Kinesthetic Cells within the Subthalamic Nucleus and Deep Brain Stimulation for Parkinson Disease.
We sought to determine the location of kinesthetic cell clusters within the subthalamic nucleus (STN) on magnetic resonance imaging, adjusted for interindividual anatomic variability by employing the medial STN border as a reference point. We retrospectively localized microelectrode recording-defined kinesthetic cells on 3-Tesla T2-weighted and susceptibility-weighted images in patients who underwent STN deep brain stimulation for Parkinson disease and averaged the stereotactic coordinates. These locations were calculated relative to the nonindividualized midcommissural point (MCP) and, in order to account for interindividual anatomic variability, also calculated relative to the patient-specific intersection of Bejjani line with the medial STN border. Two example patients were selected in order to visualize the discrepancies between the adjusted and nonadjusted theoretic kinesthetic cell clusters on magnetic resonance imaging. Relative to the MCP, average kinesthetic cell coordinates were 12.3 ± 1.2 mm lateral, 1.7 ± 1.4 mm posterior, and 2.3 ± 1.5 mm inferior. Relative to the medial STN border, mean coordinates were 3.4 ± 1.0 mm lateral, 1.0 ± 1.4 mm anterior, and 1.7 ± 1.5 mm superior on T2-sequences, and on susceptibility-weighted images mean coordinates were 3.2 ± 1.1 mm lateral, 0.8 ± 1.5 mm anterior, and 2.1 ± 1.5 mm superior. The theoretic kinesthetic cell clusters may appear outside the sensorimotor STN when using the MCP, whereas these clusters fall well within the sensorimotor STN when employing the medial STN border as a reference point. By using the medial STN border as a patient-specific anatomic reference point in STN deep brain stimulation for Parkinson disease, we accounted for interindividual anatomic variability and provided accurate insight in the clustering of kinesthetic cells within the dorsolateral STN.


Activation of caspases and apoptosis in response to low-voltage electric pulses.
Few studies have examined apoptosis induced by low-voltage electric pulses (LVEPs). LVEP-induce changes in membrane potential that are below the membrane breakdown threshold and increase membrane permeability without electroporation (pore formation) through the transport of extracellular substances via phagocytosis. We demonstrated that propidium iodide uptake and apoptosis increased in accordance with the duration and number of LVEPs in B16 cells, which showed relatively good viability under mild electric field conditions. We showed that LVEP-induced apoptosis was achieved through caspase-8 and -9 activation and subsequent caspase-3 activation. Long-duration LVEPs caused only mild cell damage, such that the apoptosis ratio (apoptosis/total cell death) in electric pulse-treated cells was similar to that in non-treated control cells. To assess the relative degree of caspase dependency in LVEP-induced apoptosis, the apoptosis rate and caspase-3 activity were analyzed using a pan-caspase inhibitor (Z-VAD-FMK). Z-VAD-FMK treatment inhibited, but did not abolish, LVEP-induced apoptosis, indicating that caspases other than caspase-3 participate in this pathway. Moreover, LVEP treatment inhibited cell growth, suggesting that LVEP treatment may be a valuable anticancer therapy. Although the mechanism of LVEP-induced apoptosis remains unclear, it may be related to dysfunctional membrane transport of Ca2+ and other extracellular substances involved in caspase activation.


Nesidioblastosis with delayed diagnosis and post-operative complications in a patient with complex psychiatric history.
Nesidioblastosis is a rare condition of organic persistent hyperinsulinaemic hypoglycaemia, with fewer than 100 cases since it was first recorded. However, an increasing prevalence suggests previous underdiagnosis due to poor knowledge and awareness. This case describes the presentation, clinical decision-making and unique challenges in diagnosis and care of a 21-year-old female with nesidioblastosis and extensive psychiatric comorbidities. She was repeatedly misdiagnosed until 2021, despite having presented to emergency departments with hypoglycaemic symptoms for over 7 years. Her symptoms were often misattributed to behaviours secondary to restrictive anorexia nervosa and borderline personality disorder. Even after appropriate diagnosis and management, she suffered a complicated post-operative course. Patients with psychiatric comorbidities are at higher risk of distress, communication difficulties and inadequate social support, all of which could be better managed with increased multidisciplinary collaboration between endocrine, surgery, psychiatry, pain management and social work. This study highlights the importance of well-rounded patient care that addresses all facets of patient health. This approach not only improves quality of care, but also reduces overall readmissions, revisions, morbidity and mortality.


[Treatment perspectives: immunotherapy with latex].
Latex allergy currently constitutes a serious problem because of the severity of its symptoms and the at-risk groups it affects. Since complete avoidance of this substance is practically impossible, in the last few years intense efforts have been made to standardize a latex extract with the aim not only of improving clinical diagnosis but also of being able to offer other therapeutic alternatives, such as specific immunotherapy.Since 1998, reports of immunotherapy with oral (three patients) subcutaneous (one patient) and sublingual latex desensitization (one patient) have been published. In all cases, clinical improvement was evident. In 2000, Laynadier published the first pilot study, a phase IIB multicenter, randomized, double-blind, placebo-controlled trial that evaluated the efficacy and safety of specific immunotherapy with latex in patients with occupational allergy. Twenty health care workers without obvious latex exposure and with latex allergy-induced symptoms of rhinitis and/or asthma were included. Treatment started with a 2-day course of rush immunotherapy in hospital and maintenance therapy was continued for 1 year. Efficacy was assessed by symptom and medication scores and by variation in the conjunctival reactivity threshold. The safety of the extract was also evaluated. In the overall analysis of symptom score, the treated group showed a marked improvement and the medication score was significantly lower in patients in the active treatment group than in the placebo group. Concerning safety, almost half the patients receiving active treatment showed local reactions starting with the first injection and four of the nine patients in this group suffered moderate-to-severe systemic reactions. In view of this first clinical trial, it can be concluded that this treatment is effective but that its tolerance is low.A second clinical trial with the same characteristics and extract is currently underway. Its aim is to validate the previous protocol, confirm the efficacy of specific immunotherapy with latex, improve its safety and, if possible, determine the optimal dose.J. Sastre et al. have recently (Formigal 2002) presented the results of the first double-blind study with latex immunotherapy using an extract standardized by the ALK-Abelló-España group. The authors included 24 patients with latex sensitization and symptoms of occupational allergy. To diagnose respiratory allergy, an inhalation challenge was performed in a closed 7-m2 chamber and, in case of contact urticaria, glove-wearing and rubbing tests were performed, using a vinyl glove as negative control. Treatment consisted of a first phase of incremental doses for 14 weeks, with 18 injections, followed by maintenance doses for 6 months. Sixteen patients received active treatment and 8 received placebo. Of the 578 doses administered, adverse effects were observed in 41 (7.1 %). There were 21 immediate systemic reactions (5.7 % of the doses) and 10 delayed systemic reactions (2.6 % of the doses). Adverse effects were more frequent in patients with underlying respiratory disease (p < 0.05). After 6 months' treatment, a clear improvement in the cutaneous response index was found in the active treatment group and in the rubbing and glove-wearing tests. The authors conclude that the immunotherapy tested was a high-risk treatment and that the greatest clinical improvement was found in cutaneous symptoms.In conclusion, although effective, latex immunotherapy is currently a high-risk treatment.


