Ursolic acid, a pentacyclic triterpene from Sambucus australis, prevents abdominal adiposity in mice fed a high-fat diet.
Currently, there is renewed interest in plant-based medicines and functional foods for the prevention and cure of obesity and its associated risk of cardiovascular disease and metabolic syndrome. In the search for potential anti-obesity compounds from natural sources, the effects of ursolic acid (UA), a pentacyclic triterpenoid widely found in medicinal herbs and fruits, was evaluated for its effects on blood glucose, lipids, and abdominal fat deposition in mice fed a high-fat diet (HFD). Adult male Swiss mice treated or not with UA (0.05%, 50 mg/L, in drinking water) were fed HFD for 15 weeks. A sibutramine (SIB)-treated group (0.05% in drinking water) was included as the positive control. Weekly body weights and food and water consumption were measured, and at the end of the study period, the levels of blood glucose and lipids, the plasma hormones insulin, ghrelin, and leptin, and the abdominal fat accumulation were analyzed. Mice treated with UA and fed HFD showed significantly (P<.05) decreased body weights, visceral adiposity, and levels of blood glucose and plasma lipids relative to their respective controls not fed UA. Also, a significant increase was observed in plasma leptin with a decrease in ghrelin, as well as of amylase and lipase activities. The SIB-treated group also manifested effects similar to those of UA except for the blood glucose level, which was not different from the HFD control. These findings suggest that UA ameliorates abdominal adiposity and decreases the levels of blood glucose and plasma lipids in mice and thus manifests an anti-obesity potential through absorptive and metabolic targets.


Risk of severe hypoglycaemia in insulin treated diabetic patients transferred to human insulin: a case control study.
To examine whether transfer from animal insulin to human insulin is associated with an increased risk of severe hypoglycaemia. Matched case-control study of insulin treated diabetic patients admitted to hospital because of hypoglycaemia during 1984-7, the period when human insulin was introduced into treatment. Case admissions and control admissions were obtained from eight public hospitals within the Swiss canton of Berne and a second control group comprised members of the Bernese section of the Swiss Diabetes Association. 94 patients with insulin treated diabetes with a total of 112 admissions for hypoglycaemia during 1984-7 (case admissions), 182 patients with insulin treated diabetes seen in the same hospitals for reasons other than hypoglycaemia with a total of 225 admissions (control admissions), and 86 insulin treated diabetic patients who were members of the Bernese section of the Swiss Diabetes Association. Type of insulin used at time of admission, glycaemic control as measured by amount of glycated haemoglobin or glucose concentration; severity of hypoglycaemia. Treatment with human insulin at admission was more common in cases than controls (52/112 (46%) admissions v 77/225 (34%); p = 0.003). 116 out of 129 (90%) of admissions taking human insulin had been transferred from animal insulin, mainly because of non-availability of porcine insulins. The ratio of rate of hypoglycaemia in those taking human insulin to the rate in those taking animal insulin was 2.4 (95% confidence interval 1.3 to 4.4). Other risk factors for hypoglycaemia were a history of hypoglycaemic coma (rate ratio of history to no history 3.8, 2.3 to 6.4) and good glycaemic control (rate ratio of good to poor control 3.9, 1.4 to 7.5). With multivariate analysis the increase in rate ratio associated with use of human insulin rose to 3.0 (1.4 to 6.4). Comparison with the diabetes association controls also showed an increased risk associated with use of human insulin (2.2; 1.1 to 4.8). Transfer of treatment from animal insulin to human insulin was associated with an increased risk of severe hypoglycaemia. Caution should be exercised when transferring diabetic patients to human insulin. Further studies are required to elucidate why this effect occurs.


[The role of social support in the relationship between stress and depression among family caregivers of older adults with dementia].
This study was to determine the mediator or moderator role of social support in the relationship between stress and depression among family caregivers of older adults with dementia. Sixty nine family caregivers were randomly selected from health care centers in P city and a face-to-face interview was conducted using questionnaires from January to May of 2002. Data were analyzed with descriptive statistics, Pearson correlation, and hierarchical multiple regression using SPSS program. Family caregivers of older adults with higher dependency in ADLs and higher problematic behaviors, provided care to the older adults for a longer period of time, and perceived less social support reported higher depression. Social support showed mediating effects between stress and depression, while did not show moderating effects. Elderly dependency on ADLs and caregiving duration decreased perceived social support and decreased social support increased depression. To increase family and social support to the caregivers of more functionally impaired elderly, family education to increase emotional support and physical assistance to the caregivers and broader and flexible application of social support such as increasing accessibility to the elderly daycare service with lower price may prove beneficial.


Experimental determination of charge carrier dynamics in carbon nitride heterojunctions.
Carbon nitride (CNx) is an emerging photocatalyst with the potential to efficiently produce solar fuels. CNx heterojunctions often show significant photocatalytic activity improvements. We review the charge carrier dynamics in a range of CNx heterojunctions including carbon-based material, black phosphorus, Ru complexes, molybdenum sulphide and metal phosphides. Time resolved photoluminescence (TRPL) and transient absorption spectroscopy (TAS) were the most common techniques employed for experimental charge carrier dynamics measurements. The low photoluminescence quantum yield of CNx appeared to limit the depth of conclusions from TRPL, with both lengthening and shortening of the TRPL lifetimes observed and attributed to enhanced charge separation. Overall, the charge carrier dynamics studies often showed a relative lifetime change of ∼2-fold and an activity improvement of >10-fold. We highlight the need for the use of a wider range of techniques to monitor the charge carrier dynamics for conclusive determination of photophysics-activity relationships and elucidation of improvement mechanisms.


Intravenous chloroprocaine attenuates hemodynamic changes associated with direct laryngoscopy and tracheal intubation.
We compared the effects of an IV administration of chloroprocaine and lidocaine on circulatory responses associated with endotracheal intubation. Thirty patients were randomly allocated to receive normal saline (placebo), lidocaine (1.5 mg/kg), or preservative-free chloroprocaine (4.5 mg/kg) 45 s before endotracheal intubation. Blood pressures and heart rate and rhythm were recorded before laryngoscopy and at 0.5, 1, 1.5, 2, 3, and 5 min after intubation. Blood samples were analyzed for catecholamine and chloroprocaine concentrations. Chloroprocaine reduced increases in blood pressure in response to intubation when compared with patients receiving normal saline and lidocaine. Systolic blood pressures at 0.5 and 1 min after intubation were significantly lower in the chloroprocaine group when compared with both the control and lidocaine groups (P < 0.05). Diastolic and mean blood pressures were significantly lower in the chloroprocaine group at all time points until 5 min after intubation (P < 0.05). Chloroprocaine and, to a lesser degree, lidocaine, produced marked attenuation of intubation-induced increases in plasma concentration of epinephrine and norepinephrine. Plasma concentrations of norepinephrine were significantly smaller in the chloroprocaine group at 0.5, 1, and 1.5 min, and plasma concentrations of epinephrine were significantly smaller at 0.5 after intubation when compared with control and lidocaine groups (P < 0.05). Measurable concentrations of chloroprocaine were recorded in plasma samples for 2 min after its administration. No adverse chloroprocaine effects (i.e., circulatory disturbances, venous irritation) were detected. The IV administration of chloroprocaine effectively blunted cardiovascular response produced by laryngoscopy and endotracheal intubation, and this effect was more pronounced when compared with IV lidocaine.


Development of a modified Winchester disability scale--the elderly at risk rating scale.
To show that the elderly at risk rating scale (EARRS) satisfies the requirements of an assessment tool for routine health checks in people over 75 and would also be suitable as a method of collecting epidemiological data on the needs of the elderly in a locality. Development and validation of a questionnaire based on a modification of the Winchester rating scale, by a series of prospective, comparative studies before the use of the instrument in a community survey. Elderly care day hospital and the community. Elderly patients referred to an elderly care day hospital; population survey of subjects over 75 living at home. Reliability of responses using the kappa statistic; comparison of the scale with the Barthel index of daily living. EARRS has satisfactory validity and reliability when repeated by the same observer or a different observer, with a mean weighted kappa score above 0.80 in both instances. As a measure of disability in the community, it is better than the Barthel score in that it avoids the ceiling effect. The score is correlated with age, social situation, and receipt of support services, and individual questions scale appropriately to adverse outcomes. The EARRS satisfies the requirements of an assessment tool for health checks in the elderly, It is suitable for both population surveys and routine practice in primary care, has proved popular with practice nurses, and is easy to complete.


Organizational connectivity among the CA1, subiculum, presubiculum, and entorhinal cortex in the rabbit.
The laminar and topographical organization of connections between the hippocampal formation and parahippocampal regions was investigated in the rabbit following in vivo injection of cholera toxin B subunit as a retro- and antero-grade tracer and biotinylated dextran amine as an anterograde tracer. We confirmed several connectional features different from those of the rat, that is, the rabbit presubiculum received abundant afferents from CA1 and had many reciprocal connections with the entorhinal cortex. On the other hand, we identified many similarities with the rat: both the CA1 and subicular afferents that originated from the entorhinal cortex were abundant; moreover, the presubiculum received many inputs from the subiculum and sent massive projections to the entorhinal cortex. By plotting retrograde and anterograde labels in two-dimensional unfolded maps of the entire hippocampal and parahippocampal regions, we found that each group of entorhinal cells that project to CA1, subiculum, and presubiculum, and also the termination of the presubiculo-entorhinal projection, was distributed in band-like zones in layers II-III, extending across the medial and lateral entorhinal cortex. Our results suggest that the rabbit has a basic connectivity that is common with that of the rat, and also has additional hippocampal-presubicular and entorhino-presubicular connections that may reflect functional evolution in learning and memory.


