INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD): development and validation.
To develop and validate INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD). Diagnostic test evaluation by cross sectional design. Four tertiary pediatric neurology centers in Delhi and Thiruvanthapuram, India. Children aged 2-9 years were enrolled in the study. INDT-ASD and Childhood Autism Rating Scale (CARS) were administered in a randomly decided sequence by trained psychologist, followed by an expert evaluation by DSM-IV TR diagnostic criteria (gold standard). Psychometric parameters of diagnostic accuracy, validity (construct, criterion and convergent) and internal consistency. 154 children (110 boys, mean age 64.2 mo) were enrolled. The overall diagnostic accuracy (AUC=0.97, 95% CI 0.93, 0.99; P<0.001) and validity (sensitivity 98%, specificity 95%, positive predictive value 91%, negative predictive value 99%) of INDT-ASD for Autism spectrum disorder were high, taking expert diagnosis using DSM-IV-TR as gold standard. The concordance rate between the INDT-ASD and expert diagnosis for 'ASD group' was 82.52% [Cohen's k=0.89; 95% CI (0.82, 0.97); P=0.001]. The internal consistency of INDT-ASD was 0.96. The convergent validity with CARS (r = 0.73, P= 0.001) and divergent validity with Binet-Kamat Test of intelligence (r = -0.37; P=0.004) were significantly high. INDT-ASD has a 4-factor structure explaining 85.3% of the variance. INDT-ASD has high diagnostic accuracy, adequate content validity, good internal consistency high criterion validity and high to moderate convergent validity and 4-factor construct validity for diagnosis of Autistm spectrum disorder.


Thalamic deep brain stimulation for midbrain tremor secondary to cystic degeneration of the brainstem.
Tremor resulting from damage to midbrain structures is poorly understood and often difficult to treat. The authors report a case of cystic degeneration of the brainstem with resultant Holmes-like tremor which was successfully treated using a stimulating electrode placed in the contralateral ventralis intermedius nucleus (VIM) of the thalamus. A 31-year-old man presented with a multilobulated, multiseptated lesion of the upper brainstem diagnosed after subacute onset of headaches. The patient subsequently developed an incapacitating left-upper-extremity tremor refractory to medical treatment. The patient underwent implantation of a deep brain stimulator in the VIM with symptomatic and functional improvement. Deep brain stimulation is an effective and safe intervention for tremor of unusual etiology. Electrode placement should be based on an understanding of the structure-function relationships underlying the various and distinct types of tremor.


The relationship between prescription medication use and ability to ambulate distances after spinal cord injury.
To investigate the relationship between prescription medication use for pain and spasticity and ambulation distances while controlling for pain severity, injury severity, age, sex, and race in participants with spinal cord injury (SCI). Secondary analysis of survey data. Specialty hospital in the Southeast United States. Adults (N=407) with traumatic SCI identified through inpatient and outpatient hospital databases. Not applicable. A questionnaire measured prescription medication use, ambulation distance, and other demographic data. A composite score of four 10-point scales from the Brief Pain Inventory was used to measure pain severity. Multinomial logistic regression was used to calculate the odds ratio (OR) of ambulation distance using 1000 ft or more as the reference group. Persons with SCI who were heavy prescription medication users (defined as weekly or daily use for pain or spasticity) were more likely to be limited to distances less than 150 (OR, 2.82; 95% confidence interval [CI], 1.57-5.04) and 150 to 999 ft (OR, 2.52; 95% CI, 1.45-4.39). Heavy prescription medication use for pain and spasticity was related inversely to a person's ability to achieve community ambulation distances of 1000 ft or more.


Behavioral modulation of neuronal calcium/calmodulin-dependent protein kinase II activity: differential effects on nicotine-induced spinal and supraspinal antinociception in mice.
Recent studies have implicated the involvement of Ca(2+)-dependent mechanisms, in particular calcium/calmodulin-dependent protein kinase II (CaM kinase II) in nicotine-induced antinociception using the tail-flick test. The spinal cord was suggested as a possible site of this involvement. The present study was undertaken to investigate the hypothesis that similar mechanisms exist for nicotine-induced antinociception in the hot-plate test, a response thought to be centrally mediated. In order to assess these mechanisms, i.c.v. administered CaM kinase II inhibitors were evaluated for their effects on antinociception produced by either i.c.v. or s.c. administration of nicotine in both tests. In addition, nicotine's analgesic effects were tested in mice lacking half of their CaM kinase II (CaM kinase II heterozygous) and compare it to their wild-type counterparts. Our results showed that although structurally unrelated CaM kinase II inhibitors blocked nicotine's effects in the tail-flick test in a dose-related manner, they failed to block the hot-plate responses. In addition, the antinociceptive effects of systemic nicotine in the tail-flick but not the hot-plate test were significantly reduced in CaM kinase II heterozygous mice. These observations indicate that in contrast to the tail-flick response, the mechanism of nicotine-induced antinociception in the hot-plate test is not mediated primarily via CaM kinase II-dependent mechanisms at the supraspinal level.


Molecular analysis and long-term clinical evaluation of three siblings with Alström syndrome.
Alström syndrome is a rare, autosomal recessive disorder characterized by a wide spectrum of clinical features including early-onset retinal degeneration leading to blindness, sensorineural hearing loss, short stature, obesity, type 2 diabetes, hyperlipidemia and dilated cardiomyopathy. Renal, hepatic and pulmonary dysfunction may occur in the later phases of the disease. The three affected sisters, from a consanguineous Turkish family, with the characteristic features of Alström syndrome, were clinically diagnosed in 1987 and followed for 20 years. DNA sequence analysis of ALMS1, the causative gene in Alström syndrome, identified a novel homozygous disease-causing mutation, c.8164C>T, resulting in a premature termination codon in exon 10 in each of the three affected sisters. Furthermore, we describe the longitudinal disease progression in this family and report new clinical findings likely associated with Alström syndrome, such as pes planus and hyperthyroidism.


Upper body clothing is a source of fungal beta-(1,3)-glucan exposure.
Beta-(1,3)-glucan is pro-inflammatory and has been associated with airway inflammation and respiratory symptoms. This study assessed beta-(1,3)-glucan levels from upper body clothing (jerseys) of 55 subjects. Beta-(1,3)-glucan levels were estimated with a modified Limulusamoebocyte lysate kinetic assay. Beta-(1,3)-glucan levels ranged widely from 2,697 to 162,690 ng/g. Beta-(1,3)-glucan levels were significantly lower from cotton jerseys and from warm water washed jerseys. Thus, jerseys are potentially a significant exposure source of beta-(1,3)-glucan.


Cellular therapy.
From a clinical perspective, prenatal transplantation has tremendous potential to broaden the current indications for reconstitution therapy and to offer a safe, efficacious, and cost-effective alternative to conventional postnatal BMT for many congenital hematopoietic diseases. Experimental work and limited clinical experience offer hope for the future. The primary experimental challenges will be to manipulate the biology of in utero HSC transplantation so that the approach will be safe and broadly applicable. This will require strategies to improve engraftment; use alternative sources of cells safely and effectively; and develop techniques for procurement, ex vivo expansion, and tissue banking of safe donor cells. The clinical challenges in the future will be to identify recipients most likely to benefit from the approach, and to define further the clinical and ethical guidelines for its application.


Novel Antidepressants in the Pipeline (Phase II and III): A Systematic Review of the US Clinical Trials Registry.
There is an imminent need for faster-acting and more effective antidepressants beyond the monoaminergic hypothesis. We systematically searched the US Clinical Trials registry for antidepressant compounds with completed phase II and III trials. Compounds that demonstrated significant superiority over placebo in the primary outcome measure in the latest phase of phase II and III trials were identified. The collateral information was gathered via a PubMed search and press releases. Nine compounds were identified. AXS-05 (a combination of dextromethorphan and bupropion) and ansofaxine hydrochloride showed a positive result over placebo in a phase III study for major depressive disorder or treatment-resistant depression. MIJ821, nitrous oxide, psilocybin, ayahuasca, facial injection of botulinum toxin A, prasterone, and casopitant demonstrated at least one positive result in phase II trials. Ayahuasca showed a greater response rate than placebo at week one, indicating the rapid antidepressant effect. These new compounds with novel mechanisms of action are expected to provide a greater variety of treatment options for depression if preliminary positive results are confirmed.


4-OI Protects MIN6 Cells from Oxidative Stress Injury by Reducing LDHA-Mediated ROS Generation.
Pancreatic beta cells are highly susceptible to oxidative stress, which plays a crucial role in diabetes outcomes. Progress has been slow to identify molecules that could be utilized to enhance cell survival and function under oxidative stress. Itaconate, a byproduct of the tricarboxylic acid cycle, has both anti-inflammatory and antioxidant properties. The effects of itaconate on beta cells under oxidative stress are relatively unknown. We explored the effects of 4-octyl itaconate-a cell-permeable derivative of itaconate-on MIN6 (a beta cell model) under oxidative stress conditions caused by hypoxia, along with its mechanism of action. Treatment with 4-OI reversed hypoxia-induced cell death, reduced ROS production, and inhibited cell death pathway activation and inflammatory cytokine secretion in MIN6 cells. The 4-OI treatment also suppressed lactate dehydrogenase A (LDHA)activity, which increases under hypoxia. Treatment of cells with the ROS scavenger NAC and LDHA-specific inhibitor FX-11 reproduced the beneficial effects of 4-OI on MIN6 cell viability under oxidative stress conditions, confirming its role in regulating ROS production. Conversely, overexpression of LDHA reduced the beneficial effects exerted by 4-OI on cells. Our findings provide a strong rationale for using 4-OI to prevent the death of MIN6 cells under oxidative stress.


Maintaining competence and competency in the care of the intra-aortic balloon pump patient.
Care of the IABP patient requires specialized knowledge and skill. Two methods exist for verifying the nurse's ability to safely care for this patient population. Competence and competency testing approach this task from two different aspects; the former assesses the nurse's potential knowledge and skills and later verifies the nurse's ability to perform and apply knowledge, skill, and standards of care in an actual "mock run" situation. Both aspects should be included in an IABP training program.


Carbonated water as a novel washing medium for mackerel (Auxis thazard) surimi production.
Effect of cold carbonated water (CW) washing on the biochemical properties and gel characteristics of mackerel surimi was evaluated. Three washing cycles were performed with different orders of washing medium including T1 (water, water and water), T2 (CW, water and water), T3 (CW, CW and water) and T4 (CW, CW and CW). The results showed that CW washing, especially T4, caused the decrease in pH, Ca2+-ATPase activity and surface hydrophobicity and led to the increase in reactive sulfhydryl content. Regardless of washing treatment, haem protein of surimi decreased significantly compared to unwashed mince. However, carbonated water did not improve haem protein removal. The highest lipid reduction was found in T1 and T2. Gels from all CW washing treatments had a comparable whiteness. Breaking force of CW surimi gel increased with increasing washing cycle (T2 < T3 < T4). Deformations of all surimi gels were not much different (~7 mm). Expressible drip increased with increasing CW washing cycle. Numbers of jointed spherical matrices were found in surimi gel microstructures. With increasing CW washing cycle, densely packed aggregates were formed. Therefore, CW washing with appropriate cycle can be used as an alternative means for mackerel surimi production.