In vitro genotoxicity testing using the micronucleus assay in cell lines, human lymphocytes and 3D human skin models.
The toxicological relevance of the micronucleus (MN) test is well defined: it is a multi-target genotoxic endpoint, assessing not only clastogenic and aneugenic events but also some epigenetic effects, which is simple to score, accurate, applicable in different cell types. In addition, it is predictive for cancer, amenable for automation and allows good extrapolation for potential limits of exposure or thresholds and it is easily measured in experimental both in vitro and in vivo systems. Implementation of in vitro micronucleus (IVMN) assays in the battery of tests for hazard and risk assessment of potential mutagens/carcinogens is therefore fully justified. Moreover, the final draft of an OECD guideline became recently available for this test. In this review, we discuss the prerequisites for an acceptable MN assay, including the cell as unit of observation, importance of cell membranes, the requirement of a mitotic or meiotic division and the assessment of cell division in the presence of the test substance. Furthermore, the importance of adequate design of protocols is highlighted and new developments, in particular the in vitro 3D human skin models, are discussed. Finally, we address future research perspectives including the possibility of a combined primary 3D human skin and primary human whole blood culture system, and the need for adaptation of the IVMN assays to assess the genotoxic potential of new materials, in particular nanomaterials.


Higher human T lymphotropic virus (HTLV) provirus load is associated with HTLV-I versus HTLV-II, with HTLV-II subtype A versus B, and with male sex and a history of blood transfusion.
High human T lymphotropic virus (HTLV)-I provirus load (VL) has been associated with an increased risk of HTLV-associated myelopathy, but little is known about variation in HTLV-I or -II VLs by demographic characteristics and risk behaviors. We measured HTLV-I and HTLV-II VLs in a large cohort of 127 HTLV-I-seropositive and 328 HTLV-II-seropositive former blood donors, by use of real-time polymerase chain reaction using tax primers. Multivariable linear regression was used to control for confounding by relevant covariates. The mean VLs were 3.28 log(10) copies/10(6) peripheral blood mononuclear cells (PBMCs) (range, 0.5-5.3 log(10) copies/10(6) PBMCs) for HTLV-I and 2.60 log(10) copies/10(6) PBMCs (range, 0.05-5.95 log(10) copies/10(6) PBMCs) for HTLV-II (P<.0001). HTLV-II VLs were higher in those subjects with subtype A infection (mean, 2.82 log(10) copies/10(6) PBMCs) than in those with subtype B infection (mean, 2.29 log(10) copies/10(6) PBMCs) (P=.005). Higher HTLV-I VL was associated with previous receipt of a blood transfusion (P=.04), and lower HTLV-II VL was associated with female sex (P=.007). These associations persisted in virus-specific multivariate linear regression models controlling for potential confounding variables. VL was significantly higher in HTLV-I than in HTLV-II infection and was higher in HTLV-II subtype A than in HTLV-II subtype B infection. Chronic HTLV VLs may be related to the infectious dose acquired at the time of infection, with higher VLs following acquisition by blood transfusion and lower VLs following sexual acquisition.


[Medical economics research on awareness of community pharmacists about raising pharmaceutical questions regarding prescriptions issued by physicians].
This study examined the impact of pharmaceutical inquiries regarding prescriptions on drug costs by surveying the actual condition of inquiries at 13 pharmacies. The study also investigated the significance of inquiries from a medical economics perspective by calculating the medical cost savings realized by preventing adverse drug reactions (ADRs). As a result, the total change in drug costs for the 13 pharmacies after pharmaceutical inquiries represented an increase of ¥9,018/month. However, upon recalculating the cost of drugs by assuming that those with an "Incomplete entry in the prescription (compared with previous prescription, etc.)" should in fact have been prescribed, and excluding them, the total drug costs for the 13 pharmacies is decreased to ¥154,743/month, translating to a cost-savings of ¥7.2/prescription. The study then undertook a comprehensive assessment based on the Diagnosis Procedure Combination (DPC) system to determine the total medical cost-savings for 5 patients in whom ADRs could have occurred if the prescriptions had not been modified as a result of pharmaceutical inquiries. The obtained figure of ¥1,188,830 suggests that pharmaceutical inquiries contribute to reduced medical costs. The findings of this study indicate that pharmaceutical inquiries regarding prescriptions by staff pharmacists not only ensure the proper delivery of drug therapy to patients, but are also effective from a medical economics perspective.


Isomeranzin suppresses inflammation by inhibiting M1 macrophage polarization through the NF-κB and ERK pathway.
Macrophage polarization plays an important role in inflammation. Regulation of the polarization has been reported to be effective therapeutics for various kinds of inflammatory diseases. The aims of the present study were to investigate the anti-inflammatory property of isomeranzin isolating from Murraya exotica as well as potential molecular mechanisms. Results showed that isomeranzin specifically reduced the M1 macrophage-associated pro-inflammatory cytokines through down-regulation of NF-κB and ERK signals. Immunoprecipitation and RNA silencing indicated suppression of isomeranzin in NF-κB activation was relying on the decreasing of TRAF6 ubiquitination. In vivo studies showed isomeranzin evidently inhibited LPS-induced sepsis for rising survival rate, improving tissue damage and lessening inflammatory cytokines. In accordance with in vitro studies, isomeranzin significantly blocked expression of p-p65 and p-ERK in lung and liver tissues. Moreover, isomeranzin ameliorated DSS and TNBS-induced colitis due to its anti-inflammatory effects. Taken together, isomeranzin suppressed inflammatory diseases by controlling M1 macrophage polarization through the NF-κB and ERK pathway.


Nuclear translocation of adeno-associated virus type 2 capsid proteins for virion assembly.
Adeno-associated virus (AAV) capsid assembly occurs in the nucleus. Newly synthesized capsid proteins VP1, VP2 and VP3 contain several basic regions (BRs), which may act as nuclear localization signals (NLSs). Mutation of BR2 and BR3, located at the VP1 and VP2 N termini, marginally reduced nuclear uptake of VP1 or VP2, but not of VP3, when expressed in the context of the whole AAV type 2 (AAV2) genome. Combined mutation of BR1, BR2 and BR3 resulted in capsids with slightly reduced amounts of VP1. Expression of isolated VP1/2 N termini revealed an influence of BR3 on nuclear transport, whilst BR1 or BR2 had no effect. However, deletion of an N-terminal fragment in front of the BR elements strongly reduced nuclear uptake of VP1/2 N termini. Mutation of BR4, present in all three capsid proteins, led to their retention in the cytoplasm and to the formation of speckles, resulting in a lack of capsid formation and a significant reduction in VP levels. In a VP fragment comprising BR2, BR3 and BR4, the BR4 element was not necessary for nuclear localization. Mutation of BR5 in the C-terminal part of the VPs resulted in a speckled protein distribution in the nucleus, strongly reduced capsid assembly, and low VP1 and VP2 levels. Taken together, these results showed that BR2 and BR3 have a weak influence on nuclear transport of VP1 and VP2, whilst combined mutation of BR1, BR2 and BR3 influences the stoichiometry of VPs in assembled capsids. BR4 and BR5 play a crucial role in capsid assembly but have no NLS activity.


How CEOs manage growth agendas.
When does it make sense for companies to grow from within? When is it better to gain new capabilities or access to markets by merging with or acquiring other companies? When should you sacrifice the bottom line in order to nurture the top line? In a thought-provoking series of essays, five executives--Kenneth Freeman of Quest Diagnostics, George Nolen of Siemens USA, John Tyson of Tyson Foods, Kenneth Lewis of Bank of America, and Robert Creifeld of Nasdaq--describe how they have approached top-line growth in various leadership roles throughout their careers. They write candidly about their struggles and successes along the way, relaying growth strategies as diverse as the companies and industries they represent. The leaders' different tactics have almost everything to do with their companies' particular strengths, weaknesses, and needs. Freeman, for instance, emphasizes the importance of knowing when to put on the brakes. When he first became CEO of Quest, he froze acquisitions for a few years so the company could focus on internal processes and "earn the right to grow." But for Greifeld, it's all about innovation, which "shakes up competitive stasis and propels even mature businesses forward." The executives agree, though, that companies can grow (and can do so profitably) by distinguishing their offerings from those of other organizations. As Ranjay Gulati of Northwestern's Kellogg School of Management points out in his introduction to the essays, no matter what strategies are in play,"it's important to remember that growth comes in many forms and takes patience.... The key is to be ready to act on whatever types of opportunities arise."


