Identification of alpha-actinin 4 and 67 kDa laminin receptor as stage-specific markers in esophageal cancer via proteomic approaches.
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in the world with a very poor prognosis. The majority of ESCC patients present with advanced metastatic disease upon diagnosis. Therefore, it is important to understand the molecular mechanism in the tumor invasion process and to find new biomarkers for early diagnosis and prognostic evaluation. Differentially expressed proteins among different stages of primary ESCCs and their matched surrounding normal tissues were compared by proteomics-based technology. The correlations between interesting proteins and clinical features of ESCC were further investigated by using ESCC tissue microarray (TMA) by immunohistochemical staining. Compared with normal tissues, a total of 18 differentially expressed proteins were identified in ESCC in this study. Among them, expression levels of alpha-actinin 4 (ACTN4) and 67 kDa laminin receptor (67LR) were progressively increased from stage I to III. Clinicopathological correlation using TMA revealed that overexpression of ACTN4 was significantly associated with advanced tumor stage (P = .026) and lymph node metastasis (P = .049), whereas overexpression of 67LR was significantly correlated with advanced tumor stage (P = .019) but not lymph node metastasis. These findings suggested that overexpression of ACTN4 and 67 LR is associated with ESCC progression and that these biomarkers may potentially be useful to prognostic evaluation, molecular biological classification, and therapeutic targeting.


A Pd-diimine catalytic inimer for synthesis of polyethylenes of hyperbranched-on-hyperbranched and star architectures.
A Pd-diimine catalytic inimer containing uniquely catalytic, initiating, and monomeric functionalities in one catalyst molecule is designed. It enables the first self-condensing vinyl copolymerization of ethylene, leading to polyethylenes of a hyperbranched-on-hyperbranched architecture. Meanwhile, it also facilitates the synthesis of star polyethylenes by tandem UV-coordinative polymerization.


'Death ... more desirable than life'? The human skeletal record and toxicological implications of ancient copper mining and smelting in Wadi Faynan, southwestern Jordan.
Skeletal material from 36 people, dating from the early Christian era, who lived by or worked in the notorious Roman copper mines of Phaeno, were analysed to determine their exposure to copper and lead. We demonstrate that many of the bones analysed had a substantially higher concentration of these cations than modern individuals exposed to metals through industrial processes. Health, toxicological and environmental implications of these data are reviewed.


Investigations on the driving forces of the fluorocarbon surfactant-assisted spontaneous imbibition using thermogravimetric analysis (TGA).
Spontaneous imbibition is crucial for the development of matrix-fractured petroleum reservoirs. To improve the ultimate oil recovery, it is essential to demonstrate the role of the surfactant solution on the imbibition process. In this study, spontaneous imbibition experiments were carried out using self-prepared oil sand that to investigate the dependence of oil recovery on the concentration of a fluorocarbon surfactant (FS-30). Emulsion and solubilization were assessed to identify the correlation between oil-water interface properties and spontaneous imbibition. Moreover, thermogravimetric analysis (TGA) was also applied to accurately determine the imbibition recovery and look into the influence of components of crude oil on spontaneous imbibition. The maximum ultimate oil recovery in this work was 70.8% using 0.3 wt% FS-30, when the oil-solid adhesion tension, the capillary pressure (P C) and solubilization factor (S F) attained extreme values of -3.7002 mN m-1, 4.8751 MPa and 242.7 mL g-1, respectively. It was found that the surface activator played a critical role in promoting the imbibition process through altering the contact angle and interfacial tension. A negative adhesive tension and a positive capillary pressure would accordingly be generated, which facilitated the departure of oil droplets from the rock surface. In addition, it was observed that a lower solubilization factor and higher emulsion stability could favour spontaneous imbibition. Finally, heavier components in oil sands were more prone to be displaced than lighter counterparts, especially when the surfactant concentration was relatively high. This study may shed light on the effect of surfactants on spontaneous imbibition and thus is of great significance in understanding the underlying mechanism of the imbibition process.


Spatial distribution of lead in enamel and coronal dentine of wistar rats.
Lead is one of the most hazardous environmental toxins known. The assessment of lead in dental hard tissues is important in the understanding of its toxic effects on oral tissues and in estimating exposure and body burden in individuals exposed to lead from the environment. However, current information on the uptake and distribution of lead in enamel and dentine is limited. The aim of this project was to study, at high resolution, the spatial distribution of lead in enamel and coronal dentine using an experimental rat model. A dose of 40 mg/L of lead nitrate was administered to pregnant female rats during the periods of gestation and lactation through drinking water. First mandibular molar teeth were removed from their 15-d-old pups and the distribution of lead was studied using a nuclear microprobe (NMP). The distribution of lead in enamel and coronal dentine showed four distinct zones with significantly different mean lead concentrations (p<0.05). High levels of lead were observed in the superficial regions of enamel and in the dentine directly adjacent to the pulp. Additionally, the results confirmed that the NMP is capable of mapping the distribution of lead in teeth at micron resolutions with a detection limit of approx 1 microg/g.


A pilot study of pain management during rehabilitation for hip and knee arthroplasty.
{\it } To evaluate the efficacy of pain management in a clinical pathway for rehabilitation after hip and knee arthroplasty, in which scheduled medications are rapidly tapered and prn medications are continued throughout the inpatient stay. {\it } A prospective cross-sectional study. {\it } General rehabilitation unit of a regional acute rehabilitation center. {\it } Twenty-nine patients admitted consecutively to the rehabilitation unit in three months. {\it } Number of pills/day of prn pain medication, pain scores at admission and discharge, frequency of constipation and nausea, Functional Independence Measure (FIM) gain, and length of stay (LOS). {\it } For all patients, prn pain medication use was 2.4 pills/day/patient; the mean FIM gain was 22.1; and the average LOS was 9.8 days. In comparison to the Vicodin group, patients on Darvocet N-100 had significantly fewer requests for prn pain medication each day (3.1 vs. 1.1, p < 0.01), significantly better FIM gains better (18.9 vs. 24.1, p < 0.05), and fewer side effects (nausea and constipation). {\it } Choosing the right pain medication is imperative for achieving optimal efficiency in clinical pathways for orthopedic rehabilitation. In this pilot study, Darvocet N-100 is the preferred narcotic over codeine and its derivatives.


A 2-Phase Merge Filter Approach to Computer-Aided Detection of Breast Tumors on 3-Dimensional Ultrasound Imaging.
The role of image analysis in 3-dimensional (3D) automated breast ultrasound (ABUS) images is increasingly important because of its widespread use as a screening tool in whole-breast examinations. However, reviewing a large number of images acquired from ABUS is time-consuming and sometimes error prone. The aim of this study, therefore, was to develop an efficient computer-aided detection (CADe) algorithm to assist the review process. The proposed CADe algorithm consisted of 4 major steps. First, initial tumor candidates were formed by extracting and merging hypoechoic square cells on 2-dimensional (2D) transverse images. Second, a feature-based classifier was then constructed using 2D features to filter out nontumor candidates. Third, the remaining 2D candidates were merged longitudinally into 3D masses. Finally, a 3D feature-based classifier was used to further filter out nontumor masses to obtain the final detected masses. The proposed method was validated with 176 passes of breast images acquired by an Acuson S2000 automated breast volume scanner (Siemens Medical Solutions USA, Inc., Malvern, PA), including 44 normal passes and 132 abnormal passes containing 162 proven lesions (79 benign and 83 malignant). The proposed CADe system could achieve overall sensitivity of 100% and 90% with 6.71 and 5.14 false-positives (FPs) per pass, respectively. Our results also showed that the average number of FPs per normal pass (7.16) was more than the number of FPs per abnormal pass (6.56) at 100% sensitivity. The proposed CADe system has a great potential for becoming a good companion tool with ABUS imaging by ensuring high sensitivity with a relatively small number of FPs.


Association between pregnancy intention and late initiation of antenatal care among pregnant women in Ethiopia: a systematic review and meta-analysis.
Antenatal care is one of the continua of reproductive health care, and inadequate antenatal care utilization results in an adverse feto-maternal outcome. Pregnancy intention is an essential factor that plays a paramount role on timing of antenatal care service. The finding of a few studies conducted on the association between pregnancy intention and late initiation of ANC among pregnant women in Ethiopia presented inconclusive. Therefore, the objective of this systematic review and meta-analysis was to determine the pooled estimate of the association between pregnancy intention and late initiation of ANC among pregnant women in Ethiopia. Both published and unpublished studies were accessed through electronic search from databases such as MEDLINE, Scopes, PubMed, CINAHL, PopLine, MedNar, Cochrane library, the JBI Library, the Web of Science, and Google Scholar. All observational studies that were conducted on the association between pregnancy intention and late initiation of ANC among pregnant women in Ethiopia were included. STATA 14.1 version was used for data analysis. A random effects model was used to estimate the pooled estimate with a 95% confidence interval (CI). The Cochrane Q test statistic and I2 tests were used to assess heterogeneity. Presence of publication bias was checked by funnel plots and Egger's statistical tests. A total of 670 published and unpublished studies were identified from several databases and fourteen studies fulfilled inclusion criteria and included in the meta-analysis. The overall pooled estimate indicates the odds of late initiation of antenatal care were 2.16 times higher among pregnant women who had unintended pregnancy as compared to pregnant women who had intended pregnancy (OR 2.16, 95% CI 1.62, 2.88). The systematic review and meta-analysis found a statistically significant effect of pregnancy intention on late initiation of antenatal care among pregnant women in Ethiopia. Increased effort should be made to improve women's behavior towards contraceptive use through health education and counseling, especially those with unintended pregnancies. Furthermore, health education, counseling, and communication campaigns related to the timing of ANC and frequency should be promoted nationally.


Retention of molars after root-resective therapy: a retrospective evaluation of up to 30 years.
Long-term retention of teeth and especially molars in function is the ultimate goal of periodontal therapy. Root-resective therapy is a treatment option for molars with advanced furcation involvement, which has been questioned because of the heterogenous success rates published in literature. This study aimed to evaluate long-term results of root-resective treatment over a period of up to 30 years. In this retrospective cohort, 90 root-resected molars in 69 patients were examined for 4-30 years (14.7 ± 6.8 years). The complete treatment sequence was performed by one of the authors in a general dental practice. Overall cumulative survival rate was 90.6% after 10 years, but then decreased considerably. Molars after root resection had a median survival time of 20 years. The incidence of endodontic complications leading to tooth extraction was only 26.7%, 50% were lost due to periodontal problems, and 16.7% because of caries. Mandibular molars had a significantly lower relative risk of loss than molars in the maxilla (HR 0.31, 95% CI 0.1-0.91, p = 0.033). Mandibular molars showed a survival probability of almost 80% even 20 years after root resection. Root-resective therapy is a predictable treatment option, when care is administered at each phase of therapy. This study provides important information about what is possible in daily practice under the outlines of public health care, when care is administered at each phase of resective therapy.


