Is in vitro fertilisation more effective than stimulated intrauterine insemination as a first-line therapy for subfertility? A cohort analysis.
To compare a strategy of two cycles of intrauterine insemination with controlled ovarian hyperstimulation (IUI/COH) vs one in vitro fertilisation (IVF) treatment programme (one fresh plus associated frozen embryo cycles) in couples presenting with unexplained, mild male or mild female subfertility. A retrospective cohort design was used and analysed according to intention-to-treat principles. A total of 272 couples underwent an intended course of two cycles of IUI/COH and 176 couples underwent one IVF treatment programme. The cumulative live birth rate (CLBR) per couple for the IUI/COH group was 27.6% compared to 39.2% for the IVF group (P = 0.01). The mean time to pregnancy was 69 days in the IUI/COH group compared to 44 days in the IVF group (P = 0.02). The IVF programme was costlier, with an incremental cost-effectiveness ratio for an additional live birth in the range of $39,637-$46,325. The multiple delivery rate was 13.3% in the IUI/COH group compared to 10.1% in the IVF group (P = 0.55). One set of triplets and one set of quadruplets followed IUI/COH treatment. One IVF treatment programme was more effective, but costlier than an intended course of two cycles of IUI/COH. With consistently higher success rates, shorter times to pregnancy and a trend to less higher order multiple pregnancies, this study supports the view that IVF is now potentially safer and more clinically effective than IUI/COH as a first-line therapy for subfertility.


Sensitivity, specificity, and clinical value of human papillomavirus (HPV) E6/E7 mRNA assay as a triage test for cervical cytology and HPV DNA test.
There is evidence that testing for human papillomavirus (HPV) E6/E7 mRNA is more specific than testing for HPV DNA. A retrospective study was carried out to evaluate the performance of the PreTect HPV-Proofer E6/E7 mRNA assay (Norchip) as a triage test for cytology and HPV DNA testing. This study analyzed 1,201 women, 688 of whom had a colposcopy follow-up and 195 of whom had histology-confirmed high-grade intraepithelial neoplasia or worse (CIN2+). The proportion of positive results and the sensitivity and specificity for CIN2+ were determined for HPV mRNA in comparison to HPV DNA and cytology. All data were adjusted for follow-up completeness. Stratified by cytological grades, the HPV mRNA sensitivity was 83% (95% confidence interval [CI] = 63 to 94%) in ASC-US (atypical squamous cells of undetermined significance), 62% (95% CI = 47 to 75%) in L-SIL (low-grade squamous intraepithelial lesion), and 67% (95% CI = 57 to 76%) in H-SIL (high-grade squamous intraepithelial lesion). The corresponding figures were 99, 91, and 96%, respectively, for HPV DNA. The specificities were 82, 76, and 45%, respectively, for HPV mRNA and 29, 13, and 4%, respectively, for HPV DNA. Used as a triage test for ASC-US and L-SIL, mRNA reduced colposcopies by 79% (95% CI = 74 to 83%) and 69% (95% CI = 65 to 74%), respectively, while HPV DNA reduced colposcopies by 38% (95% CI = 32 to 44%) and by 15% (95% CI = 12 to 19%), respectively. As a HPV DNA positivity triage test, mRNA reduced colposcopies by 63% (95% CI = 60 to 66%), having 68% sensitivity (95% CI = 61 to 75%), whereas cytology at the ASC-US+ threshold reduced colposcopies by 23% (95% CI = 20 to 26%), showing 92% sensitivity (95% CI = 87 to 95%). In conclusion, PreTect HPV-Proofer mRNA can serve as a better triage test than HPV DNA to reduce colposcopy referral in both ASC-US and L-SIL. It is also more efficient than cytology for the triage of HPV DNA-positive women. Nevertheless, its low sensitivity demands a strict follow-up of HPV DNA positive-mRNA negative cases.


Blood pressure control in patients with hypertension: a retrospective cohort study.
Hypertension (HT) is prevalent in Turkey and even with pharmacological interventions HT control rates do not meet guideline recommendations. We aimed to estimate the proportion of hypertensive patients who achieved target blood pressure (BP) and seek to determine the predictors responsible for failure of to reach goals. We conducted a retrospective cohort study involving patients with HT. A total of 437 patients were identified with a current diagnosis of HT at baseline. All available predictors for BP improvements were included in the multivariate linear regression model. Follow-up data on HT goal achievements was available for 276 (63.1%) participants. Only 18.1% of the patients at the baseline visit, and 48.6% at the follow-up visit achieved the overall SBP/DBP targets specified by the JNC-8 guideline. Significant differences were determined by baseline and 1st visit measurements of mean SBP/DBP levels (P < 0.001, P < 0.001, respectively). DM and baseline SBP were positively associated with SBP improvement (β = 8.410, P = 0.003; β = 0.692, P < 0.001, respectively), whereas being prescribing more HT medications and being older were negatively associated with improvement (β = -7.968, P = 0.005; β = -5.707, P = 0.037; respectively). DM, baseline DBP and HT duration were positively associated with DBP improvement (β = 4.539, P = 0.012; β = 0.702, P < 0.001; β = 0.023, P = 0.012; respectively), whereas additional HT medications and GFR values were negatively associated with improvement (β = -5.682, P = 0.002; β = -0.098, P = 0.005; respectively). Although the progress in achieving in BP targets was encouraging, only half of patients had reached the HT goals. Adequate pharmacological approaches and comprehensive management strategies should be implemented in hypertensive patients.


Step-by-step guide to reduce spatial coherence of laser light using a rotating ground glass diffuser.
Wide field-of-view imaging of fast processes in a microscope requires high light intensities motivating the use of lasers as light sources. However, due to their long spatial coherence length, lasers are inappropriate for such applications, as they produce coherent noise and parasitic reflections, such as speckle, degrading image quality. Therefore, we provide a step-by-step guide for constructing a speckle-free and high-contrast laser illumination setup using a rotating ground glass diffuser driven by a stepper motor. The setup is easy to build, cheap, and allows a significant light throughput of 48%, which is 40% higher in comparison to a single lens collector commonly used in reported setups. This is achieved by using only one objective to collect the scattered light from the ground glass diffuser. We validate our setup in terms of image quality, speckle contrast, motor-induced vibrations, and light throughput. To highlight the latter, we record Brownian motion of micro-particles using a 100× oil immersion objective and a high-speed camera operating at 2000 Hz with a laser output power of only 22 mW. Moreover, by reducing the objective magnification to 50×, sampling rates up to 10,000 Hz are realized. To help readers with basic or advanced optics knowledge realize this setup, we provide a full component list, 3D-printing CAD files, setup protocol, and the code for running the stepper motor.


LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling.
The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on CaV2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSR-binding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR.


Transport and metabolism of citrate by Streptococcus mutans.
Streptococcus mutans, a normal inhabitant of dental plaque, is considered a primary etiological agent of dental caries. Two virulence determinants of S. mutans are its acidogenicity and aciduricity (the ability to produce acid and the ability to survive and grow at low pH, respectively). Citric acid is ubiquitous in nature; it is a component of fruit juices, bones, and teeth. In lactic acid bacteria citrate transport has been linked to increased survival in acidic conditions. We identified putative citrate transport and metabolism genes in S. mutans, which led us to investigate citrate transport and metabolism. Our goals in this study were to determine the mechanisms of citrate transport and metabolism in S. mutans and to examine whether citrate modulates S. mutans aciduricity. Radiolabeled citrate was used during citrate transport to identify citrate metal ion cofactors, and thin-layer chromatography was used to identify metabolic end products of citrate metabolism. S. mutans was grown in medium MM4 with different citrate concentrations and pH values, and the effects on the growth rate and cell survival were monitored. Intracellular citrate inhibited the growth of the bacteria, especially at low pH. The most effective cofactor for citrate uptake by S. mutans was Fe(3+). The metabolic end product of citrate metabolism was aspartate, and a citrate transporter mutant was more citrate tolerant than the parent.


Antidepressant drug action and presynaptic alpha-receptors.
Receptors have been demonstrated on the terminations of the sympathetic adrenergic nerves. One type, the so-called alpha 2-receptors, are activated by the norepinephrine that is released from the nerve terminals into the synaptic cleft; this activation causes a reduction in the output of the transmitter (negative feedback). Recent studies have demonstrated that certain antidepressant drugs can block these alpha 2-receptors and thus prevent their inhibitory action on the release of norepinephrine. If this occurs in the brain, the increases in norepinephrine levels could help explain the antidepressant action of these agents.


A photonic-crystal optical antenna for extremely large local-field enhancement.
We propose a novel design of an all-dielectric optical antenna based on photonic-band-gap confinement. Specifically, we have engineered the photonic-crystal dipole mode to have broad spectral response (Q~70) and well-directed vertical-radiation by introducing a plane mirror below the cavity. Considerably large local electric-field intensity enhancement~4,500 is expected from the proposed design for a normally incident planewave. Furthermore, an analytic model developed based on coupled-mode theory predicts that the electric-field intensity enhancement can easily be over 100,000 by employing reasonably high-Q (~10,000) resonators.


Bile acid regulation of C/EBPbeta, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes.
Previously, we have demonstrated that deoxycholic acid (DCA)-induced signaling of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in primary hepatocytes is a protective response. In the present study, we examined the roles of the ERK and c-Jun NH(2)-terminal kinase (JNK) pathways, and downstream transcription factors, in the survival response of hepatocytes. DCA caused activation of the ERK1/2 and JNK1/2 pathways. Inhibition of either DCA-induced ERK1/2 or DCA-induced JNK1/2 signaling enhanced the apoptotic response of hepatocytes. Further analyses demonstrated that DCA-induced JNK2 signaling was cytoprotective whereas DCA-induced JNK1 signaling was cytotoxic. DCA-induced ERK1/2 activation was responsible for increased DNA binding of C/EBPbeta, CREB, and c-Jun/AP-1. Inhibition of C/EBPbeta, CREB, and c-Jun function promoted apoptosis following DCA treatment, and the level of apoptosis was further increased in the case of CREB and c-Jun, but not C/EBPbeta, by inhibition of MEK1/2. The combined loss of CREB and c-Jun function or of C/EBPbeta and c-Jun function enhanced DCA-induced apoptosis above the levels resulting from the loss of either factor individually; however, these effects were less than additive. Loss of c-Jun or CREB function correlated with increased expression of FAS death receptor and PUMA and decreased expression of c-FLIP-(L) and c-FLIP-(S), proteins previously implicated in the modulation of the cellular apoptotic response. Collectively, these data demonstrate that multiple DCA-induced signaling pathways and transcription factors control hepatocyte survival.


