Cepharanthine and Piperine ameliorate diabetic nephropathy in rats: role of NF-κB and NLRP3 inflammasome.
Hyperglycemia leads to elevation of oxidative stress and proinflammatory cytokines which are the main causes of diabetic nephropathy (DN). NLRP3 inflammasome and thioredoxin-interacting protein (TXNIP) are recently assumed to participate in the development of DN. We aimed to investigate the effects of Cepharanthine (CEP), Piperine (Pip) and their combination in streptozotocin (STZ)-induced DN focusing on their role to modulate NLRP3 and TXNIP induced inflammation. Diabetic rats were treated with intraperitoneal (i.p.) injection of CEP (10mg/kg/day), Pip (30mg/kg/day) or their combination for 8weeks. Nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) were assessed by ELISA technique. TXNIP and NLRP3 genes expressions were evaluated by real time-PCR. Diabetic rats showed significant increase in renal TXNIP and NLRP3 expression. CEP, Pip or their combination significantly decreased TXNIP and NLRP3 expression in diabetic kidneys. Hyperglycemia induced NF-κB activation leading to increased IL-1β and TNF-α levels. CEP, Pip or their combination showed significant inhibition of NF-κB together with decreased IL-1β and TNF-α levels in diabetic rats. Also, diabetic rats showed significant decrease in creatinine clearance and increase in blood glucose, serum creatinine, blood urea nitrogen, malondialdehyde, proteinuria, and kidney weight to body Weight ratio. All of these changes were reversed by CEP, Pip or their combination. The antioxidant and anti-inflammatory effects of CEP and Pip which were accompanied by inhibition of NF-κB and NLRP3 activation might be helpful mechanisms to halt the progression of DN.


Reducing computational cost of large-scale genomic evaluation by using indirect genomic prediction.
Over half a million Holsteins are being genotyped annually in the United States. The computational cost of including all genotypes in single-step genomic (ssG)BLUP is high, although it is feasible to conduct large-scale genomic prediction using an efficient algorithm such as APY (algorithm for proven and young). An effective method to further reduce the computing cost could be the use of indirect genomic predictions (IGP) for genotyped animals when they have neither progeny nor phenotypes. These young genotyped animals have no effect on the other genotyped animals and could have their genomic prediction done indirectly. The main objective of this study was to calculate IGP for various groups of genotyped animals and investigate the reduction in computing time as well as bias and accuracy of the IGP. We compared IGP with genomic (G)EBV for 18 linear type traits in US Holsteins, including 2.3 million (M) genotyped animals. The full data set consisted of 10.9M records for 18 linear type traits up to 2018 calving, 13.6M animals in the pedigree, and 2.3M animals genotyped for 79K SNP. For IGP, ssGBLUP included all genotyped animals except those with neither progeny nor phenotypes by year from 2014 to 2018 (i.e., the target animals). The SNP marker effects were computed based on GEBV for genotyped animals that had progeny, or phenotypes, or both. Further, IGP were calculated for target genotyped animals in each year group. For all genotyped animal groups from 2014 to 2018, the coefficients of determination (R2) of a linear regression of GEBV on IGP were 0.960 for males and 0.954 for females for 18 traits on average. To reduce computing costs, the SNP marker effects were calculated based on GEBV from randomly selected genotyped animals from 15K to 60K. By randomly selecting a small number of genotyped animals, the computing time was dramatically reduced. As more genotyped animals were randomly selected to calculate SNP effects, R2 was higher (more accurate) and the regression coefficient was lower (more inflated IGP). In a practical genomic evaluation in US Holsteins, to get sufficient contributions from GEBV, 25K to 35K is a rational number of genotyped animals that can be randomly selected to compute SNP effects and obtain accurate and unbiased IGP. Considering the computing time and both unbiasedness and accuracy of IGP, genomic evaluation can be conducted separately in GEBV for genotyped animals with phenotypes or progeny and in IGP for young genotyped animals. This can be a practical solution when conducting a large-scale genomic evaluation and would enable more frequent evaluation at lower cost, especially when many genotyped animals have neither phenotypes nor progeny.


Left atrial strain is associated with adverse cardiovascular events in patients with end-stage renal disease: Findings from the Cardiac, Endothelial Function and Arterial Stiffness in ESRD (CERES) study.
We lack cardiovascular (CV) markers for patients with end-stage renal disease (ESRD), and left atrial (LA) strain has not been studied definitively in this population. We examined associations of LA reservoir, conduit, and booster strain with major adverse cardiovascular events (MACE) among stable patients with ESRD on dialysis. One hundred and ninety patients in the Cardiac, Endothelial and Arterial Stiffness in ESRD study underwent echocardiography, including strain imaging. The primary outcome was 2-year composite non-fatal MACE or CV death. We performed Cox proportional hazards regression for LA strain measures, adjusting for demographics, comorbidities, left ventricular global longitudinal strain (LV GLS), E/e' and LA volume index. Mean ± SD LA reservoir strain was 24.1 ± 7.0%, and LA conduit strain 11.9 ± 5.1%. In age-adjusted analyses, lower LA reservoir strain and LA conduit strain were associated with the primary outcome (HR per 1-SD worsening LA strain parameter = 1.57 [95% CI 1.2-2.1], p = 0.003 and 1.68 [95% CI 1.2-2.3], p = 0.002, respectively). After adjusting for comorbidities, LA reservoir strain remained associated with the primary outcome and with deaths alone, and LA conduit strain with the primary outcome and hospitalizations alone (p < 0.05 for all). Associations of LA conduit strain were independent of LV GLS. Associations were stronger in participants with serum albumin <3.6 mg/dl (p for interaction 0.008). Left atrial reservoir strain and conduit strain were independently associated with MACE among patients with ESRD. Our study provides unique ascertainment of CV hospitalizations not attributed to missed dialysis, and LA conduit strain was a strong marker for this outcome.


Combined phacovitrectomy with capsular tension ring and gas tamponade for chronic cyclodialysis cleft unresponsive to conventional closure.
Traumatic cyclodialysis clefts, a rare diagnosis after blunt injury to the eye, are typically amenable to closure with either medical therapy or direct surgical cyclopexy. However, when cyclodialysis clefts cannot be closed through these methods, unorthodox techniques may be required. We describe a method to close a traumatic cyclodialysis cleft involving simultaneous vitrectomy, capsular tension ring placement, and insertion of an intraocular lens.


Proximal Femoral Nail Antirotation versus Gamma3 nail for intramedullary nailing of unstable trochanteric fractures. A randomised comparative study.
The purpose of this study was to compare the clinical results and the complication rates of a new generation of two intramedullary fixation devices: Proximal Femoral Nail Antirotation® (PFNA) and Gamma3®. We conducted a prospective randomised multicentre trial of 61 patients who underwent a PFNA fixation treatment (31 patients) or a Gamma3 nail (30 patients). We documented the fixation failure complications as well as data of the surgical procedure, the clinical and functional outcomes (the EuroQoL5 questionnaire, the Katz index score, the Short Form 36 (SF-36), and the Harris Hip Score) and the plain radiographic parameters at 3,6 and 12 months follow up. The PFNA and Gamma3 fixation devices were similar in terms of complication rates. The risk for experiencing a postoperative complication after Gamma3 nailing was 40% versus 45% after PFNA fixation. At the 6-month and 1-year follow-up evaluations, there were no significant differences in terms of range of motion, clinical scores and radiological outcomes.


A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation.
To investigate the effects of TH9507, a novel growth hormone releasing factor, on abdominal fat accumulation, metabolic and safety parameters in HIV-infected patients with central fat accumulation. Randomized, double-blind, placebo-controlled trial enrolling 61 HIV-infected patients with increased waist circumference and waist-to-hip ratio. Participants were randomized to placebo or 1 or 2 mg TH9507 subcutaneously, once daily for 12 weeks. The primary outcome was change in abdominal fat, assessed by dual energy X-ray absorptiometry and cross-sectional computerized tomography scan. Secondary endpoints included change in insulin-like growth factor-I (IGF-I), metabolic, quality of life, and safety parameters. TH9507 resulted in dose-related physiological increases in IGF-I (P < 0.01 for 1 mg (+48%) and 2 mg (+65%) versus placebo). Trunk fat decreased in the 2 mg group versus placebo (0.8, -4.6 and -9.2%; placebo, 1 and 2 mg, respectively, P = 0.014 for 2 mg versus placebo), without significant change in limb fat. Visceral fat (VAT) decreased most in the 2 mg group (-5.4, -3.6 and -15.7%; placebo, 1 and 2 mg, respectively) but this change was not significant versus placebo. Subcutaneous fat (SAT) was preserved and did not change between or within groups. Lean body mass and the ratio of VAT to SAT improved significantly in both treatment groups versus placebo. Triglyceride and the cholesterol to high-density lipoprotein ratio decreased significantly in the 2 mg group versus placebo. Treatment was generally well tolerated without changes in glucose. TH9507 reduced truncal fat, improved the lipid profile and did not increase glucose levels in HIV-infected patients with central fat accumulation. TH9507 may be a beneficial treatment strategy in this population, but longer-term studies with more patients are needed to determine effects on VAT, treatment durability, and safety.


Results of an organ preservation protocol with induction chemotherapy and radiotherapy in patients with locally advanced laryngeal carcinoma.
An alternative treatment in patients with advanced laryngeal carcinoma who are candidates for total laryngectomy is induction chemotherapy and radical radiotherapy in an organ preservation approach. We conducted a study to evaluate results of this treatment in patients with locally advanced laryngeal carcinoma, candidates for total laryngectomy, who were treated at a single institution between 1985 and 1997. During the study period, 224 began treatment with induction chemotherapy. Induction chemotherapy consisted of three cycles of cisplatin and 5-fluoruracil in the majority of cases. Four patients died as a consequence of complications associated with chemotherapy treatment. Subsequent treatment consisted of total laryngectomy in 79 patients and radical radiotherapy in 141. After radical radiotherapy, local control for patients who achieved a complete response after induction chemotherapy was 74%, significantly better than 57% in patients with a non-complete response (P=0.04). Considering the initial group of 224 patients, the frequency of organ preservation was 39%. Considering only the patients treated with induction chemotherapy and radiotherapy, the organ preservation frequency was 62%. In a multivariate study, only the response after induction chemotherapy was significantly related to organ preservation.


An anti-acetylcholine receptor monoclonal antibody cross-reacts with phosvitin.
Rabbit and mouse anti-Torpedo acetylcholine receptor antibodies cross-reacted partially with the highly phosphorylated protein, phosvitin. We have selected an anti-Torpedo acetylcholine receptor monoclonal antibody which binds specifically to phosvitin; this binding is inhibited by acetylcholine receptor. These findings suggest that a phosphorylated amino acid residue may be a part of the determinant on the acetylcholine receptor recognized by this monoclonal antibody.