MPV in Uncontrolled & Controlled Diabetics- Its Role as an Indicator of Vascular Complication.
Platelets are tiny, disc-shaped, non-nucleated structures derived from megakaryocytes. The morphological differences in measuring Mean Platelet Volume (MPV) and Platelet Distribution Width (PDW) of platelets have important implications for assessing the functional expressions of platelets. Electron microscopy reveals the presence of glycogen as prominent masses in platelets. MPV values have been generally reported to be very high in individuals with uncontrolled diabetes mellitus (DM). This study aimed to determine and compare the MPV values in uncontrolled and controlled group of Type-2 Diabetics along with healthy non-diabetic people and to correlate MPV values with age, sex and glycosylated haemoglobin (HbA1c) levels in diabetic groups. This study also aimed to determine the prevalence of retinopathy in uncontrolled and controlled group of diabetic patients. This case control study was carried out in our institution for 1 year. The patients were grouped as uncontrolled group of diabetic patients and controlled group of diabetic patients based on their HbA1c levels. 106 uncontrolled diabetic patients and 100 controlled diabetic patients were included, with 100 non-diabetic subjects as controls. Patient's profile which included all demographic particulars and medical history was obtained. Fundus examination and other ophthalmic findings of 50 uncontrolled and 50 controlled diabetic cases were recorded. The findings were analysed statistically using IBM SPSS software. In uncontrolled group of 106 diabetic patients, 54 patients were males and 52 patients were females and the mean age was 51.63±11.04, mean HbA1c was 9.86±1.91% and mean MPV was 8.93±0.90fl. In controlled group of 100 diabetic patients, 49 patients were males and 51 patients were females and the mean age was 47.88±15.17, mean HbA1c was 6.08±0.49% and mean MPV was 8.106 ± 0.72fl. In 100 non-diabetic controls 77 patients were males and 23 patients were females and the mean age was 37.97±9.69 and mean MPV was 8.02±0.86fl. Among 50 cases of uncontrolled DM, 14 uncontrolled DM patients had diabetic retinopathy with an average MPV of about 9.2±0.61fl and mean HbA1c of 10.6±1.98% whereas, 30 uncontrolled patients with no evidence of retinopathy with an average MPV of about 8.39±0.676 fl and mean HbA1C of 9.18±1.91%. MPV values are higher in uncontrolled DM patients when compared with controlled DM patients and a higher percentage of them develop microvascular complications like Diabetic Retinopathy suggesting that mean platelet volume could indicate and play a more important role in the detection of vascular complications of Diabetes.


Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL.
Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-XL inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 < 20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (Mw < 450), and unprecedented selectivity for Bcl-XL. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-XL. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-XL for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-XL and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.


Visual attention and academic performance in children with developmental disabilities and behavioural attention deficits.
Despite well-documented attention deficits in children with intellectual and developmental disabilities (IDD), distinctions across types of attention problems and their association with academic attainment has not been fully explored. This study examines visual attention capacities and inattentive/hyperactive behaviours in 77 children aged 4 to 11 years with IDD and elevated behavioural attention difficulties. Children with autism spectrum disorder (ASD; n = 23), Down syndrome (DS; n = 22), and non-specific intellectual disability (NSID; n = 32) completed computerized visual search and vigilance paradigms. In addition, parents and teachers completed rating scales of inattention and hyperactivity. Concurrent associations between attention abilities and early literacy and numeracy skills were also examined. Children completed measures of receptive vocabulary, phonological abilities and cardinality skills. As expected, the results indicated that all groups had relatively comparable levels of inattentive/hyperactive behaviours as rated by parents and teachers. However, the extent of visual attention deficits varied as a result of group; namely children with DS had poorer visual search and vigilance abilities than children with ASD and NSID. Further, significant associations between visual attention difficulties and poorer literacy and numeracy skills were observed, regardless of group. Collectively the findings demonstrate that in children with IDD who present with homogenous behavioural attention difficulties, at the cognitive level, subtle profiles of attentional problems can be delineated.


Celiac disease antibody levels reflect duodenal mucosal damage but not clinical symptoms.
This study aimed to investigate, in a real-world population, whether the histological and clinical phenotype differ at baseline and during follow-up in patients with high and low CD (celiac disease) antibody titers. The study cohort consisted of 96 consecutive patients diagnosed to have CD during the years 2010-2018. The clinical parameters, symptoms and laboratory results were registered and histomorphometry was analyzed from the available duodenal biopsies taken during the primary and follow-up esophageal-gastricduodenoscopies. Patients having immunoglobulin A transglutaminase antibody (tTG-ab) levels above 70 U/mL were classified as high titer patients. Measured by the villous-crypt ratio, the duodenal mucosa was more severely damaged in the high tTG-ab group than in the low tTG-group at baseline (n = 70, 0.61 ± 0.63 vs. 1.02 ± 0.87, p = .003) and during the follow-up when the patients were on gluten-free diet (n = 27, 1.80 ± 0.72 vs. 2.35 ± 0.64, p = .041). Interestingly, the high tTG-ab group members had fewer gastrointestinal symptoms at baseline than those in the low tTG-ab group (43% vs. 68%, p = .013) but lower vitamin D levels (68 ± 34 nmol/L vs. 88 ± 29 nmol/L, p = .034) and more often microcytosis (28% vs. 10%, p = .040). During the follow-up, these differences were no longer detected. At baseline, CD patients with high tTG-ab have more severe duodenum injury and signs of malabsorption but fewer symptoms. After gluten-free diet has been initiated, the mucosal healing in the high tTG-ab group is prolonged, but symptoms and signs of malabsorption recover equally in both groups.


The optimal fluoroscopic views to rule out intra-articular screw penetration during acetabular fracture fixation.
To determine the ideal view(s) and the minimum number of intraoperative fluoroscopic views required to rule out any intra-articular screw violation in acetabular fractures fixation. This study was conducted using a series of fluoroscopic examinations of pelvic synthetic models with screws positioned in different planes around the acetabulum. Ten screws were placed in the synthetic pelvis models in different planes of the acetabulum. Seven views were taken for each screw. Radiographic images were evaluated by 14 orthopaedic surgeons who were asked to assess joint violation and the view(s) required for assessment. The observers' accuracy rate in identifying joint violation was 82.1% for the anterior part of the anterior column and the superior part of the posterior column, 89.3% for the posterior part of the anterior column and the inferior part of the posterior column, and 92.9% for the quadrilateral plate. The sensitivity was 100% for the anterior and posterior parts of the anterior column and the inferior part of the posterior column, 87.5% for the superior part of the posterior column, and 85.7% for the quadrilateral plate. The specificity was 100% for the quadrilateral plate, 80% for the superior part of the posterior column and the posterior part of the anterior column, 78.6% for the inferior part of the posterior column, and 66.7% for the anterior part of the anterior column. There was a strong overall interobserver and intra-observer agreement with intraclass correlation coefficient (ICC) of 0.709 and 0.86, respectively. This study confirms the hypothesis that in a concave surface/joint fixation, such as the acetabulum, the probability of joint violation is unlikely if there is no evidence of it within a single fluoroscopic view. In acetabulum fracture fixation with a screw violating the joint, the screw's presence was evident within the joint space in all fluoroscopic views. However, the absence of joint violation in one fluoroscopic view was adequate to rule out joint penetration.


Exploring data sources for road traffic injury in Cameroon: Collection and completeness of police records, newspaper reports, and a hospital trauma registry.
Road traffic injury surveillance systems are a cornerstone of organized efforts at injury control. Although high-income countries rely on established trauma registries and police databases, in low- and middle-income countries, the data source that provides the best collection of road traffic injury events in specific low- and middle-income country contexts without mature surveillance systems is unclear. The objective of this study was to compare the information available on road traffic injuries in 3 data sources used for surveillance in the sub-Saharan African country of Cameroon, providing potential insight on data sources for road traffic injury surveillance in low- and middle-income countries. We assessed the number of events captured and the information available in Yaoundé, Cameroon, from 3 separate sources of data on road traffic injuries: trauma registry, police records, and newspapers. Data were collected from a single-hospital trauma registry, police records, and the 6 most widely circulated newspapers in Yaoundé during a 6-month period in 2009. The number of road traffic injury events, mortality, and other variables included commonly in injury surveillance systems were recorded. We compared these sources using descriptive analysis. Hospital, police, and newspaper sources recorded 1,686, 273, and 480 road traffic injuries, respectively. The trauma registry provided the most complete data for the majority of variables explored; however, the newspaper data source captured 2, mass casualty, train crash events unrecorded in the other sources. Police data provided the most complete information on first responders to the scene, missing in only 7%. Investing in the hospital-based trauma registry may yield the best surveillance for road traffic injuries in some low- and middle-income countries, such as Yaoundé, Cameroon; however, police and newspaper reports may serve as alternative data sources when specific information is needed.


Bone marrow examination for unexplained cytopenias reveals nonspecific findings in patients with collagen vascular disease.
Collagen vascular diseases are frequently included in the differential diagnosis for unexplained cytopenias and often prompt a bone marrow biopsy in this patient population to exclude malignancy. Few large-scale studies have characterized the bone marrow morphology in patients with collagen vascular disease, and most are limited to systemic lupus erythematosus or rheumatoid arthritis. To identify morphologic and immunohistochemical abnormalities specific to each of a wide range of collagen vascular disease cases. We examined 102 cases of collagen vascular disease and 38 controls and evaluated the complete blood count, peripheral blood morphology, bone marrow morphology, as well as immunohistochemical staining, for numerous cell lineages. Bone marrow findings, including abnormalities such as lymphoid aggregates, lipogranulomas, or abnormal localization of immature precursors, were not significantly different as compared to the control group. Bone marrow examination in patients with collagen vascular disease with cytopenias seldom provides new information. Caution should be exercised in interpreting morphologic findings suggestive of myelodysplasia since these are of a reactive nature in up to 27% of patients with collagen vascular disease. In a cost-effective diagnostic strategy, successful utilization may favor postponing a bone marrow biopsy while a more standardized autoimmune diagnostic panel is being performed.


Mn 2p resonant X-ray emission clarifies the redox reaction and charge-transfer effects in LiMn2O4.
High-energy-resolution soft X-ray emission spectroscopy (XES) was applied to understand the changes in the electronic structure of LiMn2O4 upon Li-ion extraction/insertion. Mn 2p-3d-2p resonant XES spectra were analyzed by configuration-interaction full-multiplet (CIFM) calculations, which reproduced both dd and charge-transfer (CT) excitations. From the resonant XES spectra it is found that Mn3+ and Mn4+ coexist in the initial state, while this changes into Mn4+ in the charged-state. For the discharged-state, the Mn3+ component appears again although the dd excitations are slightly modified from those for the initial state. Furthermore, negative CT energy is expected for the Mn4+ configuration, which suggests very strong hybridization between the Mn 3d and O 2p orbitals. The large difference in the CT effect between the Mn4+ and Mn3+ states should give mechanical stress to the Mn-O bond during charge-discharge cycling, leading to capacity fading.


