Association between metabolic syndrome and periodontitis: a systematic review and meta-analysis.
The aim of the present study was to evaluate the association between metabolic syndrome (MS) and periodontitis (PD), through a systematic review and meta-analysis. Original observational studies assessing the association between MS and PD in adults, published before May 11th (2017), were identified through electronic searches of MEDLINE, EMBASE and Cochrane Library databases. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline was used. For studies to be included, they had to mention the criteria used to diagnose MS and to have used at least one clinical measure to diagnose PD. There was no language restriction. Three reviewers independently identified eligible studies for possible inclusion in the systematic review and meta-analysis. The quality of the studies was evaluated by the Newcastle-Ottawa scale for observational studies. A random model meta-analysis was conducted. The strategies used to investigate heterogeneity were sequential analysis, subgroup analysis, univariate meta-regression and sensitivity analysis. Thirty-three studies met the inclusion criteria for the systematic review, and 26 had enough information to be included in the meta-analysis, totaling 52,504 patients. MS and PD were associated with an odds ratio of 1.38 (95%CI 1.26-1.51; I2 = 92.7%; p < 0.001). Subgroup analysis showed that complete periodontal examination (I2 = 70.6%; p < 0.001) partially explained the variability between studies. The present findings suggest an association between MS and PD. Individuals with MS are 38% more likely to present PD than individuals without this condition. Prospective studies should be conducted to establish cause and effect relations between MS and PD.


Value of functional imaging by PET in esophageal cancer.
In esophageal cancer, functional imaging using PET can provide important additional information beyond standard staging techniques that may eventually lead to therapeutic consequences. The most commonly used tracer is fluorodeoxyglucose (FDG), which has high avidity for both squamous cell cancer and adenocarcinoma of the esophagus. The value of FDG-PET is limited in early esophageal cancer, whereas additional information is provided in 15% to 20% of locally advanced tumors. Neoadjuvant treatment is currently the standard of care in locally advanced esophageal cancer in most countries because randomized studies have shown a significant survival benefit. Because responders and nonresponders have a significantly different prognosis, functional imaging to tailor preoperative treatment would be of interest. Metabolic imaging using FDG-PET is an established method of response evaluation in clinical trials. The value of metabolic response evaluation is known to depend on the histologic subtype and the type of preoperative treatment delivered. An association of FDG-PET-based metabolic response with clinical response and prognosis was shown for absolute standardized uptake value (SUV) or a decrease of SUV levels before, during, and after therapy. However, contradictory findings exist in the literature and prospective validation is missing. Additionally, no consensus exists on time points or cutoff levels for metabolic response evaluation. Furthermore, correct prediction of a posttherapeutic pathologic complete remission is currently not possible using FDG-PET. Of high interest is early response monitoring during preoperative chemotherapy, with potential subsequent therapy modification. This tailored approach still needs validation in prospective multicenter trials.


Identity of HeLa cell determinants acquired by vesicular stomatitis virus with a tumor antigen.
Growth of vesicular stomatitis virus (VSV) in HeLa cells results in progeny containing non-VSV antigens with a molecular weight around 75,000. The non-VSV antigens were detected by antiserums to HeLa cell determinants. These antiserums precipitate whole virions but do not neutralize them. Because one of the antiserums is directed to a tumor-specific surface antigen of HeLa cells, it appears that VSV specifically acquires such antigens during its passage through human tumor cells.


Guillain-Barré syndrome in children aged <15 years in Latin America and the Caribbean: baseline rates in the context of the influenza A (H1N1) pandemic.
In light of the influenza A (H1N1) pandemic, the Strategic Advisory Group of Experts on Immunization of the World Health Organization requested that the acute flaccid paralysis surveillance system of Latin American and the Caribbean be used to establish Guillain-Barré syndrome incidence rates. An analysis was conducted of 10,486 acute flaccid paralysis cases diagnosed as Guillain-Barré syndrome from 2000 through 2008 in children aged <15 years in Latin American and the Caribbean countries and territories. The average incidence was 0.82 cases per 100,000 children aged <15 years (range, 0.72-0.90 cases per 100,000 children), with significant differences between northern and southern countries (1.08 vs 0.57 cases per 100,000 children). The acute flaccid paralysis surveillance system represents a useful means of monitoring Guillain-Barré syndrome during the pandemic.


Systemic therapy for advanced uterine sarcoma: a systematic review of the literature.
To conduct a systematic review of the literature regarding the systemic treatment of advanced uterine sarcoma and provide an evidence-based summary of the available literature. MEDLINE, EMBASE, and the Cochrane Library databases were searched. "Uterine sarcoma," "leiomyosarcoma," "mixed mesodermal tumor," "chemotherapy," and "systemic therapy" were combined with the search terms for study designs. Three randomized controlled trials and 24 prospective phase II trials were included in the systematic review. In a randomized trial of doxorubicin versus doxorubicin plus cyclophosphamide for advanced or recurrent uterine sarcoma, doxorubicin produced an overall response rate (RR) of 19% and median survival of 11.6 months, which was similar to the response with combination chemotherapy (RR 19%, median survival 10.9 months). A randomized trial comparing ifosfamide plus cisplatin versus ifosfamide alone in mixed mesodermal tumors showed a significant improvement in RR and progression-free survival with the combination compared with ifosfamide alone, however, the combination was associated with increased toxicity including death. A randomized trial comparing doxorubicin to doxorubicin with dacarbazine in women with advanced or recurrent uterine sarcoma demonstrated a significantly higher RR with the combination (P < 0.05), but no significant difference in survival. Offering palliative chemotherapy to patients with advanced, unresectable uterine sarcoma who are symptomatic from this disease is a reasonable decision. Doxorubicin is an option for women with advanced uterine sarcoma. The combination of cisplatinum and ifosfamide is also an option for women with metastatic mixed mesodermal tumors; however, this combination is associated with significant toxicity when compared to ifosfamide alone.


Randomized comparison of intramuscular artemether and intravenous quinine in adult, Melanesian patients with severe or complicated, Plasmodium falciparum malaria in Papua New Guinea.
An open-label, randomized, controlled trial was used to compare the safety and efficacy of intramuscular artemether (a loading dose of 3.2 mg/kg, followed by 1.6 mg/kg daily for 4 days) and intravenous quinine (a loading dose of 20 mg quinine dihydrochloride/kg, followed first by 10 mg/kg every 8 h, each injection taking 4 h, for at least 48 h, and then oral quinine for a total of 7 days) in the management of strictly defined severe/complicated malaria in Melanesian adults. Four (12%) of the 33 patients who enrolled and completed follow-up died (one of the 15 who received artemether and three of the 18 who received quinine). Overall, cerebral malaria was uncommon (6%) whilst jaundice was common (76%). The time taken to clear 50% of parasites was less in those treated with artemether (median = 8 h; range = 2-24 h) than in the patients given quinine (median = 14 h; range = 2-25 h; P = 0.05). Temperature defervescence was also quicker in those treated with artemether (median = 32 hours; range = 20-112 h) than in those in the quinine group (median = 48 h; range = 28-88 h; P = 0.034). Hypoglycaemia was not observed in any patient treated with artemether but complicated therapy in 11 (79%) of the 14 patients given quinine who had not had pre-treatment spontaneous hypoglycaemia. No serious adverse effects were attributable to artemether. The Plasmodium falciparum infections observed during the 1 month of follow-up, in three patients who had received artemether and two who had been given quinine, were probably due to recrudescence. Plasmodium vivax parasitaemias were also observed during follow-up, in one or two patients in each treatment group. Artemether appears safe in Melanesian adults and is probably as effective as intravenous quinine in the treatment of severe or complicated falciparum malaria.


Challenges and Opportunities to Engaging Emergency Medical Service Providers in Substance Use Research: A Qualitative Study.
Introduction Research suggests Emergency Medical Services (EMS) over-use in urban cities is partly due to substance users with limited access to medical/social services. Recent efforts to deliver brief, motivational messages to encourage these individuals to enter treatment have not considered EMS providers. Problem Little research has been done with EMS providers who serve substance-using patients. The EMS providers were interviewed about participating in a pilot program where they would be trained to screen their patients for substance abuse and encourage them to enter drug treatment. Qualitative interviews were conducted with Baltimore City Fire Department (BCFD; Baltimore, Maryland USA) EMS providers (N=22). Topics included EMS misuse, work demands, and views on participating in the pilot program. Interviews were transcribed and analyzed using grounded theory and constant-comparison. Participants were mostly white (68.1%); male (68.2%); with Advanced Life Skills training (90.9%). Mean age was 37.5 years. Providers described the "frequent flyer problem" (eg, EMS over-use by a few repeat non-emergent cases). Providers expressed disappointment with local health delivery due to resource limitations and being excluded from decision making within their administration, leading to reduced team morale and burnout. Nonetheless, providers acknowledged they are well-positioned to intervene with substance-using patients because they are in direct contact and have built rapport with them. They noted patients might be most receptive to motivational messages immediately after overdose revival, which several called "hitting their bottom." Several stated that involvement with the proposed study would be facilitated by direct incorporation into EMS providers' current workflow. Many recommended that research team members accompany EMS providers while on-call to observe their day-to-day work. Barriers identified by the providers included time constraints to intervene, limited knowledge of substance abuse treatment modalities, and fearing negative repercussions from supervisors and/or patients. Despite reservations, several EMS providers expressed inclination to deliver brief motivational messages to encourage substance-using patients to consider treatment, given adequate training and skill-building. Emergency Medical Service providers may have many demands, including difficult case time/resource limitations. Even so, participants recognized their unique position as first responders to deliver motivational, harm-reduction messages to substance-using patients during transport. With incentivized training, implementing this program could be life- and cost-saving, improving emergency and behavioral health services. Findings will inform future efforts to connect substance users with drug treatment, potentially reducing EMS over-use in Baltimore. Maragh-Bass AC , Fields JC , McWilliams J , Knowlton AR . Challenges and opportunities to engaging Emergency Medical Service providers in substance use research: a qualitative study. Prehosp Disaster Med. 2017;32(2):148-155.