Dental student, dentist, dental assistant, and layperson perception of pink gingival porcelain color.
How pink gingival porcelain color is perceived by participants classified according to profession and sex is unclear. The purpose of this in vitro study was to evaluate the degree of correlation between the ordering of color tabs by participants classified according to profession, years of dental work experience, and sex and the ideal chromatic order based on the color coordinate L∗ (lightness). Twenty-one colored specimens made of Heraceram pink gingival porcelain were used. A group of 352 participants (118 men and 234 women) comprised of dental students (n=126), dentists (n=54), dental assistants (n=56), and laypersons (n=116) were enrolled. They were asked to order the specimens starting from the lightest to the darkest. The Kendall coefficients of concordance W and correlation T were used to determine whether the individuals in each experimental group rating the specimens were consistent and accurate. The degree of agreement between the ideal ordering and that carried out by the participants within the different professional categories was greater than 0.8 in all assessments. No statistically significant differences were found among the groups in relation to professional category, work experience, or sex (P>.05). The Kendall coefficients were higher in the ranking of the darker specimens for all groups of participants. No statistically significant differences were found among dentists, dental assistants, dental students, and laypersons in the arrangement of pink porcelain specimens according to their lightness. In addition, in all groups, the darker gingival specimens were ordered significantly better according to their lightness than the lighter specimens.


Pharmacokinetics of bromocriptine during continuous oral treatment of Parkinson's disease.
The plasma kinetics of bromocriptine (BCT), a long-acting dopamine agonist, was studied in twelve patients with Parkinson's disease, using a newly developed gas chromatographic method of analysis. Each patient received BCT for at least three weeks in a constant but different dose regimen. Concomitant treatment with 1-DOPA was not allowed. During a 6-day hospitalization period, a blood sample was taken immediately before the afternoon dose at 14.00 h (Cmin) to determine the steady-state level. On the 6th day blood samples were collected every hour during two 8 h dose intervals. The results showed a significant correlation between the mean values of the AUC and the Cmin. First order elimination kinetics appeared to be followed by BCT, at least for the plasma concentrations commonly found. Considerable inter-individual variation was demonstrated both for the dose/plasma concentration ratio and for calculated plasma clearances. No serious side-effects were observed during the investigation.


Protective effect of CO2 laser (10.6 μm) and fluoride on enamel erosion in vitro.
The aim of this study was to analyze the effect of CO(2) laser (10.6 μm) irradiation with 5-μs pulse width in prevention of enamel erosion due to citric acid exposure in vitro. One hundred forty-four bovine enamel samples were cut into 5 × 5 × 2-mm-size slabs and polished to obtain plane surfaces. Enamel surfaces were covered with acid-resistant varnish, except for a central area of 2.5 mm in diameter. The samples were divided into four groups (n = 12/group/day): C-control, no treatment; L-CO(2) laser irradiation (0.3 J/cm(2), 5 μs, 226 Hz); F-topical fluoride treatment, 1.25%F(-) (AmF/NaF) for 3 min; and FL-fluoride treatment + CO(2) laser. For erosive demineralization, samples were immersed in 40 ml of citric acid (0.05 M, pH 2.3) for 20 min two times per day during 5 days. After 1, 3, and 5 days, surface loss was measured by digital profilometer. According to the repeated measure ANOVA and post hoc comparisons, all the treatments showed statistically significant reduction of enamel loss as compared to control group, in all investigated times (p < 0.0001): L (52%,31%,37%); F (28%,24%,29%); FL (73%,55%,57%). Both CO(2) laser irradiation alone (L) and the combined laser-fluoride treatment (FL) caused less enamel loss than the fluoride group (F) in all days (p < 0.0001 for L in all times; and p < 0.0001, p = 0.0220 and p = 0.0051 for F, respectively, at days 1, 3, and 5). Under the conditions of this study, CO(2) laser irradiation (0.3 J/cm(2), 5 μs, 226 Hz) could effectively reduce enamel surface loss due to citric acid exposure, in vitro. This effect was still observed after 5 days of repeated acid exposures.


[Systemic conditions associated with central and branch retinal artery occlusions].
Retinal artery occlusions (RAO) are severe conditions threatening vision, affecting the subsequent mortality of these patients. We retrospectively reviewed the work-up performed in all patients diagnosed with retinal artery occlusions evaluated in two university hospitals in France (Tours and Angers). A total of 131 patients (131 eyes) with RAO were included, with a mean age of 69.5years and male predominance (64 %). Central retinal artery occlusion (CRAO) resulted in poor initial visual acuity (90 % less than count fingers), whereas those with branch retinal artery occlusion (BRAO) had better visual acuity (63.6 % better than 20/40). Systemic arterial hypertension (HTN) was the most common associated risk factor. Carotid stenosis was found in 50 % of cases, leading to endarterectomy in nine patients (6.9 %), while an underlying cardiac cause was implicated in 14 % of cases. Giant cell arteritis was diagnosed in five patients (3.8 %). Work-up of RAO may detect treatable cardiovascular and systemic conditions, allowing prevention of further ocular recurrence or stroke. Etiologic work-up of retinal arterial occlusion can diagnose potentially treatable underlying systemic conditions, such as giant cell arteritis, cardiac conditions and extracranial cerebrovascular disease. Giant cell arteritis has to be ruled out at the acute phase, while the role and timing of semi-urgent testing (supra-aortic Doppler echography, echocardiography, electrocardiography, lab work-up) or delayed testing (transesophageal echocardiography, brain imaging) have yet to be determined.


Resilience and its impact on the mental health of physiotherapists during the COVID-19 pandemic in São Paulo, Brazil.
To analyze whether resilience modulates the levels of depression, anxiety, stress and the impact of events in physiotherapists who work with COVID-19 patients with those who do not. A cross-sectional study was conducted from August 2020 up to October 2020. A total of 519 physiotherapists were enrolled and divided according to resilience and whether they worked with COVID-19 patients. Volunteers answered sociodemographic questionnaires, rating their depression, anxiety, and stress on a scale (DASS-21). The impact of event scale revised (IES-R) and 14-item resilience scale (14-RS) were also used. Physiotherapists with low resilience present scores significantly high of depression, anxiety, stress and impact of event compared to the high resilience group (P < .001). Additionally, working with COVID-19 patients also resulted in increased levels of depression, anxiety, stress, and impact of event compared with the NO COVID-19 group (P < .001). These responses were modulated by age, sex, number of absences from work, whether or not personal protective equipment was received, host leadership, and the practice and maintenance of regular physical activity. The responses to the questionnaires were anonymous and self-administered. We cannot assess whether these people had a previous diagnosis of depression, anxiety and stress. Low resilience and work with COVID-19 patients were associated with high levels of depression, anxiety, and stress and worse psychological impacts of events. Several aspects modulate these responses and can contribute to improving the resilience and mental health of physiotherapists who are responsible for the care of COVID-19 patients.


The diagnosis and management of MSUD in Saudi Arabia by using two different methods.
Plasma amino acid concentrations were measured in Maple Syrup Urine Disease (MSUD) infants using reversed phase high performance liquid chromatography (HPLC). The technique involved an automated data acquisition system and phenylisothiocyanate (PITC) pre-column derivatization. During a period of three years more than 14 cases of MSUD have been confirmed in our hospital suggesting an alarmingly high rate of incidence of this disease in the Kingdom as compared to the West. We present here a simple and reliable method of quantitating the branched chain and other amino acid concentrations in plasma samples of children with metabolic disorders. In addition, we also present a fluorimetric COBAS based enzymatic method for the rapid semiquantitative measurement of branched chain amino acids for a disease in which a prompt initial diagnosis is essential.


[Assessment of left ventricular twist mechanics by two-dimensional strain in severe aortic stenosis with preserved ejection fraction].
Left ventricular (LV) twist is increased in aortic stenosis (AS) and the hypothesis of a compensatory mechanism is suggested but not established. Our aim was to assess LV twist mechanics in severe AS (<1cm(2) or 0.6cm(2)/m(2)) with preserved LV ejection fraction (LVEF>50%), and to analyze its relationship with LV systolic longitudinal function, early impaired in this setting, LV diastolic function, and symptomatic status. Forty-five consecutive patients with severe AS and preserved LVEF (mean age 73±11 years, 47% female, LVEF 68±11%, 67% symptomatic) underwent a transthoracic echocardiography including a bidimensional strain analysis by speckle tracking method, and were compared to a control group matched for age and sex (n=15). Global longitudinal strain (GLS) was measured using the four, two, and three apical views, and LV twist mechanics from the basal and apical short axis views. LV twist was defined as the net difference between apical and basal rotation, and LV twisting and untwisting rate (in°/s) were derived from twist curves. Peak apical rotation, LV twist (25±8° vs 20±6), as well as peak systolic and diastolic apical rotation rate, and peak LV twisting rate were significantly higher in patients with AS when compared to controls (all, P<0.05), whereas, the other parameters of LV twist mechanics including basal rotation, were not significantly different between groups. By contrast, the GLS was significantly lower in patients with AS when compared to controls (-17.9±4 vs -20.5±2%, P<0.01). In addition, the GLS was significantly correlated to LV torsion (r=-0.42, P<0.01). Moreover, LV twist progressively impaired with the worsening of diastolic dysfunction and with symptoms onset. LV twist is increased in severe AS with preserved LVEF, compensating the impairment of systolic longitudinal function. However, above a certain threshold LV twist deteriorates, attesting the failure of the compensatory mechanisms, leading to advanced diastolic dysfunction and symptom onset.


Extracellular calcium ion depletion in frog cardiac ventricular muscle.
The extracellular free [Ca++] in frog ventricular muscle strips was monitored using single-barrel calcium ion-selective microelectrodes. During trains of repetitive stimulation, a heart rate-dependent, sustained fall (depletion) of the extracellular free [Ca++] occurs, which is most likely a consequence of net Ca++ influx into ventricular cells. The magnitude of the [Ca++]0 depletion increases for higher Ringer's solution [Ca++], and is reversibly blocked by manganese ion. Prolonged repetitive field stimulation (20-30 min) activates additional cellular Ca++ efflux, which can balance the additional Ca++ influx caused by stimulation, resulting in abolition of extratrabecular [Ca++]0 depletion in 20-30 min, and hence zero net transmembrane Ca++ flux at steady state. In the poststimulation period of quiescence, cellular Ca++ efflux persists and causes an elevation (accumulation) of the extracellular free [Ca++]. From these [Ca++]0 depletions, quantitative estimates for the net transmembrane Ca++ flux were derived using an analytical solution to the diffusion equation. In the highest Ringer's solution [Ca++] used (1 mM) the calculated net increase of the total intracellular calcium per beat was 6.5 +/- 1.4 mumol/l of intracellular space. This corresponds to an average net transmembrane Ca++ influx of 0.81 +/- 0.17 pmol/cm2/s during the 800-ms action potential. In lower bath [Ca++] the net transmembrane [Ca++] flux was proportionately reduced.