Inhibition of human cytochrome P450 enzymes by 1,2-dithiole-3-thione, oltipraz and its derivatives, and sulforaphane.
Recent studies have demonstrated that two chemoprotective agents, oltipraz (OPZ), a synthetic derivative of the natural compound 1, 2-dithiole-3-thione (D3T), and sulforaphane (SF), an isothiocyanate, are not only inducers of glutathione S-transferases but also inhibitors of some major cytochrome P450 enzymes (P450s) involved in xenobiotic metabolism. We examined P450 inhibition by the two compounds and compared two OPZ metabolites (OPZ M(3) and M(8)) and D3T using human P450s expressed in Escherichia coli membranes. OPZ was a more potent inhibitor than D3T or SF, in the following order of inhibition: P450 1A2 > 3A4 > 1A1 approximately 1B1 > 2E1. OPZ M(3) also inhibited P450s 1A2, 1A1, 1B1, and 3A4 but not more effectively than OPZ. OPZ M(8) was not inhibitory. OPZ behaved as a competitive inhibitor of P450 1A2, with a K(i) of 1.5 microM. Incubation of P450 1A2 with OPZ and NADPH led to a first-order loss of the P450 spectrum, and the loss was not blocked by glutathione. No such time-dependent loss of P450 was seen with P450 1A2 and D3T, P450 1A2 and OPZ M(3), P450 1A2 and SF, P450 3A4 and OPZ, P450 3A4 and D3T, P450 2E1 and OPZ, or P450 2E1 and D3T. The time- and concentration-dependent loss of P450 1A2 activity in the presence of OPZ was characterized with a K(i) of 9 microM and a k(inactivation) of 0.19 min(-)(1). The activation of 2-amino-3,5-dimethylimidazo[4, 5-f]quinoline (MeIQ) in an E. coli lac-based mutagenicity tester system containing functional human P450 1A2 was inhibited by OPZ (IC(50) < 1 microM) but not appreciably by 40 microM D3T. Our results indicate that OPZ is a competitive and mechanism-based inhibitor of P450 1A2, and the extent of this inhibition is significantly greater than that of other chemoprotective chemicals with P450 1A2 or other human P450s.


The Interrelated Multifactorial Actions of Cortisol and Klotho: Potential Implications in the Pathogenesis of Parkinson's Disease.
The pathogenesis of Parkinson's disease (PD) is complex, multilayered, and not fully understood, resulting in a lack of effective disease-modifying treatments for this prevalent neurodegenerative condition. Symptoms of PD are heterogenous, including motor impairment as well as non-motor symptoms such as depression, cognitive impairment, and circadian disruption. Aging and stress are important risk factors for PD, leading us to explore pathways that may either accelerate or protect against cellular aging and the detrimental effects of stress. Cortisol is a much-studied hormone that can disrupt mitochondrial function and increase oxidative stress and neuroinflammation, which are recognized as key underlying disease mechanisms in PD. The more recently discovered klotho protein, considered a general aging-suppressor, has a similarly wide range of actions but in the opposite direction to cortisol: promoting mitochondrial function while reducing oxidative stress and inflammation. Both hormones also converge on pathways of vitamin D metabolism and insulin resistance, also implicated to play a role in PD. Interestingly, aging, stress and PD associate with an increase in cortisol and decrease in klotho, while physical exercise and certain genetic variations lead to a decrease in cortisol response and increased klotho. Here, we review the interrelated opposite actions of cortisol and klotho in the pathogenesis of PD. Together they impact powerful and divergent mechanisms that may go on to influence PD-related symptoms. Better understanding of these hormones in PD would facilitate the design of effective interventions that can simultaneously impact the multiple systems involved in the pathogenesis of PD.


Satellite-based estimates of long-term exposure to fine particulate matter are associated with C-reactive protein in 30 034 Taiwanese adults.
Particulate matter (PM) air pollution is associated with the risk of cardiovascular morbidity and mortality. However, the biological mechanism underlying the associations remains unclear. Atherosclerosis, the underlying pathology of cardiovascular disease, is a chronic inflammatory process. We therefore investigated the association of long-term exposure to fine PM (PM2.5) with C-reactive protein (CRP), a sensitive marker of systemic inflammation, in a large Taiwanese population. Participants were from a large cohort who participated in a standard medical examination programme with measurements of high-sensitivity CRP between 2007 and 2014. We used a spatiotemporal model to estimate 2-year average PM2.5 exposure at each participant's address, based on satellite-derived aerosol optical depth data. General regression models were used for baseline data analysis and mixed-effects linear regression models were used for repeated data analysis to investigate the associations between PM2.5 exposure and CRP, adjusting for a wide range of potential confounders. In this population of 30 034 participants with 39 096 measurements, every 5 μg/m3 PM2.5 increment was associated with a 1.31% increase in CRP [95% confidence interval (CI): 1.00%, 1.63%) after adjusting for confounders. For those participants with repeated CRP measurements, no significant changes were observed between the first and last measurements (0.88 mg/l vs 0.89 mg/l, P = 0.337). The PM2.5 concentrations remained stable over time between 2007 and 2014. Long-term exposure to PM2.5 is associated with increased level of systemic inflammation, supporting the biological link between PM2.5 air pollution and deteriorating cardiovascular health. Air pollution reduction should be an important strategy to prevent cardiovascular disease.


Cellular and molecular changes in the early stages of chemical hepatocarcinogenesis in the rat.
The early cellular and molecular changes in the Solt-Farber model of hepatocarcinogenesis with and without initiation was studied by using histochemical, immunohistochemical, and in situ hybridization techniques. Increased cellularity was observed in the periductal space in both models 32 to 56 h after partial hepatectomy. These periductal cells and Ito cells were the only cells that became labeled with tritiated thymidine in the uninitiated liver model. Forty-five to 60% of the labeled periductal cells were positive for gamma-glutamyltranspeptidase. From the periductal area the cells that were positive for antibody raised against oval cells (OV-6) infiltrated into liver parenchyma and were followed by desmin-positive Ito cells. The number of Ito cells in the uninitiated model 6 days after partial hepatectomy was 3.5 times higher in the area occupied by oval cells than elsewhere in the liver. The first alpha-fetoprotein (AFP)-positive cells appeared either as individual cells or as pseudoductal formations 32 or 56 h after partial hepatectomy at the periphery of the periductal space in both initiated and uninitiated animals. A combination of in situ and immunohistochemistry revealed that the OV-6-positive cells were AFP positive, whereas desmin-positive cells were AFP negative. Glutathione S-transferase P (GST-P) transcripts could be found mainly in OV-6-positive oval cells. Bile duct cells were positive for GST-P and negative for transforming growth factor beta 1, whereas cells in the periductal space were positive for both of these transcripts. The GST-P-positive early preneoplastic lesions showed a similar distribution pattern as that of oval cells; the preexisting hepatocytes became trapped between small basophilic hepatocytes that showed either irregular or pseudoalveolar arrangement. This raises the question as to whether cells which are stem cell-like are among the target cells in the Solt-Farber model of hepatocarcinogenesis. Proliferation of transforming growth factor beta 1-producing, desmin-positive cells (Ito cells) and multipotent oval cells in a close proximity to each other indicates an intricate relationship between Ito cells and oval cells in liver that warrants further investigation.


Fluorinated and N-Acryloyl-Modified 3,5-Di[(E)-benzylidene]piperidin-4-one Curcuminoids for the Treatment of Pancreatic Carcinoma.
Pancreatic carcinoma is a cancer disease with high mortality. Thus, new and efficient treatments for this disease are badly needed. Curcumin has previously shown promising effects in pancreatic cancer patients; however, this natural compound suffers from inadequate efficacy and bioavailability, preventing its clinical approval. The synthetic curcuminoid EF24 was developed with activities superior to curcumin against various cancer types. In this study, a series of analogs of EF24 were investigated for anticancer effects on pancreatic carcinoma models. A distinct activity boost was achieved by straightforward N-acrylation of EF24 analogs, in particular, of compounds bearing 3-fluoro-4-methoxybenzylidene, 3,4-difluorobenzylidene, and 4-trifluoromethylbenzylidene moieties, while no improvement was seen for N-acryloyl-modified EF24. Apoptosis induction and suppression of phospho-STAT3 levels were determined, the latter corroborated by docking of active curcuminoids into STAT3. Hence, promising new clues for the development of efficient and superior curcuminoids as valuable treatment options for one of the most lethal cancer diseases were discovered in this study.


Prevalence of bone marrow involvement in systemic anaplastic large cell lymphoma: are immunohistochemical studies necessary?
The frequency of bone marrow involvement in anaplastic large cell lymphoma has been reported with great variation. A prior study found that anaplastic large cell lymphoma involvement of bone marrow was often not evident on routine stains and advocated using immunohistochemical studies. We evaluated 70 bone marrow biopsies from 41 patients with anaplastic large cell lymphoma and found 10 morphologically involved cases (14% of all biopsies, 22% of all patients). In most cases (9/10 biopsies), the involvement of the bone marrow by anaplastic large cell lymphoma was massive and, thus, was evident on the hematoxylin and eosin section. In only 1 biopsy (1% of all biopsies, 2% of all patients), the involvement was minimal and more difficult to detect. To determine if the hematoxylin and eosin evaluation missed bone marrow involvement, we used a panel of antibodies including CD30, ALK-1, epithelial membrane antigen, and granzyme. Only the 10 morphologically involved cases showed anaplastic large cell lymphoma cells with distinct CD30 expression. Other stains highlighted only a subset of the CD30-positive cases. Clinical follow-up was available for 30 patients and shows correlation of marrow involvement with lower overall survival (P = .033). Overall, marrow involvement in anaplastic large cell lymphoma was relatively uncommon, and when present, it was identified on hematoxylin and eosin sections.