Exploring the in vitro anti-inflammatory activity of gross saponins of Tribulus terrestris L. fruit by using liquid chromatography-mass spectrometry-based cell metabolomics approach.
Our previous studies confirmed the efficacy of gross saponins of Tribulus terrestris L. fruit in treating cerebral ischemia. This study aimed to investigate the related mechanisms in vitro. The lipopolysaccharide-induced BV2 cells model was constructed and treated with gross saponins at different concentrations to explore its anti-inflammatory activity. The cell metabolite changes were tracked by liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, and the metabolic biomarkers and related metabolic pathways were analyzed. Molecular biochemistry analysis was further used to verify the relevant inflammatory pathways. The results showed that the saponins reduced nitric oxide release and the secretion of tumor necrosis factor-alpha, interleukin-1β, and interleukin-6 from lipopolysaccharide-induced BV2 cells. Metabolic perturbations occurred in lipopolysaccharide-treated BV2 cells, which could be reversed by drug treatment via mainly regulating glycerophospholipid metabolism, tryptophan metabolism, purine metabolism pathways, etc. The western blot analysis demonstrated that saponin could suppress the activation of the inflammatory-related signaling pathway. The present study explored the in vitro anti-inflammatory mechanism of gross saponins of Tribulus terrestris L. fruit using an LC-MS-based cell metabolomics approach, which confirms the great potential of LC-MS for drug efficacy evaluation and can be applied in other herbal medicine-related analyses.


Combining single-cell and transcriptomic analysis revealed the immunomodulatory effect of GOT2 on a glutamine-dependent manner in cutaneous melanoma.
Background: Reprogramming in glutamine metabolism is a hallmark of cancers, while its role in cutaneous melanoma has not been studied at great length. Methods: Here, we constructed a glutamine metabolism-related prognostic signature in cutaneous melanoma with a variety of bioinformatics methods according to the glutamine metabolism regulatory molecules. Moreover, experimental verification was carried out for the key gene. Results: We have identified two subgroups of cutaneous melanoma patients, each with different prognoses, immune characteristics, and genetic mutations. GOT2 was the most concerned key gene among the model genes. We verified its role in promoting tumor cell proliferation by CCK-8 and clone formation assays. Conclusion: Our study cast new light on the prognosis of cutaneous melanoma, and the internal mechanism regulating glutamine metabolism of GOT2 may provide a new avenue for treating the cutaneous melanoma disease precisely.


A cluster of tuberculosis cases in a family.
A 40 year old Indian woman who had recently returned from a visit to India with her eldest son was diagnosed with miliary tuberculosis in January 1994. Contact tracing revealed that her three sons, aged 19, 21, and 22, all had BCG scars from vaccinations administered at birth in India and Heaf tests of grades 2-3. None of them was given chemoprophylaxis, although this was considered, as suggested by the guidelines then available (1990). About 18 months later, the eldest son was notified as a case of tuberculosis. The youngest son, who shared a room with the eldest, developed a right tuberculous pleural effusion over three years after his mother became ill. The 41 year old husband of the index case and their 21 year old son remain well at the time of this report and are being followed up. These cases highlight the importance of stringent follow up, contact tracing, good liaison between general practitioners and chest clinic staff, and chemoprophylaxis for the contacts of tuberculosis cases. Guidelines about the management of contacts of sputum positive cases over 16 years old need to be clarified. A history of a recent overseas trip should raise suspicions of infection with tuberculosis.


Safety of drug-eluting stents in patients with left ventricular dysfunction undergoing percutaneous coronary intervention.
Recent studies have reported a higher incidence of late stent thrombosis in patients undergoing drug-eluting stent (DES). Reduced left ventricular (LV) ejection fraction (EF) is considered a risk factor for this complication after both bare-metal stent (BMS) and DES implantation. Therefore, the aim of this study was to evaluate the safety of DES on long-term follow-up in patients with LV dysfunction undergoing percutaneous coronary intervention. We retrospectively selected all patients with an EF <45% undergoing percutaneous coronary intervention with implantation of > or =1 sirolimus- or paclitaxel-eluting stent at our institution. The primary endpoint of the study was all-cause mortality, retrieved using both Social Security Database and hospital records. We also compared the results of this group with a historical cohort of patients with LV dysfunction undergoing BMS implantation; 121 patients who received > or =1 DES were enrolled. The mean LVEF was 36 +/- 8%, with 20 patients (16%) with a LVEF < or =25%; 36 patients (30%) had diabetes mellitus, and DES implantation was considered off-label in 100 patients (83%). Survival at 1-, 2-, and 3-year follow-up was 94% (95% confidence interval [CI] 88 to 100), 90% (95% CI 82 to 98) and 88% (95% CI 80 to 96), respectively. In conclusion, the favorable results of this study demonstrate the safety of DES in patients with LV dysfunction.


Outer-membrane transport of aromatic hydrocarbons as a first step in biodegradation.
Bacterial biodegradation of hydrocarbons, an important process for environmental remediation, requires the passage of hydrophobic substrates across the cell membrane. Here, we report crystal structures of two outer membrane proteins, Pseudomonas putida TodX and Ralstonia pickettii TbuX, which have been implicated in hydrocarbon transport and are part of a subfamily of the FadL fatty acid transporter family. The structures of TodX and TbuX show significant differences with those previously determined for Escherichia coli FadL, which may provide an explanation for the substrate-specific transport of TodX and TbuX observed with in vivo transport assays. The TodX and TbuX structures revealed 14-stranded beta-barrels with an N-terminal hatch domain blocking the barrel interior. A hydrophobic channel with bound detergent molecules extends from the extracellular surface and is contiguous with a passageway through the hatch domain, lined by both hydrophobic and polar or charged residues. The TodX and TbuX structures support a mechanism for transport of hydrophobic substrates from the extracellular environment to the periplasm via a channel through the hatch domain.


Macrolide antibiotics, bacterial populations and inflammatory airway disease.
Chronic obstructive pulmonary disease (COPD) and other inflammatory airway conditions are major causes of morbidity and mortality worldwide. Antibiotics are used to treat acute infectious exacerbations of airway disease. However, for the macrolides, a significant and growing body of evidence indicates that anti-inflammatory effects of these antibiotics, which may be independent of their antibacterial effects, are at least partially responsible for their beneficial effect. In this review, we describe current thinking on the means whereby anti-inflammatory effects of macrolides impact chronic airway disease. The current data indicate that some macrolides have immunomodulatory activity, mediated at least in part by effects on the activation of gene transcription mediated by NF-kappabeta activation that may be separable from their antimicrobial activities, and could explain their surprising efficacy in asthma and viral infections for which the role of bacteria is not established. Other, provocative work indicates that subclinical doses of macrolides may also affect signalling within and between bacterial communities, and thus impact developmental processes such as biofilm formation that are important in the establishment and persistence of chronic infections. The current data clearly suggest that activities beyond antimicrobial effects contribute significantly to the beneficial effect of macrolide therapy on inflammatory conditions.


Long-Lived and Bright Biexcitons in Quantum Dots with Parabolic Band Potentials.
Multiple exciton physics in semiconductor nanocrystals play an important role in optoelectronic devices. This work investigates radially alloyed CdZnSe/CdS nanocrystals with suppressed Auger recombination due to the spatial separation of carriers, which also underpins their performance in optical gain and scintillation experiments. Due to suppressed Auger recombination, the biexciton lifetime is greater than 10 ns, much longer than most nanocrystals. The samples show optical gain, amplified spontaneous emission, and lasing at thresholds <2 excitons per particle. They also show broad gain bandwidth (>500 meV) encompassing 4 amplified spontaneous emission bands. Similarly enabled by slowed multiple exciton relaxation, the samples display strong performance in scintillating films under X-ray illumination. The CdZnSe/CdS samples have fast radioluminescence rise (<80 ps) and decay times (<5 ns), light yields up to 6700 photons·MeV-1, and the demonstrated capacity for incorporation into large area films for scintillation imaging.


[Efficacy of Mexidol in the correction of postcovid syndrome in patients with chronic cerebrovascular diseases].
To evaluate the effectiveness of sequential therapy with Mexidol and Mexidol FORTE 250 in the correction of postcovoid syndrome (PKS) in patients with chronic cerebrovascular diseases (CVD). The analysis of the results of examination and treatment of 110 patients with CVD who underwent COVID-19 was carried out. Patients of the main group (OH, n=55) received Mexidol (5 ml IV drip for 14 days, followed by the transition to the tablet form of Mexidol FORTE 250 1 table 3 times/day for 2 months); 55 patients of the comparison group (GS) did not receive antioxidants. All patients included in the study were conducted MRI examination and extensive neuropsychological testing. There was a significant improvement in the state of cognitive functions, regression of symptoms of asthenia, improvement of night sleep in patients with OG. The differences were statistically significant both in comparison with the baseline level and the HS. The administration of the drug does not require age-related dose adjustment and is well combined with basic therapy. The recommended regimen for the use of Mexidol: 14 days of 5 ml i/v or i/m, then taking the drug Mexidol FORTE 250 at a dose of 1 table 3 times/day for 2 months.


A comparison of the decontamination efficacy of foam-making blends based on cationic and nonionic tensides against organophosphorus compounds determined in vitro and in vivo.
The ability of foam-making blends to decontaminate the skin exposed to organophosphorus compounds was tested. The appropriate composition and rheological features (stability, grade of foaming) of tested blends were evaluated by in vitro methods and their ability to remove the contaminants from hard surface and to transform the contaminants into nontoxic compounds was evaluated by in vivo methods. The blends containing cationic and nonionic tensides as well as alkalized hydrogen peroxide seem to be the most efficacious to decontaminate the skin exposed to organophosphorus compounds according to the literature data. The composition of tested blends was optimized because particular components often have antagonistic effects. Cationic tensides support the reactivity of the blend and control the grade of foaming. Nonionic tensides control the stability of the foams but also react as retardants of the reactivity of the foams. Hydrogen peroxide is a real reacting component when it is transformed into hydrogen peroxide anion. It also acts as buffer if pH is higher than 11. Our in vivo results confirm that Desam OX (34 and 68%) and the foam-making blend containing benzalkonium chloride--Althosan MB (8%), Slovasol 2510 (2%) and hydrogen peroxide (3%) alkalized at pH 12 seem to be the most efficacious to remove contaminants (soman, VX) from the skin and transform them into nontoxic compounds. Therefore they could be used for primary decontamination of chemical casualties contaminated with nerve agents in the field condition.


