Serum and Urinary Neutrophil Gelatinase-Associated Lipocalin Levels as Early Markers of the Renal Function in Patients With Urinary Stone-Induced Hydronephrosis.
Urinary stones cause hydronephrosis, which leads to kidney function impairment. The serum creatinine level is frequently used as a marker of kidney function. However, in some patients with hydronephrosis, it does not reflect the kidney function changes in the early stages of kidney stone disease. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel indicator of the kidney function. Previous NGAL-related research has focused on its role in acute kidney injury. This study aimed to determine the usefulness of NGAL as an early marker of the kidney function in patients with urinary stones and hydronephrosis. Eighty-five patients with urinary stones who were admitted to the Shanghai Tenth People's Hospital (USP group) and 65 healthy volunteers (NC group) were recruited. Blood and urine samples collected from the study participants were evaluated using an enzyme-linked immunosorbent assay to determine the NGAL concentration. Data on the height, weight, age, medical history, and blood and urine findings were collected. Computed tomography data were collected from the USP group. Compared to in the NC group, NGAL levels were significantly elevated in the USP group (P < 0.001). However, no significant differences in the NGAL levels were observed among the USP group members with different degrees of hydronephrosis. Furthermore, no significant between-group differences in the creatinine level or the estimated glomerular filtration rate were observed. The areas under the receiver operating characteristic curves for the serum and urinary NGAL levels with hydronephrosis were 92.03 and 99.54%, respectively. The areas under the receiver operating characteristic curves for the serum and urinary NGAL levels with kidney stones were 85.05 and 91.89%, respectively. NGAL is a sensitive indicator of hydronephrosis secondary to urinary stones.


Effects of maternal toxic substance consumption during breastfeeding on lactic acid bacteria abundance and nutritional content.
Breast milk is widely recognized as the primary source of nourishment for newborns, making it an unparalleled and indispensable provider of essential nutrients, microbiological components, immunological factors, and energy content. To investigate this further, a cohort comprising 254 breastfeeding women participated in interviews, and milk samples were aseptically collected for subsequent analysis involving bromatological, microbiological, and clinical analysis. The investigation focused on the identification of specific microorganisms in breast milk and their susceptibility to the exposure of toxic substances and controlled medications. Notably, this study places particular emphasis on the significant decline in lactic acid bacteria observed in breast milk when influenced by substances such as cocaine, cannabis, crystal, and morphine. These detrimental agents have been found to adversely affect the growth of microorganisms within breast milk. On the contrary, the outcomes of this study indicate that the utilization of toxic substances does not exert a noteworthy impact on the nutritional quality of breast milk.


Pneumoperitoneum due to gastric perforation after cardiopulmonary resuscitation: case report.
Pneumoperitoneum after cardiopulmonary resuscitation may be due to mediastinal air tracking into the peritoneal cavity via the diaphragmatic hiatus or to gastric perforation. A 79-year-old woman received Advanced Cardiac Life Support measures in the intensive care unit. Chest compressions and endotracheal intubation were performed; a stable cardiac rhythm and perfusion were restored. A chest radiograph after resuscitation revealed pneumoperitoneum without pneumomediastinum. The patient underwent laparotomy; a 6-cm perforation of the posterior gastric wall along the lesser curve was detected and repaired. Gastric perforation after cardiopulmonary resuscitation should be suspected when chest radiographs obtained after resuscitation show pneumo-peritoneum without pneumomediastinum. Prompt laparotomy allows detection of gastric perforations and decreases the morbidity associated with rupture of a hollow organ. The incidence of gastric perforation after cardiopulmonary resuscitation may be decreased with early endotracheal intubation, avoidance of esophageal intubation, and expeditious placement of an orogastric tube.


The role of the mannose-binding lectin in innate immunity.
The innate immune system, which includes mannose-binding lectin (MBL), recognizes a broad range of molecular patterns on a broad range of infectious agents and is able to distinguish them from self. MBL is a liver-derived serum protein and is secreted into the serum, where it can activate an immune response before the induction of antigen-specific immunity. Circumstantial evidence in human populations suggests that low serum levels of MBL predispose to infection. To analyze the role of MBL in vivo, we created MBL-null mice and challenged these mice with infection under various conditions. Our results suggest that MBL plays an important role as a first-line host defense against certain infectious agents. In addition, it is likely that MBL is a key regulator of inflammation beyond expected roles in the infection.


[Lymphocytic subpopulations in malignant ascites of ovarian origin. Flow cytometric analysis].
A flow-cytometric analysis of ascitic fluid (AF) and peripheral blood lymphocyte subpopulations (LS) was performed on 16 patients with ovarian malignancy (OM) and 5 with metastatic peritoneal carcinomatosis (MPC). AF lymphocytes are 58% of total leukocytes in OM patients, 37% in MPC patients, while blood lymphocytes are 14% and 17%, respectively. AF absolute lymphocyte count (total and individual LS) is higher in OM patients. OM patients AF lymphocytes are: T = 70%, CD4+ = -37%, CD8+ = 32% (CD4/CD8 = 1.39), B = 5%, NK cells = 4-10%, CD25+ = 20%, CD69+ = 15%, CD71+ = 3%. In MPC patients the values are generally similar, though CD4+ cells are +7%, CD8+ cells = -14% (CD4/CD8 = 3.17), CD69+ cells = -8%. Untreated OM patients have a AF total and percent lymphocyte count higher than treated ones. Among the latter, however, the CD4/CD8 ratio as well as the number of CD4+, inducer, CD25+ and CD71+ cells are higher. In terms of percent values, the most striking differences involve total T and B lymphocytes (81-87% vs 56-62%, and 10% vs 2%, respectively). With the only exception of absolute NK cell count, OM patients show no correlation between AF and peripheral blood LS pattern. These results agree only partially with data from the literature. Pathophysiologic and clinical considerations support the practical usefulness of LS analysis in AF from OM patients.


Large Gartner cyst.
Gartner cyst is usually an asymptomatic vaginal cyst, measuring less than 2 cm, frequently found during a routine gynaecological examination. Very rarely, as these cysts are closed structures, they may increase in size because of mucus production. We describe here a case of a large Gartner cyst of approximately 8 cm, its differential diagnosis, investigation and vaginal surgical approach (with illustrations), that progressed uneventfully.


Biological response of Costa Rica Dome phytoplankton to Light, Silicic acid and Trace metals.
The Costa Rica Dome (CRD) is a unique open-ocean upwelling system, with picophytoplankton dominance of phytoplankton biomass and suppressed diatoms, yet paradoxically high export of biogenic silica. As a part of Flux and Zinc Experiments cruise in summer (June-July 2010), we conducted shipboard incubation experiments in the CRD to examine the potential roles of Si, Zn, Fe and light as regulating factors of phytoplankton biomass and community structure. Estimates of photosynthetic quantum yields revealed an extremely stressed phytoplankton population that responded positively to additions of silicic acid, iron and zinc and higher light conditions. Size-fractioned Chl a yielded the surprising result that picophytoplankton, as well as larger phytoplankton, responded most to treatments with added silicic acid incubated at high incident light (HL + Si). The combination of Si and HL also led to increases in cell sizes of picoplankton, notably in Synechococcus. Such a response, coupled with the recent discovery of significant intracellular accumulation of Si in some picophytoplankton, suggests that small phytoplankton could play a potentially important role in Si cycling in the CRD, which may help to explain its peculiar export characteristics.


Upregulated CD8+ MAIT cell differentiation and KLRD1 gene expression after inactivated SARS-CoV-2 vaccination identified by single-cell sequencing.
The primary strategy for reducing the incidence of COVID-19 is SARS-CoV-2 vaccination. Few studies have explored T cell subset differentiation and gene expressions induced by SARS-CoV-2 vaccines. Our study aimed to analyze T cell dynamics and transcriptome gene expression after inoculation with an inactivated SARS-CoV-2 vaccine by using single-cell sequencing. Single-cell sequencing was performed after peripheral blood mononuclear cells were extracted from three participants at four time points during the inactivated SARS-CoV-2 vaccination process. After library preparation, raw read data analysis, quality control, dimension reduction and clustering, single-cell T cell receptor (TCR) sequencing, TCR V(D)J sequencing, cell differentiation trajectory inference, differentially expressed genes, and pathway enrichment were analyzed to explore the characteristics and mechanisms of postvaccination immunodynamics. Inactivated SARS-CoV-2 vaccination promoted T cell proliferation, TCR clone amplification, and TCR diversity. The proliferation and differentiation of CD8+ mucosal-associated invariant T (MAIT) cells were significantly upregulated, as were KLRD1 gene expression and the two pathways of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay, and translational initiation. Upregulation of CD8+ MAIT cell differentiation and KLRD1 expression after inactivated SARS-CoV-2 vaccination was demonstrated by single-cell sequencing. We conclude that the inactivated SARS-CoV-2 vaccine elicits adaptive T cell immunity to enhance early immunity and rapid response to the targeted virus.


Persistent Disparities in Smoking Rates Among PLWH Compared to the General Population in Philadelphia, 2009-2014.
Despite reductions in smoking rates in the general population, little is known about recent smoking trends among people living with HIV (PLWH). We compared the risk for smoking and temporal trends in smoking among PLWH and the general population in the Philadelphia metropolitan area between 2009 and 2014. We used weighted logistic regression to assess the relation between HIV and smoking, and examined temporal smoking trends. The adjusted odds ratio (OR) for smoking comparing PLWH to the general population was 1.80 (95% CI 1.55-2.09) after adjusting for socio-economic, demographic, and mental health diagnosis variables. Smoking prevalence decreased in both the PLWH and general populations during the study period, and we did not observe a significant difference in rates of decline between groups (P = 0.54). Despite overall progress in smoking cessation, a disparity persisted in smoking rates between PLWH and the general population, with and without adjustment for socio-economic, demographic, and mental health variables. Further research is needed to understand the mechanisms linking HIV and tobacco use in order to inform public health efforts to reduce smoking among PLWH.