The genetic aetiology of late-onset chronic progressive cerebellar ataxia. A population-based study.
An increasing number of dominant and recessive disorders have been associated with late onset chronic progressive ataxia (LOCA) complicating the formulation of a rational diagnostic strategy. Furthermore, there is marked geographic and ethnic variation in the relative importance of these individual disorders and the cause of such observed variation remains unexplained. We have systematically investigated a population-based cohort of patients with chronic progressive LOCA for SCA 1, 2, 3, 6, 7, 8, 10, 12, 17, FXTAS and FRDA. In addition we have examined repeat length polymorphism in chromosomes from a genetically homogeneous and representative control population to investigate the association of high-normal repeats and disease prevalence. A total of 178 patients including 55 familial cases segregating in 38 kindreds and 123 sporadic were investigated. Pathological expansions were identified in 11/38 (28.9 %) of families and in 5/123 (4.1 %) of sporadic patients. The most frequent diagnoses were SCA6 (6 families and 1 sporadic patient), DRPLA (4 families) and SCA8 (1 family). In addition, one elderly female patient was identified with "possible FXTAS". Six (2 %) control patients were noted to have expanded SCA8 alleles. SCA6 and DRPLA were the most frequent genetic diagnoses identified. Patterns of high-normal allele frequency in this UK population were distinct compared to other ethnic groups but this was poorly predictive of the distribution of disease in this region. The relative contribution of new mutation formation and founder effects to the prevalence of familial ataxia is uncertain, and further exploration of these factors will require detailed analysis of disease allele haplotypes and meiotic instability of intermediate length alleles.


Assessment of myocardial perfusion by magnetic resonance imaging.
Magnetic resonance imaging (MRI) has proven useful for anatomic and functional evaluation of the heart. However, until recently assessment of myocardial perfusion has not been possible by MRI. Using newly developed ultrafast imaging sequences, images can be acquired rapidly with a high temporal resolution, which is a prerequisite for imaging the initial passage of a bolus of MR-contrast medium through the myocardium. Only gadolinium chelates, which rapidly diffuse out of vascular space, are currently approved for clinical use. The first pass of a bolus of one of these agents through hypoperfused myocardium distal to a coronary artery stenosis enhances this area less as compared to normally perfused areas. This different myocardial enhancement is often visible when looking at the series of MR images. However, intensity differences are rapidly decreasing as MR-contrast media are diluted in the systemio circulation after the first pass and diffuse to the interstitium. Therefore, only the first pass is of interest for MR-perfusion imaging. Additional and often more precise information can be derived by measuring parameters of the signal intensity time curve such as mean transit time, maximum signal intensity increase, upslope, downslope, and delay before reaching maximum signal intensity. Temporal resolution is the crucial factor in MR-perfusion imaging because it takes only 20 to 60 seconds for the contrast medium to pass through the myocardium. Therefore, this dynamic process must be imaged with a high temporal resolution. Moreover, image acquisition must be fast enough to minimize motion artefacts and to maximize the spatial coverage of the ventricle. Ultrafast gradient echo techniques and echo planar imaging are in principle capable to fulfill these demands. While ultrafast gradient echo sequences enable one to acquire a maximum of 2 slices per heartbeat, echo planar sequences need only 30 to 50 msec to completely acquire one image and are thus able to image the entire ventricle within one heartbeat. However, they are also more susceptible to image artefacts. As gradients capable of producing high quality echo planar images are not widely available, ultrafast gradient echo techniques are commonly used for MR-perfusion imaging. A good correlation between quantitative estimates of myocardial perfusion by MRI after injection of an intravascular contrast agent and microsphere measurements has been shown in animal experiments but quantitative MR perfusion measurements have not yet been performed in humans. Clinical studies have until now focused on visual and parametric analysis of signal intensity time curves. From these studies, sensitivities and specifities in the range of 60 to 90% as compared to x-ray coronary angiography and scintigraphy were reported despite the fact that only parts of the left ventricular myocardium could be assessed. However, a generally accepted method of acquiring and analysing MR perfusion images does not yet exist. Therefore, future improvements of hardware and pulse-sequences as well as the development of new blood pool contrast agents are necessary before MR-perfusion imaging will become a widely accepted and clinically useful diagnostic procedure.


Cell viability analysis using trypan blue: manual and automated methods.
One of the traditional methods of cell viability analysis is the use of trypan blue dye exclusion staining. This technique has been the standard methodology used in academic research laboratories and industrial biotechnology plants. Cells were routinely counted manually with a hemocytometer. In recent years, modern automated instrumentation has been introduced to supplement this traditional technique with the efficiency and reproducibility of computer control, advanced imaging, and automated sample handling.


Racial, ethnic, and socioeconomic disparities in confirmed COVID-19 cases and deaths in the United States: a county-level analysis as of November 2020.
The objective of this study was to investigate potential county-level disparities among racial/ethnic and socioeconomic groups in confirmed COVID-19 cases and deaths in the United States in 100,000 population. Secondary data analysis using county-level data for 3,142 US counties was conducted in 2020. Hierarchical linear regression and concentration curve analyses were performed. The combined association of COVID-19 cases and deaths was examined separately by the county population's socioeconomic characteristics. Data from the American Community Survey (ACS) 5-year estimates (2014-2018), Area Health Resources File (AHRF) 2018-2019, Kaiser Health News 2020, and 2020 COVID-19 data from Johns Hopkins University were used in this study. After adjusting for covariates, U.S. counties with a higher proportion of the Black population and a higher proportion of adults with less than a high school diploma had disproportionately higher COVID-19 cases and deaths (β > 0, p<0.05 for all relations). A higher proportion of the Hispanic population was associated with higher confirmed cases (β = 0.68, 95% CI = 0.48-0.87). The majority observed disparities in COVID-19 deaths persisted even after controlling for all-cause deaths in 2019 and COVID-19 cases per 100,000 county population. This can potentially aggravate the existing health disparities among these population groups. Identification of disproportionately impacted population groups can pave the way towards narrowing the disparity gaps and guide policymakers and stakeholders in designing and implementing population group-specific interventions to mitigate the negative consequences of the COVID-19 pandemic.


Alteration in bioenergetic regulators, SirT1 and Parp1 expression precedes oxidative stress in rats subjected to transient cerebral focal ischemia: molecular and histopathologic evidences.
The present study was undertaken to identify the time-dependent changes in bioenergetic regulators and oxidative stress markers levels and also to ascertain which occurs early in focal cerebral ischemia. The status of bioenergetic regulators (nicotinamide adenine dinucleotide, Silent information regulator Transporter 1 (SirT1) and Poly adenosine diphosphate--ribose polymerase 1 (Parp1)) and oxidative stress markers' (lipid peroxidation and nitric oxide) levels along with excitatory neurochemical glutamate, neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), and caspase 3 at various durations of reperfusion viz 0, 1, 6, 24, 72, and 166 hours was investigated in rats subjected to 2 hours of middle cerebral artery occlusion. Six hours after reperfusion, a significant downregulation in SirT1 and upregulation in Parp1 expressions were observed in striatal region of ischemic-reperfused rats compared with ischemic rats. Peak elevation in glutamate content was recorded at 72 hours, and maximum level of lipid peroxidation and nitric oxide contents were observed at 166 hours. A significant decrease in NeuN and increase in GFAP-positive cells were observed at 24 and 72 hours, respectively, in cortical, striatal, and hippocampal regions. These data reveal that change in bioenergetic regulators occurs earlier than excitotoxicity and oxidative stress in cerebral stroke. From the data, it can also be inferred that appropriate therapeutic intervention, that is, bioenergetic modulators at early period and either glutamatergic and/or antioxidant therapy at delayed period may yield a better therapeutic outcome.


A systematic literature review of how and whether social media data can complement traditional survey data to study public opinion.
In this article, we review existing research on the complementarity of social media data and survey data for the study of public opinion. We start by situating our review in the extensive literature (N = 187) about the uses, challenges, and frameworks related to the use of social media for studying public opinion. Based on 187 relevant articles (141 empirical and 46 theoretical) - we identify within the 141 empircal ones six main research approaches concerning the complementarity of both data sources. Results show that the biggest share of the research has focused on how social media can be used to confirm survey findings, especially for election predictions. The main contribution of our review is to detail and classify other growing complementarity approaches, such as comparing both data sources on a given phenomenon, using survey measures as a proxy in social media research, enriching surveys with SMD, recruiting individuals on social media to conduct a second survey phase, and generating new insight on "old" or "under-investigated" topics or theories using SMD. We discuss the advantages and disadvantages associated with each of these approaches in relation to four main research purposes, namely the improvement of validity, sustainability, reliability, and interpretability. We conclude by discussing some limitations of our study and highlighting future paths for research.


Outcomes, Trends, and Predictors of Gastrointestinal Bleeding in Patients Undergoing Transcatheter Aortic Valve Implantation (from the National Inpatient Sample).
Major bleeding has been identified as one of the most common complications after transcatheter aortic valve implantation (TAVI) with some suffering gastrointestinal bleeding (GIB). This study aimed at assessing the incidence and predictors of GIB after TAVI in the United States. We performed a retrospective analysis of data from the National Inpatient Sample database from 2011 to 2018. A total of 216,023 hospitalizations for TAVI were included. Of the included patients, 2,188 (1%) patients had GIB, whereas 213,835 (99%) patients did not have GIB. The presence of arteriovenous malformation was associated with the highest odds of having a gastrointestinal bleed (odds ratio (OR) 24.8, 95% confidence interval (CI) 17.13 to 35.92). Peptic ulcer disease was associated with an eightfold increased risk of bleeding (OR 8.74, 95% CI, 6.69 to 11.43) followed closely by colorectal cancer (OR 7.89, 95% CI, 5.33 to 11.70). Other comorbidities that were associated with higher propensity-matched rates of GIB were chronic kidney disease (OR 1.27,95% CI, 1.14 to 1.41), congestive heart failure (OR 1.18, 95% CI,1.06 to 1.32), liver disease (OR1.83, 95% CI,1.53 to 2.19), end-stage renal disease (OR 2.08,95% CI, 1.75 to 2.47), atrial fibrillation (OR1.63,95% CI, 1.49 to 1.78), and lung cancer (OR 2.80, 95% CI,1.77 to 4.41). Patients with GIB had higher propensity-matched rates of mortality than those without GIB, (12.1% vs 3.2%, p <0.01). Patients with GIB had a higher median cost of stay ($68,779 vs $46,995, p <0.01) and a longer length of hospital stay (11 vs 3 days, p <0.01). In conclusion, health care use and mortality are higher in hospitalizations of TAVI with a GIB. Baseline comorbidities like peptic ulcer disease, chronic kidney disease, liver disease, atrial fibrillation and, colorectal cancer are significant predictors of this adverse event.


