Down-modulation of antigen-induced activation of murine cultured mast cells sensitized with a highly cytokinergic IgE clone.
Accumulating evidence suggests that several IgE clones can activate mast cells during the sensitization phase even in the absence of antigen. They were found to induce pro-inflammatory cytokine release, histamine synthesis, chemotaxis, adhesion, and accelerated maturation of mast cells, although it remains unknown whether antigen-induced responses can be affected by differences of IgE clones. We compared two IgE clones, which were different in the capacity to activate mast cells during sensitization, in terms of potentials to affect antigen-induced degranulation and cytokine releases using IL-3-dependent murine bone marrow-derived cultured mast cells (BMMCs). Antigen-induced degranulation and pro-inflammatory cytokine release were augmented, when BMMCs were sensitized with elevated concentrations of a clone IgE-3, which did not induce phosphorylation of JNK and cytokine release in the absence of antigen, whereas those were significantly rather decreased, when BMMCs were sensitized with elevated concentrations of a clone SPE-7, one of the most potent cytokinergic IgE clones, which intensively induced phosphorylation of JNK. This attenuated response with SPE-7 was accompanied by decreased tyrosine phosphorylation of the cellular proteins including Syk upon antigen stimulation. SP600125, which is known to inhibit JNK, restored the levels of antigen-induced degranulation and phosphorylation of Syk in BMMCs sensitized with higher concentrations of a clone SPE-7 when it was added before sensitization. Treatment with anisomycin, a potent activator of JNK, before IgE sensitization significantly suppressed antigen-induced degranulation. These findings suggest that differences of sensitizing IgE clones can affect antigen-induced responses and activation of JNK during sensitization might suppress antigen-induced activation of mast cells.


A systematic review and meta-analysis of second-line immunosuppressants for autoimmune hepatitis treatment.
The gold-standard treatment for autoimmune hepatitis (AIH) is a prednisone/azathioprine combination. However, subgroups of patients may be unresponsive to this treatment. The aim of this study is to evaluate the efficacy of second-line immunosuppressive therapies for AIH through a systematic review and meta-analysis in adult patients. The systematic review was registered at the PROSPERO platform under number 42015019831. Databases MEDLINE (PubMed), Lilacs, Cochrane, and Scielo were searched. The keywords used were 'Hepatitis, Autoimmune' and descriptors terms (MeSH and DeCS). These terms were linked with each immunosuppressant of interest. A total of 1532 studies were identified. Of these, 1492 were excluded on the basis of title and abstract reading. Among the 40 studies retrieved for detailed full-text analysis, a total of 15 fulfilled the inclusion criteria for the analysis. The most studied second-line immunosuppressive was mycophenolate mofetil (MM). The mean reduction of aminotransferases was observed in 94.3% with tacrolimus/prednisone, 91.3% for cyclosporine/prednisone, 85.5% for budesonide, and 78.7% MM/prednisone. For MM/prednisone, the mean rate of histological remission was 88.6%, liver transplantation was indicated in 11.4%, and the mortality rate was 7.2%. Limitations were also present, such as the lack of randomized-controlled trials and prospective studies, the small number of patients, and the heterogeneity between remission criteria. This is the first systematic review and meta-analysis to compare the second-line imunossupressant therapy for AIH. The most studied second-line immunosuppressive is the MM, with a reasonable histological remission. The use of combined tacrolimus/prednisone was the most effective for the normalization of aminotransferases.


Reflecting on whiplash associated disorder through a QoL lens: an option to advance practice and research.
To examine the constructs of quality of life (QoL) as applied to whiplash associated disorder (WAD), its current state of measurement and suggestions for future application. Narrative literature review. The burden of WAD on the healthcare system is substantive. Assessment of QoL issues for people with WAD may provide a broader understanding of the patient experience. No consistent framework for QoL in WAD has been adopted, nor has preference for any QoL instrument been established. Inconsistent use of terminology for what is being measured, and the measures themselves hamper clarity on the issue. Options for assessing QoL currently include a meaningful condition-specific scale that has not undergone sufficient psychometric evaluation (Whiplash Disability Questionnaire (WDQ), or generic scales with strong psychometric properties that have not undergone sufficient relevancy evaluation (e.g. SF-36, WHOQOL BREF). Generic measures can measure overlapping constructs including heath status, utility, health-related quality of life or generic QoL. The inter-relationships between these in WAD have not been defined. Given the impact of WAD on QoL, additional clarity on tools and approaches are needed. There is a need for research on the relevance and clinical measurement properties of available condition-specific and generic tools to define a preferred measurement approach in WAD.


Human placenta-derived adherent cells prevent bone loss, stimulate bone formation, and suppress growth of multiple myeloma in bone.
Human placenta has emerged as a valuable source of transplantable cells of mesenchymal and hematopoietic origin for multiple cytotherapeutic purposes, including enhanced engraftment of hematopoietic stem cells, modulation of inflammation, bone repair, and cancer. Placenta-derived adherent cells (PDACs) are mesenchymal-like stem cells isolated from postpartum human placenta. Multiple myeloma is closely associated with induction of bone disease and large lytic lesions, which are often not repaired and are usually the sites of relapses. We evaluated the antimyeloma therapeutic potential, in vivo survival, and trafficking of PDACs in the severe combined immunodeficiency (SCID)-rab model of medullary myeloma-associated bone loss. Intrabone injection of PDACs into nonmyelomatous and myelomatous implanted bone in SCID-rab mice promoted bone formation by stimulating endogenous osteoblastogenesis, and most PDACs disappeared from bone within 4 weeks. PDACs inhibitory effects on myeloma bone disease and tumor growth were dose-dependent and comparable with those of fetal human mesenchymal stem cells (MSCs). Intrabone, but not subcutaneous, engraftment of PDACs inhibited bone disease and tumor growth in SCID-rab mice. Intratumor injection of PDACs had no effect on subcutaneous growth of myeloma cells. A small number of intravenously injected PDACs trafficked into myelomatous bone. Myeloma cell growth rate in vitro was lower in coculture with PDACs than with MSCs from human fetal bone or myeloma patients. PDACs also promoted apoptosis in osteoclast precursors and inhibited their differentiation. This study suggests that altering the bone marrow microenvironment with PDAC cytotherapy attenuates growth of myeloma and that PDAC cytotherapy is a promising therapeutic approach for myeloma osteolysis.


Manual reaction times and brain dynamics after 'awake surgery' of slow-growing tumours invading the parietal area. A case report.
Awake surgeries of slow-growing tumours invading the brain and guided by direct electrical stimulation induce major brain reorganizations accompanied with slight impairments post-operatively. In most cases, these deficits are so slight after a few days that they are often not detectable on classical neuropsychological evaluations. Consequently, this study investigated whether simple visuo-manual reaction time paradigms would sign some level of functional asymmetries between both hemispheres. Importantly, the visual stimulus was located in the saggital plane in order to limit attentional biases and to focus mainly on the inter-hemispheric asymmetry. Three patients (aged 41, 59 and 59 years) after resections in parietal regions and a control group (age = 44, SD = 6.9) were compared during simple uni- and bimanual reaction times (RTs). Longer RTs were observed for the contralesional compared to the ipsilesional hand in the unimanual condition. This asymmetry was reversed for the bimanual condition despite longer RTs. Reaction time paradigms are useful in these patients to monitor more precisely their functional deficits, especially their level of functional asymmetry, and to understand brain (re)organization following slow-growing lesions.


Arc/Arg3.1 defines dendritic cells and Langerhans cells with superior migratory ability independent of phenotype and ontogeny in mice.
The key function of migratory dendritic cells (migDCs) is to take up antigens in peripheral tissues and migrate to draining lymph nodes (dLN) to initiate immune responses. Recently, we discovered that in the mouse immune system activity-regulated cytoskeleton associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) is exclusively expressed by migDCs and is a central driver of fast inflammatory migration. However, the frequency of Arc/Arg3.1-expressing cells in different migDC subsets and Langerhans cells (LCs), their phylogenetic origin, transcription factor dependency, and functional role remain unclear. Here, we found that Arc/Arg3.1+ migDCs derived from common DC precursors and radio-resistant LCs. We detected Arc/Arg3.1+ migDCs in varying frequencies within each migDC subset and LCs. Consistently, they showed superiority in inflammatory migration. Arc/Arg3.1 expression was independent of the transcription factors Irf4 or Batf3 in vivo. In intradermal Staphylococcus aureus infection that relies on inflammatory antigen transport, Arc/Arg3.1 deletion reduced T-cell responses. By contrast, Arc/Arg3.1 deficiency did not hamper the immune response to systemic Listeria monocytogenes infection, which does not require antigen transport. Thus, Arc/Arg3.1 expression is independent of ontogeny and phenotype and although it is restricted to a small fraction within each migDC subset and LCs, Arc/Arg3.1+ migDCs are important to facilitate infectious migration.


Neurosyphilis revealed by compressive cervical spine syphilitic gumma: a case report.
Neurosyphilis is a sexually transmitted disease secondary to the invasion of the central nervous system by the Treponema pallidum. The spinal syphilitic gumma is rare. We report a case of extradural cervical spinal syphilitic gumma revealed by spinal cord compression in a 58-year-old male. The epidural lesion was removed via a posterior approach. Histological examination revealed syphilis. Syphilis serologies were positive. Brain MRI showed an associated cerebro-meningeal syphilitic gumma. Antibiotic regime based on aqueous penicillin G was introduced for 14 days. Currently, there is an increase in the frequency of syphilis and changes in its clinical manifestations. Neurosyphilis can take atypical forms. Spinal syphilitic gumma is a rare manifestation and its association with cerebral involvement is exceptional. Diagnosis is based on serologies in the blood and cerebrospinal fluid. The place of imagery, especially magnetic resonance imaging, is essential. Neurosyphilis should be discussed as a possible differential diagnosis in evaluation of spinal and cerebral lesions.


Bone Marrow Burkitt Lymphoma in a Child.
Burkitt lymphoma (BL) is a highly aggressive but potentially curable disease as long as adequately treated within due time. BL may occur primarily and exclusively in the bone marrow as a form of peripheral and extranodal disease. BL cases with isolated bone marrow involvement are challenging in regard to a prompt diagnostic process. We report a case of a sporadic extranodal subtype of isolated bone marrow BL in an 11-year-old boy. Bone marrow aspiration and biopsy, flow cytometry, and immunohistochemistry along with cytogenetics are compulsory in order to achieve the adequate diagnosis.


