Inhibition of ribonucleotide reductase and L1210 cell growth by N-hydroxy-N'-aminoguanidine derivatives.
A series of N-hydroxy-N'-aminoguanidine derivatives was studied for their effects on L1210 cell growth and ribonucleotide reductase activity. With the twelve compounds studied, there was a good correlation between the inhibition of L1210 cell growth and the inhibition of ribonucleotide reductase activity. The most potent compound required concentrations of only 1.4 and 2 microM for 50% inhibition of L1210 cell growth and ribonucleotide reductase activity respectively. These guanidine analogs specifically inhibited the conversion of [14C]cytidine and deoxycytidine nucleotides in the nucleotide pool and the incorporation of [14C]cytidine into DNA without altering the incorporation of [14C]cytidine into RNA. Ribonucleotide reductase activity in drug-treated cells was reduced markedly. Iron-chelating agents did not either increase or decrease the inhibition caused by the N-hydroxy-N'-aminoguanidine derivatives. No evidence was obtained that these derivatives selectively inactivated one of the subunits of ribonucleotide reductase. These compounds appear to inhibit ribonucleotide reductase by a mechanism different from hydroxyurea or the thiosemicarbazone derivatives.


Should I care for my mum or for my kid? Sandwich generation and depression burden in Italy.
In Italy, over the last decades, elderly care has been mostly provided by family members, especially adult offspring, and in particular daughters. This paper investigates the relationship between informal caregiving and mental distress among Italians aged 35-59, with a focus on gender effect and parenthood responsibilities. The dataset is the European Health Interview Survey (EHIS), second wave, year 2015. As far as it is known, the Italian EHIS has not been used for studies on ageing and caregiving. Using selected subsamples, a Propensity Score Matching between caregivers and non-caregivers aged 35-59 is implemented, with the aim of measuring the difference in level of depression, if any, between the two groups. Findings show that women providing their frail relatives with informal care are less likely to suffer from mental distress compared to non-carers. However, results change radically if they have children aged less than 15 at home, and a higher probability of being depressed is detected for women overwhelmed by the double responsibility of assisting both dependent relatives and their own children. Results are not significant for men.


Proposal for a scoring of the quality of the banding of chromosomes.
We propose an objective scoring of the quality of the banding of mitoses based on the number of bands (B), the length (L), and the width (W) of chromosome 7 in metaphase as used in the formula [LnB square root L/W]2. When no figure shows the quality of mitoses from which a breakpoint is described, this scoring could give information about it. It could be applied in cytogenetic cancer studies as well as for preparations with high resolution banding.


Mapping the effectiveness of the community tuberculosis care programs: a systematic review.
Tuberculosis is a significant global public health threat, especially in countries with limited resources. To improve tuberculosis care, the World Health Organization emphasizes the importance of considering a TB patient's journey across a variety of connected settings and facilities. A systematic review was conducted to map previously conducted studies to identify existing community TB implementation models, their effectiveness on cost, and treatment outcomes. Systematic search through various electronic databases MEDLINE, EBSCO (PsycINFO and CINAHL), Cochrane Library, EMBASE, WHO Regional Databases, gray literature, and hand-searched bibliographies was performed. Articles published in English between the years 2000 and 2022 with a substantial focus on community TB implementation models were considered for inclusion. Studies were excluded if the intervention was purely facility-based and those focusing exclusively on qualitative assessments. Two reviewers used standardized methods to screen titles, abstracts, and data charting. Included studies were assessed for quality using ROBINS-I and ROB 2. Analysis of study results uses a PRISMA flow diagram and quantitative approach. A total of 6982 articles were identified with 36 meeting the eligibility criteria for analysis. Electronic medication monitors showed an increased probability of treatment success rate (RR 1.0-4.33 and the 95% CI 0.98-95.4) in four cohort studies in low- and middle-income countries with the incremental cost-effectiveness of $434. Four cohort studies evaluating community health worker direct observation therapy in low- and middle-income countries showed a treatment success risk ratio of up to 3.09 with a 95% CI of 0.06-7.88. (32,41,43,48) and incremental cost-effectiveness up to USS$410. Moreover, four comparative studies in low- and middle-income countries showed family directly observed treatment success risk ratio up to 9.07, 95% CI of 0.92-89.9. Furthermore, four short message service trials revealed a treatment success risk ratio ranging from 1.0 to 1.45 (95% CI fell within these values) with a cost-effectiveness of up to 350I$ compared to standard of care. This review illustrates that community-based TB interventions such as electronic medication monitors, community health worker direct observation therapy, family directly observed treatment, and short message service can substantially bolster efficiency and convenience for patients and providers while reducing health system costs and improving clinical outcomes.


The Cardiac Sarcomere and Cell Cycle.
The lack of adult human cardiomyocyte proliferative capacity impairs cardiac regeneration such as after myocardial injury. The sarcomere, a specialized actin cytoskeletal structure that is essential for twitch contraction in cardiomyocytes, has been considered a critical factor limiting adult human cardiomyocyte proliferation through incompletely understood mechanisms. This review summarizes known and emerging regulatory mechanisms connecting the human cardiomyocyte sarcomere to cell cycle regulation including structural and signaling mechanisms. Cardiac regeneration could be augmented through targeting the inhibitory effects of the sarcomere on cardiomyocyte proliferation.


The response of elderly human articular cartilage to mechanical stimuli in vitro.
To investigate the biosynthetic response of elderly human femoral head articular cartilage to mechanical stimulation in vitro and its variation with site. Full-depth cartilage biopsies of articular cartilage were removed from defined sites on 10 femoral heads from patients aged 68-95 years. Cartilage explants were subjected to either static or cyclic (2s on/2s off) loading in unconfined compression at a stress of 1MPa for 24h, or no load. Metabolic activity was assessed by adding medium containing (35)S-sulphate and (3)H-leucine during the last 4h of loading and measuring the incorporated radioisotope. Matrix composition was measured in terms of the amounts of collagen, sulphated glycosaminoglycans (GAG) and water content. Loading of elderly human articular cartilage at 1MPa significantly inhibited incorporation of (35)S-sulphate (P=0.023) into cartilage explants. Pairwise comparisons showed that the difference in incorporation was only for static loading (43% decrease compared to unloaded) (P<0.05). (3)H-leucine incorporation appeared to follow the same trends but neither static nor cyclic load was significantly different from control (P=0.31). Significant topographical variation was found for % GAG wet and GAG:collagen but not water content, % GAG dry or collagen. Isotope incorporation rates were in the order anterior>superior>posterior. Static loading inhibits matrix biosynthesis in elderly human cartilage, and cyclic loading is not stimulatory. This is in contrast to previous studies on young bovine tissue where cyclic loading is stimulatory.


Population Dynamics of Anastrepha ludens (Loew) (Diptera: Tephritidae) on Citrus Areas in Southern Tamaulipas, Mexico.
An analysis of adult population fluctuation of Anastrepha ludens (Loew) was performed in southern Tamaulipas, Mexico from 2008 to 2011. The aim was to analyze population dynamics of A. ludens and its relationships with climatic factors in the citrus region of Llera, Tamaulipas, Mexico. Population densities were weekly examined to identify variation through the year and study period. Four periods were identified according to population size, amplitude, host availability and season of the year. The correlation between population density vs. rainfall and temperature (average, minimum and maximum) was determined by linear and multiple regression analyses. Simple linear regression analysis showed that population density with minimum temperature and rainfall was the most consistent correlation, whereas in multiple regression analysis, rainfall and maximum temperature showed more consistency. A seasonal association between the availability of commercial host, climatic variation, and population peaks of A. ludens was determined. This study may have practical implications for the design of specific control strategies, monitoring, and infestation prevention based on different phases of the pest through the year. This strategy, along with the area-wide approach implemented by the Plant Protection Service may lead to an optimization of material, financial and human resources.


Sevoflurane versus halothane for general anesthesia in pediatric patients: a comparative study of vital signs, induction, and emergence.
To compare vital signs and the speed of induction and emergence with sevoflurane versus halothane in pediatric patients. Prospective, randomized, open study. Thomas Jefferson University Hospital. 40 unpremedicated ASA Physical Status I and II children age 9 months to 16 years undergoing elective inpatient otorhinolaryngologic or orthopedic surgery. Standardized induction of anesthesia with sevoflurane (start: 1%, maximum: 7%) or halothane (start: 0.5%, maximum: 5%) in nitrous oxide/oxygen (N2O/O2). Intubation following vecuronium and 4 minutes of controlled ventilation with 2 minimum alveolar concentration (MAC) drug in O2; 1.5 MAC drug in N2O/O2 delivered for 20 minutes; then 0.75 MAC until the end of surgery. Fentanyl 1 mcg/kg was administered 15 minutes before the anticipated end of surgery, at which time anesthetics were stopped and mechanical ventilation continued until eye opening (emergence). Blood pressure, heart rate (HR), oxygen saturation, end-tidal gas concentrations, and temperature were recorded. Induction and emergence times were measured to the nearest second. Induction (loss of eyelash reflex) was faster with sevoflurane (97 +/- 31 sec) than halothane (120 +/- 36 sec; p < 0.05), despite a lower inspired sevoflurane MAC. Emergence was faster with sevoflurane (9.9 +/- 2.9 min vs. 12.5 +/- 4.7 min; p < 0.05), despite a higher MAC multiple of end-tidal sevoflurane concentration at the end of surgery. Following intubation, HR (compared with the preinduction value in the operating room) was significantly higher in the halothane group (136.8% +/- 16.3% vs. 115.0% +/- 25.6%), as was mean arterial pressure (113.2% +/- 25.5% vs. 87.8% +/- 22.6%). This finding corresponded with a higher MAC multiple of end-tidal concentration in the sevoflurane group than in the halothane group. Induction of and emergence from anesthesia was faster with sevoflurane than halothane. Airway complications were low in both groups. Vital signs were more stable with sevoflurane during induction through intubation, and were comparable during maintenance. Sevoflurane is an excellent drug for inhalational induction in pediatric patients.


[Innervation of the anterior byssus retractor muscle (ABRM) in Mytilus edulis L. III. Histochemical localisation of the terminal nerves through 5-hydroxytryptamine (author's transl)].
Detection of nerve structures containing 5-HT were described in the anterior byssus retractor muscle (ABRM) in Mytilus edulis L. after using the fluorescence microscope technique of Flack. We are able to confirm our previous results and assumptions given by histology and electron microscope studies: the neuromuscular "en passage" junctions, largely distributed within the ABRM, contain 5-HT.


