Personalized Breast Cancer Screening.
Abundant literature and clinical trials indicate that routine cancer screenings decrease patient mortality for several common cancers. However, current national cancer screening guidelines heavily rely on patient age as the predominant factor in deciding cancer screening timing, neglecting other important medical characteristics of individual patients. This approach either delays screening or prescribes excessive screenings. Another disadvantage of the current approach is its inability to combine information across hospital systems because of the lack of a coherent records system. We propose to use claims data and medical insurance transactions that use consistent and pre-established sets of codes for diagnosis, procedures, and medications to develop a clinical support tool to supply supplemental insights and precautions for physicians to make more informed decisions. Furthermore, we propose a novel machine learning framework to recommend personalized, data-driven, and dynamic screening decisions. We apply this new method to the study of breast cancer mammograms using claims data from 378,840 female patients to demonstrate that across different risk populations, personalized screening reduces the average delay in a cancer diagnosis by 2-3 months with statistical significance, with even stronger benefits for individual patients up to 10 months. Incorporating personal medical characteristics using claims data and novel machine learning methodologies into breast cancer screening improves screening delay by more dynamically considering changing patient risks. Future incorporation of the proposed methodology in health care settings could be provided as a potential support tool for clinicians.


Protocol for a cluster randomised controlled trial on information technology-enabled nutrition intervention among urban adults in Chandigarh (India): SMART eating trial.
Nutrition is an important determinant of health. At present, nutrition programs in India mainly emphasize improving maternal and child nutrition. Adult nutrition has not received due attention, though diseases like hypertension and diabetes are largely preventable through changes in dietary and physical activity behaviour. Little is known about the best approaches to improve dietary behaviours, especially the role of modern information technology (IT) in health education. We describe the protocol of the SMART Eating (Small, Measurable and Achievable dietary changes by Reducing fat, sugar and salt consumption and Trying different fruits and vegetables) health promotion intervention. A Cluster Randomised Controlled Trial will evaluate the effect of an IT-enabled intervention on nutrition behaviour among urban adults of Chandigarh, India. Formative research using a qualitative exploratory approach was undertaken to inform the intervention. The IT-enabled intervention programme includes website development, Short Message Service (SMS), e-mail reminders and interactive help by mobile and landline phones. The IT-enabled intervention will be compared to the traditional nutrition education program of distributing pamphlets in the control group. The primary outcome will be the percentage of study participants meeting the dietary intake guidelines of the National Institute of Nutrition, Hyderabad, India and the change in intake of fat, sugar, salt, fruit and vegetables after the intervention. The difference in differences method will be used to determine the net change in dietary intakes resulting from the interventions. Measurements will be made at baseline and at 6 months post-intervention, using a food frequency questionnaire. The formative research led to the development of a comprehensive intervention, focusing on five dietary components and using multi-channel communication approach including the use of IT to target urban North Indians from diverse socio-economic backgrounds. The Cluster Randomised Controlled Trial design is suitable for evaluating the effectiveness of this IT-enabled intervention for dietary behaviour change.


Schizophrenia-related cognitive dysfunction in the Cyclin-D2 knockout mouse model of ventral hippocampal hyperactivity.
Elevated activity at the output stage of the anterior hippocampus has been described as a physiological endophenotype of schizophrenia, and its development maps onto the transition from the prodromal to the psychotic state. Interventions that halt the spreading glutamatergic over-activity in this region and thereby the development of overt schizophrenia could be promising therapies. However, animal models with high construct validity to support such pre-clinical development are scarce. The Cyclin-D2 knockout (CD2-KO) mouse model shows a hippocampal parvalbumin-interneuron dysfunction, and its pattern of hippocampal over-activity shares similarities with that seen in prodromal patients. Conducting a comprehensive phenotyping of CD2-KO mice, we found that they displayed novelty-induced hyperlocomotion (a rodent correlate of positive symptoms of schizophrenia), that was largely resistant against D1- and D2-dopamine-receptor antagonism, but responsive to the mGluR2/3-agonist LY379268. In the negative symptom domain, CD2-KO mice showed transiently reduced sucrose-preference (anhedonia), but enhanced interaction with novel mice and objects, as well as normal nest building and incentive motivation. Also, unconditioned anxiety, perseveration, and motor-impulsivity were unaltered. However, in the cognitive domain, CD2-knockouts showed reduced executive function in assays of rule-shift and rule-reversal learning, and also an impairment in working memory, that was resistant against LY379268-treatment. In contrast, sustained attention and forms of spatial and object-related memory that are mediated by short-term habituation of stimulus-specific attention were intact. Our results suggest that CD2-KO mice are a valuable model in translational research targeted at the pharmacoresistant cognitive symptom domain in causal relation to hippocampal over-activity in the prodrome-to-psychosis transition.


Heterogeneity of the Type I Interferon Signature in Rheumatoid Arthritis: A Potential Limitation for Its Use As a Clinical Biomarker.
An increased expression of interferon (IFN)-responding genes (IRGs), the so-called IFN signature, has been reported in rheumatoid arthritis (RA). However, some controversy exists concerning its clinical relevance. The main aim of this study is to evaluate whether quantitative and qualitative differences in the activation of the IFN pathway may account for these findings. The expression of IFN-induced protein 44 (IFI44), IFN-induced protein 44 like (IFI44L), IFN alpha inducible protein 6, and MX dynamin-like GTPase 1 (MX1) was determined in peripheral blood in 98 RA patients (IFI6) and 28 controls. RA patients were classified into groups according to their clinical stage and treatments received: very early RA (VERA), biological disease-modifying antirheumatic drug (bDMARD) naive, and bDMARD. An additional group of 13 RA patients candidates for tumor necrosis factor alpha (TNFα) blockade was also recruited. The associations among IRGs were evaluated by network and principal component analyses. The expression of all IRGs was increased in RA to different levels. The IFN score was increased in all RA groups (VERA, bDMARD-naïve, and bDMARD), but important differences in their degree of activation and in the relationships among IRGs were observed. The IFN score correlated with the accumulated disease activity score 28-joints, and it was found to be a predictor of clinical outcome in VERA. No differences in the IFN score were observed between the bDMARD-naive and bDMARD groups, but opposite associations with the clinical parameters were noted. Interestingly, the correlations among IRGs delineate different pictures between these two groups. The IFN score at baseline predicted poor clinical outcome upon TNFα blockade. Although no absolute changes in the IFN score were found, TNFα-blockade shifted the associations among IRGs. A certain heterogeneity within the IFN signature can be recognized in RA, depending on the clinical stage. The structure of the IFN signature may be a potential explanation for the controversy in this field and must be considered to decipher its clinical relevancein RA.


Impact of energy and industrial structure on environmental quality and urbanization: evidence from a panel of BRICS countries.
Global sustainable development demands boosting renewable energy and optimizing industrial structures. This study employs a panel vector autoregressive (PVAR) model to examine the dynamic relationship between energy structure, industrial structure, environmental quality, and urbanization in the BRICS countries from 1990 to 2021. Energy structure, industrial structure, environmental quality, and urbanization cointegrate empirically. Energy mix optimization and industrial structure upgrades can improve environmental quality. Energy enhancements also supported urbanization. Accelerating industrial change could adversely impact urbanization. The impulse response results demonstrate that expanding renewable energy and tertiary industries such as financial and service boost environmental quality and urbanization. The variance decomposition investigation reveals significant "path dependence" in reducing carbon emissions and increasing urbanization. Finally, based on the findings, policy insights for enhancing environmental quality and fostering urbanization are laid out and disputed, with long-term implications for environmental managers and urban planners.


A critical analysis of approaches to targeted PTSD prevention: current status and theoretically derived future directions.
Although efforts to prevent posttraumatic stress disorder (PTSD) have met with relatively limited success, theoretically driven preventive approaches with promising efficacy are emerging. The current article critically reviews investigations of PTSD prevention programs that target persons at risk for being exposed to a traumatic event or who have been exposed to a traumatic event. This review uniquely extends prior reviews in this area by using theories of PTSD to suggest future directions in the area of PTSD prevention. The authors first discuss the primary mechanisms of action believed to account for the failure for PTSD symptoms to remit among a substantial minority of traumatic event-exposed individuals. Second, empirical progress in PTSD prevention efforts is reviewed. Third, the authors consider how existing prevention programs target these mechanisms of action. Finally, the authors consider directions for future research in the area of targeted PTSD prevention.


Multi-walled carbon nanotube-induced gene expression in vitro: concordance with in vivo studies.
There is a current interest in reducing the in vivo toxicity testing of nanomaterials in animals by increasing toxicity testing using in vitro cellular assays; however, toxicological results are seldom concordant between in vivo and in vitro models. This study compared global multi-walled carbon nanotube (MWCNT)-induced gene expression from human lung epithelial and microvascular endothelial cells in monoculture and coculture with gene expression from mouse lungs exposed to MWCNT. Using a cutoff of 10% false discovery rate and 1.5 fold change, we determined that there were more concordant genes (gene expression both up- or downregulated in vivo and in vitro) expressed in both cell types in coculture than in monoculture. When reduced to only those genes involved in inflammation and fibrosis, known outcomes of in vivo MWCNT exposure, there were more disease-related concordant genes expressed in coculture than monoculture. Additionally, different cellular signaling pathways are activated in response to MWCNT dependent upon culturing conditions. As coculture gene expression better correlated with in vivo gene expression, we suggest that cellular cocultures may offer enhanced in vitro models for nanoparticle risk assessment and the reduction of in vivo toxicological testing.


Site-specific DNA binding of nuclear factor I: effect of the spacer region.
Nuclear factor I (NFI) is a site-specific DNA binding protein required for the replication of adenovirus type 2 DNA in vitro and in vivo. To study sequence requirements for the interaction of NFI with DNA, we have measured the binding of the protein to a variety of synthetic sites. Binding sites for NFI (FIB sites) were previously shown to contain a consensus sequence composed of 2 motifs, TGG (Motif 1), and GCCAA (Motif 2), separated by a 6 or 7bp spacer region. To assess conserved sequences in the spacer region and flanking sequences which affect NFI binding, we have isolated clones from oligonucleotide libraries that contain the two motifs flanked by 3 degenerate nucleotides and separated by degenerate spacer regions of 6 or 7 nucleotides. With a 6bp spacer region, a strong bias exists for a C or A residue in the first position of the spacer. Sites with a 7bp spacer region contain a G and C or A residue at the first and second positions, respectively, of the spacer, but also possess conserved residues at other positions of the site.