Multivariate Metal-Organic Frameworks as Multifunctional Heterogeneous Asymmetric Catalysts for Sequential Reactions.
The search for versatile heterogeneous catalysts with multiple active sites for broad asymmetric transformations has long been of great interest, but it remains a formidable synthetic challenge. Here we demonstrate that multivariate metal-organic frameworks (MTV-MOFs) can be used as an excellent platform to engineer heterogeneous catalysts featuring multiple and cooperative active sites. An isostructural series of 2-fold interpenetrated MTV-MOFs that contain up to three different chiral metallosalen catalysts was constructed and used as efficient and recyclable heterogeneous catalysts for a variety of asymmetric sequential alkene epoxidation/epoxide ring-opening reactions. Interpenetration of the frameworks brings metallosalen units adjacent to each other, allowing cooperative activation, which results in improved efficiency and enantioselectivity over the sum of the individual parts. The fact that manipulation of molecular catalysts in MTV-MOFs can control the activities and selectivities would facilitate the design of novel multifunctional materials for enantioselective processes.


[Retrospective evaluation of optimal doses of fentanyl by patient-controlled epidural analgesia in management of postoperative pain after gynecological surgery in the elderly].
Patient controlled epidural analgesia (PCEA) is a useful method in alleviation of postoperative pain; however, PCEA sometimes provided inadequate pain relief in the elderly. Therefore, we investigated optimal doses of fentanyl by PCEA in management of postoperative pain after gynecological surgery in the elderly. We investigated the pain at rest using 100 mm visual analogue scale (VAS) on the 1st day and 2nd day after the operations. Patients were divided into two groups ; one was well-controlled group (WC group, VAS < 20 mm) and the other was poorly-controlled group (PC group, VAS > or =20 mm). In two groups, we retrospectively compared doses of fentanyl in PCEA, number of demand-PCEA, postoperative nausea as well as vomiting, and delirium during 48 hrs after the operations. The mean age in WC group was significantly higher than that in PC group. The total dosage of epidural fentanyl did not differ significantly between the groups. In WC group fentanyl of 0.172 microg x kg(-1) hr(-1) was given, and fentanyl 0.197 microg x kg(-1) x hr(-1) in PC group. We found that fentanyl 0.172 microg x kg(-1) x 1 hr(-1) by PCEA was the most appropriate dose for alleviation of postoperative pain after gynecological surgery in the elderly.


Oral conditions in very low and extremely low birth weight children.
The purpose of this study was to evaluate the oral conditions in very low birth weight (VLBW) and extremely low birth weight (ELBW) children. Fifty-two VLBW and ELBW 2- to 4-year-old children (V/ELBW group) were evaluated and compared with 52 normal birth weight children (NBW group). The oral examination was performed in accordance with World Health Organization criteria. The parents/guardians answered a structural questionnaire about the children's feeding and oral habits. The prenatal, natal, and neonatal information was obtained from the hospital files. The enamel defects, such as demarcated opacity and hypoplasia, had a significant association with prematurity and VLBW and ELBW. The breast-feeding and bruxism were more often in the NBW group, whereas nocturnal bottle-feeding, pacifier use, and high frequency of oral hygiene were associated with prematurity and lower birth-weight. V/ELBW group children were at a 12.5 and 6.6 times greater risk of presenting demarcated opacity and hypoplasia, respectively, than NBW children. The risk of presenting nocturnal bottle-feeding, good oral hygiene, and enamel defects was significantly higher for the V/ELBW group. Very low birth weight and extremely low birth weight were indicators of enamel defects and contributed to an increase in non-nutritive suction habits, being necessary the establishment of early preventive and interceptive measures, to avoid future severe problems.


Continuous spinal anesthesia with a microcatheter and low-dose bupivacaine decreases the hemodynamic effects of centroneuraxis blocks in elderly patients.
This prospective randomized study was designed to investigate the hemodynamic effects and quality of continuous spinal anesthesia (CSA) after rapid injection of a low dose of 0.5% bupivacaine through a 32-gauge microcatheter. The method was compared with continuous epidural (CEA) and single-dose spinal anesthesia (SSA). Seventy-seven elderly patients (ASA II-III) ranging from 57 to 94 yr old and undergoing lower limb surgery were assigned to CSA (n = 26), CEA (n = 26), and SSA groups (n = 25). In all three groups, mean arterial pressure (MAP) and heart rate (HR) were assessed continuously for 30 min after initial injection, as well as after every reinjection of local anesthetic in the CSA and CEA groups. Bupivacaine (0.5%) was used as a local anesthetic. The initial doses were 1 mL of CSA, 10 mL of CEA, and 3 mL of SSA. The reinjection doses were 1 mL of CSA and 5 mL of CEA. In the CSA group, MAP did not decrease, whereas in the CEA group, the maximum decrease was 15% +/- 3% (mean +/- SEM) for the initial injection, 12% +/- 2% for the first repetition, and 13% +/- 2% for the second repetition. In the SSA group, the largest decrease of MAP was 19% +/- 2%. All changes of MAP in the CEA and SSA groups were significantly larger compared with CSA group (P < 0.05). A total of seven patients in these two groups needed vasopressors due to a decrease of MAP of more than 30% from baseline values. Heart rate did not change.(ABSTRACT TRUNCATED AT 250 WORDS)


Behavioural and neurochemical changes induced by stress-related conditions are counteracted by the neurokinin-2 receptor antagonist saredutant.
These experiments were undertaken to assess the mechanisms underlying the antidepressant-like effects of the neurokinin-2 (NK(2)) receptor antagonist saredutant (SR48968) in rats tested in the forced swim test (FST), by analysing hippocampal brain-derived neurotrophic factor (BDNF) and plasma corticosterone [as index of hypothalamic-pituitary-adrenal (HPA) axis activity]. Male Wistar rats received three intraperitoneal injections over 24 h of vehicle, saredutant (5 mg/kg), citalopram (15 mg/kg), clomipramine (50 mg/kg). Rats were subjected to restraint stress (4 h) 24 h prior to the FST procedure. This stress procedure increased immobility and decreased swimming behaviour in the FST; furthermore, it lowered hippocampal BDNF protein expression and increased plasma corticosterone levels. Saredutant and clomipramine or citalopram, used here as positive controls, reduced the immobility time in the FST both under basal conditions and after stress exposure. This effect was not attributable to changes in locomotion, because locomotor activity was unchanged when assessed in the open field test. Pretreatment with para-cholorophenylalanine (150 mg/kg, 72 h and 48 h prior to FST) abolished the effect of citalopram and saredutant on immobility time. At neurochemical level, saredutant attenuated activation of HPA axis in stressed animals more than clomipramine or citalopram. The behavioural effects of saredutant support the hypothesis that NK(2) receptor activity is involved in stress-related disorders. These effects of saredutant may be related to normalization of the HPA axis. Moreover, saredutant increases BDNF expression in the hippocampus, confirming the role of NK(2) receptor blockade in BDNF activation following stressor application.


Effect of low-dose French maritime pine bark extract on climacteric syndrome in 170 perimenopausal women: a randomized, double-blind, placebo-controlled trial.
To evaluate the efficacy of a relatively low daily dosage of Pycnogenol French maritime pine bark extract for improvement of climacteric symptoms. In a double-blind, placebo-controlled study 170 perimenopausal women were enrolled and treated with 30 mg Pycnogenol or placebo twice daily over a period of 3 months. Climacteric symptoms were evaluated by the Women's Health Questionnaire (WHQ) and by the Kupperman index, accompanied by an investigation of sex hormones and routine blood chemistry. Seven women dropped out of each group due to noncompliance or personal reasons, but not as a result of treatment. A significant placebo effect was apparent in this study, suggesting an improvement of a majority of the WHQ categories. Compared to baseline, Pycnogenol significantly (p < 0.05) improved all symptoms with the exception of formication sensation and abnormal perceptions. Pycnogenol was found to be especially effective for improving vasomotor and insomnia/sleep problem symptoms, which were significantly better after 4 and 12 weeks than with placebo (p < 0.05). Total Kupperman's index for perimenopausal symptom severity score decreased significantly by 56% as compared to placebo (-39%) after 12 weeks of treatment (p < 0.05). Symptom score was also significantly better already after 4 weeks of treatment with Pycnogenol as compared to placebo. This study, applying a relatively low daily dose, allows identification of those climacteric symptoms which respond particularly well to supplementation with Pycnogenol.


Altering the balance of recollection and familiarity influences the revelation effect.
The revelation effect occurs when recognition test probes are more likely to be called "old" if they are preceded by a verbal processing task. Two experiments examined the role of familiarity and recollection in producing this effect. Each experiment tested the hypothesis that decreasing recollection would heighten the magnitude of the revelation effect. In Experiment 1, the revelation effect increased by delaying the recognition test. In Experiment 2, the revelation effect increased when the presentation rate of the study words was reduced. These results are discussed in terms of the variables that produce the revelation effect in episodic and nonepisodic memory judgments.


Paced mating behavior in female rats in response to different hormone priming regimens.
A female rat will display a repertoire of behaviors during a sexual encounter with a male rat including sexually receptive (the lordosis response) and proceptive (hopping, darting) behaviors. In addition, when given the opportunity, a sexually receptive female rat will approach and withdraw from the male rat, controlling the timing of the receipt of mounts, intromissions, and ejaculations, a behavior known as paced mating behavior. The present experiments tested the hypotheses (1) that progesterone regulates paced mating behavior, and (2) that multiple hormone regimens used previously to induce sexual receptivity have the same effect on paced mating behavior. Paced mating behavior was assessed in sexually receptive ovariectomized female rats after treatment with: (1) estradiol benzoate (EB; 30.0 mg/kg) followed by a range of doses of progesterone (P; 1.0-8.0 mg/kg), (2) two pulses of unesterified estradiol (E2; 2.0 microg/rat) followed by 1.0 mg/rat of P, and (3) EB alone (5.0 microg/rat) for 6 days. No differences in sexual receptivity or in paced mating behavior were observed across doses of P (1.0-8.0 mg/kg). In contrast, the number of hops and darts per min increased with the dose of P administered. E2 + P administration resulted in slightly, but significantly, lower levels of sexual receptivity along with significantly longer contact-return latencies following an intromission in relation to the other treatment conditions. In addition, female rats exhibited fewer hops and darts per min in response to E2 + P than in response to EB + 8.0 mg/kg of P. The administration of EB alone for 6 days induced levels of receptivity and paced mating behavior indistinguishable from EB + P, while eliciting significantly fewer hops and darts per min than the EB + 8.0 mg/kg P treatment condition. Hormone priming regimen had no effect on the percentage of exits displayed during the paced mating tests in any experimental phase. Dose of P had no effect on paced mating behavior in sexually receptive rats. In addition, P does not appear to be necessary for the display of paced mating behavior following long-term treatment with EB. In contrast, the pulsatile administration of E2 + P induced a different pattern of paced mating behavior in sexually receptive rats.