Racial, Ethnic, and Socioeconomic Inequities in Glucagon-Like Peptide-1 Receptor Agonist Use Among Patients With Diabetes in the US.
Randomized clinical trials have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause significant weight loss and reduce cardiovascular events in patients with type 2 diabetes (T2D). Black patients have a disproportionate burden of obesity and cardiovascular disease and have a higher rate of cardiovascular-related mortality. Racial and ethnic disparities in health outcomes are largely attributable to the pervasiveness of structural racism, and patients who are marginalized by racism have less access to novel therapeutics. To evaluate GLP-1 RA uptake among a commercially insured population of patients with T2D; identify associations of race, ethnicity, sex, and socioeconomic status with GLP-1 RA use; and specifically examine its use among the subgroup of patients with atherosclerotic cardiovascular disease (ASCVD) because of the known benefit of GLP-1 RA use for this population. This was a retrospective cohort analysis using data from OptumInsight Clinformatics Data Mart of commercially insured adult patients with T2D (with or without ASCVD) in the US. Data from October 1, 2015, to June 31, 2019, were included, and the analyses were performed in July 2020. We estimated multivariable logistic regression models to identify the association of race, ethnicity, sex, and socioeconomic status with GLP-1 RA use. A prescription for a GLP-1 RA. Of the 1 180 260 patients with T2D (median [IQR] age, 69 [59-76] years; 50.3% female; 57.7% White), 90 934 (7.7%) were treated with GLP-1 RA during the study period. From 2015 to 2019, the percentage of T2D patients treated with an GLP-1 RA increased from 3.2% to 10.7%. Among patients with T2D and ASCVD, use also increased but remained low (2.8%-9.4%). In multivariable analyses, lower rates of GLP-1 RA use were found among Asian (aOR, 0.59; 95% CI, 0.56-0.62), Black (adjusted odds ratio [aOR] 0.81; 95% CI, 0.79-0.83), and Hispanic (aOR, 0.91; 95% CI, 0.88-0.93) patients with T2D. Female sex (aOR, 1.22; 95% CI, 1.20-1.24) and higher zip code-linked median household incomes (>$100 000 [OR, 1.13; 95% CI, 1.11-1.16] and $50 000-$99 999 [OR, 1.07; 95% CI, 1.05-1.09] vs <$50 000) were associated with higher GLP-1 RA use. These results were similar to those found among patients with ASCVD. In this cohort study of US patients with T2D, GLP-1 RA use increased, but remained low overall for treatment of T2D, particularly among patients with ASCVD who are likely to derive the most benefit. Asian, Black, and Hispanic patients and those with low income were less likely to receive treatment with a GLP-1 RA. Strategies to lower barriers to GLP-1 RA use, such as lower cost, are needed to prevent the widening of well-documented inequities in cardiovascular disease outcomes in the US.


Mathematical performance before, during, and following cycling at workloads of low and moderate intensity.
Mental arithmetic performance before, during, and following low (40% maximal heart-rate reserve; approximately 90 watts exercise for 15 min.) and moderate (60% maximal heart-rate reserve; approximately 150 watts exercise for 10 min.) intensity cycling by 20 male students (M age = 28.1 yr.) was studied. Subjects were grouped, by using a median-split on their total mathematical performance scores, into a group of 10 low in arithmetic skill and a group of 10 high in arithmetic skill. The numbers and percentages of right answers to 1-min. mathematical problem-sets of either group were not different in the various conditions, suggesting that 25 min. of progressive cycling exercise did not influence mathematical problem-solving efficacy.


Relationship between intraventricular hemorrhage and acute kidney injury in premature infants and its effect on neonatal mortality.
Intraventricular hemorrhage (IVH) and acute kidney injury (AKI) are important neonatal morbidities in premature infants. This study aimed to investigate the relationship between IVH and AKI in premature infants and whether this association affects the incidence of neonatal mortality. Infants [gestational age (GA) ≤ 32 weeks; birth weight (BW) < 1500 g] were retrospectively evaluated in a large tertiary neonatal intensive care unit. Of 710 premature infants, 268 (37.7%) developed AKI. Infants with IVH were more likely to have AKI than those without IVH. Infants with severe IVH had a higher incidence of AKI than infants with mild IVH. Infants younger than 28 weeks with IVH were more likely to have AKI than those without IVH. An association between IVH grades and AKI stages was observed in the overall study population, in infants with GA < 28 weeks, and in infants with GA between 28 and 32 weeks. Mortality was increased 1.5 times in infants with IVH and AKI compared with that in infants with IVH but without AKI. Furthermore, mortality was increased in infants with IVH and AKI compared with infants without IVH or AKI. This study shows a direct relationship between the severity of IVH and the degree of AKI; both IVH and AKI increase the incidence of neonatal mortality.


Marsupialization of intramyocardial left anterior descending artery: a novel approach for easy access during revascularization.
The left anterior descending (LAD) artery is the most important vessel bypassed during coronary revascularization procedures. This artery usually runs a superficial course, making it easy for localization and grafting. However, many times it takes a course deep in the myocardium or is embedded in thick epicardial fat, which results in technical challenges to the surgeon for localization and grafting. So far, many techniques are described for overcoming these problems, but all require cardiopulmonary bypass (CPB), and in fact, intramyocardial LAD is considered a relative contraindication for off-pump coronary artery bypass grafting (OPCAB). In the present era of enhanced interest in OPCAB, these techniques are not as helpful as they are for conventional CABG with CPB. Here, we describe a novel approach of marsupialization of the LAD for revascularization of intramyocardial LAD that is useful for off-pump as well as conventional revascularization procedures and makes grafting simple and reproducible.


General one-pot strategy to prepare multifunctional nanocomposites with hydrophilic colloidal nanoparticles core/mesoporous silica shell structure.
A general and facile strategy was developed to coat hydrophilic inorganic nanoparticles directly with mesoporous silica nanoparticles (MSNs). The cationic surfactant of cetyltrimethylammonium bromide (CTAB) was adsorbed to various negatively charged CdTe quantum dots, Fe(3)O(4) nanocrystals or Au nanoparticles, introducing the bilayer of CTAB overcoating with positive charge. The subsequent sol-gel reaction of TEOS with the basic catalyst resulted in uniform nanocomposites. The concentration of CTAB and NH(4)OH in the recipe strongly influenced the number of inorganic nanoparticles in the nanocomposites and the homogeneity of MSNs shell. One dimensional Au nanorods and larger size of solid SiO(2) nanoparticles were also able to coat with MSNs using a similar synthetic procedure. The proposed method was greatly simplified without the help of any mediators or silane coupling agents and excellent mesostructural performance was readily achieved. Compared to the methods known from the literatures for the coating of hydrophobic nanoparticles, this efficient way is especially useful for trapping different hydrophilic nanoparticles with arbitrary sizes and shapes into MSNs. These highly versatile multifunctional nanocomposites, together with the pH-responsible drug release behaviors, non-toxicity to normal cells and ease of uptake into cancer cells, are expected to be utilized as drug delivery system for simultaneous imaging and therapeutic applications.


Benefits of a new Metropolis-Hasting based algorithm, in non-linear regression for estimation of ex vivo antimalarial sensitivity in patients infected with two strains.
Malaria is one of the world׳s most widespread parasitic diseases. The parasitic protozoans of the genus Plasmodium have developed resistance to several antimalarial drugs. Some patients are therefore infected by two or more strains with different levels of antimalarial drug sensitivity. We previously developed a model to estimate the drug concentration (IC50) that inhibits 50% of the growth of the parasite isolated from a patient infected with one strain. We propose here a new Two-Slopes model for patients infected by two strains. This model involves four parameters: the proportion of each strain and their IC50, and the sigmoidicity parameter. To estimate the parameters of this model, we have developed a new algorithm called PGBO (Population Genetics-Based Optimizer). It is based on the Metropolis-Hasting algorithm and is implemented in the statistical software R. We performed a simulation study and defined three evaluation criteria to evaluate its properties and compare it with three other algorithms (Gauss-Newton, Levenberg-Marquardt, and a simulated annealing). We also evaluated it using in vitro data and three ex vivo datasets from the French Malaria Reference Center. Our evaluation criteria in the simulation show that PGBO gives good estimates of the parameters even if the concentration design is poor. Moreover, our algorithm is less sensitive than Gauss-Newton algorithms to initial values. Although parameter estimation is good, interpretation of the results can be difficult if the proportion of the second strain is close to 0 or 1. For these reasons, this approach cannot yet be implemented routinely.


Mitomycin as adjunct chemotherapy with trabeculectomy.
Preliminary experience is reported in using mitomycin to improve the prognosis in trabeculectomy operations considered otherwise likely not to succeed. The medication is applied intraoperatively during an otherwise standard trabeculectomy procedure. Surgery was considered successful if the pressure was lowered to a predetermined target level, the only vision reduction was believed to be on the basis of cataract development, and there was no progression of cupping or visual field loss. With a follow-up of 6 to 42 months, the overall success rate is 84%.


Trends in Lung Cancer and Cigarette Smoking: California Compared to the Rest of the United States.
Three cigarette smoking behaviors influence lung cancer rates: how many people start, the amount they smoke, and the age they quit. California has reduced smoking faster than the rest of the United States and trends in these three smoking behaviors should inform lung cancer trends. We examined trends in smoking behavior (initiation, intensity, and quitting) in California and the rest of United States by regression models using the 1974-2014 National Health Interview Surveys (n = 962,174). Lung cancer mortality data for 1970-2013 was obtained from the National Surveillance, Epidemiology, and End Results (SEER) Program. Among those aged 18 to 35 years, California had much larger declines than the rest of the United States in smoking initiation and intensity, and increased quitting. In 2012-2014, among this age group, only 18.6% [95% confidence interval (CI), 16.8%-20.3%] had ever smoked; smokers consumed only 6.3 cigarettes/day (95% CI, 5.6-7.0); and 45.7% (95% CI, 41.1%-50.4%) of ever-smokers had quit by age 35. Each of these metrics was at least 24% better than in the rest of the United States. There was no marked California effect on quitting or intensity among seniors. From 1986 to 2013, annual lung cancer mortality decreased more rapidly in California and by 2013 was 28% lower (62.6 vs. 87.5/100,000) than in the rest of the United States. California's tobacco control efforts were associated with a major reduction in cigarette smoking among those under age 35 years. These changes will further widen the lung cancer gap that already exists between California and the rest of the United States.