[Histocompatibility antigens expressed in the epithelium of the oral mucosa during various diseases].
The AA. report the expression of the Class I and II major histocompatibility antigens on oral mucosa Class I and II antigen expression varied between various disease states exhibiting proliferative or destructive tissue responses, and this expression is consistent with major histocompatibility complex (M.H.C.)-restricted cellular interactions. Oral mucosa doesn't express HLA-DQ antigens.


Prenatal diagnosis of spontaneous rupture of the fetal bladder with color Doppler ultrasonography.
Rupture of the fetal-neonatal bladder that results in urinary ascites has rarely been reported in the literature. In this report we present the first case of spontaneous rupture of the fetal bladder in which the diagnosis was made prenatally by means of color Doppler ultrasonography.


Generalised 2D-correlation NMR analysis of a wine fermentation.
A wine fermentation has been monitored on a daily basis by (1)H NMR spectroscopy. Following data pre-processing that includes synthesis of the spectra to ensure all peaks are of constant half-width, the series of spectra were examined using generalised two-dimensional correlation techniques. Synchronous and asynchronous data maps have been generated and employed to interpret the changes in the fermentation process as a function of time. The results illustrate the potential of high resolution NMR with multivariate data analysis as a tool for process monitoring and the manner in which two-dimensional correlation mapping can aid in data interpretation.


Cryopreservation of sweetpotato (Ipomoea batatas) and its pathogen eradication by cryotherapy.
Sweetpotato (Ipomoea batatas) ranks as the seventh most important staple crop in the world and the fifth in developing countries after rice, wheat, maize and cassava. Sweetpotato is mainly grown in developing countries, which account for more than 95% of total production of the whole world. Genetic resources, including cultivated varieties and wild species, are a prerequisite for novel sweetpotato breeding in both conventional and genetic engineering programs. Various cryopreservation protocols have been developed for shoot tips and embryogenic tissues. The former explants are preferred for long-term conservation of sweetpotato genetic resources, while the latter are valuable for sweetpotato genetic improvement. This review provides update comprehensive information on cryopreservation of sweetpotato shoot tips and embryogenic tissues. Plant pathogens such as viruses and phytoplasma severely hamper high yield and high quality production of sweetpotato. Thus, usage of pathogen-free planting materials is pivotal for sustainable sweetpotato production. Cryotherapy of shoot tips can efficiently eradicate sweetpotato pathogens such as viruses and phytoplasma. The mechanism behind pathogen eradication by cryotherapy of shoot tips has been elucidated. Pathogen eradication by cryotherapy provides an alternative, efficient strategy for production of pathogen-free plants. In addition, cryopreserved tissues may also be considered to be safer for exchange of germplasm between countries and regions.


Relationship between cerebrospinal fluid amine metabolites, neuroendocrine findings and personality dimensions (Marke-Nyman scale factors) in psychiatric patients.
5-Hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the spinal fluid of 45 women hospitalized in a psychiatric department for major depression (14 cases), schizophrenia (18 cases) and alcohol dependence (13 cases). Dexamethasone suppression tests were performed following CSF examinations in all patients, and TRH stimulation tests were also made in six subjects. All biological examinations were carried out in a drug-free state. The Marke-Nyman Temperament scale was administered to all patients as soon as severe psychotic disturbances subsided and sufficient cooperation was achieved, but no later than 10 days following biological examinations. The MNT was repeated after recovery to check reliability of the test results during an episode of a psychiatric disorder. CSF amine metabolite concentrations did not differ significantly in the three patient groups; postdexamethasone average cortisol levels were above the critical level (5 micrograms/dl) in each group, the highest values being found in major depression. One of the three MNT factors was inhomogeneous among diagnostic groups (validity: low in depression and alcoholism), but the other two also differed from a healthy control population. Correlation structure between biological and psychological variables was homogeneous throughout the diagnoses and a significant inverse correlation was found only between CSF 5-HIAA and the validity factor of MNT. Maximal TSH response to TRH stimulation correlated with both solidity and stability in the MNT scale. Since MNT results proved to be stable even during an illness episode, a possible link is suggested between personality traits and central serotonin metabolism.


Characterization of drug particle surface energetics and young's modulus by atomic force microscopy and inverse gas chromatography.
Particulate interactions are dominated by aspects such as surface topography, exposed chemical moieties, environmental conditions, and thermodynamic properties such as surface free energy (gamma). The absolute value and relative magnitude of surface energies of a drug and excipients within a formulation can significantly influence manufacture, processing, and use. This study utilizes and compares the potentially complementary analytical techniques of atomic force microscopy (AFM) and inverse gas chromatography (IGC) in the quantitative determination of the surface energy of drug (budesonide) particles (micronized and unmilled) relevant to inhaled delivery. In addition, the study investigates with AFM another important parameter in determining material interactions, the local mechanical properties of the drug. AFM was used to acquire force of adhesion (Fadh) and related work of adhesion (WA) and surface energy values between individual mironized drug particles and also model substrates (graphite and mica). In addition, AFM probes were used to interrogate the surface energy of unmilled drug particles. Measurement with AFM probes also yielded localized measurements of Young's modulus for the unmilled drug. IGC was also used to probe the surface characteristics of the bulk drug material. The average values for surface energies acquired from budesonide micronized particle interactions with graphite, mica, and drug particles of the same substance were found to range from 35 to 175, 5 to 40, and 10 to 32 mJ m(-2), respectively. The unmilled material displayed a range of values of 39-88 mJ m(-2) with an average of 60 mJ m(-2). The IGC result for the surface energy of the micronized material was 68.47 +/- 1.60 mJ m(-2). The variability in surface energy from AFM, a feature particularly apparent for the micronized material was attributed to two factors, intrinsic material variations within a single particle and assumptions present within the contact mechanics model used. Here we provide a detailed description of these factors to go some way to rationalize the results. The Young's modulus of the unmilled drug was determined to be approximately 10 GPa. The range of determined surface energies between the AFM measurement on graphite, mica, and the drug is proposed to reflect the different chemistries displayed by the drug at the single particle level. The maximum values of these ranges can be related to the sites most likely to be involved in adhesion. AFM and IGC yield surface energy estimates in approximate agreement, but clearly are interrogating surfaces in different fashions. This raises questions as to the nature of the measurement being made by these approaches and to the most appropriate time to use these methods in terms of a direct relation to formulation design, manufacture, and drug delivery. Finally, we demonstrate a novel method for assessing the Young's modulus of a drug from a single particle.


Possible involvement of endogenous beta-endorphin in the pathophysiological mechanisms of Pichinde virus-infected guinea pigs.
Previously, we demonstrated that naloxone, an opiate antagonist, prolonged survival of strain 13 guinea pigs infected with Pichinde virus. Thus, endogenous opiates may be involved in the pathogenesis of this viral disease. To determine whether endogenous opiate levels were affected by Pichinde viral infection, beta-endorphin concentrations in plasma and cerebrospinal fluid (CSF) of normal and infected strain 13 guinea pigs were measured by radioimmunoassay. Cerebrospinal fluid beta-endorphin concentrations were 78.0 +/- 13.2 pg/ml on postinoculation day (PID) 7, 59.0 +/- 5.6 pg/ml on PID 12, and 58.8 +/- 5.4 pg/ml on PID 14. These values were significantly higher than baseline levels of CSF beta-endorphin: 30.8 +/- 1.9 pg/ml. Plasma beta-endorphin concentrations of infected animals increased significantly to 202.1 +/- 17.9 pg/ml on PID 7 and to 154.2 +/- 21.4 pg/ml on PID 12 from a mean baseline value of 84.2 +/- 13.1 pg/ml. After a primer intravenous injection of beta-endorphin (10, 15, or 30 micrograms/kg), followed by constant infusion of beta-endorphin (15, 45, or 90 micrograms/kg.hr) to control noninfected guinea pigs, heart rate (except with the lowest dose) and mean blood pressure decreased markedly. Under these experimental conditions, concentrations of plasma and CSF beta-endorphin increased simultaneously with different magnitude. Because both Pichinde viral infection and beta-endorphin administration produced a similar trend of cardiovascular disturbances, leading to hypotension and bradycardia, increased concentrations of plasma and CSF beta-endorphin may play a partial role in the pathophysiological mechanisms of Pichinde virus infection.


Exercise and hypertension: recent advances in exercise prescription.
Despite the pervasiveness of hypertension (HTN), the exercise dose needed to lower blood pressure (BP) remains to be quantified. The purpose of this manuscript is to discuss recent advances in exercise prescription (ExR x) for HTN. The take-home message in ExR x for those with HTN is that the antihypertensive effect is: immediate; elicited by low intensity, short-duration aerobic exercise; one of many health benefits; and individually tailored. With this message and the general rules of ExR x as a guide, those with HTN should exercise on most, preferably all, days of the week, with moderate intensity (40% to <60% of VO2 Reserve), for 30 minutes or more of continuous or accumulated physical activity per day, primarily of the endurance type, supplemented by resistance exercise. Additionally, those who are overweight should progress to a caloric energy expenditure of a minimum of 1000 kcal to more than 2000 kcal per week or more than 2.5 hours per week of moderate-intensity, aerobic exercise.


Optically tuned terahertz modulator based on annealed multilayer MoS2.
Controlling the propagation properties of terahertz waves is very important in terahertz technologies applied in high-speed communication. Therefore a new-type optically tuned terahertz modulator based on multilayer-MoS2 and silicon is experimentally demonstrated. The terahertz transmission could be significantly modulated by changing the power of the pumping laser. With an annealing treatment as a p-doping method, MoS2 on silicon demonstrates a triple enhancement of terahertz modulation depth compared with the bare silicon. This MoS2-based device even exhibited much higher modulation efficiency than the graphene-based device. We also analyzed the mechanism of the modulation enhancement originated from annealed MoS2, and found that it is different from that of graphene-based device. The unique optical modulating properties of the device exhibit tremendous promise for applications in terahertz switch.


The effect of colonic tissue electrical stimulation and celiac branch of the abdominal vagus nerve neuromodulation on colonic motility in anesthetized pigs.
Knowledge on optimal electrical stimulation (ES) modalities and region-specific functional effects of colonic neuromodulation is lacking. We aimed to map the regional colonic motility in response to ES of (a) the colonic tissue and (b) celiac branch of the abdominal vagus nerve (CBVN) in an anesthetized porcine model. In male Yucatan pigs, direct ES (10 Hz, 2 ms, 15 mA) of proximal (pC), transverse (tC), or distal (dC) colon was done using planar flexible multi-electrode array panels and CBVN ES (2 Hz, 0.3-4 ms, 5 mA) using pulse train (PT), continuous (10 min), or square-wave (SW) modalities, with or without afferent nerve block (200 Hz, 0.1 ms, 2 mA). The regional luminal manometric changes were quantified as area under the curve of contractions (AUC) and luminal pressure maps generated. Contractions frequency power spectral analysis was performed. Contraction propagation was assessed using video animation of motility changes. Direct colon ES caused visible local circular (pC, tC) or longitudinal (dC) muscle contractions and increased luminal pressure AUC in pC, tC, and dC (143.0 ± 40.7%, 135.8 ± 59.7%, and 142.0 ± 62%, respectively). The colon displayed prominent phasic pressure frequencies ranging from 1 to 12 cpm. Direct pC and tC ES increased the dominant contraction frequency band (1-6 cpm) power locally. Pulse train CBVN ES (2 Hz, 4 ms, 5 mA) triggered pancolonic contractions, reduced by concurrent afferent block. Colon contractions propagated both orally and aborally in short distances. In anesthetized pigs, the dominant contraction frequency band is 1-6 cpm. Direct colonic ES causes primarily local contractions. The CBVN ES-induced pancolonic contractions involve central neural network.