Control analysis of the importance of phosphoglycerate enolase for metabolic fluxes in Lactococcus lactis subsp. lactis IL1403.
The glycolytic enzyme phosphoglycerate enolase (PGE) catalyses the step from 2-phosphoglycerate to phosphoenolpyruvate in glycolysis. A control analysis of PGE on growth, glycolytic flux and product formation in Lactococcus lactis subsp. lactis IL1403 is presented. A library of strains with a modulated expression of PGE from 36 to 232% relative to wildtype level was constructed. Selected strains were studied with respect to growth, glycolytic flux and product formation in a chemically defined medium. On the basis of these data, flux control coefficients of PGE on the respective fluxes were calculated. At wildtype level, PGE was found to have no significant flux control on growth, glycolytic flux or product formation, but at 36% of PGE activity relative to wildtype, the flux control on the growth rate was estimated to be C(PGE)J(micro) approximately equal to 0.7, on the glycolytic flux C(PGE)J(g) approximately equal to 0.8, on lactate formation C(PGE)J(lactate) approximately equal to 1.3, on formate formation C(PGE)J(formate) approximately equal to 0.5 and on acetate formation C(PGE) J(acetate) approximately equal to 0.25. These flux control coefficients show that the metabolism of L. lactis subsp. lactis IL1403 becomes slightly more mixed acid at reduced PGE activities. Estimation of the relative turnover of PGE indicates that excess capacity of PGE in L. lactis IL1403 may be as low as twofold.


Questionnaire-based survey on distribution and clinical incidence of canine babesiosis in France.
The causative agent of canine babesiosis is the protozoan Babesia canis, transmitted by the tick Dermacentor reticulatus within France. While the parasite can be found everywhere in France however cases of infection are associated with distinct geographical foci. The aim of the study was to evaluate the clinical occurrence of canine babesiosis diagnosed in veterinary clinics in order to propose an updated map of the disease distribution in France. Questionnaires were sent via email to all canine veterinary clinics in continental France. Information collected included the number of babesiosis cases diagnosed in 2010, the number of veterinary practitioners and the location of the clinic. The total number of dogs and practitioners per administrative department were used to define the reference population. The annual incidence rate of canine babesiosis per department was calculated as the ratio between the number of babesiosis cases reported by the clinics and the total number of dogs in the clinics of the same department. Data were geo-referenced for map construction (Quantum GIS version 1.7.4). The overall annual incidence rate of clinical babesiosis among the surveyed population was 1.07% (CI95 1.05-1.09) with geographical variations between departments, ranging from 0.01% to 16.05%. Four enzootic areas were identified: South-West, Center, East and Paris area. The South-West region should be considered as a hyper-enzootic area with the higher incidence rates. Our results confirmed the burden of canine babesiosis in France. In the context of tick-borne disease emergence in Europe, the risk for canine babesiosis may become more significant in other European countries in the coming years.


Familial Hypercholesterolemia: Real-World Data of 1236 Patients Attending a Czech Lipid Clinic. A Retrospective Analysis of Experience in More than 50 years. Part II. Clinical Characteristics.
Introduction: Patients with familial hypercholesterolemia (FH) are at increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Aim of study: To perform a retrospective analysis of data to assess the effects of individual lipoproteins and other risk factors (RFs) on the development of ASCVD and to compare these parameters in individuals with versus without ASCVD. Patients and methods: Our study group included a total of 1,236 patients with FH (395 men and 841 women with a mean age of 44.8 ± 16.7 years) attending a single lipid clinic. The diagnosis of FH was established using the Dutch Lipid Clinic Network score (DLCN). Among the 1236 FH patients, 1,008 of them [854 suspected with LDL receptor-mediated FH and 154 with familial defective apolipoprotein B-100 (FDB)] were genetically analysed. Their RFs were assessed based on the patients' clinical characteristics. Results: While patients with ASCVD had higher baseline LDL-C, TC, TG and Lp(a) compared with patients without this diagnosis, this ratio was just the opposite by the follow-up. The highest statistically significant differences were seen in the baseline levels of Lp(a) and, quite surprisingly, TG. Except for Lp(a), the levels of all lipid parameters declined significantly over time. While the incidence of diabetes and arterial hypertension was not higher in our group compared with the general population, these patients were at a more significant risk of ASCVD. Conclusion: Familial hypercholesterolemia is a major RF for the development of ASCVD. While our analysis confirmed the important role of LDL-C, it also corroborated a strong correlation between ASCVD and other lipid parameters, and Lp(a) and TG in particular. Familial hypercholesterolemia is not the only RF and, to reduce cardiovascular risk of their patients, physicians have to search for other potential RFs. Patients diagnosed to have FH benefit from attending a specialized lipid clinic perse.


[Deep venous thrombosis of lower extremities in an Emergency Department. Utility of a clinical diagnosis model].
Deep vein thrombosis (DVT) is a difficult to diagnostic disease. The aim of this study was to determine the utility and accuracy of a risk stratification questionnaire and a diagnostic strategy, which were applied to patients with suspected DVT on lower extremities in an emergency department. A prospective cohort study was performed in 569 outpatients with clinical suspected DVT during 14 months. The applied questionnaire stratified patients into three pre-test probability categories. Items included signs, symptoms, risk factors and potential alternative diagnosis, which were based on a modified Wells clinical model. DVT was diagnosed by the combined use of clinical model, compression ultrasonography (CUS) and follow-up CUS one week later in those moderate-high risk patients with an initial normal test. These patients were followed over three months for the development of venous thromboembolic complications. Two hundred three (35.7%) patients were classified as having a low, 186 (32.7%) moderate and 180 (31.6%) high clinical probability. Overall, DVT was diagnosed in 153 patients (26%; CI95%, 23.2-30.7%): 144 (96%) at the initial CUS, 6 (3.5%) at the second testing and 3 over the 3-month follow-up period. 22 patients had a low pretest probability (11%; CI95%, 7-16%), 43 (23%; CI95%, 17-30%) moderate, and 88 (49%; CI95%, 41-56%) high pretest probability. The difference in the prevalence of DVP among risk categories was significant (p < 0.00001). When the high and moderate groups were joined, the model had a 86% sensitivity, a 90% negative predictive value and a 43% specificity for diagnosis of DVT. The clinical model used in this study is accurate and feasible, though it is not enough to take clinical decisions. The diagnostic strategic used is effective but not efficient.


[Inhibitory effects of rosiglitazone against endothelin-1-induced proliferation of rat cardiac myocytes: the role of PKC-c-fos pathway].
To investigate the mechanism of rosiglitazone (RSG, the activator of peroxisome proliferators activated receptor lambda) for inhibiting endothelin-1 (ET-1)-induced neonatal rat cardiac myocyte hypertrophy and the role of protein kinase C (PKC) and c-fos. In vitro cultured neonatal rat cardiac myocytes were treated with ET-1, phorbol ester (PMA, the PKC activator), ET-1+RSG, ET-1+chelerythrine (che, the PKC inhibitor), PMA+RSG, or without treatment (control), respectively. The effects of RSG on the protein content, (3)H-leucine incorporation, PKC activity and C-fos protein expression were observed in the cardiac myocytes stimulated with ET-1 or PMA. After two days of culture, the intracellular protein content in ET-1 group and PMA group were increased by 15% (339-/+15 microg/ml) and 13% (329-/+14 microg/ml) as compared with the control cells (290-/+13 microg/ml), respectively (P<0.01). Compared with the ET-1 group, cells treated with ET-1+10(-8) mol/L RSG, ET-1+10(-7) mol/L RSG, and ET-1+che showed decreased intracellular protein content by 10% (303-/+14 microg/ml, P<0.05), 12% (292-/+11 microg/ml, P<0.05), and 13% (291-/+12 microg/ml, P<0.01), respectively. The intracellular protein content in PMA+10(-7) mol/LRSG group was decreased by 10% (P<0.05) in comparison with the PMA group. RSG inhibited protein synthesis enhancement and increased (3)H-leucine incorporation induced by ET-1 and PMA, and antagonized the effects of ET-1 and PMA in promoting PKC activity and c-fos protein expression in the myocytes. The inhibitory effect of RSG on ET-1- or PMA-induced myocyte hypertrophy is associated with PKC-c-fos pathway.


Sepsis: Current Definition, Pathophysiology, Diagnosis, and Management.
Sepsis is a clinical syndrome that results from the dysregulated inflammatory response to infection that leads to organ dysfunction. The resulting losses to society in terms of financial burden, morbidity, and mortality are enormous. We provide a review of sepsis, its underlying pathophysiology, and guidance for diagnosis and management of this common disease. Current established treatments include appropriate antimicrobial agents to target the underlying infection, optimization of intravascular volume to improve stroke volume, vasopressors to counteract vasoplegic shock, and high-quality supportive care. Appropriate implementation of established treatments combined with novel therapeutic approaches promises to continue to decrease the impact of this disease.


[Guidelines for action and diagnosis in atherothrombosis in Spain: ADA Study (Action and Diagnosis in Atherothrombosis)].
The ADA Study was designed to know the usual action guidelines in Spain for the diagnosis and treatment in a cohort of patients who had a recent atherothrombotic event. Cross-sectional, observational, multicenter epidemiologic study (294 hospitals) with a total of 3,512 patients enrolled. Patients had had an atherothrombotic event in the coronary or cerebral vascular territory in the previous month or were diagnosed of symptomatic peripheral arterial disease within the last 3 months. A total of 237 investigators (155 cardiologists, 113 neurologists, and 79 vascular surgeons) participated in the study. 54.9% of patients in the study had a previous atherothrombotic event. Of these, 63.1% were on antithrombotic therapy; after the second episode, 2.6% of patients were on no preventive therapy. A great disparity and an excessive number of diagnostic tests was found to confirm the diagnosis of the current atherothrombotic event, which is in contrast with a small percentage of patients who had exams performed to confirm or rule out the atherothrombotic involvement in other vascular territories. An appropriate protocol should be established for the diagnosis and therapy of patients with the likelihood of having clinical manifestations due to an ahterothrombotic event.