Selective lesion of the developing central noradrenergic system: short- and long-term effects and reinnervation by noradrenergic-rich tissue grafts.
The possibility to selectively remove noradrenergic neurons in the locus coeruleus/subcoeruleus (LC/SubC) complex by the immunotoxin anti-dopamine-beta-hydroxylase (DBH)-saporin has offered a powerful tool to study the functional role of this projection system. In the present study, the anatomical consequences of selective lesions of the LC/SubC on descending noradrenergic projections during early postnatal development have been investigated following bilateral intraventricular injections of anti-DBH-saporin or 6-hydroxydopamine to immature (4 day old) rats. Administration of increasing doses (0.25-1.0 microg) of the immunotoxin produced, about 5 weeks later, a dose-dependent loss of DBH-immunoreactive neurons in the LC/SubC complex (approximately 45-90%) paralleled by a similar reduction of noradrenergic innervation in the terminal territories in the lumbar spinal cord. Even at the highest dose used (1.0 microg) the immunotoxin did not produce any detectable effects on dopaminergic, adrenergic, serotonergic or cholinergic neuronal populations, which, by contrast, were markedly reduced after administration of 6-hydroxydopamine. The approximately 90% noradrenergic depletion induced by 0.5 and 1.0 microg of anti-DBH-saporin remained virtually unchanged at 40 weeks post-lesion. Conversely, the approximately 45% reduction of spinal innervation density estimated at 5 weeks in animals injected with the lowest dose (0.25 microg) of the immunotoxin was seen recovered up to near-normal levels at 40 weeks, possibly as a result of the intrinsic plasticity of the developing noradrenergic system. A similar reinnervation in the lumbar spinal cord was also seen promoted by grafts of fetal LC tissue implanted at the postnatal day 8 (i.e. 4 days after the lesion with 0.5 microg of anti-DBH-saporin). In these animals, the number of surviving neurons in the grafts and the magnitude of the reinnervation, with fibers extending in both the grey and white matter for considerable distances, were seen higher than those reported in previous studies using adult recipients. This would suggest that the functional interactions between the grafted tissue and the host may recapitulate the events normally occurring during the ontogenesis of the coeruleo-spinal projection system, and can therefore be developmentally regulated. Thus, the neonatal anti-DBH-saporin lesion model, with the possibility to produce graded noradrenergic depletions, holds promises as a most valuable tool to address issues of compensatory reinnervation and functional recovery in the severed CNS as well as to elucidate the mechanisms governing long-distance axon growth from transplanted neural precursors.


Overweight is associated with decreased cognitive functioning among school-age children and adolescents.
Childhood overweight and obesity have increased substantially in the past two decades, raising concerns about their psychosocial and cognitive consequences. We examined the associations between academic performance (AP), cognitive functioning (CF), and increased BMI in a nationally representative sample of children. Participants were 2,519 children aged 8-16 years, who completed a brief neuropsychological battery and measures of height and weight as a part of the Third National Health and Nutrition Examination Survey, a cross-sectional survey conducted between 1988 and 1994. Z-scores were calculated for each neuropsychological test, and poor performance was defined as z-score <2. The association between BMI and AP was not significant after adjusting for parental/familial characteristics. However, the associations between CF remained significant after adjusting for parental/familial characteristic, sports participation, physical activity, hours spent watching TV, psychosocial development, blood pressure, and serum lipid profile. Z-scores on block design (a measure of visuospatial organization and general mental ability) among overweight children and children at risk of overweight were below those of normal-weight children by 0.22 (s.e. = 0.16) and 0.10 (s.e. = 0.10) unit, respectively (P for trend <0.05). The odds of poor performance on block design were 1.97 (95% confidence interval: 1.01-3.83) and 2.80 (1.16-6.75), respectively, among children at risk or overweight compared to normal-weight peers. Increased body weight is independently associated with decreased visuospatial organization and general mental ability among children. Future research is needed to determine the nature, persistence, and functional significance of this association.


In vitro response of retinal pigment epithelial cells exposed to chitosan materials prepared with different cross-linkers.
The interaction between cells and biopolymers is the evaluation indicator of the biocompatibility of materials. The purpose of this work was to examine the responses of retinal pigment epithelial (RPE) cells to genipin (GP) or glutaraldehyde (GTA) cross-linked chitosan by means of cell viability assays, cytokine expression analyses, and apoptosis assays. Evaluations of non-cross-linked chitosan were conducted simultaneously for comparison. Both GP and GTA treated samples with the same extent of cross-linking (around 80%) were prepared by varying cross-linking time. Our results showed that GP cross-linking was carried out by either radical polymerization of the monomers or S(N)2 nucleophilic substitution reaction involving the replacement of the ester group on the monomer with a secondary amide linkage. On the other hand, GTA could react with free amino groups of chitosan, leading to the formation of either the Schiff bases or the Michael-type adducts with terminal aldehydes. The biocompatibility of non-cross-linked chitosan membranes was demonstrated by the absence of any signs of toxicity or inflammation reaction. The present study showed that the ARPE-19 cells exposed to GTA cross-linked chitosan membranes had significantly higher cytotoxicity, interleukin-6 levels, and number of TUNEL-positive nuclei than did those exposed to GP treated samples. In addition, the materials modified with GTA trigger apoptosis at an early stage and may induce toxicity in the RPE cells later. The findings suggest that while the chitosan molecules bridged by GP are satisfactorily cytocompatible, the counterparts treated by GTA do not seem to be tolerated. In terms of material safety, the GP cross-linked chitosan may be compatible with human RPE cells and may have a potential application as delivery carriers in the treatment of posterior segment diseases.


A survey of telomerase activity in human cancer.
Research on the association of the ribonucleoprotein enzyme, telomerase, with human cancer has expanded rapidly in recent years. Essentially all major types of cancer have been screened and the presence of telomerase activity has been detected in the vast majority of cases. In this article we provide a summary, in table form, of the current data.


Post-training administration of a synthetic peptide ligand of the neural cell adhesion molecule, C3d, attenuates long-term expression of contextual fear conditioning.
The neural cell adhesion molecule (NCAM) plays a key role in synaptic plasticity and memory formation. We have recently developed a synthetic peptide, termed C3d, which, through the binding to the first, N-terminal immunoglobulin-like (Ig) module in the extracellular portion of NCAM, has been shown to promote neurite outgrowth and synapse formation in vitro, and to interfere with passive avoidance memory in rats in vivo. In this study, we investigated whether the i.c.v. administration of C3d, either 5.5 h after or 2 days before training, could be effective to modulate the strength at which emotional memory for aversive situations is established into a long-term memory. The effects of the peptide were evaluated in adult male Wistar rats trained in the contextual fear conditioning task. The results indicated that C3d significantly reduced the subsequent long-term retention of the conditioned fear response when administered 5.5 h post-training, as indicated by retention tests performed 2-3 and 7 days post-training. However, this treatment failed to influence conditioning for this task when injected 2 days pre-training. Additional experiments showed that C3d did not influence the emotional or locomotor behaviour of the animals, when tested in the open field task. Furthermore, hippocampal levels of microtubule-associated protein 2 (MAP2), Synaptophysin and NCAM were found unchanged when evaluated by enzyme-linked immunosorbent assay in crude synaptosomal preparations 2 days after peptide i.c.v. injection. Therefore, post-training injection of this synthetic peptide was efficient to attenuate the strength at which memory for contextual fear conditioning was enduringly stored, whilst it did not affect the acquisition of new memories. In addition to further support the view that NCAM is critically involved in memory consolidation, the current findings suggest that the NCAM IgI module is a potential target for the development of therapeutic drugs capable to reduce the cognitive impact induced by exposure to intensive stress experiences.


The influence of Typhoon Khanun on the return migration of Nilaparvata lugens (Stål) in eastern China.
Migratory insects adapt to and exploit the atmospheric environment to complete their migration and maintain their population. However, little is known about the mechanism of insect migration under the influence of extreme weather conditions such as typhoons. A case study was conducted to investigate the effect of typhoon Khanun, which made landfall in the eastern China in Sept. 2005, on the migration of brown planthopper, Nilaparvata lugens (Stål). The migration pathways of N. lugens were reconstructed for the period under the influence of the typhoon by calculating trajectories using the MM5, a mesoscale numerical weather prediction model, and migration events were examined in 7 counties of the Yangtze River Delta region with ancillary information. The light trap catches and field observations indicated that the migration peak of N. lugens coincided with the period when the typhoon made landfall in this region. The trajectory analyses revealed that most emigrations from this region during this period were hampered or ended in short distances. The sources of the light-trap catches were mainly located the nearby regions of each station (i.e. mostly less than 100 km away, with a few exceeding 200 km but all less than 300 km). This disrupted emigration was very different from the usual N. lugens migration which would bring them to Hunan, Jiangxi, and southern Anhui from this region at this time of year. This study revealed that the return migration of N. lugens was suppressed by the typhoon Khanun, leading to populations remaining high in the Yangtze River Delta and exacerbating later outbreaks.