STUDIES ON AN AGGLUTINOGEN (Rh) IN HUMAN BLOOD REACTING WITH ANTI-RHESUS SERA AND WITH HUMAN ISOANTIBODIES.
Studies are reported on an individual agglutinogen (Rh) in human blood which has been found to be of clinical importance because occasionally it gives rise to the formation of immune isoantibodies in man, a peculiarity which leads to untoward transfusion reactions. A method for the determination of the presence or absence of the new blood factor is described, which can be used for typing patients and prospective blood donors. Examination of families showed that the agglutinogen is inherited as a simple Mendelian dominant. The distribution of the factor Rh among white individuals and negroes may indicate racial differences. The property is probably genetically independent of the blood groups and the factors M and N.


Student and professional attitudes and interests in working with people with complex communication needs.
Speech-language pathology interest in working with people with complex communication needs was investigated in this study. Participants were third year speech-language pathology undergraduates and recent graduates who had participated in a unit on AAC. Undergraduates (n = 85) completed an Interaction with Disabled Persons attitudinal scale and a questionnaire about interest in various client groups before and after the unit. Some undergraduates (n = 34) repeated the attitudinal scale and completed another questionnaire 2 years after graduation. Recent graduates (n = 56) completed a questionnaire about working with people with complex communication needs and factors influencing work choices; 10 also participated in interviews or focus groups. We found a small but positive attitudinal shift for the undergraduates, but, along with previous disability experience, this was a weak predictor of working with this group. Working in developmental disability ranked low amongst undergraduate preferences. Most graduates were influenced in their job choices by a desire to work on a particular team and previous clinical placements. Questionnaires and interview/focus group data indicated the strong influence of clinical placements on later work choices. Participants who worked in disability appeared passionate about the work involved and offered suggestions for engaging more professionals with this group. Implications for speech-language pathology services in disability are discussed.


Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphoma.
Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and few causes have been identified. Genetic association studies may help identify environmental risk factors and enhance our understanding of disease mechanisms. 768 coding and haplotype tagging SNPs in 146 genes were examined using Illumina GoldenGate technology in a large population-based case-control study of NHL in the San Francisco Bay Area (1,292 cases 1,375 controls are included here). Statistical analyses were restricted to HIV- participants of white non-Hispanic origin. Genes involved in steroidogenesis, immune function, cell signaling, sunlight exposure, xenobiotic metabolism/oxidative stress, energy balance, and uptake and metabolism of cholesterol, folate and vitamin C were investigated. Sixteen SNPs in eight pathways and nine haplotypes were associated with NHL after correction for multiple testing at the adjusted q<0.10 level. Eight SNPs were tested in an independent case-control study of lymphoma in Germany (494 NHL cases and 494 matched controls). Novel associations with common variants in estrogen receptor 1 (ESR1) and in the vitamin C receptor and matrix metalloproteinase gene families were observed. Four ESR1 SNPs were associated with follicular lymphoma (FL) in the U.S. study, with rs3020314 remaining associated with reduced risk of FL after multiple testing adjustments [odds ratio (OR) = 0.42, 95% confidence interval (CI) = 0.23-0.77) and replication in the German study (OR = 0.24, 95% CI = 0.06-0.94). Several SNPs and haplotypes in the matrix metalloproteinase-3 (MMP3) and MMP9 genes and in the vitamin C receptor genes, solute carrier family 23 member 1 (SLC23A1) and SLC23A2, showed associations with NHL risk. Our findings suggest a role for estrogen, vitamin C and matrix metalloproteinases in the pathogenesis of NHL that will require further validation.


Non-sterile gloves and dressing versus sterile gloves, dressings and drapes for suturing of traumatic wounds in the emergency department: a non-inferiority multicentre randomised controlled trial.
Patients with traumatic wounds frequently present to the ED. Literature on whether to treat these wounds sterile or non-sterile is sparse. Non-sterile treatment has the advantage of saving resources and costs, and could be of value in health settings where sterile materials are not readily available. Our objective was to compare the rate of wound infection after suturing traumatic lacerations with non-sterile gloves and dressings versus sterile gloves, dressings and drapes in the ED. We hypothesised that non-sterile gloves and dressings would be non-inferior to sterile gloves, dressings and drapes. The non-inferiority margin was set at 2%. A multicentre single-blinded randomised controlled trial testing for non-inferiority of non-sterile gloves and dressings versus sterile gloves, dressings and drapes for suturing of traumatic wounds was performed in 3 EDs in The Netherlands. Adults with uncomplicated wounds were included from July 2012 to December 2016. At the time of treatment, patient and wound characteristics and management were documented. The outcome was wound infection, which was identified during follow-up in the treating ED at 5-14 days postprocedure. From 2468 eligible patients, 1480 were randomised in a sterile (n=747) or non-sterile (n=733) protocol. Baseline characteristics were similar in both study arms. The observed wound infection rate in the non-sterile group was 5.7% (95% CI 4.0% to 7.5%) vs 6.8% (95% CI 5.1% to 8.8%) in the sterile group. The mean difference of the wound infection rate of the two groups was -1.1% (95% CI -3.7% to 1.5%). Although recruitment ceased prior to reaching our planned sample size, the findings suggest that there is unlikely to be a large difference between the non-sterile gloves, dressings and sterile gloves, dressings and drapes for suturing of traumatic wounds in the ED. NL 34798.078.11, NTR3541.


The Centrioles, Centrosomes, Basal Bodies, and Cilia of Drosophila melanogaster.
Centrioles play a key role in the development of the fly. They are needed for the correct formation of centrosomes, the organelles at the poles of the spindle that can persist as microtubule organizing centers (MTOCs) into interphase. The ability to nucleate cytoplasmic microtubules (MTs) is a property of the surrounding pericentriolar material (PCM). The centriole has a dual life, existing not only as the core of the centrosome but also as the basal body, the structure that templates the formation of cilia and flagellae. Thus the structure and functions of the centriole, the centrosome, and the basal body have an impact upon many aspects of development and physiology that can readily be modeled in Drosophila Centrosomes are essential to give organization to the rapidly increasing numbers of nuclei in the syncytial embryo and for the spatially precise execution of cell division in numerous tissues, particularly during male meiosis. Although mitotic cell cycles can take place in the absence of centrosomes, this is an error-prone process that opens up the fly to developmental defects and the potential of tumor formation. Here, we review the structure and functions of the centriole, the centrosome, and the basal body in different tissues and cultured cells of Drosophila melanogaster, highlighting their contributions to different aspects of development and cell division.


Alzheimer's Disease: The Link Between Amyloid-β and Neurovascular Dysfunction.
While prevailing evidence supports that the amyloid cascade hypothesis is a key component of Alzheimer's disease (AD) pathology, many recent studies indicate that the vascular system is also a major contributor to disease progression. Vascular dysfunction and reduced cerebral blood flow (CBF) occur prior to the accumulation and aggregation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Although research has predominantly focused on the cellular processes involved with Aβ-mediated neurodegeneration, effects of Aβ on CBF and neurovascular coupling are becoming more evident. This review will describe AD vascular disturbances as they relate to Aβ, including chronic cerebral hypoperfusion, hypertension, altered neurovascular coupling, and deterioration of the blood-brain barrier. In addition, we will describe recent findings about the relationship between these vascular defects and Aβ accumulation with emphasis on in vivo studies utilizing rodent AD models.


Distraction and facilitation: The impact of emotional sounds in an emoji oddball task.
Emotional stimuli are argued to capture attention and consume attentional resources differently depending on their emotional content. The present study investigates the impact of the automatic detection of unexpected and to-be-ignored emotional stimuli on human behavioral responses, and aims to unravel the differences in distraction between two negative emotional stimuli: sadness and anger. Forty participants (Mage = 25.5 years) performed a visual categorization task where angry and sad emoji faces were presented after either a standard neutral tone (in 80% of trials) or a deviant emotional sound (tone changing in pitch; sad or angry sound in 10% of trials each) that was to be ignored. Deviant trials were either congruent (e.g., sad sound-sad face) or incongruent (e.g., angry sound-sad face). Although the stimuli presented to the participants were brief and to-be-ignored, results indicate that participants were significantly more distracted by sad compared to angry stimuli (seen as prolonged response times). Findings are discussed with reference to the nature of the two negative emotions.


Effect of calmodulin antagonists on phospholipase D activity in SH-SY5Y cells.
The aim of this study was to investigate the involvement of calmodulin in phospholipase D activation in SH-SY5Y cells. Cells prelabelled with [3H]-palmitic acid were incubated with calmodulin antagonists and/or other compounds. Phosphatidylethanol, a specific marker for phospholipase D activity, and phosphatidic acid were analysed. The calmodulin antagonists, calmidazolium and trifluoperazine, induced an extensive increase in phosphatidylethanol formation, and thus increased basal phospholipase D activity, in a dose- and time-dependent manner. The effect of calmidazolium on carbachol-induced activation of muscarinic receptors was also studied. Calmidazolium did not significantly affect the amount of phosphatidylethanol formed following carbachol addition. However, taking into account the increase in basal activity observed after calmidazolium addition, calmidazolium probably inhibits the muscarinic receptor-induced phospholipase D activation. In addition to phosphatidylethanol, basal phosphatidic acid levels were also increased after calmidazolium and trifluoperazine addition. Incubation with calmidazolium (10 microM) for 10 min induced a two-fold increase in phosphatidic acid. The calmidazolium-induced increase in basal phospholipase D activity was not affected by the protein kinase inhibitors H7 and staurosporine. On the other hand tyrosine kinase inhibitors abolished the calmidazolium-induced activation of phospholipase D. Calmidazolium also induced tyrosine phosphorylation in parallel to the phospholipase D activation. In conclusion, our data indicate that calmodulin antagonists induce phospholipase D activity in SH-SY5Y cells via a tyrosine kinase dependent pathway. This may point to a negative control of phospholipase D by calmodulin although a calmodulin-independent mechanism cannot be excluded. Calmodulin antagonists may be useful tools to further elucidate the mechanisms of phospholipase D regulation.