An aptamer based voltammetric biosensor for endotoxins using a functionalized graphene and molybdenum disulfide composite as a new nanocarrier.
Lipopolysaccharides (LPS), known as endotoxins, can cause a strong inflammatory response and lead to multiple organ failure in severe cases. This work reports a simple label-free voltammetric aptasensor for highly sensitive determination of LPS using a polyethyleneimine (PEI) functionalized reduced graphene oxide (rGO) and molybdenum disulfide (MoS2) composite (PEI-rGO-MoS2) as a new nanocarrier for electroactive toluidine blue (TB). The PEI-rGO-MoS2 nanocomposite with high electrical conductivity and large specific surface area can greatly increase the loading of TB and facilitate electron transfer from TB to an electrode. Then gold nanoparticles (AuNPs) were utilized to immobilize a thiolated LPS binding aptamer (LBA), which not only exhibited excellent biocompatibility, but also significantly amplified the electrochemical signal of TB. The proposed aptasensor exhibited high sensitivity for LPS and showed a wide linear range from 5.0 × 10-5 ng mL-1 to 2.0 × 102 ng mL-1 with a low limit of detection (LOD) of 3.01 × 10-5 ng mL-1, which overcame the shortcomings of traditional detection methods and achieved fast and accurate detection of LPS. Moreover, it exhibited excellent recovery and specificity upon spiking LPS in serum samples, indicating that this method has promising application in the field of trace analysis of LPS in clinical detection.


[Plastics on the eye - plastics in the eye. Human-optic materials].
Materials of identical or similiar chemical classes are used for contact optics as well as for implantable intraocular devices. All of them derive from the chemistry of industrial product developments. Materials used in and on the eye should behave indifferent. They should not provoke any reaction in the eye and not themselves be altered by the biological surroundings. For materials used in the eye an especially high purity of the polymers utilized as well as a long term light stability is to be demanded. Optical properties like transparency have to be stable over extended time periods under normal light influence. The long time stability of UV-absorbing additives in the materials used has to be verified. All materials used for IOL's - with the exception of the homopolymer of methylmethacrylate - consist of polymer mixtures forming socalled interpenetrating networks which appear as an uniform material. For the manufacturing of intraocular lense materials standardized or unanimous producer prescriptions are not existing. Based on the different polymer formulations different aging and fatigue properties are the outcome. In addition only inadequate knowledge about the long term light stability of the incorporated UV blockers is submitted. Polymeric materials used for IOL's should be subjected in addition to the test methods listed in EN-ISO 11 979/5 to chemical, polymeranalytic and mechanical substance examinations. As a standard in such examinations a polymethylmethacrylate, free of methylacrylate is proposed. Examinations of each lot should be compulsory. Identification of all ingredients of the intraocular materials should be prescribed and labeled in line with the revelations of common medical drugs prescriptions. The relevations commit the medical doctor to inform his patient about possible side effects of the intraocular implants.


RENEB Inter-Laboratory comparison 2017: limits and pitfalls of ILCs.
In case of a mass-casualty radiological event, there would be a need for networking to overcome surge limitations and to quickly obtain homogeneous results (reported aberration frequencies or estimated doses) among biodosimetry laboratories. These results must be consistent within such network. Inter-laboratory comparisons (ILCs) are widely accepted to achieve this homogeneity. At the European level, a great effort has been made to harmonize biological dosimetry laboratories, notably during the MULTIBIODOSE and RENEB projects. In order to continue the harmonization efforts, the RENEB consortium launched this intercomparison which is larger than the RENEB network, as it involves 38 laboratories from 21 countries. In this ILC all steps of the process were monitored, from blood shipment to dose estimation. This exercise also aimed to evaluate the statistical tools used to compare laboratory performance. Blood samples were irradiated at three different doses, 1.8, 0.4 and 0 Gy (samples A, C and B) with 4-MV X-rays at 0.5 Gy min-1, and sent to the participant laboratories. Each laboratory was requested to blindly analyze 500 cells per sample and to report the observed frequency of dicentric chromosomes per metaphase and the corresponding estimated dose. This ILC demonstrates that blood samples can be successfully distributed among laboratories worldwide to perform biological dosimetry in case of a mass casualty event. Having achieved a substantial harmonization in multiple areas among the RENEB laboratories issues were identified with the available statistical tools, which are not capable to advantageously exploit the richness of results of a large ILCs. Even though Z- and U-tests are accepted methods for biodosimetry ILCs, setting the number of analyzed metaphases to 500 and establishing a tests' common threshold for all studied doses is inappropriate for evaluating laboratory performance. Another problem highlighted by this ILC is the issue of the dose-effect curve diversity. It clearly appears that, despite the initial advantage of including the scoring specificities of each laboratory, the lack of defined criteria for assessing the robustness of each laboratory's curve is a disadvantage for the 'one curve per laboratory' model. Based on our study, it seems relevant to develop tools better adapted to the collection and processing of results produced by the participant laboratories. We are confident that, after an initial harmonization phase reached by the RENEB laboratories, a new step toward a better optimization of the laboratory networks in biological dosimetry and associated ILC is on the way.


Hepatic visceral larva migrans, a resilient entity on imaging: Experience from a tertiary liver center.
Hepatic visceral larva migrans (VLM) is an uncommon parasitic manifestation seen in the liver. It presents as coalescing, conglomerated, or solitary abscess cavities in the liver on imaging. We conducted a retrospective clinico-radiological analysis of 24 patients with biopsy proven VLM who were reviewed and followed up at our tertiary liver institute over a period of 4 years. The study was performed to correlate the radiological features and imaging response to therapy for hepatic VLM. The disease course, imaging findings, progressive, absolute eosinophil counts (AEC), hydatid serology, and the extent of radiological regression of the liver lesions, on follow-up were analyzed. Imaging showed a diagnostic accuracy of 42%. Hydatid serology was positive in 46% patients before starting treatment. The median pretreatment AEC of 507 showed a significant posttreatment AEC decline to median value of 117. The Wilcoxon signed ranks test showed significant decline in the AEC (P < 0.001). Radiological regression was present in all lesions. However, patients showed residual abscesses on imaging, up to 2 years on follow-up. This study reveals that AEC has a significant predictive value in diagnosis and as a marker for disease regression. Complete radiological resolution of hepatic lesions does not correlate with total clinical remission. This finding warrants the need for further studies to look into the role of prolonged medical therapy or surgery as an alternate to current therapy module in cases of hepatic visceral larva abscesses.


Local viscoelasticity at resin-metal interface analyzed with spatial-decomposition formula for relaxation modulus.
A spatial-decomposition formula is presented for viscoelasticity. In this formula, the relaxation modulus is decomposed with respect to a spatial coordinate and the local viscoelasticity is analyzed with the spatially decomposed stress-stress time correlation function. The spatial-decomposition formula is then applied to a planar interface between resin and metal by using the Kremer-Grest model at a variety of adhesion strengths. It was observed that when the resin-metal interaction is strong, the resin forms a layer structure extending over a spatial range which is larger by an order of magnitude than the segment size of the resin. The motion of the resin is suppressed there, and the effect of the interface is localized near the wall only when the adhesion is weak. Actually, the layer region is more viscous than the bulk when the resin interacts strongly with the wall, in the sense that the stress-stress correlation in the former region persists over longer times. The resin-metal interaction in the spatial scale corresponding to the segment size does not affect the equal-time correlation of the local stress significantly and modifies mainly the decay with time of the local stress of the resin within the layers. The present work demonstrates that the spatially decomposed relaxation modulus can be a general framework for analyzing the viscoelasticity at the interface and revealing the relationship of the adhesion to the stress-stress correlation in the segment-scale space and time.


Treatment of acute promyelocytic leukemia with gemtuzumab ozogamicin.
Acute promyelocytic leukemia (APL) is a form of acute myeloid leukemia characterized by peculiar biologic features and a unique sensitivity to differentiation therapy with all-trans retinoic acid (ATRA). Modern treatment approaches to APL include simultaneous combination of ATRA and anthracycline-based chemotherapy. Gemtuzumab ozogamicin is a calicheamicin-conjugated monoclonal antibody directed against CD33, a cell surface antigen highly expressed on APL cells. Engagement of CD33 by gemtuzumab results in immunoconjugate internalization and hydrolytic release of calicheamicin, which, in turn, causes irreversible DNA damage and cell death. A number of preliminary reports have highlighted the sensitivity of APL to gemtuzumab given alone or in combination with other agents. Several reasons may account for the efficacy of gemtuzumab in APL, including: (1) CD33 is detectable in virtually 100% of APL cases; (2) calicheamicin belongs to the anthracycline family, a group of chemotherapeutic agents known to be highly effective in APL; and (3) the APL blast cells lack the multidrug resistance glycoprotein 170. Due to the availability of other highly effective agents (ATRA, arsenic trioxide), relatively few APL patients have been treated thus far with gemtuzumab, and their follow-up is still short. However, it is conceivable that the use of this agent in APL will increase in the near future in light of its capability to induce molecular remission even in advanced disease. Furthermore, the use of low doses of gemtuzumab in high-risk patients might be relevant in order to reduce treatment toxicity due to conventional anthracyclines. This review summarizes the mechanism of action and toxicity profile of gemtuzumab as well as the published experience with this compound in patients with newly diagnosed and relapsed APL.