The control of chronic lymphocytic leukemia with mediastinal irradiation.
Forty patients with chronic lymphocytic leukemia have been treated with mediastinal irradiation. A full remission was achieved in 18 (45 per cent) patients, a partial response in eight (20 per cent), "WBC control" in eight (20 per cent) and no response in 6 (15 per cent). Although mediastinal irradiation benefited all stages of disease, earlier stages of disease correlated with more complete and longer response to mediastinal irradiation. Toxicity was mild and transient and included leukopenia in five patients (12 per cent), thrombocytopenia in eight patients (20 per cent), mild esophagitis in 12 patients (30 per cent) and pneumonitis in four patients (10 per cent). There were no toxic deaths and mediastinal irradiation did not adversely effect survival. Treatment was readily given on an ambulatory basis and completed within four weeks. In five of 11 patients, abnormal immunoglobulins became normal. Eleven patients had abnormal lymphocyte transformation with PHA, five had marked improvement and three had partial improvements following mediastinal irradiation. This improvement appeared to correlate with response and survival but further study is necessary to confirm this relationship. Although most patients required additional therapy within two years, eight patients have required no further therapy for periods of twenty-eight months to thirteen years.


Comparison of perinatal outcome after pre-viable preterm prelabour rupture of membranes in two centres with different rates of termination of pregnancy.
To assess perinatal outcomes after expectant management in the case of preterm prelabour rupture of membranes (PPROM) before 25 weeks of gestation, according to the rate of termination of pregnancy (TOP). Retrospective comparative cohort study. Singleton pregnancies complicated by PPROM between 15(0/7) and 24(6/7) weeks of gestation, from January 2003 to January 2007. Comparison of perinatal outcomes in two French tertiary care referral centres presumed to have different rates of TOP. Rates of TOP, survival and survival without major morbidity. A total of 113 women experienced PPROM (49 in centre A and 64 in centre B). A lower proportion of patients opted for TOP in centre A (40.8%) than in centre B (56.3%). The baseline characteristics of patients and pregnancies, and gestational age at PPROM, were not different between the two centres. Mean gestational age at delivery (28.1 versus 25.4 weeks of gestation; P < 0.01), mean latency period (45.5 versus 16.1 days; P < 0.01), mean birthweight (1295 versus 929 g; P = 0.04) and survival (46.9 versus 20.3%; P < 0.01) were significantly higher in centre A than in centre B. The percentage of neonates alive without major morbidity was also higher in centre A than in centre B (42.9 versus 20.3%; P = 0.01). Perinatal outcomes of pregnancies managed expectantly were not better in the centre where the TOP rate was higher. The perinatal risk of pregnancies complicated by pre-viable PPROM remains high.


DNA cleavage potency, cytotoxicity, and mechanism of action of a novel class of enediyne prodrugs.
We have discovered a novel class of (E)-3-acyloxy-4-(arylmethylidene)cyclodeca-1,5-diynes which exhibit promising enediyne-like DNA cleavage and cytotoxic activities. LC-MS analysis of the incubation mixture (pH 8.5, 37 degrees C) confirmed formation of 10-membered ring enediyne presumably via an allylic cation and suggested that the 1,4-benzenoid diradical might be one of the active species for DNA damage and cytotoxicity.


A new methodological approach to assess cardiac work by pressure-volume and stress-length relations in patients with aortic valve stenosis and dilated cardiomyopathy.
In experimental animals, cardiac work is derived from pressure-volume area and analyzed further using stress-length relations. Lack of methods for determining accurately myocardial mass has until now prevented the use of stress-length relations in patients. We hypothesized, therefore, that not only pressure-volume loops but also stress-length diagrams can be derived from cardiac volume and cardiac mass as assessed by cardiac magnetic resonance imaging (CMR) and invasively measured pressure. Left ventricular (LV) volume and myocardial mass were assessed in seven patients with aortic valve stenosis (AS), eight with dilated cardiomyopathy (DCM), and eight controls using electrocardiogram (ECG)-gated CMR. LV pressure was measured invasively. Pressure-volume curves were calculated based on ECG triggering. Stroke work was assessed as area within the pressure-volume loop. LV wall stress was calculated using a thick-wall sphere model. Similarly, stress-length loops were calculated to quantify stress-length-based work. Taking the LV geometry into account, the normalization with regard to ventricular circumference resulted in "myocardial work." Patients with AS (valve area 0.73+/-0.18 cm(2)) exhibited an increased LV myocardial mass when compared with controls (P<0.05). LV wall stress was increased in DCM but not in AS. Stroke work of AS was unchanged when compared with controls (0.539+/-0.272 vs 0.621+/-0.138 Nm, not significant), whereas DCM exhibited a significant depression (0.367+/-0.157 Nm, P<0.05). Myocardial work was significantly reduced in both AS and DCM when compared with controls (129.8+/-69.6, 200.6+/-80.1, 332.2+/-89.6 Nm/m(2), P<0.05), also after normalization (7.40+/-5.07, 6.27+/-3.20, 14.6+/-4.07 Nm/m(2), P<0.001). It is feasible to obtain LV pressure-volume and stress-length diagrams in patients based on the present novel methodological approach of using CMR and invasive pressure measurement. Myocardial work was reduced in patients with DCM and noteworthy also in AS, while stroke work was reduced in DCM only. Most likely, deterioration of myocardial work is crucial for the prognosis. It is suggested to include these basic physiological procedures in the clinical assessment of the pump function of the heart.


Effectiveness and implementation of a text messaging intervention to reduce depression and anxiety symptoms among Latinx and Non-Latinx white users during the COVID-19 pandemic.
Text messaging interventions are increasingly used to help people manage depression and anxiety. However, little is known about the effectiveness and implementation of these interventions among U.S. Latinxs, who often face barriers to using mental health tools. The StayWell at Home (StayWell) intervention, a 60-day text messaging program based on cognitive behavioral therapy (CBT), was developed to help adults cope with depressive and anxiety symptoms during the COVID-19 pandemic. StayWell users (n = 398) received daily mood inquiries and automated skills-based text messages delivering CBT-informed coping strategies from an investigator-generated message bank. We conduct a Hybrid Type 1 mixed-methods study to compare the effectiveness and implementation of StayWell for Latinx and Non-Latinx White (NLW) adults using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Effectiveness was measured using the PHQ-8 depression and GAD-7 anxiety scales, assessed before starting and after completing StayWell. Guided by RE-AIM, we conducted a thematic text analysis of responses to an open-ended question about user experiences to help contextualize quantitative findings. Approximately 65.8% (n = 262) of StayWell users completed pre-and-post surveys. On average, depressive (-1.48, p = 0.001) and anxiety (-1.38, p = 0.001) symptoms decreased from pre-to-post StayWell. Compared to NLW users (n = 192), Latinx users (n = 70) reported an additional -1.45 point (p < 0.05) decline in depressive symptoms, adjusting for demographics. Although Latinxs reported StayWell as relatively less useable (76.8 vs. 83.9, p = 0.001) than NLWs, they were more interested in continuing the program (7.5 vs. 6.2 out of 10, p = 0.001) and recommending it to a family member/friend (7.8 vs. 7.0 out of 10, p = 0.01). Based on the thematic analysis, both Latinx and NLW users enjoyed responding to mood inquiries and sought bi-directional, personalized text messages and texts with links to more information to resources. Only NLW users stated that StayWell provided no new information than they already knew from therapy or other sources. In contrast, Latinx users suggested that engagement with a behavioral provider through text or support groups would be beneficial, highlighting this group's unmet need for behavioral health care. mHealth interventions like StayWell are well-positioned to address population-level disparities by serving those with the greatest unmet needs if they are culturally adapted and actively disseminated to marginalized groups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04473599.


Cardiorespiratory fitness estimation in free-living using wearable sensors.
In this paper we propose artificial intelligence methods to estimate cardiorespiratory fitness (CRF) in free-living using wearable sensor data. Our methods rely on a computational framework able to contextualize heart rate (HR) in free-living, and use context-specific HR as predictor of CRF without need for laboratory tests. In particular, we propose three estimation steps. Initially, we recognize activity primitives using accelerometer and location data. Using topic models, we group activity primitives and derive activities composites. We subsequently rank activity composites, and analyze the relation between ranked activity composites and CRF across individuals. Finally, HR data in specific activity primitives and composites is used as predictor in a hierarchical Bayesian regression model to estimate CRF level from the participant's habitual behavior in free-living. We show that by combining activity primitives and activity composites the proposed framework can adapt to the user and context, and outperforms other CRF estimation models, reducing estimation error between 10.3% and 22.6% on a study population of 46 participants. Our investigation showed that HR can be contextualized in free-living using activity primitives and activity composites and robust CRF estimation in free-living is feasible.


Sex-dependent Effect of In-utero Exposure to Δ9-Tetrahydrocannabinol on Glucagon and Stathmin-2 in Adult Rat Offspring.
Administration of Δ9-tetrahydrocannabinol (Δ9-THC) to pregnant rats results in glucose intolerance, insulin resistance and reduced islet mass in female, but not male, offspring. The effects of Δ9-THC on other islet hormones is not known. One downstream target of the cannabinoid receptor, stathmin-2 (Stmn2), has recently been shown to suppress glucagon secretion, thereby suggesting Δ9-THC may also affect alpha-cell function. The aim of the present study was to determine the effects of in-utero Δ9-THC exposure on the profile of glucagon, insulin and Stmn2 in the rat offspring islet and serum. Pregnant Wistar rat dams were injected with Δ9-THC (3 mg/kg per day, intraperitoneally) or vehicle from gestational day 6 to birth. Offspring were euthanized at postnatal day 21 (PND21) or at 5 months (adult) to collect blood and pancreata. At PND21, control and Δ9-THC-exposed offspring showed that Stmn2 had a strong colocalization with glucagon (Pearson's correlation coefficient ≥0.6), and a weak colocalization with insulin (Pearson's correlation coefficient <0.4) in both males and females, with no changes by either treatment or sex. In adult female offspring in the Δ9-THC group, intensity analysis indicated an increased insulin-to-glucagon (I/G; p<0.05) ratio and a decreased glucagon-to-Stmn2 (G/S; p<0.01) ratio, and no changes in these ratios in adult males. Furthermore, Δ9-THC did not alter fasting blood glucose and serum insulin levels in either male or female adult offspring. However, female Δ9-THC-exposed offspring exhibited an increased I/G ratio (p<0.05) and decreased G/S ratio in serum by adulthood (p<0.05). Collectively, the reduced G/S ratio in both islet and serum in association with an increased serum I/G ratio has direct correlations with early glucose intolerance and insulin resistance observed exclusively in females' offspring in this prenatal cannabinoid model.