Rapidly progressing large-cell neuroendocrine carcinoma arising from the uterine corpus: A case report and review of the literature.
Large-cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine tumor. LCNECs arising from the genital organs are highly malignant and rare, with <20 cases of LCNEC developing from the uterine endometrium reported to date. We herein present the case of a patient with LCNEC of the endometrium. The patient was a 52-year-old woman, who exhibited lower abdominal pain and rapid uterine enlargement during outpatient treatment for uterine myoma. The endometrial biopsy suggested a diagnosis of poorly differentiated carcinoma or carcinosarcoma. Based on magnetic resonance imaging and positron emission tomography/computed tomography, endometrial stromal sarcoma was suspected. The serum lactate dehydrogenase level was abnormally high. Due to the suspicion of stage IIIC malignant tumor of the uterine corpus, surgery was performed. The pathological diagnosis was stage IIIC2 LCNEC of the endometrium. Recurrence occurred in the vaginal stump, and concurrent chemoradiotherapy (CCRT) was initiated 1 month after the surgery. The residual lesions markedly shrank, but metastasis to the upper abdominal region and cervix subsequently developed. CCRT was attempted, but the associated adverse effects were severe and was switched to palliative treatment. The patient eventually succumbed to the disease 309 days after surgery.


Risk factors associated with high-risk nodal disease in patients considered for active surveillance of papillary thyroid microcarcinoma without extrathyroidal extension.
Active surveillance (AS) has become an alternative treatment approach for papillary thyroid microcarcinoma (PTMC). The purpose of this study is to uncover the clinicopathological factors associated with high-risk nodal disease in order to select proper candidates for AS of PTMC. We retrospectively reviewed 5,329 patients with PTMC without extrathyroidal extension (ETE) who underwent thyroidectomy with central compartment neck dissection (CCND) between 2007 and 2021 at Seoul St. Mary's Hospital. Patients with more than five metastatic lymph nodes (MLNs) (higher-risk N1 disease) and/or lateral neck node metastases (N1b disease) were defined as having high-risk nodal disease. The clinicopathological factors associated with high-risk nodal disease were analyzed. A total of 415 (7.8%) patients had higher-risk N1 disease. These patients were younger on average, included a higher proportion of males, and had a larger tumor size and more frequent capsular invasion and multifocality compared with other patients. For the tumor size, a cutoff value of 0.65 cm was the best predictor of nodal risk groups. In a multivariate analysis, the independent risk factors associated with higher-risk N1 disease were younger age, male sex, tumor size >0.65 cm, and the presence of capsular invasion and/or multifocality. A total of 246 (4.6%) patients had N1b disease at initial diagnosis. In a multivariate analysis, the independent risk factors associated with N1b disease were younger age, male sex, tumor size >0.65 cm, and the presence of capsular invasion and/or multifocality. Young age, male sex, tumor size >0.65 cm, and presence of capsular invasion and/or multifocality can be considered risk factors for high-risk nodal disease in PTMC. Therefore, cautious observation is necessary for AS of patients with these characteristics.


Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are relapsed or refractory to ruxolitinib: A single-arm, open-label, phase 2, multicenter study.
Ruxolitinib has demonstrated efficacy in patients with myelofibrosis (MF). However, substantial number of patients may not respond after 3-6 months of treatment or develop resistance over time. In this phase 2 trial, patients with a current diagnosis of intermediate or high-risk MF who either had an inadequate splenic response or spleen regrowth after ruxolitinib treatment were enrolled. All patients received jaktinib 100 mg Bid. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR 35) at week 24. The secondary endpoints included change of MF-related symptoms, anemic response, and safety profile. From July 6, 2021, to January 24, 2022, 34 ruxolitinib-refractory or relapsed patients were enrolled, 52.9% (18 of 34) were DIPSS intermediate 2 or high risk. SVR 35 at week 24 was 32.4% (11 of 34, 95% CI 19.1%-49.2%) in all patients and 33.3% (6 of 18, 95% CI 16.3%-56.3%) in the intermediate 2 or high-risk group. A total of 50% (8 of 16) transfusion-independent patients with hemoglobin (HGB) <100 g/L at baseline had HGB elevation ≥20 g/L within 24 weeks. Furthermore, 46.4% (13 of 28) of patients had a ≥ 50% decrease in the total symptom score (TSS 50) at week 24. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were thrombocytopenia (32.4%), anemia (32.4%), and leukocytosis (20.6%). In total, 13 (38.2%) of 34 patients had serious adverse events (SAE), of which drug-related SAEs were found in 5 patients (14.7%). These results indicate that jaktinib can be a promising treatment option for patients with MF who have either become refractory to or relapsed after ruxolitinib treatment.


Caregiver-Teacher Concordance of Challenging Behaviors in Children with Autism Spectrum Disorder Served in Community Mental Health Settings.
Children with autism spectrum disorder (ASD) exhibit high rates of challenging behaviors that impair functioning and represent the primary presenting problem in mental health (MH) services. Obtaining symptom reports from multiple informants is critical for treatment planning. This study evaluated caregiver-teacher concordance of ratings of the intensity of challenging behaviors in children with ASD receiving MH services, and identified child clinical factors associated with concordance. This sample included 141 children (M = 9.07 years), their caregivers, and teachers. Caregiver-teacher concordance of challenging behaviors was low and impacted by the degree and type of child psychiatric comorbidity. Findings support need for increased attention to the range of psychiatric problems children with ASD present to tailor treatment recommendations and service delivery.


Plasmodium falciparum-infected erythrocytes induce tissue factor expression in endothelial cells and support the assembly of multimolecular coagulation complexes.
Plasmodium falciparum malaria infects 300-500 million people every year, causing 1-2 million deaths annually. Evidence of a coagulation disorder, activation of endothelial cells (EC) and increase in inflammatory cytokines are often present in malaria. We have asked whether interaction of parasitized red blood cells (pRBC) with EC induces tissue factor (TF) expression in vitro and in vivo. The role of phosphatidylserine-containing pRBC to support the assembly of blood coagulation complexes was also investigated. We demonstrate that mature forms of pRBC induce functional expression of TF by EC in vitro with productive assembly of the extrinsic Xnase complex and initiation of the coagulation cascade. Late-stage pRBC also support the prothrombinase and intrinsic Xnase complex formation in vitro, and may function as activated platelets in the amplification phase of the blood coagulation. Notably, post-mortem brain sections obtained from P. falciparum-infected children who died from cerebral malaria and other causes display a consistent staining for TF in the EC. These findings place TF expression by endothelium and the amplification of the coagulation cascade by pRBC and/or activated platelets as potentially critical steps in the pathogenesis of malaria. Furthermore, it may allow investigators to test other therapeutic alternatives targeting TF or modulators of EC function in the treatment of malaria and/or its complications.


Study of chronic pain and its associated risk factors among Japanese industry workers: the Quality of Working Life Influenced by Chronic pain (QWLIC) study.
This study was performed to identify the prevalence, influence, and risk factors associated with chronic pain among Japanese industry workers. We investigated 2,544 participants working at a manufacturing company A, a manufacturing company B, and 16 branch shops of a retail chain company C. The participants responded to self-administered questionnaires related to pain. Furthermore, data obtained from the lifestyle interview sheet of an annual health screening examination and those obtained from the questionnaires were merged. We analyzed the association between lifestyles, psychosocial factors, and chronic pain. Age- and sex-adjusted odds ratios were calculated with a 95% confidence interval using the logistic regression model. Of 2,544 participants, 1,914 (1,224 men and 690 women) completed the questionnaire, and the response rate was 75.2%. The prevalence of chronic pain over 3 months was 42.7% and that of chronic pain with work disability was 11.3%. A higher proportion of obesity, smoking habit, insomnia, psychological stress, depressive state, workaholic nature, low social support from supervisors and coworkers, high job demand, low job control, and job dissatisfaction was observed in workers with chronic pain than in workers without pain. Several risk factors of chronic pain in Japanese industry workers were found. Obesity, smoking habits, sleep disorders, workplace environment, and mental state should be taken into account as risk factors associated with chronic pain issues and general occupational health.


Involvement of Plasma Melatonin in Medication-Overuse Headache: A Cross-Sectional Study.
Patients with medication-overuse headache (MOH) are often complicated with anxiety, depression, and sleep disorders and are associated with dependence behavior and substance abuse. Melatonin has physiological properties including analgesia, regulation of circadian rhythms, soporific, and antidepressant and affects drug preference and addiction. This study aimed to investigate the role of melatonin in MOH compared with episodic migraine (EM) and healthy controls and to verify the relationship between plasma melatonin levels and psychiatric symptoms. Thirty patients affected by MOH, 30 patients with EM, and 30 matched healthy controls were enrolled. All subjects completed a detailed headache questionnaire and scales including the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index, the Leeds Dependence Questionnaire. Melatonin levels in plasma samples were measured by enzyme immunoassay method. The levels of plasma melatonin were significantly different among 3 groups of subjects (MOH, 7.74 [5.40-9.89]; EM, 9.79 [8.23-10.62]; Control, 10.16 [8.60-17.57]; H = 13.433; P = 0.001). Significantly lower levels of melatonin were found in MOH patients compared with healthy controls (P = 0.001). The level of plasma melatonin inversely correlated with the scores of HADS-Anxiety (r = -0.318, P = 0.002), HADS-Depression (r = -0.368, P < 0.001), Pittsburgh Sleep Quality Index (r = -0.303, P = 0.004), and Leeds Dependence Questionnaire (r = -0.312, P = 0.003). This study innovatively detects the plasma melatonin levels in MOH patients and explores the association between melatonin levels and psychiatric symptoms. Melatonin may be potential complementary therapy in the treatment of MOH considering its comprehensive role in multiple aspects of MOH.


Temporal masking of human auditory evoked brain stem responses using two simultaneously presented maximum length sequences.
Two simultaneously presented maximum length sequences (MLSs) were used to investigate temporal nonlinearities. Not only did the recorded auditory evoked brain stem responses to these stimuli predictably increase in latency and decrease in amplitude as a function of the temporal interactions between MLSs, but thresholds were elevated by more than 20 dB. Simultaneous MLS paradigms make it possible to investigate a number of nonlinearities in the auditory system efficiently. This study also demonstrated that binaural MLS techniques can be used to assess auditory function even in individuals with asymmetric hearing losses without fear of crossover effects.


Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion.
SIRT1 (silent information regulator 1), a conserved NAD+-dependent histone deacetylase, is closely related with various biological processes. Moreover, the important role of SIRT1 in alcoholic liver disease, nonalcoholic fatty liver and HCC had been widely reported. Recently, a novel role of SIRT1 was uncovered in organ fibrosis diseases. Here, we investigated the inhibitory effect of SIRT1 in liver fibrogenesis. SIRT1 protein was dramatically decreased in CCl4-treated mice livers. Stimulation of LX-2 cells with TGF-β1 also resulted in a significant suppression of SIRT1 protein. Nevertheless, TGF-β1-induced LX-2 cell activation was inhibited by SIRT1 plasmid, and this was accompanied by up-regulation of cell apoptosis-related proteins. Overexpression of SIRT1 also attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and COL1a. However, the important characteristic of the recovery of liver fibrosis is not only the apoptosis of activated stellate cells but also the reversal of the myofibroblast-like phenotype to a quiescent-like phenotype. Restoration of SIRT1 protein was observed in the in vivo spontaneously liver fibrosis reversion model and in vitro MDI (isobutylmethylxanthine, dexamethasone, and insulin)-induced reversed stellate cells, and forced expression of SIRT1 also promoted the reversal of activated stellate cells. Furthermore, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was increased in liver fibrosis. RNAi-mediated suppression of MALAT1 resulted in a decrease of myofibroblast markers and restoration of SIRT1 protein. These observations suggested that SIRT1 contributed to apoptosis and reversion of activated LX-2 cells and SIRT1 might be regulated by MALAT1 in liver fibrosis. Therefore, SIRT1 could be considered as a valuable therapeutic target for translational studies of liver fibrosis.


Photodynamic effects of Radachlorin on cervical cancer cells.
Photodynamic therapy (PDT) is a novel treatment modality, which produces local tissue necrosis with laser light following the prior administration of a photosensitizing agent. Radachlorin has recently been shown to be a promising PDT sensitizer. In order to elucidate the antitumor effects of PDT using Radachlorin on cervical cancer, growth inhibition studies on a HPV-associated tumor cell line, TC-1 cells in vitro and animals with an established TC-1 tumor in vivo were determined. TC-1 tumor cells were exposed to various concentrations of Radachlorin and PDT, with irradiation of 12.5 or 25 J/cm(2) at an irradiance of 20 mW/cm(2) using a Won-PDT D662 laser at 662 nm in vitro. C57BL/6 mice with TC-1 tumor were injected with Radachlorin via different routes and treated with PDT in vivo. A growth suppression study was then used to evaluate the effects at various time points after PDT. The results showed that irradiation of TC-1 tumor cells in the presence of Radachlorin induced significant cell growth inhibition. Animals with established TC-1 tumors exhibited significantly smaller tumor sizes over time when treated with Radachlorin and irradiation. PDT after the application of Radachlorin appears to be effective against TC-1 tumors both in vitro and in vivo.


Permissive role of L-thyroxine in induction of pancreatic amylase by cortisol in neonatal rats.
The effect of L-thyroxine (T4) on amylase activity in the developing rat pancreas has been investigated. Administration of T4 (0.2 microgram/g body wt) alone to intact rats on days 5-10 after birth did not induce pancreatic amylase but the enzyme was induced significantly by daily injection of cortisol (10 microgram/g body wt) alone into intact rats over the same period. In thyroidectomized, adrenalectomized rats pancreatic amylase was not induced by the injection of cortisol alone but it was induced by the administration of cortisol plus T4. Increase in enzyme activity was much less in thyroidectomized animals than in intact animals. These results suggested that T4 does not have a direct effect in increasing pancreatic amylase activity but plays a permissive role in increasing enzyme activity.


The Value of Diagnostic Work-Up in the Evaluation of White Dot Syndromes.
To determine the diagnostic yield of systemic work-up in white dot syndromes. A retrospective chart review. Eighty-six consecutive patients with a diagnosis of a white dot syndrome were identified. Forty-three had a diagnosis of birdshot chorioretinopathy. Overall, 395 diagnostic tests were performed with a diagnostic yield of 11.9%. The test with the greatest diagnostic yield was HLA-A29 typing (89%). Four patients had abnormal angiotensin converting enzyme levels. No patients had a positive rapid plasma reagin or fluorescent treponemal antibody absorption test. Four patients had positive tuberculosis testing and required treatment. The mean number of tests performed per diagnosis group ranged from 0.3 in multiple evanescent white dot syndrome to 5.6 in multifocal choroiditis and panuveitis. Diagnostic testing was found to be the most expensive in birdshot chorioretinopathy, with a mean cost of $504.82. Diagnostic yield of systemic work-up was low in this patient population. Rather than performing an exhaustive work-up, the authors advocate for a limited work-up tailored to pretest clinical suspicion. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:540-545.].


Ethical challenges and solutions regarding delirium studies in palliative care.
Delirium occurs commonly in settings of palliative care (PC), in which patient vulnerability in the unique context of end-of-life care and delirium-associated impairment of decision-making capacity may together present many ethical challenges. Based on deliberations at the Studies to Understand Delirium in Palliative Care Settings (SUNDIPS) meeting and an associated literature review, this article discusses ethical issues central to the conduct of research on delirious PC patients. Together with an analysis of the ethical deliberations at the SUNDIPS meeting, we conducted a narrative literature review by key words searching of relevant databases and a subsequent hand search of initially identified articles. We also reviewed statements of relevance to delirium research in major national and international ethics guidelines. Key issues identified include the inclusion of PC patients in delirium research, capacity determination, and the mandate to respect patient autonomy and ensure maintenance of patient dignity. Proposed solutions include designing informed consent statements that are clear, concise, and free of complex phraseology; use of concise, yet accurate, capacity assessment instruments with a minimally burdensome schedule; and use of PC friendly consent models, such as facilitated, deferred, experienced, advance, and proxy models. Delirium research in PC patients must meet the common standards for such research in any setting. Certain features unique to PC establish a need for extra diligence in meeting these standards and the employment of assessments, consent procedures, and patient-family interactions that are clearly grounded on the tenets of PC.


CYP2C76-mediated species difference in drug metabolism: a comparison of pitavastatin metabolism between monkeys and humans.
The monkey is often used to predict metabolism of drugs in humans since it generally shows a metabolic pattern similar to humans. However, metabolic profiles different from humans are occasionally seen in monkeys for some drugs including pitavastatin. Recently, we have successfully identified a monkey-specific cytochrome P450 (CYP) 2C76, which possibly accounts for a species difference between monkeys and humans because of its sequence and functional uniqueness. The present study on the role of CYP2C76 and other monkey CYP2Cs in pitavastatin metabolism, as an example, has revealed that CYP2C76 is important for the metabolism of the lactone form, indicating a major role of CYP2C76 for the difference in the metabolism of pitavastatin and possibly other drugs between monkeys and humans. The current investigation on the involvement of CYP2C76 in the metabolism of other drugs is expected to reveal further the further importance of this monkey-specific drug-metabolizing enzyme.


Hangover Symptoms, Heavy Episodic Drinking, and Depression in Young Adults: A Cross-Lagged Analysis.
The objective of this study was to examine associations between symptoms of alcohol hangover and depression, both cross-sectionally and prospectively. Data were from a survey of young adults (N = 986, 60% female) initially recruited as part of an observational study of youth smoking. Participants reported past-year hangover symptoms, past-year frequency of heavy episodic drinking (HED), and past-week depression symptoms on two occasions separated by 1 year. Path analysis was used to evaluate prospective, directional associations linking symptoms of depression and hangover after taking into account their stabilities and cross-sectional associations. Individual differences in HED frequency were accounted for to permit interpretation of residual hangover score variance in terms of susceptibility to hangover effects. Past-week depression and past-year hangover symptoms were associated at Time 1. Path analysis indicated that Time 1 depression symptoms were associated with elevated hangover symptoms a year later at Time 2. In contrast, Time 1 hangover symptoms did not predict future depression. Depression symptoms are associated with current and future hangover susceptibility. Hangover and depression overlap symptomatically and are empirically associated with one another, suggesting the possibility that common underlying causal mechanisms may contribute to both phenomena.


A plasma membrane antigen of rat glomerular epithelial cells. Antigenic determinants involving N-linked sugar residues in a 140-kilodalton sialoglycoprotein of the podocytes.
The aim of the present study was to investigate the antigenic make up of the plasma membrane of rat glomerular visceral epithelial cells (GEP). A crude plasma membrane fraction (PM) was extracted by 1% sodium dioxycholate from isolated rat glomeruli. PM was digested with neuraminidase (NRD) and purified by the Helix pomatia agglutinin (HPA)-affinity column. When studied by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the HPA-affinity purified plasma membrane fraction (HPA-PM) formed two bands, a main band of 160 kilodaltons (kd) and a smaller band of 40 kd. By Western blot analysis, the antibodies raised in a rabbit against HPA-PM (RbAHPA-PM) reacted only with the 160-kd protein of HPA-PM, or with the relevant 140-kd protein of PM when PM was digested by NRD. The 140-kd protein of PM was reactive with wheat germ agglutinin and, when treated with NRD, was reactive with HPA and peanut lectin. The 160-kd protein of HPA-PM was degraded by endoglycosidase-F and lost its reactivity with RbAHPA-PM. These results suggest that RbAHPA-PM react with antigenic sites involving N-linked sugar residues of a 140-kd sialoglycoprotein, presumably podocalyxin. Immunohistochemical studies using normal rat kidney tissues treated with NRD as substratum showed that RbAHPA-PM bound to the free surface of GEP but not with soles of the foot processes or with other structures of the kidney. In rats intravenously injected with NRD and subsequently with RbAHPA-PM, antibodies were rapidly fixed (within 1 hour) to the free surface of GEP. Immunofluorescence study showed that RbAHPA-PM also reacted with human glomeruli after treatment with NRD. These results suggest that GEP express surface sugar residues that are potential targets for direct immunologic attack.


