity ultrafiltration combined with UHPLC Q-Exactive Plus Orbitrap HRMS to detect potential α-glucosidase inhibitors in Oxalis corniculate L.
Oxalis corniculate L. (O. corniculate) was used to treat diabetes in Chinese folk as a popular tea drink. In this work, 31 compounds from O. corniculate were screened and identified as potential α-Glucosidase inhibitors (α-GIs). Among them, 6 compounds displayed stronger inhibitory activity than acarbose (IC50 = 212.9 ± 5.98 μg/mL). Especially, the most effective compounds quercetin (Qu, IC50 = 4.70 ± 0.40 μg/mL) and luteolin (Lu, IC50 = 15.72 ± 0.75 μg/mL) inhibited α-Glu in competitive and mixed manners, respectively. Moreover, fluorescence quenching, circular dichroism (CD), and molecular docking study revealed that they can arouse the changes in the secondary structure and hydrophobic micro-environment of the enzyme mainly through a hydrophobic binding. Furthermore, it was observed that oral administration of Qu (20 mg/kg) can significantly reduce postprandial blood glucose (PBG) levels in mice vs. the control group. To sum up, the above research confirmed that O. corniculate could prevent and treat postprandial hyperglycemia as a good tea drink, and the plant was an excellent source to obtain natural α-GIs.


Effect of 60 Hz magnetic field exposure on c-fos expression in stimulated PC12 cells.
Rat pheochromocytoma PC12 cells have been treated with nerve growth factor (NGF) at final concentrations of 2, 4, 8, and 16 ng/ml, and then were exposed to 60-Hz, sinusoidal magnetic fields (MF) of 12.5, 25, 50, and 100 microT (rms) for 30 min. Transcript levels for both c-fos and glyceraldehyde-3 -phosphate dehydrogenase were determined by Northern blot analysis using 32P-labeled cDNA probes. No change in c-fos expression was measured at any condition employed. Treatment of PC12 cells with a combination of agents (NGF, forskolin, and tetradecanoylphorbol acetate [TPA]) increased c-fos expression over that detected with NGF alone. MF exposure of cells treated with the three-agent regimen produced two outcomes, either no change or a doubling of c-fos expression. In subsequent experiments, cells were treated with NGF, NGF + forskolin + TPA, or pre-treated with anisomycin and then treated with NGF + forskolin + TPA. It was determined that MF exposure, like superinduction with anisomycin, increased c-fos expression only in cultures which were not yet exhibiting maximal c-fos expression. It is hypothesized that MF exposure, like anisomycin, may alter the activity of key intracellular protein kinases.


The long-term antibody response after SARS-CoV-2 prime-boost vaccination in healthy individuals. The positive influence of extended between-dose intervals and heterologous schedule.
Anti-COVID vaccination in Argentina was carried out using different protocols and variations in periods between administrations, as well as combinations of different vaccine platforms. Considering the relevance of the antibody response in viral infections, we analyzed anti-S antibodies in healthy people at different points of time following the Sputnik immunization procedure. We attended the vaccination centers in the city of Rosario, which had shorter versus longer intervals between both doses. A total of (1021) adults with no COVID-compatible symptoms (throughout the study period) were grouped according to the gap between both vaccine doses: 21 (Group A, n=528), 30 (Group B, n=147), and 70 days (Group C, n=82), as well as an additional group of individuals with heterologous vaccination (Sputnik/Moderna, separated by a 107-day interval, group D, n=264). While there were no between-group differences in baseline levels of specific antibodies, data collected several weeks after administering the second dose showed that group D had the highest amounts of specific antibodies, followed by values recorded in Groups C, B, and A. The same pattern of group differences was seen when measuring anti-S antibodies at 21 or 180 days after the first and second doses, respectively. Delayed between-dose intervals coexisted with higher antibody titers. This happened even more when using a prime-boost heterologous schedule.