News in brief: [Anglican Archbishop Desmond Tutu voices strong support for family planning].
On June 16, the Day of the African Child, Anglican Archbishop Desmond Tutu of South Africa voiced his strong support for family planning. At a Cape Town news conference, the church leader said, "Planned parenthood is an obligation of those who are Christians. Our church thinks we should use scientific methods that assist in planning of families... It is far better to have children that we want than to say you must have children, no matter what." In regard to ICPD, the archbishop said, "The call that is being put out for this UN conference...is not just a Western thing. There are very many in other parts of the world who believe the issues raised there are crucial issues." The UN Children's Fund sponsors the annual Day of the African Child to call attention to the problems facing African children. The date was chosen in memory of the children of Soweto, South Africa, who were massacred on 16 June 1976, when Africans tried to speak out against the brutality of apartheid.


Natronolimnobius aegyptiacus sp. nov., an extremely halophilic alkalithermophilic archaeon isolated from the athalassohaline Wadi An Natrun, Egypt.
An obligately aerobic extremely halophilic alkalithermophilic archaeon, strain JW/NM-HA 15T, was isolated from the sediments of Wadi An Natrun in Egypt. Phylogenetic analysis based on 16S rRNA and rpoB' gene sequences indicated that it belongs to the family Natrialbaceae of the order Natrialbales. The closest relatives were Natronolimnobius baerhuensis IHC-005T and Natronolimnobius innermongolicus N-1311T (95.3 and 94.5 % 16S rRNA gene sequence similarity, respectively). Genome relatedness between strain JW/NM-HA 15T and its neighbours was evaluated using average nucleotide identity, digital DNA-DNA hybridization and average amino acid identity with the values of 75.7-85.0, 18.1-20.0, and 70.2-71.0%, respectively. Cells were obligately aerobic, rod-shaped, non-motile, Gram-stain-negative and chemo-organotrophic. The strain grew in the presence of 2.57 M to saturating Na+ (optimum 3.25-4.60 M Na+), at pH55 °C 7.5-10.5 (optimum pH55 °C 9.0-9.5), and at 30-56 °C (optimum 52 °C). The major polar lipids consisted of phosphatidylglycerol, methylated phosphatidylglycerolphosphate and two phospholipids. The complete genome size of strain JW/NM-HA 15T is approximately 3.93 Mb, with a DNA G+C content of 64.1 mol%. On the basis of phylogenetic features, genomic relatedness, phenotypic and chemotaxonomic data, strain JW/NM-HA 15T was thus considered to represent a novel species within the genus Natronolimnobius, for which the name Natronolimnobius aegyptiacus sp. nov. is proposed. The type strain is JW/NM-HA 15T (=ATCC BAA-2088T =DSM 23470T).


Trichosanthes pericarpium Aqueous Extract Enhances the Mobilization of Endothelial Progenitor Cells and Up-regulates the Expression of VEGF, eNOS, NO, and MMP-9 in Acute Myocardial Ischemic Rats.
Trichosanthes pericarpium (TP) had been widely used to cure patients of cardiovascular disease for 2,000 years in China. This study aims to extend our previous work to explore the mechanism underlying the protective effect of TP on acute myocardial ischemia (AMI). We hypothesized that TP may display its protective effect on AMI by promoting the mobilization of endothelial progenitor cells (EPC) via up-regulating the expression level of vascular endothelial growth factor (VEGF), endothelial nitric oxide syntheses (eNOS), nitric oxide (NO), and matrix metalloproteinase 9 (MMP-9) in AMI rats. To confirm this hypothesis, we treated AMI model rats with intragastrical administration of TP aqueous extract (TPAE), and examined both changes in the number of CEPC, and the expression levels of VEGF, eNOS, NO, and MMP-9 in myocardial tissue and their plasma content in these rats. Rats in each group were randomly divided into seven subgroups. From day 1 to 7 following AMI modeling, rats in these subgroups was sequentially phlebotomized from their celiac artery after being anesthetized by chloral hydrate. We found that, compared with the AMI model rats, in rats treated by TPAE, the CEPC counts, the expression of VEGF, eNOS, NO, and MMP-9 in myocardial tissue and their plasma content all increased more rapidly 7 days after AMI and remained at higher level (P < 0.05 or P < 0.01). Our results showed that, in AMI rats, the TPAE could significantly promote the mobilization of EPC and up-regulate the expression level of VEGF, eNOS, NO, and MMP-9 in myocardium and their plasma content. Therefore, our results suggest that TAPE may regulate EPC mobilization through up-regulating the expression level of VEGF, eNOS, NO and MMP-9 in the myocardium of AMI rats.


The Impact of Hypromellose on Pharmaceutical Properties of Alginate Microparticles as Novel Drug Carriers for Posaconazole.
Fungal infections are a group of diseases which are challenging to treat because of drug-resistant fungi species, drug toxicity, and often severe patient conditions. Hence, research into new treatments, including new therapeutic substances and novel drug delivery systems, is being performed. Mucoadhesive dosage forms are beneficial to improving drug bioavailability by prolonging the residence time at the site of application. Sodium alginate is a natural polymer with favorable mucoadhesive and gelling properties, although its precipitation in acidic pH significantly disrupts the process of drug release in gastric conditions. Hypromellose is a hydrophilic, semi-synthetic cellulose derivative with mucoadhesive properties, which is widely used as a control release agent in pharmaceutical technology. The aim of this study was to evaluate the impact of hypromellose on alginate microparticles with posaconazole, designed to modify drug release and to improve their mucoadhesive properties for both oral or vaginal application.


Salmonella Oranienburg infections associated with fruit salad served in health-care facilities--northeastern United States and Canada, 2006.
During June-July 2006, a total of 41 culture-confirmed Salmonella serotype Oranienburg infections were diagnosed in persons in 10 northeastern U.S. states and one Canadian province. This report describes the epidemiologic, environmental, and laboratory investigations of this outbreak by federal, state, and local health agencies; the Food and Drug Administration (FDA); and the Canadian Food Inspection Agency. The results of the investigations determined that illness was associated with eating fruit salad in health-care facilities. Although the fruit salads were produced by one processing plant, the source of contamination was not determined. This outbreak highlights the importance of laboratory-based surveillance of Salmonella, including molecular subtyping, and timely communication of public health information.


Neuroticism is associated with altered resting-state functional connectivity of amygdala following acute stress exposure.
The amygdala, a subcortical structure responsible for fear and vigilance, is central to the stress circuitry. Aberrant amygdala connectivity with the cortical and subcortical regions is found in patients with stress-related disorders, and in healthy subjects following acute stress exposure. However, the extent to which the stress-induced alteration of amygdala functional connectivity correlates with risk-related personality measures remains unclear. Using resting-state functional magnetic resonance imaging, we evaluated the effect of acute stress, induced by aversive movies accompanied by a mild electric shock, on the functional connectivity of the basolateral amygdala (BLA) and centromedial amygdala (CMA) in 35 healthy men, and assessed the association between changes in amygdala functional connectivity and individual differences in neuroticism. We found increased BLA functional connectivity with the posterior cingulate cortex/retrosplenial and increased CMA functional connectivity with the medial prefrontal cortex following acute stress exposure. Moreover, neuroticism was positively correlated with altered functional coupling of the basolateral subregions with the anterior insular cortex, dorsal anterior cingulate cortex, and pregenual anterior cingulate cortex, which are involved in salience processing. These findings suggest that neurotic individuals may be more prone to hypervigilance following acute stress, which may potentially link neuroticism to the neurobiology underlying increased susceptibility to stress-related disorders.


A meta-analysis of gene expression quantitative trait loci in brain.
Current catalogs of brain expression quantitative trait loci (eQTL) are incomplete and the findings do not replicate well across studies. All existing cortical eQTL studies are small and emphasize the need for a meta-analysis. We performed a meta-analysis of 424 brain samples across five studies to identify regulatory variants influencing gene expression in human cortex. We identified 3584 genes in autosomes and chromosome X with false discovery rate q<0.05 whose expression was significantly associated with DNA sequence variation. Consistent with previous eQTL studies, local regulatory variants tended to occur symmetrically around transcription start sites and the effect was more evident in studies with large sample sizes. In contrast to random SNPs, we observed that significant eQTLs were more likely to be near 5'-untranslated regions and intersect with regulatory features. Permutation-based enrichment analysis revealed that SNPs associated with schizophrenia and bipolar disorder were enriched among brain eQTLs. Genes with significant eQTL evidence were also strongly associated with diseases from OMIM (Online Mendelian Inheritance in Man) and the NHGRI (National Human Genome Research Institute) genome-wide association study catalog. Surprisingly, we found that a large proportion (28%) of ~1000 autosomal genes encoding proteins needed for mitochondrial structure or function were eQTLs (enrichment P-value=1.3 × 10(-9)), suggesting a potential role for common genetic variation influencing the robustness of energy supply in brain and a possible role in the etiology of some psychiatric disorders. These systematically generated eQTL information should be a valuable resource in determining the functional mechanisms of brain gene expression and the underlying biology of associations with psychiatric disorders.


[Initial status of the medical management of pediatric and adolescent type I diabetic patients].
Based upon a large number of type I diabetics, representative of diabetes in childhood and adolescence of the GDR and taking into consideration communication in the literature, the present position is commented on autoimmune pathogenesis, immune intervention, frequency of complications, optimizing of therapy and on social-medical aspects of the diabetic child in school. Besides first degree diabetes heredity, degree of HLA identity with the index case, disturbances of glucose tolerance and insulin secretion, auto-immunological phenomena directed against islet cells have to be considered without doubt as risk factors for diabetes. But absolutely reliable markers of an imminent diabetes onset do not exist. The frequency of somatic retardations and diabetes-specific complications is low under multiple insulin injection regime, used in 87 per cent. However, their occurrence alone should stimulate to remove existing differences between clinical achievable metabolic compensation (good: 60%; bad: 2.5%) and longterm metabolic control (good: 40%; bad: 22%). In order to realize this aim, medical care is orientated mainly on qualification of patients and their parents to self-adaption of the insulin dose regime in dependence on values of home-monitoring.