Association of metabolic dysfunction-associated fatty liver disease with systemic atherosclerosis: a community-based cross-sectional study.
Data are limited on the association of metabolic dysfunction-associated fatty liver disease (MAFLD) with systemic atherosclerosis. This study aimed to examine the relationship between MAFLD and the extent of atherosclerotic plaques and stenosis, and presence of polyvascular disease (PolyVD). In this cross-sectional study, MAFLD was diagnosed based on the presence of metabolic dysfunction (MD) and fatty liver disease (FLD). MAFLD was divided into three subtypes: MAFLD with diabetes mellitus (DM), MAFLD with overweight or obesity (OW), as well as MAFLD with lean/normal weight and at least two metabolic abnormalities. Atherosclerosis was evaluated, with vascular magnetic resonance imaging for intracranial and extracranial arteries, thoracoabdominal computed tomography angiography for coronary, subclavian, aorta, renal, iliofemoral arteries, and ankle-brachial index for peripheral arteries. The extent of plaques and stenosis was defined according to the number of these eight vascular sites affected. PolyVD was defined as the presence of stenosis in at least two vascular sites. This study included 3047 participants, with the mean age of 61.2 ± 6.7 years and 46.6% of male (n = 1420). After adjusting for potential confounders, MAFLD was associated with higher extent of plaques (cOR, 2.14, 95% CI 1.85-2.48) and stenosis (cOR, 1.47, 95% CI 1.26-1.71), and higher odds of presence of PolyVD (OR, 1.55, 95% CI 1.24-1.94) as compared with Non-MAFLD. In addition, DM-MAFLD and OW-MAFLD were associated with the extent of atherosclerotic plaques and stenosis, and presence of PolyVD (All P < 0.05). However, lean-MAFLD was only associated with the extent of atherosclerotic plaques (cOR, 1.63, 95% CI 1.14-2.34). As one component of MAFLD, FLD per se was associated with the extent of plaques and stenosis in participants with MAFLD. Furthermore, FLD interacted with MD to increase the odds of presence of systemic atherosclerosis (P for interaction ≤ 0.055). MAFLD and its subtypes of DM-MAFLD and OW-MAFLD were associated with the extent of atherosclerotic plaques and stenosis, and presence of PolyVD. This study implicated that FLD might be a potential target of intervention for reducing the deleterious effects of MAFLD on systemic atherosclerosis.


The potential of complementary and alternative medicine in promoting well-being and critical health literacy: a prospective, observational study of shiatsu.
The potential contribution of complementary and alternative medicine (CAM) modalities to promote and support critical health literacy has not received substantial attention within either the health promotion or the CAM literature. This paper explores the potential of one CAM modality, shiatsu, in promoting well-being and critical health literacy. Data are drawn from a longitudinal, 6 months observational, pragmatic study of the effects and experience of shiatsu within three European countries (Austria, Spain and the UK). Client postal questionnaires included: advice received, changes made 6 months later, clients 'hopes' from having shiatsu and features of the client-practitioner relationship. At baseline, three-quarters of clients (n = 633) received advice, on exercise, diet, posture, points to work on at home or other ways of self-care. At 6 months follow-up, about four-fifths reported making changes to their lifestyle 'as a result of having shiatsu treatment', including taking more rest and relaxation or exercise, changing their diet, reducing time at work and other changes such as increased body/mind awareness and levels of confidence and resolve. Building on the findings, an explanatory model of possible ways that a CAM therapy could contribute to health promotion is presented to guide future research, both within and beyond CAM. Supporting individuals to take control of their self-care requires advice-giving within a supportive treatment context and practitioner relationship, with clients who are open to change and committed to maintaining their health. CAM modalities may have an important role to play in this endeavour.


Influence of age on accumulation of alpha-actin in satellite-cell-derived myotubes in vitro.
Because muscle satellite cells have been implicated in the process of muscle growth and mass regulation, as well as regeneration, alterations in the capacity of satellite cells to differentiate and accumulate muscle specific proteins during aging could play a role in the process of senile muscle atrophy. Skeletal muscle satellite cells were cultured from male rats from the following four age groups: neonatal rats (less than 5 days of age), growing rats (1--3 months of age, adult rats (9--12 months of age) and old rats (more than 24 months of age). A series of experiments was conducted in which cultures were harvested at daily intervals following fusion, and the amount of alpha-actin per myotube nucleus was determined. Analysis of maximum actin accumulation in myotubes from each experiment within each age group revealed no significant differences among cells derived from growing, adult or old rats; however, myotubes differentiating from neonatal muscle cells were able to accumulate more than three times as much alpha-actin per myotube nuclei as cells from the other three age groups. This result may reflect fundamental differences between authentic satellite cells and myogenic cells of prenatal origin. Aside from differences between neonatal cells and satellite cells, satellite cells from old muscle do not appear to have a diminished capacity to accumulate muscle-specific proteins following differentiation into muscle fibers.


Developing and Implementing Patients' Full-Scale Electronic Access to Their Health Record.
To increase patients' empowerment and involvement in their own health, several countries has decided to provide patients with electronic access to their health record. This paper reports on the main findings from sub-studies and pilots prior to the implementation of patients' access to their medical records in large-scale in the Northern Norway Region. The largest pilot included nearly 500 patients. Data for the participatory design process was collected through questionnaires and interviews. The results revealed that the service in general functioned as expected. The patients reported that they would continue to use the service, recommend it to others, and generally had no problems in understanding the content.


Biomedical Approach of Nanotechnology and Biological Risks: A Mini-Review.
Nanotechnology has played a prominent role in biomedical engineering, offering innovative approaches to numerous treatments. Notable advances have been observed in the development of medical devices, contributing to the advancement of modern medicine. This article briefly discusses key applications of nanotechnology in tissue engineering, controlled drug release systems, biosensors and monitoring, and imaging and diagnosis. The particular emphasis on this theme will result in a better understanding, selection, and technical approach to nanomaterials for biomedical purposes, including biological risks, security, and biocompatibility criteria.


Gene therapy for malignant mesothelioma: a novel approach for an incurable cancer with increased incidence in Louisiana.
Malignant mesothelioma (MM) is a tumor of the pleura for which there is no satisfactory treatment. It is an almost universally fatal disease, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalities is superior to no treatment at all. Because of the dismal prognosis for patients with MM, new modes of treatment are desperately needed. A promising area of research into the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-TK). By virtue of their expression of HSV-TK, the transduced cells are rendered susceptible to the antiviral drug, ganciclovir (GCV). Nearby untransduced tumor cells are killed by a so-called bystander effect. We are describing a Phase I clinical gene therapy trial for MM, which we are presently conducting at the Louisiana State University Medical Center of New Orleans. The purpose is to study the safety and to determine the maximal tolerated dose of an HSV-TK-transduced ovarian cancer cell line (PA1-STK cells) that is infused into the pleural cavities of patients. This infusion is followed by systemic administration of GCV. The hope is that administration of GCV will result in killing of both the transduced ovarian cancer cells as well as the nearby malignant cells.


Cilostazol-induced Acute Kidney Injury in A Patient With Diabetic Foot Ulcer: A Case Report and Review of Literature.
Cilostazol is an antiplatelet agent, that has been recently used as an adjunctive therapy in the management of diabetic foot ulcers. Headache, diarrhea, palpitations, and edema are reported as common side effects. A 53-year-old woman was admitted to hospital, with decreased urine output and increased serum creatinine level. She had taken Cilostazol for the first time, for only one day, so the diagnosis of acute kidney injury, probably drug-induced acute interstitial nephritis, due to Cilostazol use, was made. Her kidney function did not improve despite Cilostazol discontinuation and therefore, empirical corticosteroid therapy was initiated. Her urine output increased and her serum creatinine level significantly decreased, on the third day of treatment. She was discharged with acceptable kidney function. Follow-up visits showed gradual normalization of serum creatinine in the next 62 days. Based on our case, we may draw the conclusion that, Cilostazol may cause nephrotoxicity at any point after ingestion. DOI: 10.52547/ijkd.6980.


Mode of substrate interaction and energetics of carbon-oxygen bond formation of the dopamine beta-monooxygenase reaction.
Previous studies have shown that the dopamine beta-monooxygenase (DbetaM; E.C. 126.96.36.199)/1-(2-aminoethyl)-1,4-cyclohexadiene (CHDEA) reaction partitions between side chain and ring H-abstraction to produce the side-chain-hydroxylated product, 2-amino-1-(1, 4-cyclohexadienyl)ethanol, and the aromatized product, phenylethylamine, and that the two pathways do not crossover. [Wimalasena, K., and May, S. W. (1989) J. Am. Chem. Soc. 111, 2729-2731; Wimalasena, K., and Alliston, K. R. (1995) J. Am. Chem. Soc. 117, 1220-1224]. We now report that the ring H-abstraction pathway of the reaction further partitions to produce the ring hydroxylated product, CHDEA-6OH, and the aromatized product, PEA, at the carbon-oxygen bond formation step. The ring hydroxylation is shown to be stereospecific, exclusively producing the (S) product. The absolute stereospecificity of the ring and side-chain hydroxylations of the DbetaM/CHDEA reaction suggests that the side-chain pro-R hydrogen of the enzyme-bound substrate is close to perpendicular to the aromatic ring of the phenylethylamine substrate or cyclohexadiene ring of CHDEA. The relative activation energy parameters suggest that the partitioning of the ring H abstraction pathway between aromatized and ring hydroxylated products is due to the partitioning of the high-energy intermediates, the cyclohexadienyl radical and the Cu(II)-O(*) species, between carbon-oxygen bond formation and direct electron transfer. The relatively high activation enthalpic favorability and entropic unfavorability for the carbon-oxygen bond formation strongly suggest that the critical balancing of these two opposing forces is mandatory for the desired product formation.


Molecular mechanisms of iron uptake in eukaryotes.
Iron serves essential functions in both prokaryotes and eukaryotes, and cells have highly specialized mechanisms for acquiring and handling this metal. The primary mechanism by which the concentration of iron in biologic systems is controlled is through the regulation of iron uptake. Although the role of transferrin in mammalian iron homeostasis has been well characterized, the study of genetic disorders of iron metabolism has revealed other, transferrin-independent, mechanisms by which cells can acquire iron. In an attempt to understand how eukaryotic systems take up this essential element, investigators have begun studying the simple eukaryote Saccharomyces cerevisiae. Several genes have been identified and cloned that act in concert to allow iron acquisition from the environment. Some of these genes appear to have functional homologues in human systems. This review focuses on the recent developments in understanding eukaryotic iron uptake with an emphasis on the genetic and molecular characterization of these systems in both cultured mammalian cells and S. cerevisiae. An unexpected connection between iron and copper homeostasis has been revealed by recent genetic studies, which confirm biologic observations made several decades ago.


