Increasing Children's Physical Activity During the School Day.
Insufficient levels of daily physical activity (PA) among children in the USA and worldwide have profound implications for pediatric obesity and children's health and well-being more generally. Public health recommendations highlight the central role that schools play in providing equitable opportunities for PA for all children. This review identifies evidence-based approaches for increasing children's PA throughout the school day and discusses multilevel factors that support implementation of such approaches. Opportunities to increase school-day PA span not only in-school time (e.g., quality recess and physical education, classroom activity breaks) but also time before school (e.g., active commuting initiatives) and after school (e.g., intramural and interscholastic sports programs). For such approaches to impact children's PA, dimensions of implementation such as adoption, fidelity, penetration, implementation costs, and sustainability are critical. Multilevel factors that influence implementation include policies, school environment and organizational factors, teacher and classroom factors, child and family characteristics, and attributes of the PA approach itself. Research and field observations reinforce the importance of understanding challenges specific to working with schools, including multiple stakeholders, competing priorities, limited facilities and staff capacity, and heterogeneity of students. Thus, while schools hold promise as promoters and equalizers of PA engagement for all children, more research is needed on the levers that influence implementation of effective school-based PA policies and programs.


Atrial electrical remodeling by rapid pacing in the isolated rabbit heart: effects of Ca++ and K+ channel blockade.
Electrical remodeling describes atrial electrophysiologic changes that occur following atrial fibrillation. The mechanism(s) responsible for this phenomenon is not well understood. The purpose of this study was to examine the effects of rapid atrial pacing on atrial action potential duration, conduction time and refractoriness in the isolated rabbit heart. The effects of Ca++ and K+ blockade in this model were also studied. Monophasic action potential recordings were made from 12 epicardial atrial sites in 50 isolated perfused rabbit heart preparations. These recordings were analyzed for activation time (AT), 90% action potential duration (APD) and conduction times (CT) measured at a 250 msec cycle length. Atrial effective refractory periods (ERP) were determined at a 200 msec cycle length. All measurements were made at baseline and repeated after 2 hours of biatrial pacing at 250 msec (control group, n = 10) or 2 hours of rapid biatrial pacing (approximately 80 msec) in 4 groups: rapid pacing alone (rapid pacing group); rapid pacing in the presence of 0.1 mM verapamil (verapamil group) for L-type Ca++ channel blockade; rapid pacing with 1 mM 4-aminopyridine (4-AP group) for K+ channel blockade; and rapid pacing with 50 microM nickel chloride (Ni++ group) for T-type Ca++ channel blockade (n = 10 each group). All baseline and post pacing measurements were taken in the presence of Ca++ or K+ blockers for the respective groups. After rapid atrial pacing alone the average APD shortened by 8.2 +/- 10.4 msec compared to 3.6 +/- 12.5 msec shortening for control group (p = 0.002). The shortening of APD was uniform at all recording sites. For the rapid pacing group, CT was unchanged for right to left atrial conduction but shortened significantly for left to right atrial conduction (26.8 +/- 1.9 msec at baseline to 22.3 +/- 4.1 msec post pacing, p = 0.005). Conduction times were unchanged in the control group. The dispersion of repolarization was unchanged by rapid pacing alone. The decrease in APD from baseline to post rapid pacing was similar to the control group for those hearts treated with verapamil and 4-AP (1.5 +/- 12.3 and 4.7 +/- 10.4 msec, respectively, both p > or = 0.18 vs control group). The decrease in APD was significantly greater for the Ni++ group (11.8 +/- 14.3 msec) than for either the control group or rapid pacing group (both p < or = 0.023). The dispersion of repolarization was increased only in the 4-AP group post rapid pacing (41.7 +/- 6.2 msec at baseline to 53.5 +/- 9.6 msec post pacing, p = 0.01). ERPs were unchanged in any of the 5 groups except for a decrease in left atrial ERP in the Ni++ group after rapid pacing (98 +/- 14 msec at baseline to 88 +/- 8 msec post rapid pacing, p = 0.005). In the isolated rabbit heart model: 1) atrial APD is shortened after rapid pacing; 2) the shortening of APD is attenuated by verapamil and 4-AP but exaggerated by Ni++; 3) atrial conduction times are shortened in a direction specific manner after rapid pacing; and 4) shortening of ERP in this model is measured only in the presence of Ni++. These findings suggest that both L-type Ca++ and 4-AP sensitive channels may participate in atrial electrical remodeling.


TEAD4 predicts poor prognosis and transcriptionally targets PLAGL2 in serous ovarian cancer.
The oncogenic function of TEA domain transcription factor 4 (TEAD4) has been confirmed in multiple human malignancies, while its potential role and regulatory mechanism in serous ovarian cancer progression are left unknown. By the gene expression analyses from Gene Expression Profiling Interactive Analysis (GEPIA) database, TEAD4 expression is shown to be up-regulated in serous ovarian cancer samples. Here, we confirmed the high expression of TEAD4 in clinical serous ovarian cancer specimens. In the following functional experiments, we found that TEAD4 overexpression promoted serous ovarian cancer malignant phenotypes, including proliferation, migration and invasion in serous ovarian cancer SK-OV-3 and OVCAR-3 cells, while TEAD4 knockout exerted the opposite function. The tumor growth inhibition of TEAD4 depletion was also affirmed by a Xenograft model in mice. In addition, this phenotypic deterioration induced by TEAD4 overexpression was diminished by PLAG1 like zinc finger 2 (PLAGL2) silencing. More importantly, combined with the results of the dual-luciferase assay, the transcriptional regulation of TEAD4 on PLAGL2 promoter was evidenced. Our results showed that the cancer-promoting gene TEAD4 was involved in serous ovarian cancer progression via targeting PLAGL2 at the transcriptional level.


Left Ventricular Outflow Tract Obstruction in Aortic Arch Anomalies With Ventricular Septal Defect.
The predictors of left ventricular outflow tract obstruction (LVOTO) after the repair of coarctation of the aorta or interruption of the aortic arch (CoA/IAA) with ventricular septal defect have been investigated. However, the predictors remain controversial. We performed primary repair of CoA/IAA with ventricular septal defect for 75 patients from 1996 to 2005. Four of the 75 patients died within 5 years after primary repair without relation to LVOTO. The morphology of the aortic valve of 71 survivors was bicuspid in 23 patients and tricuspid in 48 patients. The mean follow-up was 9.2 ± 2.6 years after primary repair. There were 12 patients who showed LVOTO of 3.0 m/s or greater after primary repair. All of the 6 bicuspid patients demonstrated valvular aortic stenosis, and all of the 6 tricuspid patients showed discrete subvalvular LVOTO. In 5 of the 6 tricuspid patients, the aortic annular z-score before primary repair was -3.0 or less. A bicuspid aortic valve (p = 0.016) and the aortic annular z-score of -3.0 or less (p = 0.019) were significant risk factors for LVOTO after primary repair. At 10 years after primary repair, 82.6% and 95.6% of the bicuspid and tricuspid patients, respectively, were free from reoperation (p = 0.015). The presence of a bicuspid aortic valve and an aortic valve annular z-score of -3.0 or less before primary repair are risk factors for LVOTO, and stenotic bicuspid valves and discrete subvalvular LVOTO are the main causes of LVOTO after primary repair of CoA/IAA with ventricular septal defect. The bicuspid patients more frequently required reoperation than the tricuspid patients.


Measurement of Cerebrovascular Reactivity as Blood Oxygen Level-Dependent Magnetic Resonance Imaging Signal Response to a Hypercapnic Stimulus in Mechanically Ventilated Patients.
Impaired cerebrovascular reactivity (CVR) is an important prognostic marker of stroke. Most measures of CVR lack (1) a reproducible vasoactive stimulus and (2) a high time and spatial resolution measure of cerebral blood flow (CBF), particularly for mechanically ventilated patients. The aim of our study was to investigate the feasibility of measuring CVR using sequential gas delivery circuit and gas blender for precise targeting of end-tidal PCO2 (PetCO2), and blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) signal as a surrogate of CBF, in mechanically ventilated patients. Four patients with known moyamoya disease requiring preoperative CVR measurements under general anesthesia were studied. All patients had standard anesthesia induction and maintenance with intravenous propofol and rocuronium. Patients were intubated and manually ventilated with a self-inflating bag connected to a sequential breathing circuit. A computer-controlled gas blender supplied the gas mixture in proportions to attain target PetCO2. BOLD-MRI was performed at 3.0 Tesla magnet. Changes in signal per change in PetCO2 were calculated, and their magnitude color-coded and mapped onto the anatomic scan to form CVR maps. CVR studies were successfully performed on all patients, and the CVR values were lower in both gray and white matter bilaterally when compared with healthy volunteers. In addition, CVR maps in 3 patients showed intracerebral steal phenomenon in spite of having had cerebral revascularization procedures, indicating that they are still at risk of cerebral ischemia. BOLD-MRI CVR studies are feasible in mechanically ventilated patients anesthetized with propofol.


Accelerating clinical trial development in vaccinology: COVID-19 and beyond.
The remarkable success of the US government-backed COVID-19 vaccine development in 2020 offers several lessons on how to effectively foster rapid vaccine discovery and development. Conceptually, the formation of a public-private partnership that included innovative government and academic involvement at all levels of the program was instrumental in promulgating and overseeing the effort. Decades of NIH-sponsored research on vaccine backbones, immunogen design, and clinical trial operations enabled evaluation of vaccine candidates within months of pathogen discovery. Operation Warp Speed fostered industry participation, permitted accelerated movement from preclinical/early phase to efficacy trials, and developed structured clinical trial testing that allowed independent assessment of, yet reasonable comparison between, each vaccine platform by harmonizing protocols, endpoints, laboratories, and statistical analytical criteria for efficacy. This coordinated effort by the US government, pharmaceutical companies, regulators, and academic research institutions resulted in the streamlined, safe, and transparent development and deployment of multiple COVID-19 vaccines in under a year. Lessons learned from this collaborative endeavor should be used to advance additional vaccines of public health importance.