Differentiation of peptidergic neurones in quail-chick chimaeric embryos.
The problem raised in this work was whether peptidergic neurones with vasoactive intestinal peptide (VIP)-and substance P-like immunoreactivity could develop in chimaeric embryos in which quail neural crest cells had been implanted into chick at an early developmental stage. Differentiation of peptide-containing nerve somas was looked for in different situations: i) when the quail neural primordium had been grafted orthotopically and isochronically into the chick host either at the adrenomedullary (level of somites 18-24) or at the vagal (level of somites 1-7) levels of the neural axis; ii) when the quail adrenomedullary neural primordium had been heterotopically implanted at the vagal level of the chick host. In all conditions, VIP- and substance P-like immunoreactivity were observed in a number of quail neurones located either in the peripheral ganglia of the trunk at the level of the graft (in orthotopic grafts of the adrenomedullary neural primordium) or in the enteric ganglia of the chick gut (in the other types of grafts). The developmental stage at which the first neurones become detectable in the host conforms to the genetic characteristics of the effector cells, i.e. they differentiate at the same stage in normal quail neuroblasts and in quail neuroblasts transplanted into the chick host. In contrast, the distribution of the peptidergic neurones in the host depends on the tissue into which the neural crest cells migrate and not on their origin in the neural axis and their fate in normal development.


Determinants of quality of life in Parkinson's disease: a perspective of novel clinical subtypes.
New subtyping classification systems of Parkinson's disease (PD) have been proposed for phenotyping patients into three different subtypes: mild motor-predominant (PD-MMP), intermediate (PD-IM) and diffuse malignant (PD-DM). The quality of life (QoL) underlying the novel PD clinical subtypes is unknown. This study aimed explore the feasibility of the classification in Chinese PD patients and to investigate the potential heterogeneous determinants of QoL among the three subtypes. 298 PD patients were enrolled, including 129 PD-MMP patients, 121 PD-IM patients and 48 PD-DM patients. All patients completed the QoL assessment, clinical evaluations and neuropsychological tests. Univariate linear analysis and multiple stepwise regression analysis were performed to identify determinants of QoL. Compared to PD-MMP patients, PD-IM and PD-DM patients had more impaired QoL. The Geriatric Depression Rating Scale (GDS) score, Non-Motor Symptoms Questionnaire (NMSQ) score, Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score and Epworth Sleepiness Score (ESS) were independent contributors to QoL in PD-MMP patients. The GDS score, ESS and sniffin' sticks screening 12 test score were independent contributors to QoL in PD-IM patients. The GDS score and Mini Mental State Examination score were independent contributors to QoL in PD-DM patients. The new novel subtyping classification is feasible for Chinese PD patients. Although depression was the most crucial determinant for QoL in PD-MMP, PD-IM and PD-DM patients, the other contributors of QoL in the three subtypes were heterogeneous. These findings may prompt clinicians to target specific factors for improving QoL depending on PD subtypes.


Developmental regulation of flavin-containing monooxygenase form 1 in the liver and kidney of fetal and neonatal rabbits.
Flavin-containing monooxygenases (FMOs) comprise a multi-gene family and catalyze the oxygenation of soft nucleophilic sulfur, nitrogen, phosphorus, and selenium in xenobiotics. Previous studies have demonstrated that FMO is regulated developmentally and by the administration of certain steroid hormones. This study examined the expression of FMO form 1 in the livers and kidneys of fetal and neonatal rabbits, from day 25 of gestation through 3 weeks of age, by assaying FMO1 mRNA and protein levels, as well as catalytic activity. FMO1 mRNA and protein expression and FMO catalytic activity were present in fetal livers at the earliest time point measured (day 25 of gestation), although at levels approximately 10% of that found in adult livers. Hepatic FMO1 mRNA levels increased during and after gestation; levels were not significantly different from those measured in adult male livers. FMO1 protein content and activity rose rapidly after birth to reach 70-80% of adult levels by 3 weeks of age. The expression of FMO1 in fetal and neonatal kidneys was markedly lower than in liver. FMO1 mRNA levels never averaged more than 3.4% of adult male liver levels, but did not differ from adult kidney levels at any of the points measured. Protein levels and enzyme activity rose significantly after birth to approximately 30% of the level in adult kidneys by 3 weeks of age. The early developmental appearance of FMO1 suggests a possible role in the metabolism of xenobiotics through transplacental or lactational exposures.


Electronic and vibrational spectra of Mn rich sursassite.
The optical spectrum of Mn2+ in octahedral coordination for sursassite is characterized by well resolved bands at 580, 515, 470, 390, 340, and 295 nm (17240, 19420, 21280, 25640, 29410 and 33900 cm-1). Crystal field parameters evaluated from the observed bands are Dq=690, B=680 and C=2800 cm-1. A broad band centred around 13000 cm-1 attributed to Fe(III) ion is an impurity in sursassite confirmed from EDX analysis. Vibrational spectra have been investigated both by IR and Raman spectroscopy. The correlation between vibrational modes and the structural properties of the manganese silicate, sursassite, is made and compared with other silicates. Two vibrational modes of CO(3)2- observed; the antisymmetric stretching mode (nu3) at 1420 cm-1 (IR active) and the out-of-plane bending mode (nu2) (IR and Raman active) at approximately 875 cm-1. This confirms the Mn rich phases in sursassite as observed from SEM probably an Mn carbonate-rhodochrosite.


Total synthesis of the bacterial RNA polymerase inhibitor ripostatin B.
A modular and highly stereoselective synthesis of the title compound was developed. Key steps in the assembly of the carbon framework of ripostatin B were a stereoselective Paterson aldol reaction and a high-yielding ring-closing metathesis mediated by Grubbs first generation catalyst. The C15 hydroxy group was established through Tishchenko-Evans reduction in excellent yield and selectivity.


Dilute liquid crystals used to enhance residual dipolar couplings may alter conformational equilibrium in oligosaccharides.
The solution structures of a trisaccharide and a pentasaccharide containing the Lewis(x) motif were determined by two independent approaches using either dipolar cross-relaxation (NOE) or residual dipolar coupling (RDC) data. For the latter, one-bond 13C[bond](1)H RDC enhanced by two different mineral liquid crystals were used alone. Home-written programs were employed firstly for measuring accurately the coupling constants in the direct dimension of non-decoupled HSQC experiments, secondly for transforming each RDC data set into geometrical restraints. In this second program, the complete molecular structure was expressed in a unique frame where the alignment tensor is diagonal. Assuming that the pyranose rings are rigid, their relative orientation is defined by optimizing the glycosidic torsion angles. For the trisaccharide, a good agreement was observed between the results of both approaches (NOE and RDC). In contrast, for the pentasaccharide, strong discrepancies appeared, which seem to result from interactions between the pentasaccharide and the mesogens, affecting conformational equilibrium. This observation is of importance, as it reveals that using simultaneously NOE and RDC can be hazardous as the former represent 99% of the molecules free in solution, whereas the latter correspond to less than 1% of the structure bound to the mesogen.


A shift towards a T cell cytokine deficiency along with an anti-inflammatory/regulatory microenvironment may enable the synthesis of anti-FVIII inhibitors in haemophilia A patients.
Despite the clinical relevance of anti-factor VIII (FVIII) antibodies (anti-FVIII inhibitors) impairing haemostatic activity of haemophilia A (HA) patients, the immunological mechanisms underlying their production are unknown. Aiming to understand more clearly the immune response in patients with [HAα-FVIII(+)] and without [HAα-FVIII(-)] anti-FVIII inhibitors, we have characterized the cytokine pattern of peripheral blood leucocytes, using an in vitro stimulation of whole blood samples with plasma-derived (pFVIII) or recombinant FVIII (rFVIII). The results highlighted decreased levels of tumour necrosis factor (TNF)-α(+) neutrophils with higher interleukin (IL)-5/TNF-α ratio in HAα-FVIII(+). All HA samples displayed decreased levels of IL-10(+) monocytes when compared to the blood donor (BD) samples. HAα-FVIII(+) showed lower levels of TNF-α(+) monocytes and increased IL-10/TNF-α ratio. Analysis of adaptive immunity revealed increased levels of interferon (IFN)-γ(+) , TNF-α(+) and IL-4(+) T-cells, from both CD4(+) and CD8(+) T cells, in HAα-FVIII(-) when compared to BD. Moreover, increased frequency of IL-10(+) B cells and higher levels of α-FVIII IgG1 were observed in HAα-FVIII(-). Basal levels of cytokine(+) B-cells, similar to BD, and higher levels of α-FVIII IgG4 are major features in HAα-FVIII(+). The global cytokine profile demonstrated a major anti-inflammatory/regulatory pattern in HAα-FVIII(+), confirmed by the in vitro stimuli with pFVIII or rFVIII. The polarized anti-inflammatory/regulatory immune response in HAα-FVIII(+) and the mixed pattern with a bias towards an inflammatory cytokine profile, modulated by IL-4 in HAα-FVIII(-), may be the key element to drive the development of distinct subclasses of anti-FVIII antibodies. These finding have implications for the design of safe and effective therapeutic protocols to control inhibitors synthesis in HA patients.


Uncertain regression model with autoregressive time series errors.
Uncertain regression model is a powerful analytical tool for exploring the relationship between explanatory variables and response variables. It is assumed that the errors of regression equations are independent. However, in many cases, the error terms are highly positively autocorrelated. Assuming that the errors have an autoregressive structure, this paper first proposes an uncertain regression model with autoregressive time series errors. Then, the principle of least squares is used to estimate the unknown parameters in the model. Besides, this new methodology is used to analyze and predict the cumulative number of confirmed COVID-19 cases in China. Finally, this paper gives a comparative analysis of uncertain regression model, difference plus uncertain autoregressive model, and uncertain regression model with autoregressive time series errors. From the comparison, it is concluded that the uncertain regression model with autoregressive time series errors can improve the accuracy of predictions compared with the uncertain regression model.