Effect of skin electrode location on radiofrequency ablation lesions: an in vivo and a three-dimensional finite element study.
To assess the effect of skin electrode location on radiofrequency (RF) ablation lesion dimensions and energy requirements. Little is known about the effects of skin electrode location on RF ablation lesion dimensions and efficiency. Temperature-controlled ablation at 60 degrees C for 60 seconds was performed in six sheep. Paired lesions were created in the lateral, anterior, posterior, and septal walls of both the ventricles. For group 1 lesions, the skin electrode was positioned directly opposite the catheter tip (optimal). For group 2 lesions, we used either the standard posterior location or an anterior location if the posterior skin electrode location was used for group 1. Group 1 lesions were 5.8+/-0.8 mm deep and 9.3+/-1.9 mm wide, compared with 4.6+/-1.0 mm deep and 7.7+/-1.9 mm wide group 2 lesions (P < or = 0.001). Group 1 lesion dimensions also had less variability. A finite element model was used to simulate temperature-controlled ablation and to study the effect of skin electrode locations on lesion dimensions, ablation efficiency, and blood heating. The optimal location was 1.6 times more efficient, and the volume of blood heated to > or = 90 degrees C was 0.005 mm3 for optimal versus 2.2 mm3 for the nonoptimal location. Optimal skin electrode placement: (1) creates deeper and larger lesions; (2) reduces lesion size variability; and (3) decreases blood heating.


[Clinico-morphological characteristics of a juvenile angiofibroma of the base of the skull].
203 patients with juvenile angiofibroma of the base of the skull were assessed clinicoanatomically. In addition to a routine otorhinolaryngological examination 60 patients underwent computed tomography, radioangiography and thermography. Biopsy specimens obtained at operations were studied morphologically for 133 patients including application of histotopography in 15 cases and electron microscopy in 19 cases. Two clinicoanatomic forms of juvenile angiofibroma (JAF) have been revealed as well as 4 vascular types and variegation due to different combinations of vascular, cellular and fibrillar components. According to biologic nature of JAF it should be referred to fibromatoses.


LSFG findings of proliferative diabetic retinopathy after intravitreal injection of bevacizumab.
The authors investigate the changes of chorioretinal blood flow using laser speckle flowgraphy (LSFG) in efficacy of treatment. Intravitreal bevacizumab was injected in a patient with proliferative diabetic retinopathy. LSFG measures the relative velocity index of erythrocytes (mean blur rate) in a previously confirmed area, with neovascularization elsewhere (NVE), neovascularization of the disc (NVD), and without neovascularization. The authors compared mean blur rate before and after bevacizumab injection in each area. In LSFG images, regression of blood flow was observed at the area of neovascularization sequentially as the change of color pattern. Finally, decrease of the mean blur rate of an average 32.7% was observed in the NVE area. Similarly, a reduction of 31.9% of mean blur rate was observed in the NVD area. However, in the area of without neovascularization, reduction of mean blur rate was not observed. This suggested the useful possibility of measuring chorioretinal blood flow changes by drug intervention using LSFG analysis.


The singular epidemiology of HPV infection among French Guianese women with normal cytology.
In French Guiana, cervical cancer is the second most frequent cancer in females. The objective of the present study was to describe the prevalence of HPV infections in women with normal cervical cytology living in the remote villages of French Guiana. Before the study, the study team communicated in the remote villages on the importance of screening. All women from the target population were offered to participate. They signed informed consent during inclusion and then had a concomitant HPV-test and cervical smear. Only women with normal cytology and a good quality smear were analyzed. The detection of HPV-DNA was performed using the GREINER-BIO-ONE kit. Overall, 27.2% of women with normal cervical cytology had a positive HPV-test. There was a U-shaped evolution of prevalence with women over 50 years having the highest HPV prevalence, followed by the 20 to 29 years group. The most prevalent HPV genotypes were HPV 53(3.52%), 68(3.33%), 52(2.59%), 31(2.22%) and 16 (1.85%). The proportion of HPV 16 among HPV-infected women was 6.8%. HPV prevalence in cytologically normal women was very high. The most prevalent genotypes were very different from what is usually described in the world, and notably in South America.


Immunocytochemical identification of phenylalanine hydroxylase and albumin in cultured hepatoma cells and isolated rat hepatocytes.
Rhodamine-conjugated antibodies specific for phenylalanine hydroxylase and serum albumin were employed as cytochemical probes to identify these two proteins in H4 hepatoma cells and in isolated rat hepatocytes. Each fluorescent antibody stained the cells specifically and in a distinctive manner. In both cell types, albumin staining was discretely localized in cytoplasmic and in H4 cultures varied somewhat from cell to cell. Evidence from cultures of REB15 cells, a strain derived by cloning H4 cells in tyrosine-free medium, suggested that the staining variability of H4 cells could reflect a variability in phenylalanine hydroxylase content. Hydrocortisone-treated H4 cells and REB15 cultures contain increased amounts of phenylalanine hydroxylase; and all cells in the culture appear to be induced by the hormone. Evidence was presented to show that the albumin visualized within the isolated hepatocytes had been synthesized by these cells, and, furthermore, that quantitatively nearly all intracellular albumin in the isolated rat hepatocytes appeared to be entrained in the secretion pathway (analogous data already exist for H4 cells [Baker, R.E., and R. Shiman. 1979. J. Biol. Chem. 254:9633-9639]). By scoring specific fluorescence, 86 and 98% of the H4 cells and 89 and 98% of the isolated hepatocytes were found to contain phenylalanine hydroxylase and albumin, respectively. Therefore, almost all cells in each population appeared to synthesize both proteins. An implication of these findings is that in rat virtually all liver parenchymal cells must synthesize both phenylalanine hydroxylase and albumin.


Acylated and unacylated ghrelin confer neuroprotection to mesencephalic neurons.
The polypeptide ghrelin is an endogenous ligand at the growth hormone secretagogue receptor 1a. To ghrelin multiple functions have been ascribed including promotion of gastrointestinal motility. Postprandial ghrelin levels have been reported to be reduced in patients suffering from Parkinson disease (PD). Experimental studies revealed neuroprotective effects of ghrelin in different PD models. The purpose of the present study was (i) to further elucidate the mechanism underlying the neuroprotective action of ghrelin and (ii) to determine whether these effects occur with both the acylated and the unacylated form. The study was conducted in primary mesencephalic cultures treated with mitochondrial complex I and complex II inhibitors. We show that protective effects of ghrelin against complex I inhibition with MPP+ were independent of the acylation status of ghrelin, although acylated ghrelin appeared to be more potent. Protection by both forms was also observed when neurons were exposed to the complex II inhibitor 3-NP. Both forms led to higher oxygen consumption rates upon electron transport chain uncoupling, indicating that the two peptides may exert uncoupling effects themselves. We demonstrate that the rescue provided by ghrelin required calcium influx through L-type voltage-gated calcium channels. Whereas the protective effects of acylated ghrelin required receptor binding, effects of the unacylated form remained unaffected by treatment with a ghrelin receptor antagonist. Importantly, inhibition of ghrelin O-acyltransferase failed to reduce the activity of unacylated ghrelin. Overall, our data suggest that both acylated and unacylated ghrelin afford protection to dopamine neurons but through mechanisms that only partially overlap.


Relationship of weight to the promotion of breast cancer after menopause.
Epidemiologic and experimental evidence for a relation between high body weight and breast cancer is reviewed. A prospective study in the framework of a population-based breast cancer screening project for women over age 50 with determination of estrogen-receptor-status of cancers has provided evidence that promotion of ER-positive cases is favored by obesity and relatively inhibited by leanness. In lean postmenopausal women, clonal selection is thought to lead to a preponderance of ER-negative cells in the cancers. Initiation of breast cancer is probably unrelated to obesity. Induction of breast cancer may be rare after menopause, but existing tumors grow if they receive stimuli to which they are sensitive. A lead to further research is presented.


Precipitation-based extracellular vesicle isolation from rat plasma co-precipitate vesicle-free microRNAs.
The microRNA (miRNA) cargo contained in plasma extracellular vesicles (EVs) offers a relatively little explored source of biomarkers for brain diseases that can be obtained noninvasively. Methods to isolate EVs from plasma, however, are still being developed. For EV isolation, it is important to ensure the removal of vesicle-free miRNAs, which account for approximately two-thirds of plasma miRNAs. Membrane particle precipitation-based EV isolation is an appealing method because of the simple protocol and high yield. Here, we evaluated the performance of a precipitation-based method to obtain enriched EV-specific miRNAs from a small volume of rat plasma. We performed size-exclusion chromatography (SEC) on precipitation-isolated EV pellets and whole plasma. The SEC fractions were analysed using Nanoparticle Tracking Analysis (NTA), protein and miRNA concentration assays, and droplet digital polymerase chain reaction for four miRNAs (miR-142-3p, miR-124-3p, miR-23a, miR-122). Precipitation-isolated EVs and selected SEC fractions from the plasma were also analysed with transmission electron microscopy (TEM). Precipitation-based EV isolation co-precipitated 9% to 15% of plasma proteins and 21% to 99% of vesicle-free miRNAs, depending on the individual miRNAs. In addition, the amount of miR-142-3p, found mainly in EV fractions, was decreased in the EV fractions, indicating that part of it was lost during precipitation-based isolation. Western blot and TEM revealed both protein and lipoprotein contamination in the precipitation-isolated EV-pellets. Our findings indicate that a precipitation-based method is not sufficient for purifying plasma EV-contained miRNA cargo. The particle number measured by NTA is high, but this is mostly due to the contaminating lipoproteins. Although a part of the vesicle-free miRNA is removed, vesicle-free miRNA still dominates in plasma EV pellets isolated by the precipitation-based method.