Insomnia in Tourette Syndrome and Chronic Tic Disorder.
Insomnia is common in Tourette syndrome (TS) and chronic tic disorder (CTD), but precise prevalence estimates are lacking. In this Swedish register-based cohort study, we estimated the prevalence of insomnia in TS/CTD and quantified the magnitude of this association, accounting for familial confounders and relevant somatic and psychiatric comorbidities. Of 10,444,702 individuals living in Sweden during the period from 1997 to 2013, 5877 had a diagnosis of TS/CTD and were compared to unexposed individuals from the general population on the presence of insomnia using logistic regression models. Individuals with TS/CTD had a period prevalence of insomnia of 32.16%, compared to 13.70% of the unexposed population. This translated into a 6.7-fold increased likelihood of insomnia in TS/CTD (odds ratio adjusted [aOR] for sex, birth year, birth country, and somatic disorders = 6.74; 95% confidence interval [CI], 6.37-7.15). A full sibling comparison, designed to adjust for shared familial factors, attenuated the estimates (aOR = 5.41; 95% CI, 4.65-6.30). When individuals with attention-deficit/hyperactivity disorder (ADHD) and pervasive developmental disorders were excluded, the association was also attenuated, whereas exclusion of other psychiatric comorbidities had minimal impact. Having persistent TS/CTD, comorbid ADHD, and taking ADHD medication greatly increased the likelihood of insomnia. Insomnia is significantly associated with TS/CTD, independently from somatic disorders, familial factors or psychiatric comorbidities, although familial factors, neurodevelopmental comorbidities, and ADHD/ADHD medication may explain part of the association. Insomnia should be routinely assessed and managed in TS/CTD, particularly in chronic patients and in those with comorbid ADHD. Other sleep disorders require further study. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Structural basis of homo- and heterotrimerization of collagen I.
Fibrillar collagen molecules are synthesized as precursors, procollagens, with large propeptide extensions. While a homotrimeric form (three α1 chains) has been reported in embryonic tissues as well as in diseases (cancer, fibrosis, genetic disorders), collagen type I usually occurs as a heterotrimer (two α1 chains and one α2 chain). Inside the cell, the role of the C-terminal propeptides is to gather together the correct combination of three α chains during molecular assembly, but how this occurs for different forms of the same collagen type is so far unknown. Here, by structural and mutagenic analysis, we identify key amino acid residues in the α1 and α2 C-propeptides that determine homo- and heterotrimerization. A naturally occurring mutation in one of these alters the homo/heterotrimer balance. These results show how the C-propeptide of the α2 chain has specifically evolved to permit the appearance of heterotrimeric collagen I, the major extracellular building block among the metazoa.


Childhood enuresis.
Enuresis is not a disease, but rather a benign clinical disorder that is very common in young children. In considering the many facets of enuresis, physicians caring for children with this disorder should always remember the dictum "Primum non nocere". Most children with enuresis will be found to have primary enuresis, that is, no organic disease or psychopathology will be found. Physicians should proceed cautiously and should avoid costly, harmful and unnecessary workups. Treatment of few disorders is more dependent on the art and skill of clinical medicine than that of childhood enuresis. All of the physician's talents and compassionate nature enter into the proper evaluation of and therapy for this disorder. Physicians must keep in mind the high spontaneous cure rate. This factor alone should encourage them to be extremely optimistic about the outcome of enuresis in their pateints.


Jacob's disease: report of a rare case and literature review.
Jacob's disease is a rare condition consisting of pseudojoint formation between enlarged coronoid process and the inner surface of the zygoma. The authors report a 45-year-old female patient who presented with limited mouth opening (5 mm) and swelling of the left zygoma. No temporomandibular joint disease was diagnosed. 3D computed tomography images showed a mushroom-shaped coronoid growth with pseudojoint formation medial and superior to the zygomatic arch. Under general anaesthesia, coronoidectomy was carried out through a combined extraoral and intraoral approach. Histopathological examination revealed normal trabecular bone covered with hyaline cartilage. To the best of the authors' knowledge this case is the fifth typical mushroom-shaped Jacob's disease; only four similar cases have been reported. A review of the literature revealed only 39 histologically proved cases of Jacob's disease cases up to 2010. Aggressive physical treatment was given to improve function and maximum mouth opening, which had increased to 40 mm at 3 months follow-up. The literature concerning this condition's aetiology, pathogenesis, clinical characteristics, diagnosis, and treatment is reviewed.


Temporal trends in pulse pressure and mean arterial pressure in Chinese children and adolescents over two decades (1991-2015).
Pulse pressure (PP) and mean arterial pressure (MAP) are well-established markers of cardiovascular risk. In this study, we aimed to assess the temporal trend and associated factors of PP and MAP in Chinese children and adolescents. From the China Health and Nutrition Survey 1991-2015, a total of 11,123 children and adolescents aged 7-17 years were included. Stratified analyses and generalized estimating equation (GEE) were conducted to compare the trends of PP and MAP by age and sex over two decades, along with the calculation of average relative increase (ARI). Moreover, multivariable linear regression was used to estimate the associated factors of PP and MAP. During 1991-2015, upward trends were observed in both PP and MAP levels, with ARI of 0.30 and 0.34%, respectively. PP was higher in boys [PP1991 33.9 mmHg (95%CI, 33.40-34.33) to PP2015 35.4 mmHg (34.74-36.15)] than in girls [PP1991 33.3 mmHg (32.83-33.72) to PP2015 34.3 mmHg (33.59-34.99)]. PP was also higher in participants aged 13-17 years [PP1991 36.1 mmHg (35.63-36.62) to PP2015 38.3 mmHg (37.35-39.21)] than in those aged 7-12 years [PP1991 31.5 mmHg (31.09-31.88) to PP2015 33.7 mmHg (33.16-34.30)]. Similar results were found in MAP. Participants with high economic status, general obesity and central obesity, were more likely to have wider PP (β higheconomicstatus = 0.60, 95% CI, 0.19-1.02; β generalobesity = 1.38, 0.87-1.89; β centralobesity = 1.34, 0.70-1.97; all P-values < 0.001) and higher MAP (β higheconomicstatus = 0.82, 0.38-1.26; β generalobesity = 2.88, 2.33-3.42; β centralobesity = 3.14, 2.47-3.80; all P-values < 0.001). Body mass index (BMI) and waist circumference (WC) were positively correlated with PP (β BMI = 0.18, 0.13-0.24; β WC = 0.10, 0.08-0.12; both P-values < 0.001) and MAP (β BMI = 0.43, 0.37-0.49; β WC = 0.20, 0.18-0.22; both P-values < 0.001). In addition, rural setting and glucose level were positively associated with PP (both P < 0.05), while north region residency, uric acid, and total cholesterol were found to be positively associated with MAP (all P < 0.05). PP and MAP levels have been increasing dramatically in Chinese children and adolescents over the last two decades. Age, sex, economic status, geographic factors, anthropometric and cardiometabolic factor were positively associated with PP and MAP in pediatric population.


Effect of yohimbine on the development of morphine dependence in the rat: lack of involvement of cortical beta-adrenoceptor modifications.
The alpha-2 receptor antagonist yohimbine has been previously shown to prevent the development of morphine dependence in a rat behavioral model. This study was directed to clarify the mechanism of this interaction, which is presently unknown. Since upregulation of cortical beta-adrenoceptors has been suggested to be involved in morphine withdrawal, we have tested the possible correlation between receptor density and withdrawal behaviors in the presence of yohimbine. Sprague-Dawley male rats received a s.c. suspension of morphine (300 mg/kg) or the vehicle. Animals received saline or yohimbine (4 mg/kg, IP) 24, 28, 48 and 52 h after morphine and finally naloxone (1 mg/kg i.p) at 72 h; the subsequent signs of withdrawal (mainly wet-dog shakes and escape attempts) were recorded and the cerebral cortex dissected to study [3H]-CGP 12177 binding. Morphine-treated animals displayed a marked withdrawal behavior together with beta-adrenoceptor upregulation; nevertheless, these effects were not correlated. As expected, yohimbine prevented morphine withdrawal behavior but did not reverse the beta-adrenoceptor upregulation induced by the opiate. These results confirm previous evidence against the involvement of beta-adrenoceptor upregulation on morphine withdrawal behaviors and also permit to discard beta-adrenoceptor regulation as the neurochemical basis of the antiwithdrawal effect of yohimbine. The possible contribution of some other neurochemical effects of yohimbine are discussed to explain the inhibition of morphine dependence by that drug.


Plasmodium falciparum sporozoite invasion is inhibited by naturally acquired or experimentally induced polyclonal antibodies to the STARP antigen.
Antibody(Ab)-mediated inhibition of sporozoite invasion of hepatocytes is a mechanism that has been clearly demonstrated to act upon Plasmodium falciparum pre-erythrocytic stages in humans. Consequently we have analyzed the Ab response to a recently identified P. falciparum sporozoite surface protein, STARP, in malaria-exposed individuals and tested the inhibitory effect of these Ab upon hepatocyte invasion in vitro. STARP-specific IgG were detected in 90 and 61% of sera from regions where individuals were exposed to 100 and 1-5 infectious bites per year, respectively. These IgG were predominantly of the cytophilic IgG1 or IgG3 type. STARP and the major sporozoite surface protein, CS, elicited equivalent IgG levels in adults. When affinity purified from either African immune sera or the serum of an individual experimentally protected by irradiated sporozoite immunization, STARP-specific Ab prevented up to 90% of sporozoites from invading human hepatocytes. The dose-dependent and reproducible inhibition was more pronounced than that observed with human CS-specific Ab affinity purified under identical conditions. Substantial reduction of sporozoite invasion was also observed with Ab induced by artificial immunization with recombinant STARP protein and reactive with the native protein. Taken together with recent findings of human cytotoxic T lymphocytes specific for this antigen, these results promote the interest of studying the efficacy of STARP as a target for immune effector mechanisms operating upon pre-erythrocytic stages.