Febrile and metabolic tolerance to endotoxin and human recombinant interleukin-1 beta in rabbits.
We investigated whether or not tolerance of the febrile and metabolic responses to human recombinant interleukin-1 beta (IL-1 beta) develops in rabbits. Febrile tolerance to bacterial endotoxin was induced by daily injections of lipopolysaccharide (LPS, 5.0 micrograms/kg iv). In LPS-tolerant rabbits, the second phase of the biphasic fever induced by intravenous injections of LPS (5.0 micrograms/kg) or IL-1 beta (2.0 micrograms/kg) was significantly reduced. However, the first phase was almost the same as that observed in normal rabbits. Five daily injections of IL-1 beta (2.0 micrograms/kg iv) resulted in the development of tolerance of the febrile response to IL-1 beta. In IL-1 beta-tolerant rabbits, the second peak of the biphasic fever was significantly reduced. In addition, decreases in leukocyte count and plasma zinc induced by intravenous injections of LPS or IL-1 beta were significantly reduced in LPS- or IL-1 beta-tolerant rabbits. However the monophasic fever induced by a smaller dose of IL-1 beta (0.5 microgram/kg iv) and the first peak of the IL-1 biphasic fever were almost the same as those observed in normal rabbits. Febrile responses induced in LPS- or IL-1 beta-tolerant rabbits by intracerebroventricular injections of LPS (5.0 ng) or IL-1 beta (2.0 ng) were similar to those observed in normal rabbits. The present results suggest that tolerance of the febrile and metabolic responses to IL-1 beta is developed after repeated injections of IL-1 beta and that reduced responsiveness to IL-1 beta is partly involved in the development of LPS tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)


The disperser dilemma in cooperatively breeding birds.
In most cooperatively breeding birds, individuals do not breed with their natal group members. In order to breed, they have either to disperse into another group or wait for an opposite-sex individual to join their group. In most of these species, females disperse more than males. We develop a dynamic game-theoretic model to account for this asymmetry. When males are physically larger/heavier than females, this allows them to effectively welcome female immigrants into their natal group and overcome the local females' opposition more than vice versa. The model further assumes that the dispersal decision is not confined to a restricted time window, but is rather based on acquired information and responsive to opportunities. The model predicts that (i) females disperse more than males, and (ii) females are willing to tolerate more risks in dispersal than do males. The latter prediction is supported inter alia by the fact that in many cooperatively breeding birds, females disperse at a younger age, and further away from their natal group as compared to dispersing males.


Transportation Barriers and Use of Dental Services among Medicaid-Insured Adults.
This study explores how travel distance and other transportation barriers are associated with dental utilization in a Medicaid expansion population. We analyzed data from the Iowa Dental Wellness Plan (DWP), which provides comprehensive dental benefits for low-income adults aged 19 to 64 y as part of Iowa's Medicaid expansion. Transportation and geographical characteristics were evaluated as enabling factors within the framework of Andersen's behavioral model of health services use. In March 2015, a random sample of DWP members ( n = 4,800) was surveyed; adjusted survey response rate was 30% ( n = 1,258).The questionnaire was based on the Consumer Assessment of Healthcare Providers and Systems (CAHPS) Dental Plan Survey and assessed need for dental care, use of dental services and transportation to visits, and self-perceived oral health status. Respondent and dentist addresses were geocoded and used to calculate distance to the nearest DWP general dentist. A logistic regression model predicting utilization of dental care was developed using variables representing each domain of the behavioral model. Most respondents (57%) reported a dental visit since enrolling. Overall, 11% of respondents reported unmet dental need due to transportation problems. Median distance to the nearest general dentist was 1.5 miles. In the adjusted model, travel distance was not significantly associated with the likelihood of dental utilization. However, other transportation-related issues were significantly associated with utilization, including concern about cost of transportation and driver/passenger status. As concern about transportation cost increased, likelihood of having a dental visit decreased. Targeted approaches to assisting low-income populations with transportation barriers should be considered in designing policies and interventions to improve access to dental care. Knowledge Transfer Statement: The results of this study can be used by policy makers and public health planners when designing programs and interventions to improve access to dental care. Consideration of transportation availability and costs could improve utilization of routine dental care, especially among low-income populations.


Treatment planning for tissue integrated prosthesis.
The concept of osseointegration and its clinical application in tissue integrated prosthesis has opened up many new avenues in treatment planning for missing teeth. A protocol for controlling the sequencing of diagnostic steps in the formulation of a treatment plan has been presented. The protocol is applicable to the completely edentulous mouth, the partially edentulous jaw, the missing single tooth and the extra-oral maxillofacial prosthetic case. Use of the protocol will ensure predictable treatment results and minimize the risk of complication and failure.


Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) affects an increasing number of people worldwide. The poor survival rate of patients with HCC is manifested by an aggressive and metastatic phenotype, as well as a poor response to common therapeutic strategies. The purpose of this study was to evaluate the efficacy of nanoliposomal C6-ceramide as an antineoplastic agent in an in vivo model of human HCC. The growth-arresting and pro-apoptotic properties of nanoliposomal C6-ceramide were first evaluated in vitro in human SK-HEP-1 cells by assessing cellular viability, caspase 3/7 activity, annexin-V expression, DNA fragmentation, cell cycle distribution and AKT phosphorylation. SK-HEP-1 cells were then engrafted subcutaneously into athymic nude mice and nanoliposomal C6-ceramide was administered by tail vein injection. Tumour size was monitored over time, followed by excision of tumours to evaluate tumour vascularisation, proliferation, apoptosis and cellular signalling. Nanoliposomal C6-ceramide, but not ghost (no ceramide) nanoliposomes, induced apoptotic cell death of SK-HEP-1 cells in vitro, concomitant with an accumulation of cells in the G₂ phase of the cell cycle and decreased phosphorylation of AKT. Systemic administration of nanoliposomal C6-ceramide to mice engrafted with SK-HEP-1 tumours reduced tumour vascularisation and proliferation, induced tumour cell apoptosis, decreased phosphorylation of AKT and ultimately blocked tumour growth. These studies show that nanoliposomal ceramide is an efficacious antineoplastic agent for the treatment of in vitro and in vivo models of human HCC.


Surgical infection and malnutrition.
Malnutrition in surgical patients is associated with delayed recovery, higher rates of morbidity and mortality, prolonged hospital stay, increased healthcare costs and a higher early re-admission rate. Data synthesis after review of pertinent literature. The aetiology of malnutrition is multifactorial. In cancer patients, there is an abnormal peripheral glucose disposal, gluconeogenesis, and whole-body glucose turnover. Malnourished cancer patients undergoing major operations are at significant risk from perioperative complications such as infectious complications. Surgical aggression generates an inflammatory response which worsens intermediary metabolism. Nutritional evaluation and nutritional support must be performed in all surgical patients, in order to minimize infectious complications. Enteral nutrition early in the postoperative period is effective and well tolerated reducing infectious complications, improving wound healing and reducing length of hospital stay. Pharmaconutrition is indicated in those patients, who benefit from enteral administration of arginine, omega 3 and RNA, as well as parenteral glutamine supplementation. When proximal sutures are used, tubes allowing early jejunal feeding should be used.


Amelogenin and Enamel Biomimetics.
Mature tooth enamel is acellular and does not regenerate itself. Developing technologies that rebuild tooth enamel and preserve tooth structure is therefore of great interest. Considering the importance of amelogenin protein in dental enamel formation, its ability to control apatite mineralization in vitro, and its potential to be applied in fabrication of future bio-inspired dental material this review focuses on two major subjects: amelogenin and enamel biomimetics. We review the most recent findings on amelogenin secondary and tertiary structural properties with a focus on its interactions with different targets including other enamel proteins, apatite mineral, and phospholipids. Following a brief overview of enamel hierarchical structure and its mechanical properties we will present the state-of-the-art strategies in the biomimetic reconstruction of human enamel.


Health Inequity and "Restoring Fairness" Through the Canadian Refugee Health Policy Reforms: A Literature Review.
Refugees and refugee claimants experience increased health needs upon arrival in Canada. The Federal Government funded the Interim Federal Health Program (IFHP) since 1957, ensuring comprehensive healthcare insurance for all refugees and refugee claimants seeking protection in Canada. Over the past 4 years, the Canadian government implemented restrictions to essential healthcare services through retrenchments to the IFHP. This paper will review the IFHP, in conjunction with other immigration policies, to explore the issues associated with providing inequitable access to healthcare for refugee populations. It will examine changes made to the IFHP in 2012 and in response to the federal court decision in 2014. Findings of the review indicate that the retrenchments to the 2012 IFHP instigated health outcome disparities, social exclusion and increased costs for vulnerable refugee populations. The 2014 reforms reinstated some services; however the policy continued to produce inequitable healthcare access for some refugees and refugee claimants.


[Treatment of acute and recurrent pericarditis. What the clinical cardiologist should know].
Pericarditis is a common clinical problem, above all in its incessant and recurrent forms. Treatment should be targeted according to etiology, but this is often unfeasible with a conventional approach, because most cases are labeled as "idiopathic" in the majority of immunocompetent patients from developed countries. Clinical risk stratification of acute pericarditis may be useful to select patients who should be admitted to hospital, and in whom a complete evaluation should be performed to identify causes that require specific therapy. In idiopathic and viral pericarditis the mainstay of treatment is the use of aspirin or a nonsteroidal anti-inflammatory drug with the possible adjunct of colchicine to prevent recurrences, above all in recurrent pericarditis. Corticosteroids are too often considered and should be limited to rare, specific indications (definite rheumatologic disease, presumed autoimmune etiology, intolerance or contraindications to aspirin or non-steroidal anti-inflammatory drugs, pregnancy) being a clear risk factor for a prolonged and chronic course of the disease in idiopathic or viral forms. Despite the common fear of a possible evolution towards constrictive pericarditis, such complication is not recorded in acute and recurrent pericarditis of viral and idiopathic etiology. The prognosis is good in these cases and the risk of constriction is related to the presence of a specific etiology and not to the number of recurrences.


Equinus deformity due to haemangioma of calf muscle.
Joint deformity secondary to extensive haemangiomatous involvement of the soft tissues has been well described and is easy to diagnose. If the haemangioma is small, localised and within the belly of a muscle the diagnosis is more difficult. In equinus deformity of obscure aetiology localised calf tenderness may be the only diagnostic sign. Three children with equinus deformity caused by a small haemangioma in the calf muscles were treated by simple excision with satisfactory results.