Somatostatin receptors in gastrointestinal stromal tumors: new prognostic biomarker and potential therapeutic strategy.
Somatostatin receptors (SSTRs) already act as important roles in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with high expression levels for prognosis predicting and octreotide LAR treatment purposes but less noticed in gastrointestinal stromal tumors (GISTs). Our study aims to fully evaluate the expression levels and prognostic values of SSTRs in GIST patients. For SSTRs expression detection, qPCR were used in 25 fresh GIST specimens, and then, 453 GIST samples (405 GISTs with operation only and 48 with imatinib adjuvant therapy after surgery) were collected for tissue microarrays (TMAs) construction and confirmed by immunohistochemistry (IHC). Clinicopathological data were confirmed by pathological diagnosis and clinical recorders, recurrence-free survivals (RFS) were evaluated in 453 GIST patients. With IHC performed, SSTR1 and SSTR2 present high positive proportion (81.9% and 87.6%) in 453 GISTs in our study, and positive expression rates of SSTR3, SSTR4 and SSTR5 are 56.1%, 8.8% and 47.2%, respectively. SSTR2 and SSTR5 negative expression are associated with decreased RFS when compared to positive cases by Kaplan-Meier survival analyses with log-rank test and univariate analysis in GISTs, furthermore, SSTR2 was an independent prognostic indicator for GISTs by multivariate analysis. In our study, detection of SSRT2 and SSTR5 expression helps to predict different prognosis in GIST patients. SSTR2 is a novel independent prognostic biomarker for GISTs. With high expression performance of SSTRs in GISTs, new therapeutic strategies such as octreotide or pasireotide LAR could be taken into consideration in selected advanced GIST patients.


Consensus statement from the 2014 International Microdialysis Forum.
Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.


Targeted delivery and release of doxorubicin using a pH-responsive and self-assembling copolymer.
Developing a smart cancer drug delivery carrier with enhanced cancer-targeting and effective drug release in tumors is critical for efficient cancer chemotherapy. Herein, we designed a pH-responsive copolymer (PEG-ELP[VH4-70]) that entraps DOX into a hydrophobic core and self-assembles into smart DOX-loaded nanoparticles. The DOX-loaded nanoparticles were stabilized by Zn2+ and disrupted as the pH drops from 7.4 to 5.6. An in vitro study demonstrated that the DOX-loaded nanoparticle system exhibited efficient internalization, triggered the release of DOX into the cytoplasm and enabled the inhibition of tumors effectively. When used to deliver chemotherapeutics to a murine cancer model, PEG-ELP[VH4-70]/DOX accomplished a 4.8-fold suppressed effect relative to the free drug after intravenous injection. This simple strategy can promote preeminent stability for targeting hydrophobic drugs to tumor tissues.


Proposed structural mechanism of Escherichia coli cAMP receptor protein cAMP-dependent proteolytic cleavage protection and selective and nonselective DNA binding.
The Escherichia coli cAMP receptor protein (CRP) displays biphasic characteristics in protease and beta-galactosidase induction assays at increasing cAMP concentrations in response to ligand binding at the secondary binding site located between the primary binding site and the DNA binding domain. Two mutants were created to determine the mechanistic reason for the CRP biphasic response by inhibiting binding of cAMP to the secondary site via interference with the Arg 181 interaction with the ligand's phosphate. The S179A/R180D/E181H mutant binds two cAMP molecules per dimer, does not exhibit a biphasic response, lacks selective DNA binding, and has inhibited nonselective DNA binding. The R180K mutant binds four cAMP molecules per dimer, exhibits a biphasic response, nonselective DNA binding similar to CRP, but has inhibited selective DNA binding characteristics. The results are consistent with a 2 x 2-binding site scheme were both primary binding sites must be occupied before the secondary binding sites are occupied. A structural mechanism suggesting the secondary sites are formed by binding of cAMP to the primary sites is proposed. AMMP-generated molecular models suggest that R180 orients E181 to produce selective DNA binding, Arg 169 interactions are necessary for nonselective DNA binding, and the position of Leu 57 inhibits chymotrypsin cleavage of Phe 136. DNA binding results suggest that CRP may be the unknown transcription factor which binds to the temperature sensitive dsrA promoter.


Chemical synthesis of the EPF-family of plant cysteine-rich proteins and late-stage dye attachment by chemoselective amide-forming ligations.
Chemical protein synthesis can provide well-defined modified proteins. Herein, we report the chemical synthesis of plant-derived cysteine-rich secretory proteins and late-stage derivatization of the synthetic proteins. The syntheses were achieved with distinct chemoselective amide bond forming reactions - EPF2 by native chemical ligation (NCL), epidermal patterning factor (EPF) 1 by the α-ketoacid-hydroxylamine (KAHA) ligation, and fluorescent functionalization of their folded variants by potassium acyltrifluoroborate (KAT) ligation. The chemically synthesized EPFs exhibit bioactivity on stomatal development in Arabidopsis thaliana. Comprehensive synthesis of EPF derivatives allowed us to identify suitable fluorescent variants for bioimaging of the subcellar localization of EPFs.


A simplified approach to optimizing denture stability with lingualized occlusion.
Occlusal prematurities are destructive and destabilizing influences in complete dentures. Unless denture bases are adequately and evenly stabilized, it is virtually impossible to properly equilibrate the occlusion. One reason is that all artificial teeth in a denture unit are physically bound into a single denture base and literally act as a single tooth. Therefore, a single point of occlusal prematurity disrupts the entire denture occlusion and negatively affects the denture base stability and retention, preventing proper equilibration. This article describes a step-by-step approach using an intraoral central bearing point tracing device and lingualized occlusion to achieve an effective and simplified equilibration.


Possible roles of N- and C-terminal unstructured tails of CPI-17 in regulating Ca2+ sensitization force of smooth muscle.
CPI-17 regulates the myosin phosphatase and mediates the agonist-induced contraction of smooth muscle. PKC and ROCK phosphorylate CPI-17 at Thr38 leading to a conformational change of the central inhibitory domain (PHIN domain). The N- and C-terminal tails of CPI-17 are predicted as unstructured loops and their sequences are conserved among mammals. Here we characterized CPI-17 N- and C-terminal unstructured tails using recombinant proteins that lack the potions. Recombinant CPI-17 proteins at a physiologic level (10 µM) were doped into beta-escin-permeabilized smooth muscle strips for Ca2+ sensitization force measurement. The ectopic full-length CPI-17 augmented the PDBu-induced Ca2+ sensitization force at pCa6.3, indicating myosin phosphatase inhibition. Deletion of N- and C-terminal tails of CPI-17 attenuated the extent of PDBu-induced Ca2+-sensitization force. The N-terminal deletion dampened phosphorylation at Thr38 by protein kinase C (PKC), and the C-terminal truncation lowered the affinity to the myosin phosphatase. Under the physiologic conditions, PKC and myosin phosphatase may recognize CPI-17 N-/C-terminal unstructured tails inducing Ca2+ sensitization force in smooth muscle cells.


Patterns across multiple memories are identified over time.
Memories are not static but continue to be processed after encoding. This is thought to allow the integration of related episodes via the identification of patterns. Although this idea lies at the heart of contemporary theories of systems consolidation, it has yet to be demonstrated experimentally. Using a modified water-maze paradigm in which platforms are drawn stochastically from a spatial distribution, we found that mice were better at matching platform distributions 30 d compared to 1 d after training. Post-training time-dependent improvements in pattern matching were associated with increased sensitivity to new platforms that conflicted with the pattern. Increased sensitivity to pattern conflict was reduced by pharmacogenetic inhibition of the medial prefrontal cortex (mPFC). These results indicate that pattern identification occurs over time, which can lead to conflicts between new information and existing knowledge that must be resolved, in part, by computations carried out in the mPFC.


Ultraviolet and yellow reflectance but not fluorescence is important for visual discrimination of conspecifics by Heliconius erato.
Toxic Heliconius butterflies have yellow hindwing bars that - unlike those of their closest relatives - reflect ultraviolet (UV) and long wavelength light, and also fluoresce. The pigment in the yellow scales is 3-hydroxy-dl-kynurenine (3-OHK), which is found in the hair and scales of a variety of animals. In other butterflies like pierids with color schemes characterized by independent sources of variation in UV and human-visible yellow/orange, behavioral experiments have generally implicated the UV component as most relevant to mate choice. This has not been addressed in Heliconius butterflies, where variation exists in analogous color components, but moreover where fluorescence due to 3-OHK could also contribute to yellow wing coloration. In addition, the potential cost due to predator visibility is largely unknown for the analogous well-studied pierid butterfly species. In field studies with butterfly paper models, we show that both UV and 3-OHK yellow act as signals for H. erato when compared with models lacking UV or resembling ancestral Eueides yellow, respectively, but attack rates by birds do not differ significantly between the models. Furthermore, measurement of the quantum yield and reflectance spectra of 3-OHK indicates that fluorescence does not contribute to the visual signal under broad-spectrum illumination. Our results suggest that the use of 3-OHK pigmentation instead of ancestral yellow was driven by sexual selection rather than predation.


A strategy for the development of tissue engineering scaffolds that regulate cell behavior.
The cellular scaffold represents an extracellular matrix (ECM) in vivo and a culture substratum in vitro, and provides microenvironmental signaling cues based upon the architecture and component for cells. This review article discusses the development of ideal cellular scaffolds for maintaining the activity of functional cells, for regulating cell behavior, and for reconstructing three-dimensional multicellular masses (3-DMMs). Four culture technologies devising the materials of cellular scaffolds developed by author's group are also presented; the preparation of a multicellular spheroid utilizing a thermo-responsive polymer, the preparation of a three-dimensionally reconstructed multicellular mass (3-DRMM) with a medium circulating system utilizing cotton-gauze, a concept for organ engineering that can remodel an organ into a reconstructed organ by a continuous three-step perfusion to change the cellular scaffold, and a concept for cellomics study to culture cells on a substratum made of tissue/organ sections for histopathology (TOSHI-substratum) that conserve the microarchitecture and component of the original tissue in vivo. The former two tissue engineering technologies still lacked the method to design 3-DMMs with hierarchical tissue architectures based on cell lineages. To overcome this task, the latter two technologies that can convert tissue architecture in vivo into the three-dimensional culture mode in vitro were innovated.