Hsa-miR-429 promotes bladder cancer cell proliferation via inhibiting CDKN2B.
Hsa-miR-429 is increased in bladder cancer. Its roles in bladder cancer are poorly understood. The expression levels of hsa-miR-429 and cyclin-dependent kinase inhibitor 2B (CDKN2B) were determined using Real-Time qPCR in a total of 50 patients with bladder cancer. Bladder cancer T24 and 5637 cells were transfected CDKN2B siRNA or hsa-miR-429 mimic. CDKN2B expression levels after transfection were detected by Real-Time qPCR and Western blot assay respectively. Binding sites between hsa-miR-429 and 3'-untranslated region of CDKN2B were confirmed by Dual luciferase reporter assay. Cell proliferation was evaluated using MTT and EdU assays. Cell apoptosis was determined using ELISA assay. Higher hsa-miR-429 expression levels were associated with higher tumor grade and stage. All patients with low hsa-miR-429 expression survived 5 years, while with high hsa-miR-429 expression, only 58% survived. Hsa-miR-429 and CDKN2B were inversely expressed in bladder cancer. Hsa-miR-429 mimic decreased the expression of CDKN2B at both mRNA and protein levels. The binding site was confirmed between hsa-miR-429 and 3'-untranslated region of CDKN2B. Up-regulation of hsa-miR-429 or down-regulation of CDKN2B promoted cell growth and decreased apoptosis. Our data suggest a mechanism for hsa-miR-429 to play oncogenic roles via inhibiting CDKN2B.


Detection by immunogold labelling of P75 readthrough protein near an extremity of beet necrotic yellow vein virus particles.
RNA 2 of beet necrotic yellow vein virus carries the cistron for the 21 kd coat protein at its 5'-extremity. During translation, the coat protein cistron termination codon is suppressed about 10% of the time so that translation continues into the adjacent open reading frame to produce a 75 kd species, known as P75, which contains the coat protein sequence at its N-terminus. Immunoblotting experiments with a P75-specific antiserum showed that P75 is present in only trace amounts in purified virus preparations. Electron microscopic visualization of immunogold-labelled virions in crude tissue extracts has provided evidence for an association between P75 and at least a fraction of the BNYVV particles, with P75 being predominantly located near one end of the rod-shaped virions. This finding is discussed in the context of the current model for the role of P75 in virus assembly and vector transmission.


Altered balance between matrix gelatinases (MMP-2 and MMP-9) and their tissue inhibitors in human dilated cardiomyopathy: potential role of MMP-9 in myosin-heavy chain degradation.
End-stage of human dilated cardiomyopathy (DCM) is characterized by myocyte loss and fibrosis, and associated with ventricular dilatation and reduced cardiac function. Matrix metalloproteinases (MMPs) and their natural tissue inhibitors (TIMPs) have been involved in the myocardial remodeling. To evaluate the potential role of matrix gelatinases (MMP-2 and MMP-9) in DCM, the balance between gelatinases and TIMPs and the gelatinase localization were investigated in left free wall ventricles from six normal donors and six patients with DCM at the transplantation time. TIMP-(1, 2, 3 and 4) mRNAs were analyzed by quantitative reverse transcription-polymerase chain reaction (RT-PCR). TIMP-1 and -2 protein content was assessed by ELISA. MMP-2 and MMP-9 expression were examined by zymography and immunological techniques. All TIMPs were down-regulated in DCM hearts, especially TIMP-1 (reduced by 80%). Gel zymography revealed similar activity of MMP-2 and MMP-9 in both tissues. By in situ zymography and immunohistochemistry, active and immunoreactive gelatinases were pericardiomyocyte in control hearts and intracardiomyocyte in DCM hearts. Intracellular MMPs were associated with sarcomeric structure in DCM. To estimate a putative role of these gelatinases, several sarcomeric contractile proteins were digested in vitro by purified active MMP-9. Only myosin-heavy chain was cleaved in vitro giving 180-, 120-, 80- and 20-kDa proteolytic fragments. In vivo, two major myosin-heavy chain proteolytic fragments (80 and 20 kDa) were detected by specific monoclonal antibody against myosin-heavy chain in DCM left ventricular homogenates, only. Taken together, these data highly suggest that MMP-2 and MMP-9 may be involved in the disorganization of the contractile apparatus in DCM hearts.


Bacterial quality and safety of packaged fresh leafy vegetables at the retail level in Finland.
Consumption of packaged fresh leafy vegetables, which are convenient ready-to-eat products, has increased during the last decade. The number of foodborne outbreaks associated with these products has concurrently increased. In our study, (1) label information, (2) O2/CO2 composition, (3) bacterial quality and (4) safety of 100 fresh leafy vegetables at the retail level were studied in Finland during 2013. Bacterial quality was studied using aerobic bacteria (AB) and coliform bacteria (CB) counts, and searching for the presence of Escherichia coli, Listeria and Yersinia. The safety was studied by the presence of Salmonella, ail-positive Yersinia, stx-positive E. coli (STEC) and Listeria monocytogenes using PCR and culturing. Important label information was unavailable on several packages originating from different companies. The packaging date was missing on all packages and the date of durability on 83% of the packages. Storage temperature was declared on 62% of the packages and 73% of the packages contained information about prewashing. The batch/lot number was missing on 29% of the packages. Very low oxygen (O2) (<1%) and elevated carbon dioxide (CO2) (2-22%) concentrations were measured in all packages labelled to contain a protective atmosphere. O2 and CO2 concentrations varied widely in the rest of the packages. AB and CB counts were high in the leafy vegetable samples varying between 6.2 and 10.6 and 4.2-8.3logcfu/g, respectively. In most of the samples, the AB and CB counts exceeded 10(8) and 10(6)cfu/g, respectively. A positive correlation was observed between the AB and CB counts. E. coli was isolated from 15% of the samples and Yersinia from 33%. L. monocytogenes was isolated from two samples and ail-positive Y. enterocolitica in one. Using PCR, STEC was detected in seven samples, and Salmonella and ail-positive Y. enterocolitica in two samples each. The AB and CB mean values of products originating from different companies varied widely. High AB and CB counts and pathogenic bacteria were detected in ready-to-eat products not needing washing before use. Our study shows that the bacterial quality and safety of packaged fresh leafy vegetables is poor and label information on the packages is inadequate. More studies are needed concerning the impact of a protective atmosphere on bacterial growth, and the impact of washing for removing bacteria.


The spectrum of lymphoma in Malaysia: a histopathological study utilizing immunophenotyping.
A retrospective study was made to determine relative incidence of lymphoma subtypes in Malaysia. High grade non-Hodgkin's lymphoma was found to be common. Low grade non-Hodgkin's lymphoma and Hodgkin's disease were relatively rare in this Malaysian series. Non-Hodgkin's lymphoma of B-cell immunophenotype was four times as common as that of T-cell lineage. There was a high incidence of primary extranodal non-Hodgkin's lymphoma.


[Effectiveness of therapeutic education and respiratory rehabilitation programs for the patient with asthma].
Asthma is a chronic complex and heterogeneous disease, with great variability and has a huge impact, not only on patients who suffer the disease but also their families and society in general. The education of the asthmatic patient and their families is essential for therapeutic intervention. Through continuous, dynamic and adaptive education, changes in attitudes and behaviours of the patient and family can be achieved, and will undoubtedly lead to an improvement in their quality of life. Among other non-pharmacological interventions, respiratory rehabilitation is an alternative treatment, and is primarily aimed at patients with moderate to severe asthma. Although the latest clinical practice guidelines published in the scientific literature recommend two strategies for treatment, the results of relevant publications are diverse. The objective of this study was to describe the effectiveness of therapeutic and educational programs in respiratory rehabilitation of the asthmatic patient.


Evaluation of p21 expression and related autism-like behavior in Bisphenol-A exposed offspring of Wistar albino rats.
Bisphenol A (BPA), an endocrine disruptor, may be involved in the etiology of autism spectrum disorders (ASD); however, the mechanism of neuronal and astrocytic damage remains ambiguous. A possible role of altered expression of p21 in autistic-like behavior in rat offspring was examined with prenatal and postnatal BPA exposure. Wistar albino dams were exposed to BPA (5 mg/kg) intraperitoneally throughout pregnancy and until the third postnatal day (PND). Pups were examined on 21st PND for behavioral test. Blood samples were collected for serum lactate levels and pups were sacrificed. Right frontal cortices were dissected out and processed for H&E, immunohistochemical analysis, and gene expression. Anxiety like behavior and thigmotaxis along with reduction in serum lactate concentrations were observed in pups exposed to BPA. Decline in neuronal number and decreased astrocytic population with reduced dendritic spines were revealed by H&E and immunohistochemical analysis, respectively, in right frontal cortices. Over expression of p21 was also detected in BPA-exposed offspring. Over expression of p21 may be associated with autistic behavior. Further studies are recommended to explore the structural alterations in other white matter pathways in frontal cortices.


Characterization of the HLA-C*07:01:01G allele group in European and African-American cohorts.
The HLA-C*07:01:01G allele group consists of three nonsynonymous alleles, C*07:01:01, C*07:06 and C*07:18, plus C*07:01:02, which is synonymous to C*07:01:01. All of these alleles have identical exons 2, 3 and 4, but differ in exons 5 or 6. Therefore routine sequence-based typing (SBT) of exons 2 and 3 is unable to resolve these subtypes, resulting in ambiguous typing results in population and disease cohort studies. In the present study, we fully characterized C*07:01:01G subtypes in European and African Americans and examined their relative frequency distributions. In European Americans C*07:01:01G is predominantly represented by C*07:01:01 (94.4%), whereas C*07:01:02 (1.1%) and C*07:18 (4.5%) were detected relatively infrequently. In African Americans C*07:18 (42.4%) showed a high frequency similar to that of C*07:01:01 (44.7%) whereas C*07:06 was detected at a low frequency (4.7%). C*07:06 was found exclusively on B*44:03 carrying haplotypes in both ethnic groups, but C*07:18 showed multiple linkage relationships with HLA-B. These results demonstrate that C*07:01:01G as defined by routine SBT is a heterogeneous group of alleles, especially among individuals of African origin. If C*07:01:01G subtypes prove to bear divergent functional significance, it would be necessary to include these subtypes in routine HLA-C typing for clinical transplantation and disease association studies.


[The characteristics of perception by patients from different countries the conditions of medical care provision].
The article demonstrates that with lesser demands of Russian population concerning various aspects of public health system functioning, as compared with population of Europe, the most tolerant to the actual conditions are elderly people, especially dwelling in the families with lower material income. This fact can be considered as a stimuli to enhance the corresponding aspects of health care system functioning.


Design of a mucin-selective protease for targeted degradation of cancer-associated mucins.
Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we designed degraders that achieve substrate selectivity via recognition of a discrete peptide and glycan motif and achieve cell-type selectivity via antigen-driven cell-surface binding. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms. Engineering of a bacterial mucin-selective protease yielded a variant for fusion to a cancer antigen-binding nanobody. The resulting conjugate selectively degraded mucins on cancer cells, promoted cell death in culture models of mucin-driven growth and survival, and reduced tumor growth in mouse models of breast cancer progression. This work establishes a blueprint for the development of biologics that degrade specific protein glycoforms on target cells.