Effects of Different Polishing Systems on Surface Roughness and Crystal Structure of Zirconia.
Intraoral polishing systems have become an alternative method for reglazing, which is important to prevent or minimize rapid wear of the opposing teeth. To assess the influence of different polishing systems and duration on surface roughness and crystal structure of zirconia was compared, contributing to the preparation and effect improvement of clinical zirconia restorations. Forty-eight zirconia specimens with equal size were fabricated by cutting and sintering zirconia discs. Then X-ray diffractometer (XRD) was adopted for examination of the specimens. Six specimens were selected as the grinding-polishing group (GL) after polishing, grinding, and glazing. Then six specimens were randomly selected from the remaining specimens as the grinding-unpolished group (GR) after surface conditioning by dental diamond burs. Subsequently, based on different polishing systems and duration, the rest of specimens were divided into following groups (n = 6): Youdent-20s group (Y20), Youdent-40s group (Y40), Youdent-60s group (Y60), Toboom-20s group (T20), Toboom-40s group (T40), and Toboom-60s group (T60). Additionally, a contour graph was applied for assessing the surface roughness of zirconia, scanning electron microscope (SEM) for observing surface topography, and X-ray diffraction analysis (XRD) for determining crystal structure of zirconia. The GR group had the highest roughness, and the roughness of the specimens polished for 20 s with different polishing systems was significantly higher than those polished for 40 s and 60 s with the same polishing systems. There were no significant difference between the Y20 and T20 groups, while the roughness of the specimens in both Y40 and Y60 groups was significantly higher than that of the T40 and T60 groups. And with the increasing polishing duration, the surface morphology of the specimen was gradually smooth and the morphology was gradually regular. Besides, the surface scratches of the T group were shallower than that of the Y group at the same polishing duration. The peak value of XRD profile of the specimen after grinding and polishing process was consistent with the baseline pattern of that the original specimen. Glazing can reduce the surface roughness of the specimens. Besides, the polishing effect of Toboom (TOB) system (polishing duration = 60 s) is the best. And different polishing durations of TOB system have no significant effect on the crystal surface structure of the specimen.


Calcium-dependent chloride channels in endosomes from rabbit kidney cortex.
Ion channels in endosomal membranes from rabbit kidney cortex were studied after reconstitution into planar lipid bilayers. The most frequently observed ion channel was anion selective (PCl/PK = 13) and had a single-channel conductance of 116 pS when the cis and trans solutions contained 410 and 150 mM KCl, respectively, and a conductance of 90 pS in symmetrical 150 mM KCl solutions. The anion selectivity sequence of the channel was NO3- > F- > Br- > Cl- >> I-. The activity of the channel was voltage dependent such that hyperpolarization of the cis, or cytoplasmic, surface of the channel increased the open probability (Po). The activity of the channel was also highly dependent on the calcium activity of the cis but not the trans solution. Channels were fully active (Po > 0.7) at Ca2+ concentration > 1 microM, but channel activity was completely absent (Po < 0.001) at Ca2+ concentration < 250 nM. The effects of calcium on Po were not voltage dependent. The Cl(-)-channel blocker 2-[(2-cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden -5- yl)oxy]-acetic acid (IAA-94/95) produced a concentration-dependent reversible flickering block of the endosomal channel with a Ki of 15 microM. 4,4'-Dinitrostilbene-2,2'-disulfonic acid, a disulfonic stilbene, also produced a flickering block of the channel with a Ki of approximately 5 microM. Because endosomal Cl- channels are believed to facilitate endosomal acidification, we tested the effects of IAA-94/95 and deletion of Ca2+ on the rate of acidification of intact endosomes. Because neither maneuver affected acidification, we conclude that the 116-pS channel does not participate in endosomal acidification. This channel may be involved in other endosomal processes, e.g., cell volume regulation and control of membrane trafficking.


Growth and Stress Tolerance Comprise Independent Metabolic Strategies Critical for Staphylococcus aureus Infection.
Staphylococcus aureus is an important pathogen that leads to high morbidity and mortality. Although S. aureus produces many factors important for pathogenesis, few have been validated as playing a role in the pathogenesis of S. aureus pneumonia. To gain a better understanding of the genetic elements required for S. aureus pathogenesis in the airway, we performed an unbiased genome-wide transposon sequencing (Tn-seq) screen in a model of acute murine pneumonia. We identified 136 genes important for bacterial survival during infection, with a high proportion involved in metabolic processes. Phenotyping 80 individual deletion mutants through diverse in vitro and in vivo assays demonstrated that metabolism is linked to several processes, which include biofilm formation, growth, and resistance to host stressors. We further validated the importance of 23 mutations in pneumonia. Multivariate and principal-component analyses identified two key metabolic mechanisms enabling infection in the airway, growth (e.g., the ability to replicate and form biofilms) and resistance to host stresses. As deep validation of these hypotheses, we investigated the role of pyruvate carboxylase, which was important across multiple infection models and confirmed a connection between growth and resistance to host cell killing. Pathogenesis is conventionally understood in terms of the host-pathogen interactions that enable a pathogen to neutralize a host's immune response. We demonstrate with the important bacterial pathogen S. aureus that microbial metabolism influences key traits important for in vivo infection, independent from host immunomodulation. IMPORTANCE Staphylococcus aureus is an important bacterial pathogen that causes significant morbidity and mortality, infecting numerous bodily sites, including the respiratory tract. To identify the bacterial requirements for lung infection, we conducted a genome-wide screen in a mouse model of acute pneumonia. We discovered that metabolic genes were overrepresented in those required for lung infection. In contrast to the conventional view of pathogenesis focusing on immunomodulation, we demonstrate through phenotyping of deletion mutants in several functional assays that replicative ability and tolerance against host defenses form two key metabolic dimensions of bacterial infection. These dimensions are independent for most pathways but are coupled in central carbon metabolism and highlight the critical role of bacterial metabolism in survival against host defenses during infection.


Why African American women leave the academy: barriers to and opportunities for retention.
African American women have participated in higher education for well over a century. Although the journey has been difficult, significant achievements have been made. Today, fewer African American women doctoral recipients are choosing academic employment, and many of those who enter the academy later leave for employment in business, industry and the professions where salaries are often more attractive. Furthermore, the present decline of African American faculty women is expected to become more severe as the growth of the academic labor market levels off. If we are to successfully retain the pool of African American faculty women it is important to discover the reasons why an increasing number are voluntarily leaving the academy. This article is based on a cross-sectional study of 384 African American academic women which examines the primary barriers to faculty retention and offer suggestions to help prevent the further loss of African American women scholars.


On the mechanism of conversion of N-acyl-4-acyloxy-beta-lactams into 2-substituted 1,3-oxazin-6-ones. Can a low-barrier transition state be antiaromatic?
The mechanism of the conversion of N-acyl-4-acyloxy-beta-lactams into 1,3-oxazin-6-ones has been investigated using ab initio and density functional theories. It has been found that two pseudopericyclic reactions are involved in the whole process. The first key reaction is a retro-[4-exo-dig] cyclization instead of a thermal conrotatory electrocyclic ring opening. Magnetic characterization of the corresponding transition structure shows antiaromatic character, despite the low activation energy associated with this process. The second step is very exothermic and has no activation barrier. It corresponds to another pseudopericyclic reaction instead of a six-electron disrotatory electrocyclization. These results confirm that there is no correlation between aromaticity and pseudopericyclic reactions. In contrast, thermal-symmetry-allowed pericyclic reactions are always aromatic. Therefore, magnetic analysis of the corresponding transition structures constitutes a useful tool to distinguish between both kinds of processes.


Decreased cocaine self-administration in Kir3 potassium channel subunit knockout mice.
Multiple G protein-linked neurotransmitter systems have been implicated in the behavioral effects of cocaine. While actions of certain neurotransmitter receptor subtypes and transporters have been identified, the role of individual G protein-regulated enzymes and ion channels in the effects of cocaine remains unclear. Here, we assessed the contribution of G protein-gated, inwardly rectifying potassium (Kir3/GIRK) channels to the locomotor-stimulatory and reinforcing effects of cocaine using knockout mice lacking one or both of the key neuronal channel subunits, Kir3.2 and Kir3.3. Cocaine-stimulated increases in horizontal locomotor activity in wild-type, Kir3.2 knockout, Kir3.3 knockout, and Kir3.2/3.3 double knockout mice, with only minor differences observed between the mouse lines. In contrast, Kir3.2 and Kir3.3 knockout mice exhibited dramatically reduced intravenous self-administration of cocaine relative to wild-type mice over a range of cocaine doses. Paradoxically, Kir3.2/3.3 double knockout mice self-administered cocaine at levels significantly higher than either single knockout alone. These findings suggest that Kir3 channels play significant and complex roles in the reinforcing effect of cocaine.


[Change in the fluorescent characteristics of rat lymphocytes stained with acridine orange after acute gamma-irradiation].
Changes of parameter alpha of rat blood lymphocytes after acute gamma-irradiation have been investigated by luminescence microspectral analysis. Parameter alpha reflects the cell synthetic activity and represents the ratio of intensities of the red (640 nm) and green (530 nm) components the luminescence spectrum of acridine orange fluorochromed cells. It has been demonstrated that changes of parameter alpha occur in three stages: a) sharp decrease at the 1st or 2nd day after irradiation: b) increase with the maximum at the 4th-15th day; c) fluctuations on the level higher then the control values. At each stage there exist typical specific shapes of parameter alpha distribution histograms. These results indicate that this method may be used for control of the immune system state during gamma-radiation sickness or in the process of human cancer radiation therapy.