Rapid adaptation to internal states as a coding strategy in visual cortex?
Adaptation is a prominent feature of biological neuronal systems. A common interpretation of adaptation in terms of function is that it provides flexibility for a neuronal system to perform well under varying external conditions, for example by adjusting the input/output relation of a sensory system with reference to the ensemble of stimuli the organism currently perceives. This interpretation, however, only applies if the time-scale of adaptation is slower than the time-scale at which the environment changes. Experimentally it is observed, however, that adaptation can be very rapid. Spike-frequency adaptation of cortical neurons, for example, occurs on a time-scale of approximately 100 ms. Here we show that those rapid adaptation processes can also be understood within the framework of information theory. We start with the hypothesis that neuronal codes are designed to optimize the information a neuronal representation conveys about an input stimulus for any increasing time window beginning with stimulus onset, and we show that this implies a rapid adaptation of the neuronal code on the time-scale of stimulus presentation. Adaptation, however, does not occur because the state of the environment changes. Rather it is a reaction to changes of the organisms own internal state, e.g. the level of noise in the neuronal representation. We apply this approach to a model of an orientation hypercolumn in the primary visual cortex, and predict that inter-columnar interactions should adapt on the time-scale of a typical fixation period ( approximately 300 ms).


Pharmacogenetics of opioids for the treatment of acute maternal pain during pregnancy and lactation.
There have been an increasing number of clinical studies investigating the relationship between interindividual genetic variability and the safety and efficacy of opioid analgesics. Despite the widespread use of opioids in pregnant and lactating women for the treatment of acute pain, few studies have investigated the interplay of genetic factors and pregnancy-related physiological alterations in relation to opioid metabolism and response. Some interesting avenues of research require further pursuit- including evidence of cytochrome P450 2D6 (CYP2D6) induction during pregnancy and its effect on the generation of the active opioid metabolites morphine, oxymorphone, O-desmethyltramadol, and hydromorphone following the administration of codeine, oxycodone, tramadol, and hydrocodone respectively. Studies investigating the duration of maternal CYP2D6 induction after delivery are also needed to shed light on genotype to phenotype correlations in breastfeeding mothers using opioid analgesics in the postpartum period.


Evaluation and management of patients with inhalation injury.
Inhalation injury, present in approximately one third of burned patients treated at burn centers, increases mortality by a maximum of 20% in relation to age and extent of burn. The development of animal models of inhalation injury has made possible the identification of both the airway and vascular responses evoked by smoke inhalation. Inflammatory occlusion of terminal bronchioles and necrosis of the endobronchial mucosa render the airway and pulmonary parenchyma susceptible to infection and the resulting pneumonitis further increases mortality. Early diagnosis, best achieved by endoscopic bronchoscopy and 133xeon ventilation perfusion scan, permits timely application of high-frequency ventilation that appears to reduce the incidence of pneumonia and to decrease mortality. Pharmacologic agents give promise of ameliorating the deleterious changes of the vasculature. The recent advances in understanding inhalation injury have identified the research needed to further improve patient salvage.


Determination of carcinogenic fluorine in cigarettes using pulsed UV laser-induced breakdown spectroscopy.
A spectrometer based on pulsed UV laser-induced breakdown spectroscopy (LIBS) and a highly sensitive intensified charged coupled device camera was developed to determine the carcinogenic substances like fluorine in various brands of cigarettes available commercially. In order to achieve the high sensitivity required for the determination of trace amounts of fluoride in cigarettes and eventually the best limit of detection, the experimental parameters (influence of incident laser energy on LIBS signal intensity and time response of plasma emission) were optimized. In addition, the plasma parameters like electron temperature and electron density were evaluated using Boltzman's plot for cigarette tobacco for the first time. To the best of our knowledge, LIBS has never been applied to determine the fluorine concentration in cigarettes. Along with the detection of fluorine, other trace metals like Ba, Ca, Ni, Cu, and Na were also detected in cigarettes. For determination of the concentration of fluorine, calibration curve was drawn by preparing standard samples in various fluoride concentrations in tobacco matrix. The concentration of fluorine in different cigarette tobacco samples was 234, 317, 341, and 360 ppm respectively, which is considered to be much higher than the safe permissible limits. The limit of detection of our LIBS spectrometer was 14 ppm for fluorine.


A VTA to Basal Amygdala Dopamine Projection Contributes to Signal Salient Somatosensory Events during Fear Learning.
The amygdala is a brain area critical for the formation of fear memories. However, the nature of the teaching signal(s) that drive plasticity in the amygdala are still under debate. Here, we use optogenetic methods to investigate the contribution of ventral tegmental area (VTA) dopamine neurons to auditory-cued fear learning in male mice. Using anterograde and retrograde labeling, we found that a sparse and relatively evenly distributed population of VTA neurons projects to the basal amygdala (BA). In vivo optrode recordings in behaving mice showed that many VTA neurons, among them putative dopamine neurons, are excited by footshocks, and acquire a response to auditory stimuli during fear learning. Combined cfos imaging and retrograde labeling in dopamine transporter (DAT) Cre mice revealed that a large majority of BA projectors (>95%) are dopamine neurons, and that BA projectors become activated by the tone-footshock pairing of fear learning protocols. Finally, silencing VTA dopamine neurons, or their axon terminals in the BA during the footshock, reduced the strength of fear memory as tested 1 d later, whereas silencing the VTA-central amygdala (CeA) projection had no effect. Thus, VTA dopamine neurons projecting to the BA contribute to fear memory formation, by coding for the saliency of the footshock event and by signaling such events to the basal amygdala.SIGNIFICANCE STATEMENT Powerful mechanisms of fear learning have evolved in animals and humans to enable survival. During fear conditioning, a sensory cue, such as a tone (the conditioned stimulus), comes to predict an innately aversive stimulus, such as a mild footshock (the unconditioned stimulus). A brain representation of the unconditioned stimulus must act as a teaching signal to instruct plasticity of the conditioned stimulus representation in fear-related brain areas. Here we show that dopamine neurons in the VTA that project to the basal amygdala contribute to such a teaching signal for plasticity, thereby facilitating the formation of fear memories. Knowledge about the role of dopamine in aversively motivated plasticity might allow further insights into maladaptive plasticities that underlie anxiety and post-traumatic stress disorders in humans.


MEMS biosensors for detection of methicillin resistant Staphylococcus aureus.
This review presents the current state of the conventional methods, microfluidic based biosensors, and the commercial products used in the detection of methicillin resistant Staphylococcus aureus (MRSA), which is one of the most important threats of nosocomial infections in many parts of the world. The early detection of MRSA in the specimens of the patients is important to enable the appropriate treatment, to decrease morbidity and mortality rates, and to manage control actions in the healthcare units. Thus, rapid and inexpensive diagnostic systems with high sensitivity and specificity are essential to prevent MRSA to be an emerging public health threat. The design and fabrication of new diagnostic systems necessitates working in collaboration between different disciplines to make new challenges in the field of clinical diagnosis and to meet the demands of clinicians. It is certain that in the near future, MEMS and nanotechnology based detection methods will take the place of current methods in clinical diagnosis. The evaluation of new trends for specificity, sensitivity, cost effectiveness, disposability, low weight, ease of use, and facile access should be taken into consideration.


Confirmatory analysis of beta-lactam antibiotics in kidney tissue by liquid chromatography/electrospray ionization selective reaction monitoring ion trap tandem mass spectrometry.
Eleven beta-lactam antibiotics were analyzed in fortified and incurred beef kidney tissue using high-performance liquid chromatography/electrospray ionization/selective reaction monitoring-ion trap tandem mass spectrometry (LC/ESI-SRM-MS(n)). The analytes included: deacetylcephapirin, amoxicillin, cephapirin, desfuroylceftiofur cysteine disulfide (DCCD, a biomarker of ceftiofur), ampicillin, cefazolin, Pen G, oxacillin, cloxacillin, naficillin and dicloxicillin. Analytes were extracted with acetonitrile and water. Clean-up was performed by solid-phase extraction. Limits of confirmation in fortified tissue are as follows (tolerances or target levels in parentheses): deacetylcephapirin: 10-50 ng/g (100 ng/g); amoxacillin: 50-100 ng/g (10 ng/g); cephapirin: 10 ng/g (100 ng/g); DCCD: 500 ng/g (8000 ng/g); ampicillin: 10 ng/g (10 ng/g); cefazolin: 10 ng/g (10-50 ng/g); Pen G: 10 ng/g (50 ng/g); oxacillin: 10 ng/g (10-50 ng/g); cloxacillin: 10 ng/g (10 ng/g); naficillin: 10 ng/g (10-50 ng/g); dicloxacillin: 100-500 ng/g (10-50 ng/g). The present method was also tested on incurred kidney tissue that had previously been analyzed using a microbial assay. Good correspondence was found between the results from this new method and the bioassay. However, the present method is much more specific and, in several cases, more sensitive than the bioassay. In addition, the time of analysis is significantly shorter than the bioassay. We also found that SRM MS(n) was superior in the analysis of unknown incurred tissue than full spectrum MS(n). We also obtained an MS/MS spectrum of DCCD that is significantly at variance with previously published fragmentation spectra.


Do contamination of and exposure to chicken meat and water drive the temporal dynamics of Campylobacter cases?
Campylobacteriosis, the most frequent bacterial enteric disease, shows a clear yet unexplained seasonality. The study purpose was to explore the influence of seasonal fluctuation in the contamination of and in the behaviour exposures to two important sources of Campylobacter on the seasonality of campylobacteriosis. Time series analyses were applied to data collected through an integrated surveillance system in Canada in 2005-2010. Data included sporadic, domestically-acquired cases of Campylobacter jejuni infection, contamination of retail chicken meat and of surface water by C. jejuni, and exposure to each source through barbequing and swimming in natural waters. Seasonal patterns were evident for all variables with a peak in summer for human cases and for both exposures, in fall for chicken meat contamination, and in late fall for water contamination. Time series analyses showed that the observed campylobacteriosis summer peak could only be significantly linked to behaviour exposures rather than sources contamination (swimming rather than water contamination and barbequing rather than chicken meat contamination). The results indicate that the observed summer increase in human cases may be more the result of amplification through more frequent risky exposures rather than the result of an increase of the Campylobacter source contamination.