An argyrophil III method for the demonstration of fibrous neuroglia.
The catalytic activity of the fibrous astrocytes in the reaction of silver ions with dissolved reducing molecules is considerably increased by ethylation and a subsequent treatment with NaJO3. As a consequence, in a special physical developer they produce metallic silver at a considerably higher rate than do other tissue elements, making possible their selective demonstration. In freshly fixed materials myelin too is silverized. This can be avoided by means of pretreatments with performic acid and iodine.


A Panel of CircRNAs in the Serum Serves as Biomarkers for Mycobacterium tuberculosis Infection.
Tuberculosis (TB), one of the ancient and deadliest diseases, is a chronic immune disorder caused by Mycobacterium tuberculosis (Mtb) infection. Due to the lack of ideal diagnostic and therapeutic markers, TB is still posing a major health, social, and economic burden worldwide. Circular RNA (circRNA), a newly discovered endogenous RNA, is abundant and stable in the cytoplasm and has tissue specificity. More and more studies suggested circRNA is involved in a variety of human pathological and physiological processes. Recently, several studies have confirmed circRNAs not only existed in the serum but also could serve as ideal biomarkers for detecting diseases since the circRNAs have continuous, stable, and covalently closed circular structures and are not easily degraded by nucleases. In this study, we screened the circRNA expression profiles in active TB serum samples and healthy volunteers serum samples by circRNA microarrays. Then, we performed qRT-PCR to verified the dysregulated circRNAs and ROC curve analysis to evaluate the value of circRNAs for TB diagnosis. The results showed circRNA_051239, circRNA_029965, and circRNA_404022 could serve as biomarkers for TB diagnosis.


Accessibility for persons with mobility impairments within an informal trading site: A case study on the markets of Warwick, South Africa.
There are a number of informal trading sites across cities in sub-Saharan Africa, of which the markets of Warwick is one example. Since the informal economy is an important contributor to a city's economy as well as a source of employment, it is important for these sites to be accessible for all persons. Whilst the South African government has put structures in place to identify and remove environmental barriers in order to meet the individual needs of persons with mobility impairments and improve their quality of life, persons with mobility impairments still face barriers and restricting environments that prevent them from participating in society and its social and economic activities. This case study aimed at exploring accessibility within the markets of Warwick for persons with mobility impairments by an ergonomic assessment, augmented by voices of participants within the market. A qualitative, instrumental, single case study design was utilised with purposive sampling of the markets of Warwick as the study setting. Multiple sources of data were gathered, such as semi-structured interviews, direct observations of an environmental survey supported by photographs, and the authors' review of relevant documents. Transcriptions were analysed using NVivo 10 software programme with inductive coding. Whilst policies have been in place since 1996 to adjust infrastructure, the markets of Warwick still remain inaccessible to persons with mobility impairments and do not meet the standardised infrastructural design. The findings of this study may offer a significant understanding of the complexity of accessibility within an informal trading site and create an awareness of the limitations this has for persons with mobility impairments. Additionally, these findings may assist in effecting a positive change in terms of the infrastructure of the Markets and in continuous advocating for the rights of persons with all disabilities.


Interferon-Gamma Release Assay is Not Appropriate for the Diagnosis of Active Tuberculosis in High-Burden Tuberculosis Settings: A Retrospective Multicenter Investigation.
Interferon-gamma release assay (IGRA) has been used in latent tuberculosis (TB) infection and TB diagnosis, but the results from different high TB-endemic countries are different. The aim of this study was to investigate the value of IGRA in the diagnosis of active pulmonary TB (PTB) in China. We conducted a large-scale retrospective multicenter investigation to further evaluate the role of IGRA in the diagnosis of active PTB in high TB-epidemic populations and the factors affecting the performance of the assay. All patients who underwent valid T-SPOT.TB assays from December 2012 to November 2015 in six large-scale specialized TB hospitals in China and met the study criteria were retrospectively evaluated. Patients were divided into three groups: Group 1, sputum culture-positive PTB patients, confirmed by positive Mycobacterium tuberculosis sputum culture; Group 2, sputum culture-negative PTB patients; and Group 3, non-TB respiratory diseases. The medical records of all patients were collected. Chi-square tests and Fisher's exact test were used to compare categorical data. Multivariable logistic analyses were performed to evaluate the relationship between the results of T-SPOT in TB patients and other factors. A total of 3082 patients for whom complete information was available were included in the investigation, including 905 sputum culture-positive PTB cases, 914 sputum culture-negative PTB cases, and 1263 non-TB respiratory disease cases. The positive rate of T-SPOT.TB was 93.3% in the culture-positive PTB group and 86.1% in the culture-negative PTB group. In the non-PTB group, the positive rate of T-SPOT.TB was 43.6%. The positive rate of T-SPOT.TB in the culture-positive PTB group was significantly higher than that in the culture-negative PTB group (χ2 = 25.118, P < 0.01), which in turn was significantly higher than that in the non-TB group (χ2 = 566.116, P < 0.01). The overall results were as follows: sensitivity, 89.7%; specificity, 56.37%; positive predictive value, 74.75%; negative predictive value, 79.11%; and accuracy, 76.02%. High false-positive rates of T-SPOT.TB assays in the non-TB group limit the usefulness as a single test to diagnose active TB in China. We highly recommend that IGRAs not be used for the diagnosis of active TB in high-burden TB settings.


Development of retinal acuity in infants evaluated with pattern electroretinogram.
The electroretinographic (ERG) response to patterns of constant mean luminance (sinusoidal gratings reversed in contrast at 12 rev/s) has been recorded in infants 7 weeks to 6 months old. At each age the amplitude of the ERG for relatively fine gratings decreases with increasing spatial frequency and vanishes for a spatial frequency that can be defined as ERG acuity. It has been found that ERG acuity increases progressively with age. The acuity evaluated from cortical evoked potentials (VEP) recorded simultaneously with the ERG increases with age in parallel with ERG acuity. These findings are in agreement with data reported in the literature for the cat, indicating a parallel postnatal development of acuity at a retinal and cortical level.


Determination of tryptamine in brain tissue by capillary gas chromatography mass spectrometry (selected ion monitoring).
The development of an analytical method for the determination of brain tryptamine using capillary gas chromatography mass spectrometry (selected ion monitoring) is presented. The method involves solvent extraction of brain homogenates and further derivatization (pentafluoropropionyl derivatives) of the dried extracts. Gas chromatographic analysis is performed using a bonded phase silica fused capillary column. Selected monitoring of m/z 289 and 292 (isotope dilution technique) allows the determination of tryptamine in adult rat brain (450 +/- 73 pg g-1) (means +/- SEM), n = 6.


[Variability of corticosterone methyl oxidase (type II) deficiency. Presentation of three case reports].
We report on three cases of Corticosterone Methyl Oxidase Typ II deficiency in two siblings and one boy. All three children were presented with typical symptoms of a saltlosing syndrome (vomiting, poor drinking, weight loss, hypotonia). Hyponatremia and hyperkalemia, low plasma aldosterone concentrations when related to high plasma-renin-activities suggested deficiency in the final steps of aldosterone biosynthesis. Variable degrees of enzyme deficiency and no relation of biochemical findings to the clinical symptoms were observed. Clinical symptoms became less severe with age. Diagnosis of CMO II-deficiency was established by an abnormal high ratio of 18-hydroxycorticosterone to aldosterone, by measurement of their precursors and metabolites in plasma and urine. In one sibling negative values may have been caused by suppression of the renin-angiotensin-system due to high sodium replacement therapy.


Lichen planus sera react non-specifically with second trimester fetal skin.
Lichen planus (LP) is a relatively common papulosquamous disease of unknown etiology for which an "autoimmune" pathogenesis has been postulated. A LP-specific antigen has been found in the stratum granulosum of lesional skin, and circulating antibodies to this antigen have been found in sera of about 70% of LP patients. Specific binding of antibodies in LP sera to second trimester fetal skin has been reported (Med. Microbiol. Immunol., 1984; 172, 249). In the present study, we attempted to reproduce this work. Indirect immunofluorescence was performed using frozen sections of human foreskin or second trimester fetal skin (n = 7) incubated first with serum from 17 LP patients or 7 normal controls. The substrate was then washed and incubated with fluorescein-labelled rabbit antibodies to human immunoglobulins. Results showed that sera from both LP patients and normal controls reacted with epidermal cells of fetal skin above the basal cell layer. The foreskin substrate did not react with either sera. In conclusion, we could not confirm the differences in reactivity of LP vs. normal sera against second trimester fetal skin as previously reported. This discrepancy between the two studies may be attributed to methods of collection of fetal tissue, nonspecific binding of antibodies in serum of some LP patients, or increased levels of immunoglobulins against epidermal keratins in sera of LP patients or normal controls.


Characterization and endocrine regulation of the cytochrome P-450 dependent microsomal hydroxylation of 5 alpha-androstane-3 beta,17 beta-diol in the rat ventral prostate.
Of 11 structurally related steroids, 5 alpha-androstane-3 beta,17 beta-diol was the one most efficiently hydroxylated to polar metabolites by microsomes isolated from the rat ventral prostate. The metabolites were identified by gas chromatography-mass spectrometry as 6 alpha-,7 alpha-, and presumably 6 beta-hydroxylated 5 alpha-androstane-3 beta,17 beta-diol. The hydroxylated metabolites were separated and quantitated by high performance liquid chromatography using an aminopropylsilane hypersil column. Maximum velocity (V max) values of 0.36, 0.12, and 0.044 nmol/min X mg of microsomal protein were determined for the 6 alpha-,7 alpha-, and 6 beta-hydroxylase activities, respectively, with an apparent Michaelis-Menten constant (Km) of 30 microM for all hydroxylases. Hydroxylation of 5 alpha-androstane-3 beta,17 beta-diol in prostatic microsomes was NADPH dependent and was inhibited by several cytochrome P-450 inhibitors in vitro and by antibodies against rat liver NADPH-cytochrome P-450 reductase. The enzyme activities were stimulated by treatment of the rats with phenobarbital, beta-naphthoflavone, 5 alpha-androstane-3 beta,17 beta-diol,5 alpha-dihydrotestosterone, and methyltrienolone, whereas the activities were suppressed by ovine PRL, human GH, estradiol benzoate, cholesterol, andrenalectomy , hypophysectomy, and castration. It is concluded that the prostatic 5 alpha-androstane-3 beta,17 beta-diol hydroxylase activities represent a constitutive cytochrome P-450 form in the rat ventral prostate with a high steroid substrate specificity. Endocrine factors are involved in the regulation of the activity of the enzyme. The ratio between the three hydroxylated metabolites was constant in almost all experiments suggesting that only one cytochrome P-450 species was involved in the hydroxylation.