ATLAS: a Snakemake workflow for assembly, annotation, and genomic binning of metagenome sequence data.
Metagenomics studies provide valuable insight into the composition and function of microbial populations from diverse environments; however, the data processing pipelines that rely on mapping reads to gene catalogs or genome databases for cultured strains yield results that underrepresent the genes and functional potential of uncultured microbes. Recent improvements in sequence assembly methods have eased the reliance on genome databases, thereby allowing the recovery of genomes from uncultured microbes. However, configuring these tools, linking them with advanced binning and annotation tools, and maintaining provenance of the processing continues to be challenging for researchers. Here we present ATLAS, a software package for customizable data processing from raw sequence reads to functional and taxonomic annotations using state-of-the-art tools to assemble, annotate, quantify, and bin metagenome data. Abundance estimates at genome resolution are provided for each sample in a dataset. ATLAS is written in Python and the workflow implemented in Snakemake; it operates in a Linux environment, and is compatible with Python 3.5+ and Anaconda 3+ versions. The source code for ATLAS is freely available, distributed under a BSD-3 license. ATLAS provides a user-friendly, modular and customizable Snakemake workflow for metagenome data processing; it is easily installable with conda and maintained as open-source on GitHub at https://github.com/metagenome-atlas/atlas.


Molecular cloning of DNA complementary to bovine growth hormone mRNA.
We have cloned DNA complementary to mRNA coding for bovine growth hormone (bGH). Double-stranded DNA complementary to bovine pituitary mRNA was inserted into the Pst I site of plasmid pBR322 by the dC x dG tailing technique and amplified in E. coli x 1776. A recombinant plasmid containing bGH cDNA ws identified by hybridization to cloned rat growth hormone cDNA. It contains the entire coding and 3'-untranslated regions and 31 bases in the 5'-untranslated region. Nucleotide sequence analysis determined the sequence of the 26-amino acid signal peptide and confirmed the published amino acid sequence of the secreted hormone at all but 2 residues. Codon usage is nonrandom, with 81.7% of the codons ending in G or C. The nucleotide sequence of bGH mRNA is 83.9% homologous with rat GH mRNA and 76.5% homologous with human GH mRNA, while the respective amino acid sequence homologies are 83.5% and 66.8%.


Clinical and prognostic profile of SRSF2 and related spliceosome mutations in patients with acute myeloid leukemia.
Mutations in splicing factor (SF) genes are frequently detected in myelodysplastic syndrome, but their clinical and prognostic relevance in acute myeloid leukemia (AML) have rarely been reported. A total of 368 newly diagnosed non-M3 AML patients were included in this study. Next generation sequencing including four SF genes was performed on the genomicDNA. The clinical features and survival were analyzed using statistical analysis. We found that 64 of 368 patients harbored SF mutations. The SF mutations were much more frequently found in older or male patients. SRSF2 mutations were shown obviously co-existed with IDH2 mutation. The level of measurable residual disease after first chemotherapy was higher in SF-mutated patients compared to that in SF-wild patients, while the complete remission rate was significantly decreased. And the overall survival of SF-mutated patients was shorter than that of SF-wild patients. Moreover, our multivariable analysis suggests that the index of male, Kit mutation or ZRSR2 mutation was the independent risk factor for overall survival. SRSF2mut was associated with older age, higher proportion of peripheral blasts or abnormal cell proportion by flow cytometry. SF mutation is a distinct subgroup of AML frequently associated with clinic-biological features and poor outcome. SRSF2mut could be potential targets for novel treatment in AML.


Osthole improves glucose and lipid metabolism via modulation of PPARα/γ-mediated target gene expression in liver, adipose tissue, and skeletal muscle in fatty liver rats.
Osthole may be a dual agonist of peroxisome proliferator-activated receptors (PPAR) α/γ and ameliorate the insulin resistance (IR), but its mechanisms are not yet understood completely. We investigated the effects of osthole on PPARα/γ-mediated target genes involved in glucose and lipid metabolism in liver, adipose tissue, and skeletal muscle in fatty liver and IR rats. The rat model was established by orally feeding high-fat and high-sucrose emulsion for 9 weeks. The experimental rats were treated with osthole 5-10 mg/kg by gavage after feeding the emulsion for 6 weeks, and were sacrificed 4 weeks after administration. After treatment with osthole 5-10 mg/kg for 4 weeks, the lipid levels in serum and liver were decreased by 37.9-67.2% and 31.4-38.5% for triglyceride, 33.1-47.5% and 28.5-31.2% for free fatty acid, respectively, the fasting blood glucose, fasting serum insulin, and homeostasis model assessment of IR were also decreased by 17.2-22.7%, 25.9-26.7%, and 37.5-42.8%, respectively. Osthole treatment might simultaneously decrease the sterol regulatory element binding protein-1c, diacylglycerol acyltransferase, and fatty acid synthase mRNA expressions in liver and adipose tissue, and increase the carnitine palmitoyltransferase-1A mRNA expression in liver and glucose transporter-4 mRNA expression in skeletal muscle, especially in the osthole 10 mg/kg group (p < 0.01). Osthole can improve glucose and lipid metabolism in fatty liver and IR rats, and its mechanisms may be associated with synergic modulation of PPARα/γ-mediated target genes involved in glucose and lipid metabolism in liver, adipose tissue, and skeletal muscle.


Improved targeting of the globus pallidus interna using quantitative susceptibility mapping prior to MR-guided focused ultrasound ablation in Parkinson's disease.
Magnetic resonance guided focused ultrasound (MRgFUS) of the globus pallidus interna (GPi) has shown promise in the treatment of drug-resistant Parkinson's disease, though direct visualization of the GPi remains challenging with MRI. The purpose of this study was to compare various preoperative MR imaging techniques and to evaluate the utility of quantitative susceptibility imaging (QSM) in the depiction of the GPi prior to MRgFUS ablation. Six patients with medication refractory advanced idiopathic Parkinson's disease were referred for preoperative MR imaging prior to MRgFUS pallidotomy. Axial T1WI and T2WI, Fast Gray Matter Acquisition T1 Inversion Recovery (FGATIR), and QSM sequences were acquired. DTI tractography was performed to delineate the corticospinal tracts. Qualitative visualization scores and contrast to noise ratios (CNR) were recorded and measured on all images. QSM had significantly higher median qualitative visualization scores (3.00) compared with the T1WI (1.00), T2WI (1.50), and FGATIR sequences (1.50) (p < 0.05). QSM provided superior CNR for GPi depiction in each category (GPi-GPe and GPi-IC), respectively. For GPi-GPe, median CNR for T1WI, T2WI, FGATIR, and QSM was 1.13, 1.68, 0.79, and 10.78. For GPi-IC, median CNR for T1WI, T2WI, FGATIR, and QSM was 1.48, 4.63, 4.24, and 40.26, respectively (p < 0.05). QSM offers improved visualization of the GPi compared with the traditional and currently recommended MR sequences prior to MRgFUS ablation in patients with Parkinson's disease. These results suggest that QSM should be considered as part of all preoperative imaging protocols prior to MRgFUS pallidotomy.


Properties of β-sitostanol/DPPC monolayers studied with Grazing Incidence X-ray Diffraction (GIXD) and Brewster Angle Microscopy.
Although the influence of structurally modified sterols on artificial membranes has been intensively investigated, studies on the properties of stanols, which are saturated analogs of sterols, are very rare. Therefore, we have performed Grazing Incidence X-ray Diffraction (GIXD) experiments aimed at studying in-plane organization of a plant stanol-β-sitostanol monolayer and its mixtures with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine - DPPC at the air/water interface. The collected GIXD data, resulting in-plane parameters and BAM images provide information on molecular organization and in-plane ordering of the investigated films. It was found that the lateral organization of β-sitostanol/DPPC monolayers depends on their composition. The oblique structure of the in-plane lattice of tilted hydrophobic region of molecules, found for DPPC film, is maintained at 10 mol% of stanol in the system. However, at 30 and 90 mol% of stanol in the mixture, the arrangement of molecules is hexagonal and they are oriented perpendicularly to the interface. With the addition of stanol the extend of the in-plane order of the monolayers decreases. Moreover, in mixtures the ordered domains consist of both monolayer's components. Additionally, β-sitostanol film is of similar in-plane organization as the corresponding sterol monolayer (β-sitosterol) and stanol induces condensing effect on DPPC.


Effects of 4-vinylcyclohexene diepoxide on the cell cycle, apoptosis, and steroid hormone secretion of goat ovarian granulosa cells.
4-Vinylcyclohexene diepoxide (VCD) is a potentially hazardous industrial chemical that may enter a goat's body in various ways during industrial breeding. Ovarian granulosa cells (GCs) play a critical role in supporting follicle development and hormone synthesis. However, there are few studies on the effect of VCD on goat ovarian GCs. In this study, goat ovarian GCs were isolated and treated with VCD. The results showed that treatment with VCD increased the proportion of S phase and G2/M cells, but decreased the proportion of G1 phase. VCD treatment significantly inhibited the expression of cyclin A and cyclin-dependent kinase 2 (CDK2). But the expression levels of p21 and p27 were increased. VCD could induce an apparent increase in the proportion of apoptosis and the level of cleaved caspase 3. Treatment with VCD significantly reduced the progesterone and estrogen concentration in the medium in which goat ovarian GCs were cultured. Correspondingly, the expression level of steroidogenic acute regulatory protein (STAR) was significantly downregulated. Treatment with 0.25 and 0.5 mM VCD, the protein expression level of insulin-like growth factor 1 receptor (IGF1R) and Akt were significantly decreased. Moreover, treatment with 0.25 mM VCD significantly inhibited the phosphorylation of Akt. In conclusion, VCD exposure had cytotoxic effects such as decreased cell viability, disordered cell cycle, increased apoptosis, and interference with steroid hormone synthesis on goat GCs. These cytotoxic effects of VCD on goat GCs may be due to the downregulation of IGF1R and the inhibition of IGF1R/Akt signaling pathway.