Phytoestrogen coumestrol attenuates brain mitochondrial dysfunction and long-term cognitive deficits following neonatal hypoxia-ischemia.
Neonatal Hypoxia-Ischemia (HI) is a major cause of morbidity and mortality, and is frequently associated with short and long-term neurologic and cognitive impairments. The HI injury causes mitochondrial damage leading to increased production of reactive oxygen species (ROS). Phytoestrogens are non-steroidal plant substances structurally and functionally similar to estrogen. Coumestrol is a potent isoflavonoid with a protective effect against ischemic brain damage in adult rats. Our aim was to determine if coumestrol treatment following neonatal HI attenuates the long-term cognitive deficits induced by neonatal HI, as well as to investigate one possible mechanism underlying its potential effect. On the 7th postnatal day, male Wistar rats were submitted to the Levine-Rice HI model. Intraperitoneal injections of 20 mg/kg of coumestrol, or vehicle, were administered immediately pre-hypoxia or 3 h post-hypoxia. At 12 h after HI the mitochondrial status and ROS levels were determined. At 60th postnatal day the cognitive deficits were revealed in the Morris water maze reference and working spatial memories. Following behavioral analysis, histological assessment was performed and reactive astrogliosis was measured by GFAP expression. Results demonstrate that both pre- and post-HI administration of coumestrol were able to counteract the long-term cognitive and morphological impairments caused by HI, as well as to block the late reactive astrogliosis. The pre-HI administration of coumestrol was able to prevent the early mitochondrial dysfunction in the hippocampus of injured rat pups. Present data suggest that coumestrol exerts protection against experimental neonatal brain hypoxia-ischemia through, at least in part, early modulation of mitochondrial function.


Effects of rice bran oil enriched with n-3 PUFA on liver and serum lipids in rats.
Lipase-catalyzed interesterification was used to prepare different structured lipids (SL) from rice bran oil (RBO) by replacing some of the fatty acids with alpha-linolenic acid (ALA) from linseed oil (LSO) and n-3 long chain polyunsaturated fatty acids (PUFA) from cod liver oil (CLO). In one SL, the ALA content was 20% whereas in another the long chain n-3 PUFA content was 10%. Most of the n-3 PUFA were incorporated into the sn-1 and sn-3 positions of triacylglycerol. The influence of SL with RBO rich in ALA and EPA + DHA was studied on various lipid parameters in experimental animals. Rats fed RBO showed a decrease in total serum cholesterol by 10% when compared to groundnut oil (GNO). Similarly structured lipids with CLO and LSO significantly decreased total serum cholesterol by 19 and 22% respectively compared to rice bran oil. The serum TAGs level of rats fed SLs and blended oils were also significantly decreased by 14 and 17% respectively compared to RBO. Feeding of an n-3 PUFA rich diet resulted in the accumulation of long chain n-3 PUFA in various tissues and a reduction in the long chain n-6 PUFA. These studies indicate that the incorporation of ALA and EPA + DHA into RBO can offer health benefits.


Improving female preventive health care delivery through practice change: an Every Woman Matters study.
The levels of breast and cervical cancer screening in Nebraska primary care remain suboptimal despite awareness of their importance, and despite implementation of the Every Woman Matters program to assist low-income women. The GAPS model was used to develop a practice-based intervention to identify and reduce barriers to delivery of breast and cervical cancer screening services. Seven primary care practices actively participated in this multimethod case study. A research nurse collected data and facilitated the intervention process at each site. Qualitative data from field notes, patient encounters, and in-depth interviews of physicians and key informants were collected to describe the process of Papanicolaou and mammogram service delivery, and to identify barriers/facilitators to screening, and potential change areas. Chart reviews provided information regarding the preintervention and postintervention identification/execution of Papanicolaou smears and mammograms. Qualitative and quantitative analyses led to individual practice case studies. Cross case comparisons identified common themes. The individual practice plans for change had many commonalities, ie, developing screening databases and reminder systems. The biggest differences involved practice contexts. Despite use of the GAPS model and a financial incentive to obtain "buy in" from providers and staff, change was difficult for all but 2 of the practices. The complexity of practice context and its effect on change cannot be underestimated. Individual practice providers and staff are often unaware of the potential challenges, and unable/unwilling to overcome them.


Histological aspects and structural characteristics of the testes of Dendropsophus minutus (Anura, Hylidae).
The present study describes morphological aspects of testes and presents a general characterization of the seminiferous elements of Dendropsophus minutus (Peters, 1872). Twenty samples of the species were used; after macroscopic descriptions the testes were submitted to histological routine for microscopic analysis. Anatomically, the testes measured 1.90+/-0.13 mm, and were oval and milky-white. In relation to microscopic aspects, it was observed in D. minutus, as well as in anuran amphibians, that spermatogenesis occurs in the seminiferous tubule where elements of the germ epithelium are organized in spermatogenetic cysts. Each cyst contains cells in the same stage of differentiation. Characterization of each cellular type enables the identification and differentiation of germ lineage cells. Spermatogonia I, found at the epithelial base, are the largest of the lineage cells and are usually present in association with Sertoli cells present next to the basal membrane. During the mitotic proliferation phase, cysts containing variable numbers of spermatocytes II are originated; these spermatocytes are smaller and similar inside the cyst. Spermatocytes I are developed after some morphological changes; these spermatocytes are large cells with a spherical nucleus and different degrees of nuclear compaction. Spermatocytes II, highly numerous cells resultant from the first meiotic division, are much smaller than their antecedents. A second meiotic division produces haploid cell formation, specifically spermatids I, which through cellular differentiation form spermatids II. Spermatids II are elongated and organized in bundles supported by Sertoli cells. Spermatozoids appear during the spermiogenesis process and in their most advanced stage they lose their fascicular organization and are released in the tubular lumen, where they follow a pathway through the duct system.


Missed injuries in a level I trauma center.
Major trauma presents major diagnostic and therapeutic problems. Any delay in providing the treatment necessary may lead to increased morbidity and mortality, prolonged length of hospital stay, and increased cost. This study was undertaken to determine the extent, contributing factors, and implication of missed injuries and relate them to the three surveys in a Danish Level I trauma center. The records of all major traumatized patients admitted to the Odense University Hospital from January 1996 through December 1999 have been studied to determine the extent and type of missed injuries. The initial examination is carried out by the trauma team in the A&E department according to standard protocols. Resuscitation is carried out according to Advanced Trauma Life Support principles and details are documented in the patient journal and in a special trauma journal. Sixty-four of 786 patients (incidence, 8.1%) had 86 missed injuries. The missed injuries averaged 1.3 injuries per patient. There were 45 male and 19 female patients, with a median age of 33 years (range, 12-81 years). The median ISS was 17 (range, 4-50); 14%, 38%, and 48% of the injuries were missed in primary, secondary, and tertiary surveys, respectively. Our study demonstrates that missed injuries can occur at any stage of the management of patients with major trauma. Repeated assessments, both clinical and radiologic, are mandatory to diminish the problem. In initial assessment, one still has to treat the greatest threat to life before complete diagnosis of all injuries, but alertness to evolving injuries must remain throughout the patient's stay in hospital.


EBV and vitamin D status in relapsing-remitting multiple sclerosis patients with a unique cytokine signature.
Multiple sclerosis, a debilitating autoimmune and inflammatory disease of the central nervous system, is associated with both infectious and non-infectious factors. We investigated the role of EBV infection, vitamin D level, and cytokine signature in MS patients. Molecular and serological assays were used to investigate immune biomarkers, vitamin D level, and EBV status in 83 patients with relapsing-remitting multiple sclerosis and 62 healthy controls. In total, 98.8 % of MS patients showed a history of EBV exposure compared to 88.6 % in the healthy group (p = 0.005). EBV DNA load was significantly higher in MS patients than healthy subjects (p < 0.0001). Using a panel of biomarkers, we found a distinct transcriptional signature in MS patients compared to the healthy group with mRNA levels of CD73, IL-6, IL-23, IFN-γ, TNF-α, IL-15, IL-28, and IL-17 significantly elevated in MS patients (p < 0.0001). In contrast, the mRNA levels for TGF-β, IDO, S1PR1, IL-10, and CCL-3 were significantly lower in MS patients compared to healthy controls (p < 0.0001). No significant differences were found with the mRNA levels of IL-13, CCL-5, and FOXP3. Interestingly, in MS patients we found an inverse correlation between vitamin D concentration and EBV load, but not EBNA-1 IgG antibody levels. Our data highlight biomarker correlates in MS patients together with a complex interplay between EBV replication and vitamin D levels.


Immune reconstitution to cytomegalovirus following partially matched-related donor transplantation: impact of in vivo T-cell depletion and granulocyte colony-stimulating factor-primed peripheral blood/bone marrow mixed grafts.
Cytomegalovirus (CMV) infection and delayed immune reconstitution remains a serious obstacle for successful partially matched-related donor transplantation (PMRD). We evaluated 42 patients for the development of CMV-specific CD8+ T lymphocytes (CTL(CMV) ) following granulocyte colony-stimulating factor-primed peripheral blood (PB) and bone marrow (BM) with anti-thymocyte globulin (ATG)-based PMRD. PMRD recipients achieved a high frequency, proliferation capacity, and interferon-γ response of CTL(CMV) at 1 year post transplantation. CTL(CMV) with the central memory CD45RO+CD62L+ cell phenotype expanded in PB and BM-resident CTL(CMV) displayed distinct phenotypes when CMV was reactivated. Although the incidence of CMV reactivation was high in PMRD patients (87.67%), only 11.90% of them developed CMV disease. In conclusion, after PMRD using mixed grafts with ATG-based conditioning, immune recovery to CMV seems to be early and fast, thereby reducing the incidence of CMV disease.


Vagal Paragangliomas: From Reducing Morbidity to Improving Quality of Life.
Vagal paragangliomas are rare tumors. Advances in the imaging have aided the diagnosis and assessment of this disease. Surgery is the mainstay of the treatment however radiotherapy has been tried in the selected cases. Surgery is associated with some mortality but with a lot of morbidity in view of cranial nerve deficit. The necessity to prevent additional cranial nerve deficits needs thorough preoperative evaluation and influences the therapeutic approach. This study involves the retrograde evaluation of five patients of vagal paraganglioma histopathologically confirmed, all the patients were operated via trancervical approach. Preoperatively three of five had 9, 11 and 12th cranial nerve involvement, one had horner's syndrome. Postoperative vocal rehabilitation was done in all the patient by medialisation thyroplasty Issiki type 1. Though vagal paragangliomas are associated with mortality and morbidity. Surgical treatment should aim at reducing mortality. Vagal nerve morbidity can be taken care as a planned and staged procedure mainly involving restoring voice as rest of concerns are taken care by compensation from opposite nerves.