[Uptake of water and food from green plants in regard to host-specifity ofOncopeltus fasciatus dallas].
Turgescent plants of different species (17 species of 12 families) and of different physiological state (vegetative, flowering, with young fruits) as well as seeds (29 species of 17 families) have been investigated as food plants forOncopeltus fasciatus. The preference, especially in regard to food and water uptake, is analysed quantitatively. Nonhosts as well as leaves and stems of hostplants serve for water supply, whereby the sucking activity depends on the turgescence of the tissue. Feeding however is considered to be dominant on the reproductive organs of the examinedAslepiadaceae. Feeding punctures, in contrary to those for water uptake, are induced by specific attractants, characteristic to the species. The range of host plants ofO. fasciatus seems to be limited exclusively to the family of theAsclepiadaceae.


[Labelling meproscillarin with tritium at the C-19 position (author's transl)].
Labelling of 14-hydroxy-3beta-[4-O-methyl-alpha-L-rhamnopyranosyl)oxy]-14beta-bufa-4,20,22-trienolide (meproscillarin, Clift) by introduction of dueterium and tritium at the metabolically stable C-19 position is described.


The significance of facet joint cross-sectional area on magnetic resonance imaging in relationship to cervical degenerative spondylolisthesis.
Characteristic changes of the facet joints, including synovial cysts, facet joint hypertrophy, and facet joint effusions, on magnetic resonance imaging (MRI) and computed tomography have been associated with lumbar degenerative spondylolisthesis. The cervical facets have not been examined for associations with cervical degenerative spondylolisthesis similar to those seen in the lumbar spine. To define abnormalities of the facet joints seen on supine MRI that correlate with cervical spondylolisthesis seen on upright radiographs. Retrospective radiographic review of consecutive patients with a universally applied standard. A total of 204 consecutive patients from a single institution, with both an MRI and upright radiographs, were reviewed. Sagittal plane displacement on upright lateral radiographs was compared with MRI. The total area of the facet joint and the amount of facet joint asymmetry were measured on an axial MRI. The data were analyzed to determine a significant association between the cervical degenerative spondylolisthesis and the following: facet joint asymmetry, increased total area of the facet joint, and age. Degenerative spondylolisthesis was seen in 26 patients at C3-C4 and in 27 patients at C4-C5. Upright radiographs identified significantly more degenerative spondylolisthesis than MRIs at levels C3-C4 and C4-C5, 26 versus 6 (p<.001) at C3-C4 and 27 versus 11 (p<.001) at C4-C5. Patients with degenerative spondylolisthesis were more likely to be older, have a larger total facet area, and more facet asymmetry at C3-C4 and C4-C5 (p<.05). Supine MRIs underestimate sagittal displacement compared with upright lateral radiographs. Asymmetric facet hypertrophy at C3-C4 and C4-C5 is associated with degenerative spondylolisthesis on upright lateral films even in the absence of anterolisthesis on supine MRIs.


Lymphoid progenitor cells in severe combined immunodeficiency.
In the present study we evaluated the possibility that patients with severe combined immunodeficiency (SCID) might be deficient in lymphoid progenitor cells in bone marrow. Bone marrow from six patients with SCID was studied for the presence of cells expressing antigens associated with the earliest known stages of lymphopoiesis--terminal transferase (Tdt), the common acute lymphocytic leukemia antigen (CALLA), and p24. Four of six patients had detectable Tdt+, CALLA+, and p24+ cells, although they were quantitatively reduced compared to results from normal infant marrow. In two of six patients no bone marrow mononuclear cells expressing any of these markers were detected. These two patients were more lymphopenic than the other four SCID patients. The absence or deficiency of Tdt+, CALLA+, and p24+ bone marrow cells in some patients with SCID (two of six in the present study) is consistent with the lymphopenia seen in these patients and suggests that the underlying defects which result in SCID affect the production of immature as well as more differentiated lymphocytes.


Influence of perioperative SARS-CoV-2 infection on mortality in orthopaedic inpatients with surgically treated traumatic fractures.
SARS-CoV-2 has had an extensive influence on orthopaedic surgery practice and has been associated with an increased risk of mortality. There is limited evidence of how this pertains to acute orthopaedic surgery with inpatient care. A retrospective cohort study on traumatic fracture patients requiring inpatient care between February 25, 2020 and March 25, 2021 was conducted. Patients were grouped by perioperative SARS-CoV-2 infection, defined as a positive SARS-CoV-2 test from 7 days before to 7 days after orthopaedic surgery, and compared using linear regression and Cox proportional hazards model for primary outcome 30-day mortality and secondary outcome hospital length of stay. In total, 5174 adults with a length of stay ≥ 48 h and an orthopaedic procedure due to a registered traumatic fracture were admitted from February 25, 2020 and discharged before March 26, 2021. Among the 5174 patients, 65% (3340/5174) were female, 22% (1146/5174) were 60-74 years and 56% (2897/5174) were 75 years or older. In total, 144 (3%) had a perioperative SARS-CoV-2 infection. Perioperative SARS-CoV-2 infection was associated with an increased 30-day mortality (aOR 4.19 [95% CI 2.67-6.43], p < 0.001). The median (IQR) length of stay after surgery was 13 days (IQR 6-21) for patients with, and 7 days (IQR 2-13) for patients without, perioperative SARS-CoV-2 infection. Perioperative SARS-CoV-2 infection increased 30-day mortality risk and hospital length of stay for traumatic fracture patients requiring inpatient surgical care. Pre- and postoperative infection were both associated with similar increases in mortality risk.


Melanin-concentrating hormone-1 receptor modulates neuroendocrine, behavioral, and corticolimbic neurochemical stress responses in mice.
Repeated exposure to stressful conditions is linked to the etiology of affective disorders. The melanin-concentrating hormone-1 receptor (MCHR1) may be a novel mechanism that is involved in the modulation of stress responses and affective states. The role of MCHR1 in neuroendocrine, behavioral, and neurochemical stress, and anxiety-related responses was examined by monitoring the effects of melanin-concentrating hormone (MCH) and the selective MCHR1 antagonist, GW3430, in inbred C57Bl/6NTac and MCHR1-knockout (KO) and wild-type (WT) mice. Intracerebroventricular injection of MCH increased plasma corticosterone, and produced anxiety-related responses in the elevated plus maze. The selective MCHR1 antagonist, GW3430, blocked the neuroendocrine and behavioral effects of MCH and produced anxiolytic-like effects by itself in animal models of anxiety. Moreover, KO mice had an anxiolytic-like phenotype in behavioral models of anxiety, and GW3430 had anxiolytic-like effects in WT, but not KO mice. Lastly, stressor-evoked acetylcholine release within the prefrontal cortex of inbred and WT mice, but not KO mice, was blocked by GW3430. We show that MCH elicits anxiety-like responses and that the effects of a selective MCHR1 antagonist and the phenotype of KO mice are consistent with anxiolytic-like action. Distinct behavioral, physiological, and neurochemical stress, and anxiety-related responses were selectively modulated by the MCHR1, and these actions may involve corticolimbic regulation of stress responsivity and anxiety.


Haematological and biochemical reference intervals for three species of hydrophiine sea snakes (Hydrophis curtus, H. elegans and H. peronii) in Australia.
This study presents the first set of comprehensive reference intervals (RIs) for plasma biochemistry and haematology for three species of sea snakes common to the Indo-Pacific waters of Australia. In total 98 snakes, composed of Hydrophis curtus (n= 60), H. elegans (n = 27) and H. peronii (n = 11), were captured, clinically examined and had venous blood samples collected. All snakes were deemed healthy and in good to excellent body condition with snout to vent lengths of 40.7-73.9 cm (H. curtus), 68.9-131.4 cm (H. elegans) and 55.0-83.0 cm (H. peronii), respectively. Lymphocyte numbers, alkaline phosphatase, alanine aminotransferase, creatine kinase and lactate dehydrogenase levels were species-dependent. All other parameters are presented as a single range for the three species. Gender ratio was evenly distributed for H. curtus and H. elegans, but 8/11 (73%) of H. peronii were males. No significant differences were detected between males and females for any of the measured blood parameters. Lymph contamination was considered and accounted for. Although only three species of sea snakes are represented in this study, the RIs generated may be useful in the clinical assessment of other sea snake species.


Prevalence of left ventricular systolic dysfunction by single echocardiographic view: towards an evidence-based point of care cardiac ultrasound scanning protocol.
Limited views are often obtained in the setting of cardiac ultrasound, however, the likelihood of missing left ventricular (LV) dysfunction based on a single view is not known. We sought to determine the echo views that were least likely to miss LV systolic dysfunction in consecutive transthoracic echocardiograms (TTEs). Structured data from TTEs performed at 2 hospitals from September 25, 2017, to January 15, 2019, were screened. Studies of interest were those with reported LV dysfunction. Views evaluated were the parasternal long-axis (PLAX), parasternal-short axis at mitral (PSAX M), papillary muscle (PSAX PM), and apical (PSAX A) levels, apical 2 (AP2), apical 3 (AP3), and apical 4 (AP4) chamber views. The probability that a view contained at least 1 abnormal segment was determined and analyzed with McNemar's test for 21 adjusted pair-wise comparisons. There were 4102 TTE studies included for analysis. TTEs on males comprised 72.7% of studies with a mean LV ejection fraction of 42.8 ± 9.7%. The echo view with the greatest likelihood of encompassing an abnormal segment was the AP2 view with a prevalence of 93.4% (p < 0.001, compared to all other views). The PLAX view performed the worst with a prevalence of 82.5% (p < 0.015, compared to all other views). The best parasternal view for the detection of abnormality was the PSAX PM view at 90.4%. In conclusions, a single echo view will contain abnormal segments > 82% of the time in the setting of LV systolic dysfunction, with a prevalence of up to 93.4% in the apical windows.


The src gene product of transformed and morphologically reverted ASV-infected mammalian cells.
Morphological revertants of avian sarcoma virus transformed vole cells contain the sarcoma gene product (pp60src) in an enzymatically active form, suggesting that the presence of pp60src protein kinase activity is infussicient to induce morphological transformation. Structural analyses of pp60src from infected vole cell clones suggest that in one of the revertant clones on alteration in pp60src may be responsible for morphological reversion while in a second clone, reversion may result from an alteration in a cell gene product with which pp60src must interact. As these morphological revertant cells are tumorigenic, different cell components are required to interact with pp60src to facilitate the two events.