Differentiation of human dental pulp stem cells into functional motor neuron: In vitro and ex vivo study.
There are several therapeutic options for spinal cord injury (SCI), among these strategies stem cell therapy is a potential treatment. The stem cells based therapies have been investigating in acute phase of clinical trials for promoting spinal repair in humans through replacement of functional neuronal and glial cells. The aim of this study was to evaluate the differentiation of Human Dental Pulp Stem Cells (hDPSCs) into functional motor neuron like cells (MNLCs) and promote neuroregeneration by stimulating local neurogenesis in the adult spinal cord slice culture. The immunocytochemistry analysis demonstrated that hDPSCs were positive for mesenchymal stem cell markers (CD73, CD90 and CD105) and negative for the hematopoietic markers (CD34 and CD45). hDPSCs were induced to neurospheres (via implementing B27, EGF, and bFGF) and then neural stem cells (NSC). The NSC differentiated into MNLCs in two steps: first by Shh and RA and ; then with GDNF and BDNF administration. The NS and the NSC were assessed for Oct4, nestin, Nanog, Sox2 expression while the MNLCs were evaluated by ISLET1, Olig2, and HB9 genes. Our results showed that hDPSC can be differentiated into motor neuron phenotype with expression of the motor neuron genes. The functionality of MNLCs was demonstrated by FM1-43, intracellular calcium ion shift and co- culture with C2C12. We co-cultivated hDPSCs with adult rat spinal slices in vitro. Immunostaining and hoechst assay showed that hDPSCs were able to migrate, proliferate and integrate in both the anterolateral zone and the edges of the spinal slices.


Application of quantitative fluorescence and absorption-edge computed microtomography to image metal compartmentalization in Alyssum murale.
This paper shows that synchrotron-based fluorescence and absorption-edge computed microtomographies (CMT) are well-suited for determining the compartmentalization and concentration of metals in hyperaccumulating plant tissues. Fluorescence CMT of intact leaf, stem, and root samples revealed that Ni concentrated in stem and leaf dermal tissues and, together with Mn, in distinct regions associated with the Ca-rich trichomes on the leaf surface of the nickel hyperaccumulator Alyssum murale "Kotodesh". Metal enrichment was also observed within the vascular system of the finer roots, stem, and leaves but absent from the coarser root, which had a well-correlated metal coating. Absorption-edge CMT showed the three-dimensional distribution of the highest metal concentrations and verified that epidermal localization and Ni and Mn co-localization at the trichome base are phenomena that occurred throughout the entire leaf and may contribute significantly to metal detoxification and storage. Ni was also observed in the leaf tips, possibly resulting from release of excess Ni with guttation fluids. These results are consistent with a transport model where Ni is removed from the soil by the finer roots, carried to the leaves through the stem xylem, and distributed throughout the leaf by the veins to the dermal tissues, trichome bases, and in some cases the leaf tips.


Conjunctivitis as the only sign and symptom of COVID-19: A case report and review of literature.
Similar to several viruses, coronaviruses can affect the eye and cause conjunctivitis. In addition to ocular involvement, it causes systemic manifestations, mainly respiratory symptoms. However, conjunctivitis as the only sign and symptom of coronavirus disease 2019 (COVID-19) is a rare presentation. We present a case of a 20-year-old male patient who presented with conjunctivitis for 3 days and diagnosed on the same day with COVID-19 without other manifestations. Conjunctivitis affected both eyes and resolved over 2 weeks with artificial tears only and without any ocular complications. Conjunctivitis can be the only sign and symptom of COVID-19 in some patients. Therefore, healthcare providers, particularly ophthalmologists, should take precautions when dealing with patients presenting with conjunctivitis amid the COVID-19 pandemic.


When did your pain start?: reliability of self-reported age of onset of facial pain.
This study was designed to examine the reliability of self-reported onset of facial pain over a relatively long period, as well as factors that may influence the ability of patients to provide consistent pain onset dates. The implications of dating unreliability on assessing the temporal order of two potentially related disorders is also considered. A total of 125 women with a lifetime history of temporomandibular pain and dysfunction syndrome (TMPDS) were asked to report their pain onset date in the context of a structural health interview. Dates were compared with onset dates recorded an average of 7 years earlier in their clinical chart. Factors potentially affecting reliability of recall were also assessed. The absolute value of the discrepancy between the two reports was nearly 4 years. Only 26% reported onset dates within the same year. Forward-telescoping, in which events are recalled as occurring more recently than they actually occurred, was more common than backward-telescoping of onset dates. Intraclass correlations were good to excellent (ICC = .80 for full sample). Elapsed time between reports was the largest predictor of reporting discrepancy. These findings indicate that a single patient's report of pain onset, especially when he or she is asked to recall the onset of a long-standing pain problem, will most often lead to an underestimate of chronicity. However, high intraclass correlations indicate that patients' dating of pain onset may have satisfactory reliability for research purposes, when comparing a group of patients to one another to assess relative chronicity of pain.


Impact of specimen adequacy on the assessment of renal allograft biopsy specimens.
The Banff classification was introduced to achieve uniformity in the assessment of renal allograft biopsies. The primary aim of this study was to evaluate the impact of specimen adequacy on the Banff classification. All renal allograft biopsies obtained between July 2010 and June 2012 for suspicion of acute rejection were included. Pre-biopsy clinical data on suspected diagnosis and time from renal transplantation were provided to a nephropathologist who was blinded to the original pathological report. Second pathological readings were compared with the original to assess agreement stratified by specimen adequacy. Cohen's kappa test and Fisher's exact test were used for statistical analyses. Forty-nine specimens were reviewed. Among these specimens, 81.6% were classified as adequate, 6.12% as minimal, and 12.24% as unsatisfactory. The agreement analysis among the first and second readings revealed a kappa value of 0.97. Full agreement between readings was found in 75% of the adequate specimens, 66.7 and 50% for minimal and unsatisfactory specimens, respectively. There was no agreement between readings in 5% of the adequate specimens and 16.7% of the unsatisfactory specimens. For the entire sample full agreement was found in 71.4%, partial agreement in 20.4% and no agreement in 8.2% of the specimens. Statistical analysis using Fisher's exact test yielded a P value above 0.25 showing that - probably due to small sample size - the results were not statistically significant. Specimen adequacy may be a determinant of a diagnostic agreement in renal allograft specimen assessment. While additional studies including larger case numbers are required to further delineate the impact of specimen adequacy on the reliability of histopathological assessments, specimen quality must be considered during clinical decision making while dealing with biopsy reports based on minimal or unsatisfactory specimens.


Social Media Use and Conduct Problems in Emerging Adults.
Social media use has become pervasive in the lives of emerging adults. Although social media may provide individuals with positive opportunities for communication and learning, social media sites also may provide an outlet for youth conduct problems, such as bullying, harassment, and intentional hostility and aggression toward others. Yet, the relationship between social media use and conduct problems remains unclear. This study investigated the association between conduct disorder (CD) symptoms before age 15 and social media use during emerging adulthood in a large, nationally representative sample. Concurrent associations between antisocial personality disorder (ASPD) symptoms and social media use in emerging adults also were examined. Data for this study were based on 567 emerging adults (50.2 percent female; Mage = 20.0 years). Self-report questionnaires were completed online. Results suggested that more childhood CD symptoms were significantly associated with greater daily social media use during emerging adulthood, and that more daily social media use was significantly associated with current ASPD symptoms. Possible directional and cyclical explanations for these findings are explored. Given the pervasiveness of social media in the lives of emerging adults, these results underscore the importance of considering nuanced methods for using social media sites to encourage positive social interactions and to displace the promotion of conduct problems.


[Cleavage of DNA adsorbed on the surface of phospholipid membranes by restrictases type II].
Cleavage of phage lambda DNA by restriction endonucleases in the presence of model phosphatidylcholine membranes was studied. Bsp1, Pst1 and Bam H1 were found to cleave DNA under these conditions to a considerably decreased extent. This effect does not result from irreversible inactivation of the enzymes or their direct interaction with the membranes. The most probable explanation of the membrane inhibitory effect is the change of DNA substrate properties resulting from its Mg2+-mediated binding to the membranes.


Pneumatosis cystoides intestinalis following lupus enteritis and peritonitis.
We describe a case of systemic lupus erythematosus (SLE) with enteritis and peritonitis who later developed pneumatosis cystoides intestinalis (PCI). A 35-year-old woman with SLE relapsed with enteritis and peritonitis. Prednisolone (PSL) effectively improved her symptoms. However, 6 weeks later, she developed PCI. Tapering of PSL, administration of intravenous cyclophosphamide, prokinetic agents and antibiotics, bowel rest with intravenous hypernutrition therapy and hyperbaric oxygen therapy successfully improved PCI. Although PCI is a rare complication of SLE, the present case suggests that lupus enteritis could be a risk factor for PCI, and that high-dose PSL could cause additional insult to PCI.


Cholinergic-sympathetic interactions in the left atrium and left ventricle of conscious dogs.
The extent of cholinergic-sympathetic interaction in the heart was examined in the resting control state and after isoproterenol stimulation in eight conscious dogs. Sonomicrometer crystals and solid-state pressure transducers were implanted in the left atrium and the left ventricle to evaluate mechanical function while heart rate was held constant by atrial pacing. Edrophonium (0.5 mg/kg i.v.) was given as a single dose at rest and during increased sympathetic tone produced by continuous infusion of isoproterenol (0.08 micrograms/kg/min). In the control state, edrophonium administration caused no change in left ventricular dP/dt, fractional shortening or velocity of contraction, but produced significant (P less than .001) decreases in left atrial fractional shortening and contraction velocity. During isoproterenol infusion there were significant increases in dP/dt, the velocity of contraction and fractional shortening in both left atrium and ventricle (P less than .001). Administration of edrophonium during this increase in inotropic state produced significant (P less than .01) decreases in left ventricular dP/dt, fractional shortening and contraction velocity. Moreover, after edrophonium, left atrial fractional shortening and velocity of contraction were decreased to values that were significantly (P less than .001) less than control. Thus, cholinergic stimulation caused selective depression of left atrial systolic function at rest and depression of both left atrial and ventricular function during sympathetic stimulation.


Split-aperture laser pulse compressor design tolerant to alignment and line-density differences.
We introduce a four-pass laser pulse compressor design based on two grating apertures with two gratings per aperture that is tolerant to some alignment errors and, importantly, to grating-to-grating period variations. Each half-beam samples each grating in a diamond-shaped compressor that is symmetric about a central bisecting plane. For any given grating, the two half-beams impinge on opposite sides of its surface normal. It is shown that the two split beams have no pointing difference from paired gratings with different periods. Furthermore, no phase shift between half-beams is incurred as long as the planes containing a grating line and the surface normal for each grating of the pair are parallel. For grating pairs satisfying this condition, gratings surfaces need not be on the same plane, as changes in the gap between the two can compensate to bring the beams back in phase.