Laminectomy versus open-door laminoplasty for cervical spondylotic myelopathy: A clinical outcome analysis.
Cervical spondylotic myelopathy (CSM) is one of the most common diseases in the geriatric population. Decompressive laminectomy or laminoplasty is the predominant surgical procedure of choice, but there remains debate as to which procedure is optimal for managing CSM. Here, we retrospectively analyzed 64 patients with CSM undergoing laminectomy (39 patients) versus laminoplasty (25 patients). The data were collected included respective Japanese orthopedic association (JOA) scores, Nurick grades, and Visual analog scale (VAS) values preoperatively versus 12 months postoperatively. The JOA score after 1 month improved in both groups utilizing laminectomy or laminoplasty. However, at 12 postoperative months, the JOA scores and Nurick grades showed greater improvement following laminoplasty, despite no differences in postoperative pain and complication rates. Patients with cervical spondylotic myelopathy undergoing laminoplasty (25 patients) showed better 12-month postoperative outcomes (JOA scores and Nurick grades) versus those having laminectomies (39 patients).


Prompt tumor formation and maintenance of constitutive NF-kappaB activity of multiple myeloma cells in NOD/SCID/gammacnull mice.
Clinically and biologically relevant animal models are indispensable to evaluate both the pathophysiology and strategies for diagnosis and treatment of multiple myeloma (MM). We examined the tumorigenicity of MM cell lines KMM-1 and U-266 in an in vivo cell proliferation model using NOD/SCID/gammacnull (NOG) mice. Two cell lines were inoculated either subcutaneously (s.c.) in the post-auricular region or intravenously (i.v.) in the tail of NOG mice. The KMM-1 cell line produced a progressively growing large tumor with infiltration of the cells expressing human lambda-chain in various organs of all NOG mice, while the U-266 cell line failed to do so. Tumor cells grown in NOG mice maintained the original histomorphology, as well as expression patterns of tumor markers human lambda Ig light chain and VEGF. Tumor progression in mice also correlated with elevation of serum human soluble IL-6R and gp130. Tumor cells sustained a strong NF-kappaB activity in vivo and induced NF-kappaB components were indistinguishable from those in cells cultured in vitro. The rapid and efficient engraftment of the MM cell line in NOG mice suggests that this is a very useful animal model which could provide a novel system in which to clarify the mechanism of growth of cancer cells, as well as to develop new therapeutic regimens against MM.


Feedback control of microbubble cavitation for ultrasound-mediated blood-brain barrier disruption in non-human primates under magnetic resonance guidance.
Focused ultrasound (FUS) in combination with microbubbles is capable of noninvasive, site-targeted delivery of drugs through the blood-brain barrier (BBB). Although acoustic parameters are reproducible in small animals, their control remains challenging in primates due to skull heterogeneity. This study describes a 7-T magnetic resonance (MR)-guided FUS system designed for BBB disruption in non-human primates (NHP) with a robust feedback control based on passive cavitation detection (PCD). Contrast enhanced T1-weighted MR images confirmed the BBB opening in NHP sonicated during 2 min with 500-kHz frequency, pulse length of 10 ms, and pulse repetition frequency of 5 Hz. The safe acoustic pressure range from 185 ± 22 kPa to 266 ± 4 kPa in one representative case was estimated from combining data from the acoustic beam profile with the BBB opening and hemorrhage profiles obtained from MR images. A maximum amount of MR contrast agent at focus was observed at 30 min after sonication with a relative contrast enhancement of 67% ± 15% (in comparison to that found in muscles). The feedback control based on PCD using relative spectra was shown to be robust, allowing comparisons across animals and experimental sessions. Finally, we also demonstrated that PCD can test acoustic coupling conditions, which improves the efficacy and safety of ultrasound transmission into the brain.


Prevalence, clinical characteristics and outcome in patients with chronic heart failure and diabetes.
Chronic heart failure (CHF) and diabetes mellitus portend high morbidity and mortality because of an interrelated pathophysiologic process. This large cohort study aimed to analyze the prevalence, clinical characteristics and long-term outcome of patients with CHF and diabetes. A total of 1119 patients with NYHA functional class II - IV and left ventricular ejection fraction (LVEF) < 45% between January 1995 and May 2009 were recruited. Clinical variables, biochemical and echocardiographic measurements were retrospectively reviewed, and composite major cardiac events (MCE) including death, heart transplantation, and refractory heart failure requiring multiple hospitalizations were recorded. The prevalence of CHF with diabetes was progressively increased with time (16.9% in 1995 - 1999; 20.4% in 2000 - 2004, and 29.1% in 2005 - 2009) and age (18.5% in < 60 years, 26.6% in 60 - 80 years, and 26.6% in > 80 years). Compared with CHF patients without diabetes, those with diabetes had worse cardiac function, more abnormal biochemical changes, and higher mortality. Treatment with glucose-lowering agents significantly improved LVEF and decreased MCE. An elevated serum HbA1c level was associated with large left ventricular end-systolic diameter (P < 0.05), decreased LVEF (P < 0.01) and reduced survival (P < 0.05). Multivariable Logistic regression analysis revealed that after adjustment for confounding factors, NYHA functional class (OR 2.65, 95%CI 1.14 - 6.16, P = 0.024) and HbA1c level >or= 7% (OR 2.78, 95%CI 1.00 - 7.68, P = 0.049) were independent risk factors for adverse outcomes in CHF patients with diabetes. Prevalence of CHF with diabetes was increasing during past decades, and patients with CHF and diabetes had worse clinical profiles and prognosis. Aggressive anti-CHF and diabetes therapies are needed to improve overall outcomes for these patients.


Imaging and intervention for coronary artery disease following irradiation of malignant thymoma.
Thymomas are rare malignant epithelial growths, constituting 20% of mediastinal tumours. Resection followed by irradiation may be employed in all thymomas except for stage 1 thymomas. Mediastinal irradiation is associated with coronary artery disease. The mean duration of presentation of post-irradiation coronary artery disease is 16 years (range 3-29 years). In our patient coronary artery disease was found only a year post irradiation. A 55 year old male who presented with complaints of dyspnoea, retrosternal chest pain and heaviness since one year underwent resection for malignant thymoma followed by radiotherapy. He presented with coronary artery disease a year after undergoing mediastinal irradiation. On follow-up, patient was treated successfully by coronary artery bypass graft. This case is an unusual occurrence and suggests that mediastinal irradiation may result in significant coronary artery disease as early as within one year.


Fabrication of Adhesive Resistance Surface with Low Wettability on Ti6Al4V Alloys by Electro-Brush Plating.
Anti-adhesive Ni coatings with low wettability were successfully fabricated on Ti6Al4V substrates via an electro-brush plating method, and subsequently modified with a fluoroalkylsilane (FAS) film. The surface morphology, chemical compositions, and wettability of the as-prepared coatings were measured using scanning electron microscopy (SEM), X-ray diffractometer (XRD), Fourier transform infrared spectrophotometry (FTIR), and contact angle measurements. The results showed that the surface of Ti6Al4V substrate was endowed with flower-like structures. Each flower-like cluster was constituted by a large number of Ni ions. After surface modification of FAS, the as-prepared Ti6Al4V surface had a water contact angle as high as 151.5°, a sliding angle close to 2.1°, and a solid surface energy as low as 0.97 mJ/m². Potentiodynamic polarization tests showed that the Ni coating could provide a stable corrosion protection. In addition, the effects of processing conditions, such as working voltage, relative velocity, electrolyte concentration, and processing time, were investigated. The mechanism of the adhesive resistance was proposed, and the low wettability of Ti6Al4V surfaces was explained by Cassie⁻Baxter model. As a result, it was necessary to reduce the fraction of the solid⁻liquid interface in order to achieve anti-adhesive surface.


Sperm swimming behaviors are correlated with sperm haploid genetic variability in the Mexican tetra, Astyanax mexicanus.
The diploid genotypes of males are widely thought to determine sperm phenotypes, yet recent work shows that the haploid genetics of the individual sperm cell also contributes significantly. We tested seven sperm phenotypes, flagellar length and six behaviors, looking for correlations between genetic and phenotypic variability. While flagellar length appears to be controlled by the diploid genotype of the source, variation in three of the behavioral phenotypes, linearity, wobble, and progression are significantly correlated with the heterozygosity of the male producer. Because males that are more genetically variable produce a sperm set that is more diverse in its haploid genotypes, we suggest that the correlations may reflect significant haploid genetic control of sperm swimming behaviors.


Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally, Cxcl5 expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases.


Qualitative and Quantitative Analysis of the Major Constituents in Shexiang Tongxin Dropping Pill by HPLC-Q-TOF-MS/MS and UPLC-QqQ-MS/MS.
Shexiang Tongxin dropping pill (STP) is a traditional Chinese medicine formula that consists of total saponins of ginseng, synthetic Calculus bovis, bear gall, Venenum bufonis, borneol and Salvia miltiorrhiza. STP has been widely used in China and Southeast Asia for the treatment of cardiovascular diseases. In this study, a qualitative analytical method using high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was developed for identification of the major constituents in STP. Based on the retention time and MS spectra, 41 components were identified by comparison with reference compounds and literature data. Moreover, using ultra-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry in multiple-reaction monitoring mode, we quantified 13 of the identified constituents (ginsenoside Rg1, ginsenoside Rk3, cinobufagin, arenobufagin, bufalin, resibufogenin, tanshinone IIA, taurine, tauroursodeoxycholic acid, taurocholic acid, cholic acid, deoxycholic acid, and chenodeoxycholic acid). These results suggest that this new approach is applicable for the routine analysis and quality control of STP products and provides fundamental data for further in vivo pharmacokinetical studies.