Infection control as a topic for ward-based nursing education.
The link between nursing theory and practice remains a topic of ongoing debate. Related to this issue is the best place to effectively combine the two. The solution may be ward-based teaching programmes as part of formal continuing staff development, involving collaboration between college-based lecturers and acknowledged clinical experts. Using infection control as an example of a topic in need of regular and continual updating for qualified practitioners, it is argued that such programmes would be desirable because they would afford sufficient flexibility to fulfil individual learning needs and could be assessed to indicate whether nursing practice had been enhanced. Participants could be accredited for successful completion of ward-based programmes.


The MADIT-ICD benefit score helps to select implantable cardioverter-defibrillator candidates in cardiac resynchronization therapy.
The aim of this study is to evaluate whether the MADIT-ICD benefit score can predict who benefits most from the addition of implantable cardioverter-defibrillator (ICD) to cardiac resynchronization therapy (CRT) in real-world patients with heart failure with reduced ejection fraction (HFrEF) and to compare this with selection according to a multidisciplinary expert centre approach. Consecutive HFrEF patients who received a CRT for a guideline indication at a tertiary care hospital (Ziekenhuis Oost-Limburg, Genk, Belgium) between October 2008 and September 2016, were retrospectively evaluated. The MADIT-ICD benefit groups (low, intermediate, and high) were compared with the current multidisciplinary expert centre approach. Endpoints were (i) sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) and (ii) non-arrhythmic mortality. Of the 475 included patients, 165 (34.7%) were in the lowest, 220 (46.3%) in the intermediate, and 90 (19.0%) in the highest benefit group. After a median follow-up of 34 months, VT/VF occurred in 3 (1.8%) patients in the lowest, 9 (4.1%) in the intermediate, and 13 (14.4%) in the highest benefit group (P < 0.001). Vice versa, non-arrhythmic death occurred in 32 (19.4%) in the lowest, 32 (14.6%) in the intermediate, and 3 (3.3%) in the highest benefit group (P = 0.002). The predictive power for ICD benefit was comparable between expert multidisciplinary judgement and the MADIT-ICD benefit score: Uno's C-statistic 0.69 vs. 0.69 (P = 0.936) for VT/VF and 0.62 vs. 0.60 (P = 0.790) for non-arrhythmic mortality. The MADIT-ICD benefit score can identify who benefits most from CRT-D and is comparable with multidisciplinary judgement in a CRT expert centre.


In vitro destruction of Streptococcus pneumoniae biofilms with bacterial and phage peptidoglycan hydrolases.
Host- and phage-coded cell wall hydrolases have been used to fight Streptococcus pneumoniae growing as planktonic cells in vitro as well as in animal models. Until now, however, the usefulness of these enzymes in biofilm-grown pneumococci has gone untested. The antipneumococcal activity of different cell wall hydrolases produced by S. pneumoniae and a number of its phages was examined in an in vitro biofilm model. The major pneumococcal autolysin LytA, an N-acetylmuramoyl-l-alanine amidase, showed the greatest efficiency in disintegrating S. pneumoniae biofilms. The phage-encoded lysozymes Cpl-1 and Cpl-7 were also very efficient. Biofilms formed by the close pneumococcal relatives Streptococcus pseudopneumoniae and Streptococcus oralis were also destroyed by the phage endolysins but not by the S. pneumoniae autolysin LytA. A cooperative effect of LytA and Cpl-1 in the disintegration of S. pneumoniae biofilms was recorded.


Definition of Arabidopsis sterol-rich membrane microdomains by differential treatment with methyl-beta-cyclodextrin and quantitative proteomics.
Plasma membranes are dynamic compartments with key functions in solute transport, cell shape, and communication between cells and the environment. In mammalian cells and yeast, the plasma membrane has been shown to be compartmented into so-called lipid rafts, which are defined by their resistance to treatment with non-ionic detergents. In plants, the existence of lipid rafts has been postulated, but the precise composition of this membrane compartment is still under debate. Here we were able to experimentally clearly distinguish (i) true sterol-dependent "raft proteins" and (ii) sterol-independent "non-raft" proteins and co-purifying "contaminants" in plant detergent-resistant membranes. We used quantitative proteomics techniques involving (15)N metabolic labeling and specific disruption of sterol-rich membrane domains by methyl-beta-cyclodextrin. Among the sterol-dependent proteins we found an over-representation of glycosylphosphatidylinositol-anchored proteins. A large fraction of these proteins has functions in cell wall anchoring. We were able to distinguish constant and variable components of plant sterol-rich membrane microdomains based on their responsiveness to the drug methyl-beta-cyclodextrin. Predominantly proteins with signaling functions, such as receptor kinases, G-proteins, and calcium signaling proteins, were identified as variable members in plant lipid rafts, whereas cell wall-related proteins and specific proteins with unknown functions make up a core set of sterol-dependent plant plasma membrane proteins. This allows the plant to maintain a balance between static anchoring of cell shape forming elements and variable adjustment to changing external conditions.


An SRRC elliptically polarizing undulator prototype to examine mechanical design feasibility and magnetic field performance.
In this work, a 1 m long Sasaki-type elliptically polarizing undulator (EPU) prototype with 5.6 cm period length is used to examine the mechanical design feasibility as well as magnetic field performance. The magnetic field characteristics of the EPU5.6 prototype at various phase shifts and gap motion are described. The field errors from mechanical tolerances, magnet block errors, end field effects and phase/gap motion effects are analysed. The procedures related to correcting the field with the block position tuning, iron shimming and the trim blocks at both ends are outlined.


Continuous vs discontinuous enteral nutrition: compared effects on serum lipids and lipoproteins in humans.
The present study was designed to assess the cholesterol-lowering effect of enteral nutrition when administered either as discontinuous or as continuous infusion. Twelve neurologic patients were randomly assigned to receive exclusive continuous (n = 6) or discontinuous (n = 6) enteral feeding for 7 days. Serum lipids, apoproteins, and 24-hour urinary C-peptide concentrations were determined on days 0 and 7. The fall during continuous nutrition was significantly greater than that during discontinuous nutrition for serum cholesterol (14% vs 2.4%; p < .05), low-density lipoprotein cholesterol (17.4% vs 3.9%; p = .02), and apoprotein B (19% vs 0.2%; p < .05) concentrations. Mean 24-hour urinary C-peptide excretion increase was significantly greater (p < .05) during discontinuous (78%) than during continuous enteral nutrition (15.6%). These results suggest that the cholesterol-lowering effect of enteral nutrition was induced mainly by the continuous delivery of the nutrients and was related to changes in insulin secretion.