Impact of Tricuspid Regurgitation on Clinical Outcomes: The COAPT Trial.
The presence of tricuspid regurgitation (TR) may affect prognosis in patients with mitral regurgitation (MR). This study sought to determine the impact of TR on outcomes in patients with heart failure and severe secondary MR randomized to guideline-directed medical therapy (GDMT) or edge-to-edge repair with the MitraClip in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial. A total of 614 patients with symptomatic heart failure with moderate to severe (3+) or severe (4+) secondary MR were randomized to maximally tolerated GDMT plus MitraClip or GDMT alone; 599 had core laboratory evaluable echocardiograms. Patients were divided into 2 groups by baseline TR severity: none/trace/mild TR (≤Mild TR) (n = 501 [83.6%]) and moderate/severe TR (≥Mod TR) (n = 98 [16.4%]). Two-year composite endpoints of death or heart failure hospitalization (HFH) and the individual endpoints were analyzed. Patients with ≥Mod TR were more likely to be New York Heart Association functional class III/IV (p < 0.0001) and have a Society of Thoracic Surgeons score of ≥8 (p < 0.0001), anemia (p = 0.02), chronic kidney disease (p = 0.003), and higher N-terminal pro-B-type natriuretic peptide (p = 0.02) than those with ≤Mild TR. Patients with ≥Mod TR had more severe MR (p = 0.0005) despite smaller left ventricular volumes (p = 0.005) and higher right ventricular systolic pressure (p < 0.0001). At 2 years, the composite rate of death or HFH was higher in patients with ≥Mod TR compared with ≤Mild TR treated with GDMT alone (83.0% vs. 64.3%; hazard ratio: 1.74; 95% confidence interval: 1.24 to 2.45; p = 0.001) but not following MitraClip (48.2% vs. 44.0%; hazard ratio: 1.14; 95% confidence interval: 0.71 to 1.84; p = 0.59). Rates of death or HFH, as well as death and HFH alone, were reduced by MitraClip compared with GDMT, irrespective of baseline TR grade (pinteraction = 0.16, 0.29, and 0.21 respectively). Patients with severe secondary MR who also had ≥Mod TR had worse clinical and echocardiographic characteristics and worse clinical outcomes compared to those with ≤Mild TR. Within the COAPT trial, MitraClip improved outcomes in patients with and without ≥Mod TR severity compared with GDMT alone. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [COAPT]; NCT01626079).


Promotive effect of 4,4'-methylenebis(N,N-dimethyl)benzenamine on N-bis(2-hydroxypropyl)nitrosamine-induced thyroid tumors in Wistar rats.
The promotive effect of 4,4'-methylenebis(N,N-dimethyl)benzenamine (MDBA) on 2-stage thyroid tumorigenesis induced by N-bis(2-hydroxypropyl)nitrosamine (DHPN) in Wistar male rats was investigated. Animals were given i.p. injections of DHPN, and then a basal diet containing 0.0375% MDBA for 19 weeks. In addition, localization of the thyroid-stimulating hormone (TSH) in the pituitary gland was investigated. Levels of TSH and T4 in serum were measured by radioimmunoassay (RIA). The addition of MDBA to the diet significantly increased the incidence and numbers of preneoplastic lesion (focal hyperplasia), adenoma and carcinoma of the thyroid. TSH was usually localized in the thyroidectomy-cell in the anterior lobe of the pituitary gland, and the number of TSH-positive cells increased in the group treated with MDBA. Mean circulating levels of TSH were elevated in all MDBA-treated groups, and mean T4 levels in groups treated with MDBA were significantly lower different (P less than 0.05) than those in control groups.


Behavioural-analytical studies of the role of head movements in depth perception in insects, birds and mammals.
In this review, studies of the role of head movements in generating motion parallax which is used in depth perception are examined. The methods used and definitiveness of the results vary with the animal groups studied. In the case of insects, studies which quantify motor outputs have provided clear evidence that motion parallax evoked by head movements is used for distance estimation and depth perception. In the case of birds and rodents, training studies and analyses of the head movements themselves have provided similar indications. In the case of larger mammals, due to a lack of systematic experiments, the evidence is less conclusive.


Women with severe postpartum hemorrhage have a decreased endogenous thrombin potential before delivery.
Severe postpartum hemorrhage (PPH), defined as a blood loss ≥1000 mL, is associated with maternal morbidity and mortality. We aimed at characterizing coagulation properties of predelivery plasmas from pregnant women with thrombin generation assay and hemostatic biomarkers (plasminogen activator inhibitor-1, tissue factor [TF], and thrombomodulin). A nested case-control study was conducted within the "Study of Biological Determinants of Bleeding Postpartum," a French prospective cohort study, in order to compare women with severe PPH (cases) and controls matched for age, body mass index, term, and mode of delivery. Plasma was collected at entry in the delivery room, and blood loss was measured objectively. The predelivery endogenous thrombin generation potential (ETP) was measured in plasma using calibrated automated thrombinography and low TF concentration. Hemostatic biomarkers were measured using ELISA kits. A total of 142 women (71 cases and 71 controls) were investigated. There was no difference in the median lag phase, thrombin peak, and time to peak between cases and controls. However, median predelivery ETP was lower in cases than in controls (2170 vs 2408 nM.min, P < .0001), independently of mode of delivery and PPH etiology. Median plasminogen activator inhibitor-1 and TF levels were higher in cases compared with controls (107.4 vs 68.1 ng/mL, P = .0003; 34.4 vs 27.4 pg/mL, P = .007), whereas thrombomodulin levels did not differ between the 2 groups. Among thrombin generation assay parameters, predelivery ETP levels may have a predictive value for severe PPH.


Crystalline silica-induced leukotriene B4-dependent inflammation promotes lung tumour growth.
Chronic exposure to crystalline silica (CS) causes silicosis, an irreversible lung inflammatory disease that may eventually lead to lung cancer. In this study, we demonstrate that in K-ras(LA1) mice, CS exposure markedly enhances the lung tumour burden and genetic deletion of leukotriene B4 receptor-1 (BLT1(-/-)) attenuates this increase. Pulmonary neutrophilic inflammation induced by CS is significantly reduced in BLT1(-/-)K-ras(LA1) mice. CS exposure induces LTB4 production by mast cells and macrophages independent of inflammasome activation. In an air-pouch model, CS-induced neutrophil recruitment is dependent on LTB4 production by mast cells and BLT1 expression on neutrophils. In an implantable lung tumour model, CS exposure results in rapid tumour growth and decreased survival that is attenuated in the absence of BLT1. These results suggest that the LTB4/BLT1 axis sets the pace of CS-induced sterile inflammation that promotes lung cancer progression. This knowledge may facilitate development of immunotherapeutic strategies to fight silicosis and lung cancer.


Comparative ecophysiology of Encelia farinosa and Encelia frutescens : I. energy balance considerations.
Encelia farinosa and Encelia frutescens are drought-decidous shrubs whose distributions overlap throughout much of the Sonoran Desert. During hot and dry periods, leaves of E. farinosa utilize increased leaf reflectance to reduce leaf temperature, whereas leaves of E. frutescens have substantially higher leaf conductances and rely on increased transpirational cooling to reduce leaf temperature. E. farinosa is common on the dry slope microhabitats, whereas E. frutescens occurs only in wash microhabitats where greater soil moisture is available to provide the water necessary for transpirational cooling. E. farinosa tends not to persist in wash microhabitats because of its greater susceptibility to flashfloods. The consequences and significance of increased leaf reflectance versus increased transpirational cooling to leaf temperature regulation are discussed.


Neochordal Goldilocks: Analyzing the biomechanics of neochord length on papillary muscle forces suggests higher tolerance to shorter neochordae.
Estimating neochord lengths during mitral valve repair is challenging, because approximation must be performed largely based on intuition and surgical experience. Little data exist on quantifying the effects of neochord length misestimation. We aimed to evaluate the impact of neochord length on papillary muscle forces and mitral valve hemodynamics, which is especially pertinent because increased forces have been linked to aberrant mitral valve biomechanics. Porcine mitral valves (n = 8) were mounted in an ex vivo heart simulator, and papillary muscles were fixed to high-resolution strain gauges while hemodynamic data were recorded. We used an adjustable system to modulate neochord lengths. Optimal length was qualitatively verified by a single experienced operator, and neochordae were randomly lengthened or shortened in 1-mm increments up to ±5 mm from the optimal length. Optimal length neochordae resulted in the lowest peak composite papillary muscle forces (6.94 ± 0.29 N), significantly different from all lengths greater than ±1 mm. Both longer and shorter neochordae increased forces linearly according to difference from optimal length. Both peak papillary muscle forces and mitral regurgitation scaled more aggressively for longer versus shorter neochordae by factors of 1.6 and 6.9, respectively. Leveraging precision ex vivo heart simulation, we found that millimeter-level neochord length differences can result in significant differences in papillary muscle forces and mitral regurgitation, thereby altering valvular biomechanics. Differences in lengthened versus shortened neochordae scaling of forces and mitral regurgitation may indicate different levels of biomechanical tolerance toward longer and shorter neochordae. Our findings highlight the need for more thorough biomechanical understanding of neochordal mitral valve repair.


Dietary carbohydrate influences the colocalization pattern of Glucagon-like Peptide-1 with neurotensin in the chicken ileum.
Glucagon-like peptide (GLP)-1 colocalizes with neurotensin (NT) in the same enteroendocrine cells (EECs) of the chicken ileum. The present study was designed to clarify the influence of dietary carbohydrate (CHO) on the colocalization pattern of GLP-1 with NT in the chicken distal ileum. Male White Leghorn chickens at 6 weeks of age (n = 15) were divided into three groups, a control and two experimental (low-CHO and CHO-free), with five chickens in each, and fed control or experimental diets for 7 d. Distal ileum was collected from each bird as a tissue sample and subjected to double immunofluorescence staining to detect GLP-1 and NT. Three types of EEC, GLP-1+/NT+, GLP-1+/NT- and GLP-1-/NT+, were demonstrated in the chicken ileum. GLP-1+/NT+ cells in the control group had a spindle-like shape with a long cytoplasmic process, but those in the experimental groups were round and lacked a cytoplasmic process. The ratio of GLP-1+/NT+ cells was significantly decreased in the two experimental groups compared with that in the control group. The ratio of GLP-1+/NT+ cells was significantly lower than those of GLP-1+/NT- and GLP-1-/NT+ cells in the two experimental groups. Most cells that were immunoreactive for GLP-1 and NT antisera lacked signals of proglucagon (PG) and NT precursor (NTP) mRNA in the experimental groups. The number of EECs expressing PG and NTP mRNA signals showed tendencies for decreases with a reduction of dietary CHO level. These findings suggest that dietary CHO could be a significant regulator of the pattern of colocalization pattern of GLP-1 with NT in the chicken ileum.