Novel analogs of allopregnanolone show improved efficiency and specificity in neuroprotection and stimulation of proliferation.
The natural neurosteroid allopregnanolone exerts beneficial effects in animal models of neurodegenerative diseases, nervous system injury and peripheral neuropathies. It not only has anti-apoptotic activity, but also promotes proliferation of progenitor cells. With respect to using it as a therapeutic tool, such pleiotropic actions might create unwanted side effects. Therefore, we have synthesized allopregnanolone analogs and analyzed their neuroprotective and proliferative effects to identify compounds with higher efficiency and less ambiguous biological actions. Proliferation-promoting effects of 3α and 3β isomers of 3-O-allyl-allopregnanolone and 12 oxo-allopregnanolone were studied in adult subventricular zone stem cell cultures and in primary hippocampal cultures by measuring 5-ethynyl-2'-deoxyuridine incorporation. Neuroprotective activity against amyloid beta 42-induced cell death was determined by quantifying caspase 3/7 activity. The 3α isomers significantly stimulated proliferation in all culture systems, whereas the 3β isomers were ineffective. The stimulatory effect of 3α-O-allyl-allopregnanolone was significantly higher than that of allopregnanolone. In neural stem cell cultures, 3α-O-allyl-allopregnanolone specifically enhanced proliferation of Nestin-positive progenitors. In addition, it promoted the differentiation of doublecortin-positive neurons. In neural stem cell cultures treated with amyloid beta 42, both the α and β isomers of O-allyl- allopregnanolone showed increased neuroprotective activity as compared to allopregnanolone, completely preventing amyloid-induced caspase 3/7 activation. The 12 oxo-allopregnanolone analogs were ineffective. These results identify structural allopregnanolone analogs with higher anti-apoptotic and proliferation-promoting activity than the natural neurosteroid. Interestingly, stereoisomers of the analogs were found to have distinct profiles of activity raising the possibility of exploiting the neuroprotective properties of neurosteroids with or without simultaneously stimulating neurogenesis. Cover Image for this issue: doi: 10.1111/jnc.13344.


Improving the ability of straw biochar to remediate Cd contaminated soil: KOH enhanced the modification of K3PO4 and urea on biochar.
In recent years, the improvement of soil cadmium (Cd) contamination remediation effect of biochar by modification has received wide attention. However, the effect of combined modification on biochar performance in soil Cd contamination remediation and the mechanism are still unclear. In this study, cotton straw biochar and maize straw biochar were co-modified by KOH (0, 3, 5 mol L-1), K3PO4, and urea. Then, two modified biochars with high Cd adsorption capacity were selected to test the soil Cd contamination remediation effect through a pot experiment. The results showed that the combined modification by using KOH, K3PO4, and urea significantly increased the specific surface area and nitrogen (N) and phosphorus (P) contents of biochar, providing more adsorption sites for Cd. Among the modified biochar, the cotton straw biochar modified with KOH (3 mol L-1), K3PO4, and urea (m3-CSB) had the highest adsorption capacity (111.25 mg g-1), which was 7.86 times that of cotton straw biochar (CSB). The m3-CSB for adsorption isotherm and kinetics of Cd conformed to the Langmuir model and Pseudo-second-order kinetic equation, respectively. In the pot experiment, under different exogenous Cd levels (0 (Cd0), 4 (Cd4), and 8 (Cd8) mg kg-1), m3-CSB treatment decreased soil available Cd content the most (51.68%-63.4%) compared with other biochar treatments. Besides, m3-CSB treatment significantly promoted the transformation of acid-soluble Cd to reducible, oxidizable, and residual Cd, reducing the bioavailability of Cd. At the Cd4 level, the application of m3-CSB significantly reduced cotton Cd uptake compared to CK, and the maximum reduction of Cd content in cotton fibers was as high as 81.95%. Therefore, cotton straw biochar modified with KOH (3 mol L-1), K3PO4, and urea has great potential in the remediation of soil Cd contamination.


Non-operative management of acute upper cervical injuries.
The results of a closed, non-operative type of treatment in acute upper cervical injury have been reviewed, especially as they relate to the use of the halo cast or vest. The morbidity with the use of this device has been minimal and there has been no mortality. Early patient mobilization has been readily achieved and in the case of the Hangman's, Jefferson's, and odontoid fractures, stable solid bony healing has been achieved in nearly all cases. Similar results have been noted in the C-1 arch fracture, as well as the acute post-infectious subluxations of C-1/C-2. In a small number of cases involving traumatic C-1/C-2 and occipital/atlas subluxation, there has occurred a significant incidence of instability, despite adequate closed treatment. This has been likely to be due to the serious ligamentous disruption in these cases and it would appear that surgical fusion may be the preferential form of initial treatment in this group of injuries.


Reduced alpha2 power is associated with slowed information processing speed in multiple sclerosis.
Cognitive impairment is common in multiple sclerosis (MS), significantly impacts daily functioning, is time-consuming to assess, and is prone to practice effects. We examined whether the alpha band power measured with magnetoencephalography (MEG) is associated with the different cognitive domains affected by MS. Sixty-eight MS patients and 47 healthy controls underwent MEG, T1- and FLAIR-weighted magnetic resonance imaging (MRI), and neuropsychological testing. Alpha power in the occipital cortex was quantified in the alpha1 (8-10 Hz) and alpha2 (10-12 Hz) bands. Next, we performed best subset regression to assess the added value of neurophysiological measures to commonly available MRI measures. Alpha2 power significantly correlated with information processing speed (p < 0.001) and was always retained in all multilinear models, whereas thalamic volume was retained in 80% of all models. Alpha1 power was correlated with visual memory (p < 0.001) but only retained in 38% of all models. Alpha2 (10-12 Hz) power in rest is associated with IPS, independent of standard MRI parameters. This study stresses that a multimodal assessment, including structural and functional biomarkers, is likely required to characterize cognitive impairment in MS. Resting-state neurophysiology is thus a promising tool to understand and follow up changes in IPS.


Protracted benefit from paradoxical kinesia in typical and atypical parkinsonisms.
Paradoxical kinesia (PK) is the sudden resolution of a previously stabilized akinesia in an advanced idiopathic Parkinson's disease (IPD) patient facing an immediate threat. We are reporting the effect of PK, as a consequence of a life threatening event (earthquake), in a group of 14 patients with parkinsonism and dementia in Hoehn/Yahr (H/Y) stage 3-5. All the patients presented an extraordinary motor response during the earthquake that has recently stricken the Italian city of L'Aquila. All of them were able to safely escape unaided and, in some cases, to assist their families, despite they suffered before from severe night time akinesia and gait difficulties with postural instability requiring assistance. In five patients, the improvement of motor disabilities, particularly of freezing, lasted for 2-5 months.


The influence of sparse data sampling on population pharmacokinetics: a post hoc analysis of a pharmacokinetic study of morphine in healthy volunteers.
Intensive sampling of patients for drugs with complex pharmacokinetic profiles is difficult to perform in the clinic or hospitalized patient setting. We seek to address whether sparse sampling can obtain pharmacokinetic parameter values similar to those with traditional modeling from a post hoc analysis of 2 previous clinical trials. This study investigated whether population-guided, sparse-sampling pharmacokinetic analysis of morphine in 14 healthy volunteers allowed for optimal characterization of concentration-time profiles for a validation population of 5 young male patients receiving morphine. Data were analyzed using nonparametric adaptive grid (NPAG) population modeling to investigate optimal compartmental structure and the influence of sparse sampling (ie, 9 versus 3 samples per subject) on parameter identification. These results were compared with traditional standard 2-stage (STS) pharmacokinetic modeling. The coefficients of determination (R(2)), mean error (ME), and root-mean-square error were used to assess the predictive performance of the various sampling models against a validation population. Seventy-nine percent of the healthy volunteers were male, with a mean age of 36 (17) years and a mean weight of 68 (10) kg. NPAG modeling identified that intravenous morphine was best represented by a 3-compartment pharmacokinetic profile and that sparse sampling with a least 3 blood samples per subject resulted in virtually identical measures of central tendency as the more intensively sampled dataset. A validation cohort of 5 male patients undergoing elective surgery had a mean age of 26 (4) years and a mean weight of 80 (13) kg. Using mean parameter estimates generated from sparse sampling and the 3-compartment model structure, simulated profiles were compared against measured concentrations in this validation cohort. Sparse sampling using NPAG achieved similar values of predictive performance as mean parameter values from the more intensively sampled, with an ME of -1.0 ng/mL and precision of 26.2 ng/mL compared with 0.76 ng/mL and 25.8 ng/mL, respectively. Traditional (STS) modeling techniques resulted in the greatest degree of underprediction within the validation group (ME = 4.43 versus 0.76 ng/mL, STS and NPAG-9, respectively; P < 0.0001). This post hoc analysis suggests that intensive sampling for discerning complex, 3-compartment pharmacokinetic models, such as morphine, may not be necessary. Sparse sampling achieved accurate model structure recognition and parameter identification for predicting concentrations of very complex drug-dosage regimens.


Vaginal fistulas in Crohn's disease.
Twenty-eight patients with vaginal fistulas complicating Crohn's disease, seen between 1970 and 1987, are described. Twelve required early operation; five of them had rectal excision. Conservative management was used in 16 patients but in none of these did the fistula close spontaneously. Subsequent proctocolectomy was required in seven patients though two patients with high vaginal fistulas were managed by total colectomy, end ileostomy, and oversewing of the rectal stump. Only two high fistulas resulting from ileal Crohn's disease resolved with resection and anastomosis of the diseased segment alone. Local repair was unsuccessful despite repeated operations in two of five patients. Two patients died of malignancy arising within a chronic vaginal fistula. Although some vaginal fistulas complicating Crohn's disease cause little disability and can be managed symptomatically, they do not heal by conservative therapy or by a proximal defunctioning stoma alone. In time, severe bowel symptoms develop in the majority of patients and necessitate proctectomy.