[Urodynamic evaluation of the effect of neural therapy in motor and sensory urgency].
We treated 10 patients with motor or sensory urgency by paraurethral injection of a local anesthetic. After clinical and urodynamic work-up we applied 2.5 ml of 1% lidocain solution with Kollidon to delay absorption (Xyloneural) transvaginally to the right and left of the urethro-vesical junction. Each treatment cycle consisted of 3 injections with 2-week intervals between injections. 2 weeks after the last injection a repeat urodynamic investigation was done. All patients were improved by therapy: after the 3rd injection 3/10 women were free of symptoms, 6/10 women reported marked improvement, and one woman slight improvement of the symptoms of urgency and frequency. The mean bladder volume at the first sensation to void increased significantly after neural therapy (p = 0.02); other urodynamic parameters were not affected by neural therapy. No side effects were observed. We conclude that the paraurethral injection of a local anaesthetic is a simple and effective treatment in motor and sensory urgency.


Deep Brain Magnetic Stimulation Promotes Neurogenesis and Restores Cholinergic Activity in a Transgenic Mouse Model of Alzheimer's Disease.
Alzheimer's disease (AD) is characterized by progressive decline of memory and cognitive functions. Deep magnetic stimulation (DMS), a noninvasive and nonpharmacological brain stimulation, has been reported to alleviate stress-related cognitive impairment in neuropsychiatric disorders. Our previous study also discovered the preventive effect of DMS on cognitive decline in an AD mouse model. However, the underlying mechanism must be explored further. In this study, we investigated the effect of DMS on spatial learning and memory functions, neurogenesis in the dentate gyrus (DG), as well as expression and activity of the cholinergic system in a transgenic mouse model of AD (5XFAD). Administration of DMS effectively improved performance in spatial learning and memory of 5XFAD mice. Furthermore, neurogenesis in the hippocampal DG of DMS-treated 5XFAD mice was clearly enhanced. In addition, DMS significantly raised the level of acetylcholine and prevented the increase in acetylcholinesterase activity as well as the decrease in acetyltransferase activity in the hippocampus of 5XFAD mice. These findings indicate that DMS may be a promising noninvasive tool for treatment and prevention of AD cognitive impairment by promoting neurogenesis and enhancing cholinergic system function.


Reversible tremor and myoclonus associated with topiramate-fluvoxamine coadministration.
The antiepileptic agent topiramate has proved its efficacy in a variety of other conditions as well, including several kinds of tremor and migraine prophylaxis. We report on the case of a 42-year-old depressive female patient with comorbid migraine attacks, whereby the adjunction of topiramate as an antimigraine agent at the dosage of 50 mg/d to her antidepressive treatment with fluvoxamine at 300 mg/d triggered--the prima facie paradoxical for topiramate--side effects of tremor and myoclonus. Topiramate was immediately discontinued, and patient's abnormal movements subsided completely within 24 to 72 hours. Topiramate was possibly the cause of patient's abnormal movements enhanced by fluvoxamine's potential to induce also tremor and myoclonus. Therefore, clinicians should be aware of the potentially severe adverse reactions that might occur during concomitant treatment with fluvoxamine and topiramate.


A pilot study on 25-hydroxyvitamin D status according to sun exposure in pregnant women in Antwerp, Belgium.
Vitamin D deficiency in utero or early neonatal life may have a major impact on children's health. Little is known on vitamin D deficiency in pregnant women in Belgium, non on the impact of wearing head and/or body cover. This was a preliminary exploration of the vitamin D status in pregnant women visiting the antenatal clinic in the Antwerp University Hospital. From August 1 2009 until November 30 2009 we systematically determined 25-hydroxy vitamin D (25-OH vitamin D) in each blood sample taken from pregnant women visiting the antenatal clinic. We also registered the degree of head/body cover and inquired for intake of vitamin supplements. Our population consisted of 171 women, mostly primiparous, of which 86% were not covered. The mean value of 25-OH vitamin D was 28 ng/ml. Non-covered women had a mean of 29,5 ± 12,2 (SD) ng/ml, the partially covered group had a mean of 17,2 ± 7,2 (SD) ng/ml and the completely covered group had a mean of 22,5 ± 12,9 (SD) ng/ml. The difference in serum concentrations between the 3 groups was statistically significant (Anova, p < 0,00001). There were significantly more covered than non-covered women with a vitamin D concentration lower than 30 ng/ml (OR6.2; 95% CI: 1,8-21,7; p < 0,05). There was no effect of gestational age, maternal age, gravidity, parity and intake of supplements on vitamin D levels. There was a siginificant seasonal effect from summer to fall, with Vitamine D levels lowering from August to November (linear regression, p < 0,05). Low vitamin D levels seem to be frequent and covered woman are at a higher risk of deficiency.


Risk prediction models with incomplete data with application to prediction of estrogen receptor-positive breast cancer: prospective data from the Nurses' Health Study.
A number of breast cancer risk prediction models have been developed to provide insight into a woman's individual breast cancer risk. Although circulating levels of estradiol in postmenopausal women predict subsequent breast cancer risk, whether the addition of estradiol levels adds significantly to a model's predictive power has not previously been evaluated. Using linear regression, the authors developed an imputed estradiol score using measured estradiol levels (the outcome) and both case status and risk factor data (for example, body mass index) from a nested case-control study conducted within a large prospective cohort study and used multiple imputation methods to develop an overall risk model including both risk factor data from the main cohort and estradiol levels from the nested case-control study. The authors evaluated the addition of imputed estradiol level to the previously published Rosner and Colditz log-incidence model for breast cancer risk prediction within the larger Nurses' Health Study cohort. The follow-up was from 1980 to 2000; during this time, 1,559 invasive estrogen receptor-positive breast cancer cases were confirmed. The addition of imputed estradiol levels significantly improved risk prediction; the age-specific concordance statistic increased from 0.635 +/- 0.007 to 0.645 +/- 0.007 (P < 0.001) after the addition of imputed estradiol. Circulating estradiol levels in postmenopausal women appear to add to other lifestyle factors in predicting a woman's individual risk of breast cancer.


Surface-mediated production of hydroxyl radicals as a mechanism of iron oxide nanoparticle biotoxicity.
Emerging applications of nanosized iron oxides in nanotechnology introduce vast quantities of nanomaterials into the human environment, thus raising some concerns. Here we report that the surface of γ-Fe(2)O(3) nanoparticles 20-40 nm in diameter mediates production of highly reactive hydroxyl radicals (OH(•)) under conditions of the biologically relevant superoxide-driven Fenton reaction. By conducting comparative spin-trapping EPR experiments, we show that the free radical production is attributed primarily to the catalytic reactions at the nanoparticles' surface rather than being caused by the dissolved metal ions released by the nanoparticles as previously thought. Moreover, the catalytic centers on the nanoparticle surface were found to be at least 50-fold more effective in OH(•) radical production than the dissolved Fe(3+) ions. Conventional surface modification methods such as passivating the nanoparticles' surface with up to 935 molecules of oleate or up to 18 molecules of bovine serum albumin per iron oxide core were found to be rather ineffective in suppressing production of the hydroxyl radicals. The experimental protocols developed in this study could be used as one of the approaches for developing analytical assays for assessing the free radical generating activity of a variety of nanomaterials that is potentially related to their biotoxicity.


Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?
Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.


Follow-up after intensive care treatment: a questionnaire survey of intensive care aftercare in Denmark.
Rehabilitation efforts after treatment in the intensive care unit (ICU) are termed intensive care aftercare. It includes both early in-hospital follow-up after ICU-discharge and late follow-up after hospital discharge. This study aims to investigate the current ICU-aftercare activities in Denmark. We conducted an electronic questionnaire survey, which was distributed by e-mail to the heads of all 31 general ICUs in Denmark. Specialized ICUs were not included. The questionnaire was divided into the following sections: early ICU-aftercare, late ICU-aftercare, future development and demographics. Thirty-one ICUs were invited to participate. The response rate was 100%. Overall, 26 of 31 ICUs (84%) offered ICU-aftercare, with the following distribution: early ICU-aftercare (58%), late ICU-aftercare (57%) and both (29%). There were no significant associations between hospital size and provision of ICU-aftercare. For early ICU-aftercare, the most common eligibility criteria were based on ICU length of stay (LOS) (44%) and a decision based upon doctors' discretion (22%). Incidence of guidelines for early ICU-aftercare (44%) and checklists at patient contact (35%) were sparse. The most common early ICU-aftercare items were as follows: respiratory care (82%), tracheostomy care (59%) and nutritional care (59%). For late ICU-aftercare, the most common eligibility criterion was LOS (41%). Guidelines (71%), but not checklist at patient contact (35%), were more common. Most frequent late ICU-aftercare interventions were review of ICU-diaries (59%) and patient charts (53%). Eighty-four per cent of Danish ICUs offered ICU-aftercare to their patients. There was an abundant heterogeneity of eligibility criteria and ICU-aftercare interventions.


Methyl displacements from cyclopentadienyl ring planes in sterically crowded (C5Me5)3M complexes.
The displacements of the methyl substituents away from the metal and out of the cyclopentadienyl ring plane are compared in sterically crowded (C(5)Me(5))(3)M complexes vs sterically normal f-element complexes in an attempt to evaluate the utility of this parameter in predicting unusual (C(5)Me(5))(1-) ring reactivity. The out-of-plane displacements of 16 sterically crowded tris(cyclopentadienyl) complexes of general formula (C(5)Me(5))(3)M, (C(5)Me(4)R)(3)M (R = Et, (i)Pr, (t)()Bu, SiMe(3)), (C(5)Me(5))(3)MX (X = anion), and (C(5)Me(5))(3)ML (L = neutral ligand) are compared with [(C(5)Me(5))(2)U](2)(C(6)H(6)), (C(5)Me(5))(2)Sm(PC(4)H(2)(t)Bu(2)), and 33 representative examples of f-element bis(cyclopentadienyl) complexes with normal cyclopentadienyl behavior and coordination numbers ranging from 6 to 10. In general, the methyl displacement values of sterically crowded complexes overlap with those in the other complexes, which demonstrates that the basis of the structural distortions is complex. However, if the most extreme out-of-plane displacement in each of the sterically crowded complexes is examined vs the analogous maximum out-of-plane displacement in less crowded systems, there appears to be a basis for predicting cyclopentadienyl reactivity.