A cross-sectional survey of environmental health in remote Aboriginal communities in Western Australia.
The Australian Aboriginal population experiences significantly poorer health than the non-Aboriginal population. The contribution of environmental risk factors in remote communities to this health disparity is poorly understood. To describe and quantify major environmental risk factors and associated health outcomes in remote Aboriginal communities in Western Australia. The association between environmental health indicators, community infrastructure and reported health outcomes was analysed using linear and logistic regression of survey data. Housing/overcrowding was significantly associated with increased reports of hearing/eyesight (OR 3.01 95 % CI 1.58-5.73), skin (OR 2.71 95 % CI 1.31-5.60), gastrointestinal (OR 3.51 95 % CI 1.49-8.26) and flu/colds (OR 2.47 95 % CI 1.27-4.78) as health concerns. Dust was significantly associated with hearing/eyesight (OR 3.16 95 % CI 1.82-5.48), asthma/respiratory (OR 2.48 95 % CI 1.43-4.29) and flu/colds (OR 3.31 95 % CI 1.88-5.86) as health concerns. Poor environmental health is prevalent in remote Aboriginal communities and requires further delineation to inform environmental health policy.


MARCH7-mediated ubiquitination decreases the solubility of ATG14 to inhibit autophagy.
Autophagy is a fundamental biological process critical to all eukaryotic cellular life. Although autophagy has been increasingly studied, how its process is precisely coordinated remains an open question. ATG14 (ATG14L/Barkor) is known to play a crucial role in both autophagosome formation and autophagosome-lysosome fusion. However, how ATG14 is regulated, especially at the post-translation level, is still not clear. Here, we report that MARCH7 (membrane-associated ring-CH-type finger 7), an E3 ubiquitin ligase, inhibits autophagy by ubiquitinating ATG14. MARCH7 significantly promotes K6-, K11-, and K63-linked mixed polyubiquitination on ATG14, triggering the aggregation of ATG14 and reducing its solubility in cells. Functionally, we find that MARCH7 depletion decreases the number of aggresome-like induced structures (ALISs). Mechanistically, we show that ubiquitinated ATG14 has fewer interactions with STX17, leading to the inhibition of autophagy flux. Collectively, our study reveals a mechanism in regulating autophagy and suggests a potential strategy for the treatment of autophagy-related diseases.


Impact of Telemedicine in the Screening for Congenital Heart Disease in a Center from Northeast Brazil.
To describe the incidence of congenital heart disease before and after the establishment of a telemedicine screening program, in a reference center from Northeast Brazil. This is a descriptive, retrospective and comparative study based on the institutional data from a reference center in perinatology for a period of 16 years. Institutional data were collected from a 16-year period (2001-15). Data were divided into two periods: prior to (2001-11) and after (2012-15) the establishment of a telemedicine screening program. After the implementation of the screening process, almost all kinds of heart disease showed a significant increase in their incidence (p < 0.05). With this, the incidence of major heart diseases approached those specified in developed regions. The implementation of a screening process model for congenital heart diseases can change the context of patients with congenital heart diseases in poor regions.


The development and evaluation of a low-cost microdensitometer for use with the 2-deoxy-D-glucose method of functional brain mapping.
The conversion of a standard laboratory compound microscope into a microdensitometer for use in the 2-deoxy-D-glucose autoradiographic method of functional mapping in the brain is described. A solid-state detector was attached to the camera port of a Zeiss Universal Microscope and minor modifications to the microscope optics were made to produce a microdensitometer with a field of view 0.15 mm in diameter. Details are presented showing the modifications to the microscope which do not permanently destroy its functional ability to perform as a viewing microscope. A simple electronic circuit is presented to digitally display the output of the photo detector. Calibration of the instrument in terms of optical density or 2-deoxy-D-glucose activity is also described. The primary design goal was the construction of a simple, reliable, inexpensive microdensitometer that could be assembled by laboratory personnel. This densitometer should allow laboratories on modest budgets to have access to quantitative methods for the study of brain functional activity at a cost considerably less than the price of a commercial microdensitometer.


Challenging diagnosis of abdominal tuberculosis in children: case report.
Tuberculosis (TB) remains a significant cause of morbidity and mortality in the modern world. Abdominal TB is a rare form of extrapulmonary TB that has been found to affect children without comorbidities in particular, although exact numbers are unavailable because of lack of data and its rarity. The diagnosis of abdominal TB remains a challenge because of its unspecific clinical features and unclear recommendations regarding the best diagnostic tools. We report 4 cases of children with abdominal TB diagnosed at The Hospital of Lithuanian University of Health Sciences Kaunas clinics from 2008 to 2018 at the Department of Paediatric Surgery. All these cases are exceptional. The final diagnosis of abdominal TB was confirmed only after diagnostic laparoscopy and biopsy. Moreover, we suggest that QuantiFERON test and ascitic fluid analysis with serum ascites albumin gradient and adenosine deaminase tests should be performed before more invasive interventions. Laparoscopy with biopsy should be performed only in unclear cases.


Perspectives on the regulatory biology of the B lymphocyte.
B lymphocytes with receptors specific for a particular hapten have been prepared through an antigen-affinity procedure. Methods have been developed for the clonal stimulation of these cells in vitro, with a single, hapten-specific B cell as the unequivocal target. Many stimulatory combinations involve multivalent antigen and one or more antigen non-specific, non-MHC restricted T lymphocyte-derived growth and differentiation factors. These factors, of which there are at least 4 or 5, are progressively being defined and should soon become available through recombinant DNA technology. Judicious use of factor combinations and selected antigens should soon answer whether "T-independent" and "T-dependent" B cells are truly separate subsets. A contact between multivalent antigen and immature B cell in the absence of these co-stimulatory factors can lead to the receipt and storage of a negative signal by the B cell. The B cell is not killed, but rather rendered anergic. Whether clonal anergy among B cells is an important mechanism in physiologic self-tolerance remains to be determined.


Percolation transitions in compressed SiO2 glasses.
Amorphous-amorphous transformations under pressure are generally explained by changes in the local structure from low- to higher-fold coordinated polyhedra1-4. However, as the notion of scale invariance at the critical thresholds has not been addressed, it is still unclear whether these transformations behave similarly to true phase transitions in related crystals and liquids. Here we report ab initio-based calculations of compressed silica (SiO2) glasses, showing that the structural changes from low- to high-density amorphous structures occur through a sequence of percolation transitions. When the pressure is increased to 82 GPa, a series of long-range ('infinite') percolating clusters composed of corner- or edge-shared tetrahedra, pentahedra and eventually octahedra emerge at critical pressures and replace the previous 'phase' of lower-fold coordinated polyhedra and lower connectivity. This mechanism provides a natural explanation for the well-known mechanical anomaly around 3 GPa, as well as the structural irreversibility beyond 10 GPa, among other features. Some of the amorphous structures that have been discovered mimic those of coesite IV and V crystals reported recently5,6, highlighting the major role of SiO5 pentahedron-based polyamorphs in the densification process of vitreous silica. Our results demonstrate that percolation theory provides a robust framework to understand the nature and pathway of amorphous-amorphous transformations and open a new avenue to predict unravelled amorphous solid states and related liquid phases7,8.


Comparison of Transdiagnostic Treatment and Specialized Social Anxiety Treatment for Children and Adolescents With Social Anxiety Disorder: A Randomized Controlled Trial.
Pediatric social anxiety disorder consistently shows the poorest treatment response of all anxiety disorders. The current study compared a generic cognitive-behavioral therapy (CBT) treatment for pediatric anxiety against a modified (social anxiety) treatment that incorporated specific components to target theoretically important maintaining processes. A total of 200 children and adolescents (mean age = 9.5 years, SD = 2.2 years; 47% boys) diagnosed with social anxiety disorder as either their principal or additional disorder were randomly allocated to either the generic or the modified treatment. Both treatments were based on a manualized, empirically validated program (Cool Kids) and comprised 10 sessions over 12 weeks. Assessments comprised structured diagnostic interview and parent and youth reports, and covered diagnoses, symptoms, life impairment, and assessment of maintaining processes at posttreatment and 6-month follow-up. The treatments did not differ significantly on the primary outcome (remission of social anxiety disorder) at either posttreatment (remission in generic = 41%; modified = 44%) or follow-up (remission in generic = 51%; modified = 69%), although the latter approached significance (p = .08). They also did not differ at either time point on most secondary measures of outcome. The only maintaining process that changed more under modified treatment was attention to the current task. Despite some positive hints in the data, there was little evidence that the modified intervention significantly improved treatment of pediatric social anxiety disorder, despite incorporating strategies to address putative maintaining mechanisms. The similar improvement between treatments on most maintaining processes suggests that new and innovative strategies may be needed to better target these processes. Efficacy of Cognitive Behavioural Treatment for Socially Anxious Youth; https://www.anzctr.org.au/; 12616001065482.


Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent, regionally selective bimodal effects on striatal dopamine kinetics in vivo.
Parkinson's disease (PD) is a debilitating condition that is caused by a relatively specific degeneration of dopaminergic (DAergic) neurons of the substantia nigra pars compacta. L-DOPA was introduced as a viable treatment option for PD over 40 years ago and still remains the most common and effective therapy for PD. Though the effects of L-DOPA to augment striatal DA production are well known, little is actually known about how L-DOPA alters the kinetics of DA neurotransmission that contribute to its beneficial and adverse effects. In this study, we examined the effects of L-DOPA administration (50 mg/kg carbidopa + 0, 100, and 250 mg/kg L-DOPA) on regional electrically stimulated DA response kinetics using fast-scan cyclic voltammetry in anesthetized rats. We demonstrate that L-DOPA enhances DA release in both the dorsal striatum (D-STR) and nucleus accumbens (NAc), but surprisingly causes a delayed inhibition of release in the D-STR. In both regions, L-DOPA progressively attenuated reuptake kinetics, predominantly through a decrease in Vmax . These findings have important implications on understanding the pharmacodynamics of L-DOPA, which may be informative for understanding its therapeutic effects and also common side effects like L-DOPA-induced dyskinesias (LID). L-DOPA is commonly used to treat Parkinsonian symptoms, but little is known about how it affects presynaptic DA neurotransmission. Using in vivo fast-scan cyclic voltammetry, we show L-DOPA inhibits DA reuptake in a region-specific and dose-dependent manner, and L-DOPA has paradoxical effects on release. These findings may be important when considering mechanisms for L-DOPA's therapeutic benefits and adverse side-effects.