Dynamic Brain Activity Following Auricular Point Acupressure in Chemotherapy-Induced Neuropathy: A Pilot Longitudinal Functional Magnetic Resonance Imaging Study.
The objective of this study was to investigate the dynamic brain activity following auricular point acupressure (APA) in chemotherapy-induced neuropathy (CIN). Participants received 4 weeks of APA in an open-pilot trial with repeated observation. Along with the clinical self-reported CIN outcomes, objective outcomes were measured over the course of the treatment by physiological changes in pain sensory thresholds from quantitative sensory testing (QST) and repeated functional magnetic resonance imaging scans. After 4 weeks of APA, participants had reported clinically significant improvements (ie, ≥30%) in a reduction of CIN symptoms (including pain, numbness, tingling, and stiffness) in lower extremity stiffness (32%), reduced foot sensitivity (13%), and higher pain threshold (13%). Across the 11 intrinsic brain networks examined, there was a trend toward significance of the connectivity of the basal ganglia network (BGN) to the salience network (SAL), which was decreased pre-APA versus immediate-APA (effect size [ES] = 1.04, P = .07). The BGN also demonstrated decreased connectivity with the language network pre-APA versus delayed imaging post-APA (ES = -0.92, P = .07). Furthermore, there was increased executive control network (ECN) and SAL within-network connectivity comparing pre-APA to delayed imaging post-APA, trending toward significance (ES = 0.41, P = .09 and ES = 0.17, P = .09, respectively). The changes in connectivity and activity within or between the ECN, SAL, and BGN from pre- to post-APA suggest ongoing alterations in brain functional connectivity following APA, particularly in the insula, anterior cingulate, and dorsolateral prefrontal cortices, which play significant roles in pain, memory, and cognitive function.


The Mechanism of Lavender Essential Oil in the Treatment of Acute Colitis Based on "Quantity-Effect" Weight Coefficient Network Pharmacology.
This study aimed to introduce a new weight coefficient combined with network pharmacology to predict the potential active components, action targets, and signal pathways of lavender essential oil and to investigate the therapeutic effect of lavender essential oil on colitis through animal experiments. The component targets of lavender essential oil were mined from the Pubchem and SwissTargetPrediction databases, and the relative content of lavender essential oil was compared with OB (oral bioavailability) to establish a "quantity-effect" weight coefficient. Online databases such as GeneCards and String were used to construct a "lavender essential oil compound target disease target" network to extract the key targets of core compounds acting on diseases. The clusterProfiler package in R language programming of Rstudio software was used to analyze the enrichment of the related targets by Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG), and the enriched pathways were reordered according to the "quantity-effect" weight coefficient of the targets they participated in. Following up on the findings, the pharmacodynamic test showed that, after injecting lavender essential oil into mice, the levels of inflammatory cytokines including EGFR, TNF-α, and IFN-γ in serum and colon tissue decreased, and lavender essential oil could mediate Th17 cell differentiation by reducing dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) colonic mucosal damage. The results indicated that lavender essential oil can alleviate DSS-induced colonic mucosal injury in ulcerative Colitis mice. Based on the network pharmacology of the "quantity-effect" weight coefficient, this study indicated that lavender essential oil can regulate the level of inflammatory factors, inhibit inflammatory reactions through a multicomponent and multitarget strategy, and ultimately alleviate the colonic mucosal injury of UC mice. Through the weight coefficient network pharmacology mining, it was concluded that the Th17 cell differentiation, PI3K-Akt signaling pathway, and Th1 and Th2 cell differentiation of lavender essential oil in the treatment of UC may be the key pathway for the treatment of the disease. Through the establishment of a weight coefficient combined with network pharmacology and the combination of dose and effect, it shows that network pharmacology may provide a better basis for the treatment of disease mechanism.


Proanthocyanidin synthesis in Theobroma cacao: genes encoding anthocyanidin synthase, anthocyanidin reductase, and leucoanthocyanidin reductase.
The proanthocyanidins (PAs), a subgroup of flavonoids, accumulate to levels of approximately 10% total dry weight of cacao seeds. PAs have been associated with human health benefits and also play important roles in pest and disease defense throughout the plant. To dissect the genetic basis of PA biosynthetic pathway in cacao (Theobroma cacao), we have isolated three genes encoding key PA synthesis enzymes, anthocyanidin synthase (ANS), anthocyanidin reductase (ANR) and leucoanthocyanidin reductase (LAR). We measured the expression levels of TcANR, TcANS and TcLAR and PA content in cacao leaves, flowers, pod exocarp and seeds. In all tissues examined, all three genes were abundantly expressed and well correlated with PA accumulation levels, suggesting their active roles in PA synthesis. Overexpression of TcANR in an Arabidopsis ban mutant complemented the PA deficient phenotype in seeds and resulted in reduced anthocyanidin levels in hypocotyls. Overexpression of TcANS in tobacco resulted in increased content of both anthocyanidins and PAs in flower petals. Overexpression of TcANS in an Arabidopsis ldox mutant complemented its PA deficient phenotype in seeds. Recombinant TcLAR protein converted leucoanthocyanidin to catechin in vitro. Transgenic tobacco overexpressing TcLAR had decreased amounts of anthocyanidins and increased PAs. Overexpressing TcLAR in Arabidopsis ldox mutant also resulted in elevated synthesis of not only catechin but also epicatechin. Our results confirm the in vivo function of cacao ANS and ANR predicted based on sequence homology to previously characterized enzymes from other species. In addition, our results provide a clear functional analysis of a LAR gene in vivo.


Drinking Patterns, Gender and Health III: Avoiding vs. Seeking Healthcare.
Inability to predict most health services use and costs using demographics and health status suggests that other factors affect use, including attitudes and practices that influence health and willingness to seek care. Alcohol consumption has generated interest because heavy, chronic consumption causes adverse health consequences, acute consumption increases injury, and moderate drinking is linked to better health while hazardous drinking and alcohol-related problems are stigmatized and may affect willingness to seek care. A stratified random sample of health-plan members completed a mail survey, yielding 7884 respondents (2995 male/4889 female). We linked survey data to 24 months of health-plan records to examine relationships between alcohol use, gender, health-related attitudes, practices, health, and service use. In-depth interviews with a stratified 150-respondent subsample explored individuals' reasons for seeking or avoiding care. Quantitative results suggest health-related practices and attitudes predict subsequent service use. Consistent predictors of care were having quit drinking, current at-risk consumption, cigarette smoking, higher BMI, disliking visiting doctors, and strong religious/spiritual beliefs. Qualitative analyses suggest embarrassment and shame are strong motivators for avoiding care. Although models included numerous health, functional status, attitudinal and behavioral predictors, variance explained was similar to previous reports, suggesting more complex relationships than expected. Qualitative analyses suggest several potential predictive factors not typically measured in service-use studies: embarrassment and shame, fear, faith that the body will heal, expectations about likelihood of becoming seriously ill, disliking the care process, the need to understand health problems, and the effects of self-assessments of health-related functional limitations.


Differential expression of the multiple chaperonins of Mycobacterium smegmatis.
Mycobacterium smegmatis contains three chaperonin (cpn60) genes homologous to the Escherichia coli groEL gene. One of these (cpn60.1) is required for biofilm formation, but is nonessential, whereas a second (cpn60.2) is essential. Mycobacterium smegmatis is unique among Mycobacteria in having a third chaperonin gene, cpn60.3. The cpn60.1 gene has a gene upstream (cpn10) that is homologous to the gene for the E. coli co-chaperonin GroES. Phylogenetic analysis of the mycobacterial homologues suggests that early gene duplication and sequence divergence gave rise to the cpn60.1 and cpn60.2 genes found in all Mycobacteria species, while cpn60.3 appears to have been acquired by horizontal gene transfer. Here, we show that cpn60.2 and cpn10 are expressed more strongly than cpn60.1, while cpn60.3 shows very low levels of expression. The expression of all the genes, except cpn60.3, is significantly induced by heat shock, but much less so by other stresses. We mapped mRNA 5'-ends for the cpn10 and cpn60.1 genes, and measured the promoter activity of the upstream regions of both genes. The results show that the mRNA for this operon is cleaved between the cpn10 and cpn60.1 genes. These results are consistent with the evolution of a distinct function for the cpn60.1 gene.


Voltage-regulated water flux through aquaporin channels in silico.
Aquaporins (AQPs) facilitate the passive flux of water across biological membranes in response to an osmotic pressure. A number of AQPs, for instance in plants and yeast, have been proposed to be regulated by phosphorylation, cation concentration, pH change, or membrane-mediated mechanical stress. Here we report an extensive set of molecular dynamics simulations of AQP1 and AQP4 subject to large membrane potentials in the range of ±1.5 V, suggesting that AQPs may in addition be regulated by an electrostatic potential. As the regulatory mechanism we identified the relative population of two different states of the conserved arginine in the aromatic/arginine constriction region. A positive membrane potential was found to stabilize the arginine in an up-state, which allows rapid water flux, whereas a negative potential favors a down-state, which reduces the single-channel water permeability.


Topical calcipotriol in childhood psoriasis.
The use of topical calcipotriol in adults with psoriasis is safe and effective. Our purpose was to study the efficacy and safety of calcipotriol in children. A multicenter, prospective, 8-week, double-blind, parallel group study was conducted in 77 children. Response to treatment was assessed by means of the Psoriasis Area and Severity Index (PASI) in that the intensity of redness, thickness, and scaliness as well as the area involved are scored. The children were 2 to 14 years of age and had stable psoriasis, involving less than 30% of the body surface. Forty-three children were assigned to receive calcipotriol ointment and 34 to receive placebo. Nine children dropped out of the study, six in the calcipotriol-treated group and three in the placebo-treated group. Both treatment groups (calcipotriol and placebo) showed significant improvement in PASI from baseline to the end of treatment, and the difference was not statistically significant. No serious side effects, in particular including those relating to calcium and bone metabolism, were recorded. Calcipotriol ointment was statistically significantly more effective than its vehicle in terms of the investigator's overall assessment and reduction in redness and scaliness but not in terms of PASI score.


[Assessment of individual clinical outcomes: regarding an electroconvulsive therapy case].
Evaluation of therapeutic results and of the efficacy and effectiveness of treatments is an area of interest both for clinicians and researchers. In general, randomized controlled trial designs have been used as the methodology of choice in which intergroup comparisons are made having a minimum of participants in each arm of treatment. However, these procedures are seldom used in daily clinical practice. Despite this fact, the evaluation of treatment results for a specific patient is important for the clinician in order to address if therapeutic goals have been accomplished both in terms of statistical significance and clinical meaningfulness. The methodology based on the reliable change index (Jacobson y Truax)1 provides an estimate of these two criteria. The goal of this article is to propose a procedure to apply the methodology with a single case study of a woman diagnosed with major depression and treated with electroconvulsive therapy.