Predictive Factors of Favorable Visual Outcomes After Surgery of Tuberculum Sellae Meningiomas: A Multicenter Retrospective Cohort Study.
Because of their proximity to the visual structures, tuberculum sellae meningiomas are frequently revealed by ophthalmologic impairment. The goal of surgery is gross total resection and improvement of visual function. The purpose of the present study was to identify the predictors of favorable visual outcomes after surgery of tuberculum sellae meningioma. We retrospectively collected tuberculum sellae meningiomas treated at 2 neurosurgical centers from 2010 to 2020. We collected the clinical, imaging and surgical data and analyzed their effects on the visual outcome. A favorable visual outcome was defined as an increase in visual acuity of ≥0.2 point and/or an increase of >25% of the visual field or complete recovery. A total of 50 patients were included. At 4 months after surgery, 30 patients (60%) had experienced visual improvement. The predictors of a favorable visual outcome were a symptom duration of <6 months, preoperative visual acuity >0.5, a smaller tumor size, and tumor with T2-weighted/fluid attenuated inversion recovery hypersignal on magnetic resonance imaging. During surgery, a soft tumor and a clear brain-tumor interface were associated with favorable visual outcomes. Preoperative optic coherence tomography measurements of the retinal nerve fiber layer thickness >80 μM and ganglion cell complex thickness >70 μM were also associated with a better ophthalmologic outcome. In tuberculum sellae meningiomas, rapid surgical treatment must be performed to optimize vision improvement. A hyperintense lesion on T2-weighted/fluid attenuated inversion recovery magnetic resonance imaging and minor vision impairment at the initial ophthalmologic presentation might give hope for a favorable outcome. Performing optic coherence tomography measurements before surgery could clarify patients' expectations regarding their recovery.


Neutrophil migration induced by staphylococcal enterotoxin type A in mice: a pharmacological analysis.
Staphylococcal enterotoxin type A induced marked neutrophil migration into the mouse peritoneal cavity and was dependent on the number of resident macrophages. This migratory response was dose- (16-64 microg of staphylococcal enterotoxin type A/cavity) and time-dependent, peaking at 12 h and disappearing after 72 h. Dexamethasone (0.5 mg/kg) inhibited the neutrophil migration induced by staphylococcal enterotoxin type A (32 microg; 42% inhibition). A similar response was observed with the platelet-activating factor-acether receptor antagonist, BN 52021 (ginkgolide B, 3-(1,1-dimethylethyl)-hexahydro-1,4-7b-trihydroxy-8-methyl-9H-1,7alph a (epoxymethano-1H,6alphaH-cyclopenta (c) furo (2,3-b) furo (3', 2': 3,4) cyclopenta (1,2-d) furan-5, 9, 12 (4H)-trione); 10 mg/kg; 57% inhibition), the histamine H2 receptor antagonist, cimetidine (2 mg/kg; 31% inhibition), the lipoxygenase inhibitor, BWA4C (N-(3-phenoxycinnamyl) acetohydroxamic acid); 10 mg/kg; 73% inhibition), and capsaicin (trans-8-methyl-N-vanillyl-6-nonamide), a sensory C-fiber neuropeptide depletor. In contrast, indomethacin (5 mg/kg) had no effect on staphylococcal enterotoxin type A-induced chemotaxis. We conclude that the peritonitis induced by staphylococcal enterotoxin type A in mice is macrophage-dependent. The mechanism whereby staphylococcal enterotoxin type A stimulates macrophages to induce neutrophil recruitment remains to be elucidated.


Simultaneous quantitation of sphingoid bases and their phosphates in biological samples by liquid chromatography/electrospray ionization tandem mass spectrometry.
We developed a liquid chromatography/electrospray ionization tandem mass spectrometry method for the simultaneous quantitative determination of C18 sphingosine (Sph), C18 dihydrosphingosine (dhSph), C18 phytosphingosine (pSph), C18 sphingosine-1-phosphate (S1P), C18 dihydrosphingosine-1-phosphate (dhS1P), and C18 phytosphingosine-1-phosphate (pS1P). Samples were prepared by simple methanol deproteinization and analyzed in selected reaction monitoring modes. No peak tailing was observed on the chromatograms using a Capcell Pak ACR column (1.5 mm i.d. × 250 mm, 3 μm, Shiseido). The calibration curves of the sphingoids showed good linearity (r > 0.996) over the range of 0.050-5.00 pmol per injection. The accuracy and precision of this method were demonstrated using four representative biological samples (serum, brain, liver, and spleen) from mice that contained known amounts of the sphingoids. Samples of mice tissue such as plasma, brain, eye, testis, liver, kidney, lung, spleen, lymph node, and thymus were examined for their Sph, dhSph, pSph, S1P, dhS1P, and pS1P composition. The results confirmed the usefulness of this method for the physiological and pathological analysis of the composition of important sphingoids.


Dispersal limitation driving phoD-harboring bacterial community assembly: A potential indicator for ecosystem multifunctionality in long-term fertilized soils.
Elucidating the association between the phoD-harboring bacterial community and soil ecosystem multifunctionality, which is crucial for the comprehension of the phoD-harboring bacterial role and contribution in agro-ecosystems, is an essential but rarely investigated subject. Here, we explored the phoD-harboring bacterial community in long-term fertilized soils using amplicon sequencing and multiple analysis methods including the null, neutral, and niche breadth models. We found distance-decay relationships of community similarities against geographical distance on a large spatial scale. Community dissimilarity was significantly lower in the organic fertilization treatment (M) than that in the no (CK) and mineral (NPK) fertilizer treatments. Dispersal limitation governed community assembly in CK, M, NPK, and whole samples, with corresponding relative contributions of 58.2%, 58.3%, 52.8%, and 54.4%, respectively. Electrical conductivity, total carbon, total nitrogen, total phosphorus, organic phosphorus, and available phosphorus were responsible for the community assembly of phoD-harboring bacteria. Multiple model analysis revealed that the phoD-harboring bacterial community was less constrained by the environment and presented flexible metabolism in soils with the M fertilization treatment. phoD-harboring bacteria presented more conflicting interaction and exhibited significantly higher ecosystem multifunctionality in soils with the M fertilization treatment than that in the CK and NPK fertilization treatments. To our knowledge, this is the first study to report a less environment-constrained phoD-harboring bacterial community might lead to a larger difference in ecosystem multifunctionality in fertilized soils. Therefore, we suggest phoD-harboring bacterial community assembly could be a biotic indicator for evaluating soil ecosystem multifunctionality.


Brain receptor binding characteristics and pharmacokinetic-pharmacodynamic analysis of thyrotropin-releasing hormone analogues.
Thyrotropin-releasing hormone (TRH) receptor binding in the rat brain after intravenous (i.v.) injections of novel TRH analogues, taltirelin and montirelin, was examined and the data were analyzed in relation to their plasma concentrations which were simultaneously determined. Taltirelin and montirelin inhibited specific [3H]-Me-TRH binding in the rat brain and their Ki values were 311 and 35.2 nM, respectively. The i.v. injection of taltirelin and montirelin (0.1-3 mg/kg) produced a significant reduction in [3H]-Me-TRH binding sites (Bmax values) in the rat brain. The reduction by both agents tended to reach a maximum after 60 min and lasted up to at least 120 min. On the other hand, the i.v. injection of both agents had little significant effect on the apparent dissociation constant (Kd) for [3H]-Me-TRH in the rat brain. Plasma concentrations of taltirelin and montirelin in rats peaked immediately after i.v. injection, and thereafter they decreased with t 1/2 of 23.0 and 14.1 min, respectively. Counter-clockwise hysteresis between the plasma concentration and receptor occupancy of these agents was observed after the i.v. injection of taltirelin and montirelin, and the temporal delay between plasma concentration and brain receptor occupancy was successfully minimized using the "effect compartment" model in combination with the "linear-effect" model. We concluded that taltirelin and montirelin exert a fairly potent effect following sustained occupation of brain TRH receptors under in vivo condition. Thus, both agents could be clinically useful for the treatment of CNS disorders.


The acute lymphoblastic leukemia of Down Syndrome - Genetics and pathogenesis.
Children with Down Syndrome (DS) are at markedly increased risk for acute lymphoblastic leukemia (ALL). The ALL is of B cell precursor (BCP) phenotype. T-ALL is only rarely diagnosed as well as infant leukemia. Gene expression profiling and cytogenetics suggest that DS-ALL is an heterogeneous disease. More than half of the leukemias are characterized by aberrant expression of the thymic stromal lymphopoietin (TSLP) receptor CRLF2 caused by genomic rearrangements. These rearrangements are often associated with somatic activating mutations in the receptors or in the downstream components of the JAK-STAT pathway. The activation of JAK-STAT pathway suggests that targeted therapy with JAK or downstream inhibitors may be effective for children with DS-ALL. The basis of the increased risk of BCP-ALL and in particular of the CRLF2 aberrations is presently unknown. Neither is it known which genes on the trisomic chromosome 21 are involved.


Pulsed focused ultrasound enhances the therapeutic effect of mesenchymal stromal cell-derived extracellular vesicles in acute kidney injury.
Acute kidney injury (AKI) is characterized by rapid failure of renal function and has no curative therapies. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) are known to carry therapeutic factors, which have shown promise in regenerative medicine applications, including AKI. However, there remains an unmet need to optimize their therapeutic effect. One potential avenue of optimization lies in pulsed focused ultrasound (pFUS), where tissues-of-interest are treated with sound waves. pFUS has been shown to enhance MSC therapy via increased cell homing, but its effects on cell-free EV therapy remain largely unexplored. We combine pFUS pretreatment of the kidney with MSC-derived EV therapy in a mouse model of cisplatin-induced AKI. EVs significantly improved kidney function, reduced injury markers, mediated increased proliferation, and reduced inflammation and apoptosis. While pFUS did not enhance EV homing to the kidney, the combined treatment resulted in a superior therapeutic effect compared to either treatment alone. We identified several molecular mechanisms underlying this synergistic therapeutic effect, including upregulation of proliferative signaling (MAPK/ERK, PI3K/Akt) and regenerative pathways (eNOS, SIRT3), as well as suppression of inflammation. Taken together, pFUS may be a strategy for enhancing the therapeutic efficacy of MSC-derived EV treatment for the treatment of AKI.


Synthesis, structure and photophysical properties of a 2-(1'-hydroxypyrenyl)benzothiazole.
A pyrene-based 2-aryl-benzothiazole derivative, 2-(1'-hydroxypyrenyl)benzothiazole (1H2PBT), was synthesized. Its crystal structure and photophysical properties were investigated. In comparison with the generally studied parent compound, 2-(2'-hydroxyphenyl)benzothiazole (HBT), 1H2PBT exhibited red-shifted absorption and emission in solution, as well as impressive solid state emission with high efficiency (0.35).