Flexor tenosynovectomy in carpal tunnel syndrome as a screening tool for early diagnosis of amyloidosis.
Amyloidosis is a heterogeneous group of diseases that most often presents with advanced cardiac pathology. Another presentation of the disease can include symptoms consistent with carpal tunnel syndrome; however, the true incidence of amyloidosis in patients with carpal tunnel syndrome remains unclear. We performed a retrospective chart review on all patients who underwent an open carpal tunnel release, with tenosynovium biopsy by a single surgeon between 01/2000 and 12/2018. Samples were stored in formalin following hematoxylin-eosin or congo red staining. A total of 199 patients were excluded for incomplete records, and carpal tunnel release performed for traumatic or infectious etiologies. Histologic findings of the attending pathologist were examined and categorized as follows: amyloidosis, fibrous tissue, tenosynovitis/inflammation edematous, benign tenosynovium, and gout. Exactly 898 open carpal tunnel releases were performed, and 699 patients were included for final analysis. In all patients, biopsies for histology with hematoxylin-eosin (HE) staining were taken; in those HE stains where amylogenic proteins were suspected (73 or 10.4%), a subsequent congo red staining was additionally performed which confirmed the diagnosis of amyloidosis in 10 patients (1.4% of the carpal tunnel procedures). Overall, 10 patients were identified and constituted 1.4% of all HE stains (n = 10/699) and 13.7% of all congo red stains (n = 10/73). Our results suggest that the incidence of amyloidosis in the general CTS patient population may be as high as 1.4% with routine screening by synovial biopsy and the diagnosis should be considered as a potential cause. Level of Evidence: III, retrospective study.


Diversified caregiver input to upgrade the Young Children's Participation and Environment Measure for equitable pediatric re/habilitation practice.
Practitioner and family experiences of pediatric re/habilitation can be inequitable. The Young Children's Participation and Environment Measure (YC-PEM) is an evidence-based and promising electronic patient-reported outcome measure that was designed with and for caregivers for research and practice. This study examined historically minoritized caregivers' responses to revised YC-PEM content modifications and their perspectives on core intelligent virtual agent functionality needed to improve its reach for equitable service design. Caregivers were recruited during a routine early intervention (EI) service visit and met five inclusion criteria: (1) were 18 + years old; (2) identified as the parent or legal guardian of a child 0-3 years old enrolled in EI services for 3 + months; (3) read, wrote, and spoke English; (4) had Internet and telephone access; and (5) identified as a parent or legal guardian of a Black, non-Hispanic child or as publicly insured. Three rounds of semi-structured cognitive interviews (55-90 min each) used videoconferencing to gather caregiver feedback on their responses to select content modifications while completing YC-PEM, and their ideas for core intelligent virtual agent functionality. Interviews were transcribed verbatim, cross-checked for accuracy, and deductively and inductively content analyzed by multiple staff in three rounds. Eight Black, non-Hispanic caregivers from a single urban EI catchment and with diverse income levels (Mdn = $15,001-20,000) were enrolled, with children (M = 21.2 months, SD = 7.73) enrolled in EI. Caregivers proposed three ways to improve comprehension (clarify item wording, remove or simplify terms, add item examples). Environmental item edits prompted caregivers to share how they relate and respond to experiences with interpersonal and institutional discrimination impacting participation. Caregivers characterized three core functions of a virtual agent to strengthen YC-PEM navigation (read question aloud, visual and verbal prompts, more examples and/or definitions). Results indicate four ways that YC-PEM content will be modified to strengthen how providers screen for unmet participation needs and determinants to design pediatric re/habilitation services that are responsive to family priorities. Results also motivate the need for user-centered design of an intelligent virtual agent to strengthen user navigation, prior to undertaking a community-based pragmatic trial of its implementation for equitable practice.


Sociodemographic factors as determinants of disease, disability and quality of life trajectories in early rheumatoid arthritis: A multi-ethnic inception cohort study.
This study aims to describe the association between sociodemographic factors and trajectories of disease, disability and health-related quality of life (HRQoL) in early rheumatoid arthritis (ERA). Data were collected prospectively over 3 years in the Singapore Early Arthritis Cohort study. Trajectories were modeled using multi-trajectory group-based trajectory modeling (GBTM) and determinants of trajectory membership were identified using multinomial logistic regression. Two hundred and thirteen patients were included: 58.2% Chinese, 16.4% Malay, 21.6% Indian, mean (SD) age 51.3 (12.6) years and symptom duration 21.8 (15.3) weeks. In the multi-trajectory analysis, three groups of disease trajectories and corresponding disability and HRQoL trajectories were identified: group 1 (moderate disease rapid response, 49.9%), group 2 (high disease rapid response, 31.1%) and group 3 (high disease slow response, 19.1%). Malay patients had higher relative risk ratio (RRR) of being in trajectory groups 2 and 3 compared to group 1 (RRR = 2.30, 95% CI 1.05-3.98 and RRR = 4.02, 95% CI 1.45-6.43, respectively) while patients with tertiary education had lower relative risk (RRR = 0.56, 95% CI 0.45-0.89 and RRR = 0.33, (95% CI 0.14-0.83, respectively). In the analysis of individual outcomes, ethnicity, education level and body mass index were determinants of the heterogeneous disease activity trajectories. Gender and education level were determinants of the disability trajectories. Only gender was a determinant of the HRQoL trajectories. Further, 96.2% of the patients were treated with conventional synthetic disease-modifying antirheumatic drugs. Disparities in sociodemographic factors should be taken into consideration in formulating treatment strategies in ERA.


The influence of the swine major histocompatibility genes (SLA) on variation in serum immunoglobulin (Ig) concentration.
Variation in serum IgG and IgM concentration was determined in three homozygous SLA-defined strains of miniature swine (SLAa, SLAc and SLAd) and one recombinant strain SLAg (ABcDd) as part of a study of SLA and other genetic effects on immune response. Data were obtained from 119 8-week-old piglets from 29 litters by 12 sires and analyzed using a SAS linear model for the effects of SLA haplotype, sire, dam, litter, sex, season of birth and sow parity. SLA haplotype (P less than 0.10) and other genetic effects due to sire (P less than or equal to 0.001) and dam (P less than or equal to 0.002) contributed to the variation in serum IgG concentrations. Season of birth and sow parity also affected IgG concentration as did litter effects. Least squares mean comparisons indicated that pigs of the dd, dg and gg haplotypes had significantly higher serum IgG than did pigs of the other haplotypes. Heritability estimates for IgG, calculated by paternal half-sib correlation, ranged from 0.31 to 0.27, indicating that selection for increased serum IgG concentrations would be possible. For serum IgM concentrations, only the effect of litter was significant at P less than or equal to 0.001 and P less than or equal to 0.009 by the radial immunodiffusion test read at 24 or 48 h. Since sire variance components estimates were negative, heritabilities were not calculated for IgM and are assumed to be zero.


[SIADH and vaptans].
The vaptans are non-peptide arginine-vasopressin-receptor antagonists, that are orally and intravenously active. A few vaptans have undergone sufficient clinical development to be on the market. In the EU only tolvaptan is accepted to treat hyponatremia related to SIADH. The place of this new treatment is compared with water restriction, demeclocyclin, furosemide and urea.


Hyperphalangeal bones induced in rat pups by maternal treatment with nifedipine.
Hyperphalangeal bones were found in postnatal rat pups of mothers treated with nifedipine during pregnancy. The anomaly occurred only at the region between the middle and distal phalanges of the 3rd and 4th fingers and toes. The critical periods of the anomaly were days 13 and 14 of pregnancy for the fingers, and days 14 and 15 of pregnancy for the toes. The incidences were dose-related, being more than 90% in both fingers and toes at a single dose of 150 mg/kg, and even more marked at the 4th digits than at the 3rd digits. Neither right/left difference nor sex difference was manifested in the incidence of the anomaly.


Rapid determination of selenium in various substrates by electron capture gas-liquid chromatography.
In the proposed procedure for the determination of selenium, 0.5-1 g of sample is wet ashed with concentrated nitric acid. After adding 1,2-diamino-4,5-dichlorobenzene to the digest at pH 1, the resulting dichloropiazselenol derivatives is extracted with toluene. The extract is purified by column chromatography over Florisil and analyzed by gas-liquid chromatography with electron capture detection. Recoveries of selenium added to various substrates ranged from 72 to 102%. The limit of detection is approximately 0.01 ppm, but smaller amounts can be determined by increasing the sample size or by concentration of the final extract.


TORC1 regulation of dendrite regrowth after pruning is linked to actin and exocytosis.
Neurite pruning and regrowth are important mechanisms to adapt neural circuits to distinct developmental stages. Neurite regrowth after pruning often depends on differential regulation of growth signaling pathways, but their precise mechanisms of action during regrowth are unclear. Here, we show that the PI3K/TORC1 pathway is required for dendrite regrowth after pruning in Drosophila peripheral neurons during metamorphosis. TORC1 impinges on translation initiation, and our analysis of 5' untranslated regions (UTRs) of remodeling factor mRNAs linked to actin suggests that TOR selectively stimulates the translation of regrowth over pruning factors. Furthermore, we find that dendrite regrowth also requires the GTPase RalA and the exocyst complex as regulators of polarized secretion, and we provide evidence that this pathway is also regulated by TOR. We propose that TORC1 coordinates dendrite regrowth after pruning by coordinately stimulating the translation of regrowth factors involved in cytoskeletal regulation and secretion.


Mutational landscape of cancer-driver genes across human cancers.
The genetic mutations that contribute to the transformation of healthy cells into cancerous cells have been the subject of extensive research. The molecular aberrations that lead to cancer development are often characterised by gain-of-function or loss-of-function mutations in a variety of oncogenes and tumour suppressor genes. In this study, we investigate the genomic sequences of 20,331 primary tumours representing 41 distinct human cancer types to identify and catalogue the driver mutations present in 727 known cancer genes. Our findings reveal significant variations in the frequency of cancer gene mutations across different cancer types and highlight the frequent involvement of tumour suppressor genes (94%), oncogenes (93%), transcription factors (72%), kinases (64%), cell surface receptors (63%), and phosphatases (22%), in cancer. Additionally, our analysis reveals that cancer gene mutations are predominantly co-occurring rather than exclusive in all types of cancer. Notably, we discover that patients with tumours displaying different combinations of gene mutation patterns tend to exhibit variable survival outcomes. These findings provide new insights into the genetic landscape of cancer and bring us closer to a comprehensive understanding of the underlying mechanisms driving the development of various forms of cancer.