Sequence-Based Deep Learning Frameworks on Enhancer-Promoter Interactions Prediction.
Enhancer-promoter interactions (EPIs) in the human genome are of great significance to transcriptional regulation, which tightly controls gene expression. Identification of EPIs can help us better decipher gene regulation and understand disease mechanisms. However, experimental methods to identify EPIs are constrained by funds, time, and manpower, while computational methods using DNA sequences and genomic features are viable alternatives. Deep learning methods have shown promising prospects in classification and efforts that have been utilized to identify EPIs. In this survey, we specifically focus on sequence-based deep learning methods and conduct a comprehensive review of the literature. First, we briefly introduce existing sequence- based frameworks on EPIs prediction and their technique details. After that, we elaborate on the dataset, pre-processing means, and evaluation strategies. Finally, we concluded with the challenges these methods are confronted with and suggest several future opportunities. We hope this review will provide a useful reference for further studies on enhancer-promoter interactions.


Treatment of vitreomacular traction with intravitreal ocriplasmin preceded by anterior chamber paracentesis: case reports.
To evaluate the efficacy of an intravitreal ocriplasmin injection using anterior chamber paracentesis to release symptomatic vitreomacular traction (VMT). Five patients with symptomatic VMT were enrolled. All patients underwent a complete ophthalmologic examination including acquisition of spectral-domain optical coherence tomography. Before intravitreal injection of ocriplasmin, anterior chamber paracentesis was performed in the study eye to induce mild ocular hypotonia. Control visits were performed the day after the injection, at 1 week, and after 1, 2, and 3 months. In 4 patients, we had complete release of VMT and visual improvement after the intravitreal ocriplasmin injection preceded by anterior chamber paracentesis. No adverse events were observed. In our small case series, anterior chamber paracentesis performed before intravitreal ocriplasmin seemed to increase the efficacy of the drug in the resolution of symptomatic VMT. Our success estimate is imprecise due to small sample size (95% confidence interval 0.28 to 0.99) and no definitive conclusion can be reached. Further research is worth being conducted to assess the potential usefulness of paracentesis before ocriplasmin injection to increase vitreoretinal traction release rate.


The impact of the gut microbiota on T cell ontogeny in the thymus.
The intestinal microbiota is critical for the development of gut-associated lymphoid tissues, including Peyer's patches and mesenteric lymph nodes, and is instrumental in educating the local as well as systemic immune system. In addition, it also impacts the development and function of peripheral organs, such as liver, lung, and the brain, in health and disease. However, whether and how the intestinal microbiota has an impact on T cell ontogeny in the hymus remains largely unclear. Recently, the impact of molecules and metabolites derived from the intestinal microbiota on T cell ontogeny in the thymus has been investigated in more detail. In this review, we will discuss the recent findings in the emerging field of the gut-thymus axis and we will highlight the current questions and challenges in the field.


Hematological toxicity after robotic stereotactic body radiosurgery for treatment of metastatic gynecologic malignancies.
To evaluate hematological toxicity after robotic stereotactic body radiosurgery (SBRT) for treatment of women with metastatic abdominopelvic gynecologic malignancies. A total of 61 women with stage IV gynecologic malignancies treated with abdominopelvic SBRT were analyzed after ablative radiation (2400 cGy/3 divided consecutive daily doses) delivered by a robotic-armed Cyberknife SBRT system. Abdominopelvic bone marrow was identified using computed tomography-guided contouring. Fatigue and hematologic toxicities were graded by retrospective assignment of common toxicity criteria for adverse events (version 4.0). Bone marrow volume receiving 1000 cGy (V10) was tested for association with post-therapy (median 32 days [25%-75% quartile, 28-45 days]) white- or red-cell counts, hemoglobin levels, and platelet counts as marrow toxicity surrogates. In all, 61 women undergoing abdominopelvic SBRT had a median bone marrow V10 of 2% (25%-75% quartile: 0%-8%). Fifty-seven (93%) of 61 women had received at least 1 pre-SBRT marrow-taxing chemotherapy regimen for metastatic disease. Bone marrow V10 did not associate with hematological adverse events. In all, 15 grade 2 (25%) and 2 grade 3 (3%) fatigue symptoms were self-reported among the 61 women within the first 10 days post-therapy, with fatigue resolved spontaneously in all 17 women by 30 days post-therapy. Neutropenia was not observed. Three (5%) women had a grade 1 drop in hemoglobin level to <10.0 g/dL. Single grade 1, 2, and 3 thrombocytopenias were documented in 3 women. Abdominopelvic SBRT provided ablative radiation dose to cancer targets without increased bone marrow toxicity. Abdominopelvic SBRT for metastatic gynecologic malignancies warrants further study.


Performance of diagnostic ultrasound to identify causes of hydramnios.
We aimed to assess the diagnostic yield of ultrasonography in the identification of the etiology of hydramnios, and the added value of MRI or amniocentesis. We conducted a single-center retrospective study including pregnancies with confirmed hydramnios (defined as deepest pocket ≥8 cm) between January 2013 and May 2017. Twin pregnancies, secondary hydramnios discovered after the diagnosis of a causal pathology, and pregnancies of unknown outcome were excluded. All pregnancies underwent a targeted scan, and selected cases underwent MRI or amniocentesis. A total of 158 patients with confirmed hydramnios were included. Hydramnios was associated with a fetal pathology in 37 cases (23.4%), with diabetes in 39 (24.6%), isolated macrosomia in 16 (10.1%), and considered idiopathic in 66 (41.7%). Ultrasonography established a diagnosis of the underlying pathology in 73% of cases. Amniocentesis was done in 31 cases (20%) and it allowed diagnosis of chromosome anomalies, esophageal atresia, myotonic dystrophy congenital type, Prader-Willi syndrome, and Bartter syndrome. MRI was done in 15 cases (10%) and it allowed one additional diagnosis of esophageal atresia. The diagnostic yields of MRI and amniocentesis were 91.7% and 95.2%, respectively. There were five false positive diagnoses at ultrasonography, and one false positive diagnosis at MRI. Hydramnios can be associated with a wide variety of underlying pathologies. Diagnostic ultrasound can attain a diagnosis in the majority of cases. Amniocentesis offers a valuable complementary assessment.


Can the DSM's major depression bereavement exclusion be validly extended to other stressors? Evidence from the NCS.
To evaluate whether the DSM's distinction between uncomplicated (normal) vs. complicated (disordered) bereavement-related depressive episodes can be validly extended to non-bereavement stressor-related depression (SRD). Previous findings supporting the uncomplicated/complicated SRD distinction's discriminant validity were criticized as tautological because of definitional biases (e.g., 'uncomplicated' requires brief duration, yet duration was a validator). We tested whether uncomplicated/complicated SRD validator differences are tautological or real. Using National Comorbidity Survey data, we compared uncomplicated SRDs, complicated SRDs, and endogenous/psychotic MDD on levels of eight pathology validators. We identified definitional biases affecting six validators, and corrected them by deleting the biasing definitional components and recalculating validator levels. After correction of biases, uncomplicated SRDs had significantly lower pathology levels than both complicated SRDs and endogenous/psychotic MDD on seven of eight validators, disconfirming the tautology hypothesis. Regression analysis revealed that 'uncomplicated' cannot be equated with 'mild'. Extending the 'uncomplicated' durational threshold from 2 to 6 months yielded equal or stronger discriminant validity, suggesting the arbitrariness of the current durational criterion. Uncomplicated SRDs' lower pathology levels are because of real syndromal differences, not definitional tautologies. The uncomplicated/complicated distinction has discriminant validity when extended to non-bereavement SRDs as an indicator of normality vs. disorder.


Predicting Formulation Conditions During Ultrafiltration and Dilution to Drug Substance Using a Donnan Model with Homology-Model Based Protein Charge.
In the manufacturing of therapeutic monoclonal antibodies (mAbs), the final steps of the purification process are typically ultrafiltration/diafiltration (UF/DF), dilution, and conditioning. These steps are developed such that the final drug substance (DS) is formulated to the desired mAb, buffer, and excipient concentrations. To develop these processes, process and formulation development scientists often perform experiments to account for the Gibbs-Donnan and volume-exclusion effects during UF/DF, which affect the output pH and buffer concentration of the UF/DF process. This work describes the development of an in silico model for predicting the DS pH and buffer concentration after accounting for the Gibbs-Donnan and volume-exclusion effects during the UF/DF operation and the subsequent dilution and conditioning steps. The model was validated using statistical analysis to compare model predictions against experimental results for nine molecules of varying protein concentrations and formulations. In addition, our results showed that the structure-based in silico approach used to calculate the protein charge was more accurate than a sequence-based approach. Finally, we used the model to gain fundamental insights about the Gibbs-Donnan effect by highlighting the role of the protein charge concentration (the protein concentration multiplied with protein charge at the formulation pH) on the Gibbs-Donnan effect. Overall, this work demonstrates that the Gibbs-Donnan and volume-exclusions effects can be predicted using an in silico model, potentially alleviating the need for experiments.


Cellular mechanisms involved in morphine-mediated suppression of CTL activity.
Based on a plethora of data from many laboratories, we have proposed the following mechanisms by which morphine alters immune homeostasis and immunocompetence in vivo (Fig. 2). Specifically, the administration of morphine subcutaneously via routing through blood interacts directly with opioid receptors on cells of the immune system or on receptors within the central nervous system. Although there is currently no evidence to support the direct involvement of morphine on lymphocyte opioid receptors, in vitro studies show the existence of functional, naloxone-sensitive opioid receptors (25). In addition, pharmacological and biochemical characterization of lymphocyte opioid receptors has been shown to be consistent in many instances, with the profile of neural-derived opioid receptors (25-27). Finally, recent molecular studies using oligonucleotide primers specific for the delta-class opioid receptor cloned from NG-108-15 cells (28) have been used in reverse transcription-polymerase chain reactions to generate a 400 bp product in SL which has 100% sequence homology with a published opioid receptor cloned from a brain library (35). However, future studies are necessary to establish the role of lymphocyte opioid receptors following the in vivo administration of opioids (e.g. fentanyl, methadone, and morphine). Since the administration of morphine subcutaneously appears to predominately interact with brain opioid receptors (3) located in the mesencephalon (5), other neuroendocrine systems become candidates for activation and subsequent direct modulation of immune function: (i) the HPA axis and (ii) the sympathetic nervous system (SNS).(ABSTRACT TRUNCATED AT 250 WORDS)