Development and validation of a method for simultaneous separation and quantification of 5 different sugars in canine urine.
The objective of this project was to develop and validate a method for concurrent separation and quantification of methylglucose, rhamnose, xylose, sucrose, and lactulose in canine urine by using high pressure anion exchange liquid chromatography and pulsed amperometric detection. The method was validated by evaluating dilutional parallelism, spiking recovery, intra-assay variability, and inter-assay variability. Observed to expected ratios for 3 urine samples, and all sugars, ranged from 77.6% to 106.9% for a 1:2 dilution, 85.2% to 121.4% for a 1:4 dilution, and 91.6% to 163.7% for a 1:8 dilution. Observed to expected ratios for spiking recovery of 3 urine samples, all sugars, and 5 different spiking solutions, ranged from 85.5% to 116.7 % (mean +/- SD, 100.5 +/- 6.0%). The intra-assay coefficients of variation were 1.6%, 3.4%, and 4.7% for methylglucose; 1.6%, 2.0%, and 3.6% for rhamnose; 2.7%, 1.4%, and 1.1% for xylose; 9.8%, 3.4%, and 4.0% for sucrose; and 3.2%, 3.3%, and 3.3% for lactulose. Inter-assay coefficients of variation were 3.2%, 5.7%, and 4.2% for methylglucose; 4.3%, 5.4%, and 6.4% for rhamnose; 3.3%, 5.0%, and 4.2% for xylose; 9.4%, 9.9%, and 9.4% for sucrose; and 6.1%, 4.9%, and 2.7% for lactulose. In conclusion, a method for simultaneous separation and quantification of 5 sugars in canine urine was established and found to be linear, accurate, precise, and reproducible. This method may prove useful in the simultaneous evaluation of gastric permeability, small intestinal permeability, and small intestinal mucosal function in dogs with gastrointestinal disorders.


Decreases in free cholesterol and fatty acid unsaturation in renal cell carcinoma demonstrated by breath-hold magnetic resonance spectroscopy.
Increased utilization of cross-sectional imaging has resulted in increased detection of incidental renal tumors. The noninvasive characterization of renal tissue has important implications for the diagnosis of renal malignancies and treatment monitoring. Recently, multiple breath-hold averaged proton magnetic resonance spectroscopy ((1)H-MRS) performed at high field has enabled the use of this noninvasive metabolic profiling technique for the investigation of the abdomen. Multiple breath-hold averaged (1)H-MRS at high field (3T) was obtained in the kidneys of 10 healthy volunteers and in renal cell carcinoma tumors of 14 patients. The spectra of normal kidneys showed four main groups of resonances: 1) at 5.4-5.6 ppm, attributed to C6 of cholesterol and the unsaturated parts of the olefinic region of fatty acids; 2) at 4.7 ppm, attributed to the residual water signal; 3) at 3.2 ppm, attributed to trimethylamine moiety of choline metabolites; and 4) at 1.3 and 0.9 ppm, attributed to the methylenes and terminal methyls of lipids. The ratio of the signal at 5.4 ppm to that of 1.3 ppm was 19-fold lower in renal cell carcinomas than in healthy kidneys, tied P = 0.0003 Mann-Whitney U-test, suggesting a decrease in both free cholesterol and the degree of unsaturation of fatty acids in the malignant tissue. This metabolic shift is in agreement with previous ex vivo studies of human renal cell carcinoma. The ability to detect renal metabolic shifts noninvasively may improve the specificity of preoperative renal tissue characterization and may provide a new modality for treatment monitoring.


Conformational analysis of methyl 6-O-[(R)- and (S)-1-carboxyethyl]-alpha-D-galactopyranoside by MM and Langevin dynamics simulations.
The conformational space of methyl 6-O-[(R)- and (S)-1-carboxyethyl]-alpha-D-galactopyranoside has been investigated. A grid search employing energy minimization at each grid point over the three major degrees of freedom, namely phi, psi and omega, identified low energy regions. The R-isomer shows five low energy conformers within ca. 1 kcal mol(-1) of the global energy minimum. The S-isomer has two conformers within a few tenths of a kcal mol(-1) of the global energy minimum. Langevin dynamics simulations have been have been performed at 300 K for 30 ns of each isomer. The phi dihedral angle has as its major conformer (g-) for the R-isomer whereas it is the (g+) conformer for the S-isomer. For the psi dihedral angle the (t) conformer has the highest population for both isomers. The dihedral angle omega has the (g+) conformer most highly populated, both for the R- and S-isomer. The above five and two conformational states for the R- and S-isomers, respectively, make up 90% in each case of the populated states during the Langevin dynamics (LD) simulations. Rate constants for the omega dihedral angle have been calculated based on a number correlation function. Three bond homo- and heteronuclear, i.e. proton and carbon-13, coupling constants have been calculated from the dynamics trajectories for comparison to experimental values. The heteronuclear coupling constant H2',C6 has been measured for the S-isomer and found to be 3.3 Hz. The J value calculated from the LD simulations, namely 2.6 Hz, is in fair agreement with experiment. A comparison to the X-ray structure of the R-isomer shows that the conformation of the crystalline compound occupies the low energy region most highly populated as a single R-conformer (30%) during the LD simulations.


The properties of uridine diphosphate glucuronyltransferase(s) which catalyse the synthesis of steroid glucuronides in microsomal fractions from guinea-pig liver.
The properties of the UDP-glucuronyltransferase(s) of guinea-pig liver that catalyse the synthesis of steroid glucuronides were examined. There are many similarities between apparently different substrate-specific forms of these enzymes in that all are activated by bivalent metal ions, and all contain at least 2 thiol groups important for enzyme activity. On the other hand, there are significant differences between the enzymes conjugating steroids and those conjugating non-steroids. Only the latter are activated by UDP-N-acetylglucosamine, which enhances their relatively poor affinity for UDP-glucuronic acid. The steroid-conjugating forms of UDP-glucuronyltransferase are not activated by UDP-N-acetylglucosamine and have relatively high apparent affinities for UDP-glucuronic acid. The rate of glucuronidation of testosterone was inhibited by treatment with phospholipase A. Treatment with cholate or Triton X-100 did not enhance the rates of glucuronidation of any steroid tested. The data indicate several similarities between different forms of UDP-glucuronyltransferase, suggesting that there is a large family of related proteins. At the same time there are important differences in the parameters that modulate the rates of different glucuronidation reactions.


Synaptic interactions increase optic flow specificity.
Representations of optic flow are encoded in fly tangential neurons by pooling the signals of many retinotopically organized local motion-sensitive inputs as well as of other tangential cells originating in the ipsi- and contralateral half of the brain. In the so called HSE cell, a neuron involved in optomotor course control, two contralateral input elements, the H1 and H2 cells, mediate distinct EPSPs. These EPSPs frequently elicit spike-like depolarizations in the HSE cell. The synaptic transmission between the H2 and the HSE cell is analysed in detail and shown to be very reliable with respect to the amplitude and time-course of the postsynaptic potential. As a consequence of its synaptic input, the HSE cell responds best to wide-field motion, such as that generated on the eyes when the animal turns about its vertical body axis. It is shown that the specificity of the HSE cell for this type of optic flow is much enhanced if rapid membrane depolarizations, such as large-amplitude EPSPs or spike-like depolarizations, are taken into account rather than the average membrane potential.


Why should addiction medicine be an attractive field for young physicians?
The clinical practice and science of addiction are increasingly active fields, which are attracting professionals from diverse disciplines such as psychology and neurobiology. Our scientific knowledge of the pathophysiology of addiction is rapidly growing, along with the variety of effective treatments available to clinicians. Yet, we believe that the medical specialties of addiction medicine/psychiatry are not attracting the interest and enthusiasm of young physicians. What can be done? We offer the opinions of two experience addiction psychiatrists. In the US, there has been a decline in the number of psychiatrists seeking training or board certification in addiction psychiatry; about one-third of graduates with such training are not practicing in an addiction psychiatry setting. There is widespread neglect of addiction medicine/psychiatry among the medical profession, academia and national health authorities. This neglect is unfortunate, given the enormous societal costs of addiction (3-5% of the gross domestic product in some developed countries), the substantial unmet need for addiction treatment, and the highly favourable benefit to cost yield (at least 7:1) from treatment. We believe that addiction medicine/psychiatry can be made more attractive for young physicians. Helpful steps include widening acceptance as a medical specialty or subspecialty, reducing the social stigma against people with substance use disorders, expanding insurance coverage and increasing the low rates of reimbursement for physicians. These steps would be easier to take with broader societal (and political) recognition of substance use disorders as a major cause of premature death, morbidity and economic burden.


Direct vital microscopic study of defective leukocyte-endothelial interaction in diabetes mellitus.
The number of leukocytes rolling along the venular endothelium of the vascular network of the internal spermatic fascia was determined in nondiabetic control rats and diabetic rats with television microscopy. A marked decrease in the number of rolling cells was observed in animals rendered diabetic by the injection of alloxan 10, 30, or 180 days before relative to matching controls. Blood leukocyte counts, however, were equivalent in both control and diabetic rats. Under the influence of a local inflammatory stimulus, cells emerged into the perivascular tissue in control animals, and this was accompanied by a reduction in the number of rolling leukocytes. In diabetic rats, the number of rolling leukocytes remained unaltered, and only a few cells accumulated in the connective tissue adjacent to the vessel. Reversal of the defective leukocyte-endothelial interaction was attained by treatment of diabetic animals with insulin. Inhibitors of arachidonic acid metabolism were ineffective to improve leukocyte-endothelial interactions in diabetic animals. Control rats injected intravenously with lyophilized plasma constituents, obtained after dialysis of diabetic rat plasma with 12,000-Mr retention dialysis tubing, behaved as diabetic animals in that they exhibited a reduced number of leukocytes rolling along the venular endothelium. In contrast, material obtained from control rat plasma produced no effect. Heating of active samples for 1 h at 56 degrees C resulted in the complete loss of the inhibitory effect. We conclude that a substance or substances present in diabetic plasma induce a defective leukocyte-endothelial interaction that further impairs resistance to infection.