Reexpansion of atelectasis caused by use of continuous positive airway pressure (CPAP) before radiation therapy (RT).
Although radiation therapy (RT) is an effective treatment for malignant atelectasis, its accurate delivery is challenging because of difficulty differentiating between tumor and atelectatic lung. Furthermore, reexpansion of lung during treatment repositions tumor and normal structures necessitating replanning to ensure treatment accuracy. Facilitating lung reexpansion before initiation of RT may improve RT treatment accuracy, spare normal tissue, and reduce obstructive symptoms. We report a case of reexpansion of right upper lobe (RUL) atelectasis caused by use of continuous positive airway pressure (CPAP) before RT. A 52-year-old woman presented with dyspnea and cough. Imaging studies showed an RUL mass with atelectasis. Bronchoscopy showed extrinsic compression of the RUL and middle lobe bronchi. Biopsy showed small cell lung cancer. Staging with positron emission tomography-computed tomography (CT) and contrast enhanced CT of brain showed no other disease. Following 4 cycles of platinum-based chemotherapy, CT imaging showed a decrease in tumor volume, but persistent RUL atelectasis. She agreed to participate in an institutional study to evaluate the use of CPAP to reduce respiratory motion and immobilize tumors during RT. During CPAP training, she complained of vertigo, headache, and weakness and refused simulation. The next day she reported less dyspnea and completed training and CT simulation without difficulty. CT simulation with CPAP showed reexpansion of the RUL. Lung volume increased from 2170 to 3767 mL (74 %). Gross tumor volume, clinical volume, and planning volume decreased 46%, 45%, and 38%, respectively. Mean lung dose and mean heart dose decreased 20% and 51%, respectively. CPAP was used daily for 1 hour before and during treatment. Cone beam CT scans showed that the RUL remained inflated throughout treatment. This is the first reported use of CPAP for reexpansion of atelectasis before RT planning and treatment. Reexpansion of atelectasis improved RT planning, decreased dose to uninvolved lung, and removed the need for replanning. Further study of CPAP as an initial intervention to improve RT delivery in patients with malignant atelectasis is warranted.


Assessment of adherence to the CONSORT statement for quality of reports on randomized controlled trial abstracts from four high-impact general medical journals.
The extended Consolidated Standards of Reporting Trials (CONSORT) Statement for Abstracts was developed to improve the quality of reports of randomized controlled trials (RCTs) because readers often base their assessment of a trial solely on the abstract. To date, few data exist regarding whether it has achieved this goal. We evaluated the extent of adherence to the CONSORT for Abstract statement for quality of reports on RCT abstracts by four high-impact general medical journals. A descriptive analysis of published RCT abstracts in The New England Journal of Medicine (NEJM), The Lancet, The Journal of American Medical Association (JAMA), and the British Medical Journal (BMJ) in the year 2010 was conducted by two reviewers, independently extracting data from a MEDLINE/PubMed search. We identified 271 potential RCT abstracts meeting our inclusion criteria. More than half of the abstracts identified the study as randomized in the title (58.7%; 159/271), reported the specific objective/hypothesis (72.7%; 197/271), described participant eligibility criteria with settings for data collection (60.9%; 165/271), detailed the interventions for both groups (90.8%; 246/271), and clearly defined the primary outcome (94.8%; 257/271). However, the methodological quality domains were inadequately reported: allocation concealment (11.8%; 32/271) and details of blinding (21.0%; 57/271). Reporting the primary outcome results for each group was done in 84.1% (228/271). Almost all of the abstracts reported trial registration (99.3%; 269/271), whereas reports of funding and of harm or side effects from the interventions were found in only 47.6% (129/271) and 42.8% (116/271) of the abstracts, respectively. These findings show inconsistencies and non-adherence to the CONSORT for abstract guidelines, especially in the methodological quality domains. Improvements in the quality of RCT reports can be expected by adhering to existing standards and guidelines as expressed by the CONSORT group.


The binocular distance: a new way to estimate fetal age.
Fetal ocular biometry has been previously established and reported. The purpose of this communication is to report an equation to predict fetal age from the binocular distance. The error of the estimation is also reported. The potential value of this measurement is illustrated in a case of thanatophoric dysplasia.


[N-acetylcysteine inhibits the proliferation of hydrogen peroxide treated fibroblast-like synoviocytes in rats with adjuvant arthritis (AA) via blocking Nrf2/Keap1 pathway].
Objective To investigate the effect of N-acetylcysteine (NAC) on the proliferation of fibroblast-like synoviocytes (FLS) treated with low concentration of hydrogen peroxide (H2O2) in rats with adjuvant arthritis (AA) and its mechanism. Methods Twenty SD rats were divided into a normal group and a model group (10 rats in each group). The model group was established by subcutaneous injection of Freund's complete adjuvant into the toe of rats, and the rats were sacrificed 28 days later. The contents of serum malondialdehyde (MDA) were detected by thiobarbituric acid method; the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined by hydroxylamine method and colorimetry respectively; and Nrf2 and Keap1 proteins in ankle synovial tissues of AA rats were detected by immunohistochemistry. AA-FLS were isolated, cultured, and identified by digestion of ankle joint slides of AA rats in vitro. The effects of NAC at different concentrations (final concentration 0, 0.3, 0.9, 3, 10, 30, 90, 180 μmol/L) on the activity of AA-FLS treated with H2O2 at low concentration (5 μmol/L) were detected by CCK-8 assay. The content of mitochondrial reactive oxygen species (ROS) in AA-FLS was detected by MitoSOX fluorescent probe. The effects of NAC (final concentration 0, 3, 10, 30 μmol/L) on Nrf2 and Keap1 protein expressions in AA-FLS treated with H2O2 at low concentration were detected by Western blotting. Results Compared with those in the control group, in AA model, the MDA level increased and SOD and GSH-Px levels decreased in serum, and the Nrf2 protein increased and the Keap1 protein decreased in synovial tissue. Immunocytochemical staining confirmed that the isolated and cultured cells were AA-FLS; NAC inhibited the proliferation of AA-FLS treated with H2O2 in a concentration-dependent manner, and the mitochondrial ROS content and the protein expressions of Nrf2 and Keap1 decreased. Conclusion NAC can inhibit the proliferation of AA-FLS treated with H2O2, which may be related to blocking Nrf2/Keap1 pathway.


[Tissue plasminogen activator and inhibitor and the severity and extensiveness of vascular lesions in peripheral atherosclerosis of the legs].
The aim of work was to study whether activity and antigen level of tissue plasminogen activator (t-PA) and activity of plasminogen activator inhibitor (PAI-1) were related to severity and extensiveness of vascular lesions in peripheral obliterative atherosclerotic disease (POAD). The study group consisted of 25 patients in II (13), III (10) and IV (2) degrees of disease acc. to Fontaine'a. In the blood t-PA activity and antigen and activity of PAI-1 were determined. In the patients with more severe POAD higher t-PA antigen and increased t-PA complexed with PAI-1 were observed. In patients with unisegmental POAD twice t-PA activity than in patients with polysegmental atherosclerotic lesions was detected.


The detection of small airways disease.
In order to investigate the relationship between pulmonary function and disease of the membranous and respiratory bronchioles, we studied 96 patients who required lobectomy for removal of a solitary pulmonary nodule. A subgroup of patients with forced expiratory volume in one second (FEV1) greater than 80% predicted were further analyzed to determine if abnormalities in tests designed to detect peripheral airways disease actually correlated with the pathology found in these airways. Analysis of the data shows that inflammation in both respiratory and membranous bronchioles, goblet cell metaplasia of the epithelium in membranous bronchioles, and decreasing muscle in the respiratory bronchioles are the pathologic features that are associated with deterioration of the FEV1. When the FEV1 is greater than 80% of the predicted value, inflammation of the respiratory bronchioles and fibrosis of both membranous and respiratory bronchioles increase with decreasing FEV1. Tests of specialized pulmonary function appear to correlate with epithelial pathologic parameters of membraneous bronchioles and inflammation and fibrosis of respiratory bronchioles. When patients with FEV1 greater than 80% predicted were subdivided according to the number of abnormal tests of small airways function, there was a significant increase in inflammation of the walls of respiratory bronchioles when 2 tests were abnormal and increases in both airway wall and intralumenal inflammatory cells as well as increased wall fibrosis when 3 tests were abnormal. We conclude that when the FEV1 is greater than 80% predicted, abnormalities in the tests for small airway disease reflect pathologic changes in the respiratory bronchioles.