Deafening noise down-regulates dopamine transmission in the hub of the central auditory system.
The cumulative effects of noise are experienced across society regardless of occupation and age. Previous research has connected noise induced hearing disorders to neuronal changes within auditory brain regions, such as the inferior colliculus (IC), where the ascending and descending auditory neurons converge. Nevertheless, the neurochemical adaptations in the central auditory system underlining these disorders are not fully understood. Based on existing body of evidence that implicates dopamine (DA) in the central auditory processes, we hypothesized that alteration in the DA neurotransmission in the IC is a major neuroadaptation associated with noise-induced hearing loss. Using adult Sprague Dawley rat model in conjunction with an electrochemical method and immunoassay, this hypothesis was explored by characterizing the impact of noise on the DA system in the IC. Herein, slice fast scan cyclic voltammetry (FSCV) data revealed attenuation in stimulated DA release in the subjects exposed to deafening noise (10 kHz, 118 dB SPL, 1/3 octave band noise for 4 h) 24 h prior to the neurochemical measurements. DA receptor 2 (D2) functionality was also investigated as part of a possible negative feedback mechanism for the noise induced alteration, however no significant difference was observed between the noise exposed versus the control subjects. On the other hand, immunocytochemistry of the IC displayed marked difference in D2 receptor distributions overall and specifically, in the central and external nucleus of the IC. Taken together, these data link decrease DA neurotransmission in the IC to noise-induced hearing loss and show that while deafening noise does not directly impact the functionality of the D2 receptors, it does diminish the receptor density. Overall, these changes in the IC were demonstrated to be long-term and could be mediated by oxidative stress.


Demographic Analysis of Pedicle Diameter, and Estimated Pedicle Screw Length of the Lumbar Spine in a Diverse Population.
Recent literature confirms the importance of understanding the variability in pedicle morphology among races. These studies suggest that more detailed and reliable measurements of pedicles should be undertaken. However, there is limited data on average pedicle diameters (PDs) or estimated pedicle screw lengths (EPSLs) between diverse racial populations. We sought to determine the differences in PD and EPSL in the lumbar spine between various races: "Asian," "Black," "White," and "Hispanic" to aid in perioperative planning during instrumented spinal fusion. Axial cuts of 404 patients were inspected to obtain their transverse outer cortical PD as measured through the isthmus, and EPSL by measuring the posterior entry point at the longest distance, which perpendicularly transected the measured isthmic diameter, to the anterior vertebral cortex from L1 to L5. We examined the average PD and PD range at each level for each race. To determine the significance, we used a mixed analysis of variance and a post hoc analysis. In this retrospective chart review the races were found to be significantly different in PD and EPSL (P < .001). Post hoc analysis using Dunn-Bonferroni correction showed that Asians had significantly smaller PDs than Blacks and Whites (P < .002 and P < .014, respectively). The White and Hispanic population had significantly longer EPSLs when compared to Blacks and Asians from L1 to L5 (P < .01). This study demonstrates that there are significant differences in pedicle morphology among races that must be taken into consideration when inserting pedicle screws during lumbar spinal fusion. Knowledge of these differences is of the utmost importance in order to limit complications while improving fixation. 3. Pedicle morphology is variable between races and understanding these differences is important for the safe placement of pedicle screws.


Factors associated with weight loss during radiotherapy in patients with stage I or II head and neck cancer.
The purpose of the study was to identify factors associated with weight loss during radiotherapy (RT) in patients with stage I or II head and neck (HN) cancer. This study was conducted as part of a phase III chemoprevention trial. A total of 540 patients were randomized. The patients were weighed before and after RT. Patients' characteristics, dietary intake, health-related quality of life (HRQOL), tumor characteristic, treatment characteristics, and acute adverse effects of RT were evaluated at baseline and during RT. Factors independently associated with weight loss during RT were identified using the multiple linear regression (P ≤ 0.05). The mean weight loss during RT was 2.2 kg (standard deviation, 3.4). In bivariate analyses, the occurrence of adverse effects of RT and most of the HRQOL dimensions evaluated during RT were correlated with weight loss. In the multivariate analysis, eight factors were associated with a greater weight loss: all HN cancer sites other than the glottic larynx (P < 0.001), TNM stage II disease (P = 0.01), higher pre-RT body weight (P < 0.001), dysphagia before RT (P < 0.005), higher mucosa adverse effect of RT (P = 0.03), lower dietary energy intake during RT (P < 0.001), lower score of the digestive dimension on the Head and Neck Radiotherapy Questionnaire (P < 0.001) and a higher score of the constipation symptom on the EORTC QLQ-C30 during RT (P = 0.02). The results underline the importance of maintaining energy intake in early stage HN cancer patients during RT and the importance of preventing and treating adverse effects.


Dexmedetomidine inhibits the growth and metastasis of esophageal cancer cells by down-regulation of lncRNA MALAT1.
This study aims to evaluate the effect of dexmedetomidine (DEX)-on esophageal cancer (EC) via regulating long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). The effect of DEX on MALAT1 expression and EC cell viability was detected. EC cells were divided into Blank, DEX, scrambled/MALAT1 siRNA, and DEX + control/MALAT1 groups, followed by a series of experiments including quantitative reverse-transcription polymerase chain reaction (qRT-PCR), western blotting, 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT), Annexin V-FITC/PI staining, wound healing, and Transwell assays. Additionally, mice were subjected to the subcutaneous injection of Eca109 cells transfected by control/MALAT1 activation lentiviral vector to construct EC models with the DEX treatment, and then the tumor volume and the expression of Ki-67 and active caspase-3 were determined. DEX reduced the expression of MALAT1 in EC cells in a dose-dependent manner. DEX inhibited the viability of EC cells, but increased the cell apoptosis, which, however, was reversed by MALAT1 overexpression. Moreover, MALAT1 overexpression abolished the inhibitory effect of DEX on the epithelial-mesenchymal transition (EMT) of EC cells, with enhanced migration and invasion. Furthermore, DEX succeeded in decreasing the tumor volume with the down-regulation of MALAT1. In comparison with the DEX group, mice in the DEX + MALAT1 group had larger tumors, with the up-regulation of Ki-67 and the down-regulation of active caspase-3. DEX can reduce the expression of MALAT1 in EC cells, thereby inhibiting the proliferation, invasion and migration, as well as EMT, and promoting the apoptosis of EC cells.


Prevalence of skin and other cancers in patients with psoriasis.
The prevalence of skin and internal malignancies was estimated from the general practitioners' notes of 2247 patients with psoriasis and 4494 age- and sex-matched controls. The prevalence of skin cancer in the psoriatics was 155% that of controls, but this was not significant at the 5% level. Subgroup analysis showed an increase in skin cancers in women (P < 0.05). There was no difference in the age of onset of skin cancers between psoriatics and controls and there was no evidence of a cumulative therapeutic risk. There was no difference in the prevalence of non-skin cancers between psoriatics and controls.


A Chemiluminescent Tetraaryl Diborane(4) Tetraanion.
Two subvalent, redox-active diborane(4) anions, [3]4- and [3]2- , carrying exceptionally high negative charge densities are reported: Reduction of 9-methoxy-9-borafluorene with Li granules without stirring leads to the crystallization of the B(sp3 )-B(sp2 ) diborane(5) anion salt Li[5]. [5]- contains a 2,2'-biphenyldiyl-bridged B-B core, a chelating 2,2'-biphenyldiyl moiety, and a MeO substituent. Reduction of Li[5] with Na metal gives the Na+ salt of the tetraanion [3]4- in which two doubly reduced 9-borafluorenyl fragments are linked via a B-B single bond. Comproportionation of Li[5] and Na4 [3] quantitatively furnishes the diborane(4) dianion salt Na2 [3], the doubly boron-doped congener of 9,9'-bis(fluorenylidene). Under acid catalysis, Na2 [3] undergoes a formal Stone-Wales rearrangement to yield a dibenzo[g,p]chrysene derivative with B=B core. Na2 [3] shows boron-centered nucleophilicity toward n-butyl chloride. Na4 [3] produces bright blue chemiluminescence when exposed to air.


Copper alters hypoxia sensitivity and the behavioural emersion response in the amphibious fish Kryptolebias marmoratus.
Elevated levels of metals have been reported in mangrove ecosystems worldwide. Mangrove fishes also routinely experience severe environmental stressors, such as hypoxia. In the amphibious fish Kryptolebias marmoratus (mangrove rivulus), a key behavioural response to avoid aquatic stress is to leave water (emersion). We hypothesized that copper (Cu) exposure would increase the sensitivity of this behavioural hypoxia avoidance response due to histopathological effects of Cu on gill structure and function. K. marmoratus were exposed to either control (no added Cu) or Cu (300μg/L) for 96h. Following this period, fish were exposed to an acute hypoxic challenge (decline in dissolved oxygen to ∼0% over 15min), and the emersion response was recorded. Gills were examined for histological changes. Fish exposed to Cu emersed at a higher dissolved oxygen level (7.5±0.6%), relative to the control treatment group (5.8±0.4%). Histological analysis showed that the gill surface area increased and the interlamellar cell mass (ILCM) was reduced following Cu exposure, contrary to our prediction. Overall, these data indicate that Cu induces hypoxia-like changes to gill morphology and increases the sensitivity of the hypoxia emersion response.


Acid diffusion through rat duodenal mucosal cap.
Acid induced duodenal injury occurs immediately following exposure to strong acid but does not worsen despite continuous perfusion with the acid. A thick gelatinous cap is found overlying the duodenum when examined histologically. The purpose of this study was to quantitate the resistance to acid diffusion by native duodenal mucus and the cap material. Rat duodenum was perfused with acid. The mucus from control and acid-perfused animals was harvested and the diffusion coefficient measured. Mucus from the duodenums of anesthetized rats was mixed with bromphenol blue and placed into capillary tubes. The tubes were submersed in 0.15 N HCI at 37 degrees C. The color change from blue to yellow was measured with time as the HCl migrated through the tube. From the distance and time data, the diffusion coefficient could be calculated. Controls of bromphenol blue in water were studied. The diffusion coefficient for HCl in water was 30.1+/-0.9 x 10(-6) cm2/sec, nearly identical to the standard value reported in the literature. For the duodenal mucus adherent to the epithelial surface, it was 1.1+/-0.1 x 10(-6) cm2/sec. Following perfusion with 0.15 N HCl, a 279.6+/-44-microm-thick mucus cap formed over the duodenum that had a diffusion coefficient of 1.8+/-.3 x 10(-8) cm2/sec. In response to injury, the duodenum protects against continued damage by producing a mucoid cap that it highly resistant to acid diffusion.


A missing link in thymic dendritic cell development.
Negative selection in the thymus prevents the generation of self-reactive T cells through the deletion of thymocytes with high affinity for self-antigens. Within the thymus, self-antigens are presented by thymic epithelial cells and DCs. Both cell types can mediate negative selection, although the relative contribution of each cell type remains elusive. Similar to DCs of other lymphoid organs, thymic DCs come in different flavors. Over the past years, various lines of evidence have emerged that either favor a common origin for some thymic DCs and thymocytes or, conversely, indicate the existence of separate intrathymic T lineage and DC precursors. In this issue of the European Journal of Immunology, a study reports the identification of an intrathymic DC precursor that is likely to be unrelated to the earliest physiological T-cell progenitors. Thus this intrathymic DC precursor may constitute a "missing link" between extrathymic DC precursor-types, which are able to generate DCs in secondary lymphoid organs and intrathymic DCs, and supports the notion that intrathymic DCs and thymocytes arise from different precursors.