Acupuncture attenuates cognitive deficits and increases pyramidal neuron number in hippocampal CA1 area of vascular dementia rats.
Decreased cognition is recognized as one of the most severe and consistent behavioral impairments in dementia. Experimental studies have reported that acupuncture may improve cognitive deficits, relieve vascular dementia (VD) symptoms, and increase cerebral perfusion and electrical activity. Multi-infarction dementia was modeled in rats with 3% microemboli saline suspension. Two weeks after acupuncture at Zusanli (ST36), all rats were subjected to a hidden platform trial to test their 3-day spatial memory using the Morris water maze test. To estimate the numbers of pyramidal neuron, astrocytes, and synaptic boutons in hippocampal CA1 area, we adopted an unbiased stereology method to accurately sample and measure the size of cells. We found that acupuncture at ST36 significantly decreased the escape latency of VD rats. In addition, acupuncture significantly increased the pyramidal neuron number in hippocampal CA1 area (P < 0.05) and tended to decrease the number of astrocytes (P = 0.063). However, there was no significant change in the synaptic bouton number of hippocampal CA1 area in any of the groups (P > 0.05). These findings suggest that acupuncture may improve cognitive deficits and increase pyramidal neuron number of hippocampal CA1 area in VD rats.


Potassium N-(6-amino-3,4-dihydro-3-methyl-5-nitroso-4-oxopyrimidin-2-yl)-(S)-aspartate N-(6-amino-3,4-dihydro-3-methyl-5-nitroso-4-oxopyrimidin-2-yl)-(S)-aspartic acid 4.88-hydrate: a two-dimensional coordination polymer.
In the title compound, K(+).C(9)H(10)N(5)O(6)(-).C(9)H(11)N(5)O(6).4.88H(2)O, the cations are eight-coordinate. There is a one-dimensional coordination-polymer substructure, built from K and O atoms only, in the form of chains of distorted confacial octahedra, and these are linked into sheets by the neutral organic ligand. The sheets are linked into a single framework by a combination of N-H.O and O-H.O hydrogen bonds.


Determinants of double product: a cross-sectional study of urban residents in Japan.
The current study aimed to investigate the determinants of high double product (DP) by evaluating the association between resting DP, which is calculated as systolic blood pressure (SBP) multiplied by heart rate (HR), and blood test results and lifestyle factors. This research included 973 participants in the baseline survey of the KOBE study, which included a cohort of urban residents. The possible DP determinants were identified by examining the association between lifestyle factors and laboratory findings and DP by analyzing covariance adjusted for sex and age. Logistic regression analysis was performed with high DP (SBP × HR ≥ 9145 mmHg beats/min or quintile according to sex) as outcome and DP determinants as independent variables. Age, hematocrit, and gamma-glutamyl transferase (log) level were positively associated with a high DP in both men and women. In addition, a high DP was positively associated with Homeostatic Model Assessment for Insulin Resistance score in women alone. Meanwhile, the amount of exercise was negatively associated with a high DP in men alone. High DP values at rest were associated with insulin resistance, gamma-glutamyl transferase, and the amount of exercise in participants without underlying disease.


Stereoselective binding of a 2,3-benzodiazepine to human serum albumin. Effect of conformation on tofizopam binding.
The binding of Tofizopam enantiomers to human serum albumin has been investigated by ultrafiltration and affinity chromatography. In solution, Tofizopam molecules exist in two conformations which slowly interconvert into each other. Both conformers of (R)-Tofizopam have the same binding constant of 4.8 X 10(3) M-1. The binding of the (S)-enantiomer, however, depends on the conformation. The minor and major (S)-conformers were characterized by association constants of 2.3 X 10(3) and 15.1 X 10(3) M-1, respectively. Thus, the stereoselectivity of binding differs for the two conformations of the enantiomers. Kinetic parameters for the interconversion of conformations have been determined. Tofizopam displaces both bound diazepam and warfarin.