Relationship between response to induction chemotherapy and disease control in patients with advanced laryngeal carcinoma included in an organ preservation protocol.
The aim of the study is to analyze the relationship between the degree of response to induction chemotherapy and the disease control in patients with locally advanced laryngeal carcinomas candidates to total laryngectomy. This retrospective study includes 389 patients with T3-T4 laryngeal tumors candidates to total laryngectomy, diagnosed between 1985 and 2013, treated with induction chemotherapy in an organ preservation protocol. Five-year local recurrence-free survival for patients receiving conservative treatment with radiotherapy after a complete response to induction chemotherapy was 75.4%; for patients with partial response greater than 50%, it was 62.0%; and for patients with the absence of response, it was 32.7%. There were significant differences in local recurrence-free survival and laryngeal dysfunction-free survival according to the response to induction chemotherapy (P = 0.0001) at the expense of patients with absence of response to induction chemotherapy. Patients with partial response greater than 50% treated with radiotherapy had a tendency to have worse local recurrence-free survival and laryngeal dysfunction-free survival than patients with complete response, but the differences did not reach statistical significance. Patients with the absence of response after induction chemotherapy had significant differences in disease-specific survival according to the second treatment: for patients treated with surgery it was 70.2%, whereas for patients treated with radiotherapy, it was 28.2% (P = 0.0001). In patients with the absence of response to induction chemotherapy, conservative treatment with radiotherapy implies a significant decrease in survival.


Hospital Acquired Infections in Surgical Patients: Impact of COVID-19-Related Infection Prevention Measures.
Hospital acquired infections are common, costly, and potentially preventable adverse events. This study aimed to determine the effect of the COVID-19 pandemic-related escalation in infection prevention and control measures on the incidence of hospital acquired infection in surgical patients in a low COVID-19 environment in Australia. This was a retrospective cohort study in a tertiary institution. All patients undergoing a surgical procedure from 1 April 2020 to 30 June 2020 (COVID-19 pandemic period) were compared to patients pre-pandemic (1 April 2019-30 June 2019). The primary outcome investigated was odds of overall hospital acquired infection. The secondary outcome was patterns of involved microorganisms. Univariable and multivariable logistic regression analysis was performed to assess odds of hospital acquired infection. There were 5945 admission episodes included in this study, 224 (6.6%) episodes had hospital acquired infections in 2019 and 179 (7.1%) in 2020. Univariable logistic regression analysis demonstrated no evidence of change in odds of having a hospital acquired infection between cohorts (OR 1.08, 95% CI 0.88-1.33, P = 0.434). The multivariable regression analysis adjusting for potentially confounding co-variables also demonstrated no evidence of change in odds of hospital acquired infection (OR 0.93, 95% CI 0.74-1.16, P = 0.530). Increased infection prevention and control measures did not affect the incidence of hospital acquired infection in surgical patients in our institution, suggesting that there may be a plateau effect with these measures in a system with a pre-existing high baseline of practice.


High-performance photoelectrochemical immunosensor based on featured photocathode-photoanode operating system.
Photocathodic immunosensors generally exhibit fortified anti-interference abilities than photoanodic ones against the detection in biological specimens. Yet, the weak photocurrent signals of the photocathodes have limited evidently the detection performance. Herein, an efficient and feasible photoelectrochemical (PEC) immunosensor was developed on the basis of the featured photocathode-photoanode operating system. In the proposal, the elaborated PEC immunosensor integrated photocathode with photoanode, and the immune recognition occurred just on the photocathode. To illustrate the performance, α-fetoprotein (AFP) was selected as a target antigen (Ag) for detection. TiO2 nanoparticles were decorated with AgInS2 quantum dots (AIS QDs) to fabricate the TiO2/AIS photoanode, and the carbon nanotubes (CNTs) were modified with CuInS2 nanoflowers (CIS NFs) to prepare the CNT/CIS photocathode for the capture AFP antibody (Ab) anchoring. Target Ag detection depended on significant decrease of the photocurrent signal produced by large steric hindrance of the captured AFP molecules. Coupling excellent photoelectric property with anti-interference ability in this elegant PEC immunosensor, sensitive and specific probing of target Ag was realized. The proposed photocathode-photoanode integrating strategy provides a promising way to explore other high-performance PEC immunosensors against the detection in biological matrixes.


Affective disorders and multiple sclerosis: a controlled study on 65 Italian patients.
A high prevalence of major mood disorders in multiple sclerosis (MS) patients has been reported. In this study, we investigated the frequency of previous or present major mood disorders in 65 patients with clinically definite multiple sclerosis (Poser criteria) and in 31 polyneuropathy (PNP) patients. All patients underwent a questionnaire designed after DSM-IV definitions for major mood disorders. A higher lifetime risk for development of a major mood disorder was evident in MS patients (log rank test, p<0.001). Of all MS patients with a major mood disorder, at least 34% had one first-degree relative affected by a mood disorder, while the corresponding figure was 14% among PNP cases. Our data confirm the high lifetime risk for depression in MS patients and suggest that, at least in a subset of MS patients with depression, the genetic basis for depression operates with similar mechanisms as those at work in families with primary depression. However, this is not necessarily true for other subsets of depressed MS patients' families.


Antioxidant, anti-inflammatory and renoprotective effects of acidic-hydrolytic polysaccharides by spent mushroom compost (Lentinula edodes) on LPS-induced kidney injury.
Increasing evidences have demonstrated that the reactive oxygen species play important roles in the initiation and progress of LPS-induced kidney injury (KI). The present work investigated the antioxidant, anti-inflammatory and renoprotective effects of acidic spent mushroom compost polysaccharides (ASMCP) by Lentinula edodes against the LPS-induced KI in mice. The results demonstrated that ASMCP showed anti-inflammatory effects on reducing the serum levels of TNF-α, IL-6 and IL-1β, inhibiting the elevation of lipid peroxidation, lowering the serum levels of BUN, CRE and UA, and improving the antioxidant status by enhancing renal enzyme activities (SOD, GSH-Px, CAT and T-AOC). Furthermore, the histological observations of renal cortex and renal medulla also indicated the potential renoprotective effects of ASMCP. These conclusions suggested that ASMCP might be suitable for functional foods and a potentially effective candidate medicine for the treatment of KI.


Rapid detection of the New Delhi metallo-b-lactamase 1 (NDM-1) gene by loop-mediated isothermal amplification (LAMP).
New Delhi Metallo-b-lactamase (NDM-1) is an enzyme emerging around the world conferring resistance to a wide range of β-lactams agents and whose early detection is extremely important. We proposed to standardize the detection of the blaNDM-1 gene using the LOOP-mediated isothermal amplification technique (LAMP). In all, 14 Gram-negative bacterial strains isolated from patients presenting pneumonia associated with mechanical ventilation were used for the blaNDM-1 standardization by LAMP. Klebsiella pneumoniae ATCC BAA-2473 and two clinical strains were used as a positive control. All results were compared to the reaction in polymerase chain reaction (PCR), considered gold standard for this detection. There was an excellent correlation between the two techniques employed, since all measured clinical strains were negative in both employed tests and two clinical, and a reference strains were positive. The lamp technique seems to be an excellent option for the rapid detection of blaNDM-1. The amplification time is much shorter than other molecular techniques, the PCR machine is not necessary, it is easy of implementation and costs is low.


Polymorphisms of the peroxisome proliferator-activated receptor-γ (rs1801282) and its coactivator-1 (rs8192673) are associated with obesity indexes in subjects with type 2 diabetes mellitus.
The aim of this study was to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 (PGC-1α) gene (rs8192673) are associated with obesity indexes (BMI, waist circumference) in subjects with type 2 diabetes mellitus (T2DM) in Caucasian population. The second aim was to find an association of both polymorphisms with T2DM. Two exonic SNPs of both genes rs1801282 of the PPAR-γ gene and rs8192673 of the PGC-1α gene) were genotyped in 881 unrelated Slovene subjects (Caucasians) with T2DM and in 348 subjects without T2DM (control subjects). Female homozygotes with the CC genotype of the rs8192673 had higher waist circumference in comparison with subjects with other genotypes. Homozygotes (females, males) with wild allele (Pro) of the rs1801282 (Pro12Ala polymorphism) had higher waist circumference in comparison with subjects with other genotypes. In the study, there were no differences in the distributions of the rs8192673 and the rs1801282 genotypes between patients with T2DM and controls. Linear regression analyses for both polymorphisms were performed and demonstrated an independent effect of the rs1801282 of the PPAR-γ on waist circumference in subjects with T2DM, whereas an independent effect on waist circumference was not demonstrated for the rs8192673 of the PGC-1α gene. In a large sample of the Caucasians the rs8192673 of the PGC-1α gene and the rs1801282 of the PPAR-γ gene were associated with waist circumference in subjects with T2DM.


Structural elucidation of A-74528, an inhibitor for 2',5'-phosphodiesterase isolated from Streptomyces sp.
A-74528 (1) is a metabolite of Streptomyces sp. discovered in the screening for 2',5'-oligoadenylate phosphodiesterase inhibitors. The planar structure of 1 was mainly elucidated by NMR techniques including natural abundance INADEQUATE, and the relative configuration and the conformation were elucidated by the analyses of NOEs and assessment of dihedral angles predicted by QUANTA/CHARMm computations and coupling constants. It was proved that 1 is a highly fused polyketide with a side-chain branching site that never appeared before from the nature.


Study of the disintegration of loess modified with fly ash and Roadyes.
The disintegration property of loess is the wetting and subsequent disintegration of loess in water, which is generally an important index for resistance to erosion and disintegration of wet loess slopes and foundations. In this study, a disintegration instrument is developed in this laboratory and used to study the disintegration properties of fly ash-modified loess in foundations and Roadyes-modified loess in subgrades. Disintegration tests are used to compare samples of loess modified with different amounts of fly ash and Roadyes, different water contents and different dry densities; the influence of fly ash and Roadyes content on the disintegration of modified loess is analyzed. The differences in disintegration properties between the pure loess and modified loess are compared to explore the evolution of disintegration properties of modified loess and the optimal incorporation levels of fly ash and Roadyes. The experimental results show that the incorporation of fly ash reduces the disintegration of loess, while the incorporation of Roadyes likewise decreases the disintegration of loess. The disintegration of the loess modified with the two curing agents is better than that of the pure loess and loess mixed with a single curing agent; the optimal incorporation levels are 15% fly ash and 0.5‰ Roadyes. Comparing the evolution of the disintegration curves of samples of loess with different modifications shows is a linear relationship between time and amount of disintegration for pure loess and Roadyes-modified loess. Thus, a linear disintegration model is established in which the parameter P is the disintegration rate. According to the exponential relationship between time and amount of disintegration of fly ash-modified loess and loess modified with both fly ash and Roadyes, an exponential disintegration model is established in which the water stability parameter Q affects the strong and weak disintegration of the modified loess. The relationship between the water stability of the loess (modified with added fly ash and Roadyes) in water and the initial water content and dry density is analyzed. The water stability of the loess first increases and then decreases with increasing initial water content and gradually increases with increasing dry density. When the sample density is the maximum dry density, the sample has the best water stability. These research results provide a basis for the application of loess modified with added fly ash and Roadyes.