Revisiting the Definition of Bronchopulmonary Dysplasia: Effect of Changing Panoply of Respiratory Support for Preterm Neonates.
Several definitions of bronchopulmonary dysplasia are clinically used; however, their validity remains uncertain considering ongoing changes in the panoply of respiratory support treatment strategies used within neonatal units. To identify the optimal definition of bronchopulmonary dysplasia that best predicts respiratory and neurodevelopmental outcomes in preterm infants. Retrospective cohort study at tertiary neonatal intensive care units. Preterm infants born at less than 29 weeks' gestation between 2010 and 2011 who were admitted to neonatal intensive care units participating in the Canadian Neonatal Network and completed follow-up assessments in a Canadian Neonatal Follow-Up Network clinic at 18 to 21 months. Various traditional bronchopulmonary dysplasia criteria based on respiratory status at different postmenstrual ages. Serious respiratory morbidity, neurosensory impairment at 18 to 21 months of age, and a composite outcome of respiratory or neurosensory morbidity or death after discharge. Adjusted odds ratios (AORs) and 95% CIs were calculated. Of 1914 eligible survivors, 1503 were assessed (mean gestational age was 26.3 weeks; 68% were white, 9% were black, and 23% were other race/ethnicity), 88 had serious respiratory morbidity, 257 infants had neurosensory impairment, and 12 infants died after discharge. Definitions using oxygen requirement alone as the criterion at various postmenstrual ages were less predictive compared with those using the criterion of oxygen/respiratory support (RS) (receiving supplemental oxygen and/or positive-pressure RS); among those, oxygen/RS at 36 weeks had the highest AOR and area under the curve (AUC) for all outcomes. Further analyses of oxygen/RS at each week between 34 and 44 weeks' postmenstrual age indicated that the predictive ability for serious respiratory morbidity increased from 34 weeks (AOR, 1.8; 95% CI, 0.9-3.4, AUC, 0.721) to 40 weeks (AOR, 6.1; 95% CI, 3.4-11.0; AUC, 0.799). For serious neurosensory impairment, the AOR and AUC at 40 weeks' PMA (AOR, 1.5, 95% CI, 1.0-2.1; AUC, 0.740) were only marginally below their peak values at 37 weeks' PMA (AOR, 1.8; 95% CI, 1.3-2.6; AUC, 0.743). Defining bronchopulmonary dysplasia by the use of oxygen alone is inadequate because oxygen/RS is a better indicator of chronic respiratory insufficiency. In particular, oxygen/RS at 40 weeks' PMA was identified as the best predictor for serious respiratory morbidity, while it also displayed a good ability to predict neurosensory morbidity at 18 to 21 months.


[The effect of different regimens of intracellular electrostimulation on the dynamics of neuronal adaptation processes].
Was studied the influence of rhythmic, random and contingent intracellular electrostimulation on the character of the initial spike activity of individual identified and nonidentified neurons of the isolated CNS of Lymnaea stagnalis snail under the conditions of the controlled experiment. Stimulation and recording of neuron activity were realized via the same microelectrode. In the process of neuron adaptation to the regimens of stimulation used two phases were distinguished being estimated with the help of various statistic criteria. The expression and stability of observed adaptive alterations of endogenous rhythm system were different during the phases determined. At the first phase which reflected a search for the strategy of the optimization of input external influences, the dispersion of interspike intervals and disorder of discharge patterns increased. The true neuron adaptation was developed at the second phase and observed only at contingent reinforcement. Such an adaptation was followed by steady alterations of endogenous rhythm system resulted in minimization or maximization of frequency of associative auto-reinforcements. Alterations accompanying the effect of optimization of external influences were the most expressive at the end of the epoch of corresponding contingent stimulation and remained for some minutes after its cessation. In the paper are discussed the possible mechanisms of the observed endo-neuronal adaptive reconstructions of spike activity.


Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia.
Ionized calcium binding adaptor molecule 1, Iba1, is an EF hand calcium binding protein whose expression is restricted to macrophages/microglia. In this study, Iba1 was shown to colocalize with F-actin in membrane ruffles induced by macrophage colony-stimulating factor and in phagocytic cups formed during zymosan phagocytosis. Expression of mutant Iba1 carrying either N- or C-terminal deletions or carrying a substitution in the calcium binding domain, suppressed the membrane ruffling and the phagocytosis. These results indicate that Iba1 is a key molecule in membrane ruffling and the phagocytosis of macrophages/microglia. Furthermore, Iba1 colocalized with a small GTPase Rac in the membrane ruffles and the phagocytic cups. The Iba1 mutants also suppressed membrane ruffling induced by dominant active Rac1V12, but do not affect microspikes by Cdc42V12 and stress fibers by RhoAV14. These observations suggest that Iba1 is involved in Rac and calcium signaling pathways.


Digital Connectivity: The Sixth Vital Sign.
Digital health and telehealth connectivity have become important aspects of clinical care. Connected devices, including continuous glucose monitors and automated insulin delivery systems for diabetes, are being used increasingly to support personalized clinical decisions based on automatically collected data. Furthermore, the development, demand, and coverage for telehealth have all recently expanded, as a result of the COVID-19 pandemic. Medical care, and especially diabetes care, are therefore becoming more digital through the use of both connected digital health devices and telehealth communication. It has therefore become necessary to integrate digital data into the electronic health record and maintain personal data confidentiality, integrity, and availability. Connected digital monitoring combined with telehealth communication is known as virtual health. For this virtual care paradigm to be successful, patients must have proper skills, training, and equipment. We propose that along with the five current vital signs of blood pressure, pulse, respiratory rate, temperature, and pain, at this time, digital connectivity should be considered as the sixth vital sign. In this article, we present a scale to assess digital connectivity.


Effects and Safety of Magnesium Sulfate on Neuroprotection: A Meta-analysis Based on PRISMA Guidelines.
To evaluate the evidence of effects and safety of magnesium sulfate on neuroprotection for preterm infants who had exposure in uteri. We searched electronic databases and bibliographies of relevant papers to identify studies comparing magnesium sulfate (MgSO4) with placebo or other treatments in patients at high risk of preterm labor and reporting effects and safety of MgSO4 for antenatal infants. Then, we did this meta-analysis based on PRISMA guideline. The primary outcomes included fatal death, cerebral palsy (CP), intraventricular hemorrhage, and periventricular leukomalacia. Secondary outcomes included various neonatal and maternal outcomes. Ten studies including 6 randomized controlled trials and 5 cohort studies, and involving 18,655 preterm infants were analyzed. For the rate of moderate to severe CP, MgSO4 showed the ability to reduce the risk and achieved statistically significant difference (odd ratio [OR] 0.61, 95% confidence interval [CI] 0.42-0.89, P = 0.01). The comparison of mortality rate between the MgSO4 group and the placebo group only presented small difference clinically, but reached no statistical significance (OR 0.92, 95% CI 0.77-1.11, P = 0.39). Summarily, the analysis of adverse effects on babies showed no margin (P > 0.05). Yet for mothers, MgSO4 exhibited obvious side-effects, such as respiratory depression, nausea and so forth, but there exited great heterogeneity. MgSO4 administered to women at high risk of preterm labor could reduce the risk of moderate to severe CP, without obvious adverse effects on babies. Although there exit many unfavorable effects on mothers, yet they may be lessened through reduction of the dose of MgSO4 and could be tolerable for mothers. So MgSO4 is both beneficial and safety to be used as a neuroprotective agent for premature infants before a valid alternative was discovered.


Comments on "Overview and thermodynamic modelling of deep eutectic solvents as co-solvents to enhance drug solubilities in water".
This communication highlights the significance of the final pH of the solution and the potential instability of deep eutectic solvent (DES) within aqueous solutions, and introducing a challenging aspect regarding solute solubilization by DESs.


Chemically modified tetracycline (CMT-8) and estrogen promote wound healing in ovariectomized rats: effects on matrix metalloproteinase-2, membrane type 1 matrix metalloproteinase, and laminin-5 gamma2-chain.
Estrogen deficiency is associated with impaired cutaneous wound healing. Remodeling of the extracellular matrix in wound healing involves the action of matrix metalloproteinases on basement membrane zone components, especially laminin-5. We studied the effects of estrogen and a potent matrix metalloproteinase inhibitor, chemically modified non-antimicrobial tetracycline, CMT-8, on wound healing in ovariectomized rats. At the tissue level, laminin-5 gamma2-chain expression was decreased and the migration-inductive 80 kDa form of laminin-5 gamma2-chain was absent in ovariectomized rats when compared with sham and CMT-8- or estrogen-treated ovariectomized animals as detected by Western blotting. The highest levels of gelatinolytic activity (matrix metalloproteinase-2 and -9) were found in sham animals. Levels were reduced in ovariectomized rats and were lowest after treating ovariectomized rats with CMT-8 or estrogen as analyzed by functional activity assay and zymography. The total amount of membrane type 1-matrix metalloproteinase was unchanged in all groups. We conclude that CMT-8 and estrogen can promote wound healing in ovariectomized rats, not only by normalizing wound bed total collagen content and structure, but also by recovering the expression and processing of key molecules in wound healing, i.e., laminin-5 gamma2-chain. This study shows, for the first time, the role of estrogen and CMT-8 in laminin-5 gamma2-chain modulation in vivo.


General guidelines for biomedical software development.
Most bioinformatics tools available today were not written by professional software developers, but by people that wanted to solve their own problems, using computational solutions and spending the minimum time and effort possible, since these were just the means to an end. Consequently, a vast number of software applications are currently available, hindering the task of identifying the utility and quality of each. At the same time, this situation has hindered regular adoption of these tools in clinical practice. Typically, they are not sufficiently developed to be used by most clinical researchers and practitioners. To address these issues, it is necessary to re-think how biomedical applications are built and adopt new strategies that ensure quality, efficiency, robustness, correctness and reusability of software components. We also need to engage end-users during the development process to ensure that applications fit their needs. In this review, we present a set of guidelines to support biomedical software development, with an explanation of how they can be implemented and what kind of open-source tools can be used for each specific topic.