The function and origin of follicular dendritic cells.
Follicular dendritic cells (dendritic reticular cells) in germinal centres bind antigen-antibody complexes via C3 receptors and retain the complexes at their surface for long periods of time. The follicular dendritic cells (FDC) are distinct from macrophages and from dendritic cells found in T-dependent areas, and are not derived from bone marrow stem cells. On histological evidence it has been proposed that they are derived from reticulum cells. Complexes are probably transported to FDC by a subpopulation of B cells in the marginal zone. Binding of complexes to FDC causes germinal centre enlargement and is a very efficient, and possibly essential stimulus to the generation of B memory cells which recognize epitopes on antigen or antibody in the complexes. An hypothesis is discussed which draws together these observations and suggests that antigen on FDC plays a central role in control of humoral immunity.


Learning Curve of Total Hip Arthroplasty in Direct Anterior Approach without Requiring Corrective Osteotomy for Hip Dysplasia.
To explore the learning curve of total hip arthroplasty in direct anterior approach (DA-THA) without requiring corrective osteotomy for patients with unilateral developmental dysplasia of the hip (DDH) through the evaluation of clinical and radiographic results. From December 2015 to January 2021, we retrospectively evaluated a surgeon's first 100 patients with unilateral hip dysplasia (Crowe I-III) who underwent DA-THA. All procedures were performed by a fellowship-trained joint surgeon. Cementless hemispheric porous-coated acetabular cups and tapered cementless stems were used in all hips. The radiographic data, including leg length, the height of the center of rotation, femoral head offset, the cup anteversion and inclination angle, were measured. The cumulative sum analysis (CUSUM) and risk-adjusted cumulative sum analysis (RA-CUSUM) were used to determine the learning curve of DA-THA for each patient's operation time. By analyzing the operation time, complication rate, postoperative length of hospitalization and creatine kinase (before surgery and the third day after surgery), estimated blood loss, Harris score, radiographic data were compared between the different stages of the learning curve. The mean follow-up time was 35.45 ± 16.82 months. The CUSUM method obtained the maximum turning point of the curve at 43 cases, which divided the learning curve into Learning Period and Mastery Period. The CUSUM learning curve was best modeled as a cubic curve with the equation: CUSUM (min) = 0.001x3 - 0.495x2 + 33.60x - 10.00, which had a higher R2 value of 0.967. The pre-operative data, creatine kinase, estimated blood loss and postoperative Harris scores of the two stages were not statistically significant (P > 0.05). The mean operation time was 118 min in the Learning Period and 87 min in the Mastery Period. Statistically significant differences were detected in the operation time (P < 0.001), postoperative length of hospitalization(P = 0.024), and postoperative leg length discrepancy (P = 0.012) between the two stages. The overall complication rates were 27.9% in the Learning Period and 12.3% in the Mastery Period (p = 0.049). The overall outliers of radiographic data were 34 cases in the Learning Period and 31 cases in the Mastery Period (79.07% vs 54.39%, P = 0.010). The DA-THA is a valuable alternative to achieve satisfactory clinical results for mild-to-moderate DDH patients. Furthermore, accurate analysis of the learning curve of DA-THA for hip dysplasia by the CUSUM method showed that the surgeons need to finish about 43 cases to master the technique.


Polygenic risk for schizophrenia and bipolar disorder in relation to cardiovascular biomarkers.
Individuals with schizophrenia and bipolar disorder are at an increased risk of cardiovascular disease (CVD), and a range of biomarkers related to CVD risk have been found to be abnormal in these patients. Common genetic factors are a putative underlying mechanism, alongside lifestyle factors and antipsychotic medication. However, the extent to which the altered CVD biomarkers are related to genetic factors involved in schizophrenia and bipolar disorder is unknown. In a sample including 699 patients with schizophrenia, 391 with bipolar disorder, and 822 healthy controls, we evaluated 8 CVD risk biomarkers, including BMI, and fasting plasma levels of CVD biomarkers from a subsample. Polygenic risk scores (PGRS) were obtained from genome-wide associations studies (GWAS) of schizophrenia and bipolar disorder from the Psychiatric Genomics Consortium. The CVD biomarkers were used as outcome variables in linear regression models including schizophrenia and bipolar disorder PGRS as predictors, age, sex, diagnostic category, batch and 10 principal components as covariates, controlling for multiple testing by Bonferroni correction for the number of independent tests. Bipolar disorder PGRS was significantly (p = 0.03) negatively associated with BMI after multiple testing correction, and schizophrenia PGRS was nominally negatively associated with BMI. There were no other significant associations between bipolar or schizophrenia PGRS, and other investigated CVD biomarkers. Despite a range of abnormal CVD risk biomarkers in psychotic disorders, we only found a significant negative association between bipolar disorder PGRS and BMI. This has previously been shown for schizophrenia PGRS and BMI, and warrants further exploration.