Measurement Properties of the Psoriasis Symptom Inventory Electronic Daily Diary in Patients with Moderate to Severe Plaque Psoriasis.
The Psoriasis Symptom Inventory (PSI) is a patient-reported outcome instrument that measures the severity of psoriasis signs and symptoms. This study evaluated measurement properties of the PSI in patients with moderate to severe plaque psoriasis. This secondary analysis used pooled data from a phase 3 brodalumab clinical trial (AMAGINE-1). Outcome measures included the PSI, Psoriasis Area and Severity Index (PASI), static Physician's Global Assessment (sPGA), psoriasis-affected body surface area, 36-item Short-Form Health Survey version 2, and the Dermatology Life Quality Index (DLQI). The PSI was evaluated for dimensionality, item performance, reliability (internal consistency and test-retest), construct validity, ability to detect change, and agreement between PSI response and response measures based on the PASI, sPGA, and DLQI. Results supported unidimensionality, good item fit, ordered responses, and PSI scoring. The PSI demonstrated reliability: baseline Cronbach's alpha ≥ 0.92 and intraclass correlation coefficients ≥ 0.95. Correlations between PSI total score and DLQI item 1 (r = 0.86), DLQI symptoms and feelings (r = 0.87), and 36-item Short-Form Health Survey version 2 bodily pain (r = -0.61) supported convergent validity. PSI scores differed significantly (P < 0.001) among severity groups based on the PASI (< 12/≥ 12), sPGA (0-1/2-3/4-5), body surface area (< 5%/5%-10%/> 10%), and DLQI (≤ 5/> 5) at weeks 8 and 12. At week 12, the PSI detected significant changes in severity based on PASI responses (< 50/50- < 75/≥ 75) and sPGA (0-1/≥ 2), and showed good agreement (k ≥ 0.66) between PSI response and PASI, sPGA, and DLQI responses. The PSI demonstrated excellent validity, reliability, and ability to detect change in the severity of psoriasis signs and symptoms.


Real-time three-dimensional echocardiography: an update.
Real-time three-dimensional echocardiography (RT3DE) is the only on-line 3D method based on real-time volumetric scanning, as compared with other 3D imaging techniques such as computed tomography and magnetic resonance imaging, which are based on post-acquisition reconstruction and not on volumetric scanning. In recent years, several studies have revealed possible advantages of 3DE in daily clinical practice. The aim of this manuscript is to give a brief review of the development of the clinical applications of RT3DE.


The effects of scopolamine on memory for time in rats and pigeons.
In Experiment 1, pigeons were trained to match short (2 s) and long (8 s) sample durations to red and green comparison stimuli and red and green samples to vertical and horizontal line comparisons. They received injections of scopolamine hydrobromide (0.02 mg/kg), scopolamine methylbromide (0.02 mg/kg), or saline, and the delay interval was manipulated (0, 1, 3, and 9 s). In Experiment 2, rats were trained to discriminate short (2 s) or long (12 s) durations of house-light illumination using a choice procedure. During the test phase of each trial, the left and right levers were presented with the cue light on above one of them (cued lever) while the other was off (uncued lever). For half of the rats, the correct response following the short sample was to press the cued lever, whereas following the long sample, it was to press the uncued lever. This was reversed for the remaining rats. The rats received injections of scopolamine hydrobromide (0.15 mg/kg), scopolamine methylbromide (0.15 mg/kg), or saline, and the delay interval was manipulated (0, 1, 3, and 9 s). In pigeons, scopolamine equivalently disrupted both temporal and nontemporal memory. Memory for time, in both rats and pigeons, was significantly poorer following scopolamine injections than following methylscopolamine or saline injections. No choose-short effect was observed in either rats or pigeons during saline test sessions. The data indicate that central cholinergic blockade in both pigeons and rats disrupts the accuracy of delayed temporal discriminations. However, scopolamine does not appear to accelerate the rate at which memory for temporal events is foreshortened.


Comparison of direct and indirect costs of internal fixation and cast treatment in acute scaphoid fractures: a randomized trial involving 52 patients.
The most cost-effective treatment of scaphoid fractures has not yet been determined. In a prospective trial, 52 employed or selfemployed patients with scaphoid fractures were randomized to closed (cast) or surgical treatment. There were 3 complications in the surgical group and 1 in the cast group. Median time off work was numerically but not statistically significantly greater after cast than after surgery (74/39 days). Manual workers (manuals) had a longer time away from work than non-manual employees/individuals who were selfemployed (non-manuals; median 84 days and 16 days, respectively; p < 0.001) and they had a longer time off work after cast than after surgery (median 100 days and 61 days; p = 0.03). Hospital costs were lower after cast than after surgery (p < 0.001). Work disability costs were numerically but not statistically significantly higher after cast than after surgery, and similarly, the total costs were lower after cast than after surgery. Work disability costs and total costs were higher in manuals than in non-manuals (p < 0.001). Non-manuals had lower total costs after cast than after surgery (p = 0.05). There was a longer period of absence from work after cast than after surgery in manuals, but not in non-manuals. In non-manuals, total costs were lower after cast than after surgery. Socioeconomic classification had a greater influence on cost than mode of treatment.


The regulation of endocrine-disrupting chemicals to minimize their impact on health.
Endocrine-disrupting chemicals (EDCs) are substances generated by human industrial activities that are detrimental to human health through their effects on the endocrine system. The global societal and economic burden posed by EDCs is substantial. Poorly defined or unenforced policies can increase human exposure to EDCs, thereby contributing to human disease, disability and economic damage. Researchers have shown that policies and interventions implemented at both individual and government levels have the potential to reduce exposure to EDCs. This Review describes a set of evidence-based policy actions to manage, minimize or even eliminate the widespread use of these chemicals and better protect human health and society. A number of specific challenges exist: defining, identifying and prioritizing EDCs; considering the non-linear or non-monotonic properties of EDCs; accounting for EDC exposure effects that are latent and do not appear until later in life; and updating testing paradigms to reflect 'real-world' mixtures of chemicals and cumulative exposure. A sound strategy also requires partnering with health-care providers to integrate strategies to prevent EDC exposure in clinical care. Critical next steps include addressing EDCs within global policy frameworks by integrating EDC exposure prevention into emerging climate policy.


The effect of triclosan-coated sutures in wound healing. A double blind randomised prospective pilot study.
Wound infection and dehiscence are both major contributors to postoperative morbidity. One potential cause or co-factor is the use of suture material. A recently introduced subcutaneous suture is coated with triclosan (TC), an antiseptic drug. It is suggested to reduce wound complications. To investigate the effect of TC on wound healing a double blind prospective pilot study in women undergoing a breast reduction was performed. Each patient was her own control. After randomisation the TC-coated sutures were used either on the left or right side. The contralateral side was used as the control. The incidence of dehiscence was studied. Twenty-six patients were included. In the TC breasts there was a wound dehiscence in 16 cases, whereas in the control breasts in seven cases a dehiscence was observed (P=0.023). These results suggest that TC-coated sutures should be used with caution. These sutures have already been introduced on to the market without good clinical studies and might have potential adverse effects as shown by these data.


Pelvic organ prolapse symptoms in relation to POPQ, ordinal stages and ultrasound prolapse assessment.
Adequate staging of pelvic organ prolapse is important in clinical practice and research. The ability of the POPQ, ordinal stages and ultrasound prolapse assessment were evaluated for their ability to discriminate between women with and without prolapse symptoms. The leading edge of the predominant compartment in the three assessment systems was used for the calculation of receiver operating characteristics curves. Two hundred and sixty five (265) consecutive women were evaluated. The area under the receiver operating characteristics curve for the three staging systems ranged from 0.715 to 0.783. POPQ staging and ordinal staging performed equally well in the prediction of prolapse symptoms (p = 0.780), and both performed better as compared with ultrasound prolapse assessment (p = 0.048 and p = 0.015, respectively). Prolapse staging can equally be performed by the POPQ and ordinal stages systems as far as the discrimination between women with and without prolapse symptoms is concerned. The ultrasound prolapse assessment does not perform better as compared with these two systems.


Medically unnecessary cesarean section births: introduction to a symposium.
Between 1965 and 1986, the United States cesarean section rate increased from 4.5 to 24.1%. Increasingly, childbearing women and their advocates, along with many others, have recognized that a large proportion of cesareans confers a broad array of risks without providing any medical benefit. A growing literature examines the diverse causes of medically unnecessary cesareans and the diverse effects of surgical birth on women, infants, and families. Various programs and policies have been proposed or implemented to reduce cesarean rates. In recent decades, many other nations have also experienced a sharply escalating cesarean section rate. It is reasonable to conclude that a largely uncontrolled international pandemic of medically unnecessary cesarean births is occurring. The level of political, analytic, and programmatic activity that has occurred in the U.S. regarding medically unnecessary surgical births does not seem to be paralleled in other nations with sharply escalating rates. This symposium was organized with the objective of presenting the U.S. experience with various dimensions of the problem of medically unnecessary cesareans to an international audience. Although preliminary and inadequate, it is hoped that this experience will encourage policy leaders and investigators throughout the world to recognize and address the problem of run-away cesarean section births. The first section of this introduction summarizes the U.S. experience with medically unnecessary cesareans from the perspective of trends, causes, consequences, and solutions. The second section covers the same topics, presenting selected material from various other nations throughout the world. In the course of these overviews, I introduce the symposium's seven contributions, most of which focus on circumstances in the U.S.


The nociceptin receptor promotes autophagy through NF-kB signaling and is transcriptionally regulated by E2F1 in HCC.
Opioids and their receptors are involved in cancer progression. However, the roles of the nociceptin receptor (NOP) and its antagonist (JTC801) in hepatocellular carcinoma (HCC) are poorly understood. The prognostic value of NOP expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human HCC cohort. The biological role and mechanism of NOP in HCC tumor growth were determined in vitro and in vivo. We found that NOP was associated with the clinicopathological features and survival outcomes of HCC patients. NOP overexpression promoted HCC growth in vitro and in vivo. Mechanistically, NOP activated NF-kB signaling to promote autophagy, which inhibited apoptosis, in HCC cells. An inhibitor of autophagy, 3-MA, and an inhibitor of NF-kB, JSH-23, attenuated the function of NOP in HCC. E2F1 was identified as a transcription factor of NOP. The oncogenic role of NOP was positively regulated by E2F1. Furthermore, JTC801, a selective antagonist of NOP, abolished the function of NOP by inhibiting NF-kB signaling and autophagy. Our study demonstrates that NOP is an oncogene in HCC. We provide a potential therapeutic candidate and prognostic predictor for HCC. JTC801 could become a potential drug for HCC therapy.