Antibiofilm potential over time of a tricalcium silicate material and its association with sodium diclofenac.
The objectives of this study are to investigate, over time, the antimicrobial activity against polymicrobial biofilms and ability to inhibit biofilm formation, of Biodentine (BD) alone and with 5% and 10% sodium diclofenac (DC). The antimicrobial activity of BD alone and modified with 5% and 10% DC against polymicrobial biofilm growth in dentin was determined by a modified direct contact test. The study groups were (1) BD; (2) BD + 5% DC; and (3) BD + 10% DC. The viability of microorganisms after 1 and 4 weeks was quantified by means of an ATP assay and flow cytometry. The antibiofilm efficacy of the materials, preventing polymicrobial biofilm formation over time, was assessed by confocal laser scanning microscopy (CLSM). The results obtained with both the ATP test and flow cytometry showed that BD alone and with 5% and 10% DC exerted antibiofilm activity with respect to the control, in the two evaluated times (p < 0.001). Comparison between groups showed a tendency of increased antimicrobial effect, both over time and depending on the DC concentration. These results coincide with those obtained in CLSM analysis, where efficacy increased with time and DC concentration. Biodentine, over time, showed antimicrobial and antibiofilm efficacy on polymicrobial biofilms. The addition of 5% and 10% DC to BD enhanced this effect, in a concentration- and time-dependent manner.


Fast-track vs. delayed insertion of the levonorgestrel-releasing intrauterine system after early medical abortion - a randomized trial.
To compare levonorgestrel (LNG) 52-mg intrauterine system (IUS) expulsion rates with fast-track (≤3 days) or delayed (2-4 weeks) insertion following mifepristone and misoprostol medical abortion. In this pilot trial, we randomized 108 women at ≤63 days' gestation to fast-track (n=55) or delayed (n=53) insertion. Follow-up visits occurred at 2-4 weeks, 3 months and 1 year. We assessed total and partial expulsion at 3 months and 1 year, adverse effects and bleeding profiles. We had follow-up data at 3 months and 1 year for 41 (74.5%) and 37 (69.8%) women in the fast-track group and 31 (56.4%) and 28 (52.8%) women in the delayed group. By 3 months, expulsion occurred in six (12.5%) women after fast-track and one (2.3%) woman after delayed insertion [risk ratio (RR) 5.50, 95% confidence interval (CI) 0.69-43.90]; most (n=5) of these were partial expulsions in the fast-track group. By 1 year, expulsion had occurred in seven (14.6%) and five (11.5%) women in the fast-track and delayed groups, respectively (RR 1.28, 95% CI 0.44-3.75). We found no differences in rates of vacuum aspiration, residual tissue, infection and bleeding or bleeding patterns within 3 months of insertion. Fast-track insertion of the LNG 52-mg IUS after medical abortion is feasible but may result in higher expulsion rates compared to delayed insertion. Due to lack of statistical power and high lost-to-follow-up rates, we were unable to fully address this question. Fast-tract initiation of LNG 52-mg IUS contraception after medical abortion is feasible. It results in higher expulsion rates than delayed insertion but may improve postabortal intrauterine contraception uptake.


Anal cancer FDG-PET standard uptake value: correlation with tumor characteristics, treatment response and survival.
The present work studies the correlation of (18) F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) standardized uptake value (SUV) with tumor characteristics, clinical response and prognosis in a series of anal canal cancer patients treated with chemo-radiotherapy. Fifty-five patients were included in the present analysis. PET maximum SUV (SUVmax) of primary tumor was calculated for each patient. The correlation with clinical parameters, tumor response and survival data were analyzed. SUVmax significantly correlated with T-stage (p = 0.01) and histology (p = 0.03). Median SUVmax was higher for lesions with partial response (PR, 21/55, 38%) than for lesions with complete response (CR, 34/55, 62%) but without statistical significance (p = 0.17). The actuarial disease-free survival (DFS) and overall survival (OS) rates were 53.0 and 77.8% at 2 years and 41.3 and 58.6% at 5 years, respectively. Median SUVmax did not statistically correlate with clinical response or survival. CR and T1-T2 stage were statistically significant prognostic factors for disease-free survival (p < 0.0001 and p = 0.02, respectively) and CR was significant also for overall survival (p < 0.0001). Our data suggest that pre-treatment FDG-PET/CT SUVmax cannot directly predict tumor response and survival, but it is strongly associated with tumor characteristics such as primary tumor stage and histology, being the first one of the most important and validated prognostic factors for anal cancer.


Opioid peptides reduce synaptic transmission in the nucleus accumbens.
Behavioral studies implicate the nucleus accumbens (NAcc) as a brain area pivotal for the rewarding effects of opiates like heroine and morphine. Therefore, we studied the effect of a variety of opioids on membrane properties and responses to synaptic stimulation in a slice preparation of the NAcc using intracellular recording. Superfusion of opioid peptides did not affect the membrane potential or input resistance of NAcc neurons, but significantly reduced both depolarizing and hyperpolarizing synaptic potentials. Naloxone superfusion significantly reversed the depressant effects of the mu and delta receptor agonists (but not those of the kappa agonist) on synaptic transmission, suggesting involvement of opiate receptors. These results imply that the predominant effect of opiates in NAcc is a reduction of synaptic transmission.


Combined effects of engineered tendon matrix and GDF-6 on bone marrow mesenchymal stem cell-based tendon regeneration.
To examine whether an engineered tendon matrix (ETM) environment and growth and differentiation factor-6 (GDF-6) have synergistic effects on the tenogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and the quality of tendon repair. ETM and GDF-6 promote tenogenic differentiation of BMSCs in vitro. Implantation of GDF-6-incorporated ETM containing BMSCs into a tendon injury model significantly improved the histological and mechanical properties of the repaired tendon. GDF-6-incorporated ETM containing BMSCs represents a promising strategy for tendon injury repair.


Safety and clinical efficacy of flexible sigmoidoscopy and colonoscopy for gastrointestinal bleeding after myocardial infarction. A six-year study of 18 consecutive lower endoscopies at two university teaching hospitals.
The risks versus benefits of flexible sigmoidoscopy and colonoscopy performed within three weeks of myocardial infarction were studied in nine consecutive patients who underwent sigmoidoscopy and in nine consecutive patients who underwent colonoscopy at two university hospitals. Indications for sigmoidoscopy were red blood per rectum in seven and occult blood in the stools in two. Sigmoidoscopy provided the diagnosis in three, including colon cancer in two and bleeding internal hemorrhoids in one, and provided helpful information in three. Sigmoidoscopy led to colon cancer surgery in two patients, and polypectomy of a 1-cm adenoma in one. Of two highly unstable patients before sigmoidoscopy, one developed second-degree heart block and frequent premature ventricular contractions 3 hr after sigmoidoscopy. No sigmoidoscopic complications occurred in the seven relatively clinically stable patients. Indications for colonoscopy included red blood per rectum in five, occult blood in the stools in three, and melena in one. Colonoscopy provided the diagnosis in five, including one each with colon cancer, internal hemorrhoids, large adenoma, ischemic colitis, and angiodysplasia. Colonoscopy resulted in colon cancer surgery in one patient and endoscopic polypectomies in three patients. Of two moderately unstable patients before colonoscopy, one developed asymptomatic bradycardia during colonoscopy. No colonoscopic complications occurred in the seven clinically stable patients. This study suggests that recent myocardial infarction is not an absolute contraindication to sigmoidoscopy or colonoscopy, that sigmoidoscopy is beneficial in medically stable patients with significant gastrointestinal bleeding, and that colonoscopy may be beneficial in selected, highly stable patients with significant gastrointestinal bleeding.(ABSTRACT TRUNCATED AT 250 WORDS)


Tensiometry as a measure of improvement in knot quality in undergraduate medical students.
This study examined the validity of tensiometry as an objective method of assessing the improvements in the quality of knots and technical performance due to practice on suturing and knot-tying skills. We evaluated the quality of 1,830 knots produced by undergraduate medical students before training (pre-test), after (post-test), and after a week retention (retention-test) using tensiometry. These results were compared to expert-based assessments of products and performance. Tensiometry, as well as expert-based assessments can detect changes in the quality of knots and technical performance from pre to post and retention-test ( p<0.05). However, these three methods may assess different dimensions of the same products and actions. The development of trainee evaluation criteria for the acquisition of surgical skills is a crucial element in surgical education. Based on our patterns of results it is hypothesized that tensiometry can serve as an economic first approximation of the quality of knots and suturing performance.


Isolation and culture of rodent osteoprogenitor cells.
Osteoblasts are the cells responsible for formation of new bone throughout life. Rats are one of the most widely studied mammalian species in skeletal biology and serve as useful models for many aspects of human skeletal physiology. The availability of genetically modified mice as research tools has greatly enabled our understanding of how specific genes contribute to the process of skeletogenesis. In order to explore the impact of biochemical, genetic, or pharmacological manipulation on bone formation, various osteogenic cell culture systems have been developed. Two of the most widely accepted rodent osteogenic culture models, using osteoprogenitor cells isolated from calvaria or bone marrow, are described in this chapter.


Evaluation of boron nitride nanotubes and hexagonal boron nitrides as nanocarriers for cancer drugs.
Boron nitride nanotubes (BNNTs) and hexagonal boron nitrides (hBNs) are novel nanostructures with high mechanical strengths, large surface areas and excellent biocompatibilities. Here, the potential use of BNNTs and hBNs as nanocarriers was comparatively investigated for use with cancer drugs. Doxorubicin (Dox) and folate are used as model drugs and targeting agents, respectively. The obtained results indicate that BNNTs have about a threefold higher Dox loading capacity than hBNs. It was also found that cellular uptake of folate-Dox-BNNTs was much higher when compared with Dox-BNNTs for HeLa cells, due to the presence of folate receptors on the cell surface, leading to increased cancer cell death. In summary, folate and Dox conjugated BNNTs are promising agents in nanomedicine and may have potential drug delivery applications.


Patient-reported outcome measures in drugs for neurological conditions approved by European Medicines Agency 2017-2022.
Regulatory agencies have been responsive to public demand for inclusion of the patient experience in evaluating and approving therapies. Over the years, patient-reported outcome measures (PROMs) have become increasingly prevalent in clinical trial protocols; however, their influence on regulators, payers, clinicians, and patients' decision-making is not always clear. We recently conducted a cross-sectional study aimed at investigating the use of PROMs in new regulatory approvals of drugs for neurological conditions between 2017 and 2022 in Europe. We reviewed European Public Assessment Reports (EPARs) and recorded on a predefined data extraction form whether they considered PROMs, their characteristics (e.g., primary/secondary endpoint, generic/specific instrument) and other relevant information (e.g., therapeutic area, generic/biosimilar, orphan status). Results were tabulated and summarized by means of descriptive statistics. Of the 500 EPARs related to authorized medicines between January 2017 and December 2022, 42 (8%) concerned neurological indications. Among the EPARs of these products, 24 (57%) reported any use of PROMs, typically considered as secondary (38%) endpoints. In total, 100 PROMs were identified, of which the most common were the EQ-5D (9%), the SF-36 (6%), or its shorter adaptation SF-12, the PedsQL (4%). Compared to other disease areas, neurology is one where the use of patient-reported outcomes evidence is inherently part of the clinical evaluation and for which core outcome sets exist. Better harmonization of the instruments recommended for use would facilitate the consideration of PROMs at all stages in the drug development process.