Transjugular intrahepatic portosystemic shunt worsens the hyperdynamic circulatory state of the cirrhotic patient: preliminary report of a prospective study.
The aim of this prospective nonrandomized study was to assess the immediate and short-term sequelae of transjugular intrahepatic portosystemic shunting on the circulatory hyperdynamic state of the cirrhotic patient. Twelve transjugular portosystemic shunting procedures were performed in 12 cirrhotic patients for sclerotherapy failure (10 cases) and/or intractable ascites (4 cases). Self-expandable stents 10 mm in diameter were used in all cases. Portal pressure measurement and right-heart catheterization were performed before and 30 min and 1 mo after the procedure. The portoatrial pressure gradient decreased from 15 +/- 3 to 7 +/- 3 mm Hg 30 min after surgery (p < 0.0001) to 8 +/- 3 mm Hg 1 mo after surgery (p < 0.001, in comparison with basal values). The cardiac index increased from 4.5 +/- 1.3 to 5.7 +/- 1.5 L/min.m2 30 min after surgery (p < 0.001) to 7.4 +/- 1.4 L/min.m2 1 mo after surgery (p < 0.001). Systemic vascular resistance decreased from 808 +/- 323 to 646 +/- 209 dyne.sec.cm-5 30 min after surgery (p < 0.01) to 467 +/- 101 dyne.sec.cm-5 1 mo after surgery (p < 0.05). This study demonstrates that transjugular portosystemic shunting rapidly and significantly worsens the hyperdynamic circulatory state of the cirrhotic patient. Although apparently noninvasive, this procedure should be considered with caution in cirrhotic patients with limited cardiac reserve.


[Hexylresorcinol induces chromosome aberrations in mouse peripheral blood cells].
Hexylresorcinol has been demonstrated to induce chromosome aberrations in eukaryotic cells at doses of 0.5, 0.05, and 0.005 mg/g body weight. The metabolic transformation of hexylresorcinol in mice decreases its genotoxic effect. The mutagenic effect is retained for three days only after the administration of the highest dose of hexylresorcinol (0.5 mg/g); during the first two days, lower doses are also genotoxic. Therefore, hexylresorcinol doses lower than 0.5 mg/g body weight are metabolized within two days to the extent precluding the expression of the cytotoxic effect. After a single administration to mice, exogenous hexylresorcinol is transformed at a rate of 0.0025-0.025 mg/day.


Assessing oral health of crack users in Brazil: Perceptions and associated factors, findings from a mixed methods study.
This study explores associated factors and perceptions of oral health among crack users recruited in open drug scenes in Brazil. A mixed methods approach was used. The quantitative component analysed findings from a large (N = 7381), population-based survey. The outcomes under analysis were 'self-perception of oral health' and 'self-reporting of problems affecting the mouth, teeth and gingiva (gums)'. The qualitative component comprised a focus group, with 12 individuals recruited from a drug treatment clinic. Lower self-perception of oral health problems vis-à-vis a higher prevalence of problems affecting the mouth, teeth, and gingiva were found in users who had a lower level of education, used substances daily, had worse self-perception of physical health, did not receive health care and regularly used alcohol and/or tobacco. The results show an association between substance use and decline in oral health, as well as the lack of health services focusing on such issues. Oral health services should be emphasised as a gateway to the health system. So far, the putative cross-referral between services and professionals working in oral health and other health professionals working in the field of drug dependence has not been observed.