Treatment of pharmaceutical wastewater using interior micro-electrolysis/Fenton oxidation-coagulation and biological degradation.
The synthesis of steroid hormones produces wastewater that is difficult to manage and characterize due to its complex components and high levels of toxicity and bio-refractory compounds. In this work, interior micro-electrolysis (IME) and Fenton oxidation-coagulation (FOC) were investigated as wastewater pretreatment processes in combination with biological treatments using a hydrolysis acidification unit (HA) and two-stage biological contact oxidation (BCO) in laboratory and field experiments. In laboratory experiments with an average initial COD load of about 15,000 mg/L, pH of 4, Fe-C/water (V/V) ratio of 1:1, air/water ratio of 10, and reaction time of 180 min, IME achieved a COD removal efficiency of 31.8% and a 1.7-fold increase in the BOD5/COD (B/C) ratio of wastewater. The Fe(2+) concentration of 458.5 mg/L in the IME effluent meets the requirements of the Fenton oxidation (FO) process. FOC further reduced the COD with an efficiency of 30.1%, and the B/C ratio of the wastewater reached 0.59. Excitation-emission matrix (EEM) analysis showed that complex higher molecular weight organic compounds in the wastewater were degraded after the pretreatment process. In addition, a field experiment with a continuous flow of 96 m(3)/d was conducted for over 90 d. The combined process system operated steadily, though the Fe-C fillings should be soaked in a sulfuric acid solution (5‰) for 12 h to recover activity every two weeks. The COD and BOD5 concentrations in the final effluent were less than 90 mg/L and 15 mg/L, respectively.


Cloning and nucleotide sequence of the crtI gene encoding phytoene dehydrogenase from the cyanobacterium Aphanocapsa PCC6714.
The membrane-bound phytoene dehydrogenase (PD) is an enzyme in carotenoid biosynthesis which is essential in all microorganisms and plants containing these colored pigments. Despite its key role in the regulation of carotenogenesis, the biochemistry and molecular biology of PD are poorly understood. We have cloned, sequenced and expressed a portion of the PD-encoding gene, crtI, from the blue-green algae Aphanocapsa PCC6714. The gene codes for a 532-amino acids (aa) protein, with a calculated Mr of 52,598 Da. Two regions of the aa sequence share significant homology with PD from the purple bacterium Rhodobacter capsulatus, including a 30-aa region which has been proposed to be specific for dehydrogenases in carotenoid biosynthesis.


Prophylactic use of levosimendan in preoperative setting for surgical repair of congenital heart disease in children.
Low cardiac output syndrome (LCOS) is a significant cause of morbidity and the leading cause of mortality after pediatric cardiac surgery. Levosimendan has been shown safe and effective in pediatrics to treat LCOS. We aimed to review our local strategy with preoperative prophylactic Levosimendan infusion to minimize LCOS after heart surgery in identified high-risk patients. Retrospective monocentric study. As there is no reliable cardiac output measurement in children, we recorded hemodynamic parameters as surrogates of cardiac output after extracorporeal circulation through an electronic patient survey system at different time points. Seventy-two children received Levosimendan before surgery between 2010 and 2019. As expected, most patients were newborns and infants with prolonged open-heart surgeries. Median cardiopulmonary bypass time was 182 [137-234] min, and aortic clamping time was 95 [64-126] min. The postoperative hemodynamic parameters, vasoactive-inotropic score, and urine output remained stable throughout the first 48 h. Only a tiny portion of the patients had combined surrogate markers of LCOS with a maximal median arterial lactate of 2.6 [1.9-3.5] mmol/L during the first six postoperative hours, which then progressively normalized. The median arterio-venous difference in oxygen saturation was 31 [23-38] % between 12 and 18 h post-surgery and gradually decreased. The median venous-to-arterial CO2 difference was the highest at 10 [7-12] mmHg between 12 and 18 h post-surgery. Nine patients (13%) required extracorporeal membrane oxygenation. No patient required dialysis or hemofiltration. Mortality was 0%. Before congenital heart surgery, preoperative prophylactic administration of Levosimendan seems effective and safe for decreasing occurrence and duration of LCOS in high-risk children.


Cold nebulization used to prevent heat loss during laparoscopic surgery: an experimental study in pigs.
Prolonged abdominal laparoscopy is responsible for a significant drop in core body temperature. Various modifications of the conditioning for the insufflating carbon dioxide (CO(2)) to prevent the specific hypothermia related to the insufflated gas have been tested. This study aimed to investigate the effects on core temperature of insufflation with unheated humidified CO(2) using the Aeroneb system compared with the use of standard gas and gas made hot and wet using a warming and humidifying system (Pall system). A prospective four-session study was conducted to investigate a homogeneous group of four pigs. After inducation of general anesthesia, all the animals were treated successively with the following protocols in a randomized order at 8-day intervals: control (no pneumoperitoneum), standard (unheated, unhumidified CO(2)), Aeroneb (unheated, humidified CO(2) by cold nebulization), and Pall (heated, humidified CO(2)). The core temperature of the animals was recorded every 10 min. Analysis of variance (ANOVA) confirmed a difference between the insufflation conditions in the evolution of temperature over time (p = 0.004). The method of contrast showed the following results. After 30 min, the core temperature of the Aeroneb group fell significantly less than that of the standard group (p = 0.036). After 100 min, the core temperature of the Pall group fell significantly less than that of the standard group (p = 0.024). After 80 min, the core temperature of the standard group fell significantly more than that of the control group (p = 0.035). In the Aeroneb group, the core temperature dropped less than in the Pall and control groups, but the difference did not reach statistical significance. Cold humidification of insufflating CO(2) prevents heat loss associated with pneumoperitoneal insufflation at least as efficaciously as warmed humidification of the gas.


Retrograde Trans-Amputation Embolectomy of Common, Superficial and Deep Femoral Arteries for Inflow Revascularisation During Above-Knee Amputation: A Case Report and Review of the Literature.
Primary above-knee amputation (AKA) may at times be the only option for unsalvageable acute lower limb ischemia. However, occlusion of the femoral arteries may result in poor inflow and contribute to wound complications such as stump gangrene and sepsis. Previously attempted inflow revascularisation techniques include surgical bypass and percutaneous angioplasty and/or stenting. We present a case of a 77-year-old lady with unsalvageable acute right lower limb ischemia secondary to cardioembolic occlusion of the common (CFA), superficial (SFA) and deep (PFA) femoral arteries. We performed a primary AKA with inflow revascularisation using a novel surgical technique involving endovascular retrograde embolectomy of the CFA, SFA and PFA via the SFA stump. The patient made an uneventful recovery without any wound complications. Detailed description of the procedure is followed by a discussion of the literature on inflow revascularisation in the treatment and prevention of stump ischemia.


A Compositional Analysis of Physical Activity, Sedentary Time, and Sleep and Associated Health Outcomes in Children and Adults with Cystic Fibrosis.
This study sought to investigate the association of light physical activity (LPA), moderate-to-vigorous physical activity (MVPA), sedentary time (SED), and sleep with lung function in children and adults with CF. In total, 86 children (41 females; 13.6 ± 2.8 years; FEV1%predicted: 86 ± 1%) and 43 adults (21 females; 24.6 ± 4.7 years; FEV1%predicted: 63 ± 21%) with CF participated in this study. Wrist-worn accelerometery was used to assess PA, SED and sleep. Compositional linear regression models were conducted following normalisation via isometric log-ratio transformations. Sequential binary partitioning was applied to investigate the impact of reallocating 10 to 30 min between each behaviour on FEV1%predicted. A decline in FEV1%predicted was predicted with the reallocation of 30 min from MVPA to SED or LPA or sleep to any other behaviour in children (-3.04--0.005%) and adults (-3.58--0.005%). Conversely, improvements in FEV1%predicted were predicted when 30 min was reallocated to MVPA from LPA or SED in children (0.12-1.59%) and adults (0.77-2.10%), or when 30 min was reallocated to sleep from any other behaviour in both children (0.23-2.56%) and adults (1.08-3.58%). This study supports the importance of MVPA and sleep for maintaining and promoting lung function in people with CF.


In vitro human osteoblast and extracellular matrix changes after transforming growth factor beta 1 treatment.
Normal bone tissue is characterised by a balancing of osteoblast and osteoclast activity. The activity and differentiation of these cells are regulated by vitamins, hormones and cytokines. The action of these factors on bone tissue cells depends on the composition and mineralisation of extracellular bone matrix. In particular, transforming growth factor beta 1 (TGFbeta1) acts on collagen fibres, glycosaminoglycan secretion and on the enzymes correlated to the turnover of glycosaminoglycans. The normal functions of bone tissue also depend on its mineralisation, which is highly altered in the process of uraemia. In this study, we analysed in vitro the effect of transforming growth factor beta on osteoblast proliferation, collagen synthesis and glycosaminoglycan secretion with 3H-thymidine, 3H-proline or 3H-glucosamine incorporation, and on enzymes, such as beta-N-acetyl-D-glucosaminidase and beta-glucuronidase, involved in extracellular matrix turnover. Moreover, phosphatase alkaline activity and osteocalcin related to mineralisation of extracellular matrix were determined. Our data show that TGFbeta1 significantly decreases 3H-thymidine and 3H-proline incorporation and increases (p < or = 0.01) extracellular sulphated glycosaminoglycan synthesis. It also increases osteocalcin levels, phosphatase alkaline, beta-N-acetyl-D-glucosaminidase and beta-glucoronidase activities. TGFbeta1 changes the synthesis of extracellular matrix components by osteoblasts. These variations favour the action of cytokine and osteoclasts. Since the TGFbeta1 accumulates in bone tissue and increases during uraemia, with due limitations this action leads to an imbalance between synthesis and degradation and could explain bone alterations in uraemic patients.


Predicting maternal healthcare seeking behaviour in Afghanistan: exploring sociodemographic factors and women's knowledge of severity of illness.
Little is known whether women's knowledge of perceived severity of illness and sociodemographic characteristics of women influence healthcare seeking behavior for maternal health services in Afghanistan. The aim of this study was to address this knowledge gap. Data were used from the Afghanistan Health Survey 2018. Women's knowledge in terms of danger signs or symptoms during pregnancy was assessed. The signs or symptoms were bleeding, swelling of the body, headache, fever, or any other danger sign or symptom (e.g., high blood pressure). A categorical variable of knowledge score was created. The outcome variables were defined as ≥ 4 ANC vs. 0-3 ANC; ≥ 4 PNC vs. 0-3 PNC visits; institutional vs. non-institutional deliveries. A multivariable generalized linear model (GLM) was used. Data were used from 9,190 ever-married women, aged 13-49 years, who gave birth in the past two years. It was found that 56%, 22% and 2% of women sought healthcare for institutional delivery, ≥ 4 ANC, ≥ 4 PNC visits, respectively, and that women's knowledge is a strong predictor of healthcare seeking [odds ratio (OR)1.77(1.54-2.05), 2.28(1.99-2.61), and 2.78 (2.34-3.32) on knowledge of 1, 2, and 3-5 signs or symptoms, respectively, in women with ≥ 4 ANC visits when compared with women who knew none of the signs or symptoms. In women with ≥ 4 PNC visits, it was 1.80(1.12-2.90), 2.22(1.42-3.48), and 3.33(2.00-5.54), respectively. In women with institutional deliveries, it was 1.49(1.32-1.68), 2.02(1.78-2.28), and 2.34(1.95-2.79), respectively. Other strong predictors were women's education level, multiparity, residential areas (urban vs. rural), socioeconomic status, access to mass media (radio, TV, the internet), access of women to health workers for birth, and decision-making for women where to deliver. However, age of women was not a strong predictor. Our findings suggest that pregnant women's healthcare seeking behaviour is influenced by women's knowledge of danger signs and symptoms during pregnancy, women's education, socioeconomic status, access to media, husband's, in-laws' and relatives' decisions, residential area, multiparity, and access to health workers. The findings have implications for promoting safe motherhood and childbirth practices through improving women's knowledge, education, and social status.