Plasma renin activity and plasma aldosterone concentration in infants with various sodium intakes.
Plasma renin activity (PRA) and plasma aldosterone concentration (PA) were measured in 20 healthy infants 2-12 months of age, after taking a commercial modified cow's milk formula with 8.2 mmol/l sodium for at least five days, and after at least five days on a home-made, undiluted acidified cow's milk formula with 12.6 mmol/l sodium. The mean sodium intakes were 1.20 and 1.87 mmol/kg of body weight per day respectively. The arithmetic means for the corresponding PRA were 6.16 and 1.08 ng/ml . h (difference not significant) and the corresponding arithmetic means for PA were 603 and 355 pg/ml, the difference being highly significant (P less than 0.01). It is concluded that one has to consider the sodium intake in the milk formula when studying plasma aldosterone in infancy.


First face composite-tissue transplant recipient successfully treated for cytomegalovirus infection with preemptive valganciclovir treatment.
Little is known about cytomegalovirus (CMV) infection after face transplantation, since only two of the 11 cases of face transplantation reported worldwide have documented a CMV infection after transplantation. Herein, we present the first report of a composite-tissue face allotransplant recipient at high risk for CMV infection (D(+)/R(-) [CMV serpositive donor positive/CMV seronegative receptor]) undergoing preemptive treatment. Preemptive treatment was safe and effective for controlling CMV infection and thus promoting early acquisition of a CMV-specific immune response that protected the patient from late-onset CMV disease.


Prenatal detection of an inverted X chromosome in a male.
An unusual case of an X chromosome with a pericentric inversion (p11.3q21.3) was detected prenatally in a male fetus. This inversion has not been previously characterized. Although the inverted chromosome was transmitted through the mother, no living males on the maternal side were detected with the aberrant chromosome. Replication studies were performed on cultures of maternal peripheral blood lymphocytes, and it was determined that the inverted X chromosome was early replicating in approximately half of the cells. Following genetic counseling, the pregnancy was continued and a healthy male infant was delivered at term. Cytogenetic analysis of peripheral blood performed in the newborn period confirmed the prenatal findings. The child is developing normally at 3 years of age.


An attenuated variant of the GDVII strain of Theiler's virus does not persist and does not infect the white matter of the central nervous system.
The DA strain of Theiler's virus causes a persistent and demyelinating infection of the white matter of spinal cord, whereas the GDVII strain causes a fatal gray-matter encephalomyelitis. Studies with recombinant viruses showed that this difference in phenotype is controlled mainly by the capsid. However, conflicting results regarding the existence of determinants of persistence in the capsid of the GDVII strain have been published. Here we show that a GDVII virus whose neurovirulence has been attenuated by an insertion in the 5' noncoding region does not persist in the central nervous systems of mice. Furthermore, this virus infects the gray matter efficiently, but not the white matter. These results confirm the absence of determinants of persistence in the GDVII capsid. They suggest that the DA capsid controls persistence by allowing the virus to infect cells in the white matter of the spinal cord.


AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications.
The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic subunit of two multi-protein complexes, referred to as mTORC1 and mTORC2. Signaling downstream of mTORC1 has a critical role in leukemic cell biology by controlling mRNA translation of genes involved in both cell survival and proliferation. mTORC1 activity can be downmodulated by upregulating the liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway. Here, we have explored the therapeutic potential of the anti-diabetic drug, metformin (an LKB1/AMPK activator), against both T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples from T-ALL patients displaying mTORC1 activation. Metformin affected T-ALL cell viability by inducing autophagy and apoptosis. However, it was much less toxic against proliferating CD4(+) T-lymphocytes from healthy donors. Western blot analysis demonstrated dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cells treated with metformin. Remarkably, metformin targeted the side population of T-ALL cell lines as well as a putative leukemia-initiating cell subpopulation (CD34(+)/CD7(-)/CD4(-)) in patient samples. In conclusion, metformin displayed a remarkable anti-leukemic activity, which emphasizes future development of LKB1/AMPK activators as clinical candidates for therapy in T-ALL.


Benzoxazinoid biosynthesis in dicot plants.
Benzoxazinoids are common defence compounds of the grasses and are sporadically found in single species of two unrelated orders of the dicots. In the three dicotyledonous species Aphelandra squarrosa, Consolida orientalis and Lamium galeobdolon the main benzoxazinoid aglucon is 2,4-dihydroxy-2H-1,4-benzoxazin-3(4H)-one (DIBOA). While benzoxazinoids in Aphelandra squarrosa are restricted to the root, in Consolida orientalis and Lamium galeobdolon DIBOA is found in all above ground organs of the adult plant in concentrations as high as in the seedling of maize. The initial biosynthetic steps in dicots and monocots seem to be identical. Indole is most probably the first specific intermediate that is oxygenated to indolin-2-one by a cytochrome P450 enzyme. C. orientalis has an active indole-3-glycerolphosphate lyase for indole formation that evolved independently from its orthologous function in maize. The properties and evolution of plant indole-3-glycerolphosphate lyases are discussed.


Long-term treatment outcome of minor salivary gland carcinoma of the hard palate.
Minor salivary gland carcinoma of the hard palate is rare, and its long-term survival rate is high, making it difficult to evaluate the prognostic factors and the efficacy of treatment. This study was designed to evaluate the treatment outcome of minor salivary gland carcinoma of the hard palate. 103 cases of minor salivary gland carcinoma of the hard palate treated with surgery alone or underwent surgery combined with post-operative radiotherapy hospitalized in Cancer Center, Sun Yet-Sen University, from 1968 to 2008 were reviewed retrospectively. The most common histologic types were adenoid cystic carcinoma in 48 patients(46.6%), mucoepidermoid carcinoma in 37(35.92%), malignant mixed tumor in 15(14.56%), and acinic cell carcinoma in 3(2.91%). The median follow-up time was 74.83 months (range 0.9-356.57 months). Overall outcomes at 5 and 10 years were overall survival (OS), 77.9% and 65.7%; recurrence-free survival (RFS), 64.4% and 53.2%; and disease specific survival (DSS), 77.9% and 67.7%, respectively. There was no significant difference in overall survival (P=0.52), recurrence-free survival (P=0.762) and disease specific survival (P=0.449) between patients who underwent surgery alone and those who underwent surgery plus post-operative radiotherapy. Surgery has been accepted as the primary treatment for minor salivary gland carcinoma of hard palate. Sufficient surgical excision with adequate margins is essential for a favorable outcome. We advocate using radiotherapy in the post-operative context for patients with poorly differentiated, cervical lymph node metastasis, positive or close margins, and large primary lesions.


Bacterial zinc transporters and regulators.
Zn2+ homeostasis in bacteria is achieved by export systems and uptake systems which are separately regulated by their own regulators. Three types of Zn2+ export systems that protect cells from high toxic concentrations of Zn2+ have been identified: RND multi-drug efflux transporters, P-type ATPases, and cation-diffusion facilitators. The RND type exporters for Zn2+ are only found in a few gram-negative bacteria; they allow a very efficient export across the cytoplasmic membrane and the outer membrane of the cell. P-type ATPases and cation-diffusion facilitators belong to protein families that are also found in eukaryotes. The exporters are regulated in bacteria by MerR-like repressor/activators or by ArsR-like repressors. For the high-affinity uptake of Zn2+, several binding-protein-dependent ABC transporters belonging to one class have been identified in different bacteria. Zn2+ ABC transporters are regulated by Zur repressors, which belong to the Fur protein family of iron regulators. Little is known about low-affinity Zn2+ uptake under zinc-replete conditions. One known example is the phosphate uptake system Pit, which may cotransport Zn2+ in Escherichia coli. Similarly, the citrate-metal cotransporter CitM in Bacillus subtilis may help to supply Zn2+.


Clinicopathological and prognostic significance of PD-L1 expression in colorectal cancer: a meta-analysis.
To systematically evaluate the correlation between PD-L1 expression and clinicopathological features and prognosis of colorectal cancer (CRC). Seven databases (PubMed, Cochrane Library, EMBASE, Web of Science, CBM, Wanfang, and CNKI) were searched through May 2020. Risk of bias and quality of evidence were assessed by using the Newcastle-Ottawa scale (NOS), and meta-analysis was carried out by using the Review Manager 5.3 software on the studies with the quality evaluation scores ≥ 6. Meta-regression analysis was used to determine the independent role of PD-L1 expression on CRC prognosis after adjusting clinicopathological features and treatment methods. A total of 8823 CRC patients in 32 eligible studies. PD-L1 expression was correlated with lymphatic metastasis (yes/no; OR = 1.24, 95% CI (1.11, 1.38)), diameter of tumor (≥ 5 cm/< 5 cm; OR = 1.34, 95% CI (1.06, 1.70)), differentiation (high-middle/low; OR = 0.68, 95% CI (0.53, 0.87)), and vascular invasion (yes/no; OR = 0.80, 95% CI (0.69, 0.92)). PD-L1 expression shortened the overall survival (hazard ratio (HR) = 1.93, 95% CI (1.66, 2.25)), disease-free survival (HR = 1.76, 95% CI (1.50, 2.07)), and progression-free survival (HR = 1.93, 95% CI (1.55, 2.41)). Meta-regression showed that PD-L1 expression played a significant role on poor CRC OS (HR = 1.95, 95% CI (1.92, 3.98)) and disease-free survival (HR = 2.14, 95% CI (0.73, 4.52)). PD-L1 expression independently predicted a poor prognosis of CRC.