Pathological mechanisms of cigarette smoking, dietary, and sedentary lifestyle risks in vascular dysfunction: mitochondria as a common target of risk factors.
In the past century, the lifespan of the human population has dramatically increased to the 80 s, but it is hindered by a limited health span to the 60 s due to an epidemic increase in the cardiovascular disease which is a main cause of morbidity and mortality. We cannot underestimate the progress in understanding the major cardiovascular risk factors which include cigarette smoking, dietary, and sedentary lifestyle risks. Despite their clinical significance, these modifiable risk factors are still the major contributors to cardiovascular disease. It is, therefore, important to understand the specific molecular mechanisms behind their pathological effects to develop new therapies to improve the treatment of cardiovascular disease. In recent years, our group and others have made a progress in understanding how these risk factors can promote endothelial dysfunction, smooth muscle dysregulation, vascular inflammation, hypertension, lung, and heart diseases. These factors, despite differences in their nature, lead to stereotypical alterations in vascular metabolism and function. Interestingly, cigarette smoking has a tremendous impact on a very distant site from the initial epithelial exposure, namely circulation and vascular cells mediated by a variety of stable cigarette smoke components which promote vascular oxidative stress and alter vascular metabolism and function. Similarly, dietary and sedentary lifestyle risks facilitate vascular cell metabolic reprogramming promoting vascular oxidative stress and dysfunction. Mitochondria are critical in cellular metabolism, and in this work, we discuss a new concept that mitochondria are a common pathobiological target for these risk factors, and mitochondria-targeted treatments may have a therapeutic effect in the patients with cardiovascular disease.


Preparation of the Partially Methylated Alditol Acetates Derived from CS Tetrasaccharides Containing Galactose for the Gas Chromatography/Mass Spectrometry Analysis.
Chondroitin sulfate (CS), a member of the glycosaminoglycan (GAG) family of carbohydrates, is composed of linear, sulfated repeating disaccharide sequences of N-acetyl-D-galactosamine (GalNAc) and glucuronic acid (GlcA). Recently, a keratan sulfate (KS) disaccharide [GlcNAc6S(β1-3)Galactose(β1-]-branched CS-E was identified from the clam species M. chinensis. This protocol details a methodology to analyze the glycosidic linkages of galactose in KS disaccharide-branched CS by GC-MS analysis. A complementary method for the identification and characterization of KS-branched CS in M. chinensis can be found in Higashi et al. (2016).


The Role of Amyloid-β, Tau, and α-Synuclein Proteins as Putative Blood Biomarkers in Patients with Cerebral Amyloid Angiopathy.
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β protein (Aβ) within brain blood vessels that develops in elderly people and Alzheimer's disease (AD) patients. Therefore, the investigation of biomarkers able to differentiate CAA patients from AD patients and healthy controls (HC) is of great interest, in particular in peripheral fluids. The current study aimed to detect the neurodegenerative disease (ND)-related protein (i.e., Aβ1-40, Aβ1-42, tau, and α-synuclein) levels in both red blood cells (RBCs) and plasma of CAA patients and HC, evaluating their role as putative peripheral biomarkers for CAA. For this purpose, the proteins' concentration was quantified in RBCs and plasma by homemade immunoenzymatic assays in an exploratory cohort of 20 CAA patients and 20 HC. The results highlighted a significant increase of Aβ1-40 and α-synuclein concentrations in both RBCs and plasma of CAA patients, while higher Aβ1-42 and t-tau levels were detected only in RBCs of CAA individuals compared to HC. Moreover, Aβ1-42/Aβ1-40 ratio increased in RBCs and decreased in plasma of CAA patients. The role of these proteins as candidate peripheral biomarkers easily measurable with a blood sample in CAA needs to be confirmed in larger studies. In conclusion, we provide evidence concerning the possible use of blood biomarkers for contributing to CAA diagnosis and differentiation from other NDs.


Radiation Therapy for Painful Bone Metastases: Fractionation, Recalcification, and Symptom Control.
Bone is a common site for metastases, which may cause pain and other skeletal-related events (SRE) in patients with advanced cancer. Since the 1980s, prospective clinical trials have demonstrated the high efficacy of external beam radiotherapy (EBRT) for pain relief from focal, symptomatic lesions. In uncomplicated bone metastases, which include those without pathologic fracture, evidence of cord compression, or prior surgical intervention, improvement or complete pain relief with radiotherapy is as high as 60%, with no difference in efficacy when radiotherapy is delivered in a single or multiple fractions. The ability to treat with a single fraction makes EBRT an attractive therapy even for patients with poor performance status and/or life expectancy. Even in patients with complicated bone metastases (eg cord compression), several randomized trials have demonstrated similar rates of pain relief in addition to improved functional outcomes such as ambulation. In this review, we summarize the role of EBRT for alleviating painful bone metastases and explore its role for other endpoints including functional outcomes, recalcification, and prevention of SREs.


High sensitivity to site directed mutagenesis of the peptide segment connecting phosphorylation and Ca2+ binding domains in the Ca2+ transport ATPase.
Nine residues (Leu321, Lys329, Asn330, Val333, Arg334, Leu336, Pro337, Val339 and Glu340), within the peptide segment intervening between the catalytic domain and the Ca2+ binding domain of the sarcoplasmic reticulum (SERCA 1) ATPase, were individually mutated to Ala. The mutated proteins were recovered in the microsomal fraction of COS-1 cells following transient expression, and exhibited inhibition of Ca2+ uptake and ATPase hydrolytic activity, while forming discernable levels of phosphorylated intermediate. Mutation of Glu340 to Gln (rather than to Ala) was much less effective, suggesting that the functional consequence of the mutation is related to structural perturbation, rather than loss of the acidic side chain. The high sensitivity of this peptide segment to single mutations suggests that its structural integrity is required for functional linkage of the phosphorylation and Ca2+ binding domains.


Feasibility of high-intensity interval training with hyperoxia vs. intermittent hyperoxia and hypoxia in cancer patients undergoing chemotherapy - Study protocol of a randomized controlled trial.
Exercise has been well demonstrated to potentially reduce chemotherapy-induced side effects and possibly aid slowing down tumor growth in cancer patients but exercise training adherence is typically low. Thus, training regimens which are perceived less strenuous but do not compromise the training-induced beneficial adaptations will help to increase adherence to exercise and reduce attrition. This 4-armed study aims to investigate the effects of high intensity interval training (HIIT) in hyperoxia versus intermittent hyperoxia and hypoxia in cancer patients undergoing chemotherapy. Forty-eight cancer patients will be randomized into either of three intervention groups or a no-training control group. Patients in the intervention groups will perform twice weekly HIIT on a cycle ergometer in hyperoxia, intermittent hyperoxia and hypoxia or normoxia. Study outcomes will be assessed before and after 4 weeks of training, while selected measures will also be performed pre- and post the first and last training session. The primary aim of this study is to investigate the feasibility, compliance, tolerance and safety of the training. Secondary endpoints will include measures of quality of life, aerobic capacity, transcutaneous oxygen saturation, red blood cell deformability, as well as the assessment of anabolic and catabolic hormone concentrations, reactive oxygen species, cytokine profiles and NK-cell cytotoxicity. To the best of our knowledge, this is the first study investigating the combined effects of exercise with modified fraction of inspired O2 in cancer patients. As such, we provide a novel approach for exercise as an adjuvant therapy in cancer patients undergoing chemotherapy.


Ultrafast hot-hole injection modifies hot-electron dynamics in Au/p-GaN heterostructures.
A fundamental understanding of hot-carrier dynamics in photo-excited metal nanostructures is needed to unlock their potential for photodetection and photocatalysis. Despite numerous studies on the ultrafast dynamics of hot electrons, so far, the temporal evolution of hot holes in metal-semiconductor heterostructures remains unknown. Here, we report ultrafast (t < 200 fs) hot-hole injection from Au nanoparticles into the valence band of p-type GaN. The removal of hot holes from below the Au Fermi level is observed to substantially alter the thermalization dynamics of hot electrons, reducing the peak electronic temperature and the electron-phonon coupling time of the Au nanoparticles. First-principles calculations reveal that hot-hole injection modifies the relaxation dynamics of hot electrons in Au nanoparticles by modulating the electronic structure of the metal on timescales commensurate with electron-electron scattering. These results advance our understanding of hot-hole dynamics in metal-semiconductor heterostructures and offer additional strategies for manipulating the dynamics of hot carriers on ultrafast timescales.


Anthelmintics. Current concepts in the treatment of helminthic infections.
This article discusses the anthelmintics now in common use and describes their mode of action and toxic side effects. The drugs reviewed include: pyrantel pamoate, mebendazole, piperazine, thiabendazole, niclosamide, praziquantel, niridazole, oxamniquine and diethylcarbamazine. Most of the common roundworm intestinal infections respond to treatment with pyrantel pamoate, which has the advantage of single-dose therapy. Trichuriasis requires therapy with mebendazole, while the filariases are treated with diethylcarbamazine. There is no specific therapy for trichinellosis, but its symptoms can be alleviated. Intestinal cestode infections respond to treatment with niclosamide and cerebral cysticercosis to praziquantel, but echinococcal hydatid disease still requires surgical intervention in certain cases, although prolonged treatment with mebendazole shows promise. The greatest recent advance in the therapy of helminthiases is the development of praziquantel which effectively treats the most severe of these infections.


Upgraded Cobas Ampliprep-Cobas TaqMan version 2.0 HIV-1 RNA quantification assay versus first version: correction of underestimations.
The large underestimations of HIV RNA quantification observed in 17 patients with the first version of Cobas TaqMan assay have been successfully corrected in the upgraded version 2.0. In comparison with the Abbott RealTime assay, the mean difference that was 1.18 log(10) copies/ml is now zero. The discrepancies have disappeared.


Improvements in Parental Sleep, Fear of Hypoglycemia, and Diabetes Distress With Use of an Advanced Hybrid Closed-Loop System.
Parental sleep quality may contribute to glycemic control in youth with type 1 diabetes. In this article we present sleep analysis from a multicenter, randomized trial of children ages 6-13 years with type 1 diabetes evaluating the Tandem Control-IQ (CIQ) hybrid closed-loop (HCL) system. Pittsburgh Sleep Quality Index (PSQI) scores were assessed at baseline to identify parents as "poor" sleepers (PSQI >5). Glycemic and psycho-behavioral outcomes before and after CIQ use were analyzed in poor sleepers (n = 49) and their children. Nocturnal time in range (P < 0.001) and time hyperglycemic (P < 0.001), Hypoglycemia Fear Survey for Parents score (P < 0.001), Problem Areas in Diabetes scale score (P < 0.001), PSQI score (P < 0.001), and Hypoglycemia Fear Survey for Children score (P = 0.025) significantly improved. Of poor sleepers, 27 became good sleepers (PSQI score <5). Use of CIQ in youth with type 1 diabetes ages 6-13 years significantly improved sleep and psychosocial measures in parent poor sleepers, coinciding with improvements in child nocturnal glycemia, highlighting the relationship between HCL systems and parent sleep quality.