Safety and tolerability of antiretrovirals during pregnancy.
Combination antiretroviral therapy (CART) dramatically decreases mother-to-child HIV-1 transmission (MTCT), but maternal adverse events are not infrequent. A review of 117 locally followed pregnancies revealed 7 grade ≥ 3 AEs possibly related to antiretrovirals, including 2 hematologic, 3 hepatic, and 2 obstetric cholestasis cases. A fetal demise was attributed to obstetric cholestasis, but no maternal deaths occurred. The drugs possibly associated with these AE were zidovudine, nelfinavir, lopinavir/ritonavir, and indinavir. AE or intolerability required discontinuation/substitution of nevirapine in 16% of the users, zidovudine in 10%, nelfinavir in 9%, lopinavir/ritonavir in 1%, but epivir and stavudine in none. In conclusion, nevirapine, zidovudine, and nelfinavir had the highest frequency of AE and/or the lowest tolerability during pregnancy. Although nevirapine and nelfinavir are infrequently used in pregnancy at present, zidovudine is included in most MTCT preventative regimens. Our data emphasize the need to revise the treatment recommendations for pregnant women to include safer and better-tolerated drugs.


Views of European Drug Development Stakeholders on Treatment Optimization and Its Potential for Use in Decision-Making.
The current drug development paradigm has been criticized for being too drug-centered and for not adequately focusing on the patients who will eventually be administered the therapeutic interventions it generates. The drug-driven nature of the present framework has led to the emergence of a research gap between the pre-approval development of anticancer medicines and their post-registration use in real-life clinical practice. This gap could potentially be bridged by transitioning toward a patient-centered paradigm that places a strong emphasis on treatment optimization, which strives to optimize the way health technologies are applied in a real-world environment. However, questions remain concerning the ideal features of treatment optimization studies and their acceptability among key stakeholders. The aim of this study was to explore the views of key stakeholders in the drug development process regarding the concept of treatment optimization. Semi-structured interviews were conducted between December 2018 and May 2019 with 26 participants across ten EU Member States and six different stakeholder groups, including academic clinicians as well as representatives of patient organizations, regulatory authorities, health technology assessment agencies, payers, and industry. Based on the input of the experts interviewed, clarification was obtained regarding the optimal features of treatment optimization studies in terms of their conduct, funding, timing, design, and setting. Moreover, a number of opportunities and challenges of undertaking such trials were identified. Inter-stakeholder discussion during their design was seen as desirable. There was also broad support among the participants for regulatory measures to facilitate treatment optimization, although there was no agreement on the optimal scale and nature of these initiatives. Furthermore, the interviewees believed that the evidence strength of well-designed treatment optimization studies performed according to rigorous quality standards is greater than or at least equal to that of classical clinical trials. In addition, there was a strong consensus that the results of treatment optimization studies should be taken into account during the decision-making of regulators, payers, and/or clinicians. Stakeholders involved in drug development consider treatment optimization studies to be valuable tools to address current evidence gaps and support their implementation into the existing research framework.


Identification of 1,3,4-oxadiazoles as tubulin-targeted anticancer agents: a combined field-based 3D-QSAR, pharmacophore model-based virtual screening, molecular docking, molecular dynamics simulation, and density functional theory calculation approach.
Cancer is one of the most prominent causes of death worldwide and tubulin is a crucial protein of cytoskeleton that maintains essential cellular functions including cell division as well as cell signalling, that makes an attractive drug target for cancer drug development. 1,3,4-oxadiazoles disrupt microtubule causing G2-M phase cell cycle arrest and provide anti-proliferative effect. In this study, field-based 3D-QSAR models were developed using 62 bioactive anti-tubulin 1,3,4-oxadiazoles. The best model characterized by PLS factor 7 was rigorously validated using various statistical parameters. Generated 3D-QSAR model having high degree of confidence showed favourable and unfavourable contours around 1,3,4-oxadiazole core that assisted in defining proper spatial positioning of desired functional groups for better bioactivity. A five featured pharmacophore model (AAHHR_1) was developed using same ligand library and validated through enrichment analysis (BEDROC160.9 value = 0.59, Average EF 1% = 27.05, and AUC = 0.74). Total 30,212 derivatives of 1,3,4-oxadiazole obtained from PubChem database was prefiltered through validated pharmacophore model and docked in XP mode on binding cavity of tubulin protein (PDB code: 1SA0) which led into the identification of 11 HITs having docking scores between -7.530 and -9.719 kcal/mol while the reference compound Colchicine exerted docking score of -7.046 kcal/mol. Following the analysis of MM-GBSA and ADME studies, HIT1 and HIT4 emerged as the two promising hits. To verify their thermodynamic stability at the target site, molecular dynamic simulations were carried out. Both HITs were further subjected to DFT analysis to determine their HOMO-LUMO energy gap for ensuring their biological feasibility. Finally, molecular docking based structural exploration for 1,3,4-oxadiazoles to set up a lead of Formula I for further advancements of tubulin polymerization inhibitors as anti-cancer agents.Communicated by Ramaswamy H. Sarma.


Blood Management Strategies to Reduce Transfusions After Elective Lower-Extremity Joint Arthroplasty Surgeries: One Tertiary Care Hospital's Early Experience With an Alternative Payment Model-a Total Joint "Bundle".
Blood loss associated with lower-extremity total joint arthroplasty (TJA) often results in anemia and the need for red blood cell transfusions (RBCTs). This article reports on a quality improvement initiative aimed at improving blood management strategies in patients undergoing TJA. A multifaceted intervention (preoperative anemia assessment, use of tranexamic acid, discouragement of autologous preoperative blood collection, restrictive RBCT protocols) was implemented. The results were stratified into 3 intervention periods: 1, pre; 2, peri; and 3, post. Fractional logistic regression was used to describe differences between various intervention periods. During the study period, 2511 patients underwent TJA. Compared with the preintervention period, there was 81.8% decrease in total units of RBCT during the postintervention period. Using activity-based costing (~$1000/unit), the annualized saving in RBC expenditure was $480 000. A multidisciplinary approach can be successful and sustainable in reducing RBCT and its associated costs for patients undergoing TJA.


[Echographic differential diagnosis of post-traumatic motility disorders of the eye].
Following an analysis of echographic findings in 94 patients with posttraumatic ocular motility disorders, a flow-chart for detecting the basic pathomechanism was worked out. Normal muscle diameter is observed in entrapment of the perimuscular tissues or in a recent palsy, whereas increased muscle thickness suggests hematoma or incarceration, and thinned muscles an atrophy. A lack of change in muscle diameter when the patient looks in the direction in which motility is restricted is characteristic of atrophy or palsy, whereas an increase in muscle diameter is a sign of incarceration if a fracture has also been detected by echography; if not, muscle hematoma can be diagnosed.


Efficacy of Azoxystrobin on Mycotoxins and Related Fungi in Italian Paddy Rice.
The efficacy of azoxystrobin was evaluated in the presence of mycotoxigenic fungi and relative mycotoxins in Italian paddy rice during the growing season in the field. Three experimental fields were considered and the applied experimental design was a strip plot with three replicates; rice samples were collected at four different growing stages. The efficacy of the fungicide treatment on rice fungal population was demonstrated with around 20% less total fungal incidence in sprayed samples compared to untreated ones; the same decrease was noted also in Fusarium spp. species but not in Aspergillus versicolor. Of the mycotoxins considered, ochratoxin A (OTA) and aflatoxins (AFBs) were never detected, deoxynivalenol (DON) was found in 46% of samples at levels always lower than 100 µg/kg, while sterigmatocystin (STC) occurred in all the paddy rice samples collected after flowering, with a maximum value of 15.5 µg/kg. Treatment with azoxystrobin was not effective in reducing DON contamination, but it had an important and significant effect on STC content, showing a decrease of 67% in the sprayed samples.


[Study of analgesic effect of novel imidazoline derivatives and their effect on arterial pressure during pain].
In rat experiments new imidazoline derivatives caused a pain-relieving effect and inhibited a rise in arterial pressure in pain. Fluoride derivatives of imidazoline in doses of 1, 2, and 4 mg/kg induced long-term analgesia, had no effect on the background arterial blood pressure (AP), and significantly reduced its nociceptive pressor responses. The bromide derivatives of imidazoline showed no noticeable pain-relieving activity but reduced the nociceptive AP shifts. The background AP parameters did not change in this case. The prospects of directed chemical modification of imidazoline derivatives to obtain new analgesics capable of reducing the undesirable hemodynamic manifestations of pain are discussed.


Outcome of extremely low gestational age newborns (ELGANs) following a pro-active treatment approach: a Swiss single centre experience over 10 years.
To determine the impact of a pro-active treatment approach on outcome of extremely low gestational age neonates (ELGANs; gestational age [GA] <28 weeks) born at the perinatal centre of Lucerne, Switzerland. We assessed rates of survival, severe neonatal morbidity and neuro-developmental impairment (NDI) of all ELGANs born alive and treated at our centre between 2000 and 2009. The results were compared with published data from contemporary national and international cohorts. Over the 10-year study period, a total of 216 ELGANs were born alive at the perinatal centre of Lucerne. The survival rate was 74% for all live-born infants, and 81% for those admitted to the neonatal intensive care unit. Among the 160 survivors, 25% sustained at least one major neonatal morbidity; severe brain injury (i.e., periventricular/intraventricular haemorrhage grade 3 or 4 and/or cystic periventricular leukomalacia) affected 10%; moderate or severe bronchopulmonary dysplasia 16%; retinopathy of prematurity ≥ stage 3 1%; and necrotising enterocolitis 2%. Neuro-developmental outcome data at 18 to 24 months was available for 92% of all survivors: 88% had no or mild NDI, whereas moderate and severe NDI were present in 10% and 2%, respectively. When compared with published national or international data, our pro-active treatment approach to ELGANs was associated with higher or equal survival rates without increasing rates of severe neonatal morbidity or neuro-developmental impairment at the age of 18 to 24 months.


Overview of occupational medicine training among US family medicine residency programs.
Family physicians deliver a significant proportion of occupational medicine (OM) services. In 1984, the American Academy of Family Physicians (AAFP) endorsed recommended curriculum guidelines in OM for family medicine residency programs. This study's purpose was to determine (1) whether family medicine residency programs have met the AAFP recommendations by providing residents with exposure to OM, (2) what methods and resources are used by programs that incorporate OM into their curricula, and (3) what barriers exist for programs that do not provide OM training. A survey questionnaire was mailed to all family medicine residency program directors (n=449). A total of 290 questionnaires were received, for a response rate of 64.5%. The majority (91.7%) believed there was a need for OM training. However, only 68.2% offered specific training. Approximately half the programs had faculty with OM experience. Most programs included OM in their curricula through a series of lectures and/or as part of a community medicine rotation. Barriers to providing OM training included lack of faculty with clinical OM expertise, time, interest among faculty and residents, and perceived need. The results demonstrated that approximately two thirds of the responding family medicine residency programs currently offer OM training and that several barriers exist to providing that training.