Temporal association between serum gelsolin levels and clinical events in a patient with severe falciparum malaria.
Actin is present in high concentrations in most eukaryotic cells and can polymerize into filaments under physiological buffer conditions. As a result of tissue injury and cell lysis, large quantities of actin are released locally and may obstruct the downstream microvasculature, causing further damage to already injured organs. It has been postulated that this mechanism contributes to the development of the adult respiratory distress syndrome and to the diverse complications of falciparum malaria. Actin scavenging proteins--e.g., gelsolin--counteract the effects of extracellular actin, but the capacity of these plasma proteins can be overwhelmed by massive tissue injury. We examined the temporal relationship between serum levels of gelsolin (and tumor necrosis factor-alpha) and the clinical findings for a patient with severe falciparum malaria. The level of gelsolin decreased and then increased as the patient's status first worsened and then improved. We could not determine whether gelsolin served a biologically important function in this patient's recovery or was simply an epiphenomenon of disease activity. Gelsolin levels may be an early prognostic indicator in patients with a systemic inflammatory response syndrome. Moreover, the potential therapeutic role of recombinant human plasma gelsolin in patients with delayed organ dysfunction that commonly follows a self-limited initial insult merits investigation.


Past and present concepts in flow cytometry: a European perspective.
The development of flow cytometric instrumentation, methods and research concepts in Europe has been a continuous driving force for the general scientific advancement in this area over the years. This review addresses early European concepts of continuing interest with regard to instrumentation, data analysis, clinical and eperimental DNA analysis, cell function and microbiology at their worldwide first appearence while flow cytometric immunology and immunophenotyping will be covered separately. Flow cytometry represents an efficient approach to the enormous complexity of molecular cell architecture and cell function by the analysis of apparent molecular cell phenotypes in heterogeneous cell samples. The present merger of flow and image cytometry into the method independent cytomics discipline increases the potential of cell analysis very significantly. It opens the way for predictive medicine as well as for predictive cytopathology and predictive cytology in everyday clinical and medical practice. Current progress is driven by joint advances in molecular fluorescence technologies and instrument development. This complements the analysis of genome sequence information in an efficient way.


Discovery of Novel Small-Molecule Scaffolds for the Inhibition and Activation of WIP1 Phosphatase from a RapidFire Mass Spectrometry High-Throughput Screen.
Wild-type P53-induced phosphatase 1 (WIP1), also known as PPM1D or PP2Cδ, is a serine/threonine protein phosphatase induced by P53 after genotoxic stress. WIP1 inhibition has been proposed as a therapeutic strategy for P53 wild-type cancers in which it is overexpressed, but this approach would be ineffective in P53-negative cancers. Furthermore, there are several cancers with mutated P53 where WIP1 acts as a tumor suppressor. Therefore, activating WIP1 phosphatase might also be a therapeutic strategy, depending on the P53 status. To date, no specific, potent WIP1 inhibitors with appropriate pharmacokinetic properties have been reported, nor have WIP1-specific activators. Here, we report the discovery of new WIP1 modulators from a high-throughput screen (HTS) using previously described orthogonal biochemical assays suitable for identifying both inhibitors and activators. The primary HTS was performed against a library of 102 277 compounds at a single concentration using a RapidFire mass spectrometry assay. Hits were further evaluated over a range of 11 concentrations with both the RapidFire MS assay and an orthogonal fluorescence-based assay. Further biophysical, biochemical, and cell-based studies of confirmed hits revealed a WIP1 activator and two inhibitors, one competitive and one uncompetitive. These new scaffolds are prime candidates for optimization which might enable inhibitors with improved pharmacokinetics and a first-in-class WIP1 activator.


Survival after a nationwide introduction of robotic surgery in women with early-stage endometrial cancer: a population-based prospective cohort study.
The purpose of the study was to evaluate the association between a nationwide introduction of robotic minimally invasive surgery (RMIS) and survival in women with early-stage endometrial cancer. Prospective data on consecutive women with early-stage endometrial cancer who underwent surgery during January 2005 to June 2015 in Denmark were identified in the nationwide Danish Gynaecological Cancer Database. Data were linked with national registries regarding comorbidity, education, income and death. The cohort was divided according to the time they underwent surgery: Group 1 before RMIS introduction in their respective region and Group 2 after RMIS introduction. Five-year overall survival was compared by multivariate Cox proportional hazards models stratified by histopathological risk between Groups 1 and 2 and between surgical modalities within Group 2: total abdominal hysterectomy (TAH), laparoscopic minimally invasive surgery (LMIS) and RMIS. Women in Group 1 (N = 3091) had significantly lower overall survival compared with those in Group 2 (N = 2563; hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.05-1.42). Age, smoking, socioeconomic status, American Society of Anaesthesiologists (ASA) score, comorbidity and histopathological risk influenced the overall survival. Following RMIS adoption, TAH was associated with higher mortality compared with LMIS and RMIS (HR, 1.42; 95% CI 1.02-1.97 and HR, 1.70; 95% CI 1.31-2.19 for LMIS and RMIS, respectively). There was no significant survival difference between RMIS and LMIS (HR, 1.19; 95% CI 0.85-1.68). The national introduction of robotic surgery for early-stage endometrial cancer was associated with improved survival irrespective of age, body mass index, ASA score, comorbidity, smoking, socioeconomic status and histopathological risk.


Inhibition of histone deacetylation enhances endotoxin-stimulated transcription but does not reverse endotoxin tolerance.
Covalent modification of histones and the subsequent remodeling of chromatin have emerged as important mechanisms in regulating gene expression. In particular, recent identification of the enzyme families responsible for the steady-state balance of histone acetylation has served to redefine our understanding of these modifications as fundamental biochemical processes regulating transcription. Current evidence suggests that histone acetylation correlates positively with gene activation, while histone deacetylation acts to repress transcription. In this study, we examined the role of histone modification in the inflammatory response to endotoxin. We focused on the endotoxin-stimulated expression of the interleukin-1beta promoter and tested the hypotheses that persistent histone deacetylation was responsible for the decreased expression of this promoter observed after prolonged exposure to endotoxin, a manifestation of a phenomenon known as endotoxin tolerance. We found that histone deacetylase inhibitors enhanced endotoxin-stimulated transcription; however, deacetylation inhibitors could neither block the development of tolerance nor restore endotoxin sensitivity in a tolerant cell. Deacetylase inhibitors could not restore LPS-mediated transcription in tolerant cells. These results show that histone acetylation/deacetylation regulates, at least in part, the endotoxin-induced expression of inflammatory genes and that repressed transcription observed in endotoxin tolerance is not caused by enhanced activity of histone deacetylases.


Analysis of LaCrosse virus S mRNA 5' termini in infected mosquito cells and Aedes triseriatus mosquitoes.
Nucleotide sequences were determined for the 5' termini of La Crosse virus (LAC) S segment mRNA from persistently infected mosquito cell cultures (C6/36 from Aedes albopictus) and embryos (Aedes triseriatus). LAC primes transcription of its mRNA with "scavenged" 5' caps and adjacent oligonucleotides from host mRNAs, and these non-virus-encoded 5'-terminal extensions are heterogeneous in infected mammalian cells. The nature of mosquito host-derived primers has not been previously investigated. During early C6/36 cell infection, LAC mRNA 5'-terminal sequences were heterogeneous, but variability decreased as infection persisted. One predominant sequence, 5' CCACTCGCCACT (sequence 1), was observed throughout C6/36 cell infection but was more prevalent after 15 days postinfection. This LAC mRNA 5'-terminal sequence comprised 81% of the scavenged host oligonucleotides from vertically infected A. triseriatus eggs during embryogenesis. As these embryos progressed in the dormant overwintering stage (diapause), the predominant scavenged sequence became 5' AGGAAAAGATGGT (sequence 2), and sequence 1 became less prevalent. As the eggs emerged from diapause, the LAC mRNA 5' termini were more variable; 33% had sequence 1, and the remainder were heterogeneous. In post-diapausing eggs, 100% of viral mRNAs had sequence 1 at their 5' termini. Molecular analyses thus revealed continuous but selective LAC cap scavenging during persistent C6/36 cell infection and during embryogenesis and diapause in A. triseriatus eggs. The variety of host-derived sequences was limited in both biosynthetically active (embryonating) and dormant (diapausing) eggs.