Computational analysis of a species D human adenovirus provides evidence of a novel virus.
A human adenovirus (HAdV) species D, was isolated from a hospitalised child with severe lower respiratory infection. It was initially detected in the nasopharyngeal aspirate of the child followed by conventional PCR amplification of the hexon, penton base, and fibre genes. Sanger DNA sequencing and phylogenetic analyses showed characteristics of a recombinant genome not described before. Next Generation Sequencing analysis was performed to reconstruct its complete DNA genome after viral isolation in adenocarcinoma human cell line (A549). A complete genomic sequence of 35.2 kb in length, with a G+C content of 57 % was obtained, related to HAdV-D29 (96 % identity). Imputed serology analysis demonstrated its novel type with a nucleotide sequence identity of 95.3 % (hexon loop 1) and 96 % (hexon loop 2) to HAdV-D9. The penton base gene showed a novel sequence, distantly related to HAdV-D44. The E3 and E4 regions evolved significantly from their ancestors. The fibre gene was almost identical to the knob region of HAdV-D15 but showed an unrelated shaft sequence. In conclusion the genomics of this novel HAdV, designated the HAdV-D83 [P83H9F15] prototype and bearing a new penton base gene, supports the importance of viral evolution to understand modified tissue tropism, enhanced transmission, or altered virulence.


Whole genome expression and biochemical correlates of extreme constitutional types defined in Ayurveda.
Ayurveda is an ancient system of personalized medicine documented and practiced in India since 1500 B.C. According to this system an individual's basic constitution to a large extent determines predisposition and prognosis to diseases as well as therapy and life-style regime. Ayurveda describes seven broad constitution types (Prakritis) each with a varying degree of predisposition to different diseases. Amongst these, three most contrasting types, Vata, Pitta, Kapha, are the most vulnerable to diseases. In the realm of modern predictive medicine, efforts are being directed towards capturing disease phenotypes with greater precision for successful identification of markers for prospective disease conditions. In this study, we explore whether the different constitution types as described in Ayurveda has molecular correlates. Normal individuals of the three most contrasting constitutional types were identified following phenotyping criteria described in Ayurveda in Indian population of Indo-European origin. The peripheral blood samples of these individuals were analysed for genome wide expression levels, biochemical and hematological parameters. Gene Ontology (GO) and pathway based analysis was carried out on differentially expressed genes to explore if there were significant enrichments of functional categories among Prakriti types. Individuals from the three most contrasting constitutional types exhibit striking differences with respect to biochemical and hematological parameters and at genome wide expression levels. Biochemical profiles like liver function tests, lipid profiles, and hematological parameters like haemoglobin exhibited differences between Prakriti types. Functional categories of genes showing differential expression among Prakriti types were significantly enriched in core biological processes like transport, regulation of cyclin dependent protein kinase activity, immune response and regulation of blood coagulation. A significant enrichment of housekeeping, disease related and hub genes were observed in these extreme constitution types. Ayurveda based method of phenotypic classification of extreme constitutional types allows us to uncover genes that may contribute to system level differences in normal individuals which could lead to differential disease predisposition. This is a first attempt towards unraveling the clinical phenotyping principle of a traditional system of medicine in terms of modern biology. An integration of Ayurveda with genomics holds potential and promise for future predictive medicine.


Improvement in self-reported confidence in nurses' professional skills in the emergency department.
The aim of this study was to assess nurses' self-reported confidence in their professional skills before and after an extensive Emergency Department (ED) reform in Kanta-Häme Central Hospital. Emergency nurses participated in transitional training commencing two years before the establishment of the new organization in 2007. Training was followed by weekly practical educational sessions in the new ED. During this process nurses improved their transition skills, defined house rules for the new clinic and improved their knowledge of new technology and instruments. The main processes involving critically ill ED patients were described and modelled with an electronic flow chart software.During the transitional training nurses compiled lists of practical skills and measures needed in the ED. These were updated after feedback from physicians in primary and secondary care and head physicians in Kanta-Häme Central Hospital. The final 189-item list comprised 15 different categories, each containing from 4 to 35 items. Based on the work described above, a questionnaire was developed to reflect ED nurses' skills in clinical measures but also to estimate the need for professional education and practical training. Nurses working in the ED were asked to fill the questionnaire in January 2007 (response rate 97%) and in January 2011 (response rate 98%). Nurses' self-reported confidence in their professional skills improved significally in eight classes out of fifteen. These classes were cannulations, urinary catheterizations, patient monitoring, cardiac patients, equipment, triage and nurse practising, psychiatric patients as well as infection risk. Best results were noted in urinary catheterizations, patient monitoring and infection risk. When studying the group of nurses participating in both surveys in 2007 and 2011, improvements were observed in all fifteen categories. All but two of these changes were significant (p<0.05). During an extensive reform of emergency services, we noted a significant improvement in the professional skills of nurses. This improvement was especially consistent among nurses working in the ED during the whole transition process. Nurses' education and training program in the ED may be successfully put into practice when based on co-operation between nurses and physicians dedicated to emergency services.


Combined Quantum Mechanical and Quasi-Classical State-to-State Dynamical Study on the Isotopic Effect in H/D + LiH+/LiD+ → H2/HD/D2 + Li+ Reactions.
Coriolis-coupled quantum mechanical (QM-CC) and quasi-classical trajectory (QCT) calculations are carried out to investigate the dynamics of the H(D) + LiH+(v = 0, j = 0) → H2(HD) (v', j') + Li+ reactions on the ground electronic state potential energy surface reported by Martinazzo et al. (Martinazzo et al., J. Chem. Phys. 2003, 119, 11241). The QM-CC and QCT results at the initial state-selected and state-to-state levels are used to investigate the validity and accuracy of the QCT method for these exoergic barrierless reactions. Furthermore, the QCT method is used to understand the isotopic effects on reaction observables like total and state-to-state integral cross section, differential cross section, product energy disposal, and rate constants of H(D) + LiH+(v = 0, j = 0) → H2(HD) (v', j') + Li+ and H(D) + LiD+(v = 0, j = 0) → HD(D2) (v', j') + Li+ reactions. Attempts are also made to understand the impact of the isotopic substitution on the reaction mechanism. It is observed that QM-CC and QCT results closely follow each other at the initial state-selected and state-to-state levels. Noticeable kinematic effects of reagents on the reactivity and mechanism of the reactions are also observed.


The use of group sequential, information-based sample size re-estimation in the design of the PRIMO study of chronic kidney disease.
Chronic kidney disease is associated with a marked increase in risk for left ventricular hypertrophy and cardiovascular mortality compared with the general population. Therapy with vitamin D receptor activators has been linked with reduced mortality in chronic kidney disease and an improvement in left ventricular hypertrophy in animal studies. PRIMO (Paricalcitol capsules benefits in Renal failure Induced cardia MOrbidity) is a multinational, multicenter randomized controlled trial to assess the effects of paricalcitol (a selective vitamin D receptor activator) on mild to moderate left ventricular hypertrophy in patients with chronic kidney disease. Subjects with mild-moderate chronic kidney disease are randomized to paricalcitol or placebo after confirming left ventricular hypertrophy using a cardiac echocardiogram. Cardiac magnetic resonance imaging is then used to assess left ventricular mass index at baseline, 24 and 48 weeks, which is the primary efficacy endpoint of the study. Because of limited prior data to estimate sample size, a maximum information group sequential design with sample size re-estimation is implemented to allow sample size adjustment based on the nuisance parameter estimated using the interim data. An interim efficacy analysis is planned at a pre-specified time point conditioned on the status of enrollment. The decision to increase sample size depends on the observed treatment effect. A repeated measures analysis model, using available data at Week 24 and 48 with a backup model of an ANCOVA analyzing change from baseline to the final nonmissing observation, are pre-specified to evaluate the treatment effect. Gamma-family of spending function is employed to control family-wise Type I error rate as stopping for success is planned in the interim efficacy analysis. If enrollment is slower than anticipated, the smaller sample size used in the interim efficacy analysis and the greater percent of missing week 48 data might decrease the parameter estimation accuracy, either for the nuisance parameter or for the treatment effect, which might in turn affect the interim decision-making. The application of combining a group sequential design with a sample-size re-estimation in clinical trial design has the potential to improve efficiency and to increase the probability of trial success while ensuring integrity of the study.


Economic evaluation of an intervention program with the aim to improve at-work productivity for workers with rheumatoid arthritis.
Evaluating the cost effectiveness and cost utility of an integrated care intervention and participatory workplace intervention for workers with rheumatoid arthritis (RA) to improve their work productivity. Twelve month follow-up economic evaluation alongside a randomized controlled trial (RCT) within specialized rheumatology treatment centers. Adults diagnosed with RA between 18-64 years, in a paid job for at least eight hours per week, experiencing minor difficulties in work functioning were randomized to the intervention (n = 75) or the care-as-usual (CAU) group (n = 75). Effect outcomes were productivity and quality of life (QALYs). Costs associated with healthcare, patient and family, productivity, and intervention were calculated from a societal perspective. Cost effectiveness and cost utility were assessed to indicate the incremental costs and benefits per additional unit of effect. Subgroup and sensitivity analyses evaluated the robustness of the findings. At-work productivity loss was about 4.6 hours in the intervention group and 3.5 hours in the care as usual (CAU) group per two weeks. Differences in QALY were negligible; 0.77 for the CAU group and 0.74 for the intervention group. In total, average costs after twelve months follow-up were highest in the intervention group (€7,437.76) compared to the CAU group (€5,758.23). The cost-effectiveness and cost-utility analyses show that the intervention was less effective and (often) more expensive when compared to CAU. Sensitivity analyses supported these findings. The integrated care intervention and participatory workplace intervention for workers with RA provides gains neither in productivity at the workplace nor in quality of life. These results do not justify the additional costs.