A systematic review of the risk management frameworks for potentially toxic chemical elements.
In the last 50 years, various frameworks have been used to control and manage potentially toxic chemical risks; however, these chemicals continue to negatively impact environmental and human health. This work was intended to provide a systematic review of the literature on essential aspects of current risk management frameworks for potentially toxic chemicals. The frameworks were reviewed using Organisation for Economic Co-operation and Development (OECD) principles that focus on elements, successes, shortcomings, similarities, and dissimilarities premised on the experiences of many countries. Keywords such as heavy metals, health risk, industrial chemicals, potentially toxic elements, chemical pollutants, and risk management framework were utilised to search the literature from databases and other sources. Ten risk framework documents selected from an initial yield of 1349 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow processes met the inclusion criteria. The key elements of risk frameworks that were identified included the risk assessment paradigm, iteration, tiered approach, weight of evidence, uncertainty analysis, and multi-criteria decision analysis among others. Notable gaps in risk frameworks that required improvements to effectively manage health risks posed by potentially toxic chemicals were identified. While existing risk frameworks have made significant contributions to human health and environmental protection, new and comprehensive frameworks are needed to address the novel and dynamic risks posed by toxic industrial chemicals. Also, there is a need to promote the use of risk management frameworks in developing countries through technology transfer and the provision of financial assistance to improve environmental and public health protection from toxic chemicals.


Production of bioactive cellulose films reconstituted from ionic liquids.
A new method for introducing enzymes into cellulosic matrixes which can be formed into membranes, films, or beads has been developed using a cellulose-in-ionic-liquid dissolution and regeneration process. Initial results on the formation of thin cellulose films incorporating dispersed laccase indicate that active enzyme-encapsulated films can be prepared using this methodology and that precoating the enzyme with a second, hydrophobic ionic liquid prior to dispersion in the cellulose/ionic liquid solution can provide an increase in enzyme activity relative to that of untreated films, presumably by providing a stabilizing microenvironment for the enzyme.


Adaptation of aquatic microbial communities to pollutant stress.
The importance of microbial adaptation in the removal of environmental pollutants and in maintaining active microbial communities in impacted ecosystems is discussed using the biodegradation of p-nitrophenol and the volatilization of mercuric mercury as examples. A molecular mechanism of adaptation is suggested by enrichment of mercury resistance (mer) genes in some communities upon exposure to mercury.


To be or not to be a living donor: questionnaire to parents of children who have undergone renal transplantation.
Between 1981 and 1994, 67 transplantations were performed in 59 children below 16 years of age at Huddinge University Hospital. In most of the cases, one of the parents was the donor. The aim of this study was to evaluate how the transplantation influenced the parents. One hundred sixteen individual questionnaires were sent out to the donor parents and to the parents who for different reasons had not been donors. Of special interest was to investigate the emotional reactions, the social consequences, the relationship to the child, and the parents' attitudes toward donation. Thirty-five donors and 41 nondonors replied. The majority of both donors and nondonors were satisfied with the medical information. The nondonors expressed more stress and anxiety before the transplantation. More than half of the donors experienced the operation as more painful than they had expected. Despite this fact, the nondonors showed significantly more psychosomatic/psychiatric symptoms than the donors after the operation. The donors reported an improved relation to the recipient child after the transplantation to a greater extent than the nondonors. Half of the donors reported an improved self-esteem after the donation. None of the donors regretted their donation and all of them would do the same again. This study indicates that ethical and psychological risks in parental kidney donation should not be regarded as a major obstacle. However, irrespective of the parents being a donor or not, they wanted more psychosocial support both before, during, and after the transplantation.


Prone position for the prevention of lung infection.
Pulmonary infection is frequent in brain injured patients. It has been identified as an independent predictor of unfavorable neurological outcome, calling for attempts of prevention. We recently evaluated intermittent prone positioning for the prevention of ventilator-associated pneumonia (VAP) in comatose brain injured patients, in a randomized study. 25 patients were included in the prone position (PP) group: they were positioned on prone four hours once daily until they could get up to sit in an armchair; 26 patients were included in the supine position (SP) group. The main characteristics of the patients from the two groups were similar at randomization. The primary end-point was the incidence of lung worsening, defined by an increase in the Lung Injury Score by at least one point since the time of randomization. The incidence of lung worsening was lower in the PP group (12%) than in the SP group (50%) (p=0.003). The incidence of VAP was 38.4% in the SP group and 20% in the PP group (p=0.14). There was no serious complication attributable to prone positioning. In conclusion, the beneficial effect of prone positioning for prevention of lung infection in brain injured patients is not well established. However, in those patients, prone positioning is able to avoid the worsening of pulmonary function, especially in oxygenation.


Relic DNA obscures DNA-based profiling of multiple microbial taxonomic groups in a river-reservoir ecosystem.
Numerous studies have investigated the spatiotemporal variability in water microbial communities, yet the effects of relic DNA on microbial community profiles, especially microeukaryotes, remain far from fully understood. Here, total and active bacterial and microeukaryotic community compositions were characterized using propidium monoazide (PMA) treatment coupled with high-throughput sequencing in a river-reservoir ecosystem. Beta diversity analysis showed a significant difference in community composition between both the PMA untreated and treated bacteria and microeukaryotes; however, the differentiating effect was much stronger for microeukaryotes. Relic DNA only resulted in underestimation of the relative abundances of Bacteroidota and Nitrospirota, while other bacterial taxa exhibited no significant changes. As for microeukaryotes, the relative abundances of some phytoplankton (e.g. Chlorophyta, Dinoflagellata and Ochrophyta) and fungi were greater after relic DNA removal, whereas Cercozoa and Ciliophora showed the opposite trend. Moreover, relic DNA removal weakened the size and complexity of cross-trophic microbial networks and significantly changed the relationships between environmental factors and microeukaryotic community composition. However, there was no significant difference in the rates of temporal community turnover between the PMA untreated and treated samples for either bacteria or microeukaryotes. Overall, our results imply that the presence of relic DNA in waters can give misleading information of the active microbial community composition, co-occurrence networks and their relationships with environmental conditions. More studies of the abundance, decay rate and functioning of nonviable DNA in freshwater ecosystems are highly recommended in the future.


Allelopathy of the invasive plant Bidens frondosa on the seed germination of Geum japonicum var. chinense.
Five gradient concentrations (0.02, 0.04, 0.06, 0.08, and 0.10 g/mL) of leaching liquors from the roots, stems, and leaves of the invasive plant Bidens frondosa were used as conditioning fluid to examine its influence on seed germination conditions of the native plant Geum japonicum var. chinense in Huangshan. All leaching liquors of organs suppressed the seed germination of Geum japonicum var. chinense and reduced the final germination percentage and rate, and increased the germination inhibition rate, with a bimodal dependence on concentration. The leaching liquor inhibited the seed germination significantly at the concentration of 0.02 g/mL respectively. The seed germination was also inhibited as the concentration reached to 0.04 g/mL and beyond. Hence the allelopathic effects of the organs were significantly enhanced respectively. This phenomenon represented the presence of allelopathy substances in the root, stem and leaf of Bidens frondosa.


Assessing the incremental costs and savings of introducing electronic immunization registries and stock management systems: evidence from the better immunization data initiative in Tanzania and Zambia.
Poor data quality and use have been identified as key challenges that negatively impact immunization programs in low- and middle-income countries (LMICs). In addition, many LMICs have a shortage of health personnel, and staff available have demanding workloads across several health programs. In order to address these challenges, the Better Immunization Data (BID) Initiative introduced a comprehensive suite of interventions, including an electronic immunization registry aimed at improving the quality, reliability, and use of immunization data in Arusha Region, Tanzania, and Southern Province of Zambia. The objective of this study was to assess the incremental costs of implementing the BID interventions in immunization programs in these two countries. We conducted a micro-costing study to estimate the economic costs of service delivery and logistics for the immunization programs with and without the BID interventions in a sample of health facilities and district program offices in each country. Structured questionnaires were used to interview immunization program staff at baseline and post-intervention to assess annual resource utilization and costs. Cost outcomes were reported as annual cost per facility, cost per district and changes in resource costs due to the BID interventions (i.e., costs associated with health worker time, start-up costs, etc.). Sub-group analyses were conducted by health facility to assess variation in costs by volume served and location (rural versus urban). One-way sensitivity analyses were conducted to identify influential parameters. Costs were reported in 2017 US dollars. In Tanzania, the average annual reduction in resource costs was estimated at US$10,236 (95% confidence interval: $7,606-$14,123) per health facility, while the average annual reduction in resource costs per district was estimated at $6,542. In Zambia, reductions in resource costs were modest at an estimated annual average of $628 (95% confidence interval: $209-$1,467) per health facility and $236 per district. Resource cost reductions were mainly attributable to reductions in time required for immunization service delivery and reporting. One-way sensitivity analyses identified key cost drivers, all related to reductions in health worker time. The introduction of electronic immunization registries and stock management systems through the BID Initiative was estimated to result in potential time savings in both countries. Health worker time was the area most impacted by the interventions, suggesting that time savings gained could be utilized for patient care. Information generated through this work provides evidence to inform stakeholder decision-making for scale-up of the BID interventions in Tanzania and Zambia and to inform other Low-to-Middle-Income Countries (LMICs) interested in similar interventions.


[Association of angiotensin converting enzyme polymorphism and echocardiographic measures in young siblings of hypertensive parents].
To evaluate angiotensin converting enzyme gene (ACE) polymorphism with transthoracic bidimensional echocardiogram of normotensive young medical students, siblings of hypertensive parents comparing them with those with normotensive parents. We had studied 80 normotensive youngs divided in two groups. Hypertensive parents' normotensive young medical students 40 x Normotensive parents' and normotensive medical students. Exclusion criteria were hypertension, obesity, smoke, use of oral contraceptives, as well as those who use chronically drugs or the presence of any disease. The group has been enrolled between 1994 to 1996. 50 students made transthoracic bidimensional echocardiogram. The statistical analysis was done by "T-student" test. The evaluation of polymorphism ACE gene was studied in 80 people in each step: 1) 5 mL of blood in EDTA tube, 2) extraction of DNA, 3) evaluation of DNA concentration by electrophoresis analyses; 4) Polymerase chain reaction with primer of ACE gene, 5) Analysis of polymorphism ACE gene by electrophoresis 6) Statistical analysis by Chi-square test. The group of students with hypertensive parents presented thicker interventricular septum (7.82 mm +/- 0.69 against 7.38 mm +/- 0.8, p<0.05). On the other hand, we didn't find differences between the groups concerning ACE gene genotype: students with hypertensive parents DD: 42.5%, DI: 37.5%, II: 20% against Students with normotensive parents: DD: 37.5%, DI: 32.5%, II: 30%, (p=0.58), in addition we also did not find differences concerning the alleles Group of hypertensive parents: D: 61.25%, I: 38.75% versus normotensive parents: D: 53.75%, I: 46.25%, p=0.33. We divided these groups into two in relation to the mean thickness of interventricular septum and left ventricular mass and we did not find any difference: in students with hypertensive parents group septum > 7.82 mm: DD: 32%, DI: 24%, II: 20% x septum < 7.82 mm: DD: 8%, DI: 12%, II: 4%, p=0.7) in normotensive parents group septum septum > 7.38 mm: DD: 28%, DI: 12%, II: 12% x septum < 7.38 mm: DD: 16%, DI: 16%, II: 16%, p=0.59). The study of the left ventricular mass in hypertensive parents group mass > 131.52 g: DD: 20.69%, DI: 13.79%, II: 6.9% x mass < 131.52 g DD: 24.24%, DI: 17.24%, II: 17.24%, (p=0.72) in normotensive parents group mass > 117.11 g: DD: 30.43%, DI: 8.7%, II: 8.7% x mass < 117.11 g: DD: 13.04%, DI: 21.74%, II: 17.39%, (p=0.17). We found differences between the thickness of the interventricular septum of normotensive students sibling of hypertensive parents and normotensive parents. On the other hand we didn't find any difference between the two groups concerning the ACE gene polymorphism as well as any relation of ACE gene and thickness of interventricular septum and interventricular left ventricular mass.