Barriers to palliative care in people with chronic obstructive pulmonary disease in home care: A qualitative study of the perspective of professional caregivers.
To examine the experiences with palliative care in people with chronic obstructive pulmonary disease among professional caregivers in a Danish home care setting. Many patients with advanced chronic obstructive pulmonary disease depend on professional caregivers in the primary sector to provide assistance and care. However, chronic obstructive pulmonary disease patients receive no or only very little palliative care compared to patients with cancer although they may have many burdensome symptoms. Qualitative explorative study. In 2013-2014, ten professional caregivers from three districts in a Danish municipality were followed during home visits to patients with chronic obstructive pulmonary disease and individual interviews about palliative care were subsequently conducted. In 2014, 66 professional caregivers, representing eleven home care districts, participated in ten group discussions about palliative care needs in this group of patients. Data were analysed using qualitative descriptive analysis. The study revealed a nonawareness of palliative care for patients with chronic obstructive pulmonary disease among the professional caregivers who expressed vague understanding of palliative care and lack of knowledge about the disease. Organisational barriers, such as lack of time and continuity in patient care, lack of opportunity to discuss palliative care and lack of peer learning were experienced as challenging in the provision of palliative care. Nonawareness and organisational barriers led to difficulties in identifying palliative care needs and reluctance to initiate conversations about palliative care. The findings indicate a need for education, training and reflection among professional caregivers in home care. Also, organisational changes may be needed to reduce the barriers to palliative care. The findings uncovered barriers to palliative care that must be addressed. Targeted educational programmes and organisational changes may increase the ability to identify palliative care needs and initiate and evaluate palliative interventions.


Glycoengineering of HCELL, the human bone marrow homing receptor: sweetly programming cell migration.
The successful clinical implementation of adoptive cell therapeutics, including bone marrow transplantation and other stem cell-based treatments, depends critically on the ability to deliver cells to sites where they are needed. E-selectin, an endothelial C-type lectin, binds sialofucosylated carbohydrate determinants on its pertinent ligands. This molecule is expressed in a constitutive manner on bone marrow and dermal microvascular endothelium, and inducibly on post-capillary venules at all sites of tissue injury. Engagement of E-selectin with relevant ligand(s) expressed on circulating cells mediates initial "tethering/rolling" endothelial adhesive interactions prerequisite for extravasation of blood-borne cells at any target tissue. Most mammalian cells express high levels of a transmembrane glycoprotein known as CD44. A specialized glycoform of CD44 called "Hematopoietic Cell E-/L-selectin Ligand" (HCELL) is a potent E-selectin ligand expressed on human cells. Under native conditions, HCELL expression is restricted to human hematopoietic stem/progenitor cells. We have developed a technology called "Glycosyltransferase-Programmed Stereosubstitution" (GPS) for custom-modifying CD44 glycans to create HCELL on the surface of living cells. GPS-based glycoengineering of HCELL endows cell migration to endothelial beds expressing E-selectin. Enforced HCELL expression targets human mesenchymal stem cell homing to marrow, licensing transendothelial migration without chemokine signaling via a VLA-4/VCAM-1-dependent "Step 2-bypass pathway." This review presents an historical framework of the homing receptor concept, and will describe the discovery of HCELL, its function as the bone marrow homing receptor, and how enforced expression of this molecule via chemical engineering of CD44 glycans could enable stem cell-based regenerative medicine and other adoptive cell therapeutics.


PPPYVEPTAP motif is the late domain of human T-cell leukemia virus type 1 Gag and mediates its functional interaction with cellular proteins Nedd4 and Tsg101 [corrected].
The human T-cell leukemia virus type 1 (HTLV-1) Gag polyprotein contains two adjacent proline-rich motifs (sequence PPPYVEPTAP) in the C terminus of the matrix domain [corrected]. Proline-to-alanine mutations were introduced into either or both motifs of HTLV-1 to determine the effect on the release of HTLV-1 virus-like particles from 293T cells. The release of both single mutants was significantly reduced, whereas a double mutation in both motifs abolished the release of the HTLV-1 particles. Two-hybrid and in vitro binding assays showed that the HTLV-1 Gag polyprotein binds both Tsg101 and Nedd4 proteins. The interaction with HTLV-1 Gag required the central WW domain of Nedd4 and the ubiquitin enzyme variant (UEV) domain of Tsg101. We expressed various fragments of Nedd4 and Tsg101 proteins in 293T cells and tested for their ability to interfere with virion release mediated by the HTLV-1 Gag-Pro polyprotein. Fragments consisting of the N-terminal UEV domain of Tsg101 and the central WW and C-terminal Hect domains of Nedd4 protein all caused transdominant inhibition of HTLV-1 particle release. Similarly, inhibition of the proteasome significantly decreased HTLV-1 particle release. Furthermore, the WW domain overexpression caused an early arrest of HTLV-1 particle morphogenesis before the membrane is deformed into the typical half-shell structure. This result suggests that Nedd4 is involved early in budding of HTLV-1.


Urinary delta-ALA: a potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganese.
Lead (Pb), arsenic (As) and manganese (Mn) are neurotoxic elements that often occur in mixtures for which practically no information is available on biomarkers (BMs) for the evaluation of exposure/effects. Exposures to these metals may increase delta-aminolevulinic acid (delta-ALA), which in itself may potentiate neurotoxicity. The objective of this study was to investigate the utility of urinary delta-ALA (delta-ALA-U) levels as BM of exposure and/or neurotoxic effects induced by this mixture. Five groups of Wistar rats were treated for 8 days with Pb (5mg/kg), As (60mg/L), Mn (10mg/kg), the 3-metal mixture (same doses of the single metals), and control group. Motor activity was evaluated and 24-h urine collected before and after the treatment. 24-hours (h) after the last dose, the rats were sacrificed and the brains removed for analyses. Delta-ALA and metal levels were determined in brain and urine. Co-treated rats showed a significant (p<0.05) correlation between increased Pb, As, Mn and delta-ALA levels in the brain and decreased motor activity. Delta-ALA-U concentrations were higher in the mixture-treated group than the sum of the delta-ALA-U levels in each single-treated groups and discriminated (p<0.05) between the mixture and untreated rats. Moreover, delta-ALA-U was correlated (p<0.05) with brain delta-ALA levels. These results establish that treatments with this metal mixture exacerbate behavioral dysfunction, increasing most prominently brain Pb levels. This study is the first to establish that delta-ALA-U levels represent a sensitive BM of exposure/neurotoxic effect to this metal mixture.


Small sample sorting of primary adherent cells by automated micropallet imaging and release.
Primary patient samples are the gold standard for molecular investigations of tumor biology yet are difficult to acquire, heterogeneous in nature and variable in size. Patient-derived xenografts (PDXs) comprised of primary tumor tissue cultured in host organisms such as nude mice permit the propagation of human tumor samples in an in vivo environment and closely mimic the phenotype and gene expression profile of the primary tumor. Although PDX models reduce the cost and complexity of acquiring sample tissue and permit repeated sampling of the primary tumor, these samples are typically contaminated by immune, blood, and vascular tissues from the host organism while also being limited in size. For very small tissue samples (on the order of 10(3) cells) purification by fluorescence-activated cell sorting (FACS) is not feasible while magnetic activated cell sorting (MACS) of small samples results in very low purity, low yield, and poor viability. We developed a platform for imaging cytometry integrated with micropallet array technology to perform automated cell sorting on very small samples obtained from PDX models of pancreatic and colorectal cancer using antibody staining of EpCAM (CD326) as a selection criteria. These data demonstrate the ability to automate and efficiently separate samples with very low number of cells.


Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16- Monocytes From COVID-19 Patients.
The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16- monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1β secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation and also its long-term outcomes.


Controversies in the management of endometrial cancer.
Endometrial cancer (EC) remains the most common malignancy of the female genital tract. The median age at diagnosis is the sixth decade, with abnormal uterine bleeding at the presentation in 90% of the patients. Surgical treatment, including complete hysterectomy, removal of remaining adnexal structures, and an appropriate surgical staging, represents the milestone of curative therapy for patients with EC. Adjuvant therapy is necessary in patients at high risk of recurrence. Conservative treatment approaches should be used in selected cases for women with a desire of fertility preservation. This review summarizes the management of EC and discusses current controversies regarding the role of lymphadenectomy and radiotherapy in patients with intermediate-risk tumors confined to the uterus.


Attention deficit disorder ('minimal brain dysfunction') in adults. A replication study of diagnosis and drug treatment.
This study replicated an earlier one dealing with the diagnosis and treatment of attention deficit disorder (ADD, or minimal brain dysfunction) in adults. Subjects who met provisional operational criteria for adult ADD were entered in a random-assignment, parallel, double-blind trial of placebo and pemoline, a noneuphorigenic psychostimulant drug effective in children with ADD. There was improvement in both the pemoline group and the placebo group, but the difference in improvement was not statistically significant. When the analyses were confined to that subgroup of patients whose parents had described them in the 95th percentile of childhood "hyperactivity" or when the hyperactivity score was partialled out statistically, pemoline was demonstrably more effective than placebo. Revised operational criteria for adult ADD are proposed.


Mechanism of reaction of myoglobin with the lipid hydroperoxide hydroperoxyoctadecadienoic acid.
The reaction between myoglobin and the lipid hydroperoxide 13(S)-hydroperoxy-9,11(cis,trans)-octadecadienoic acid (HPODE) was studied kinetically by spectrophotometric, polarographic and analytical methods. Metmyoglobin catalysed the decomposition of HPODE, resulting in peroxide, oxygen and conjugated diene depletion, together with the transient production of ferryl myoglobin. The reaction stoichiometry was 2:1:1 for peroxide to oxygen to conjugated diene, whereas the myoglobin remained generally intact. This stoichiometry and the rates of change of conjugated diene and ferryl myoglobin concentrations were not completely consistent with previously proposed mechanisms. We propose a novel mechanism in which HPODE reacts with both ferric myoglobin and ferryl myoglobin to form a redox cycle. Both peroxyl and alkoxyl radicals are produced, explaining the observed stoichiometry of peroxide, oxygen and conjugated diene depletion and the transient appearance of ferryl myoglobin. Computer simulation shows that this mechanism is fully capable of reproducing the observed time courses of all components.