Photodynamic action of chlorpromazine on adenovirus 5:repairable damage and single strand breaks.
Chlorpromazine, a substituted phenothiazine, commonly used as a sedative, has been found to photosensitize the inactivation of human adenovirus 5 to wavelengths of light between 330 and 390 nm. The slope of the inactivation curve is three fold greater when fibroblasts from people having xeroderma pigmentosum (XP) were used as viral hosts than when normal fibroblasts were used, showing that at least two-thirds of the damage produced in the virions is repairable by normal human fibroblasts. The phototreatment of chlorpromazine sensitized virions also results in the production of DNA strand breaks, which correlate fairly well with the production of lethal viral damage as measured in XP fibroblasts. These findings suggest that the photosensitization of the skin observed in patients treated with chlorpromazine might be due to DNA damage.


Fibrin but not adsorbed fibrinogen supports fibronectin assembly by spread platelets. Effects of the interaction of alphaIIb beta3 with the C terminus of the fibrinogen gamma-chain.
We investigated the assembly of soluble fibronectin by lysophosphatidic acid-activated platelets adherent to fibrinogen or fibrin. More fibronectin was assembled by activated platelets spread on fibrin matrices than by platelets spread on adsorbed fibrinogen. The difference between platelets adherent to fibrinogen and fibrin occurred under both static and flow conditions. Similar differences were seen in binding of the 70-kDa N-terminal fragment of fibronectin that recognizes fibronectin assembly sites on adherent cells. Antibody and peptide blocking studies demonstrated that alphaIIb beta3 integrin mediates platelet adhesion to fibrinogen, whereas both alphav beta3 and alphaIIb beta3 mediate platelet adhesion to fibrin. The hypothesis that engagement of the C-terminal QAGDV sequence of the fibrinogen gamma-chain by alphaIIb beta3 inhibits the ability of the platelet to assemble fibronectin was tested by several experiments. Activated platelets adherent to adsorbed mutant fibrinogen lacking the QAGDV sequence (gammadelta5FG) were assembly-competent, as were platelets adherent to adsorbed normal fibrinogen that had been pretreated with the 7E9 antibody to the C terminus of the gamma-chain. Moreover, adsorbed normal fibrinogen but not gammadelta5FG suppressed the ability of co-adsorbed fibronectin to direct assembly of soluble fibronectin by spread platelets. The suppressive effect was lost when a surface of co-adsorbed fibronectin and fibrinogen was pretreated with 7E9. These results support a model in which the engagement of alphaIIb beta3 by the C-terminal sequence of the fibrinogen gamma-chain initiates signals that suppress subsequent fibronectin assembly by spread platelets. This interaction is less dominant when platelets adhere to fibrin, resulting in enhanced fibronectin assembly.


A standardized method for computed tomography of the orbits.
A standardized method for the CT exploration of the orbital region has been searched for. This method makes it possible to visualize the entire orbital region with a minimum of 4 tomographic scans, each section 6 mm thick. The reference line chosen for this exploration is parallel to the optic nerve and joins the projection of the inferior border of the orbit on the lateral view with the upper border of the ear to the scalp. After each tomographic scan the patient is moved so that the new scanning line is still parallel to the reference line but distant by 9 mm from the previous one.


Lithium intoxication-induced dysgeusia accompanied by glossalgia in a patient receiving lithium carbonate: a case report.
Lithium carbonate is widely used as a first-line therapeutic agent for the depressive and manic phases of bipolar disorder. Although limb tremors and hypothyroidism are well-known side effects of lithium carbonate, other rare adverse reactions can also occur. A 53-year-old Japanese woman diagnosed with lithium intoxication developed dysgeusia and glossalgia during treatment with lithium carbonate. She also showed symptoms of a swaying gait, finger tremors, and dysarthria. All of these symptoms subsided when her blood lithium concentration was reduced to a level below that which induces intoxication. We present a rare case of lithium carbonate-induced dysgeusia accompanied by glossalgia. Early detection of these symptoms is important in clinical settings because they can be overlooked until patients lose their appetite, which severely impairs their quality of life.


Comparison of the effects of nitric oxide donors and calcium channel blockers on the intrinsic myogenic tone of sheep isolated internal anal sphincter.
Chronic anal fissure is associated with considerable pain and anal hypertonia. Numerous clinical studies attest to the effectiveness of individual nitro-containing drugs and organic calcium channel blockers in this condition but there are few comparative studies. Isolated segments of sheep internal anal sphincter were prepared for isometric tension recording. The effect of various drugs on myogenic tone was examined in the absence or presence of sodium orthovanadate (SOV), an agent used to mimic anal hypertonia by increasing myogenic tone. All the drugs tested produced concentration-dependent inhibition of myogenic tone, with the maximum effect ranging from 66.4 per cent (verapamil) to 100 per cent (sodium nitroprusside). Sodium nitroprusside and diltiazem were the most potent, followed by glyceryl trinitrate (GTN), nifedipine and verapamil, which had similar potency, and finally nicorandil. The potency of GTN and diltiazem was reduced threefold in the presence of 1 mmol/l SOV. The combined effect of GTN and diltiazem was greater than the effect of either agent alone, even in the presence of 3 mmol/l SOV. Nitro-containing drugs and organic calcium channel blockers are potent inhibitors of anal sphincter myogenic tone that may be used in combination to treat chronic anal fissure.


Serum immunoreactive relaxin in women during a 24-h period.
Serum relaxin concentrations were measured every 30 min during a 24-h period in nonpregnant and pregnant women. Relaxin was undetectable in all serum samples obtained from 3 nonpregnant women. Relaxin was detectable in all serum samples obtained from 2 pregnant women. However, neither episodic secretion of relaxin nor a 24-h rhythm in relaxin secretion was discernible in these women.


Gadoxetate-enhanced dynamic contrast-enhanced MRI for evaluation of liver function and liver fibrosis in preclinical trials.
To facilitate translational drug development for liver fibrosis, preclinical trials need to be run in parallel with clinical research. Liver function estimation by gadoxetate-enhanced dynamic contrast-enhanced MRI (DCE-MRI) is being established in clinical research, but still rarely used in preclinical trials. We aimed to evaluate feasibility of DCE-MRI indices as translatable biomarkers in a liver fibrosis animal model. Liver fibrosis was induced in Sprague-Dawley rats by thioacetamide (200 mg, 150 mg, and saline for the high-dose, low-dose, and control groups, respectively). Subsequently, DCE-MRI was performed to measure: relative liver enhancement at 3-min (RLE-3), RLE-15, initial area-under-the-curve until 3-min (iAUC-3), iAUC-15, and maximum-enhancement (Emax). The correlation coefficients between these MRI indices and the histologic collagen area, indocyanine green retention at 15-min (ICG-R15), and shear wave elastography (SWE) were calculated. Diagnostic performance to diagnose liver fibrosis was also evaluated by receiver-operating-characteristic (ROC) analysis. Animal model was successful in that the collagen area of the liver was the largest in the high-dose group, followed by the low-dose group and control group. The correlation between the DCE-MRI indices and collagen area was high for iAUC-15, Emax, iAUC-3, and RLE-3 but moderate for RLE-15 (r, - 0.81, - 0.81, - 0.78, - 0.80, and - 0.51, respectively). The DCE-MRI indices showed moderate correlation with ICG-R15: the highest for iAUC-15, followed by iAUC-3, RLE-3, Emax, and RLE-15 (r, - 0.65, - 0.63, - 0.62, - 0.58, and - 0.56, respectively). The correlation coefficients between DCE-MRI indices and SWE ranged from - 0.59 to - 0.28. The diagnostic accuracy of RLE-3, iAUC-3, iAUC-15, and Emax was 100% (AUROC 1.000), whereas those of RLE-15 and SWE were relatively low (AUROC 0.777, 0.848, respectively). Among the gadoxetate-enhanced DCE-MRI indices, iAUC-15 and iAUC-3 might be bidirectional translatable biomarkers between preclinical and clinical research for evaluating histopathologic liver fibrosis and physiologic liver functions in a non-invasive manner.


Laparoscopic pyeloplasty for ureteropelvic junction obstruction of the lower moiety in a completely duplicated collecting system: a case report.
There are only a few reports on laparoscopic pyeloplasty in kidney abnormalities and only one case for laparoscopic pyeloplasty in a duplicated system. Increasing experience in laparoscopic techniques allows proper treatment of such anomalies. However, its feasibility in difficult cases with altered kidney anatomy such as that of duplicated renal pelvis still needs to be addressed. We present a case of a 22-year-old white Caucasian female patient with ureteropelvic junction obstruction of the lower ureter of a completely duplicated system that was managed with laparoscopic pyeloplasty. Crossing vessels were identified and transposed. The procedure was carried out successfully and the patient's symptoms subsided. Follow-up studies demonstrated complete resolution of the obstruction. Since laparoscopic pyeloplasty is still an evolving procedure, its feasibility in complex cases of kidney anatomic abnormalities is herein further justified.