The influence of periportal (pipestem) fibrosis on long term results of surgical treatment for schistosomotic portal hypertension.
To evaluate the degree of influence that periportal fibrosis has on clinical development and the long term results of surgical treatment on patients with hepatic-splenic schistosomiasis with previous gastrointestinal hemorrhages. During the period of 1992-1998, 111 patients underwent surgical treatment for the treatment of hepatic-splenic schistosomiasis with previous gastrointestinal hemorrhages. The degree of fibrosis was classified as: degree I - the portal spaces show a rich increase of young connective cells, a slight collagen production and a varying presence of inflammatory infiltrate. The periportal blade unchangeable (29/111); degree II - there is an expansion of the connective tissue with the emission of radial collagen septa, producing a star shaped aspect (38/111); degree III - the connective septa form bridges with other portal spaces or with the vein, with evident angiomatoid neo-formation (44/111). The patients with periportal fibrosis degree I present recurrent hemorrhages statistically less than patients with periportal fibrosis degrees II and III, and that the intensity of the periportal fibrosis is not the only pathophysiological factor of the esophageal varices, gastric varices, prevalence of post-operative portal vein thrombosis and hematological and biochemical alterations of the patients with pure mansoni schistosomiasis.


Lamprey GnRH-III stimulates FSH secretion in barrows.
Although studies have indicated that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release can be dissociated in the pig, the underlying mechanisms are still to be answered. Since it was demonstrated that lamprey gonadotropin-releasing hormone (l-GnRH-III) has preferential FSH-releasing potency in several mammalian species, we have investigated the gonadotropin-releasing activity of l-GnRH-III in barrows. Each of nine barrows (body weight: 85-90 kg; age: 207 days) received 2 ml saline (S-barrow), followed by 150 microg l-GnRH-III (1.6-1.7 microg/kg body weight) dissolved in 2 ml saline intramuscularly 7 days later. Three pre-treatment and 13 post-treatment blood samples were taken at intervals of 30 min to 8 h to assess basal and treatment-associated concentrations of FSH and LH, respectively, by radioimmunoassay. Animals were defined as having responded to treatment if, 2 h post-treatment, plasma FSH and/or LH levels were >3 SD of the respective basal concentrations. There was no treatment-associated FSH response after saline treatment, but a clear FSH response in all l-GnRH-III-injected barrows. On average, the maximum FSH level (205% of the basal concentration) was observed at 1 h post-treatment. Mean FSH values were elevated until 10 h post-treatment. There was no LH response either to saline or to l-GnRH-III. In conclusion, this study demonstrates a selective FSH-releasing activity of 150 microg l-GnRH-III in barrows. Further studies are needed to investigate whether this effect is ubiquitous in the pig and what the physiological relevance is.


Primary gastric malignant melanoma: challenge in preoperative diagnosis.
Primary gastric melanoma is an extremely rare clinical entity. The clinical manifestation is not specific and usually similar with other common malignancies at this site, such as gastric cancer and lymphoma. And there are no specific radiological features either. Preoperative diagnosis via biopsy is usually difficult, since melanoma pigment could be absent in the biopsy tissue. Here, we report a case of a 50-year-old woman with a mass in the stomach found by gastroscopy. Biopsy was taken twice preoperatively under gastroscope and it was diagnosed as gastric carcinoma and neuroendocrine tumor respectively. Radical surgery was performed with gastrectomy and D2 lymph node dissection. Postoperative pathological examination finally made a definite diagnosis of gastric melanoma by immunohistochemistry. We summarize the reasons for preoperative misdiagnosis and discuss the difficulty in diagnosing gastric melanoma according to literature.


BF3·Et2O-catalyzed formal [3 + 2] reaction of aziridinofullerenes with carbonyl compounds.
The BF3·Et2O-catalyzed formal [3 + 2] reaction of aziridinofullerenes with various carbonyl compounds for the easy preparation of fullerooxazolidines has been developed. Moreover, the reaction of aziridinofullerene with ethyl formate affords the simplest fullerooxazole without substituent.


Medication-related calls received by a national telenursing triage and advice service in Australia: a retrospective cohort study.
Telenursing triage and advice services are increasingly being used to deliver health advice. Medication-related queries are common, however little research has explored the medication-related calls made to these services. The aim of this study was to examine the profile of medication-related calls to a national telenursing triage and advice service and the medications involved. This was a retrospective cohort study of medication-related calls received by Australia's national helpline (healthdirect helpline) in 2014, which provides free advice from registered nurses. We examined the volume of medication-related calls over time, user profiles for patients and callers, and call characteristics and we also investigated medications involved in the calls by their generic names and therapeutic classes. Of 675,774 calls, 3.8% (n = 25,744) were medication-related, which was the largest category of calls. The average call length was 10 min. Over half of callers (55.4%) were advised to deliver self-care. Of 7,459 calls where the callers reported they did not know what to do prior to calling, 56.8% were advised to self-care and 3.5% were transferred to the Poisons Information Centre immediately. Of 1,277 calls where callers reported that they had originally intended to call an ambulance or attend an emergency department (ED), none were advised to do so. Advice most frequently requested was about analgesics and antipyretics, followed by non-steroidal anti-inflammatory agents. The telenursing triage and advice helpline offered quick and easily accessible advice, and provided reassurance to patients and callers with medication-related queries. The service also potentially diverted some patients from attending an ED unnecessarily.


Pathophysiological Mechanisms Underlying Unilateral Vocal Fold Paralysis in Female Patients: An Ultrasonographic Study.
Laryngeal ultrasonography (LUS) has been suggested as an alternative diagnostic tool for unilateral vocal fold paralysis (UVFP). The present study applied LUS and quantitative laryngeal electromyography (LEMG) in female UVFP patients to investigate the pathophysiologic mechanisms of UVFP. In this cross-sectional study, vocal fold (VF) length parameters included resting and phonating VF length measured using B-mode LUS, and color Doppler vibrating length (CDVL) measured using the color Doppler mode. Forty female patients with UVFP were enrolled, among whom 11 and 29 were assigned to the thyroarytenoid (TA) muscle+cricothyroid (CT) muscle group (with CT involvement) and the TA (without CT involvement) group, respectively. In the TA group, the turn frequency in thyroarytenoid-lateral cricoarytenoid (TA-LCA) on the paralyzed side, as observed through LEMG, correlated with the VF length during the resting phase (R=0.368, P=0.050) and CDVL values (R=0.627, P=0.000) on the paralyzed side. In the TA+CT group, the turn ratio in the CT muscle correlated with the normalized phonatory vocal length change (nPLC; R=0.621, P=0.041) on the paralyzed side. CDVL and nPLC are two parameters that can be utilized to predict the turn frequencies of TA-LCA in UVFP cases without CT involvement, and the turn ratio of CT in cases of UVFP with CT involvement, respectively. The findings suggest that LUS, as a noninvasive tool, can serve as an alternative method for assessing the severity of laryngeal nerve injury and offer valuable insights into the pathophysiology of UVFP.


The impact of intermittent versus continuous exposure to EGFR tyrosine kinase inhibitor on selection of EGFR T790M-mutant drug-resistant clones in a lung cancer cell line carrying activating EGFR mutation.
Drug-resistant cell lines are essential tools for investigating the mechanisms of resistance to molecular-targeted anti-cancer drugs. However, little is known about how to establish clinically relevant drug-resistant cell lines. Our study examined the impact of a drug-free period on the establishment of a cell line with clinically relevant resistance to molecular-targeted drugs. We used PC9 cells, a lung cancer cell line carrying EGFR mutation, because this is a validated target for EGFR tyrosine kinase inhibitors (TKI). PC9 cells were intermittently or continuously exposed to increasing concentrations of gefitinib (0.01 μM to 1.0 μM) and the emergence of the most common acquired resistance mutation in EGFR, T790M, was determined. T790M was detected at a 25-fold lower drug concentration in cells continuously exposed to gefitinib (PC9/GRc) than in cells intermittently exposed to gefitinib (PC9/GRi) (0.04 μM vs 1.0 μM, respectively). The mutation frequencies at those drug concentrations were 19.8% and 8.0% in PC9/GRc and PC9/GRi cells, respectively. After drug-free culture for 8 weeks, resistance to gefitinib decreased in the PC9/GRi cells but not in the PC9/GRc cells. In the PC9/GRc cells, the frequency of the T790M mutation was consistently about 20% from 0.04 μM to 1.0 μM of gefitinib. In the PC9/GRc cells, the T790M mutation was detected in all single-cell clones, at frequencies ranging from 7.0% to 37.0%, with a median of 19.5% (95% confidence interval, 17.3%-20.9%). In conclusion, compared with intermittent drug exposure, continuous exposure might select better minor drug-resistant clones when creating cell lines resistant to molecular-targeted drugs.