Characterization of Patients with Chronic Myeloid Leukemia Unresponsive to Tyrosine Kinase Inhibitors Who Underwent Allogeneic Hematopoietic Stem Cell Transplantation.
Background: Tyrosine kinase inhibitors (TKIs) were the first drugs to use an intracellular signaling molecule as a therapeutic target. Unresponsiveness to TKIs limits therapeutic options, making allogeneic hematopoietic stem cell transplantation (HSCT) the only option leading to molecular remission. The aim of this study is to characterize CML patients unresponsive to first- and/or second-generation TKI therapy who underwent HSCT and to describe the main factors associated with treatment failure. Subjects and Methods: Twenty one CML patients who underwent allogeneic HSCT and had previously used first- and/or second-generation TKIs from January 2005 to May 2014. Results: Of the 21 patients, 52.4% were male, with a median age of 49 years (23-65 years) and 85.7% had chronic phase CML at the time of diagnosis; 28.6% showed inadequate treatment adherence to TKI therapy. Thirteen patients were resistant and eight were intolerant to TKIs; additionally, nine did not have T315I mutation. Ten transplantations involved related donors, and more than a half of patients (11) died, three of which due to graft failure. Most patients who survived transplantation were in the chronic phase of disease at the time of HSCT. Conclusion: The population was composed mainly of young age patients at diagnosis, male, white, and coming from areas in the state of Rio Grande do Sul other than Porto Alegre and metropolitan region. Low adherence to TKI therapy may be related to unresponsiveness to treatment, especially in patients with acquired resistance, or this low adherence, together with the presence of molecular changes, may have led to the need for HSCT.


Telemedicine Breastfeeding Consultation: The Saudi Experience.
Background Telemedicine is widely used in health specialties. Yet, the experience of telemedicine use and its effectiveness in breastfeeding support is a research gap. The purpose of this study was to describe the pattern of telemedicine use for breastfeeding support in Saudi Arabia and to explore patients' satisfaction with the service. Methods A cross-sectional survey was conducted in outpatient settings at Ministry of Health facilities in several Saudi regions. The number of breastfeeding consultations over one year (2021) was analyzed in terms of region, month, method of consultation, and women's maternity status. Data on patient satisfaction and telemedicine techniques were gathered during 2022. Results Across the 16 regions enrolled in the project, 51,571 remote breastfeeding consultations were conducted, representing 28.2% of the total consultations. The eastern region reported the highest percentage (40.7%), and the southern region reported the lowest (2.4%). Almost two-thirds of the consultations were provided to lactating mothers (62.91%). Most data (90%) were collected from breastfeeding clinics in hospitals, and nurses were the main primary health care providers. The mean was 4,255 consultations per month. In terms of technology, telemedicine consultations were mostly conducted by phone (50%) and WhatsApp (38%). Satisfaction with telemedicine was reported by 80% of the participants, with a statistical difference found in those favoring telemedicine over in-person care (p=0.032), particularly for those using phone consultations and Telegram (p<0.001). WhatsApp respondents had the commonest neutral responses (p<0.001). Conclusion Telemedicine breastfeeding care has been widely established with high patient satisfaction. A national protocol outpatient lactation services with an intergrated hospital and primary care services and involvement of different health care professionals are recommended. Although breastfeeding counselling is proven to have a positive change on breastfeeding indicators, telemedicine tool per se needs further work on its role in breastfeeding indicators. Triage of cases to be evaluated face-to-face or referral to a specialist after telemedicine lactation care is an area for future work.


Application of solution-processed metal oxide layers as charge transport layers for CdSe/ZnS quantum-dot LEDs.
We fabricated and characterized quantum-dot light emitting devices (QLEDs) that consisted of a CdSe/ZnS quantum-dot (QD) emitting layer, a hole-transporting nickel oxide (NiO) layer and/or an electron-transporting zinc oxide (ZnO) layer. Both the p-type NiO and n-type ZnO layers were formed by using sol-gel processes. All the fabricated CdSe/ZnS QLEDs showed similar electroluminescence spectra that originated from the green CdSe/ZnS QDs. However, different combinations of hole- and electron-transporting layers resulted in efficiency variations. In addition to the control of the respective concentrations of holes and electrons within a multilayer device structure, which determines the luminance and efficiency of QLEDs, the use of metal oxide layers is advantageous for long-term stability of QLEDs because they are air stable and can block the permeation of water vapor and oxygen in ambient air to a QD emitting layer. Moreover, the wet chemistry processing for their formation makes metal oxide layers attractive for low cost and/or large area manufacture of QLEDs.


Readmission rates after transcatheter aortic valve replacement in high- and extreme-risk patients with severe aortic stenosis.
In high- or extreme-risk patients undergoing transcatheter aortic valve replacement, readmissions have not been adequately studied and are the subject of increased scrutiny by healthcare systems. The objectives of this study were to determine the incidence of 30-day and 1-year cardiac and noncardiac readmissions, identify predictors of readmission, and assess the association between readmission and 1-year mortality. A retrospective review was performed on 714 patients who underwent transcatheter aortic valve replacement from September 2007 to January 2015 at Emory University. Patients' median age was 83 years, and 46.6% were female. Early all-cause readmission for the cohort was 10.5%, and late readmission was 18.8%. Anemia was related to both early all-cause (hazard ratio [HR], 0.74) and cardiovascular-related readmission (HR, 0.60). A 23-mm valve implanted was associated with early all-cause readmission (HR, 1.73). Length of hospital stay was related to late all-cause (HR, 1.14) and cardiovascular-related readmission (HR, 1.21). Postoperative permanent stroke had an impact on late cardiovascular-related readmission (HR, 3.60; 95% confidence interval, 1.13-11.49). Multivariable analysis identified anemia as being associated with 30-day all-cause readmission, and anemia and postoperative stroke were associated with 30-day cardiovascular-related readmission. Readmissions seemed to be related to 1-year mortality (HR, 2.04; 95% confidence interval, 1.33-3.12). We show some baseline comorbidities and procedural complications that are directly associated with early and late readmissions, and anemia and postoperative stroke were associated with an increase in mortality. Moreover, we found that readmission was associated with double the hazard of death within 1 year. Whether treatment of identified risk factors could decrease readmission rates and mortality warrants further investigation.


Flavone markedly affects phenotypic expression of beta-lactam resistance in methicillin-resistant Staphylococcus aureus strains isolated clinically.
Flavone and its derivatives had very weak antibacterial effects on methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus, but dramatically intensified MRSA's susceptibility to beta-lactams. We named these compounds "ILSMR (intensifier of beta-lactam-susceptibility in MRSA)." We also found discrepancies among MRSA strains in their responses to flavone; some strains showed phenotypic susceptibility to methicillin while others showed phenotypic resistance to it. To understand the mechanism underlying this discrepancy, we characterized 20 MRSA strains in detail, analyzed their conventional and molecular typings, and examined each strain's resistance to beta-lactams, with COL serving as a reference. Neither SCCmec typing nor coagulase typing explained the diverse effects of flavone on the beta-lactam MICs of these strains. Likewise, changes in pulsed-field gel electrophoresis (PFGE) type were not associated with the profiles of ILSMR effects. However, the present observations suggest that the ILSMR effects on MRSA is strain-specific, and that this effect depends on an as-yet unknown mechanism that is essential for the expression of the phenotype conferring beta-lactam resistance to MRSA strains, independently of an interaction with the mecA-encoded penicillin-binding protein 2a or with the beta-lactamase.


Alternative splicing of fibroblast growth factor 1 (FGF-1) transcripts: a cellular dilemma in determining exon selection and exclusion.
During reverse transcription and polymerase chain reaction (RT-PCR) of kidney RNA using fibroblast growth factor 1 (FGF-1) gene-specific primers, we amplified five fragments with the sizes of 507, 410, 310, 285, and 216 bp. Cloning of the 507-, 310-, and 216-bp fragments revealed that the latter two share the same sequences to the 507-bp DNA but missing 197 and 291 bp, respectively. Characterization of the corresponding genomic DNA sequences showed that the three cDNA are alternative splicing products of the same gene. We further showed that these three transcripts are also present in brain in similar proportions albeit in a much lesser extent. Repeated attempts to clone the 410-bp fragment resulted in isolation of three additional cDNA clones; each has the inclusion of a distinct novel exon. Because each novel exon is delimited by the splicing donor and acceptor sequences, these cDNA clones are not likely to be RT-PCR artifacts. Yet their mRNA levels are extremely low, because we could not detect the corresponding PCR products on ethidium bromide-stained gels nor by Southern hybridization. These novel exons may be routinely used in different tissues. The nature of the 410- and 285-bp products was shown to be heteroduplexing among the 507-, 310-, and 216-bp PCR products. Identification of the three novel FGF-1 exons, which we designate exons -1B, -1E, and -1F, will facilitate the studies of the mechanisms of regulated alternative splicing.


[The reliability of data in ecopathologic investigations].
The reliability of information gathered during ecopathological investigations is a constant concern, requiring a rigorous strategy to limit risks of error. These risks are all the more important when there are human shortcomings (farmer or investigator) as opposed to technical shortcomings (results of laboratory tests). A dual strategy can be implemented to guarantee reliability: ensuring reliable collection of data by attention to the human element (selection of farmers, training of investigators, organisation of professional partners), and ensuring the collection of reliable data by attention to facts (quality of the questionnaire, harmonization of procedures, objective interpretation of qualitative findings, quality of data-processing support, timing of data collection, verification procedures). The argument is supported by numerous examples provided by teams of ecopathologists.


Metabolism, macromolecular synthesis, and nuclear behavior of Cryptococcus albidus at 37 C.
The temperature-sensitive events which prevent Cryptococcus albidus from growing at 37 C were investigated. Cultures incubated at 37 C immediately after inoculation did not increase in optical density nor in cell numbers, and by 24 h 90% of cells in such cultures were deformed and dead. When cultures in log phase were shifted from 23 to 37 C the optical density increased but the cell numbers did not. Morphological observations revealed that the increase in turbidity at 37 C represented enlargement and distortion of cells without appreciable replication. Uptake and incorporation of (14)C-leucine were similar at 23 and 37 C. There was no difference in (14)CO(2) evolution from cells at either temperature. Uptake and incorporation of adenine-8-(14)C into RNA was slightly lower in cells incubated at 37 C. There was, however, a 60% reduction in incorporation of adenine-8-(14)C into DNA after 3 hr at 37 C. Nuclear staining revealed that nuclear migration did not occur in cells incubated at 37 C. Thus the data indicate that both adenine incorporation into DNA and nuclear migration prior to nuclear division by C. albidus are temperature sensitive.