[Basic principles of epidemiological studies of epilepsy].
Until recently there were few epidemiological studies of epilepsy. This was probably due to lack of knowledge of concepts of epidemiology and lack of common criteria for the design of investigations. Fortunately, in recent years many studies have been published in both developed and undeveloped countries, in different age groups and dealing with all aspects of epilepsy. We wish to describe the main concepts of neuroepidemiology and methods of epidemiological measurements as applied to epilepsy. We describe the criteria for planning an epidemiological study including concept of the problem, selection of the model and methods and finally treatment of the data and interpretation of the results. We analyze the sample being studied and its variables. We define the concepts of clinical trial, field trial, transverse studies, sampling, study of cohorts, case control, metanalysis, sensitivity and specificity of a test. We quote the definitions and basic criteria of the International League against Epilepsy when beginning an epidemiological study of epilepsy. Finally, we review the most recent epidemiological studies, with particular emphasis on those carried out in our setting. Epidemiological studies are fundamental to the establishment of conclusions and advances in the investigation of epilepsy. The support of an epidemiologist is essential.


Two G-box-like elements essential to high gene expression of SlAKR4B in tomato leaves.
Aldo-keto reductases (AKRs) play important roles in aldehyde detoxification as well as primary and secondary metabolism in plants. We previously reported inducible expression of a Solanum lycopersicum AKR4B (SlAKR4B) in tomato leaves treated with salicylic acid and jasmonic acid, and high promoter activity of SlAKR4B in tomato leaf protoplasts. In this study, we investigated the expression response of SlAKR4B in the tomato leaves with infiltration treatment and the cis-element(s) involved in high promoter activity. Gene expression analysis in tomato leaf protoplasts and buffer-infiltrated tomato leaves suggested that cell damage caused the increased expression of SlAKR4B. Promoter activity of SlAKR4B was significantly reduced by mutation of two G-box like elements. It is suggested that the two G-box like elements are responsible for the high promoter activity.


Telemedicine in northern Norway.
The University Hospital of Tromsø has been involved in a variety of telemedicine activities since the late 1980s, including teleradiology, telepathology, teledermatology, remote endoscopy, remote gastroscopy, teleechocardiography, transmission of electrocardiograms, telepsychiatry, electronic delivery of laboratory results and distance learning for health professionals. Since 1993 the department of telemedicine in Tromsø has been designated the national centre of competence in telemedicine. With a wealth of experience to draw from, a critical number of health-care professionals exposed to and using telemedicine routinely, the support of the Norwegian health authoriues, a national centre guiding telemedicine research, no licensing barriers within the country, nationwide ISDN and reimbursement for telemedicine services, the future of telemedicine in Norway looks promising.


Grain Boundary Structures and Collective Dynamics of Inversion Domains in Binary Two-Dimensional Materials.
Understanding and controlling the properties and dynamics of topological defects is a lasting challenge in the study of two-dimensional materials, and is crucial to achieve high-quality films required for technological applications. Here grain boundary structures, energies, and dynamics of binary two-dimensional materials are investigated through the development of a phase field crystal model that is parametrized to match the ordering, symmetry, energy, and length scales of hexagonal boron nitride. Our studies reveal some new dislocation core structures for various symmetrically and asymmetrically tilted grain boundaries, in addition to those obtained in previous experiments and first-principles calculations. We also identify a defect-mediated growth dynamics for inversion domains governed by the collective atomic migration and defect core transformation at grain boundaries and junctions, a process that is related to inversion symmetry breaking in binary lattice.


Isothermal flame balls: effect of autocatalyst decay.
The steady, spherically symmetric solutions to the reaction-diffusion equations based on a simple autocatalytic reaction followed by the decay of the autocatalyst are considered. Three parameters-the orders with respect to the autocatalyst in the autocatalysis p and in the decay q and the rate of decay of the autocatalyst relative to its autocatalytic production K-determine the steady concentration profiles. Numerical integrations for a fixed value of the order of the autocatalyst show that the concentration profiles have different forms depending on whether q<p or q>/=p. In the former case, there is a critical decay rate K(crit) for solutions to exist, with multiple solutions for K<K(crit). In the latter case, there is a single solution for each value of K. This difference in the nature of the solution is confirmed by an analysis for p large. The temporal stability of the isothermal flame balls is examined, with temporally stable solutions being possible, provided that the ratio of the diffusion coefficient of the autocatalyst to that of the reactant is sufficiently small. The change in stability appears only when there are multiple solutions and is through a subcritical Hopf bifurcation.


Cardiac Troponin T and I Release After a 30-km Run.
Prolonged endurance-type exercise is associated with elevated cardiac troponin (cTn) levels in asymptomatic recreational athletes. It is unclear whether exercise-induced cTn release mirrors a physiological or pathological underlying process. The aim of this study was to provide a direct comparison of the release kinetics of high-sensitivity cTnI (hs-cTnI) and T (hs-cTnT) after endurance-type exercise. In addition, the effect of remote ischemic preconditioning (RIPC), a cardioprotective strategy that limits ischemia-reperfusion injury, was investigated in a randomized controlled crossover manner. Twenty-five healthy volunteers completed an outdoor 30-km running trial preceded by RIPC (4 × 5 min 220 mm Hg unilateral occlusion) or control intervention. hs-cTnT, hs-cTnI, and sensitive cTnI (s-cTnI) concentrations were examined before, immediately after, 2 and 5 hours after the trial. The completion of a 30-km run resulted in a significant increase in circulating cTn (time: all p <0.001), with maximum hs-cTnT, hs-cTnI, and s-cTnI levels of 47 ± 27, 69 ± 62, and 82 ± 64 ng/L (mean ± SD), respectively. Maximum hs-cTnT concentrations were measured in 60% of the participants at 2 hours after exercise, compared with maximum hs-cTnI and s-cTnI concentrations at 5 hours in 84% and 80% of the participants. Application of an RIPC stimulus did not reduce exercise-induced cTn release (time × trial: all p >0.5). In conclusion, in contrast to acute myocardial infarction, maximum hs-cTnT levels after exercise precede maximum hs-cTnI levels. Distinct release kinetics of hs-cTnT and hs-cTnI and the absence of an effect of RIPC favors the concept that exercise-induced cTn release may be mechanistically distinct from cTn release in acute myocardial infarction.


Strategies to improve the efficiency and quality of mutant breeding using heavy-ion beam irradiation.
Heavy-ion beam irradiation (HIBI) is useful for generating new germplasm in plants and microorganisms due to its ability to induce high mutagenesis rate, broad mutagenesis spectrum, and excellent stability of mutants. However, due to the random mutagenesis and associated mutant breeding modalities, it is imperative to improve HIBI-based mutant breeding efficiency and quality. This review discusses and summarizes the findings of existing theoretical and technical studies and presents a set of tandem strategies to enable efficient and high-quality HIBI-based mutant breeding practices. These strategies: adjust the mutation-inducing techniques, regulate cellular response states, formulate high-throughput screening schemes, and apply the generated superior genetic elements to genetic engineering approaches, thereby, improving the implications and expanding the scope of HIBI-based mutant breeding. These strategies aim to improve the mutagenesis rate, screening efficiency, and utilization of positive mutations. Here, we propose a model based on the integration of these strategies that would leverage the advantages of HIBI while compensating for its present shortcomings. Owing to the unique advantages of HIBI in creating high-quality genetic resources, we believe this review will contribute toward improving HIBI-based breeding.