External Cervical Resorption: A Volumetric Analysis on Evolution of Defects over Time.
The aim of this study was to assess the temporal evolution of external cervical resorption (ECR) defects using a volumetric quantification method. Cone-beam computed tomographic (CBCT) images of patients diagnosed with ECR who chose not to receive treatment and attended recalls were collected. ECR defects were segmented in CBCT images at baseline and recall, and their volumes were quantified. The volumetric ratio of resorption defects/teeth was calculated. Three-dimensional classification of defects at baseline and recall and the prevalence of root surface perforations ≥1 mm were determined. The Wilcoxon matched pairs signed rank test, chi-square test, and linear regression models were used to analyze the data. Fifteen patients with 20 teeth diagnosed with ECR and an average recall time of 21 months were included. Nine (45%) teeth showed a change in 3-dimensional classification at recall. The volume of resorption defects (P = .0001) and the volumetric ratio of resorption defects/teeth (P = .0001) increased over time. The prevalence of root surface perforations ≥1 mm was higher at recall (n = 17, 85%) compared with baseline (n = 9, 45%) (P = .008). Linear regression models showed significant associations between the resorption defect volume at recall compared with baseline (P < .0001; 95% confidence interval, 0.053-0.081) and the volumetric ratio of resorption defects/teeth at recall compared with baseline (P < .0001; 95% confidence interval, 0.205-0.356). There was no association between the volume of resorption defects at recall with the length of the recall period, sex, or age (P > .05). When left untreated, ECR defects can increase in size and develop more root surface perforations. ECR has a dynamic nature, and its volumetric increase over time does not result from uniform/linear expansion of the defects.


Decision-analytical model with lifetime estimation of costs and health outcomes for one-time screening for abdominal aortic aneurysm in 65-year-old men.
Abdominal aortic aneurysm (AAA) causes about 2 per cent of all deaths in men over the age of 65 years. A major improvement in operative mortality would have little impact on total mortality, so screening for AAA has been recommended as a solution. The cost-effectiveness of a programme that invited 65-year-old men for ultrasonographic screening was compared with current clinical practice in a decision-analytical model. In a probabilistic Markov model, costs and health outcomes of a screening programme and current clinical practice were simulated over a lifetime perspective. To populate the model with the best available evidence, data from published papers, vascular databases and primary research were used. The results of the base-case analysis showed that the incremental cost per gained life-year for a screening programme compared with current practice was 7760, and that for a quality-adjusted life-year was 9700. The probability of screening being cost-effective was high. A financially and practically feasible screening programme for AAA, in which men are invited for ultrasonography in the year in which they turn 65, appears to yield positive health outcomes at a reasonable cost.


[Cloning and characterization of a novel rat gene RSD-7 differentially expressed in testis].
To isolate and identify the differentially expressed genes in spermatogenesis for the understanding molecular mechanism of spermatogenesis. Screening of the cDNA library, Northern blot, expression and purification in E. coli with GST expression system, immunocytochemical staining of testis sections were used. (1) A cDNA fragment designated as RSD-7 was isolated from rat testis cDNA library. It was 1,238 bp in length, coding a protein of 232 amino acids with the GenBank accession number AF315467. The encoding protein of RSD-7 cDNA had a Ubiquitin-like domain. (2) Northern blot indicated that RSD-7 was uniquely expressed in rat testis, and in the testis RSD-7 emerged on the 30th postnatal day and expressed until 120th postnatal day. (3) Expression and purification of RSD-7 protein in E. coli with GST expression system and were used to obtain anti-RSD-7 antibody. (4) Immunolocalization of RSD-7 in rat testis revealed that it is expressed only in Sertoli cells. Transcription pattern of RSD-7 and localization of RSD-7 protein in testis have been made, which established the base for the functional study of RSD-7.


Physical therapy techniques in the treatment of the head and neck patient.
Limited jaw openings, which may develop following surgery and radiation therapy is a significant clinical problem. Some patients develop restricted oral opening because of extensive fibrosis and scarring of the affected tissues. The aid of the physical therapist is invaluable in the treatment of these patients.


Optimized deep learning architecture for brain tumor classification using improved Hunger Games Search Algorithm.
One of the worst diseases is a brain tumor, which is defined by abnormal development of synapses in the brain. Early detection of brain tumors is essential for improving prognosis, and classifying tumors is a vital step in the disease's treatment. Different classification strategies using deep learning have been presented for the diagnosis of brain tumors. However, several challenges exist, such as the need for a competent specialist in classifying brain cancers by deep learning models and the problem of building the most precise deep learning model for categorizing brain tumors. We propose an evolved and highly efficient model based on deep learning and improved metaheuristic algorithms to address these challenges. Specifically, we develop an optimized residual learning architecture for classifying multiple brain tumors and propose an improved variant of the Hunger Games Search algorithm (I-HGS) based on combining two enhancing strategies: Local Escaping Operator (LEO) and Brownian motion. These two strategies balance solution diversity and convergence speed, boosting the optimization performance and staying away from the local optima. First, we have evaluated the I-HGS algorithm on the IEEE Congress on Evolutionary Computation held in 2020 (CEC'2020) test functions, demonstrating that I-HGS outperformed the basic HGS and other popular algorithms regarding statistical convergence, and various measures. The suggested model is then applied to the optimization of the hyperparameters of the Residual Network 50 (ResNet50) model (I-HGS-ResNet50) for brain cancer identification, proving its overall efficacy. We utilize several publicly available, gold-standard datasets of brain MRI images. The proposed I-HGS-ResNet50 model is compared with other existing studies as well as with other deep learning architectures, including Visual Geometry Group 16-layer (VGG16), MobileNet, and Densely Connected Convolutional Network 201 (DenseNet201). The experiments demonstrated that the proposed I-HGS-ResNet50 model surpasses the previous studies and other well-known deep learning models. I-HGS-ResNet50 acquired an accuracy of 99.89%, 99.72%, and 99.88% for the three datasets. These results efficiently prove the potential of the proposed I-HGS-ResNet50 model for accurate brain tumor classification.


Bioavailability of amfepramone hydrochloride sustained release pellets formulation in healthy subjects.
The relative bioavailability and pharmacokinetic profile of two amfepramone (diethylpropion) hydrochloride oral preparations were evaluated in 12 normal volunteers using a newly developed gas-liquid chromatographic procedure to monitor the unchanged drug and its two major metabolites in urine, plasma and saliva. The sustained release pellets formulation (Regenon retard) provided excellent bioavailability and gave broad plateau levels extending over 6 to 8 h after administration, which were intermediate between the "peaks and troughs" shown by the same total dose of the free drug in three equal portions at 4-h intervals.


Genistein activated adenosine 5'-monophosphate-activated protein kinase-sirtuin1/peroxisome proliferator-activated receptor γ coactivator-1α pathway potentially through adiponectin and estrogen receptor β signaling to suppress fat deposition in broiler chickens.
Genistein can be used as a dietary additive to control fat deposition in animals, while its mechanism is poorly understood. In this study, a total of 144 male broilers were randomly divided into 4 groups. Birds were fed standard diets supplemented with 0, 50, 100 or 150 mg of genistein/kg from 21 to 42 d of age. Results showed that genistein treatment decreased the relative weight of abdominal fat and triglyceride contents in broiler chickens. Genistein downregulated hepatic lipid droplets accumulation and upregulated the activity of lipoprotein lipase and hepatic lipase and the concentration of adiponectin. Furthermore, the liver X receptor α, sterol regulatory element-binding protein 1c (SREBP-1c), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) mRNA expressions were decreased, whereas adiponectin receptor 2, peroxisome proliferator-activated receptor α, adipose triglyceride lipase, and carnitine palmitoyl transferase-I (CPT-I) mRNA abundances were increased in the liver of broilers treated with genistein. In addition, genistein increased the NAD+ concentration and NAD+/NADH ratio in the liver. Genistein increased estrogen receptor β (ERβ), forkhead box O1, nicotinamide phosphoribosyl transferase, sirtuin1 (SIRT1), phospho (p)-adenosine 5'-monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), p-ACC, and CPT-I protein levels, whereas the SREBP-1c and FAS levels were decreased. These data indicated that genistein might reduce fat accumulation in broiler chickens via activating the AMPK-SIRT1/PGC-1α signaling pathway. The activation of this signaling pathway might be achieved by its direct effect on improving the adiponectin secretion or its indirect effect on upregulation of ERβ expression level through paracrine acting of adiponectin.


Asymmetric visual representation of sex from human body shape.
We efficiently infer others' states and traits from their appearance, and these inferences powerfully shape our social behaviour. One key trait is sex, which is strongly cued by the appearance of the body. What are the visual representations that link body shape to sex? Previous studies of visual sex judgment tasks find observers have a bias to report "male", particularly for ambiguous stimuli. This finding implies a representational asymmetry - that for the processes that generate a sex percept, the default output is "male", and "female" is determined by the presence of additional perceptual evidence. That is, female body shapes are positively coded by reference to a male default shape. This perspective makes a novel prediction in line with Treisman's studies of visual search asymmetries: female body targets should be more readily detected amongst male distractors than vice versa. Across 10 experiments (N = 32 each) we confirmed this prediction and ruled out alternative low-level explanations. The asymmetry was found with profile and frontal body silhouettes, frontal photographs, and schematised icons. Low-level confounds were controlled by balancing silhouette images for size and homogeneity, and by matching physical properties of photographs. The female advantage was nulled for inverted icons, but intact for inverted photographs, suggesting reliance on distinct cues to sex for different body depictions. Together, these findings demonstrate a principle of the perceptual coding that links bodily appearance with a significant social trait: the female body shape is coded as an extension of a male default. We conclude by offering a visual experience account of how these asymmetric representations arise in the first place.


Non-invasive imaging reveals convergence in root and stem vulnerability to cavitation across five tree species.
Root vulnerability to cavitation is challenging to measure and under-represented in current datasets. This gap limits the precision of models used to predict plant responses to drought because roots comprise the critical interface between plant and soil. In this study, we measured vulnerability to drought-induced cavitation in woody roots and stems of five tree species (Acacia aneura, Cedrus deodara, Eucalyptus crebra, Eucalytus saligna, and Quercus palustris) with a wide range of xylem anatomies. X-ray microtomography was used to visualize the accumulation of xylem embolism in stems and roots of intact plants that were naturally dehydrated to varying levels of water stress. Vulnerability to cavitation, defined as the water potential causing a 50% loss of hydraulic function (P50), varied broadly among the species (-4.51 MPa to -11.93 MPa in stems and -3.13 MPa to -9.64 MPa in roots). The P50 of roots and stems was significantly related across species, with species that had more vulnerable stems also having more vulnerable roots. While there was strong convergence in root and stem vulnerability to cavitation, the P50 of roots was significantly higher than the P50 of stems in three species. However, the difference in root and stem vulnerability for these species was small; between 1% and 31% of stem P50. Thus, while some differences existed between organs, roots were not dramatically more vulnerable to embolism than stems, and the differences observed were less than those reported in previous studies. Further study is required to evaluate the vulnerability across root orders and to extend these conclusions to a greater number of species and xylem functional types.