A revised consideration on the use of very aged donors for liver transplantation.
The upper age limit for organ donation for liver transplantation has increased over the past few years. A retrospective case control study was carried out to evaluate the outcome of 36 liver transplants (group A) performed with grafts procured from donors over 70 years old in the period 1996 to April 2000, matched with 36 transplants (group B) chronologically performed thereafter with organs procured from donors below the age of 40 yr. The groups were comparable as regards main clinical characteristics. Mean follow-up was 14.5 months. Clinical and laboratory parameters of the donors, cold ischemia period, intraoperative blood transfusions, 30-d mortality, incidence of primary graft nonfunction, acute rejection episodes, arterial complications and long-term survival of recipients were considered. The main postoperative biochemical parameters were also collected and compared. A liver biopsy was obtained in 20/36 old donors, revealing less than 25% of steatosis in all but one, which showed steatosis involving 70% of the hepatocytes. There were two postoperative deaths (5.6%) in group A and one (2.8%) in group B (p = NS). Seven postoperative arterial complications (19.4%) occurred in group A, leading to the patient's death because of rupture of the hepatic artery in one case, to successful surgical revascularization in three cases and to retransplantation in three cases. Only one patient in group B (2.8%) experienced hepatic artery thrombosis (p = 0.055). One-year patient survival rates were 77.4% for group A and 88.8% for group B (p = NS); 1-yr graft survival rates were 73.3% for group A and 85.7% for group B (p = NS). In conclusion, donors over 70 should not be excluded a priori for liver transplantation in elective settings. Great attention should be paid to the pathological conditions of arterial vessels caused by atherosclerosis, i.e. the presence of calcified plaques on the hepatic artery, which might represent the source of severe complications.


Multiple imputation to account for missing data in a survey: estimating the prevalence of osteoporosis.
Nonresponse bias is a concern in any epidemiologic survey in which a subset of selected individuals declines to participate. We reviewed multiple imputation, a widely applicable and easy to implement Bayesian methodology to adjust for nonresponse bias. To illustrate the method, we used data from the Canadian Multicentre Osteoporosis Study, a large cohort study of 9423 randomly selected Canadians, designed in part to estimate the prevalence of osteoporosis. Although subjects were randomly selected, only 42% of individuals who were contacted agreed to participate fully in the study. The study design included a brief questionnaire for those invitees who declined further participation in order to collect information on the major risk factors for osteoporosis. These risk factors (which included age, sex, previous fractures, family history of osteoporosis, and current smoking status) were then used to estimate the missing osteoporosis status for nonparticipants using multiple imputation. Both ignorable and nonignorable imputation models are considered. Our results suggest that selection bias in the study is of concern, but only slightly, in very elderly (age 80+ years), both women and men. Epidemiologists should consider using multiple imputation more often than is current practice.


Physical model for recognition tunneling.
Recognition tunneling (RT) identifies target molecules trapped between tunneling electrodes functionalized with recognition molecules that serve as specific chemical linkages between the metal electrodes and the trapped target molecule. Possible applications include single molecule DNA and protein sequencing. This paper addresses several fundamental aspects of RT by multiscale theory, applying both all-atom and coarse-grained DNA models: (1) we show that the magnitude of the observed currents are consistent with the results of non-equilibrium Green's function calculations carried out on a solvated all-atom model. (2) Brownian fluctuations in hydrogen bond-lengths lead to current spikes that are similar to what is observed experimentally. (3) The frequency characteristics of these fluctuations can be used to identify the trapped molecules with a machine-learning algorithm, giving a theoretical underpinning to this new method of identifying single molecule signals.


Cocaine Use and Liver Disease are Associated with All-Cause Mortality in the Miami Adult Studies in HIV (MASH) Cohort.
Liver disease is a frequent cause of morbidity and mortality in HIV infection. We examined the relationship of cocaine use, liver disease progression and mortality in an HIV-infected cohort. Consent was obtained from 487 HIV+ participants, a subset of the Miami Adult Studies on HIV (MASH) cohort. Participants were eligible if they were followed for at least two years, completed questionnaires on demographics and illicit drug use and had complete metabolic panels, CD4 cell counts and HIV-viral loads. FIB-4 was calculated and cut-off points were used for staging liver fibrosis. Death certificates were obtained. Participants were 65% men, 69% Black and 81% were on ART at recruitment. Cocaine was used by 32% of participants and 29% were HIV/HCV co-infected. Mean age was 46.9 ± 7.7 years, mean CD4 cell count was 501.9 ± 346.7 cells/μL and mean viral load was 2.75 ± 1.3 log10 copies/mL at baseline. During the follow-up, 27 patients died, with a mortality rate of 28.2/1000 person-year. Cocaine was used by 48% of those who died (specific mortality rate was 13/1000 person-year). Those who died were more likely to use cocaine (HR=3.8, P=0.006) and have more advanced liver fibrosis (HR=1.34, P<0.0001), adjusting for age, gender, CD4 cell count and HIV-viral load at baseline and over time. Among the HIV mono-infected participants, cocaine users were 5 times more likely to die (OR=5.09, P=0.006) than participants who did not use cocaine. Cocaine use and liver fibrosis are strong and independent predictors of mortality in HIV infected and HIV/HCV co-infected adults. Effective interventions to reduce cocaine use among people living with HIV (PHLW) are needed.


The volume-quality relationship in antibiotic prescribing: when more isn't better.
For many surgeries and high-risk medical conditions, higher volume providers provide higher quality care. The impact of volume on more common medical conditions such as acute respiratory infections (ARIs) has not been examined. Using electronic health record data for adult ambulatory ARI visits, we divided primary care physicians into ARI volume quintiles. We fitted a linear regression model of antibiotic prescribing rates across quintiles to assess for a significant difference in trend. Higher ARI volume physicians had lower quality across a number of domains, including higher antibiotic prescribing rates, higher broad-spectrum antibiotic prescribing, and lower guideline concordance. Physicians with a higher volume of cases manage ARI very differently and are more likely to prescribe antibiotics. When they prescribe an antibiotic for a diagnosis for which an antibiotic may be indicated, they are less likely to prescribe guideline-concordant antibiotics. Given that high-volume physicians account for the bulk of ARI visits, efforts targeting this group are likely to yield important population effects in improving quality.


Electrophysiological properties of microglial cells in normal and pathologic rat brain slices.
Microglial cells serve as pathologic sensors of the brain. They are highly abundant in all regions of the central nervous system (CNS) and are characterized by a ramified morphology within the normal tissue. In the present study, we have developed a procedure to study the membrane properties of identified, in situ microglia in acutely isolated brain slices from rat cortex, striatum and facial nucleus. Unlike the well characterized cultured microglial cells, ramified microglia of the slice are characterized by little, if any, voltage-gated membrane currents and a very low membrane potential. They are thus distinct from neurons, other glial cells and nonbrain macrophages. To study the consequences of microglial activation on the membrane channel pattern, we compared cells in the normal facial nucleus and at defined times after facial nerve axotomy. Within 12 h of axotomy, microglial cells expressed a prominent inward rectifier current and thus acquired the physiological properties of cultured microglia. Within 24 h of the lesion, the cells expressed an additional outward current, which is typical for lipopolysaccharide (LPS)-activated microglia in vitro. Seven days after the lesion, at a time of major regenerative processes in the facial nucleus, the physiological properties of microglial cells had reverted to those present prior to the pathological event. (i) ramified microglial cells represent a physiologically unique population of cells in the brain; (ii) are distinct from their cultured counterparts; and (iii), undergo a defined pattern of physiological states in the course of pathologic events.


Circular RNA circBCBM1 promotes breast cancer brain metastasis by modulating miR-125a/BRD4 axis.
Circular RNAs (circRNAs) play critical roles in tumorigenesis and the progression of various cancers. We previously identified a novel upregulated circRNA, circBCBM1 (hsa_circ_0001944), in the context of breast cancer brain metastasis. However, the potential biological function and molecular mechanism of circBCBM1 in breast cancer brain metastasis remain largely unknown. In this study, we confirmed that circBCBM1 was a stable and cytoplasmic circRNA. Functionally, circBCBM1 promoted the proliferation and migration of 231-BR cells in vitro and growth and brain metastasis in vivo. Mechanistically, circBCBM1 acted as an endogenous miR-125a sponge to inhibit miR-125a activity, resulting in the upregulation of BRD4 (bromodomain containing 4) and subsequent upregulation of MMP9 (matrix metallopeptidase 9) through Sonic hedgehog (SHH) signaling pathway. Importantly, circBCBM1 was markedly upregulated in the breast cancer brain metastasis cells and clinical tissue and plasma samples; besides, circBCBM1 overexpression in primary cancerous tissues was associated with shorter brain metastasis-free survival (BMFS) of breast cancer patients. These findings indicate that circBCBM1 is involved in breast cancer brain metastasis via circBCBM1/miR-125a/BRD4 axis. CircBCBM1 may serve as a novel diagnostic and prognostic biomarker and potential therapeutic target for breast cancer brain metastasis.


Complications and predictive factors for the successful treatment of flatback deformity (fixed sagittal imbalance).
This is an analysis of consecutive cases of flatback deformity (fixed sagittal imbalance), treated by one of two surgeons at a university hospital. To define factors that contribute to results with treatment of flatback syndrome, classify types of sagittal deformities, and discuss complications. There are few reports that detail the results and complications of current instrumentation and osteotomy techniques for correction of fixed sagittal deformities. Twenty-eight patients treated with osteotomies for sagittal imbalance were eligible for 2-year minimum follow-up (average, 3.6 years). Patients were classified (segmental imbalance, Type 1; or global imbalance, Type 2) and evaluated by upright radiographs, chart review, and a questionnaire. Twenty-eight (100%) patients returned the questionnaire, and 28 had current radiographs. Five treatment groups were evaluated based on osteotomy type (anterior, posterior [Smith-Petersen], both, or pedicle subtraction) and use of anterior structural grafting. All patients were treated with modern bilateral hook-rod-screw constructs. Mean correction at the osteotomy levels was 25 degrees for Type 1 deformities and 30 degrees for Type 2 (P < 0.05). Sagittal correction averaged 6.6 cm in Type 2 deformities (P < 0.05). Questionnaire analysis showed a significant and persistent reduction in subjective pain level. There were seven patients with 11 total complications and no neurologic deficits. Associations among patients who were not satisfied with their results (n = 4) included insufficient sagittal correction (P = 0.045), pseudarthrosis (P = 0.045), coronal imbalance, and four or more medical comorbidities (P = 0.03). Satisfaction with the results of treatment may be reduced in patients with four or more major co-existent medical problems, insufficient sagittal correction, and resultant pseudarthrosis.