Random-Phase Approximation Methods.
Random-phase approximation (RPA) methods are rapidly emerging as cost-effective validation tools for semilocal density functional computations. We present the theoretical background of RPA in an intuitive rather than formal fashion, focusing on the physical picture of screening and simple diagrammatic analysis. A new decomposition of the RPA correlation energy into plasmonic modes leads to an appealing visualization of electron correlation in terms of charge density fluctuations. Recent developments in the areas of beyond-RPA methods, RPA correlation potentials, and efficient algorithms for RPA energy and property calculations are reviewed. The ability of RPA to approximately capture static correlation in molecules is quantified by an analysis of RPA natural occupation numbers. We illustrate the use of RPA methods in applications to small-gap systems such as open-shell d- and f-element compounds, radicals, and weakly bound complexes, where semilocal density functional results exhibit strong functional dependence.


Suggested diagnostic reference levels for paediatric X-ray examinations in India.
Exposure of children to ionising radiation is considered to carry higher risk than that of adults; therefore a need to suggest diagnostic reference levels (DRLs) for the common paediatric diagnostic X-ray procedures was recognised for the X-ray machines meeting the requirements of the recently implemented Safety Code for Medical Diagnostic X-ray Equipment and Installations in India. Measurements were carried out for entrance surface air kerma (free in air) in conventional paediatric X-ray diagnostic examinations among four age groups: <1, 1-4, 5-9 and 10-15 y. A total of 2240 air kerma measurements at different fixed focus to skin distances were studied for 7 paediatric diagnostic examinations with 11 different projections on 62 X-ray machines installed in 22 selected hospitals in the country. The third quartile values of air kerma per paediatric examination for the age group of 5-9 y were considered as values of paediatric DRLs. The suggested values of DRLs are 0.2 mGy for chest AP/PA, 0.3 mGy for chest LAT, 0.7 mGy for lumber spine AP, 1.3 mGy for lumber spine LAT, 0.3 mGy for thoracic spine AP, 0.6 mGy for thoracic spine LAT, 0.5 mGy for abdomen AP, 0.7 mGy for pelvis AP, 0.6 mGy for skull PA, 0.5 mGy for skull LAT and 0.8 mGy for hip joints AP.


Cancer-associated serum globulin demonstrated by polyacrylamide gel electrophoresis.
We evaluated the ability of polyacrylamide gel electrophoresis (PAGE) to measure protein band No. 1 (PB1) in serum as a means of discriminating between the sera of cancer patients and controls. Serum samples from 123 cancer patients, 155 subjects without clinically diagnosed cancer, and 6 members of families with a high incidence of cancer (total, 284) were obtained in Israel. An additional 214 serum samples from 80 cancer patients and 134 subjects without cancer were obtained from the Mayo Clinic-National Cancer Institute Serum Bank. Although a significantly higher proportion of serum specimens from cancer patients had positive results for PB1 by the PAGE method, the test at its current stage of development does not seem sufficiently discriminating for use in screening for cancer.


Diffusing capacity dependent on lung volume and age in normal subjects.
In this study we determined reference values of total diffusing capacity of carbon monoxide (DLCO) and DLCO per liter alveolar volume (DLCO/VA) at total lung capacity (TLC) and at lung volumes below TLC in sitting position. In 55 healthy nonsmoking volunteers (20-85 yr old), we determined reference values at TLC level in which age was the only parameter. In a subgroup (n = 16) these references did not change by correction for normal variability in hemoglobin concentration. In all volunteers DLCO decreased and DLCO/VA increased with decreasing VA. The increase in DLCO/VA was linear and less in older subjects. We derived equations to calculate reference values of DLCO/VA for lung volumes at and below TLC with two methods: 1) "random coefficients linear" model, which calculates the reference values directly, and 2) a conversion method, which calculates DLCO/VA for lower VA levels from reference values at TLC. An advantage of the conversion method is the suitability of DLCO/VA reference values at TLC of other populations. A disadvantage is the greater standard deviation of these reference values compared with those obtained by the random coefficients linear method. DLCO can be found by multiplying DLCO/VA with VA.


PIM1: a promising target in patients with triple-negative breast cancer.
Triple-negative breast cancers (TNBCs) have poor prognosis, and chemotherapy remains the mainstay of therapy because of lack of discovered possible target. MYC were found overexpressed in TNBCs compared with other subtypes and especially in those resistant to chemotherapy, but the inhibition has been challenging to achieve. Recently, the cooperation of PIM1 and MYC was identified involved in cell proliferation, migration and apoptosis of TNBCs, which has been reported in hematological malignancy and prostatic cancer. Inhibition of PIM1 can promote the apoptosis of tumor cells and enhance sensitivity to chemotherapy. Notably, PIM1-null mice develop normally and are fertile, suggesting the side effects can be tolerated. Thus, PIM1 may be a promising target in TNBCs and further investigation, both in vivo and in vitro, needs to be carried out.


Immune response and safety of inactivated SARS-CoV-2 vaccines during pregnancy: a real-world observational study.
As pregnant women are excluded from clinical trials of inactivated SARS-CoV-2 vaccines, it is important to assess the immune response in women receiving the vaccination while unknowingly pregnant. In a multicenter cross-sectional study, we enrolled 873 pregnant women aged 18-45 years. Serum antibody levels induced by inactivated vaccines were determined. Adverse events were collected by self-reported survey after vaccination. Logistic regression model and restricted cubic spline model were used to investigate the association of factors with antibody positivity. As the doses of the vaccine increase, neutralizing antibody (NAb) positivity was 98.3%, 39.5%, and 9.5% in pregnant women, respectively. The dose of vaccine and duration since vaccination were associated with NAb positivity. The OR of two and three doses of vaccines were 7.20 and 458.33 (P < 0.05). NAb levels and duration since vaccination showed a linear relationship in pregnant women vaccinated two doses, with a decrease to a near seropositivity threshold at 22 weeks. Adverse events were mainly mild or moderate after vaccinated during pregnancy, with no increase in incidence compared with whom vaccinated during pre-pregnancy. The use of inactivated vaccines during pregnancy induced favorable immune persistence, and the incidence of adverse events did not increase.


Static load test performance of a telescoping structure for an automatically deployable ROPS.
The automatically deployable ROPS was developed as part of an innovative project to provide passive protection against overturn fatality to operators of new tractors used in both low-clearance and unrestricted-clearance tasks. The primary objective of this phase of the research was to build a telescoping structure that would prove that a ROPS can be built that will (1) reliably deploy on signal, (2) rise in a sufficiently short amount of time, (3) firmly latch in its deployed position, and (4) satisfy SAE J2194 testing requirements. The two-post structure had previously been found to meet deployment time criteria, and design analyses indicated that neither the slip-fit joint nor the latch pins would fail at test loading. Four directions of static loading were applied to the structure to satisfy SAE requirements. For the series of static loading tests, the raised structure was found to maintain a protective clearance zone after all loads were applied. The structure is overly stiff and should be redesigned to increase its ability to absorb ground-impact energy. Results of dynamic tests and field upset tests are reported in companion articles. The next phase of development is to optimize the structure so that it will plastically deform and absorb energy that would otherwise be transferred to the tractor chassis.


Development of the computerized dental cast form analyzing system--three dimensional diagnosis of dental arch form and the investigation of measuring condition.
To analyze the functional and morphological harmonies of the tooth and dental arch, a computerized system to measure a dental cast and to detect the apex of dental cusps and angle points of incisors was developed. Detailed morphology in the measured dental cast could be displayed distinctively by computer graphics (CG) with a surface model. Accuracy in determining the position of the apex of the dental cusp was examined by increasing the measuring pitch from 50 microns to 400 microns, the error increased gradually with increased measuring pitch. Taking the measuring error, the time for measurement and the memory size for analysis into account, a measuring pitch of 200 microns was determined to be reasonable. Three-dimensional data measurements from the apex of the dental cusp in molar, and the mesial and distal angles in canine and incisor were fitted to a polynomial formula. In the present measured model, the 4th order polynomial formula was used for the dental arch, and the 2nd order polynomial formula was used for the anteroposterior and lateral occlusal curves. These formulae could be simultaneously superimposed on the surface model of the dental cast, and displayed using CG.