Second primary cancers in people who had cancer as children: an Australian Childhood Cancer Registry population-based study.
To investigate the incidence of second primary cancers in people diagnosed with cancer during childhood. Retrospective, population-based study; analysis of Australian Childhood Cancer Registry data. People alive at least two months after being diagnosed before the age of 15 years with a primary cancer, 1983-2013, followed until 31 December 2015 (2-33 years' follow-up). Risks of second primary cancer compared with the general population, expressed as standardised incidence ratios (SIRs). Among 18 230 people diagnosed with cancer during childhood, 388 (2%) were later diagnosed with second primary cancers; the estimated 30-year cumulative incidence of second cancers was 4.4% (95% CI, 3.8-5.0%). The risk of a new primary cancer was five times as high as for the general population (SIR, 5.13; 95% CI, 4.65-5.67). Relative risk of a second primary cancer was greatest for people who had childhood rhabdomyosarcoma (SIR, 19.9; 95% CI, 14.4-27.6). Relative risk was particularly high for children who had undergone both chemotherapy and radiotherapy (SIR, 9.80; 95% CI, 8.35-11.5). Relative risk peaked during the 5 years following the first diagnosis (2 to less than 5 years: SIR, 10.3; 95% CI, 8.20-13.0), but was still significant at 20-33 years (SIR, 2.58; 95% CI, 2.02-3.30). The most frequent second primary cancers were thyroid carcinomas (65 of 388, 17%) and acute myeloid leukaemias (57, 15%). Survivors of childhood cancer remain at increased risk of a second primary cancer well into adulthood. As the late effects of cancer treatment probably contribute to this risk, treatments need to be refined and their toxicity reduced, without reducing their benefit for survival.


Buprenorphine and methadone differentially alter early brain development in human cortical organoids.
Buprenorphine (BUP) and methadone (MTD) are used for medication-assisted treatment (MAT) in opioid use disorder. Although both medications show improved maternal and neonatal outcomes compared with illicit opioid use during pregnancy, BUP has exhibited more favorable outcomes to newborns than MTD. The underlying cellular and molecular mechanisms for the difference between BUP and MTD are largely unknown. Here, we examined the growth and neuronal activity in human cortical organoids (hCOs) exposed to BUP or MTD. We found that the growth of hCOs was significantly restricted in the MTD-treated but not in the BUP-treated hCOs and BUP attenuated the growth-restriction effect of MTD in hCOs. Furthermore, a κ-receptor agonist restricted while an antagonist alleviated the growth-restriction effect of MTD in hCOs. Since BUP is not only a μ-agonist but a κ-antagonist, the prevention of this growth-restriction by BUP is likely due to its κ-receptor-antagonism. In addition, using multielectrode array (MEA) technique, we discovered that both BUP and MTD inhibited neuronal activity in hCOs but BUP showed suppressive effects only at higher concentrations. Furthermore, κ-receptor antagonist nBNI did not prevent the MTD-induced suppression of neuronal activity in hCOs but the NMDA-antagonism of MTD (that BUP lacks) plays a role in the inhibition of neuronal activity. We conclude that, although both MTD and BUP are μ-opioid agonists, a) the additional κ-receptor antagonism of BUP mitigates the MTD-induced growth restriction during neurodevelopment and b) the lack of NMDA antagonism of BUP (in contrast to MTD) induces much less suppressive effect on neural network communications.


Probabilistic modeling of selective stimulation of the human sciatic nerve with a flat Interface Nerve Electrode.
Proper ankle control is critical to both standing balance and efficient walking. This study hypothesized that a Flat Interface Nerve Electrode (FINE) placed around the sciatic nerve with a fixed number of contacts at predetermined locations and without a priori knowledge of the nerve's underlying neuroanatomy can selectively control each ankle motion. Models of the human sciatic nerve surrounded by a FINE of varying size were created and used to calculate the probability of selective activation of axons within any arbitrarily designated group of fascicles. Simulations suggest that currently available implantable technology cannot selectively recruit each target plantar flexor individually but can restore plantar flexion or dorsiflexion from a site on the sciatic nerve without spillover to antagonists. Successful activation of individual ankle muscles in 90% of the population can be achieved by utilizing bipolar stimulation and/or by increasing the number of contacts within the cuff.


Discovery of novel inhibitors of human galactokinase by virtual screening.
Classic Galactosemia is a potentially lethal autosomal recessive metabolic disorder caused by deficient galactose-1-phosphate uridyltransferase (GALT) that results in the buildup of galactose-1-phosphate (gal-1-p) in cells. Galactokinase (GALK1) is the enzyme responsible for converting galactose into gal-1-p. A pharmacological inhibitor of GALK1 is hypothesized to be therapeutic strategy for treating galactosemia by reducing production of gal-1-p. In this study, we report the discovery of novel series of GALK1 inhibitors by structure-based virtual screening (VS). Followed by an extensive structural modeling and binding mode analysis of the active compounds identified from quantitative high-throughput screen (qHTS), we developed an efficient pharmacophore-based VS approach and applied for a large-scale in silico database screening. Out of 230,000 compounds virtually screened, 350 compounds were cherry-picked based on multi-factor prioritization procedure, and 75 representing a diversity of chemotypes exhibited inhibitory activity in GALK1 biochemical assay. Furthermore, a phenylsulfonamide series with excellent in vitro ADME properties was selected for downstream characterization and demonstrated its ability to lower gal-1-p in primary patient fibroblasts. The compounds described herein should provide a starting point for further development of drug candidates for the GALK1 modulation in the Classic Galactosemia.


Ultrasonographic evidence of intra-abdominal umbilical vein dilatation: is it a true varix?
Fetal intraabdominal umbilical vein (FIUV) dilatation, or varix, is a rare ultrasonographic (US) finding of focal dilatation of the umbilical vein. This article describes FIUV tortuosity in cases with suspected varix and provides ultrasonographic criteria for its diagnosis. Cases of suspected FIUV varix referred to our unit for final diagnosis and follow-up were studied. Each woman underwent comprehensive US evaluations that included basic grayscale scan and color Doppler scan. In 12 singleton pregnancies, primary grayscale scan confirmed FIUV dilatation. Supplementary color Doppler scans, however, revealed linear bidirectional blood flow and FIUV tortuosity in all cases. Color Doppler scans did not depict true FIUV dilatations or varix but rather a tortuous course of the vein. A normal pregnancy outcome can be expected in these cases.


Efficacy of cognitive stimulation therapy virtual program for older adults with dementia in COVID-19 isolation.
Cognitive stimulation virtual therapy (CSVT) is an evidence-based psychosocial intervention for people with mild-to-moderate dementia due to various etiological factors. The aim of the present study was to assess the efficacy of a cognitive stimulation virtual therapy CSVT program, in individuals who have vascular or Alzheimer dementia in COVID-19 isolation. Older adults with mild vascular or Alzheimer dementia (N = 20) were assigned to one of two programs: one group (N = 10) attended during six months, two sessions per week program of the cognitive stimulation virtual therapy CSVT program, while the other, active control group (N = 10) took part in alternative activities. The following tests were applied to their primary caregivers. A short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and quality of life (Quality of Life (QoL) RESULTS: Compared with the active controls, the cognitive stimulation virtual therapy CSVT program showed a greater improvement in general cognitive functioning after the intervention (i.e. score increase on the IQCODE test). A trend towards improvement was also identified in short term/working memory and perceived quality of life (Quality of life (QoL) of elderly with dementia). The primary caregivers also perceived an improvement in mood, stress, anxiety and quality of sleep after the start of the virtual therapy during COVID-19 isolation. The present results support the efficacy of cognitive stimulation virtual therapy CSVT program in people with dementia during COVID-19 isolation.


Symmetry and asymmetry in idiotypic interactions.
At the level of antibody molecules, the partners in an idiotypic interaction are functionally equivalent, and the distinction between "idiotype" and "anti-idiotype" is merely operational. This point must be taken into account in the interpretation of regulatory experiments with "idiotypic" and "antiidiotypic" antibodies. Indeed, consistent interpretations of certain sets of data can be obtained if "idiotype" and "antiidiotype" are used as operational terms for functionally equivalent molecules with complementary binding sites. For interacting antibody populations, symmetrical and asymmetrical situations can occur. The latter case is when an antibody family whose members express a set of idiotypes in various combinations--a typical situation in germ-line encoded immune responses--interacts with a heterogenous population of anti-idiotypes, the common denominators of which are binding sites for the common idiotopes expressed in the idiotypic antibody family. Through this type of interaction, one can explain in a first approximation the experiments of Urbain, Cazenave and others in which antiidiotypic antibody populations (ab2) induce antibodies (ab3) which resemble the original idiotypic population (ab1) idiotypically, but not primarily in antigen-binding specificity. Such a model would also describe an idiotypic network in which germline-encoded recurrent idiotypes (expressed in antibody families of the type described above) interact with anti-idiotypes generated by somatic mutation.


Spectral properties of Co(II)- and Ni(II)-activated rabbit muscle pyruvate kinase.
Stoichiometry, kinetics, and optical properties of rabbit muscle pyruvate kinase activated with Co(II), Ni(II), Mg(II), and Mn(II) were studied. The stoichiometry of metal binding to enzyme was found to be 4 metal ions per tetrameric enzyme for Co(II) and Ni(II) by carrying out circular dichroic titrations. Cu(II) and Fe(II) were inactive. Ca(II) and Zn(II) were not activating, and were inhibitory with respect to all of the active cations. The temperature dependence of the optimal velocity is similar for all activating metals. The pH rate profiles suggest that there are two classes of enzyme activation by metal ions. Mg(II) and Mn(II) are quite similar to each other while Co(II) and Ni(II) are different from them but similar to each other. Absorption, natural, and magnetic CD in the visible region were used to probe the environment of the activating divalent cation in Ni(II)- and Co(II)-activated pyruvate kinase and their complexes with substrates and inhibitors...


Failure of SCS MR-Conditional Modes Due to High Impedance: A Review of Literature and Case Series.
Magnetic resonance imaging (MRI) conditional modes are a novel feature for certain Food and Drug Administration (FDA)-approved spinal cord stimulation (SCS) devices. However, there is a paucity of literature around the limitation of MRI-conditional modes ("MRI safe"), specifically in clinical scenarios where urgent MRIs may be needed. One such limitation is load impedance, referring to the circuit's resistance to the current being generated by the system. High impedance can limit the MRI-conditional mode capability, presenting potential harm to a patient undergoing an MRI or make an MRI unable to be completed. Three cases were identified, and informed consent was obtained. All information was obtained via retrospective chart review. In this case series of three patients where MRI-conditional SCS systems were unable to be placed in "MRI safe" settings, preventing timely MRI study completion in the setting of high impedance, all three were required to undergo alternative imaging including CT scans, and two patients ultimately had the system explanted and one chose to be re-implanted after completion of scans. This case series highlights the need for further investigation of impedance in SCS systems and potential limitations for future MRI usage. The review of literature of impedance in SCS shows both device- and physiologic-related etiologies for changes in impedance that warrant consideration by the implanting physician.