Evaluating the Stability of RNA-Seq Transcriptome Profiles and Drug-Induced Immune-Related Expression Changes in Whole Blood.
Methods were developed to evaluate the stability of rat whole blood expression obtained from RNA sequencing (RNA-seq) and assess changes in whole blood transcriptome profiles in experiments replicated over time. Expression was measured in globin-depleted RNA extracted from the whole blood of Sprague-Dawley rats, given either saline (control) or neurotoxic doses of amphetamine (AMPH). The experiment was repeated four times (paired control and AMPH groups) over a 2-year span. The transcriptome of the control and AMPH-treated groups was evaluated on: 1) transcript levels for ribosomal protein subunits; 2) relative expression of immune-related genes; 3) stability of the control transcriptome over 2 years; and 4) stability of the effects of AMPH on immune-related genes over 2 years. All, except one, of the 70 genes that encode the 80s ribosome had levels that ranked in the top 5% of all mean expression levels. Deviations in sequencing performance led to significant changes in the ribosomal transcripts. The overall expression profile of immune-related genes and genes specific to monocytes, T-cells or B-cells were well represented and consistent within treatment groups. There were no differences between the levels of ribosomal transcripts in time-matched control and AMPH groups but significant differences in the expression of immune-related genes between control and AMPH groups. AMPH significantly increased expression of some genes related to monocytes but down-regulated those specific to T-cells. These changes were partially due to changes in the two types of leukocytes present in blood, which indicate an activation of the innate immune system by AMPH. Thus, the stability of RNA-seq whole blood transcriptome can be verified by assessing ribosomal protein subunits and immune-related gene expression. Such stability enables the pooling of samples from replicate experiments to carry out differential expression analysis with acceptable power.


Early complications and late sequelae of induced abortion: a review of the literature.
An attempt to evaluate the recent literature on somatic complications of induced abortion shows that a great amount of data of widely varying quality has been collected. Many areas of research are still not covered in a way that permits valid conclusions to be drawn. Two important points emerge from the review: first, there is a need for uniform definitions of complications and some uniformity in the analysis of data collected; secondly, carefully selected control groups are needed in this kind of research. The areas most urgently requiring further study differ from country to country. From a global point of view, the existence or inexistence of significant late sequelae and the influence of the patient's health status on the complication rate seem to be of the highest priority.


Pulveribacter suum gen. nov., sp. nov., isolated from a pig farm dust collector.
An aerobic, Gram-stain-negative, polar-flagellated, rod-shaped bacterium, designated as SC2-7T, was isolated from the dust collector at a pig farm located in Wanju-gun, Jeollabuk-do, Republic of Korea. Growth occurred at 10-37 °C (optimum, 28-30 °C), pH 6.0-10.0 (optimum, 7.0-8.0) and in the presence of 0-3 % (w/v) NaCl (optimum, 0 %) on Reasoner's 2A medium. The phylogenetic tree based on the 16S rRNA gene sequences revealed that strain SC2-7T was a member of the family Comamonadaceae, forming a robust cluster with the genera Alicycliphilus, Oryzisolibacter and Melaminivora. The 16S rRNA gene sequences of strain SC2-7T showed the highest sequence similarities to Alicycliphilus denitrificans K601T (97.2 %), Oryzisolibacter propanilivorax EPL6T (97.0 %), Melaminivora alkalimesophila CY1T (96.9 %), Diaphorobacter polyhydroxybutyrativorans SL-205T (96.6 %), Diaphorobacter nitroreducens NA10BT (96.6 %) and Melaminivora jejuensis KBB12T (96.5 %). The tree based on the gyrA gene sequences also showed that strain SC2-7T fell into a phylogenetic position similar to that based on the 16S rRNA gene sequences. The polar lipids present were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, an unidentified aminolipid and an unidentified phospholipid. The predominant quinone was ubiquione-8. The major fatty acids were summed feature 3 (including C16 : 1ω6c and/or C16 : 1ω7c), C16 : 0 and summed feature 8 (including C18 : 1ω6c and/or C18 : 1ω7c). The genomic DNA G+C content was 69.1 mol%. On the basis of the phenotypic, phylogenetic and chemotaxonomic data presented here, strain SC2-7T represents a novel species of a new genus, for which the name Pulveribacter suum gen. nov., sp. nov., is proposed. The type strain of Pulveribacter suum is SC2-7T (=KACC 19309T=NBRC 113102T).


Reactive oxygen species act remotely to cause synapse loss in a Drosophila model of developmental mitochondrial encephalopathy.
Mitochondrial dysfunction is a hallmark of many neurodegenerative diseases, yet its precise role in disease pathology remains unclear. To examine this link directly, we subtly perturbed electron transport chain function in the Drosophila retina, creating a model of Leigh Syndrome, an early-onset neurodegenerative disorder. Using mutations that affect mitochondrial complex II, we demonstrate that mild disruptions of mitochondrial function have no effect on the initial stages of photoreceptor development, but cause degeneration of their synapses and cell bodies in late pupal and adult animals. In this model, synapse loss is caused by reactive oxygen species (ROS) production, not energy depletion, as ATP levels are normal in mutant photoreceptors, and both pharmacological and targeted genetic manipulations that reduce ROS levels prevent synapse degeneration. Intriguingly, these manipulations of ROS uncouple synaptic effects from degenerative changes in the cell body, suggesting that mitochondrial dysfunction activates two genetically separable processes, one that induces morphological changes in the cell body, and another that causes synapse loss. Finally, by blocking mitochondrial trafficking into the axon using a mutation affecting a mitochondrial transport complex, we find that ROS action restricted to the cell body is sufficient to cause synaptic degeneration, demonstrating that ROS need not act locally at the synapse. Thus, alterations in electron transport chain function explain many of the neurodegenerative changes seen in both early- and late-onset disorders.


A clinical prediction model based on interpretable machine learning algorithms for prolonged hospital stay in acute ischemic stroke patients: a real-world study.
Acute ischemic stroke (AIS) brings an increasingly heavier economic burden nowadays. Prolonged length of stay (LOS) is a vital factor in healthcare expenditures. The aim of this study was to predict prolonged LOS in AIS patients based on an interpretable machine learning algorithm. We enrolled AIS patients in our hospital from August 2017 to July 2019, and divided them into the "prolonged LOS" group and the "no prolonged LOS" group. Prolonged LOS was defined as hospitalization for more than 7 days. The least absolute shrinkage and selection operator (LASSO) regression was applied to reduce the dimensionality of the data. We compared the predictive capacity of extended LOS in eight different machine learning algorithms. SHapley Additive exPlanations (SHAP) values were used to interpret the outcome, and the most optimal model was assessed by discrimination, calibration, and clinical utility. Prolonged LOS developed in 149 (22.0%) of the 677 eligible patients. In eight machine learning algorithms, prolonged LOS was best predicted by the Gaussian naive Bayes (GNB) model, which had a striking area under the curve (AUC) of 0.878 ± 0.007 in the training set and 0.857 ± 0.039 in the validation set. The variables sorted by the gap values showed that the strongest predictors were pneumonia, dysphagia, thrombectomy, and stroke severity. High net benefits were observed at 0%-76% threshold probabilities, while good agreement was found between the observed and predicted probabilities. The model using the GNB algorithm proved excellent for predicting prolonged LOS in AIS patients. This simple model of prolonged hospitalization could help adjust policies and better utilize resources.


Hemodynamic effect of external counterpulsation is a different measure of impaired cerebral autoregulation from vasoreactivity to breath-holding.
External counterpulsation (ECP) is a novel method to increase cerebral blood flow, which may benefit acute ischaemic stroke patients. Our aim was to identify whether the hemodynamic effect of ECP is associated with cerebral vasoreactivity to breath-holding. Thirty-seven recent ischaemic stroke patients with large artery steno-occlusive disease were recruited together with 20 healthy controls. All underwent ECP treatment and a breath-holding test combined with transcranial Doppler monitoring on bilateral middle cerebral arteries was performed. The data of the stroke patients were designated as ipsilateral or contralateral based on the side of the infarct, whilst the average of both sides was used in controls. The cerebral augmentation index (CAI) was used to evaluate the augmentation effects of ECP. Cerebral vasoreactivity was assessed by using the breath-holding index (BHI). Middle cerebral artery mean flow velocities significantly increased in the stroke group after ECP but not in controls. BHIs were much smaller in the stroke group than in the controls. The CAI did not correlate with the BHI in either the ipsilateral or contralateral side of the stroke group or in controls. For stroke patients, BHI was significantly lower on the ipsilateral side than the contralateral side, but the CAI showed no difference between the two cerebral hemisphere sides. The CAI of stroke patients was significantly related to mean blood pressure change on the ipsilateral side. The dynamic augmentation effects of ECP as measured by the CAI were different from the well established vasoreactivity to breath-holding. The CAI is suggested as a measure of how well the brain accommodates blood flow augmentation during ECP.


[Patterns in the occurrence and the submicroscopic organization of elongated metaphase chromosomes isolated from the cell].
Chinese hamster metaphase chromosomes were investigated under different conditions of isolation. Light microscopic study demonstrated different forms of stretched chromosomes, from those in which merely a small region is stretched to rope-like structures 20-25 microns long with diameter of about 0.4 micron. The ratio between the number of stretched and of compact chromosomes is dependent on the concentration of bivalent cations, on the pH and temperature of the isolation buffer. A study of the submicroscopic organization of stretched chromosomes revealed lengthwise fibrils that disappeared after the treatment with 0.6 NaCl and staphylococcal nuclease. Distinct aggregates were seen, whose array is maintaining the stretched chromosome structure. It is suggested that stretched chromosomes appear due to the existing in vivo lability of bonds between the main chromosome components involved in organization of chromatin fiber packing. It is proposed that the structure obtains rigidity in the course of isolation with bivalent cations.