Mitochondria-derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension.
Increasing evidence suggests that mitochondrial dysfunction in pulmonary endothelial cells (ECs) plays a causative role in the initiation and progression of pulmonary hypertension (PH); how mitochondria become dysfunctional in PH remains elusive. Mitochondria-derived vesicles (MDVs) are small subcellular vesicles that excise from mitochondria. Whether MDV deregulation causes mitochondrial dysfunction in PH is unknown. The aim of this study was to determine MDV regulation in ECs and to elucidate how MDV deregulation in ECs leads to PH. MDV formation and mitochondrial morphology/dynamics were examined in ECs of EC-specific liver kinase B1 (LKB1) knockout mice (LKB1ec-/-), in monocrotaline-induced PH rats, and in lungs of patients with PH. Pulmonary ECs of patients with PH and hypoxia-treated pulmonary ECs exhibited increased mitochondrial fragmentation and disorganized mitochondrial ultrastructure characterized by electron lucent-swelling matrix compartments and concentric layering of the cristae network, together with defective MDV shedding. MDVs actively regulated mitochondrial membrane dynamics and mitochondrial ultrastructure via removing mitofission-related cargoes. The shedding of MDVs from parental mitochondria required LKB1-mediated mitochondrial recruitment of Rab9 GTPase. LKB1ec-/- mice spontaneously developed PH with decreased mitochondrial pools of Rab9 GTPase, defective MDV shedding, and disequilibrium of the mitochondrial fusion-fission cycle in pulmonary ECs. Aerosol intratracheal delivery of adeno-associated virus LKB1 reversed PH, together with improved MDV shedding and mitochondrial function in rats in vivo. We conclude that LKB1 regulates MDV shedding and mitochondrial dynamics in pulmonary ECs by enhancing mitochondrial recruitment of Rab9 GTPase. Defects of LKB1-mediated MDV shedding from parental mitochondria instigate EC dysfunction and PH.


Tightly linked morpholino-nucleoside chimeras: new, compact cationic oligonucleotide analogues.
The polyanionic phosphodiester backbone of nucleic acids contributes to high nuclease sensitivity and low cellular uptake and is therefore a major obstacle to the biological application of native oligonucleotides. Backbone modifications, particularly charge alterations is a proven strategy to provide artificial oligonucleotides with improved properties. Here, we describe the synthesis of a new type of oligonucleotide analogues consisting of a morpholino and a ribo- or deoxyribonucleoside in which the 5'-amino group of the nucleoside unit provides the nitrogen of the morpholine ring. The synthetic protocol is compatible with trityl and dimethoxytrityl protecting groups and azido functionality, and was extended to the synthesis of higher oligomers. The chimeras are positively charged in aqueous medium, due to the N-alkylated tertiary amine structure of the morpholino unit.


A randomized trial of a self-regulation intervention for women with asthma.
Women with asthma have greater mortality and morbidity than men in the United States. To date, there has been no rigorous evaluation of an intervention focused on the particular problems in asthma management faced by women. This study was a randomized clinical trial of a self-regulation, telephone counseling intervention emphasizing women's concerns, and sex and gender role factors in their management of asthma. A total of 808 women with diagnosed asthma were randomly assigned to the intervention group or a usual-care control group, including conventional asthma education. Interviews and medical record data were collected to assess psychosocial factors, and the behavioral factors of functioning, quality of life, symptoms, and health-care use at baseline and the subsequent 1 year. Generalized estimating equations, identity link, logit link, and log link were employed to analyze the data. Compared to control subjects, the women receiving treatment had greater annual reductions in the average number of nights with asthma symptoms (p = 0.04), days of missed work/school (p = 0.03), emergency department visits (p = 0.04), unscheduled office visits (p = 0.01), and scheduled office visits (p = 0.04). They had greater recognition of asthma symptoms during the menstrual cycle (p = 0.0003), had decreased asthma symptoms with sexual activity (p = 0.008), and had greater improvement in quality of life (p = 0.0005), self-regulation (p = 0.03), and self-confidence to manage asthma (p = 0.001). The intervention improved women's clinical status, functioning, quality of life, and health-care use. A program with a focus on asthma management problems particular to women can significantly assist female asthma patients.


Human immunodeficiency virus-1/surface glycoprotein 120 induces apoptosis through RNA-activated protein kinase signaling in neurons.
Previous work has demonstrated that the surface glycoprotein (gp120) of human immunodeficiency virus-1 (HIV-1) can induce damage and apoptosis of neurons both in vitro and in vivo. In this report, we provide evidence that double-stranded RNA-activated protein kinase (PKR), a stress kinase, is involved in HIV/gp120-associated neurodegeneration. In cultures of mixed cortical cells, HIV/gp120 increased the protein level of PKR. Additionally, PKR was phosphorylated in neurons but not glia after exposure to gp120. The use of two independent pharmacological inhibitors of PKR activity abrogated neuronal cell death induced by gp120. Cortical neurons from PKR knock-out mice were significantly protected from neurotoxicity induced by gp120, further validating the pivotal proapoptotic function of PKR. gp120-induced phosphorylated PKR localized prominently to neuronal nuclei; PKR inhibition or the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] abrogated this effect. PKR inactivation also inhibited gp120-induced caspase-3 activation, consistent with its neuroprotective effect. Finally, brain tissue from individuals diagnosed with HIV-associated dementia (HAD), but not HIV infection alone, contained the activated form of PKR, which localized predominantly to neuronal nuclei. Together, these results identify PKR as a critical mediator of gp120 neurotoxicity, suggesting that activation of PKR contributes to the neuronal injury and cell death observed in HAD.


[Brain abscess in a third-level hospital: epidemiology and prognostic factors related to mortality].
To document the epidemiology, causes, treatment and prognostic factors associated with mortality of patients with brain abscess in a tertiary medical center. Observational retrospective cohort study of patients with cerebral abscess admitted at a tertiary hospital during 13 years. The case records of 71 patients admitted to a tertiary hospital between January 1992 and December 2005 and diagnosed of brain abscess were review. Brain abscess occurred at all ages, more frequently in men than in women. Fever, headache and altered mental status were common presenting symptoms. The most common site of infection was the frontal lobe (28 patients). Seventeen patients had multiple abscesses. Staphylococcal infection was seen most commonly. Computed tomography provided sufficient diagnostic information in all cases. Twenty six patients had early surgical drainage. Thirty four patients were admitted to the intensive care Unit (ICU). The overall mortality was 21% (15 patients), all of that related to the infection. Six patients died in ICU. More than 65 years of age (OR, 1.0; CI 95%, 1.0-1.1), medical treatment without surgery (OR, 8.9; CI 95%, 1.1-73.8), presence of multiple abscesses, (OR, 6.0; CI 95%, 1.0-34.9), immunosuppression (OR, 21.5; CI 95%, 2.9-157.2) and delay in starting antibiotherapy (OR, 1.5 per day of delay; CI 95%, 1.0-2.1) were independent predictors of in-hospital death. In spite of improvement in diagnosis and treatment of patients with cerebral abscess, mortality is still high. Factors related to patient underlying diseases and the delay in the start an antibiotic treatment were associated with increased mortality (50% increase of mortality risk per day in the delay of starting antibiotherapy).


Impaction grafting of lumbar pedicle defects: a biomechanical study of a novel technique for pedicle screw revision.
The two most common revision options available for the management of loose pedicle screws are larger-diameter screws and cement augmentation into the vertebral body for secondary fixation. An alternative revision method is impaction grafting (pedicoplasty) of the failed pedicle screw track. This technique uses the impaction of corticocancellous bone into the pedicle and vertebral body through a series of custom funnels to reconstitute a new pedicle wall and a neomedullary canal. The goal of this study was to compare the biomechanics of screws inserted after pedicoplasty (impaction grafting) of a pedicle defect to those of an upsized screw and a cement-augmented screw. For this biomechanical cadaveric study the investigators used 10 vertebral bodies (L1-5) that were free of metastatic disease or primary bone disease. Following initial screw insertion, each screw was subjected to a pullout force that was applied axially along the screw trajectory at 5 mm per minute until failure. Each specimen was instrumented with a pedicoplasty revision using the original screw diameter, and on the contralateral side either a fenestrated screw with cement augmentation or a screw upsized by 1 mm was inserted in a randomized fashion. These revisions were then pulled out using the previously mentioned methods. Initial screw pullout values for the paired upsized screw and pedicoplasty were 717 ± 511 N and 774 ± 414 N, respectively (p = 0.747) (n = 14). Revised pullout values for the paired upsized screw and pedicoplasty were 775 ± 461 N and 762 ± 320 N, respectively (p = 0.932). Initial pullout values for the paired cement augmentation and pedicoplasty were 792 ± 434 N and 880 ± 558 N, respectively (p = 0.649). Revised pullout values for the paired cement augmentation and pedicoplasty were 1159 ± 300 N and 687 ± 213 N, respectively (p < 0.001). Pedicle defects are difficult to manage. Reconstitution of the pedicle and creation of a neomedullary canal appears to be possible through the use of pedicoplasty. Biomechanically, screws that have been used in pedicoplasty have equivalent pullout strength to an upsized screw, and have greater insertional torques than those with the same diameter that have not been used in pedicoplasty, yet they are not superior to cement augmentation. This study suggests that although cement augmentation appears to have superior pullout force, the novel pedicoplasty technique offers promise as a viable biological revision option for the management of failed pedicle screws compared with the option of standard upsized screws in a cadaveric model. These findings will ultimately need to be further assessed in a clinical setting.


Development and validation of an automated algorithm for identifying patients at higher risk for drug-induced acute kidney injury.
Using information from institutional electronic health records, we aimed to develop dynamic predictive models to identify patients at high risk of acute kidney injury (AKI) among those who received a nephrotoxic medication during their hospital stay. Candidate predictors were measured for each of the first 5 hospital days where a patient received a nephrotoxic medication (risk model days) to predict an AKI, using logistic regression with reduced backward variables elimination in 100 bootstrap samples. An AKI event was defined as an increase of serum creatinine ≥ 200% of a baseline SCr within 5 days after a risk model day. Final models were internally validated by replication in 100 bootstrap samples and a risk score for each patient was calculated from the validated model. As performance measures, the area under the receiver operation characteristic curves (AUC) and the number of AKI events among patients who had high risk scores were estimated. The study population included 62,561 admissions followed by 1,212 AKI events (1.9 events/100 admissions). We constructed 5 risk models corresponding to the first 5 hospital days where patients were exposed to at least one nephrotoxic medication. Validated AUCs of the 5 models ranged from 0.78 to 0.81. Depending on risk model day, admissions ranked in the 90th percentile of the risk score captured between 43% to 49% of all AKI events. A dynamic prediction model was built successfully for inpatient AKI with excellent discriminative validity and good calibration, allowing clinicians to focus on a select high-risk population that captures the majority of AKI events.