Pregnancy outcomes after recurrent pregnancy loss: a longitudinal cohort study on stress and depression.
Are self-reported symptoms of stress and depression associated with pregnancy outcomes within the first year after referral to a tertiary recurrent pregnancy loss unit? Prospective cohort study with online questionnaires using the Major Depression Inventory (MDI) and Cohen's Stress Scale (PSS) at referral and after 1 year. The study was conducted between 2010 and 2014. A total of 301 women who had experienced recurrent pregnancy loss completed the first questionnaire. One year after referral, 185 women (61%) completed a follow-up questionnaire. A score above the threshold for major depression on the MDI at referral was not a predictor for outcome in the first pregnancy after referral; OR (95% CI) for live birth 1.71 (0.66 to 4.44), neither was increasing scores on the PSS: OR 0.98 (95% CI 0.94 to 1.02). At follow-up, women who had achieved a pregnancy resulting in a live birth had significantly lower scores on both the MDI: 13.45 (11.05) versus 11.04 (11.07); difference -2.41 (95% CI -4.60 to -0.23); and the PSS: mean 17.69 (7.59) versus 13.03 (6.83); difference -4.66 (95% CI -6.04 to -3.28), respectively. This was not the case for women who did not have a successful pregnancy. Women who experienced recurrent pregnancy loss after a successful birth were less likely to report symptoms corresponding to major depression than women who had only experienced losses (n = 7 [5%] versus 19 [12%]; P = 0.04). Self-reported emotional distress did not affect future chance of live birth. A live born child decreased emotional distress.


Involvement of botulinum C3-sensitive GTP-binding proteins in alpha 1-adrenoceptor subtypes mediating Ca(2+)-sensitization.
The mechanisms of alpha 1-adrenoceptor agonist-mediated sensitization of the contractile apparatus of smooth muscle to Ca2+ were studied in beta-escin-permeabilized thoracic arterial smooth muscle of rabbit. Addition of norepinephrine (10 microM) plus guanosine 5'-triphosphate (GTP, 50 microM) significantly enhanced Ca2+ sensitivity as compared with the addition of 0.3 microM Ca2+ alone (pCa6.5). In beta-escin-skinned smooth muscle of chloroethylclonidine-treated tissues, the enhancement of Ca(2+)-contraction produced by norepinephrine or clonidine was completely inhibited by guanosine 5'-O-(beta-thiodiphosphate) (GDP beta-S, 1 mM). In addition, Clostridium botulinum C3, which inactivates low molecular weight GTP-binding protein families, abolished norepinephrine- or clonidine-induced Ca(2+)-sensitization, but did not affect clonidine-induced translocation of protein kinase C to the membrane. The norepinephrine-enhanced Ca2+ sensitivity was partially reversed by a pretreatment with a selective myosin light chain kinase inhibitor (8R*, 9S*, 11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-14-n- propoxy-2,3,9,10-tetrahydro-8,11-epoxy,1H,8H,11H-2,7b,11a- triazadibenzo[a,g]cycloocta[cde]trinden-1-one (KT5926, 500 nM), but those of clonidine and in the chloroethylclonidine-treated tissues norepinephrine were not. These results suggest that Ca(2+)-sensitization produced by the activation of the alpha 1-adrenoceptor subtypes is linked via a low molecular weight GTP-binding protein (Rho), and the regulations of phosphorylation in contractile elements.


Protoporphyrin IX-mediated sonodynamic action induces apoptosis of K562 cells.
The present study aims to investigate apoptosis of human leukemia K562 cells induced by protoporphyrin IX (PpIX)-mediated sonodynamic therapy (PpIX-SDT). The uptakes of intracellular PpIX in K562 cells were detected by flow cytometry. The sub-cellular localization of PpIX was imaged by confocal microscope. The cytotoxic effect of PpIX-SDT was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenylter-trazolium bromide tetrazolium) assay. Apoptosis was evaluated by chromatin condensation with DAPI (4'-6-diamidino-2-phenylindole) staining, decrease of mitochondria membrane potential (MMP), re-distribution of Bax, and the expression changes of the key apoptosis-associated protein (Caspase-3 and polypeptide poly (ADP-robose) polymerase). The possible mechanism of SDT-induced apoptosis was investigated by detecting by intracellular ROS (reactive oxygen species) generation and effect of ROS scavenger-NAC (N-acetylcysteine) on SDT induced apoptosis. The intracellular PpIX increased quickly within 2 h after PpIX administration and PpIX mainly localized in the mitochondria. Compared with PpIX alone and ultrasound alone groups, the synergistic cytotoxicity of PpIX plus ultrasound was significantly boosted. In addition, the ultrasound induced some extent of chromatin condensation and MMP loss was greatly enhanced by the presence of 2 μg/ml PpIX, where PpIX alone treatment showed no or only slight effect. Time-dependent Bax translocation, caspase-3 activation and PARP cleavage were detected in SDT treatment groups. Besides, intracellular ROS production was significantly enhanced after SDT, and the general ROS scavenger NAC could obviously alleviate the SDT-caused cell viability loss, MMP loss, Bax redistribution and nuclear changes. These results indicated that PpIX-mediated sonodynamic action could induce apoptosis on K562 cells, and the intracellular ROS was involved in the PpIX-SDT induced apoptosis.


Using Trigger Films as a Bariatric Sensitivity Intervention: Improving Nursing Students' Attitudes and Beliefs About Caring for Obese Patients.
Nurse educators are uniquely positioned to improve obesity-related attitudes and beliefs among prelicensure nursing students. A bariatric sensitivity intervention using 6 trigger films with facilitated debriefing was designed and delivered to 70 first-semester baccalaureate nursing students. Attitudes and beliefs significantly improved immediately after the intervention on 3 of the 5 attitude measures and on the belief measure. Improvements in beliefs/attitudes were sustained 30 days after the intervention but may require content reinforcement throughout the curriculum for long-term effects.


Ventriculobiliary Shunts, Another Option.
The basic management of hydrocephalus includes shunts to the peritoneum and atrium. However, there are particularly complex patients in whom it is necessary to look for atypical places for implanting the distal catheter. Since 2000, 1,325 shunts have been implanted in pediatric patients. Only 3 patients required a ventriculobiliary shunt. We report 3 cases: a 7-year-old boy with a surgically treated complex heart disease, a 16-month-old girl with hydrocephalus secondary to a brain tumor and multiple bacteremias secondary to an infection of the central venous reservoir, and a 4-year-old girl with nonreabsorptive hydrocephalus caused by intraventricular bleeding due to premature birth, necrotizing enterocolitis and shunt infections with abdominal pseudocysts, which caused multiple abdominal septations and, finally, a nonreabsorptive peritoneum. At present, cases 1 [45 months after ventriculobiliary shunt (VBS)] and 3 (27 months after VBS) are symptom free, while case 2 (14 months after VBS) died of infectious respiratory complications. The gold standard for the treatment of nonreabsorptive hydrocephalus is a ventriculoperitoneal shunt, the second option is a ventriculoatrial shunt, and the third option is uncertain. In our short experience, a ventriculo-gallbladder shunt is a good option when there is no abdominal hypertension.


Surgical management of giant calcified thoracic disc herniation and the role of neuromonitoring. The outcome of large mono centric series.
Giant thoracic disc herniations (GTDH) are considered a subgroup of TDHs with worse functional outcomes, a high calcification rate, and a considerable risk of complications. We aimed to determine whether there is a relationship between the extent of calcification of GTDH and outcomes concerning the risk of complications, the surgical technique, and changes in neuromonitoring signals. We present a retrospective analysis of 76 patients undergoing surgery for calcific GTDH. We introduced and defined a radiological definition of the calcified disc into"fully calcified" and "partially calcified." We performed a statistical analysis between clinical and radiological variables, type of surgical procedure, the extent of excision, neuro-monitoring signals, and outcome, comparing a group of 58 "fully-calcified TDH" patients and 18 "partially-calcified TDH" patients. Fully calcified TDHs, compared with partially calcified TDHs, do not have significant differences in outcome (worse outcome 4/58-6.9% versus 0/18, p = 0.25) and complications (10/58-17.24% versus 4/18-22.2%, p = 0.63); Fully calcified TDH is associated with a higher risk of alterations in neurophysiological potentials (14/58-24.1% versus 0/18, p = 0.02) and subtotal excision (18/58-31% versus 2/18-11%, p = 0.15), without significant differences between the approaches used. Fully calcified TDH group has a similar outcome and complication rate as the partially calcified TDH group, but they are associated with higher intraoperative neuromonitoring signal changes. We introduced a new classificationsystem that guides the approach and helps tocounsel the patients.


Glucose-lowering drugs, cognition, and dementia: The clinical evidence.
Type 2 diabetes mellitus (T2DM) is an important risk factor for dementia. The possibility to mitigate this risk by controlling T2DM is compelling; however, different glucose-lowering drugs have different effects on the brain by virtue of their different mechanisms of action. The clinical and epidemiological data appear mixed, warranting careful critical evaluation of the human studies. Here we examine the evidence in the context of dementia prevention and treatment, both for people with and without T2DM. We discuss the evidence on this scaffold of research directions, identifying methodological complexities in the extant literature (e.g. comparator discrepancies, changes in the therapeutic landscape), and the implications of different outcome measures (e.g. neuropsychological). We consider possible implications of cerebrovascular protection vs. effects on progression of neurodegenerative proteinopathy, and we present a research roadmap for glucose-lowering drugs in cognitive neurology, including neuroimaging, and fluid biomarkers. We conclude that there is great potential to advance personalized strategies to prevent and treat dementia with glucose-lowering drugs.