Accuracy of subjective measurements made with or without previous scores: an important source of error in serial measurement of subjective states.
Pain severity was assessed on visual analogue scale in 4 groups of patients receiving long-term therapy. A comparison was made between pain measurements made with and without access to initial scores. The differences between these measurements increased with the duration of treatment. Patients tended to overestimate their pain severity when previous scores were not available. It is suggested that initial scores should be made available when serial measurements of pain are made in long-term experiments.


Transfusion-related adverse reactions: Data from the National Healthcare Safety Network Hemovigilance Module - United States, 2013-2018.
Despite current blood safety measures, transfusion recipients can experience transfusion-related adverse reactions. Monitoring these reactions can aid in understanding the effectiveness of current transfusion safety measures. Data from the National Healthcare Safety Network Hemovigilance Module were used to quantify adverse reaction risk. Facilities reporting at least one month of transfused blood components and transfusion-related adverse reactions during January 2013-December 2018 were included. Adverse reaction rates (number per 100,000 components transfused) were calculated for transfused components stratified by component type, collection, and modification methods. During 2013-2018, 201 facilities reported 18,308 transfusion-related adverse reactions among 8.34 million blood components transfused (220/100,000). Adverse reactions were higher among apheresis (486/100,000) and pathogen-reduced platelets (579/100,000) than apheresis red blood cells (197/100,000). Allergic reactions (41%) were most common. There were 23 fatalities and 9% of all adverse reactions were serious (severe, life-threatening, or fatal). Reactions involving pulmonary complications (transfusion-associated circulatory overload, transfusion-related acute lung injury and transfusion-associated dyspnea) accounted for 35% of serious reactions but 65% of fatalities. Most (76%) of the 37 transfusion-transmitted infections were serious; none involved pathogen-reduced components. One in 455 blood components transfused was associated with an adverse reaction although the risk of serious reactions (1 in 6224) or transfusion-transmitted infections (1 in 225,440) was lower. Some serious reactions identified were preventable, suggesting additional safety measures may be beneficial. Higher reaction rates identified among pathogen-reduced platelets require further study. These findings highlight the importance of monitoring reactions through national hemovigilance to inform current safety measures and the need for strategies to increase healthcare facility participation.


The Diagnostic Utility of Growth Ultrasound for the Indication of Maternal Overweight or Obesity.
The objective of this study was to evaluate the diagnostic utility of serial growth ultrasounds for the indication of maternal overweight or obesity. This is a retrospective cohort study of all women with a body mass index ≥25 kg/m2 who underwent at least one growth ultrasound at ≥24 weeks gestation and delivered at a single tertiary care institution between January 2010 and December 2013. Women were excluded if they had other medical indications for growth ultrasounds. Ultrasounds were divided into three gestational age epochs: 24 to 316/7 weeks, 32 to 356/7 weeks, and ≥36 weeks. Outcomes examined included the accuracy of sonographic detection of fetal growth restriction (FGR) and fetal overgrowth compared with diagnoses of small for gestational age (SGA) and large for gestational age (LGA) based on the birth weight. The test characteristics of ultrasound and the number needed to screen (NNS) to detect growth abnormalities at the time of birth were estimated for each condition and gestational age epoch. The NNS for the detection of fluid abnormalities was also assessed. During the study period, 3,945 eligible sonograms were performed in 2,928 women. FGR was identified on ultrasound in 42 (1.4%) women, fetal overgrowth in 94 (3.2%) women, oligohydramnios in 35 (1.2%) women, and hydramnios in 41 (1.4%) women. The NNS for the diagnoses of SGA, LGA, oligohydramnios, and hydramnios at delivery was at least 137 prior to 32 weeks of gestation and decreased (i.e., at least 45 and 16, for 32 to 356/7 weeks and ≥36 weeks, respectively) with advancing gestational age epochs. If growth ultrasounds are to be performed for the sole indication of maternal overweight or obesity, consideration should be given to delaying initiation until at least 32 weeks of gestation given the infrequency of growth and fluid abnormalities identified earlier. · There are limited data to support serial growth ultrasounds in overweight and obese women.. · The sensitivity of ultrasound for growth abnormalities at <32 weeks is low in women with BMI ≥25. · Consideration should be given to delaying initiation of growth ultrasounds until at least 32 weeks.


GENE GENEALOGIES WITHIN THE ORGANISMAL PEDIGREES OF RANDOM-MATING POPULATIONS.
Using computer simulations, we generated and analyzed genetic distances among selectively neutral haplotypes transmitted through gene genealogies with random-mating organismal pedigrees. Constraints and possible biases on haplotype distances due to correlated ancestry were evaluated by comparing observed distributions of distances to those predicted from an inbreeding theory that assumes independence among haplotype pairs. Results suggest that: 1) mean time to common ancestry of neutral haplotypes can be a reasonably good predictor of evolutionary effective population size; 2) the nonindependence of haplotype paths of descent within a given gene genealogy typically produces significant departures from the theoretical probability distributions of haplotype distances; 3) frequency distributions of distances between haplotypes drawn from "replicate" organismal pedigrees or from multiple unlinked loci within an organismal pedigree exhibit very close agreement with the theory for independent haplotypes. These results are relevant to interpretations of current molecular data on genetic distances among nonrecombining haplotypes at either nuclear or cytoplasmic loci.


Hepatoprotective and antioxidant activity of quercetin loaded chitosan/alginate particles in vitro and in vivo in a model of paracetamol-induced toxicity.
The toxic liver impairment caused by free radical injury or excessive reactive oxigen species (ROS) formation could be effectivelly attenuated by natural antioxidants. The present study aimed to explore and compare the hepatoprotective and antioxidant effects of free and encapsulated quercetin in in vitro and in vivo models of hepatotoxicity. Thus, quercetin was encapsulated in chitosan/alginate nanoparticles by gelation method. Both empty and quercetin-loaded nanoparticles revealed good safety profile in vitro, determined by the lack of cytotoxicity in human hepatoma HepG2 cells. The pretreatment of HepG2 cells with encapsulated quercetin (10μg/ml) significantly attenuated the decrease in cell viability in H2О2-induced oxidative stress (0.1mM H2О2), thus showing an effective in vitro protection. In vivo evaluation of the antioxidant and hepatoprotective potential of free and encapsulated quercetin was performed in a model of paracetamol - induced liver injury in male Wistar rats. The oral pretreatment with encapsulated quercetin (0.18mg/kg b.w., 7days) significantly diminished the increased levels of serum transaminases ALT and AST, attenuated the lipid peroxidation and restored the levels of gluthation (a marker of cell antioxidant defence system). The protective effects of quercetin encapsulated in chitosan-based nanoformulation were superior to those of free quercetin. The results of the study suggest that the encapsulation of quercetin in chitosan/alginate nanoformulations might represent an effective therapeutic approach against oxidative stress induced liver injury.


Risk Factor Characterization of Ischemic Stroke Subtypes Among West Africans.
To identify the qualitative and quantitative contributions of conventional risk factors for occurrence of ischemic stroke and its key pathophysiologic subtypes among West Africans. The SIREN (Stroke Investigative Research and Educational Network) is a multicenter, case-control study involving 15 sites in Ghana and Nigeria. Cases include adults aged ≥18 years with ischemic stroke who were etiologically subtyped using the A-S-C-O-D classification into atherosclerosis, small-vessel occlusion, cardiac pathology, other causes, and dissection. Controls were age- and gender-matched stroke-free adults. Detailed evaluations for vascular, lifestyle, and psychosocial factors were performed. We used conditional logistic regression to estimate adjusted odds ratios with 95% CI. There were 2431 ischemic stroke case and stroke-free control pairs with respective mean ages of 62.2±14.0 versus 60.9±13.7 years. There were 1024 (42.1%) small vessel occlusions, 427 (17.6%) large-artery atherosclerosis, 258 (10.6%) cardio-embolic, 3 (0.1%) carotid dissections, and 719 (29.6%) undetermined/other causes. The adjusted odds ratio (95% CI) for the 8 dominant risk factors for ischemic stroke were hypertension, 10.34 (6.91-15.45); dyslipidemia, 5.16 (3.78-7.03); diabetes, 3.44 (2.60-4.56); low green vegetable consumption, 1.89 (1.45-2.46); red meat consumption, 1.89 (1.45-2.46); cardiac disease, 1.88 (1.22-2.90); monthly income $100 or more, 1.72 (1.24-2.39); and psychosocial stress, 1.62 (1.18-2.21). Hypertension, dyslipidemia, diabetes were confluent factors shared by small-vessel, large-vessel and cardio-embolic subtypes. Stroke cases and stroke-free controls had a mean of 5.3±1.5 versus 3.2±1.0 adverse cardio-metabolic risk factors respectively (P<0.0001). Traditional vascular risk factors demonstrate important differential effect sizes with pathophysiologic, clinical and preventative implications on the occurrence of ischemic stroke among indigenous West Africans.


[Visual improvement of an amblyopic eye in an adult patient after visual loss in the non-amblyopic eye].
The sensitive period for a successful amblyopia treatment is limited to the age of 11 to 13 years. We present a 60-year-old patient with complete visual loss on his dominant eye after retinal arterial occlusion. The fellow eye had a known severe amblyopia with a corrected visual acuity of 0.1. After retinoscopy the patient received a full correction for his amblyopic eye and the vision increased to 0.25. After three months follow-up visual acuity was 0.5 for single optotypes. Even in adulthood a attempt at full correction of an amblyopic eye after loss of vision in the dominant eye should be performed for optimising the quality of life.