Cilostazol attenuates cardiac oxidative stress and inflammation in hypercholesterolemic rats.
Atherosclerosis is a multifactorial chronic disease associated with pro-inflammatory and pro-oxidative cardiovascular states. Cilostazol, a selective phosphodiesterase 3 inhibitor (PDE3), is clinically used in the treatment of intermittent claudication and secondary prevention of cerebral infarction. The aim of this study was to evaluate the cardioprotective effects of cilostazol and the molecular mechanisms involved in hypercholesterolemic rats. Male Wistar rats were divided into four groups: control group (C) and control + cilostazol group (C+CILO), that were fed a standard chow diet, and hypercholesterolemic diet group (HCD) and HCD + cilostazol (HCD+CILO) that were fed a hypercholesterolemic diet. Cilostazol treatment started after 30 days for C+CILO and HCD+CILO groups. Animals were administered cilostazol once a day for 15 days. Subsequently, serum and left ventricles were extracted for evaluation of lipid profile, inflammatory, and oxidative biomarkers. The HCD group displayed increased serum lipid levels, inflammatory cytokines production, and cardiac NF-kB protein expression and decreased cardiac Nrf2-mediated antioxidant activity. Conversely, the cilostazol treatment improved all these cardiac deleterious effects, inhibiting NF-kB activation and subsequently decreasing inflammatory mediators, reestablishing the antioxidant properties through Nrf2-mediated pathway, including increased SOD, GPx, and catalase expression. Taken together, our results indicated that cilostazol protects hypercholesterolemia-induced cardiac damage by molecular mechanisms targeting the crosstalk between Nrf2 induction and NF-kB inhibition in the heart.


"Not just eliminating the mosquito but draining the swamp": A critical geopolitics of Turkish Monitoring Center for Drugs and Drug Addiction and Turkey's approach to illicit drugs.
In the 1970s, Turkey ceased to be a significant producer state of illicit drugs, but it continued to serve as a key route for the trade of drugs between East and West. Over the past decade, however, authorities identified two concerns beyond its continued transit state status. These reported problems entail both new modes of production and a rising incidence of drug abuse within the nation-state - particularly among its youth. Amid these developments, new law enforcement institutions emerged and acquired European sponsorship, leading to the establishment of TUBİM (the Turkish Monitoring Center for Drugs and Drug Addiction). Coordinating with and reporting to the European Union agency EMCDDA (the European Monitoring Center for Drugs and Drug Addiction), TUBİM's primary assigned duties entail the collection and analysis of data on drug abuse, trafficking, and prevention, the geographic identification of sites of concern (e.g. consumption, drug-related crimes, and peoples undergoing treatment), and the production of annual national reports. In this article, we examine the geopolitical origins of TUBİM as Turkey's central apparatus for confronting drug problems and its role as a vehicle for policy development, interpretation, and enforcement. In doing so, we emphasize the political and spatial dimensions inherent to the country's institutional and policy-driven approaches to contend with drug-related problems, and we assess how this line of attack reveals particular ambiguities in mission when evaluated from scales at world regional, national, and local levels. In sum, we assess how Turkey's new institutional and legislative landscapes condition the state's engagements with drug use, matters of user's health, and policy implementation at local scales and amid ongoing political developments.


Developmental processes regulate craniofacial variation in disease and evolution.
Variation in development mediates phenotypic differences observed in evolution and disease. Although the mechanisms underlying phenotypic variation are still largely unknown, recent research suggests that variation in developmental processes may play a key role. Developmental processes mediate genotype-phenotype relationships and consequently play an important role regulating phenotypes. In this review, we provide an example of how shared and interacting developmental processes may explain convergence of phenotypes in spliceosomopathies and ribosomopathies. These data also suggest a shared pathway to disease treatment. We then discuss three major mechanisms that contribute to variation in developmental processes: genetic background (gene-gene interactions), gene-environment interactions, and developmental stochasticity. Finally, we comment on evolutionary alterations to developmental processes, and the evolution of disease buffering mechanisms.


Systemic cancer metastasis in a meningioma: report of two cases and review of the literature.
"Tumour-to-tumour" phenomenon is a rare event; meningioma has been reported as the most common primary intracranial tumour to harbour metastases, the majority of which arise from breast and lung carcinomas. Several hypotheses have been previously proposed to explain this occurrence, but the exact mechanisms responsible for the development of metastases in meningiomas are not known. Magnetic resonance imaging (MRI) and spectroscopy could be useful to hypothesize this uncommon event, but its preoperative diagnosis remains highly difficult. Two patients are reported, with breast and renal carcinoma metastases in an intracranial meningioma. Pathogenetic mechanisms and neuroimaging features are discussed. A brief review of the literature is presented.


Regulation of chemosensory receptor expression and sensory signaling by the KIN-29 Ser/Thr kinase.
Sensory signals regulate multiple developmental and behavioral circuits in C. elegans, providing a genetically tractable system in which to investigate the mechanisms underlying the acquisition and integration of sensory information. kin-29 mutants are defective in the expression of a set of chemoreceptor genes, and exhibit characteristics associated with altered sensory signaling, including increased lifespan, decreased body size, and deregulated entry into the dauer developmental stage. kin-29 encodes a Ser/Thr kinase with similarity to the MARK and AMPK/SNF1 family of kinases. We show that KIN-29 acts cell-autonomously and non-cell-autonomously in sensory neurons to regulate chemoreceptor expression, body size, and the dauer decision, suggesting that kin-29 function is essential for the correct acquisition and transduction of sensory information.


Crude liver membrane fractions as substrate preserve liver-specific functions in long-term, serum-free rat hepatocyte cultures.
Over time, rat hepatocytes cultured on collagen lose the capacity to express liver-specific functions. The influence on this degradation process of an alternative substratum--crude membrane fractions prepared from the liver of the same rat strain--was investigated. Freshly isolated rat hepatocytes were cultured in serum-free Williams E medium supplemented with aprotinin, selenium, dexamethasone, and insulin in flasks coated with a mixture of rat liver crude membrane fractions:collagen type I (100:1). The cells adhered firmly, exhibiting minimal spreading and remaining grouped in columns or in cell islands, and retained their liver-specific functions for more than 1 wk. Hepatocytes secreted substantially higher amounts of albumin than cells cultured on collagen-coated dishes, and on Days 1 and 9 in culture the total P-450 content was 72 and 40%, respectively, of that of freshly isolated cells. On Day 6, the 7-ethoxyresorufin-O-deethylase and the aldrin epoxidase activities were still more than 50% that of freshly isolated hepatocytes. Exposure to phenobarbital on Days 3 to 6 increased the total cytochrome P-450 content twofold; exposure to 3-methylcholanthrene increased the activity of the corresponding cytochrome P-450 isoforms to 20 times that observed in untreated cultures and 6 times that observed in freshly isolated cells. Thus, given the ease with which they are prepared, the use of crude membrane fractions combined with culture medium supplemented with aprotinin and selenium can facilitate the preparation of reproducible cultures suitable for long-term in vitro pharmacotoxicologic studies using rat hepatocytes.


CircPOLR2A Promotes Proliferation and Impedes Apoptosis of Glioblastoma Multiforme Cells by Up-regulating POU3F2 to Facilitate SOX9 Transcription.
Glioblastoma multiforme (GBM) is the most common cancer in nervous system around the world. Little advancement has been achieved in promoting prognosis of GBM patients. Circular RNAs (circRNAs) are suggested as crucial effectors in modulating GBM development. Hsa_circRNA_092437 (circPOLR2A), an up-regulated circRNA in GBM cells, has not been studied yet. In this study, RT-qPCR and western blot assays were applied to detect RNA and protein levels. Cell proliferation and apoptosis were analyzed via functional assays. Subcellular fractionation assay was carried out to determine circPOLR2A distribution in cells. Bioinformatics analysis and mechanism assays were done for detecting relationships among different factors. Rescue assays were performed to confirm validity of circPOLR2A/SOX9 axis. According to experimental results, circPOLR2A was up-regulated in GBM cells and promoted GBM cell proliferation while inhibiting GBM cell apoptosis. CircPOLR2A mainly existed in cell cytoplasm and sponged miR-2113 to positively regulate POU3F2 expression. POU3F2 activated the transcription of SOX9 through interacting with SOX9 promoter (1-500). Rescue assays validated that circPOLR2A influenced GBM cell proliferation and apoptosis via SOX9. To conclude, circPOLR2A enhanced the transcription of SOX9 through miR-2113/POU3F2 axis, thus exacerbating GBM cells growth.


High performance liquid chromatography-charged aerosol detection applying an inverse gradient for quantification of rhamnolipid biosurfactants.
A method using high performance liquid chromatography coupled to charged-aerosol detection (HPLC-CAD) was developed for the quantification of rhamnolipid biosurfactants. Qualitative sample composition was determined by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The relative quantification of different derivatives of rhamnolipids including di-rhamnolipids, mono-rhamnolipids, and their precursors 3-(3-hydroxyalkanoyloxy)alkanoic acids (HAAs) differed for two compared LC-MS instruments and revealed instrument dependent responses. Our here reported HPLC-CAD method provides uniform response. An inverse gradient was applied for the absolute quantification of rhamnolipid congeners to account for the detector's dependency on the solvent composition. The CAD produces a uniform response not only for the analytes but also for structurally different (nonvolatile) compounds. It was demonstrated that n-dodecyl-β-d-maltoside or deoxycholic acid can be used as alternative standards. The method of HPLC-ultra violet (UV) detection after a derivatization of rhamnolipids and HAAs to their corresponding phenacyl esters confirmed the obtained results but required additional, laborious sample preparation steps. Sensitivity determined as limit of detection and limit of quantification for four mono-rhamnolipids was in the range of 0.3-1.0 and 1.2-2.0μg/mL, respectively, for HPLC-CAD and 0.4 and 1.5μg/mL, respectively, for HPLC-UV. Linearity for HPLC-CAD was at least 0.996 (R(2)) in the calibrated range of about 1-200μg/mL. Hence, the here presented HPLC-CAD method allows absolute quantification of rhamnolipids and derivatives.


Quantitative analysis of the intra-beam respiratory motion with baseline drift for respiratory-gating lung stereotactic body radiation therapy.
This study aimed to quantitatively clarify the baseline drift for each respiratory cycle in two respiratory-gating methods using the intra-beam respiratory motion data of lung cancer patients. The residual motion and dose distribution were calculated based on intra-beam respiratory motion data with the baseline drift. To quantify the baseline drift $\Delta$ during irradiation, it was defined as the inclination between the detected expiration point and the expiration point in the next cycle in the anterior-posterior (AP), cranial-caudal (CC) and left-right (LR) directions obtained using an in-house programme. The baseline drift value reached up to 0.74 mm/s in the CC direction as per the respiratory motion data of 10 patients. The homogeneity index (HI) of the phase-gating method tended to increase because the target was irradiated even when the amplitude position of the target differed from period to period. In contrast, the amplitude-gating method enabled irradiation considering the amplitude position of the target because the gating window was set considering the amplitude position of the respiratory motion. The respiratory-gating methods and respiratory phase in respiratory-gating lung stereotactic body radiation therapy (SBRT) must be determined based on the respiratory motion of the patients.