Congenitally corrected transposition of the great arteries.
Congenitally corrected transposition of the great arteries (cTGA) is an uncommon cardiac malformation characterized by discordant atrioventricular and ventriculoarterial connections. Most cases of cTGA are associated with cardiac anomalies. As the ventricular outflow tract may appear to arise correctly from the right and left ventricles, cases of cTGA with a mild associated anomaly are rarely detected prenatally. Parallel vessels are evident in cTGA, but this sign is also present in complete TGA. We report a case of cTGA diagnosed in utero at 29 weeks' gestation. The fetus was diagnosed as TGA and referred to our hospital at 28 weeks' gestation. cTGA was found at 29 weeks' gestation in our hospital, and no additional cardiac anomalies were seen prenatally. After birth, patent ductus arteriosus with bidirectional flow was present. Careful examination of the four-chamber view suggested atrioventricular discordance. Identification of a parallel course of the great vessels, with the aorta anterior and to the left of the pulmonary trunk (l-transposition), may help accurate prenatal diagnosis of cTGA.


Overview of the management of atrial fibrillation: what is the current state of the art?
Management of Atrial Fibrillation. There are three fundamental approaches to the management of atrial fibrillation (AF): rate control, rhythm control, and anticoagulation. Selecting a course of treatment requires a thorough knowledge of these therapeutic alternatives. This article explores treatment options, including the relative benefits of rate control versus rhythm control, which are complicated by the lack of highly effective and safe antiarrhythmic drugs. Anticoagulation is also an important issue in AF management, and warfarin effectively reduces the incidence of thromboembolic events in AF patients. The use of warfarin, however, presents its own complications. We conclude that individualization of therapy is paramount when treating AF.


Inflammatory pseudotumours of the urinary bladder in dogs resembling human myofibroblastic tumours: a report of eight cases and comparative pathology.
Eight cases of inflammatory myofibroblastic tumours (IMT) of the urinary bladder in dogs are described, including their clinical, imaging, morphological, and histopathological aspects. Old small breed female dogs were more commonly affected. Haematuria was the main clinical sign, often associated with dysuria and crystalluria. The IMT appeared as single or multiple, polypoid, firm masses, measuring 1-7 cm. Histologically, the masses were well delineated, covered by a benign hyperplastic urothelium and diffusely infiltrated by a mixed inflammatory component. The cells were spindle-shaped, adopting a fascicular, pallisading or whirling organisation and were vimentin and variably desmin and actin positive. The nuclei were globular, containing open chromatin and prominent nucleoli. Mild to moderate pleomorphism and little mitotic activity were present. These morphological features are compatible with human myofibroblastic inflammatory tumours.


Exploring policy compliance of the South African informal milk-producing segment.
Our study assessed whether municipal health services were informed about and exerted adequate control over the informal milk-producing sector in South Africa. The results indicated that municipal health services had limited control. Only one municipality was authorised to allow the sale of raw milk in its area. In most metropolitan and district municipalities, the distribution of raw milk continues, even where no statutory investigations assessed the ability to control the practice. The national and provincial government should recognise and support capacity building to enable municipalities to exercise power and perform their functions regarding informal milk distribution, part of the informal sector that has provided opportunities for employment and additional income. This constitutes a challenge particularly in monitoring and control of high-risk foods.


Highly Transparent and Self-Healable Solar Thermal Anti-/Deicing Surfaces: When Ultrathin MXene Multilayers Marry a Solid Slippery Self-Cleaning Coating.
Solar anti-/deicing can solve icing problems by converting sunlight into heat. One of the biggest problems, which has long been plaguing the design of solar anti-/deicing surfaces, is that photothermal materials are always lightproof and appear black, because of the mutual exclusiveness between generating heat and retaining transparency. Herein, a highly transparent and scalable solar anti-/deicing surface is reported, which enables the coated glass to exhibit high transparency (>77% transmittance at 550 nm) and meanwhile causes a >30 °C surface temperature increase relative to the ambient environment under 1.0 sun illumination. Such a transparent anti-/deicing surface can be fabricated onto a large class of substrates (e.g., glass, ceramics, metals, plastics), by applying a solid omniphobic slippery coating onto layer-by-layer-assembled ultrathin MXene multilayers. Hence, the surface possesses a self-cleaning ability to shed waterborne and oil-based liquids thanks to residue-free slipping motion. Passive anti-icing and active deicing capabilities are, respectively, obtained on the solar thermal surface, which effectively prevents water from freezing and simultaneously melts pre-formed ice and thick frost. The self-cleaning effect enables residue-free removal of unfrozen water and interfacially melted ice/frost to boost the anti-/deicing efficiency. Importantly, the surface is capable of self-healing under illumination to repair physical damage and chemical degradation.


Biochar for simultaneously enhancing the slow-release performance of fertilizers and minimizing the pollution of pesticides.
Biochar has been extensively studied as a promising carrier material for fertilizers and an ideal adsorbent for the removal of pesticides. Yet, the application of biochar for simultaneously eliminating the pollution from the agricultural use of fertilizers and pesticides remains unexplored. Herein, we develop P-loaded biochar-based fertilizers (PBC) by the co-pyrolysis of cotton straw and H3PO4. The slow-release performance of PBC and their adsorption properties toward pesticides are investigated. The results indicate that the PBC leads to the improvement of adsorption performance, with the maximum adsorption capacities of lambda-cyhalothrin (LAC) for PBC and pristine biochar are 55.90 mg/g and 42.71 mg/g, respectively. Additionally, the adsorption of LAC is beneficial for the improvement of slow-release performance of PBC. The release ratios of P from PBC within 30 days reach 100.0% and 83.5% in water and LAC solution, respectively, demonstrating the existence of synergistic effects between the adsorption of pesticides and the slow release of nutrients. The mechanistic investigation reveals that the pretreatment of H3PO4 facilitates to activate more surface functional groups of PBC, contributing greatly to the improved adsorption of LAC. The adsorption of LAC reduces the BET of PBC with pore filling, enabling slower release rate of nutrients from PBC.


[General Estimation of Cardiovascular Risk].
The assessment of individual cardiovascular disease risk (CVD) is essential for a cost-effective prevention of cardiovascular morbidity and mortality. While almost half of the population have a very low CVD risk approximately 1/5th of the population have a CVD risk >20% over the next 10 years.Modern risk scores like the ESC-SCORE2 help to identify those in need of intensified preventive efforts based on basic risk factors like smoking, systolic blood pressure, total cholesterol, age, and sex. According to current ESC-guidelines all men >45 years and all women >55 years should be assessed with SCORE2, which is the best calibrated and validated scoring system for Europe.The calculation of total cardiovascular risk also permits to calculate an individual heart-age, which makes it easier for the individual patient to understand his own risk profile. Most current risk estimation systems can be accessed online under u-prevent.com/calculators.


Considerations in the Development of Small-Diameter Vascular Graft as an Alternative for Bypass and Reconstructive Surgeries: A Review.
Current design strategies for small diameter vascular grafts (< 6 mm internal diameter; ID) are focused on mimicking native vascular tissue because the commercially available grafts still fail at small diameters, notably due to development of intimal hyperplasia and thrombosis. To overcome these challenges, various design approaches, material selection, and surface modification strategies have been employed to improve the patency of small-diameter grafts. The purpose of this review is to outline various considerations in the development of small-diameter vascular grafts, including material choice, surface modifications to enhance biocompatibility/endothelialization, and mechanical properties of the graft, that are currently being implanted. Additionally, we have taken into account the general vascular physiology, tissue engineering approaches, and collective achievements of the authors in this area. We reviewed both commercially available synthetic grafts (e-PTFE and PET), elastic polymers such as polyurethane and biodegradable and bioresorbable materials. We included naturally occurring materials by focusing on their potential application in the development of future vascular alternatives. Until now, there are few comprehensive reviews regarding considerations in the design of small-diameter vascular grafts in the literature. Here-in, we have discussed in-depth the various strategies employed to generate engineered vascular graft due to their high demand for vascular surgeries. While some TEVG design strategies have shown greater potential in contrast to autologous or synthetic ePTFE conduits, many are still hindered by high production cost which prevents their widespread adoption. Nonetheless, as tissue engineers continue to develop on their strategies and procedures for improved TEVGs, soon, a reliable engineered graft will be available in the market. Hence, we anticipate a viable TEVG with resorbable property, fabricated via electrospinning approach to hold a greater potential that can overcome the challenges observed in both autologous and allogenic grafts. This is because they can be mechanically tuned, incorporated/surface-functionalized with bioactive molecules and mass-manufactured in a reproducible manner. It is also found that most of the success in engineered vascular graft approaching commercialization is for large vessels rather than small-diameter grafts used as cardiovascular bypass grafts. Consequently, the field of vascular engineering is still available for future innovators that can take up the challenge to create a functional arterial substitute.


Physician Wellness Across the Professional Spectrum.
Physician wellness and burnout are areas of increasing exploration. Physicians are more likely than the general population to suffer the effects of burnout and neglect their own wellness; medicine and its training are deeply engrained with the care of others, often to the detriment of self. The effects vary based on the stage of career for medical trainees and physicians. However, strategies exist to screen for and help alleviate the negative effects of burnout and to improve wellness among physicians. This will continue to be an area warranting further exploration despite increasing awareness regarding the health and well-being of physicians.


Multi-virulence-locus sequence typing clarifies epidemiology of recent listeriosis outbreaks in the United States.
Multi-virulence-locus sequence typing (MVLST) was used to analyze isolates from two major listeriosis outbreaks in the United States in 1998 and 2002 that were due to consumption of contaminated hot dogs and turkey deli meat, respectively. MVLST demonstrated high epidemiological relevance and indicated that the two outbreaks were the result of one epidemic.


Two case reports of neuroinvasive West Nile virus infection in the Almaty region, Kazakhstan.
West Nile virus (WNV) is a member of the genus Flavivirus, which transmitted to humans mainly by mosquitoes. Recent pilot serosurveillance data from the Almaty region, Kazakhstan, suggest widespread WNV circulation in this area. This report includes two cases of neuroinvasive WNV infection in the same family living in a rural area near Tekeli city, Eskeldinsky district, Almaty region, Kazakhstan. Occurring concurrently and manifesting as WNV infection with febrile illness and symptoms of meningoencephalitis. The study performed retrospective analysis of clinical histories and achieved serum samples obtained from patients with febrile and meningoencephalitic syndromes of unknown origin in the Almaty region spanning from April 1 to October 31, 2019. All sera samples obtained from patients with clinically suspected cases of acute WNV infection were retrospectively tested for WNV and tick-borne encephalitis virus by commercial immunoassays. Two cases were selected. We report two cases that occurred in August 2019 in a rural area near Tekeli city. Previously healthy 28- and 19-year-old husband and wife with febrile illness and neurological manifestations were hospitalized with the diagnosis of meningoencephalitis of unknown etiology and treated empirically. Retrospective serological analysis showed the presence of high titers of IgG against WNV on day 9 after onset of symptoms in cases. This is the first report of aseptic meningitis with WNV infection in the background in Kazakhstan. The obtained data suggest circulation of WNV in the Almaty region and emphasize importance of laboratory testing for WNV in suspicious cases occurring in the region.