Analysing the performance of low-cost air quality sensors, their drivers, relative benefits and calibration in cities-a case study in Sheffield.
Traditional real-time air quality monitoring instruments are expensive to install and maintain; therefore, such existing air quality monitoring networks are sparsely deployed and lack the measurement density to develop high-resolution spatiotemporal air pollutant maps. More recently, low-cost sensors have been used to collect high-resolution spatial and temporal air pollution data in real-time. In this paper, for the first time, Envirowatch E-MOTEs are employed for air quality monitoring as a case study in Sheffield. Ten E-MOTEs were deployed for a year (October 2016 to September 2017) monitoring several air pollutants (NO, NO2, CO) and meteorological parameters. Their performance was compared to each other and to a reference instrument installed nearby. E-MOTEs were able to successfully capture the temporal variability such as diurnal, weekly and annual cycles in air pollutant concentrations and demonstrated significant similarity with reference instruments. NO2 concentrations showed very strong positive correlation between various sensors. Mostly, correlation coefficients (r values) were greater than 0.92. CO from different sensors also had r values mostly greater than 0.92; however, NO showed r value less than 0.5. Furthermore, several multiple linear regression models (MLRM) and generalised additive models (GAM) were developed to calibrate the E-MOTE data and reproduce NO and NO2 concentrations measured by the reference instruments. GAMs demonstrated significantly better performance than linear models by capturing the non-linear association between the response and explanatory variables. The best GAM developed for reproducing NO2 concentrations returned values of 0.95, 3.91, 0.81, 0.005 and 0.61 for factor of two (FAC2), root mean square error (RMSE), coefficient of determination (R2), normalised mean biased (NMB) and coefficient of efficiency (COE), respectively. The low-cost sensors offer a more affordable alternative for providing real-time high-resolution spatiotemporal air quality and meteorological parameter data with acceptable performance.


[Pathogenesis of beta-lactam-resistant Haemophilus influenzae isolated from sputum].
Haemophlus influenzae persists in the respiratory tract and sometimes causes respiratory tract infections. To evaluate the pathogenesis of beta-lactam-resistant Haemophilus influenzae, we classified 193 Haemophilus influenzae strains isolated from sputum of patients with respiratory tract disease in 24 beta-lactamase positive (BLP) strains, 65 beta-lactamase negative ampicillin resistant (BLNAR) strains and 104 beta-lactamase negative ampicillin sensitive (BLNAS) strains and reviewed the pathogenesis of the strains. The pathogenesis of the strains was evaluated as definite pathogen, presumptive pathogen, colonization and contamination. It was judged to be the definite pathogen that many bacteria isolated from high quality sputum of the patients with respiratory tract infections. Presumptive pathogen was considered to be the bacteria provided from the patient with respiratory infections when the quality of the sputum or quantity of bacteria did not satisfy superscription basis. We considered the bacteria to be colonization or contamination isolated from patients without infections. The breakdown of definite pathogen/presumptive pathogen/colonization/contamination in each by groups was BLP (8/4/8/4), BLNAR (26/14/15/10), BLNAS (36/20/31/17). The ratio of definite or presumptive pathogen was 50% in BLP, 62% in BLNAR and 54% in BLNAS and the significant difference was not recognized in these. Pathogenesis of beta-lactam-resistant Haemophilus influenzae is estimated to be equal with beta-lactam-sensitive Haemophilus influenzae.


A candidate tumor suppressor gene, H37, from the human lung cancer tumor suppressor locus 3p21.3.
Frequent allelic loss and homozygous deletions within chromosome 3p in human lung cancers have suggested that the 3p21.3 (370-kb) region contains a critical tumor suppressor gene(s) (TSG). With the exact identity/characteristics of such a gene(s) still unconfirmed, a lack of inactivating structural mutations in the expressed genes contained within this region may indicate that the 3p TSG(s) do not fit into the classical "two-mutation" model. This report characterizes a candidate 3p TSG, H37, located within the 370-kb region. Reduced expression of the H37 transcript was found in 9 of 11 (82%) of primary non-small cell lung cancers (NSCLCs) when compared with adjacent normal tissues. Generation of an H37 antibody followed by immunohistochemical analysis of primary NSCLC specimens demonstrated that 46 of 62 (73%) of these cancers contain reduced levels of H37 protein when compared with adjacent normal bronchial cells. Moreover, introduction of the H37 cDNA into human breast cancer cells deleted of 3p21-22 reduced both anchorage-dependent and -independent cell growth in vitro. Subsequent transfection of H37 cDNA into one of the human lung cancer cell lines homozygously deleted in this region resulted in a very low yield of H37-expressing clones. H37 also suppressed anchorage-dependent and -independent growth of A9 mouse fibrosarcoma cells and inhibited tumor formation in nude mice. These data indicate a potential role for H37 as one of the 3p TSGs in human lung cancer.


From the concept of totipotency to biofortified cereals.
I was a college teacher when opportunity opened a path into academia. A fascination with totipotency channeled me into research on tissue culture. As I was more interested in contributions to food security than in scientific novelty, I turned my attention to the development of genetic modification technology for cereals. From my cell culture experience, I had reasons not to trust Agrobacterium for that purpose, and I developed direct gene transfer instead. In the early 1990s, I became aware of the problem of micronutrient deficiency, particularly vitamin A deficiency in rice-eating populations. Golden Rice, which contains increased amounts of provitamin A, was probably instrumental for the concept of biofortification to take off. I realized that this rice would remain an academic exercise if product development and product registration were not addressed, and this is what I focused on after my retirement. Although progress is slowly being made, had I known what this pursuit would entail, perhaps I would not have started. Hopefully Golden Rice will reach the needy during my lifetime.


The diabetes subgroup baseline characteristics of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial.
The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial is the first cardiovascular outcome trial designed to compare initial use of 2 different fixed-dose antihypertensive regimens, benazepril plus hydrochlorothiazide vs benazepril plus amlodipine, on cardiovascular end points in hypertensive patients at high cardiovascular risk secondary to previous major events or presence of diabetes mellitus (DM). Of the 11,464 patients, 60.4% had DM. Compared with non-DM patients, DM patients were less likely to have previous myocardial infarctions (15% vs 37%) or strokes (8% vs 21%). Those with DM were more likely to be female (43% vs 34%), black (15% vs 8%), overweight (body mass index, 32 vs 29 kg/m(2)). At baseline, DM patients were more likely to have the metabolic syndrome, manifested by higher levels of fasting glucose (145 vs 101 mg/dL) and triglycerides (178 vs 150 mg/dL) and slightly lower high-density lipoprotein cholesterol values (48 vs 51 mg/dL) compared to the non-DM cohort. Although estimated glomerular filtration rate (80 vs 76 mL/min/1.73 m(2)) was similar in the DM and non-DM groups, presence of both albuminuria (8.7% vs 3.5%) and microalbuminuria (29% vs 20%) were more prevalent in the DM group. After 6 months of treatment, blood pressure control rates (<140/90 mm Hg) using blinded data (both therapeutic groups combined) for DM demonstrated that 42.8% of DM patients had blood pressure levels <130/80 mm Hg. ACCOMPLISH will provide valuable guidance on optimizing treatment strategies in hypertensive patients at high cardiovascular risk with and without DM.


Optoelectrical modeling of solar cells based on c-Si/a-Si:H nanowire array: focus on the electrical transport in between the nanowires.
By coupling optical and electrical modeling, we have investigated the photovoltaic performances of p-i-n radial nanowires array based on crystalline p-type silicon (c-Si) core/hydrogenated amorphous silicon (a-Si:H) shell. By varying either the doping concentration of the c-Si core, or back contact work function we can separate and highlight the contribution to the cell's performance of the nanowires themselves (the radial cell) from the interspace between the nanowires (the planar cell). We show that the build-in potential (V bi) in the radial and planar cells strongly depends on the doping of c-Si core and the work function of the back contact respectively. Consequently, the solar cell's performance is degraded if either the doping concentration of the c-Si core, or/and the work function of the back contact is too low. By inserting a thin (p) a-Si:H layer between both core/absorber and back contact/absorber, the performance of the solar cell can be improved by partly fixing the V bi at both interfaces due to strong electrostatic screening effect. Depositing such a buffer layer playing the role of an electrostatic screen for charge carriers is a suggested way of enhancing the performance of solar cells based on radial p-i-n or n-i-p nanowire array.


Exploiting the vitamin B12 pathway to enhance oral drug delivery via polymeric micelles.
Vitamin B12 (VB12)-modified dextran-g-polyethyleneoxide cetyl ether (DEX-g-PEO-C16) was synthesized by linking VB12 residues to a DEX-g-PEO-C16 copolymer via a 2,2'-(ethylenedioxy)bis(ethylamine) spacer. The level of VB12 substitution on the DEX-g-PEO-C16 copolymer reached 1.68% (w/w). In aqueous solution, DEX-based copolymers form micelles that can entrap within their hydrophobic core up to 8.5% w/w of cyclosporin A (CsA), a poorly water soluble immunosuppressant. The permeability of Caco-2 cell membranes to CsA incorporated in VB12 modified and unmodified polymeric micelles was monitored in the presence and absence of intrinsic factor (IF). The apical (AP) to basolateral (BL) permeation of CsA through Caco-2 cell monolayers after 24 h of transport was significantly higher (1.8 and 2.3 times in absence and presence of IF, respectively) in the case of CsA loaded in VB12-modified polymeric micelles, compared to CsA in unmodified micelles. The results point to possible improvement in the application of polysaccharide-based polymeric micelles as targeted polymeric drug carriers for the oral delivery of poorly water soluble drugs.


Age and sex differences in niche use at molt and its effect on plumage coloration characteristics in a bird.
Bird plumage is often very colorful and can communicate the quality of the bearer to conspecifics. These plumage-based signals of quality are composed of multiple pigments (e.g., melanin and carotenoids). Therefore, sex and age classes, which often show marked differences in plumage coloration, may have different dietary needs for the different plumage components and this might promote preferences for different dietary niches at different molting stages. However, no study has addressed the role that changes in niche use play in the expression of multiple component plumage signals in birds. We used stable isotope analysis to test the hypothesis that niche use is related to age and sex and to differently cultured plumage patches, yellow carotenoid-based and black melanin-based, in great tits Parus major. We recorded high niche overlap between plumage patches, although δ15N was higher in black than yellow plumage. Niche overlap was relatively low for age classes and relatively high for sex classes, and age classes showed a contrasting pattern of niche overlap between carotenoid- and melanin-based plumages. Moreover, δ13C, but not δ15N, had a significant negative relationship with carotenoid-based plumage, which was only apparent in juveniles. Taken together, our results demonstrate that niche use had a moderate influence on plumage coloration characteristics of great tit individuals, mostly associated with δ13C rather than with δ15N and with age rather than with sex. Therefore, our study is significant because it confirms the relevance of niche use during ornament production in free-living birds.