[Malignant lymphomas of various histological types in pike from the eastern portion of the Baltic Sea].
Malignant lymphomas have been found in pikes (Esox lucius L.) caught in the eastern part of the Baltic Sea. The frequency of the disease has increased in recent years. Three different histological types of malignant lymphoma are described in 32 pikes: poorly differentiated diffuse lymphocytic lymphoma, mixed (histiocytoid-lymphocytic) diffuse lymphoma and undifferentiated (anisomorphic) diffuse lymphoma.


Predictive factors and treatment outcomes of Steinstrasse following shock wave lithotripsy for ureteral calculi: A Bayesian regression model analysis.
This study aims to assess the predictive factors and treatment outcomes of Steinstrasse formation following shock wave lithotripsy (SWL) for ureter stone. The medical records of 1,418 ureter stone patients who underwent one-session SWL from November 2005 to May 2013 at our medical institute were retrospectively reviewed. Finally, 551 patients met inclusion criteria. Maximal length and location of stone, stone attenuation (Hounsfield units), and skin-to-stone distance (SSD) were determined on pretreatment non-contrast computed tomography. Of 551 patients, 12 patients (2.2% of total cohort) developed Steinstrasse after one-session SWL. The Steinstrasse incidence was significantly associated with stone size, stone attenuation value, and SSD. Prophylactic ureter stenting was not a statistically significant predictor of Steinstrasse formation. After propensity-score matching, Steinstrasse group showed a significant shorter SSD compare to non-Steinstrasse group. Multivariate logistic regression and Bayesian analysis revealed that stone size, stone attenuation and SSD were significant predictor of Steinstrasse formation following SWL for ureter stone. The Steinstrasse resolved spontaneously in six patients and remaining six patients were treated by additional SWL. None of patients with Steinstrasse required ureteral stenting, percutaneous drainage, or consequent surgical intervention. Steinstrasse formation following SWL for ureter stone was rare event but nonnegligible. Large stone size, high stone attenuation and short SSD were significant predictors of Steinstrasse formation following SWL for ureter stone. Majority of patients with Steinstrasse formation could be treated conservatively in this clinical scenario.


Structure, Health Benefits, Mechanisms, and Gut Microbiota of Dendrobium officinale Polysaccharides: A Review.
Dendrobium officinale polysaccharides (DOPs) are important active polysaccharides found in Dendrobium officinale, which is commonly used as a conventional food or herbal medicine and is well known in China. DOPs can influence the composition of the gut microbiota and the degradation capacity of these symbiotic bacteria, which in turn may determine the efficacy of dietary interventions. However, the necessary analysis of the relationship between DOPs and the gut microbiota is lacking. In this review, we summarize the extraction, structure, health benefits, and related mechanisms of DOPs, construct the DOPs-host axis, and propose that DOPs are potential prebiotics, mainly composed of 1,4-β-D-mannose, 1,4-β-D-glucose, and O-acetate groups, which induce an increase in the abundance of gut microbiota such as Lactobacillus, Bifidobacterium, Akkermansia, Bacteroides, and Prevotella. In addition, we found that when exposed to DOPs with different structural properties, the gut microbiota may exhibit different diversity and composition and provide health benefits, such as metabolism regulations, inflammation modulation, immunity moderation, and cancer intervention. This may contribute to facilitating the development of functional foods and health products to improve human health.


Working with symptoms of a respiratory infection: staff who care for high-risk individuals.
While many health care workers (HCWs) who have respiratory infections take sick leave, others work following illness onset. Little is known about attendance practices of HCWs caring for persons with spinal cord injuries (SCI), a group at high risk for respiratory complications. Cross-sectional survey of HCWs. Logistic regression identified factors associated with having a respiratory infection and examined if awareness of facility level institutional control measures and/or individual level factors influenced working while symptomatic. Response rate was 53% (n = 820). Respiratory infections were reported by 36%; of those, 86% attended work while symptomatic. HCWs aged 50 and above were less likely (odds ratio [OR] 0.58, P = 0.003) and those with a chronic condition were more likely (OR 2.24, P < 0.000) to have had a respiratory infection. HCWs who indicated that their facility institutes droplet precautions (OR 0.42, P = 0.034), restricts staff movement between wards, (OR 0.26, P = 0.002), and restricts contact between patients (OR 0.32, P = 0.009) were significantly less likely to work while symptomatic. It is alarming that 86% of HCWs attended work while symptomatic, given the consequences that respiratory infection can have on persons with SCI. HCW awareness of outbreak control measures within their facilities appeared to influence their attendance decisions, suggesting the importance of policy placement and information dissemination.


Small baseline volume of left hippocampus is associated with subsequent conversion of MCI into dementia: the Göteborg MCI study.
Earlier studies have reported that hippocampal atrophy can to some extent predict which patients with mild cognitive impairment (MCI) will subsequently convert to dementia, and that converters have an enhanced rate of hippocampal volume loss. To further validate the hypothesis that hippocampal atrophy predicts conversion from MCI to dementia, to relate baseline hippocampal volume to different forms of dementia, and to investigate the role of hippocampal side differences and rate of volume loss over time. The subjects (N=68) include patients with MCI at baseline and progression to dementia at the two-year follow-up (N=21), stable MCI patients (N=21), and controls (N=26). Among the progressing patients, 13 were diagnosed as having AD. The Göteborg MCI study is a clinically based longitudinal study with biannual clinical assessments. Hippocampal volumetry was performed manually on the MRI investigations at baseline and at the two-year follow-up. Hippocampal volumetry could predict conversion to dementia in both the AD and the non-AD subgroup of converters. Left hippocampal volume in particular discriminated between converting and stable MCI. Cut off points for individual discrimination were shown to be potentially useful. The converting MCI group had a significantly higher rate of hippocampal volume loss as compared to the stable MCI group. In MCI patients, hippocampal volumetry at baseline gives prognostic information about possible development of AD and non-AD dementia. Contrary to earlier studies, we found that left hippocampal volume has the best predictive power. Reliable predictions appear to be possible in many individual cases.


[Pre-implantation evaluation using medical imagery: scanner or Scanora?].
A pre-implant investigation by way of medical imaging techniques may be effected by means of traditional X-ray clichés. However, a proper appreciation of the bone volume and the relations between the different bone structures is only possible by means of a three-dimensional evaluation. As a matter of fact, "sectional" pictures can be made by means of the "Scanner", but also by means of the "Scanora". The following article gives a detailed description of the "Scanora" technique and compares it with the "Dentascan" technique.


An electromyographic evaluation of dual role breathing and upper body muscles in response to front crawl swimming.
The upper body trunk musculature is key in supporting breathing, propulsion, and stabilization during front crawl swimming. The aim of this study was to determine if the latissimus dorsi, pectoralis major, and serratus anterior contributed to the development of inspiratory muscle fatigue observed following front crawl swimming. Fourteen trained swimmers completed a 200-m front crawl swim at 90% of race pace. Maximal inspiratory and expiratory mouth pressures (PImax and PEmax) were assessed before (baseline) and after each swim, and electromyography was recorded from the three muscles. Post-swim PImax fell by 11% (P < 0.001, d = 0.57) and the median frequency (MDF: a measure of fatigue) of the latissimus dorsi, pectoralis major, and serratus anterior fell to 90% (P = 0.001, d = 1.57), 87% (P = 0.001, r = -0.60) and 89% (P = 0.018, d = 1.04) of baseline, respectively. The fall in serratus anterior MDF was correlated with breathing frequency (r = 0.675, P = 0.008) and stroke rate (r = 0.639, P = 0.014). The results suggest that the occurrence of inspiratory muscle fatigue was partly caused by fatigue of these muscles, and that breathing frequency and stroke rate particularly affect the serratus anterior.


Surgical treatment of prolactin-secreting pituitary adenomas: early results and long-term outcome.
Medical therapy with dopaminergic drugs is the preferred initial treatment for symptomatic prolactin (PRL)-secreting adenomas; but in recent years, there has been a renewed interest in surgery. The aim of this study is to report a large series of patients operated for prolactinoma in the last 10 yr. A total of 120 consecutive patients (93 female, 27 male) underwent surgery from January 1990 to December 1999. Their mean age at surgery was 29.7 +/- 0.9 yr. Fifty-nine patients (49.2%) had a microadenoma, and the remaining 61 (50.8%) had a macroadenoma, of which 24 (20%) were intrasellar and 37 (30.8%) were extrasellar adenoma. Magnetic resonance imaging signs of invasion of the cavernous sinus were detected in 18 patients (15.0%). Thirty-one patients (25.8%) had never been treated before, whereas the remaining 89 (74.2%) had received dopaminergic drugs. After surgery, normalization of PRL levels occurred in 77 patients (64.2%). Logistic regression analysis showed that the only predictive factor of unsuccessful surgery was a high preoperative PRL level. Recurrence of hyperprolactinemia occurred in 13 of the 77 cured patients (16.9%) during a mean follow-up of 50.2 +/- 3.0 months; the 5-yr disease-free survival was 75.9%. Extrasellar extension of the tumor and presence of a postoperative PRL response to TRH were associated with a lower risk of relapse. In summary, surgery normalized PRL levels and relieved symptoms of hyperprolactinemia in most patients. Recurrence of hyperprolactinemia occurred within 4 yr after surgery. Transsphenoidal surgery can be offered as a definitive therapy, especially to patients with intrasellar tumors.