Interaction between udenafil and tamsulosin in rats: non-competitive inhibition of tamsulosin metabolism by udenafil via hepatic CYP3A1/2.
Orthostatic hypotension has been observed when PDE 5 (cGMP-specific phosphodiesterase type 5) inhibitors are co-administered with alpha-adrenoceptor antagonists. Here we assessed the pharmacokinetic and haemodynamic interactions between udenafil and tamsulosin in rats, as both drugs are metabolized via rat hepatic cytochrome P450 3A1/2. Interactions between the two drugs were evaluated in rats after simultaneous 1 or 15 min i.v. infusion or after p.o. administration of udenafil (30 mg x kg(-1)) and/or tamsulosin (1 mg x kg(-1)). In vitro metabolism of tamsulosin with udenafil was measured to obtain the inhibition constant (K(i)) and [I]/K(i) ratio of udenafil. The total area under the plasma concentration-time curve from time zero to time infinity (AUC)s (or AUC(0-4 h)) of tamsulosin were significantly greater after 15 min of i.v. infusion or after oral administration with udenafil, compared with tamsulosin alone. The hepatic first-pass metabolism of tamsulosin was inhibited by udenafil, and the inhibition in vitro was in a non-competitive mode. The arterial systolic blood pressure was significantly lower at 5, 10 and 60 min after oral co-administration of the drugs. The significantly greater AUC of tamsulosin after i.v. and p.o. administration of both drugs may be attributable to non-competitive inhibition of cytochrome P450 3A1/2-mediated hepatic tamsulosin metabolism by udenafil. The inhibition was also observed in human liver S9 fractions, suggesting that a reassessment of the oral dosage of tamsulosin is necessary when udenafil and tamsulosin are co-administered to patients with benign prostatic hyperplasia.


Triplex doppler ultrasonography to describe the uterine arteries during diestrus and progesterone profile in pregnant and non-pregnant bitches of different sizes.
Hemodynamics of uterine vascularization is modified throughout pregnancy to meet the increasing demand of the growing fetuses and triplex doppler ultrasonography is widely used in human medicine to study the uterine arteries and assess the fetal and placental conditions. The aim of our study was to confirm this observation in the bitch, to evaluate differences between bitches of different sizes and to study abnormal pregnancies. Forty-four bitches were monitored during the estrous period to determine ovulation and every 10 days from ovulation to 50 days post-ovulation: the resistivity (RI) and pulsatility (PI) indexes of the right uterine artery were measured as well as usual assessment of fetal development and follow up of the luteal function. Thirty-three out of forty-four bitches were pregnant, including 6 abnormal pregnancies (resorption of more than 10% of the embryos). We also divided them in four weight categories: 8 were small (<10 kg), 13 medium (10-25 kg), 13 large (>25-40 kg) and 10 were giant breeds (>40 kg). We observed that RI and PI decreased over time and were significantly lower for pregnant bitches compared to non-pregnant ones from 30 days post-ovulation. In contrast, RI and PI did not significantly vary with the size of the bitches and we could not determine a significant impact of abnormal pregnancies either. In conclusion, we found no significant difference related to the size of bitches in the RI and PI. The only significant difference between pregnant and non-pregnant bitches was observed from 30 days post-ovulation.


Characterization of an outbreak of malaria in a non-endemic zone on the coastal region of Ecuador.
Malaria is a vector-borne disease widely distributed in the Amazon region and the coastal area of northern Ecuador. Its epidemiology involves related factors such as human settlements, vector reproduction sites, mobility, productive activity, and the response capacity of health systems, among others. To describe malaria transmission by Plasmodium vivax in a non-endemic area of Ecuador by analyzing the epidemiological and entomological factors involved. We conducted the epidemiological study of the cases reported in the Salinas canton and the characterization of vector breeding sites through captures of larvae and adult mosquitoes by human capture of resting mosquitoes. We detected 21 cases of malaria with local transmission related to the presence of initial cases in Venezuelan migrant patients and identified Anopheles albimanus as the predominant vector in natural breeding sites such as estuaries, wells, and water channels. We detected an outbreak of malaria triggered by imported cases from Venezuela. Climatic, social, environmental, and ecological conditions have favored the development of the vector maintaining the transmission cycle. Strategies to control imported malaria should be multiple including early case detection and control of productive breeding sites to avoid local transmission.


THE APPLICATION OF CELL-FREE FETAL DNA (cff-DNA) AND SIBLINGS DNA METHODS IN THE PROCESS OF PATERNITY TEST THROUGH CODIS STR LOCI (CSF1PO, THO1, TPOX, AND vWA).
The non-invasive cff-DNA and siblings DNA methods are the latest breakthroughs in the forensic identification process. The use of cff-DNA and siblings DNA as non-invasive techniques in the forensic identification process has, hitherto, not been widely proven. This was an analytic observational study. The sample of this study consisted of peripheral blood of women in the second trimester of pregnancy and their two biological children. The kinship analysis was carried out through siblings' DNA and cff-DNA from the mothers through CODIS STR loci (CSF1PO, THO1, TPOX, and vWA). The means of allele sharing between full siblings in loci CSF1PO, THO1, TPOX, and vWA were 0 (13.75%), 1 (44.75%), and 2 (41.50%). The allele sharing found in the study is in line with the one in previous research conducted by Wenk (1998) and the theory proposed by O'Connor (2011), indicating that one allele sharing dominates, contrasting with the finding of previous research conducted by Sosiawan (2020) revealing that 2-allele sharing was more superior. The variation is caused by the ethnicity having a different genetic contribution among the population. The variation can be attributed to historical and demographical processes leading to genetic drift. The mean of SI in 1 allele sharing in CODIS STR loci (CSF1PO, THO1, TPOX, and vWA) has the highest value of 44.5%. The use of cff-DNA of pregnant women as one of the non-invasive techniques can serve as an alternative material in a paternity test.


Structure of the essential MTERF4:NSUN4 protein complex reveals how an MTERF protein collaborates to facilitate rRNA modification.
MTERF4 is the first MTERF family member shown to bind RNA and plays an essential role as a regulator of ribosomal biogenesis in mammalian mitochondria. It forms a complex with the rRNA methyltransferase NSUN4 and recruits it to the large ribosomal subunit. In this article, we characterize the interaction between both proteins, demonstrate that MTERF4 strongly stimulates the specificity of NSUN4 during in vitro methylation experiments, and present the 2.0 Å resolution crystal structure of the MTERF4:NSUN4 protein complex, lacking 48 residues of the MTERF4 C-terminal acidic tail, bound to S-adenosyl-L-methionine, thus revealing the nature of the interaction between both proteins and the structural conservation of the most divergent of the human MTERF family members. Moreover, the structure suggests a model for RNA binding by the MTERF4:NSUN4 complex, providing insight into the mechanism by which an MTERF family member facilitates rRNA methylation.


Fragmentation of replicating chromosomes triggered by uracil in DNA.
The dut mutants of Escherichia coli fail to hydrolyze dUTP and thus incorporate uracil into their DNA, suffering from chromosomal fragmentation. The postulated mechanism for the double-strand DNA breaks is clustered uracil excision, which requires high density of DNA-uracils. However, we did not find enough uracil residues or excision nicks in the DNA of dut mutants to account for clustered uracil excision. Using a dut recBC(Ts) mutant of E.coli to inquire into the mechanism of uracil-triggered chromosomal fragmentation, we show that this fragmentation requires DNA replication and, in turn, inhibits replication of the chromosomal terminus. As a result, origin-containing sub-chromosomal fragments accumulate in dut recBC conditions, indicating preferential demise of replication bubbles. We propose that the basic mechanism of the uracil-triggered chromosomal fragmentation is replication fork collapse at uracil-excision nicks. Possible explanations for the low level terminus fragmentation are also considered.


A new species Myxodavisia jejuensis n. sp. (Myxosporea: Sinuolineidae) isolated from cultured olive flounder Paralichthys olivaceus in South Korea.
A new myxosporean parasite, Myxodavisia jejuensis n. sp. (Myxozoa; Bivalvulida) is described from the urinary bladder of olive flounder Paralichthys olivaceus cultured on Jeju Island, Korea. Two long lateral appendages with whip-like extensions were attached to mature spores of triangular to semi-circular shape. The spores were measured at 13.1 ± 1.1 μm in length, 17.2 ± 1.0 μm in thickness, and 13.1 ± 1.0 μm in width. Two spherical polar capsules, with a diameter of 5.0 ± 0.4 μm, were observed on opposite sides in the middle of the spore. The suture line was straight or slightly sinuous on the middle of spores. The 18S rDNA from M. jejuensis n. sp. was used in BLAST and molecular phylogenetic analysis. The results demonstrated that M. jejuensis n. sp. was closest to Sinuolinea capsularis and that the infection site tropism was correlated with the phylogeny of marine myxosporeans. In addition, we designed specific primers to detect the 18S rDNA gene of M. jejuensis n. sp.; the results showed specific amplification in M. jejuensis n. sp. among the myxosporeans isolated from the urinary bladder of the cultured olive flounder.


Complete transcatheter versus surgical approach to aortic stenosis with coronary artery disease: A systematic review and meta-analysis.
This meta-analysis aimed to evaluate outcomes of transcatheter aortic valve replacement (TAVR) with percutaneous coronary intervention (PCI) versus surgical aortic valve replacement (SAVR) with coronary artery bypass grafting (CABG). The MEDLINE, EMBASE, and Cochrane Library databases were searched through November 2021 to identify studies comparing TAVR + PCI and SAVR + CABG for severe aortic stenosis with concurrent coronary artery disease. Outcomes of interest were all-cause mortality, repeat coronary intervention, rehospitalization, myocardial infarction, and stroke during follow-up, and 30-day periprocedural outcomes. Two randomized controlled trials and 6 observational studies including a total of 104,220 patients (TAVR + PCI, n = 5004; SAVR + CABG, n = 99,216) were included. The weighted mean follow-up period was 30.2 months. TAVR + PCI was associated with greater all-cause mortality and coronary reintervention during follow-up period (hazard ratio, 1.35; 95% confidence interval [CI], 1.11-1.65; P = .003, hazard ratio, 4.14; 95% CI, 1.74-9.86; P = .001, respectively), 30-day permanent pacemaker implantation rate (odds ratio [OR], 3.79; 95% CI, 1.61-8.95; P = .002), and periprocedural vascular complications (OR, 6.97; 95% CI, 1.85-26.30; P = .004). In contrast, TAVR + PCI was associated with a lower rate of 30-day acute kidney injury (OR, 0.32; 95% CI, 0.20-0.50; P = .0001). Rehospitalization, myocardial infarction, stroke during follow-up, and other periprocedural outcomes including 30-day mortality were similar in both groups. In patients with severe aortic stenosis and coronary artery disease, TAVR + PCI was associated with greater all-cause mortality at follow-up compared with SAVR + CABG. Heart Team approach to assess TAVR candidacy remains imperative.


Structural analysis and biological activities of C25-amino and C25-nitro vitamin D analogs.
Intense synthetic efforts have been directed towards the development of noncalcemic analogs of 1,25-dihydroxyvitamin D3. We describe here the structural analysis and biological evaluation of two derivatives of 1,25-dihydroxyvitamin D3 with modifications limited to the replacement of the 25-hydroxyl group by a 25-amino or 25-nitro groups. Both compounds are agonists of the vitamin D receptor. They mediate biological effects similar to 1,25-dihydroxyvitamin D3, the 25-amino derivative being the most potent one while being less calcemic than 1,25-dihydroxyvitamin D3. The in vivo properties of the compounds make them of potential therapeutic value.