A simple method for the preparation of paraffin-embedded cell blocks from fine needle aspirates, effusions and brushings.
A simple method for the preparation of paraffin-embedded cell blocks from cytologic specimens obtained by fine needle aspiration, by brushing or from effusions is described. The cells are fixed in suspension in 50% ethanol for one hour and pelleted by centrifugation in a 50-mL plastic tube. The fixative is removed, and the pellet is suspended in 3 mL of acetone for dehydration for ten minutes and thereafter repelleted. The acetone is then removed, and the cell pellet is dried at 60 degrees C for one hour. Melted paraffin is added onto the dry warmed cell mass and allowed to solidify at room temperature. A conical paraffin block with the cells in the top is obtained and can be handled as a routine tissue block.


Assembly of gold nanorods functionalized by zirconium-based metal-organic frameworks for surface enhanced Raman scattering.
Surface-enhanced Raman scattering (SERS) is a promising detection technique providing outstanding molecular fingerprint identification and high sensitivity of analytes. Developing sensitive and stable SERS substrates is highly desirable but remains a challenge. We herein report a wet-chemistry approach for the preparation of (Au nanorod core)@(Zr-based metal-organic framework shell) (Au nanorod@Zr-MOF) nanostructures with the Zr-MOF shell thickness ranging from 3 nm to 90 nm. The stacked Au nanorod@Zr-MOF composites exhibit remarkably improved SERS sensitivity because the MOF shell enriches the molecules to the abundant plasmonic hotspots between the Au nanorod cores. The optimized Au nanorod@Zr-MOF structures exhibit superior SERS activity for detecting 4'-mercaptobiphenylcarbonitrile molecules at a concentration as low as 2 × 10-10 M, with the SERS enhancement factor 2 and 8 times as high as that of ordered bare Au nanorod arrays and random stacking bare Au nanorods, respectively. This study enriches the library of hybrid nanostructures of plasmonic nanocrystals and MOFs, providing an integrated SERS platform with molecular enrichment capability for the realization of sensitive and quantitative analyte identification.


Absence of memory B cells in patients with common variable immunodeficiency.
The molecular basis of common variable immunodeficiency (CVID) is unknown. To assess humoral immunity in CVID, we selected 24 patients with early or late onset of disease. X-linked agammaglobulinemia (XLA), X-linked hyper-IgM syndrome (XHIM), and non-XHIM were excluded based on clinical phenotype, assessment of the immune response, presence of Bruton's tyrosine kinase (Btk) in monocytes or platelets, and normal expression of CD40 ligand by activated T cells. The number of circulating B cells was within the normal range or reduced. IgD(-) CD27(+) memory B cells were markedly reduced or absent in all 24 patients and IgD(+) CD27(+) B cells were diminished in 8 patients. Circulating B cells from all 6 patients examined, including CVID patients with IgD(+) CD27(+) cells, failed to undergo somatic hypermutation in immunoglobulin-variable (V)-region genes, similar to cord blood B cells. B cells from CVID patients produced IgM and IgG, but not IgA upon the engagement of Ig receptor and CD40 in the presence of IL-2 and IL-10. B cells from all but 5 patients secreted IgE when stimulated by CD40 crosslinking in the presence of IL-4. The observation of defective memory B cells with abnormal cell marker expression and function demonstrates that naive CVID B cells including those expressing IgD(+) CD27(+), in analogy to cord blood and hyper-IgM syndrome B cells, may be responsible for their failure to differentiate into plasma cells and to produce high-affinity antibodies of different isotypes.


Advances and potential treatment for Philadelphia chromosome-positive adult acute lymphoid leukaemia.
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) is the most common subtype of ALL in adults. Conventional chemotherapy-based approaches that are effective in other precursor B cell ALL cases have a poor chances of cure in patients with a Ph+ diagnosis. Therefore, allogeneic stem cell transplantation performed during the first remission is the recommended therapy. Recently, the availability of imatinib mesylate and other tyrosine kinase inhibitors and small molecules that affect the BCR/ABL signalling pathways has introduced a new therapeutic opportunity, and could change the treatment paradigm and prognosis for these patients. In this article, the results from clinical trials using imatinib in relapsed/refractory patients and as front-line therapy are described. In addition, preliminary experiences with novel tyrosine kinase inhibitors in imatinib-resistant Ph+ ALL are discussed.


Shaping the Cortical Landscape: Functions and Mechanisms of Top-Down Cortical Feedback Pathways.
Cortical feedback pathways are proposed to guide cognition and behavior according to context and goal-direction. At the cellular level, cortical feedback pathways target multiple excitatory and inhibitory populations. However, we currently lack frameworks that link how the cellular mechanisms of cortical feedback pathways underlie their cognitive/behavioral functions. To establish this link, we expand on the framework of signal routing, the ability of cortical feedback pathways to proactively modulate how feedforward signals are propagated throughout the cortex. We propose that cortical feedback modulates routing through multiple mechanisms: preparing intended motor representations, setting the trigger conditions for evoking cortical outputs, altering coupling strengths between cortical regions, and suppressing expected sensory representations. In developing this framework, we first define the anatomy of cortical feedback pathways and identify recent advances in studying their functions at high specificity and resolution. Second, we review the diverse functions of cortical feedback pathways throughout the cortical hierarchy and evaluate these functions from the framework of signal routing. Third, we review the conserved cellular targets and circuit impacts of cortical feedback. Fourth, we introduce the concept of the "cortical landscape," a graphical depiction of the routes through cortex that are favored at a specific moment in time. We propose that the cortical landscape, analogous to energy landscapes in physics and chemistry, can capture important features of signal routing including coupling strength, trigger conditions, and preparatory states. By resolving the cortical landscape, we may be able to quantify how the cellular processes of cortical feedback ultimately shape cognition and behavior.


Number of eggs in egg-noodles.
The official method to determine the number of eggs present in egg-noodles is the digitonin method. By applying this method the total content of sterols is determined and expressed as total sterols. The official method is time consuming, not very accurate and its performance is very complicated. Its results are not very reliable either because the composition of the wheat is not considered. In this paper some markers are proposed to verify the correct ratio between eggs and triticum durum (TD) semolina used to prepare egg-noodles. Markers are selected ratios between sterols and FAME. The lipid extract is trans-esterified and injected into a gas chromatograph. The ratio between the areas of the selected components gives the markers. This method is proposed to substitute or alternate the official method because is more accurate and time saving.


[An experimental study of split-double-bundle posterior cruciate ligament reconstruction in single femoral tunnel].
To compare the single femoral tunnel split-double-bundle posterior cruciate ligament (PCL) reconstruction with the single-bundle PCL reconstruction and to discuss the advantages of the modified reconstruction method. Fourteen donated fresh-frozen human knee specimens were biomechanically tested, which included knee specimens from 12 males and 2 females, and their ages ranged from 20 to 31 years. The specimen length of the femur and the tibia was 20 cm. The tibial posterior translation and the PCL strains were first measured when PCL was in an intact state (the intact group, n=14). Then, PCL was cut (the cut group, n=14). The posterior translation was measured when a posterior load was applied. After that, the specimens were randomly divided into two groups: the single-bundle group (n=7) and the double-bundle group (n= 7). When the posterior load was applied to the tibia, the bundle strain and the tibial posterior translation were measured with the knees flexed at 0, 30, 60, 90 and 120 degrees, respectively. While a 100 N posterior force was applied, the posterior tibial displacement of the intact PCL knee ranged from 1.97+/-0.29 mm to 2.60+/-0.23 mm at the different knee flexion angles. In the PCL-cut state, the tibial displacement increased significantly from 11.27+/-1.06 mm to 14.94+/-0.67 mm (P<0.05). After the single-bundle reconstruction, the posterior tibial translation ranged from 1.99+/-0.19 mm to 2.72+/-0.38 mm at the different knee flexion angles. In the split-double-bundle reconstruction, the posterior tibial translations ranged from 2.27+/-0.32 mm to 3.05 +/- 0.44 mm. The graft of the single-bundle reconstruction was tensioned from 0 degrees to 120 degrees, and the tibial displacement increased significantly at 90 degrees compared with that at the other angles (P<0.05). In the double-bundle reconstruction, the anterolateral bundle and the posteromedial bundle were tensioned in a reciprocal fashion, and the tibial displacement had no significant difference at the five kinds of the flexion angles. The single femoral tunnel split-double-bundle PCL reconstruction can restore the posterior tibial displacement at different flexion angles, and the tibial displacement in the single-bundle PCL reconstruction knee can be increased when the knee flexion is at 90 degrees. In the double-bundle reconstruction, the graft can be tensioned in a reciprocal fashion and the biomechanical features can be nearer to those of the normal PCL bundles.


Synthesis and Characterization of Pyridine Acetohydrazide Derivative for Antimicrobial Cotton Fabric.
An increase in textile resistance to antimicrobial agents has posed a pressing need for the development of new antimicrobials. Therefore, the antimicrobial characteristics of thiophene and pyridine acetohydrazide derivatives have been developed as novel textile-modified complexes exhibiting antibacterial agents. Synthesis and characterization of pyridyl-thienyl acetohydrazide derivative (AHZ) using NMR (13C and 1H) and FTIR. Modification of cotton fabric (CF) with acetohydrazide (AHZ) and metal chlorides of divalent Cr, Mn, Co, Ni, Cu, and Zn and trivalent Fe, and Cr. SEM-EDX and Fourier-transform infrared were utilized to characterize cellulose-based cotton fabric (CF) attached to AHZ and their metal (M) complexes. Antimicrobial activity was examined against two types of bacteria, namely S. aureus and E. coli, and two types of fungi, namely C. albicans and A. flavus. All modified samples exhibited higher efficiency towards bacterial strains than fungal strains. In addition, cellulose modified with Ni (II) confers the most antibacterial protection efficiency.