Evidence that the pathway of transferrin receptor mRNA degradation involves an endonucleolytic cleavage within the 3' UTR and does not involve poly(A) tail shortening.
The stability of transferrin receptor (TfR) mRNA is regulated by iron availability. When a human plasma-cytoma cell line (ARH-77) is treated with an iron source (hemin), the TfR mRNA is destabilized and a shorter TfR RNA appears. A similar phenomenon is also observed in mouse fibroblasts expressing a previously characterized iron-regulated human TfR mRNA (TRS-1). In contrast, mouse cells expressing a constitutively unstable human TfR mRNA (TRS-4) display the shorter RNA irrespective of iron treatment. These shorter RNAs found in both the hemin-treated ARH-77 cells and in the mouse fibroblasts are shown to be the result of a truncation within the 3' untranslated regions of the mRNAs. The truncated RNA is generated by an endonuclease, as most clearly evidenced by the detection of the matching 3' endonuclease product. The cleavage site of the human TfR mRNA in the mouse fibroblasts has been mapped to single nucleotide resolution to a single-stranded region near one of the iron-responsive elements contained in the 3' UTR. Site-directed mutagenesis demonstrates that the sequence surrounding the mapped endonuclease cleavage site is required for both iron-regulated mRNA turnover and generation of the truncated degradation intermediate. The TfR mRNA does not undergo poly(A) tail shortening prior to rapid degradation since the length of the poly(A) tail does not decrease during iron-induced destabilization. Moreover, the 3' endonuclease cleavage product is apparently polyadenylated to the same extent as the full-length mRNA.


Uptake characteristics of oligonucleotides in the isolated rat liver perfusion system.
The objective of this study was to examine the hepatic disposition characteristics of 20-mer model phosphodiester oligonucleotide (PO) and its partially phosphorothioated (PS3) and fully phosphorothioated (PS) derivatives in the single-pass isolated rat liver perfusion system. [32P]-labeled oligonucleotides were momentarily introduced into this system through the portal vein as a bolus input mode, and the venous outflow patterns were evaluated using statistical moment analysis. The apparent volumes of distribution of these oligonucleotides were greater than those of reference substances for vascular space (erythrocytes) and extracellular space (human serum albumin), indicating a significant interaction between oligonucleotides and the liver. Significant hepatic uptake of oligonucleotides was also observed. About 20%, 36%, and 52% of the injected dose (3 micrograms/rat) was taken up by the liver during a single passage after bolus injection of PO, PS3, and PS, respectively. In the case of PS injection, slow efflux from the liver was observed in the latter phase of perfusion. This suggests that the hepatic uptake process of these oligonucleotides greatly depended on their types. The results of collagenase perfusion experiments suggest that PS3 oligonucleotides were taken up by both liver parenchymal and nonparenchymal cells. The amount of total recovery in the liver decreased substantially by coadministration of polyinosinic acid, dextran sulfate, polycytidic acid and 4-acetamido-4'-isothiocyano-stilbene-2,2'-disulfonic acid. This suggests that PS3 was taken up by the liver as an anionic molecule in a nonspecific manner.


A conformation of cyclosporin A in aqueous environment revealed by the X-ray structure of a cyclosporin-Fab complex.
The conformation of the immunosuppressive drug cyclosporin A (CsA) in a complex with a Fab molecule has been established by crystallographic analysis to 2.65 angstrom resolution. This conformation of CsA is similar to that recently observed in the complex with the rotamase cyclophilin, its binding protein in vivo, and totally different from its conformation in an isolated form as determined from x-ray and nuclear magnetic resonance analysis. Because the surfaces of CsA interacting with cyclophilin or with the Fab are not identical, these results suggest that the conformation of CsA observed in the bound form preexists in aqueous solution and is not produced by interaction with the proteins.


Dietary fat, abdominal obesity and smoking modulate the relationship between plasma complement component 3 concentrations and metabolic syndrome risk.
Chronic inflammation plays a role in the pathogenesis of metabolic syndrome (MetS) and cardiovascular disease (CVD). Complement component 3 (C3) is a novel cardiometabolic risk factor. Whether dietary fat intake modulates MetS risk conferred by elevated C3 concentrations is unknown. Our objective is to investigate the relationship between C3 concentrations and risk of the MetS and its phenotypes, and to further examine whether dietary fat intake modulates these relationships. Biochemical, dietary and lifestyle measurements were determined in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n=1754). Elevated C3 concentrations (>median) were associated with increased risk of impaired insulin sensitivity [OR 1.78, CI 1.34-2.36, P<0.0001], insulin resistance [OR 1.73, CI 1.31-2.89, P=0.0001], abdominal obesity [OR 2.15, CI 1.43-3.24, P=0.0002] and low HDL cholesterol [OR 1.40, CI 1.05-1.86, P=0.02] compared to low C3 concentrations. Increased MetS risk conferred by elevated C3 concentrations [OR 3.11, 95% CI 2.52-3.82, P<0.0001] was further accentuated among high dietary fat consumers [OR 4.80, 95% CI 2.77-8.33, P<0.0001] (particularly of saturated [OR 4.05, 95% CI 2.33-7.05, P<0.0001] and monounsaturated fat [OR 4.48, 95% CI 2.62-7.56, P<0.0001]), and smokers [OR 3.83, 95% CI 2.12-6.94, P<0.0001], however this effect was abolished in abdominally lean individuals [OR 1.46, 95% CI 0.69-3.14, P=0.33]. Dietary fat (intake and composition), abdominal obesity and smoking modulate the relationship between elevated plasma C3 concentrations and MetS risk.


[Surgical therapy of reflux esophagitis in patients with normal lower esophageal sphincter pressure].
In a group of 12 patients with reflux esophagitis resistant to the medical treatment and normal LES pressure, gastric emptying and bile-gastric (B.G.) reflux (HIDA-CCK test) were determined. All of the patients had delayed gastric emptying associated in seven with high levels of B.G. reflux. Two of the patients had an unsuccessful fundoplication two years ago and five have been cured of duodenal 3 or gastric 2 ulcer with antacids. Although there was an evolution to an ulcer scar in all of these patients the abdominal post-prandial pain persisted and some of them maintained occasional bilious vomiting. Deep gastritis with dysplasia and metaplasia of the gastric mucosa was demonstrated in all of these five patients. The esophagitis was an isolated phenomenon in 3 patients, one had a peptic esophageal stricture above de cardia, and another one a Barrett esophagus. A proximal gastric vagotomy (PGV) and pyloroplasty was performed in patients with delayed gastric emptying without BG reflux. The other 7 patients with concomitant high BG reflux were treated by a duodenal diversion to a Roux-en-Y loop and P.G.V. Esophageal and gastric symptoms disappeared soon after surgery. Esophageal biopsies were normal six months after surgery and the intense gastritis changed to a less serious form of superficial gastritis. It is concluded that delayed gastric emptying associated or not with high values of BG reflux can be the most important pathogenic factor that cause reflux esophagitis in this group of patients. The improvement of gastric emptying and elimination of BG reflux can be the proper method to treat these situations.


New Approaches to Coding Information using Inverse Scattering Transform.
Remarkable mathematical properties of the integrable nonlinear Schrödinger equation (NLSE) can offer advanced solutions for the mitigation of nonlinear signal distortions in optical fiber links. Fundamental optical soliton, continuous, and discrete eigenvalues of the nonlinear spectrum have already been considered for the transmission of information in fiber-optic channels. Here, we propose to apply signal modulation to the kernel of the Gelfand-Levitan-Marchenko equations that offers the advantage of a relatively simple decoder design. First, we describe an approach based on exploiting the general N-soliton solution of the NLSE for simultaneous coding of N symbols involving 4×N coding parameters. As a specific elegant subclass of the general schemes, we introduce a soliton orthogonal frequency division multiplexing (SOFDM) method. This method is based on the choice of identical imaginary parts of the N-soliton solution eigenvalues, corresponding to equidistant soliton frequencies, making it similar to the conventional OFDM scheme, thus, allowing for the use of the efficient fast Fourier transform algorithm to recover the data. Then, we demonstrate how to use this new approach to control signal parameters in the case of the continuous spectrum.


Effect of Tumor Burden on Tumor Aggressiveness and Immune Modulation in Prostate Cancer: Association with IL-6 Signaling.
Local treatment is known to improve survival in men with locally advanced prostate cancer (LAPC), but the underlying mechanisms remain unclear. In the present study, we examined the role of tumor burden in tumor aggressiveness, as well as the pathway responsible for these changes. We used human and murine prostate cancer cell lines to examine the role of tumor burden in tumor aggressiveness, as well as its correlation with cancer stem cell (CSC) marker levels and IL-6 signaling. Furthermore, 167 prostate cancer biopsy specimens were analyzed in terms of correlations of IL-6 and CD44 levels with clinical patient characteristics. Data from preclinical models showed that larger tumor burden was associated with more aggressive tumor growth associated and increased CD44 expression. Using cellular experiments and orthotopic tumor models, we showed that CD44+ prostate cancer cells have CSC-like properties, enhanced epithelial-mesenchymal transition (EMT), and a more immunosuppressive microenvironment. There was a significant correlation between IL-6 and CD44 levels based on in vitro testing of clinical samples. Blockade of IL-6/STAT3 signaling attenuated the expression of CD44, CSC-like properties, and aggressive tumor behavior in vitro and in vivo. In conclusion, CD44 expression is significantly associated with tumor aggressiveness in prostate cancer and activation of IL-6 signaling leads to a suitable microenvironment for the induction of CD44 expression. Based on our study, reduced tumor burden was associated with attenuated IL-6 signaling and augmented tumor rejection in the microenvironment, which might mediate the benefit of clinical adoption with aggressive local therapy.