The rabies virion-associated 100-kDa polypeptide (VAP100) is a host-derived minor component of the viral envelope.
We investigated a minor polypeptide component of 100-kDa detected in the rabies virion (referred to as VAP100) by using a monoclonal antibody (mAb), #16743, which was shown to recognize the SDS-denatured VAP100 antigen by immunoblot analyses. Although the VAP100 antigen was hardly detectable in the cell by usual immunoblot methods with this mAb, we could detect the antigen by a luminescent immunoblot method as well as by immunoprecipitation from the metabolically radiolabeled cell lysates and virions. Fluorescent antibody (FA) staining with mAb #16743 detected the uniformly distributed antigen on the formalin-fixed normal BHK-21 cells, while slight accumulation of the antigen was also seen in the Golgi area when the cells were permeabilized by treatment with Triton X-100 after fixation. Rabies virus infection induced alteration of the behavior of VAP100 to show a spotted distribution pattern in virus-infected cells. Double FA staining with mAb #16743 and rabbit antibody against the rabies virus envelope antigen demonstrated colocalized distribution of the viral envelope antigens and VAP100 in the cell. From these results, we think that VAP100 is a membrane-associated component of the cell, and its colocalized distribution with the viral envelope antigens in the cell implicates an intimate association of the VAP100 with viral envelope protein(s) and a reflection of possible involvement in the efficient incorporation of VAP100 into the virion.


Outcomes of Percutaneous Nephrolithotomy in Preschool Age Group: A Single-Center Study.
Objective: To determine the factors affecting the outcomes of percutaneous nephrolithotomy (PCNL) in patients in infantile/toddler and preschool age group. Materials and Methods: The data of 186 renal units from 152 patients who underwent PCNL were retrospectively analyzed. Patients under ≤72 months of age were included in the study. The patients were divided into two groups according to their age: infantile/toddler and preschool group. Demographics and stone features were compared between infantile/toddler and preschool age groups. Effects of different factors on complications and stone-free rates were investigated. Comparisons in the study were done using SPSS 24.0 software for Windows. Results: The mean age of the patients was 40.5 ± 16.5 months, and the female/male ratio was 87/99. The median stone burden was 1.92 cm2 (0.12-20). Stone-free rates were 75.3% and 84.4% when cases with Clinically Insignificant Residual Fragments were also included. The numbers of patients with Clavien grade 1, grade 2, and grade 3b complications were 7 (3.8%), 39 (21%), and 9 (4.8%), respectively. There was no difference between infantile/toddler and preschool children in terms of stone-free and complication rates (p = 0.082, p = 0.088, respectively). Mini PCNL and tubeless-totally tubeless- urinary diversion techniques were more frequently performed in the infantile/toddler group compared to the preschool group (p = 0.001, p = 0.028, respectively). Presence of staghorn stone was the only significant factor for complications, while the number of stones was significant for stone-free rates for patients ≤72 months (p = 0.012, p = 0.001, respectively). Stone burden was the only predictive factor for complications in patients aged ≤36 months, while number of stones was predictive for success in patients aged between 37 and 72 months (p = 0.034, p = 0.006, respectively). Conclusion: PCNL is a feasible and effective method in preschool age group with acceptable complications and high success rates. Presence of staghorn stone is predictive for complications, while number of stones is predictive for success in the preschool age group.


[Trematodes of the genus Diplostomum Nordmann, 1832 from fishes of Lake Ladoga].
Metacercariae of the genus Diplostomum Nordmann, 1842 from fishes of Lake Ladoga were investigated. Sixteen trematode species of this genus were found. The species D. parviventosum Dubois, 1932, known previously only in Lithuania, was for the first time recorded in Lake Ladoga. The description and figure of its metacercaria are provided. Data on the infestation of different fish species by diplostomids are also given. Changes in the infestation of fishes by the Diplostomum metacercariae for a long-term period are analysed.


Duty to speak up in the health care setting a professionalism and ethics analysis.
Staff and students working in health care settings are sometimes reluctant to speak up when they perceive patients to be at risk for harm. In this article, we describe four incidents that occurred at our institution (Mayo Clinic). In two of them, health care professionals failed to speak up, which resulted in harm; in the other two, they did speak up, which prevented harm and improved patient care. We analyzed each scenario using the Physician's Charter on Medical Professionalism and prima facie ethics principles to determine whether principles were violated or upheld. We conclude that anyone who works in a health care setting has a duty to speak up when a patient faces harm. We also provide guidance for health care institutions on promoting a culture in which speaking up is encouraged and integrated into routine practice.


Distinct roles of an alternative sigma factor during both free-swimming and colonizing phases of the Vibrio cholerae pathogenic cycle.
Vibrio cholerae, the bacterium that causes cholera, has a pathogenic cycle consisting of a free-swimming phase outside its host, and a sessile virulent phase when colonizing the human small intestine. We have cloned the V. cholerae homologue of the rpoN gene (encoding sigma54) and determined its role in the cholera pathogenic cycle by constructing an rpoN null mutant. The V. cholerae rpoN mutant is non-motile; examination of this mutant by electron microscopy revealed that it lacks a flagellum. In addition to flagellar synthesis, sigma54 is involved in glutamine synthetase expression. Moreover, the rpoN mutant is defective for colonization in an infant mouse model of cholera. We present evidence that the colonization defect is distinct from the non-motile and Gln phenotypes of the rpoN mutant, implicating multiple and distinct roles of sigma54 during the V. cholerae pathogenic cycle. RNA polymerase containing sigma54 (sigma54-holoenzyme) has an absolute requirement for an activator protein to initiate transcription. We have identified three regulatory genes, flrABC (flagellar regulatory proteins ABC) that are additionally required for flagellar synthesis. The flrA and flrC gene products are sigma54-activators and form a flagellar transcription cascade. flrA and flrC mutants are also defective for colonization; this phenotype is probably independent of non-motility. An flrC constitutive mutation (M114-->I) was isolated that is independent of its cognate kinase FlrB. Expression of the constitutive FlrCM114-->I from the cholera toxin promoter resulted in a change in cell morphology, implicating involvement of FlrC in cell division. Thus, sigma54 holoenzyme, FlrA and FlrC transcribe genes for flagellar synthesis and possibly cell division during the free-swimming phase of the V. cholerae life cycle, and some as yet unidentified gene(s) that aid colonization within the host.


Analysis of behavioural responses to an ACTH analog in CXB/By recombinant inbred mice.
Male mice of the C57BL/6By and BALB/cBy inbred strains, their reciprocal F1 hybrids, and 7 recombinant inbred strains, were tested for open-field activity, a shock-motivated successive reversal position discrimination problem in a T-maze, and a toggle box exploration task. The test battery was repeated one month later. Finally, mice were tested for the acquisition and extinction of a taste aversion conditioned by ethanol injection. Mice of each strain were tested after injection with saline or one of 3 doses of an ACTH analogue. Highly significant genotypic differences were found for all measures, an expected result. The strain distribution pattern seen in the toggle box suggested single gene mediation of exploratory activity after habituation. One aspect of avoidance responding and extinction of conditioned taste aversion also yielded strain distribution pattern consistent with single gene control. Peptide treatment reduced internal field crossings in the open field. This effect was not strain dependent. Peptide treatment had no effect on T-maze learning, conditioned taste aversion, or toggle-box exploration.


Histologic and ultrastructural analysis in a case of massive failure of Zirconia ball head.
The in vivo histological and ultrastructural analysis of periprosthetic tissue collected at time of revision surgery for failure of a 28 mm yttria-tetragonal zirconium oxide polycrystal (YTZP) ball head, 2 years after implantation is reported. Histologic analysis showed Zirconia particles, rounded to polygonal ranging from 2m to more than 10m intra or extra cellular in a stroma without vessels with few giant cells. Scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDAX) showed the different shape from rounded to polygonal of Zirconia. SEM analysis of the internal part of Zirconia ball head showed the presence of different fracture lines especially in the internal surface (Hip International 2002; 4: 388-93).


Bioinformatic analysis of expressed sequence tags derived from a compatible Alternaria brassicicola-Brassica oleracea interaction.
SUMMARY Alternaria brassicicola is a necrotrophic fungal pathogen that causes black spot disease on members of the Brassicaceae plant family. In order to identify candidate fungal pathogenicity genes and characterize a compatible host response, a suppression subtractive hybridization (SSH) cDNA library enriched for A. brassicicola and Brassica oleracea genes expressed during the interaction was created, along with a fungal cDNA library representing genes expressed during nitrogen starvation (NS). A total of 3749 and 2352 expressed sequence tags (ESTs) were assembled into 2834 and 1264 unisequence sets for the SSH and NS libraries, respectively. We compared two methods to identify the origins (plant vs. fungal) of ESTs in the SSH library using different classification procedures, with and without the availability of a database representing the A. brassicicola whole genome sequence and Brassicaceae-specific genes. BLASTX analyses of the 2834 unisequence set using the GenBank non-redundant database identified 114 fungal genes. Further BLASTN analyses of the genes with unidentifiable origin using a database consisting of the 1264 fungal unisequence set from the nitrogen-starved library identified 94 additional fungal genes. By contrast, BLASTN analyses of the same SSH unisequence set using a partially assembled A. brassicicola whole genome draft sequence identified a total of 310 unisequenes of fungal origin. Our results indicated that even a small number of organism-specific EST sequences can be very helpful to identify pathogen genes in a library derived from infected tissue, partially overcoming the limitation of the public databases for little studied organisms. However, using the whole genome draft sequence of A. brassicicola we were able to identify approximately 30% more fungal genes in the SSH library than without utilizing this resource. The putative role of specific fungal and plant genes identified in this study in a compatible interaction is discussed.


Opioidergic Regulation of Emotional Arousal: A Combined PET-fMRI Study.
Emotions can be characterized by dimensions of arousal and valence (pleasantness). While the functional brain bases of emotional arousal and valence have been actively investigated, the neuromolecular underpinnings remain poorly understood. We tested whether the opioid and dopamine systems involved in reward and motivational processes would be associated with emotional arousal and valence. We used in vivo positron emission tomography to quantify μ-opioid receptor and type 2 dopamine receptor (MOR and D2R, respectively) availability in brains of 35 healthy adult females. During subsequent functional magnetic resonance imaging carried out to monitor hemodynamic activity, the subjects viewed movie scenes of varying emotional content. Arousal and valence were associated with hemodynamic activity in brain regions involved in emotional processing, including amygdala, thalamus, and superior temporal sulcus. Cerebral MOR availability correlated negatively with the hemodynamic responses to arousing scenes in amygdala, hippocampus, thalamus, and hypothalamus, whereas no positive correlations were observed in any brain region. D2R availability-here reliably quantified only in striatum-was not associated with either arousal or valence. These results suggest that emotional arousal is regulated by the MOR system, and that cerebral MOR availability influences brain activity elicited by arousing stimuli.