Novel Nortriterpenes from Phlomis umbrosa.
We isolated 8 novel 28-noroleanane-derived spirocyclic triterpenoids with unusual skeleton structures, phlomisone (1), phlomistetraol A (2), phlomistetraol B (3), phlomistetraol C (4), phlomispentaol (5), phlomishexaol A (6), phlomishexaol B (7), and phlomisin (8), from the ethanol extract of Phlomis umbrosa rhizomes. Their structures were elucidated on the basis of spectroscopic methods, including 1D, 2D nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HR-MS), and X-ray analyses. Compounds 1-3, 5, and 7 exhibited positive cytotoxic activities against the carcinoma cell lines Hela and L929 in vitro, and these bioactive data suggested that the C-18 and C-21 positions had oxygenated functions that can improve the activity of the compound.


From systems biology to dynamical neuropharmacology: proposal for a new methodology.
The concepts and methods of systems biology are extended to neuropharmacology in order to test and design drugs for the treatment of neurological and psychiatric disorders. Computational modelling by integrating compartmental neural modelling techniques and detailed kinetic descriptions of pharmacological modulation of transmitter-receptor interaction is offered as a method to test the electrophysiological and behavioural effects of putative drugs. Even more, an inverse method is suggested as a method for controlling a neural system to realise a prescribed temporal pattern. In particular, as an application of the proposed new methodology, a computational platform is offered to analyse the generation and pharmacological modulation of theta rhythm related to anxiety.


A new model of reversible sinus sagittalis superior thrombosis in the rat: magnetic resonance imaging changes.
The causes of cerebral sinus and vein occlusion and the accompanying parenchymal changes remain largely unexplained. The clinical variability and low incidence of the disease complicate systematic clinical investigations. Animal studies are indispensable; however, existing animal models of sinus thrombosis do not allow for long-term follow-up studies and are not suitable for pharmacological recanalization because sinus thrombosis is induced by ligation and injection of thrombogenic substances and does not resemble sinus thrombosis in humans. We induced thrombosis of the superior sagittal sinus (SSS) by careful topical application of ferric chloride onto the SSS of rats, leading to highly reproducible occlusions. Magnetic resonance imaging was performed immediately after initiation of thrombosis and on postoperative Days 1, 2, and 7. Diffusion- and T2-weighted images allowed for calculation of the apparent diffusion coefficient and T2 relaxation time. Vascular status was assessed by venous magnetic resonance angiography. Neurological deficits were assessed with the rotarod test. Seven days after induction of thrombosis, partial recanalization (50.7% of the SSS remaining occluded) was accompanied by a resolution of early generalized changes of the apparent diffusion coefficient and of T2 relaxation time, indicating edema of the entire brain parenchyma. Compared with sham-treated animals, clinical skills in the experimental group improved over time, which was statistically independent from the degree of recanalization. Histopathological analysis revealed no signs of cerebral infarction. This is the first animal model of SSS thrombosis that offers the possibility to investigate pathophysiological aspects of the disease as well as the influence of therapy on the nature of disease progression.


Factors associated with the subspecialty choices of internal medicine residents in Canada.
Currently, there are more residents enrolled in cardiology training programs in Canada than in immunology, pharmacology, rheumatology, infectious diseases, geriatrics and endocrinology combined. There is no published data regarding the proportion of Canadian internal medicine residents applying to the various subspecialties, or the factors that residents consider important when deciding which subspecialty to pursue. To address the concern about physician imbalances in internal medicine subspecialties, we need to examine the factors that motivate residents when making career decisions. In this two-phase study, Canadian internal medicine residents participating in the post graduate year 4 (PGY4) subspecialty match were invited to participate in a web-based survey and focus group discussions. The focus group discussions were based on issues identified from the survey results. Analysis of focus group transcripts grew on grounded theory. 110 PGY3 residents participating in the PGY4 subspecialty match from 10 participating Canadian universities participated in the web-based survey (54% response rate). 22 residents from 3 different training programs participated in 4 focus groups held across Canada. Our study found that residents are choosing careers that provide intellectual stimulation, are consistent with their personality, and that provide a challenge in diagnosis. From our focus group discussions it appears that lifestyle, role models, mentorship and the experience of the resident with the specialty appear to be equally important in career decisions. Males are more likely to choose procedure based specialties and are more concerned with the reputation of the specialty as well as the anticipated salary. In contrast, residents choosing non-procedure based specialties are more concerned with issues related to lifestyle, including work-related stress, work hours and time for leisure as well as the patient populations they are treating. This study suggests that internal medicine trainees, and particularly males, are increasingly choosing procedure-based specialties while non-procedure based specialties, and in particular general internal medicine, are losing appeal. We need to implement strategies to ensure positive rotation experiences, exposure to role models, improved lifestyle and job satisfaction as well as payment schedules that are equitable between disciplines in order to attract residents to less popular career choices.


Chloroform-induced cytolethality in freshly isolated male B6C3F1 mouse and F-344 rat hepatocytes.
Chloroform is carcinogenic in rodents but is not mutagenic or DNA reactive. Chloroform-induced hepatocarcinogenesis in rodents is believed to be secondary to events associated with cytotoxicity and cell proliferation. Understanding the mechanisms of chloroform toxicity may provide insights into the mechanisms of carcinogenicity. The goal of these studies was to characterize the cytotoxicity of chloroform in male B6C3F1 mouse and F-344 rat hepatocytes in vitro. We used an in vitro suspension-culture system that reproduced the exposure of the liver to chloroform and the expression of toxicity in vivo. Simulations of a physiologically based dosimetry model for chloroform indicated that the livers of mice and rats were exposed to chloroform concentrations up to 5 mM for 3 h after hepatotoxic doses of chloroform. Freshly isolated male mouse and rat hepatocytes were exposed to chloroform in sealed flasks and then cultured for 24 h as monolayers. Following a 2- or 3-h exposure in suspension, chloroform induced concentration-dependent cytotoxicity (lactate dehydrogenase release) in culture at concentrations higher than 1 mM. Cytolethality was not increased under reduced oxygen tension, indicating that reductive metabolism does not contribute to chloroform-induced toxicity. A threshold of 1 mM chloroform was also found for glutathione (GSH) depletion, with a 50% depletion at 3.8 mM after 2 h. Addition of dithiothreitol, a reducing agent, did not prevent chloroform-induced toxicity, indicating that oxidation of sulfhydryl groups is not critical for toxicity. The lack of protein sulfhydryl group depletion is consistent with this conclusion. Cotreatment with the cytochrome P450 inhibitor 1-phenylimidazole prevented both cytolethality and GSH depletion, indicating that metabolism is necessary for chloroform-induced toxicity. Both species exhibited similar sensitivity toward chloroform toxicity, indicating that toxicity is not sufficient to explain different susceptibility in heptocarcinogenicity. As chloroform metabolism is saturated in the micromolar range, our results indicate that both metabolism and exposure of the liver cells to high concentrations of chloroform are required for toxicity.


A New Paradigm of Technology-Enabled 'Vital Signs' for Early Detection of Health Change for Older Adults.
Environmentally embedded (nonwearable) sensor technology is in continuous use in elder housing to monitor a new set of 'vital signs' that continuously measure the functional status of older adults, detect potential changes in health or functional status, and alert healthcare providers for early recognition and treatment of those changes. Older adult participants' respiration, pulse, and restlessness are monitored as they sleep. Gait speed, stride length, and stride time are calculated daily, and automatically assess for increasing fall risk. Activity levels are summarized and graphically displayed for easy interpretation. Falls are detected when they occur and alerts are sent immediately to healthcare providers, so time to rescue may be reduced. Automated health alerts are sent to healthcare staff, based on continuously running algorithms applied to the sensor data, days and weeks before typical signs or symptoms are detected by the person, family members, or healthcare providers. Discovering these new functional status 'vital signs', developing automated methods for interpreting them, and alerting others when changes occur have the potential to transform chronic illness management and facilitate aging in place through the end of life. Key findings of research in progress at the University of Missouri are discussed in this viewpoint article, as well as obstacles to widespread adoption.


Renal stromal miRNAs are required for normal nephrogenesis and glomerular mesangial survival.
MicroRNAs are small noncoding RNAs that post-transcriptionally regulate mRNA levels. While previous studies have demonstrated that miRNAs are indispensable in the nephron progenitor and ureteric bud lineage, little is understood about stromal miRNAs during kidney development. The renal stroma (marked by expression of FoxD1) gives rise to the renal interstitium, a subset of peritubular capillaries, and multiple supportive vascular cell types including pericytes and the glomerular mesangium. In this study, we generated FoxD1(GC);Dicer(fl/fl) transgenic mice that lack miRNA biogenesis in the FoxD1 lineage. Loss of Dicer activity resulted in multifaceted renal anomalies including perturbed nephrogenesis, expansion of nephron progenitors, decreased renin-expressing cells, fewer smooth muscle afferent arterioles, and progressive mesangial cell loss in mature glomeruli. Although the initial lineage specification of FoxD1(+) stroma was not perturbed, both the glomerular mesangium and renal interstitium exhibited ectopic apoptosis, which was associated with increased expression of Bcl2l11 (Bim) and p53 effector genes (Bax, Trp53inp1, Jun, Cdkn1a, Mmp2, and Arid3a). Using a combination of high-throughput miRNA profiling of the FoxD1(+)-derived cells and mRNA profiling of differentially expressed transcripts in FoxD1(GC);Dicer(fl/fl) kidneys, at least 72 miRNA:mRNA target interactions were identified to be suppressive of the apoptotic program. Together, the results support an indispensable role for stromal miRNAs in the regulation of apoptosis during kidney development.


Non-equilibrium thermodynamic sensitivity of oxidative phosphorylation.
A new method was developed to analyse the dynamic properties of oxidative phosphorylation, in particular the sensitivity of the phosphate potential with respect to fluctuating cellular ATP utilization. This treatment is based on the eigenvalue sensitivity analysis of an experimentally supported non-equilibrium thermodynamic model of oxidative phosphorylation. Such an analysis allows direct access to the kinetic information, while circumventing the awkward conventional numerical integration of a set of nonlinear differential equations. This procedure revealed, for the parameters characteristic for liver of starved rats in vivo, that the sensitivity of oxidative phosphorylation to a fluctuating ATP utilization is minimal at a degree of coupling q = 0.95. This means that the phosphate potential is highly buffered with respect to fluctuating energy demands at the degree of coupling. This value of q agrees well with the degree of coupling qeef, at which net ATP production of oxidative phosphorylation--at optimal efficiency--occurs in the most economic way. This simultaneous maximization of kinetic stability and economic thermodynamic efficiency at the same degree of coupling appears to be a coincidence.