Abnormalities of resting state functional connectivity are related to sustained attention deficits in MS.
Resting state (RS) functional MRI recently identified default network abnormalities related to cognitive impairment in MS. fMRI can also be used to map functional connectivity (FC) while the brain is at rest and not adhered to a specific task. Given the importance of the anterior cingulate cortex (ACC) for higher executive functioning in MS, we here used the ACC as seed-point to test for differences and similarities in RS-FC related to sustained attention between MS patients and controls. Block-design rest phases of 3 Tesla fMRI data were analyzed to assess RS-FC in 31 patients (10 clinically isolated syndromes, 16 relapsing-remitting, 5 secondary progressive MS) and 31 age- and gender matched healthy controls (HC). Participants underwent extensive cognitive testing. In both groups, signal changes in several brain areas demonstrated significant correlation with RS-activity in the ACC. These comprised the posterior cingulate cortex (PCC), insular cortices, the right caudate, right middle temporal gyrus, angular gyri, the right hippocampus, and the cerebellum. Compared to HC, patients showed increased FC between the ACC and the left angular gyrus, left PCC, and right postcentral gyrus. Better cognitive performance in the patients was associated with increased FC to the cerebellum, middle temporal gyrus, occipital pole, and the angular gyrus. We provide evidence for adaptive changes in RS-FC in MS patients compared to HC in a sustained attention network. These results extend and partly mirror findings of task-related fMRI, suggesting FC may increase our understanding of cognitive dysfunction in MS.


Effect of toothbrushes and denture brushes on heat-polymerized acrylic resins.
It is important to choose an appropriate brush for denture cleaning to prevent damage to the surface properties of prosthetic devices. The purpose of this study was to evaluate the abrasiveness of toothbrushes and denture brushes on boiled and microwave-processed acrylic resins. Specimens of 4 resin brands were prepared (n = 30). Five brands of brushes (n = 6) were used in a toothbrushing machine, first for 17,800 strokes and then for an additional 35,600 strokes (total of 53,400), at a load of 200 g. An analytical balance and a profilometer were used to assess the weight and surface roughness, respectively, before and after 17,800 and 53,400 strokes. Analysis of variance and Tukey tests were used for data analysis (α = 0.05). Weight loss increased with time, while surface roughness remained the same. There were no statistically significant differences among toothbrushes and denture brushes in the resulting weight loss (17,800 strokes, 1.83 mg; 53,400 strokes, 3.78 mg) or surface roughness (17,800 or 53,400 strokes, 0.14 µm). The weight loss values after 53,400 brush strokes indicated that Clássico (2.28 mg) and VIPI Wave (2.75 mg) presented significantly greater abrasion resistance than Lucitone 550 (3.36 mg) and Onda-Cryl (2.85 mg) (P < 0.05). The type of brush and the polymerization method did not influence resin wear after brushing.


Mood stabilizers during breastfeeding: a review.
The postpartum period is an exceptionally high-risk time for recurrence of depression, mania, or psychosis for women with bipolar disorder. Puerperal prophylaxis with mood stabilizers decreases this risk. To allow patients and clinicians to make informed decisions about mood-stabilizer use during breastfeeding, there is a need for a critical review and analysis of the data. A search of MEDLINE (1966-1998) and the Lithium Database, Madison Institute of Medicine, was conducted to obtain articles about lithium, valproate, carbamazepine, gabapentin, or lamotrigine use during lactation. Search terms used were pregnancy, teratogenesis, breastfeeding, lactation, breast milk levels and lithium, anticonvulsants, mood stabilizers. No other search restrictions were used. Unpublished data on gabapentin and lamotrigine were provided by the manufacturers. The search revealed 11 cases of lithium use during breastfeeding, 8 of which reported infant serum levels. Two cases reported symptoms consistent with lithium toxicity in the infants. Thirty-nine cases of valproate use during breastfeeding were found, 8 of which reported infant serum levels. There was 1 report of thrombocytopenia and anemia in an infant. Fifty cases of carbamazepine use during breastfeeding were found, 10 of which reported infant serum levels. Two infants experienced hepatic dysfunction. One unpublished study of gabapentin in breast milk was found. Three reports of lamotrigine use during breastfeeding were found. Available information remains limited to uncontrolled studies and case reports. Carbamazepine and valproate, but not lithium, have generally been considered compatible with breastfeeding. The overall paucity of data, data confounded by polypharmacy and infant age differences, and adverse reactions reported with all established mood stabilizers dictate a reassessment of these recommendations. We propose that a woman's historical response to medication and the clinical circumstances be the primary considerations when choosing a mood stabilizer during breastfeeding, rather than strict adherence to categorical assignments.


Middle lobe syndrome: a clinicopathological study of 21 patients.
Middle lobe syndrome (MLS) is an uncommon lung disorder involving the right middle lobe and/or lingula and is characterized by a spectrum of clinical and pathological lesions ranging from recurrent atelectasis or pneumonias to bronchiectasis. Despite several series reporting the clinical features of MLS, histopathological descriptions are rare. We reviewed the clinical characteristics and pathological findings in 21 patients with MLS who underwent surgical resections. Six male and 15 female patients between the ages of 5 and 80 years (mean, 47 years) were studied. All patients were symptomatic and complained of chronic cough (8), hemoptysis (6), chest pain (4), dyspnea (3), or fever (2). The right middle lobe was involved in 11 patients, the lingula in four patients, and both right middle lobe and lingula in six patients. Chest radiographs, bronchograms, and/or computed tomography scans were available for review in 19 patients and showed consolidation (8), bronchiectasis (9), patchy infiltrates (5), and atelectasis (4) in various combinations. Pathological findings included bronchiectasis in 10 patients, chronic bronchitis/bronchiolitis with lymphoid hyperplasia in seven, patchy organizing pneumonia in six, atelectasis in five, granulomatous inflammation in five, and abscess formation in four. Three patients with granulomatous inflammation had associated atypical mycobacterial infection. Broncholithiasis was confirmed by pathological examination in one patient. No pathological cause for bronchial obstruction was identified in the remaining 20 patients, although one was thought to have had broncholithiasis on the basis of preoperative bronchoscopy. The presence of bronchiectasis, bronchitis or bronchiolitis, organizing pneumonia, or atelectasis in specimens from the right middle lobe or of lingula in the absence of an identifiable cause of bronchial obstruction should suggest a diagnosis of MLS.


Technique for enumeration of heterotrophic and phototrophic nanoplankton, using epifluorescence microscopy, and comparison with other procedures.
A new method is described that uses the fluorochrome primulin and epifluorescence microscopy for the enumeration of heterotrophic and phototrophic nanoplankton (2 to 20 mum). Phototrophic microorganisms are distinguished from heterotrophs by the red autofluorescence of chlorophyll a. Separate filter sets are used which allow visualization of the primulin-stained nanoplankton without masking chlorophyll a fluorescence, thus allowing easy recognition of phototrophic cells. Comparison with existing epifluorescence techniques for counting heterotrophic and phototrophic nanoplankton shows that primulin provides more accurate counts of these populations than the fluorescein isothiocyanate or proflavine techniques. Accuracy is comparable to that with the acridine orange technique, but this method requires only one filter preparation for the enumeration of both phototrophic and heterotrophic populations.


Abbreviation and acronym disambiguation in clinical discourse.
Use of abbreviations and acronyms is pervasive in clinical reports despite many efforts to limit the use of ambiguous and unsanctioned abbreviations and acronyms. Due to the fact that many abbreviations and acronyms are ambiguous with respect to their sense, complete and accurate text analysis is impossible without identification of the sense that was intended for a given abbreviation or acronym. We present the results of an experiment where we used the contexts harvested from the Internet through Google API to collect contextual data for a set of 8 acronyms found in clinical notes at the Mayo Clinic. We then used the contexts to disambiguate the sense of abbreviations in a manually annotated corpus.


Helping Dementia Caregivers Through Technology.
It is estimated there are between 43.5 and 65.7 million caregivers in the United States who provide unpaid care for older adults. Although the number of informal caregivers is expected to continue to increase, few programs have been established in home healthcare agencies to support these caregivers. This article describes a project that used a unique Web site to connect caregivers of people with dementia in a geographic region with an interprofessional group of healthcare providers and caregiver peers. Virtual Healthcare Neighborhood (VHN) was developed and maintained by an interprofessional group of healthcare providers from nursing, physical therapy, clinical counseling, and dental hygiene. The VHN provided weekly information on topics relevant to caring for a loved one with dementia at home as well as Question and Answer and Social Support Blogging sections for use by participants. This project was viewed as a positive and helpful method to provide support for caregivers of homebound older adults that could be easily replicated by home healthcare agencies.


A Multi-objective Mathematical Programing Model for the Problem of P-envy Emergency Medical Service Location.
To prevent the great dangers caused by emergency situations, providing rapid and high-quality emergency aid highly depends on the location of emergency medical centers. The purpose of this research is to present a multi-objective mathematical programing model based on the minimum P-envy algorithm to locate and construct emergency medical services (EMS). Maximizing the coverage in order to increase the probability of survival of different categories of patients, minimizing the costs of constructing EMS and optimizing the ratio of regions having the right to emergency medical services is one of the fundamental challenges in the health care system of countries. In this paper, a model for maximum utilization of EMS considering budget limitations is presented. In this study, since the problem is NP-Hard, the Genetic Algorithm (GA) and Simulated Annealing (SA) algorithm were used to solve this problem. The parameters of the metaheuristic algorithms were tuned using the Taguchi method. Several instance problems were solved to compare the performance of 2 algorithms. The results demonstrate that the validity of the proposed model. Also, the mean of the solutions obtained by GA for small, medium, and large-size problems are better than the SA algorithm. Also, the GA algorithm obtained more efficient solutions than the SA algorithm.


Predation drives local adaptation of phenotypic plasticity.
Phenotypic plasticity is the ability of an individual genotype to alter aspects of its phenotype depending on the current environment. It is central to the persistence, resistance and resilience of populations facing variation in physical or biological factors. Genetic variation in plasticity is pervasive, which suggests its local adaptation is plausible. Existing studies on the adaptation of plasticity typically focus on single traits and a few populations, while theory about interactions among genes (for example, pleiotropy) suggests that a multi-trait, landscape scale (for example, multiple populations) perspective is required. We present data from a landscape scale, replicated, multi-trait experiment using a classic predator-prey system centred on the water flea Daphnia pulex. We find predator regime-driven differences in genetic variation of multivariate plasticity. These differences are associated with strong divergent selection linked to a predation regime. Our findings are evidence for local adaptation of plasticity, suggesting that responses of populations to environmental variation depend on the conditions in which they evolved in the past.


Colorectal perforation in renal transplant recipients.
Of 525 patients who received 585 renal transplants, seven developed colonic perforations from 6 to 27 days post-transplantation. Six were undergoing antirejection therapy at the time of perforation. Prompt diagnosis was made and colonic resection carried out immediately under broad spectrum antibiotic coverage. Primary gastrointestinal reconstruction was performed in one instance and colonic exclusion in the others. One patient died from the insult; three are alive eight to 42 months after perforation; and three succumbed to late unrelated problems at two, three, and 24 months. Early diagnosis, immediate thorough debridement of the peritoneal cavity, and colonic exclusion carry the best prognosis.