Central and peripheral sensitivity to temporally modulated stimuli presented to the sighting and nonsighting eyes.
Thirty-two visually normal observers showed reduced sensitivity to uniform field flicker in the fovea of the nonsighting eye relative to the sighting eye. The two eyes showed equal sensitivity to flicker in the peripheral retina. This result with visually normal observers is analogous to that found in observers with functional amblyopia. It is also consistent with the hypothesis that amblyopic and normal suppressive processes share a common mechanism.


Comparison of edge vascular response after sirolimus- and paclitaxel-eluting stent implantation.
To compare the edges vascular response, we analyzed the intravascular ultrasound (IVUS) parameters after implantation of the sirolimus-eluting stent (SES) or the paclitaxel-eluting stent (PES). Two hundred-two angina patients (123 men; 61.5 ± 9.2 years of age, SES: n = 91, PES: n=111) were enrolled. Both edge segments of the stent were analyzed. The change (Δ) of each parameter at follow-up was calculated. The edge restenosis rate was higher in the PES group. However, the Δ Vessel, Δ Plaque and Δ Lumen volume at 5mm edge segments were not different between the two groups except the Δ Plaque volume at the distal segment, higher in the PES than the SES group (6.6 ± 15.7 vs. 1.0 ± 13.1mm(3), P=.016). In the PES group, lumen area at the both 1mm edge segments decreased because of plaque progression (proximal, 1.9 ± 1.5 to 2.2 ± 2.0mm(2), P=.095; distal, 0.6 ± 1.1 to 1.0 ± 1.4mm(2), P=.018) with negative remodeling (proximal, 9.9 ± 2.4 to 9.4 ± 2.6mm(2), P=.004; distal, 7.6 ± 2.4 to 7.2 ± 2.4mm(2), P=.052). Conversely, lumen area at these segments increased due to plaque regression (proximal, 3.2 ± 1.8 to 2.1 ± 1.6mm(2), P=.000; distal, 1.5 ± 1.4 to 0.9 ± 1.3mm(2), P=.000) even though there was negative remodeling in the SES group (proximal, 10.1 ± 2.4 to 9.6 ± 2.3mm(2), P=.019; distal, 7.8 ± 2.3 to 7.5 ± 2.3mm(2), P=.074). The Δ Plaque and Δ Lumen area at the both 1mm edge segments were more prominent in the PES group. Compared to SES, PES was associated with luminal reduction accompanied by plaque progression with negative remodeling at edge segments.


On the effects ofFusarium-contaminated wheat and the feed intake level on ruminal fermentation and toxin-turnover of cows.
The aim of the study was to examine the effects of dry matter intake level and the feeding ofFusarium-contaminated wheat on the toxin-turnover and ruminal fermentation of dairy cows. Fourteen dairy cows equipped with ruminal and duodenal cannulae were used. All animals were fed the same diet, only the daily feed amounts were adjusted to the current performance stage of the cow. On a dry matter basis, the diet consisted of 60% concentrate including 55% wheat (Fusarium-contaminated wheat [Mycotoxin period] or control wheat [Control period]). Each cow was fed with both the contaminated and the control wheat. TheFusarium-contamination of the wheat significantly decreased the flow of undegraded protein at the duodenum with increased intakes of organic matter. The duodenal flow of microbial protein and the activities of aspartate aminotransferase (ASAT), glutamate dehydrogenase (GLDH) and gamma glutamyl transferase (γ-GT) in the serum were not affected by dietary treatment, but increased with feed intake. The duodenal flow of deoxynivalenol (DON) and de-epoxy DON related to DON intake ranged between 12 and 77% when theFusarium-contaminated wheat was fed. DON was almost completely metabolized to de-epoxy DON independent of the feed intake level. The zearalenone (ZON) flow at the duodenum increased moderately with increasing ZON/feed intake.


Bone mineral density following surgical oophorectomy and tamoxifen adjuvant therapy for breast cancer.
In premenopausal women treated for breast cancer, loss of bone mineral density (BMD) follows from menopause induced by chemotherapy or loss of ovarian function biochemically or by surgical oophorectomy. The impact on BMD of surgical oophorectomy plus tamoxifen therapy has not been described. In 270 Filipino and Vietnamese premenopausal patients participating in a clinical trial assessing the impact of the timing in the menstrual cycle of adjuvant surgical oophorectomy on breast cancer outcomes, BMD was measured at the lumbar spine and femoral neck before this treatment, and at 6, 12, and 24 months after surgical and tamoxifen therapies. In women with a pretreatment BMD assessment and at least 1 other subsequent BMD assessment, no significant change in femoral neck BMD was observed over the 2-year period (-0.006 g/cm2 , -0.8%, P = .19), whereas in the lumbar spine, BMD fell by 0.045 g/cm2 (4.7%) in the first 12 months (P < .0001) and then began to stabilize. Surgically induced menopause with tamoxifen treatment is associated with loss of BMD at a rate that lessens over 2 years in the lumbar spine and no significant change of BMD in the femoral neck.


Herpes simplex type 1 activates glycolysis through engagement of the enzyme 6-phosphofructo-1-kinase (PFK-1).
Viruses such as HIV, HCV, Mayaro and HCMV affect cellular metabolic pathways, including glycolysis. Although some studies have suggested that the inhibition of glycolysis affects HSV-1 replication and that HSV-1-infected eyes have increased lactate production, the mechanisms by which HSV-1 induces glycolysis have never been investigated in detail. In this study, we observed an increase in glucose uptake, lactate efflux and ATP content in HSV-1-infected cells. HSV-1 triggered a MOI-dependent increase in the activity of phosphofructokinase-1 (PFK-1), a key rate-limiting enzyme of the glycolytic pathway. After HSV-1 infection, we observed increased PFK-1 expression, which increased PFK-1 total activity, and the phosphorylation of this enzyme at serine residues. HSV-1-induced glycolysis was associated with increased ATP content, and these events were critical for viral replication. In summary, our results suggest that HSV-1 triggers glycolysis through a different mechanism than other herpesviruses, such as HCMV. Thus, this study contributes to a better understanding of HSV-1 pathogenesis and provides insights into novel targets for antiviral therapy. ►HSV-1 activates glycolysis by PFK-1 activation. ►In HSV-1-infected cells PFK-1 synthesis is up-regulated and phosphorylated at serine residues. ►PFK-1 knockdown impairs HSV-1 replication. ►HSV-1-mediated glycolysis activation increases ATP content.


Prediction of adolescents doing physical activity after completing secondary education.
The purpose of this study, based on the self-determination theory (Ryan & Deci, 2000) was to test the prediction power of student's responsibility, psychological mediators, intrinsic motivation and the importance attached to physical education in the intention to continue to practice some form of physical activity and/or sport, and the possible relationships that exist between these variables. We used a sample of 482 adolescent students in physical education classes, with a mean age of 14.3 years, which were measured for responsibility, psychological mediators, sports motivation, the importance of physical education and intention to be physically active. We completed an analysis of structural equations modelling. The results showed that the responsibility positively predicted psychological mediators, and this predicted intrinsic motivation, which positively predicted the importance students attach to physical education, and this, finally, positively predicted the intention of the student to continue doing sport. Results are discussed in relation to the promotion of student's responsibility towards a greater commitment to the practice of physical exercise.


Portable near-infrared and Raman spectroscopic devices as complementary tools for instantaneous quality control of turmeric powder.
Process analytical technology (PAT) guidance is implemented in the quality assurance of phytocompounds to achieve the Industry 4.0 concept. Near-infrared (NIR) and Raman spectroscopies are feasible for rapid, reliable quantitative analysis through transparent packaging without removing the samples from their original containers. These instruments can serve PAT guidance. This study aimed to develop online portable NIR and Raman spectroscopic methods for quantifying total curcuminoids in turmeric samples through a plastic bag. The method mimicked an in-line measurement mode in PAT compared with placing samples into a glass vessel (at-line mode). Sixty-three curcuminoid standard-spiked samples were prepared. Then, 15 samples were randomly selected as fixed validation samples, and 40 of the 48 remaining samples were chosen as calibration set. The results obtained from the partial least square regression (PLSR) models constructed by using the spectra acquired from NIR and Raman were compared with the reference values from high-performance liquid chromatography (HPLC). The optimum PLSR model of at-line Raman was achieved with three latent variables and a root mean square error of prediction (RMSEP) of 0.46. Meanwhile, the PLSR model of at-line NIR with one latent variable offered an RMSEP of 0.43. For the in-line mode, PLSR models created from Raman and NIR spectra had one latent variable with RMSEP of 0.49 and 0.42, respectively. The R2 values for prediction were 0.88-0.92. The models established from the spectra from portable NIR and Raman spectroscopic devices with the appropriate spectral pretreatments allowed the determination of total curcuminoid contents through plastic bag.


Cutaneous ulceration resembling pyoderma gangrenosum in the primary antiphospholipid syndrome: a report of two additional cases and review of the literature.
The antiphospholipid antibody syndrome has been associated with various cutaneous manifestations, the most common of which may be leg ulceration. Cutaneous ulcers with clinical features suggestive of pyoderma gangrenosum have been reported in this setting only rarely. We report here two additional cases of the association between antiphospholipid antibody syndrome and pyoderma gangrenosum-like skin lesions. These patients suffered from the primary antiphospholipid syndrome. We suggest that clinicians assay for antiphospholipid antibodies when a clinical diagnosis of pyoderma gangrenosum is entertained.


Temperature-adaptive rooftop covering with synergetic modulation of solar and thermal radiation for maximal energy saving.
The energy consumption for maintaining desired indoor temperature accounts for 20% of primary energy use worldwide. Passive rooftop modulation of solar/thermal radiation without external energy input has a great potential in building energy saving. However, existing passive rooftop modulation techniques failed to simultaneously modulate solar/thermal radiation in response to rooftop surface temperature which is closely related to the building thermal loads, leading to limited or even counter-productive overall energy saving. Here, we report the development of a surface temperature-adaptive rooftop covering with synergetic solar and thermal modulations. The covering, made of a scalable metalized polyethylene film, demonstrated excellent solar absorptance modulation (72.5%) and thermal emissivity modulation (79%) in response to its temperature change from 22°C (indoor heating setpoint) to 25°C (indoor cooling setpoint), and vice versa. Building energy simulations demonstrate that the proposed rooftop covering can achieve all-season energy savings across all climate regions.