A qualitative study of state-level zoonotic disease surveillance in new England.
Zoonotic diseases are infectious diseases transmittable between animals and humans and outbreaks of these diseases in animals can signify that humans are also infected (or vice versa). Thus, communication between animal and human health agencies is critical for surveillance. Understanding how these agencies conduct surveillance and share information is important for the development of successful automated zoonotic monitoring systems. Individual interviews were conducted with 13 professionals who perform animal or human zoonotic disease surveillance in one of the New England states. Questions centred on existing surveillance methods, collaborations between animal and human health agencies, and technological and data needs. The results showed that agencies routinely communicate over suspected zoonotic disease cases, yet there are barriers preventing automated electronic linking of health data of animals and humans. These include technological barriers and barriers due to sensitivity and confidentiality of information. Addressing these will facilitate the development of electronic systems for integrating animal and human zoonotic disease surveillance data.


Adenosine inhibits the transfected Na+-H+ exchanger NHE3 in Xenopus laevis renal epithelial cells (A6/C1).
1. Adenosine influences the vectorial transport of Na+ and HCO3- across kidney epithelial cells. However, its action on effector proteins, such as the Na+-H+ exchanger NHE3, an epithelial brush border isoform of the Na+-H+ exchanger (NHE) gene family, is not yet defined. 2. The present study was conducted in Xenopus laevis distal nephron A6 epithelia which express both an apical adenosine receptor of the A1 type (coupled to protein kinase C (PKC)) and a basolateral receptor of the A2 type (coupled to protein kinase A (PKA)). The untransfected A6 cell line expresses a single NHE type (XNHE) which is restricted to the basolateral membrane and which is activated by PKA. 3. A6 cell lines were generated which express exogenous rat NHE3. Measurements of side-specific pHi recovery from acid loads in the presence of HOE694 (an inhibitor with differential potency towards individual NHE isoforms) detected an apical resistant Na+-H+ exchange only in transfected cell lines. The sensitivity of the basolateral NHE to HOE694 was unchanged, suggesting that exogenous NHE3 was restricted to the apical membrane. 4. Stimulation of the apical A1 receptor with N 6-cyclopentyladenosine (CPA) inhibited both apical NHE3 and basolateral XNHE. These effects were mimicked by the addition of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) and partially prevented by the PKC inhibitor calphostin C which also blocked the effect of PMA. 5. Stimulation of the basolateral A2 receptor with CPA inhibited apical NHE3 and stimulated basolateral XNHE. These effects were mimicked by 8-bromo-cAMP and partially prevented by the PKA inhibitor H89 which entirely blocked the effect of 8-bromo-cAMP. 6. In conclusion, CPA inhibits rat NHE3 expressed apically in A6 epithelia via both the apical PKC-coupled A1 and the basolateral PKA-coupled A2 adenosine receptors.


How the National Health Insurance Coverage policy changed the use of lenvatinib for adult patients with advanced hepatocellular carcinoma: a retrospective cohort analysis with real world big data.
To establish a long-term mechanism to control the cost burden of drugs, the Chinese government organized seven rounds of price negotiations for the national reimbursement drug list (NRDL) from 2016 to the end of 2022. The study aimed to evaluate the impact of the National Health Insurance Coverage (NHIC) policy on the use of lenvatinib as the first-line treatment for advanced hepatocellular carcinoma (HCC) within a specific medical insurance region from the micro perspective of individual patient characteristics. The data of HCC patients that received lenvatinib from September 2019 to August 2022 was retrieved from the Medical and Health Big Data Center and longitudinally analyzed. Contingency table chi-square statistics and binary logistic regression analysis were used to compare the differences in the categorical variables. Interrupted time-series (ITS) regression analysis was performed to evaluate the changes in the utilization of lenvatinib over 36 months. Multiple linear regression was used to analyze the impact of receiving lenvatinib on the total hospitalization expenses of hospitalized patients with advanced HCC. A total of 12,659 patients with advanced HCC were included in this study. The usage rate of lenvatinib increased from 6.19% to 15.28% over 36 months (P < 0.001). By controlling the other factors, consistent with this, the probability of patients with advanced HCC receiving lenvatinib increased by 2.72-fold after the implementation of the NHIC policy (OR = 2.720, 95% CI:2.396-3.088, P < 0.001). Older, residency in rural areas, lack of fixed income, treatment at hospitals below the tertiary level, and coverage by urban-rural residents' basic medical insurance (URRBMI) were the factors affecting the use of lenvatinib among patients with advanced HCC (P < 0.05). After the implementation of the NHIC policy, the total hospitalization expenses increased (Beta=-0.040, P < 0.001). However, compared to patients who received lenvatinib, the total hospitalization expenses were higher for those who did not receive the drug (US$5022.07 ± US$5488.70 vs. US$3701.63 ± US$4330.70, Beta = 0.062, P < 0.001). The NHIC policy has significantly increased the utilization of lenvatinib. In addition, we speculate that establishing multi-level medical insurance systems for economically disadvantaged patients would be beneficial in improving the effectiveness of the NHIC policy in the real world.


Use of serial analysis of gene expression (SAGE) technology.
Serial analysis of gene expression, or SAGE, is an experimental technique designed to gain a direct and quantitative measure of gene expression. The SAGE method is based on the isolation of unique sequence tags (9-10 bp in length) from individual mRNAs and concatenation of tags serially into long DNA molecules for a lump-sum sequencing. The SAGE method can be applied to the studies exploring virtually any kinds of biological phenomena in which the changes in cellular transcription are responsible. SAGE is a highly competent technology that can not only give a global gene expression profile of a particular type of cell or tissue, but also help us identify a set of specific genes to the cellular conditions by comparing the profiles constructed for a pair of cells that are kept at different conditions. In this review, we present an outline of the original method, several studies achieved by using the method as a major strategic tool, technological difficulties and intrinsic problems that emerged, and improvements and modifications of the method to cope with these drawbacks. We then present our modified SAGE procedure that generates longer sequence tags (14 bp) rather in detail, and the profile (80K profile) derived from HeLa cells that is composed of 80000 tags obtained from a single library. In addition, a series of smaller profiles (2, 4, 10, 20 and 40K) was made by dividing the 80K profile. When we compared these smaller profiles with respect to tag counts for a number of genes, it became apparent that counts of most gene tags increase stably and constantly as the size of profiles increase, while several genes do not. This may be another problem we have to keep in mind, when the profiles are compared for the identification of 'specific genes'.


Syringe-injectable mesh electronics integrate seamlessly with minimal chronic immune response in the brain.
Implantation of electrical probes into the brain has been central to both neuroscience research and biomedical applications, although conventional probes induce gliosis in surrounding tissue. We recently reported ultraflexible open mesh electronics implanted into rodent brains by syringe injection that exhibit promising chronic tissue response and recording stability. Here we report time-dependent histology studies of the mesh electronics/brain-tissue interface obtained from sections perpendicular and parallel to probe long axis, as well as studies of conventional flexible thin-film probes. Confocal fluorescence microscopy images of the perpendicular and parallel brain slices containing mesh electronics showed that the distribution of astrocytes, microglia, and neurons became uniform from 2-12 wk, whereas flexible thin-film probes yield a marked accumulation of astrocytes and microglia and decrease of neurons for the same period. Quantitative analyses of 4- and 12-wk data showed that the signals for neurons, axons, astrocytes, and microglia are nearly the same from the mesh electronics surface to the baseline far from the probes, in contrast to flexible polymer probes, which show decreases in neuron and increases in astrocyte and microglia signals. Notably, images of sagittal brain slices containing nearly the entire mesh electronics probe showed that the tissue interface was uniform and neurons and neurofilaments penetrated through the mesh by 3 mo postimplantation. The minimal immune response and seamless interface with brain tissue postimplantation achieved by ultraflexible open mesh electronics probes provide substantial advantages and could enable a wide range of opportunities for in vivo chronic recording and modulation of brain activity in the future.


Methodological Rigor and Temporal Trends of Cardiovascular Medicine Meta-Analyses in Highest-Impact Journals.
Background Well-conducted meta-analyses are considered to be at the top of the evidence-based hierarchy pyramid, with an expansion of these publications within the cardiovascular research arena. There are limited data evaluating the trends and quality of such publications. The objective of this study was to evaluate the methodological rigor and temporal trends of cardiovascular medicine-related meta-analyses published in the highest impact journals. Methods and Results Using the Medline database, we retrieved cardiovascular medicine-related systematic reviews and meta-analyses published in The New England Journal of Medicine, The Lancet, Journal of the American Medical Association, The British Medical Journal, Annals of Internal Medicine, Circulation, European Heart Journal, and Journal of American College of Cardiology between January 1, 2012 and December 31, 2018. Among 6406 original investigations published during the study period, meta-analyses represented 422 (6.6%) articles, with an annual decline in the proportion of published meta-analyses (8.7% in 2012 versus 4.6% in 2018, Ptrend=0.002). A substantial number of studies failed to incorporate elements of Preferred Reporting Items for Systematic Reviews and Meta-Analyses or Meta-Analysis of Observational Studies in Epidemiology guidelines (51.9%) and only a minority of studies (10.4%) were registered in PROSPERO (International Prospective Register of Systematic Reviews). Fewer manuscripts failed to incorporate the Preferred Reporting Items for Systematic Reviews and Meta-Analyses or Meta-Analysis of Observational Studies in Epidemiology elements over time (60.2% in 2012 versus 40.0% in 2018, Ptrend<0.001) whereas the number of meta-analyses registered at PROSPERO has increased (2.4% in 2013 versus 17.5% in 2018, Ptrend<0.001). Conclusions The proportion of cardiovascular medicine-related meta-analyses published in the highest impact journals has declined over time. Although there is an increasing trend in compliance with quality-based guidelines, the overall compliance remains low.