Performing neurological observations.
Trauma to the brain from injury or illness can cause sustained, raised intracranial pressure. In such patients, neurological observations are a fundamental aspect of nursing care and the ability to make and record such observations accurately is an essential nursing skill. Neurological observations are a collection of information on the function and integrity of a patient's central nervous system-the brain and and spinal cord. This article will discuss the tools used in their observation, including the Glasgow Coma Scale tool, pupillary response, and limb power observations, and provide a 'how-to' guide on neurological observations.


Does vitamin E prevent or promote cancer?
The cancer preventive activity of vitamin E has been suggested by many epidemiologic studies. However, several recent large-scale human trials with α-tocopherol, the most commonly recognized and used form of vitamin E, failed to show a cancer preventive effect. The recently finished follow-up of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) even showed higher prostate cancer incidence in subjects who took α-tocopherol supplementation. The scientific community and the general public are faced with a question: "Does vitamin E prevent or promote cancer?" Our recent results in animal models have shown the cancer preventive activity of γ- and δ-tocopherols as well as a naturally occurring mixture of tocopherols, and the lack of cancer preventive activity by α-tocopherol. On the basis of these results as well as information from the literature, we suggest that vitamin E, as ingested in the diet or in supplements that are rich in γ- and δ-tocopherols, is cancer preventive; whereas supplementation with high doses of α-tocopherol is not.


Effect of enteral feeding on hepatic steatosis induced by total parenteral nutrition.
This study was designed to test the hypothesis that deprivation of enteral feeding contributes to the development of total parenteral nutrition (TPN)-induced hepatic dysfunction and that alterations of gut hormones are involved in its pathogenesis. Twenty-one adult Sprague-Dawley rats were randomized into three groups: group 1 received chow feeding ad libitum (288 kcal/kg per day); group 2 received dextrose-based TPN (320 +/- 5 kcal/kg per day); and group 3 received TPN (315 +/- 15 kcal/kg per day) plus chow feeding ad libitum (74 +/- 1 kcal/kg per day). After 7 days, portal blood was assayed for insulin, glucagon, gastrin, peptide YY, secretin, and vasoactive intestinal polypeptide; systemic blood for determination of liver function tests and serum lipid analysis. Liver biopsies were taken for histology and staining for fat, and the remainder of the livers were removed for tissue lipid analysis. TPN induced striking hepatic steatosis with prominent histologic changes and accumulation of lipids, mainly triglycerides and cholesterol ester, in the liver. Addition of enteral feeding to TPN-treated animals significantly reduced the histologic changes as well as lipid accumulation in the liver. Portal plasma levels of gastrin and peptide YY were reduced in animals maintained on TPN alone, with no change in secretin or vasoactive intestinal polypeptide levels. Enteral supplementation increased peptide YY levels in group 3, but not to normal, while gastrin secretion remained decreased. The serum triglyceride levels were decreased in both TPN groups; no differences were detected in the serum cholesterol levels or liver function tests.(ABSTRACT TRUNCATED AT 250 WORDS)


Mechanical and electrical responses to alpha-adrenoceptor activation in the circular muscle of guinea-pig stomach.
1 In the circular muscle of the corpus region of the guinea-pig stomach, the effects of catecholamines on mechanical activity were studied with simultaneous recording of membrane potential by use of intracellular microelectrodes. In order to investigate responses mediated through alpha-adrenoceptors, the beta-adrenoceptors were blocked by propranolol (10(-6) M) in most experiments. 2 Adrenaline (less than 10(-6) M) produced a monophasic contraction with little change in membrane potential. At higher concentrations (greater than 10(-5) M), adrenaline usually produced an early transient contraction followed by a slow tonic contraction. During the early phase, the membrane was hyperpolarized and slow waves were reduced in amplitude. 3 The phasic contractions superimposed on the late slow phase of the contractile response were higher in frequency and larger in amplitude than in controls before adrenaline application. These changes were associated with an increase in the amplitude and frequency of slow waves, and with a spike-like component appearing on the top of each slow wave. 4 Adrenaline-induced changes in mechanical and electrical activity were inhibited by prazosin, but largely unaffected by yohimbine. In some preparations, there was a transient weak inhibition of phasic contraction before muscle tone was increased by adrenaline, and this became more pronounced in the presence of yohimbine. 5 Phenylephrine, selective for alpha 1-receptors, produced responses very similar to those of adrenaline, whereas agonists selective for alpha 2-receptors, clonidine and B-HT 920, produced only a small slow contraction without any clear change in membrane potential. 6 It is concluded that in the circular muscle of guinea-pig stomach, the contractile response and changes in the electrical slow wave activity produced by adrenaline are both mediated mainly through the activation of alpha-receptors.


Anti-SARS-CoV-2 antibody decay after vaccination and immunogenicity of the booster dose of the BNT162b2 mRNA vaccine in patients with psoriatic arthritis on TNF inhibitors.
Scanty data on the anti- SARS-CoV-2 IgG level decay after two-dose BNT162b2 vaccination have been published in patients with psoriatic arthritis (PsA) on TNF inhibitors (TNFi). Similarly, no reports on the immunogenicity of a booster dose in such patients have been provided yet.We aimed to investigate the IgG level decay after two-dose BNT162b2 vaccination and the immunogenicity and safety of the booster dose in PsA patients on TNFi. Forty patients with classified PsA on TNFi undergoing booster dose with the BNT162b2 mRNA SARS- CoV-2 vaccine (BioNTech/Pfizer) were enrolled. Fifteen days after the third shot, serum IgG levels against SARS-CoV-2 (Abbott®ARCHITECT i2000SR, positivity cut-off 50 AU/mL) were assayed in all patients. Clinimetrics and treatment data were gathered. TNFi treatment was not discontinued. Sera from healthcare professionals were considered as healthy controls for 1:1 propensity score-matching. Student's t-test and logistic regression were used for investigating differences in immunogenicity between groups and predictors of antibody response. Even though the decay of IgG levels showed similar magnitude between groups, PsA patients had a lower IgG level than matched controls at 4 months after two-dose vaccination (2009.22±4050.22 vs. 6206.59±4968.33 AU/mL, respectively p=0.0006). Booster dose restored IgG levels to a similar extent in both groups (15846.47±12876.48 vs. 20374.46±12797.08 AU/ml p=0.20, respectively). Clinical Disease Activity Index (CDAI) did not change before and after vaccination (6.68±4.38 vs. 4.95±4.20, p=0.19). A BNT162b2 booster dose should be recommended in PsA patients on TNFi as its administration restores anti-SARS-CoV-2 IgG levels similar to healthy individuals.


Searching beyond the Lamppost to Reduce Breast Cancer Disparities.
Racial and ethnic differences in breast cancer occur by race/ethnicity in both incidence and mortality rates. Women of lower socioeconomic status likewise have poorer outcomes. When race alone is considered, incidence rates in the United States are highest among White women (130.8 per 100,000), with Black women close behind (126.7 per 100,000). Incidence is lowest among Asian/Pacific Islander women, at 93.2 per 100,000. Mortality differences are more pronounced, with Black women 40% more likely to die from breast cancer than White women (28.4 per 100,000 and 20.3 per 100,000, respectively). Mortality rates for Asian/Pacific Islander women (11.5 per 100,000) are far lower than for Black and White women. When age is considered, additional differences between Black and White women appear, in part accounted for by types of breast cancer experienced. Women of other racial/ethnic groups and socioeconomic status have received less scientific attention. In this article, we provide a brief overview of the evidence for social determinants of breast cancer and argue that the current reliance on race over racism and ethnicity contributes to our inability to eliminate breast cancer disparities in the United States and elsewhere in the world. We suggest alternatives to the current approach to research in breast cancer disparities.


Wac: a new Augmin subunit required for chromosome alignment but not for acentrosomal microtubule assembly in female meiosis.
The bipolar spindle forms without centrosomes naturally in female meiosis and by experimental manipulation in mitosis. Augmin is a recently discovered protein complex required for centrosome-independent microtubule generation within the spindle in Drosophila melanogaster cultured cells. Five subunits of Augmin have been identified so far, but neither their organization within the complex nor their role in developing organisms is known. In this study, we report a new Augmin subunit, wee Augmin component (Wac). Wac directly interacts with another Augmin subunit, Dgt2, via its coiled-coil domain. Wac depletion in cultured cells, especially without functional centrosomes, causes severe defects in spindle assembly. We found that a wac deletion mutant is viable but female sterile and shows only a mild impact on somatic mitosis. Unexpectedly, mutant female meiosis showed robust microtubule assembly of the acentrosomal spindle but frequent chromosome misalignment. For the first time, this study establishes the role of an Augmin subunit in developing organisms and provides an insight into the architecture of the complex.


Patch clamped single pancreatic zymogen granules: direct measurements of ion channel activities at the granule membrane.
Pancreatic acinar cells are involved in the secretion of digestive enzymes. Digestive enzymes in pancreatic acinar cells are stored in membrane-bound secretory vesicles called zymogen granules (ZGs). The swelling of ZGs is implicated in the regulation of the expulsion of intravesicular contents during secretion. The molecular mechanism of ZG swelling has been previously elucidated. It has been further demonstrated that the water channel aquaporin-1, the potassium channel IRK-8, and the chloride channel CLC-2, are present in the ZG membrane and involved in ZG swelling. However, a direct measurement of these ion channels at the ZG membrane in intact ZGs had not been performed. The aim of this study was to investigate the electrical activity of single ZGs and verify the types of channels found within their membrane. ZGs from pancreatic acinar cells were isolated from the pancreas of Sprague-Dawley rats. Direct measurements of whole vesicle currents, in the presence and absence of ion channel blockers (quinine, glyburide and DIDS), were recorded following successful patching of single ZGs. In this study, we were able, for the first time, to patch single ZGs and study ion channels in their membrane. We were able to record currents across the ZG membrane and, utilizing ion channel blockers, confirm the presence of the chloride channels CLC-2 and the potassium channel IRK-8 (Kir6.1), and additionally demonstrate the presence of a second chloride channel CLC-3.