Genetic polymorphism of orosomucoid (ORM) in populations of the United Kingdom, Indian subcontinent, and Cambodia.
The genetic variation of the human serum orosomucoid (ORM) was investigated by isoelectric focusing (IEF) followed by immunofixation in 15 different populations from East Midlands (United Kingdom), India, Sri Lanka, and Cambodia. Statistically significant differences were observed between various Asiatic and British populations, however differences within Asiatic and European populations were minor. The distribution of ORM1 alleles in populations investigated to date suggests an interesting east-west geographical cline. There is a suggestion that present day wide polymorphism at the ORM1 locus may be influenced by selection.


Cost of renal replacement therapy in Turkey.
By the end 2000, 22224 patients were on renal replacement therapy (RRT) in Turkey. We investigated the cost of RRT in three medical faculties and one private dialysis centre. Yearly expenses were US dollars 22759 for haemodialysis (HD), US dollars 22350 for continuous ambulatory peritoneal dialysis (CAPD), and US dollars 23393 and US dollars 10028, respectively, for the first and second years of transplantation (Tx). In the first year, renal Tx was significantly more expensive than CAPD. However, after the first year of renal transplantation, Tx became significantly more economical than both CAPD and HD. The sum of all yearly RRT expenses for the country was US dollars 488958709, which corresponds to nearly 5.5% of Turkey's total health expenditure. Measures such as early construction of vascular access, promoting home dialysis and the reuse of the dialysers, strict control of the use of some expensive drugs like erythropoietin and active vitamin D, and also increasing the number of transplantations, especially if pre-emptive transplantation is possible, should be taken into account in order to reduce these expenses.


Preparation of 9-deoxo-4"-deoxy-6,9-epoxyerythromycin lactams "motilactides": potent and orally active prokinetic agents.
A series of new, highly potent and orally active "motilactides", 9-deoxo-4"-deoxy-6,9-epoxyerythromycin lactams was designed, synthesized, and evaluated for their gastrointestinal motor stimulating activity. These compounds were acid stable and showed good oral efficacy.


Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CDK5RAP2-PDGFRA fusion gene.
Chronic myeloproliferative disorders with rearrangements of the platelet-derived growth factor receptor A (PDGFRA) gene at chromosome band 4q12 have shown excellent responses to targeted therapy with imatinib. Here we report a female patient who presented with advanced phase of a chronic eosinophilic leukemia. Cytogenetic analysis revealed an ins(9;4)(q33;q12q25) in 5 of 21 metaphases. FISH analysis with flanking BAC probes indicated that PDGFRA was disrupted. A novel mRNA in-frame fusion between exon 13 of the CDK5 regulatory subunit associated protein 2 (CDK5RAP2) gene, a 40-bp insert that was partially derived from an inverted sequence stretch of PDGFRA intron 9, and a truncated PDGFRA exon 12 was identified by 5'-RACE-PCR. CDK5RAP2 encodes a protein that is believed to be involved in centrosomal regulation. The predicted CDK5RAP2-PDGFRA protein consists of 1,003 amino acids and retains both tyrosine kinase domains of PDGFRA and several potential dimerization domains of CDK5RAP2. Despite achieving complete cytogenetic and molecular remission on imatinib, the patient relapsed with imatinib-resistant acute myeloid leukemia that was characterized by a normal karyotype, absence of detectable CDK5RAP2-PDGFRA mRNA, and a newly acquired G12D NRAS mutation.


Endocrine activities and cellular stress responses in the marsh frog Pelophylax ridibundus exposed to cobalt, zinc and their organic nanocomplexes.
Metal-containing materials are extensively used in industry, personal care products and medicine, and their release in the environment causes concern for the potential impacts on aquatic organisms. We assessed endocrine disrupting potential of N-vinyl-2-pyrrolidone-based nanoparticles (Me-PSs) containing cobalt (Co(2+)) or zinc (Zn(2+)), using the marsh frog Pelophylax ridibundus as a model. Adult males were exposed for 14 days to waterborne Co(2+) (50μg/L), Zn(2+) (100μg/L) or corresponding concentrations of Co-PS, Zn-PS, or parental polymeric compound (PS). The indices of thyroid activity, vitellogenesis, cytochrome P450-dependent monooxygenases activity (EROD) and cytotoxicity markers were evaluated. Exposure to Co(2+) led to the elevation of serum thyrotropin (TSH) and hepatic deiodinase activities accompanied by the up-regulation of EROD activity. In contrast, the action of the polymer-containing substances (Co-PS, Zn-PS and PS) as well as free Zn(2+) caused a prominent decrease of EROD activity and a decrease in serum cortisol and TSH concentrations. Exposures to Zn(2+), Zn-PS and PS upregulated vitellogenesis in males. All exposures except Co(2+) caused neurotoxicity as indicated by the depletion of cholinesterase. These results demonstrate toxicity of Co- and Zn-containing Me-PSs and their parental compounds (Zn(2+) and PS) in frogs and indicate distinct mechanisms of Co(2+) action. Broad disruption of the hormonal pathways and reduced capacity for organic xenobiotic detoxification may have deleterious impacts on amphibian populations from habitats exposed to metallorganic pollution.


Fixed drug eruption in Bangladeshi population: confirmed by provocative test.
Fixed drug eruption is designated as a typical allergic reaction occurring due to exposure to a medicine. This common dermatological condition is often being ignored for its causative agent as well as the patient's sufferings sometimes become unpredictable. The objective of this large population study is to identify the causative agents responsible for fixed drug eruption. The study is comprised of 120 suspected patients of fixed drug eruption. History, classic clinical features of well circumscribed erythema, edema, and violaceous pigmentation, and the recurrence of the eruptions on the same sites upon re-administering drug were used as diagnostic criteria. The drug(s) causing allergic reactions were confirmed by provocation tests. The incidence of drug eruption was found distributed in 0.62% amongst all dermatology outpatient attendees. The male to female ratio recorded was 7:2. The highest number of cases was observed within in the age group of 21-35 years. The provocation tests were positive in 92 among 120. The genitalia and lips/face were the most commonly affected site for fixed drug eruption. The drug sulphonamide (including co-trimoxazole) accounted for the highest number of cases of eruptions (28.33 %). The other drugs, in order of frequency, responsible for the cause of eruptions were identified as nonsteroidal anti-inflammatory drugs, tetracycline, metronidazole, herbal medicine, paracetamol, fluconazole, penicillin, Griseofulvin, and homeopathic medicine, etc. Drug reactions are very frequently experienced by dermatologists in their day-to-day practice. The patients are often ignorant of the drugs consumed and often do not accept them as an etiologic factor. A detailed drug history as well as the complaints will be helpful before undertaking the provocation test.


Impact of an HIV Care Coordination Program on the Timeliness of Viral Suppression and Immune Recovery Among Clients Newly Diagnosed with HIV.
We compared the time to immune recovery and viral suppression (VS) among people newly diagnosed with HIV who enrolled in the HIV Care Coordination Program (CCP), a comprehensive medical case management program, with a propensity matched group of newly diagnosed people who did not enroll. CCP enrollees had more rapid VS (≤ 200 copies/mL) [hazards ratio (HR) 1.17; 95% confidence interval 1.02-1.34] but no more rapid immune recovery (≥ two successive CD4 counts > 500 cells/mm3) (HR 0.98; 0.84-1.13). Relative to usual care, the CCP may expedite VS (though not immune recovery) for newly diagnosed HIV patients and therefore lower forward transmission risk.


Density-dependent effects in a parasitic nematode, Elaphostrongylus rangiferi, in the snnail intermediate host.
Density-dependent effects in Elaphostrongylus rangiferi, a parasitic nematode in the CNS and muscular system of reindeer, were studied in a laboratory population of the snail intermediate host, Arianta arbustorum. The rates in parasite growth, development and mortality were all affected by parasite density. The effects on growth and development were, however, much more marked, than the effect on mortality.All density-dependent rates were intensified by decreasing snail size, and by snail starvation. The snail host showed marked tissue reactions against infection, and the intensity of these reactions increased with increasing parasite density. The mechanism behind the observed density-dependent rates is discussed, and is tentatively concluded to be competition for nutritive substances in the host tissue.The importance of a density-dependent developmental rate in natural populations of this parasite is discussed, and it is hypothesized that this effect may counteract the strong temperature-dependent developmental rate of E. rangiferi In a more general context it is pointed out that density-dependent developmental rates, although common amongst animal populations, has been neglected in models of population dynamics. Developmental rates are usually represented by a constant time lag in such models, but should be treated as a density-dependent variable.


Mechanical Thrombectomy for the Treatment of Anterior Cerebral Artery Occlusion: A Systematic Review of the Literature.
The overall safety and efficacy of mechanical thrombectomy for anterior cerebral artery strokes remain unclear. Our aim was to summarize procedural and clinical outcomes in patients who underwent mechanical thrombectomy for treatment of anterior cerebral artery ischemic stroke. A systematic literature review was performed using PubMed, Ovid MEDLINE, and the Web of Science from inception until March 4, 2022. We identified 9 studies with a total of 168 patients with mechanical thrombectomy-treated anterior cerebral artery occlusions. Recanalization, procedural data, and clinical outcome at last follow-up were collected and summarized. Categoric variables were reported as proportions. The χ2 test of independence or the Kruskal-Wallis test was performed to assess the relationship between selected variables and the anterior cerebral artery embolus type (ie, primary isolated anterior cerebral artery, primary combined anterior cerebral artery, and secondary anterior cerebral artery occlusion) or the mechanical thrombectomy technique. For mechanical thrombectomy-treated anterior cerebral artery occlusions, recanalization modified TICI 2b/3 was achieved in 80%, postprocedural complications occurred in 17% of patients, and the 90-day mortality rate was 19%. The rate of symptomatic intracranial hemorrhage varied depending on the anterior cerebral artery embolus type (χ2 = 8.45, P = .01). This analysis did not consider factors such as small-study effects that affect reliability and limit interpretation. Mechanical thrombectomy for the treatment of anterior cerebral artery occlusions is safe and efficacious, offering a favorable rate of recanalization and procedural complications. Mechanical thrombectomy-treated anterior cerebral artery occlusions appear to have lower rates of short-term good functional outcomes and an increased risk of symptomatic intracerebral hemorrhage compared with mechanical thrombectomy-treated MCA/ICA occlusions. Single and multicenter studies are needed to further examine the safety and efficacy of mechanical thrombectomy-treated anterior cerebral artery occlusions.