Developmental toxicity assessment of arsenic acid in mice and rabbits.
To evaluate potential effects of exposure to inorganic arsenic throughout major organogenesis, CD-1 mice and New Zealand White rabbits were gavaged with arsenic acid dosages of 0, 7.5, 24, or 48 mg/kg/d on gestation days (GD) 6 through 15 (mice) or 0, 0.19, 0.75, or 3.0 mg/kg/d on GD 6 through 18 (rabbits) and examined at sacrifice (GD 18, mice; GD 29, rabbits) for evidence of toxicity. Two high-dose mice died, and survivors at the high and intermediate doses had decreased weight gains. High-dose-group fetal weights were decreased; no significant decreases in fetal weight or increases in prenatal mortality were seen at other dosages. Similar incidences of malformations occurred in all groups of mice, including controls. At the high dose in rabbits, seven does died or became moribund, and prenatal mortality was increased; surviving does had signs of toxicity, including decreased body weight. Does given lower doses appeared unaffected. Fetal weights were unaffected by treatment, and there were no effects at other doses. These data revealed an absence of dose-related effects in both species at arsenic exposures that were not maternally toxic. In mice, 7.5 mg/kg/d was the maternal No-Observed-Adverse-Effect-Level (NOAEL); the developmental toxicity NOAEL, while less well defined, was judged to be 7.5 mg/kg/d. In rabbits, 0.75 mg/kg/d was the NOAEL for both maternal and developmental toxicity.


Thallium stable isotope fractionation in white mustard: Implications for metal transfers and incorporation in plants.
We studied thallium (Tl) isotope fractionation in white mustard grown hydroponically at different Tl doses. Thallium isotope signatures in plants indicated preferential incorporation of the light 203Tl isotope during Tl uptake from the nutrient solution. Negative isotope fractionation was even more pronounced in dependence on how much the available Tl pool decreased. This finding corresponds to the concept of isotope overprinting related to a high contamination level in the growing media (solution or soil). Regarding Tl translocation in plants, we observed a large Tl isotope shift with an enrichment in the heavy 205Tl isotope in the shoots relative to the roots in treatments with low/moderate solution Tl concentrations (0.01/0.05 mg Tl/L), with the corresponding α205/203Tl fractionation factors of ˜1.007 and 1.003, respectively. This finding is probably a consequence of specific (plant) reactions of Tl replacing K in its cycle. The formation of the S-coordinated Tl(I) complexes, potentially affecting both Tl accumulation and Tl isotope fractionation in plants, however, was not proven in our plants, since we did not have indication for that on the basis of X-ray absorption spectroscopy, suggesting that Tl was mainly present as free/hydrated Tl+ ion or chemically bound to O-containing functional groups.


Mechanically induced formation and maturation of 3D-matrix adhesions (3DMAs) in human mesenchymal stem cells.
Mechanical signal is important for regulating stem cell fate, but the molecular mechanisms involved are unclear. Cell-matrix adhesions are important molecular mechanosensors that their formation and maturation are force-dependent processes. However, most studies focused on the role of cell contractility or substrate stiffness in these processes. How external mechanical force stimulates the formation and maturation of cell-matrix adhesions is largely unknown. Here, by using human mesenchymal stem cells (hMSCs)-collagen microtissues as a 3D model, we found that upon short-term dynamic compression, integrin αV binding, focal adhesion formation, and subsequent FAK activation, are stimulated. This compression-stimulated FAK signaling also leads to YAP activation, suggesting crosstalk between integrin-based signaling and mechanosensing. More importantly, long-term compression induces maturation of α5-integrin based adhesions to form long, slender 3D-matrix adhesions (3DMAs), which are distinct from 2D focal adhesions in composition and morphology and previously found only in cell-derived matrices and native tissues. Mechanical preconditioning hMSCs with long-term compression loading induces the formation of mature integrin α5-dependent 3DMAs and potentiates their osteogenesis. Collectively, this work shows that active mechanical stimulation can modulate cell-matrix interactions significantly at the cell-material interfaces in a dynamic manner, and affects cell fate decisions, demonstrating the significance of loading-based functional tissue engineering.


Practice nurse health checks for adults with intellectual disabilities: a cluster-design, randomised controlled trial.
Adults with intellectual disabilities have substantial health inequalities and poor access to health care. We assessed whether practice nurse-delivered health checks could improve the health of adults with intellectual disabilities compared with standard care. In this cluster-design, single-blind, randomised controlled trial, we included general practices in Scotland, UK. From June to December, 2011, we randomly assigned (1:1) these general practices to either health checks plus standard care (health-checks group), or standard care only (control group), and we recruited the patients from these practices. Randomisation was done with stratification by number of GPs per practice and number of registered patients with intellectual disabilities (<20 or ≥20). Two research assistants were masked to allocation, and undertook the review of 9 month medical records and interviews. Participants and carers were not masked. The intervention was one health check designed especially for people with intellectual disabilities delivered by a practice nurse. The objective was improvement in health and health care 9 months after randomisation, and the primary outcome was the incidence of newly detected health needs being met by this timepoint. Whether needs were met was established by the investigators being masked to group allocation. The analysis was by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN43324841. Between June 26 and Dec 20, 2011, we recruited 38 practices. 85 participants (from 16 practices) were randomly assigned to intervention and 67 (from 17 practices) to standard care; five of the identified practices did not supply any participants. 83 intervention and 66 standard care participants completed the trial. More newly detected health needs were met in the intervention group than in the control standard care group (median 1 [range 0-8], 76·4% met [SD 36·5] vs 2 [0-11], 72·6% met [35·4]; odds ratio [OR] 1·73 [95% CI 0·93-3·22], p=0·085), although this difference was not significant. Significantly more health monitoring needs were met in the intervention group than standard care (median 2 [0-20], 69·9% [SD 34·2] vs 2 [0-22], 56·8% [29·4], OR 2·38 [95% CI 1·31-4·32, p=0·0053]). The probability that health checks are cost effective was between 0·6 and 0·8, irrespective of the cost-effectiveness threshold level. Costs per patient were -£71·48 for health checks and -£20·56 for standard care. The difference (-£50·92) was not significant [95% CI -434 to 362]. No adverse events were attributable to the intervention. Health checks given by practice nurses to adults with intellectual disabilities produced health-care improvements that were more conducive to longer-term health than standard care given to this population. The intervention dominated standard care, being both cheaper and more effective. Health-check programmes might therefore be indicated for adults with intellectual disabilities. Scottish Government Change Fund, NHS Greater Glasgow and Clyde Research and Development.


Amelioration of neuronal cell death in a spontaneous obese rat model by dietary restriction through modulation of ubiquitin proteasome system.
Dietary restriction (DR) has been shown to increase longevity, delay onset of aging, reduce DNA damage and oxidative stress and prevent age-related decline of neuronal activity. We previously reported the role of altered ubiquitin proteasome system (UPS) in the neuronal cell death in a spontaneous obese rat model (WNIN/Ob rat). In this study, we investigated the effect of DR on obesity-induced neuronal cell death in a rat model. Two groups of 40-day-old WNIN/Ob rats were either fed ad libitum (Ob) or pair-fed with lean. The lean phenotype of WNIN/Ob rats served as ad libitum control. These animals were maintained for 6.5months on their respective diet regime. At the end of the study, cerebral cortex was collected and markers of UPS, endoplasmic reticulum (ER) stress and autophagy were analyzed by quantitative real-time polymerase chain reaction, immunoblotting and immunohistochemistry. Chymotrypsin-like activity of proteasome was assayed by the fluorimetric method. Apoptotic cells were analyzed by TUNEL assay. DR improved metabolic abnormalities in obese rats. Alterations in UPS (up-regulation of UCHL1, down-regulation of UCHL5, declined proteasomal activity), increased ER stress, declined autophagy and increased expression of α-synuclein, p53 and BAX were observed in obese rats and DR alleviated these changes in obese rats. Further, DR decreased TUNEL-positive cells. In conclusion, DR in obese rats could not only restore the metabolic abnormalities but also preserved neuronal health in the cerebral cortex by preventing alterations in the UPS.


Impact of metals in surface matrices from formal and informal electronic-waste recycling around Metro Manila, the Philippines, and intra-Asian comparison.
We report concentrations, enrichment factors, and hazard indicators of 11 metals (Ag, As, Cd, Co, Cu, Fe, In, Mn, Ni, Pb, and Zn) in soil and dust surface matrices from formal and informal electronic waste (e-waste) recycling sites around Metro Manila, the Philippines, referring to soil guidelines and previous data from various e-waste recycling sites in Asia. Surface dust from e-waste recycling sites had higher levels of metal contamination than surface soil. Comparison of formal and informal e-waste recycling sites (hereafter, "formal" and "informal") revealed differences in specific contaminants. Formal dust contained a mixture of serious pollutant metals (Ni, Cu, Pb, and Zn) and Cd (polluted modestly), quite high enrichment metals (Ag and In), and crust-derived metals (As, Co, Fe, and Mn). For informal soil, concentration levels of specific metals (Cd, Co, Cu, Mn, Ni, Pb, and Zn) were similar among Asian recycling sites. Formal dust had significantly higher hazardous risk than the other matrices (p<0.005), excluding informal dust (p=0.059, almost significant difference). Thus, workers exposed to formal dust should protect themselves from hazardous toxic metals (Pb and Cu). There is also a high health risk for children ingesting surface matrices from informal e-waste recycling sites.


Caspase activation accompanying cytochrome c release from mitochondria is possibly involved in nitric oxide-induced neuronal apoptosis in SH-SY5Y cells.
It is well known that caspases are produced as proforms, which are proteolytically cleaved and activated during apoptosis or programmed cell death. We report here that caspases are activated during apoptosis by treatment with NOC18, a nitric oxide (NO) donor. Our present experiments have examined the way in which NO induces neuronal cell death, using a new type of NO donor that spontaneously releases only NO without enzymatic metabolism. NOC18 induced apoptosis in human neuroblastoma SH-SY5Y cells in a concentration- and time-dependent manner as estimated by DNA fragmentation assay, FACScan analysis, and nuclear morphology. Oxyhemoglobin, an NO trapper, suppressed NOC18-triggered DNA fragmentation, indicating that NO from NOC18 is a real activator in this study. Upon the induction of apoptosis, an increase in caspase-3-like protease activity, but not caspase-1, was observed. Procaspase-2 protein, an inactive form of caspase-2, decreased dramatically. In addition, NOC18 also resulted in poly (ADP-ribose) polymerase (PARP) cleavage, yielding an 85-kDa fragment typical of caspase activity. Oxyhemoglobin blocked the decrease of procaspase-2 and the cleavage of PARP by NOC18 in a concentration-dependent manner. Moreover, NO elicited the release of cytochrome c into the cytosol during apoptosis. These results suggest that both stimulation of caspase activity and cytochrome c release are partly involved in NO-induced neuronal apoptosis.