Targeting of cholera toxin A (ctxA) gene by zinc finger nuclease: pitfalls of using gene editing tools in prokaryotes.
The study was launched to use zinc finger nuclease (ZFN) technology to disrupt the cholera toxin gene (ctxA) for inhibiting CT toxin production in Vibrio cholera (V. cholera). An engineered ZFN was designed to target the catalytic site of the ctxA gene. The coding sequence of ZFN was cloned to pKD46, pTZ57R T/A vector, and E2-crimson plasmid and transformed to Escherichia coli (E. coli) Top10 and V. cholera. The efficiency of ZFN was evaluated by colony counting. No expression was observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blotting in transformed E. coli. The ctxA gene sequencing did not show any mutation. Polymerase chain reaction on pKD46-ZFN plasmid had negative results. Transformation of E. coli Top10 with T/A vectors containing whole ZFN sequence led to 7 colonies all of which contained bacteria with self-ligated vector. Transformation with left array ZFN led to 24 colonies of which 6 contained bacteria with self-ligated vector and 18 of them contained bacteria with vector/left array. Transformation of V. cholera with E2-crimson vectors containing whole ZFN did not produce any colonies. Transformation with left array vectors led to 17 colonies containing bacteria with vector/left array. Left array protein band was captured using western blot assay. ZFN might have off target on bacterial genome causing lethal double-strand DNA break due to lack of non-homologous end joining (NHEJ) mechanism. It is recommended to develop ZFNs against bacterial genes, engineered packaging host with NHEJ repair system is essential.


Exercise training modifies the bone and endocrine response to graded reductions in energy availability in skeletally mature female rodents.
Reductions in energy availability leading to weight loss can induce loss of bone and impact important endocrine regulators of bone integrity. We sought to elucidate whether endurance exercise (EX) can mitigate bone loss observed in sedentary (SED) skeletally mature rodents subjected to graded energy deficits. Female virgin rats (n=84, 5-mo-old; 12/group) were randomized to baseline controls and either sedentary (SED) or exercise (EX) conditions, and within each exercise status to adlib-fed (ADLIB), or moderate (MOD) or severe (SEV) energy restriction diets for 12 weeks. Rats assigned to EX groups performed treadmill running to increase weekly energy expenditure by 10%. MOD-ER-SED, SEV-ER-SED, MOD-ER-EX and SEV-ER-EX were fed modified AIN93M diets with 20%, 40% 10%, and 30% less energy content, respectively, with 100% of all other nutrients provided. Energy availability (EA) was effectively reduced by ~14% and ~30% in the MOD-ER and SEV-ER groups, respectively. MOD-ER for 12 weeks resulted in few negative impacts on bone and, except for serum leptin in MOD-ER-SED rats, no significant changes in endocrine factors. By contrast, SEV-ER in SED rats resulted in significantly lower total body and femoral neck bone mass, and reduced serum estradiol, IGF-1 and leptin. EX rats experiencing the same reduction in energy availability as SEV-ER-SED exhibited higher total body mass, lean mass, total BMC, and higher serum IGF-1 at the end of 12 weeks. Bone mechanical properties at 3 bone sites (mid-femur, distal femur, femoral neck) were minimally impacted by ER but positively affected by EX. These findings indicate that combining increased EX energy expenditure with smaller reductions in energy intake to achieve a targeted reduction in EA provides some protection against loss of bone mass and lean mass in skeletally mature female rats, likely due to better preservation of circulating IGF-1, and that bone mechanical integrity is not significantly degraded with either moderate or severe reduced EA.


Genetic deficiency of GABA differentially regulates respiratory and non-respiratory motor neuron development.
Central nervous system GABAergic and glycinergic synaptic activity switches from postsynaptic excitation to inhibition during the stage when motor neuron numbers are being reduced, and when synaptic connections are being established onto and by motor neurons. In mice this occurs between embryonic (E) day 13 and birth (postnatal day 0). Our previous work on mice lacking glycinergic transmission suggested that altered motor neuron activity levels correspondingly regulated motor neuron survival and muscle innervation for all respiratory and non respiratory motor neuron pools, during this period of development [1]. To determine if GABAergic transmission plays a similar role, we quantified motor neuron number and the extent of muscle innervation in four distinct regions of the brain stem and spinal cord; hypoglossal, phrenic, brachial and lumbar motor pools, in mice lacking the enzyme GAD67. These mice display a 90% drop in CNS GABA levels ( [2]; this study). For respiratory-based motor neurons (hypoglossal and phrenic motor pools), we have observed significant drops in motor neuron number (17% decline for hypoglossal and 23% decline for phrenic) and muscle innervations (55% decrease). By contrast for non-respiratory motor neurons of the brachial lateral motor column, we have observed an increase in motor neuron number (43% increase) and muscle innervations (99% increase); however for more caudally located motor neurons within the lumbar lateral motor column, we observed no change in either neuron number or muscle innervation. These results show in mice lacking physiological levels of GABA, there are distinct regional changes in motor neuron number and muscle innervation, which appear to be linked to their physiological function and to their rostral-caudal position within the developing spinal cord. Our results also suggest that for more caudal (lumbar) regions of the spinal cord, the effect of GABA is less influential on motor neuron development compared to that of glycine.


Cornea donation in Germany: Obtaining consent.
Tissue donation is important to reverse cornea-related blindness. Unfortunately, the willingness to make a decision concerning organ and tissue donation while still alive remains low despite all efforts. By analyzing anonymized archived data from 25 654 next-of-kin interviews from our database over a period of 5 years (2013-2018), it was found that only 20.8% of all potential cornea donors have declared their own wishes. While still alive, refusal was communicated more often than consent by potential donors. Overall consent rates were 39.2%, with parents and siblings consenting more often than other relatives and females refusing more often than male family members. Personal interviews and interviews via telephone handled by staff known to the family resulted in better consent rates (up to 75.6%) with male interviewers receiving higher consent rates in general. The gender of the approached relatives in relation to a male/female interviewer was of low importance. The results also show that it is important to allow discussion about that topic between family members-the more relatives that were involved the higher the probability of consent.


Positive identification of Newcastle disease virus vaccine strains and detection of contamination in vaccine batches by restriction site analysis of the matrix protein gene.
Twelve vaccine batches prepared from avirulent vaccine strains of Newcastle disease virus produced by seven manufacturers were identified by analysis of the matrix (M) protein gene with restriction enzymes MboI and HinfI. The analyses have revealed the presence of the strain indicated by the manufacturers (namely B-1, LaSota or Ulster 2C), except in one case when the vaccine contained strain V4 Queensland instead of VGGA as indicated. In addition, several batches of both monovalent and combined vaccines containing strain LaSota of the same company consistently disclosed contamination with strain B-1. The mixed nature of the preparations was verified not only by the dual patterns of restriction fragments but also by separating the two components and identifying them individually. Restriction analysis of the M gene, by allowing positive identification of each of the lentogenic vaccine strains, should provide an improvement in controlling vaccine batches by revealing homologous contaminants or exchange of the vaccine strain.


Striato-cortical connections in Parkinson's and Alzheimer's diseases: Relation to cognition.
Functional connectivity is abnormal in PD and in early Alzheimer's disease. The objective of this study was to evaluate resting-state striato-cortical connectivity in PD and Alzheimer's disease and assess their relation to cognitive outcomes. Groups with mild cognitive impairment as a result of different pathologies (PD vs. Alzheimer's disease) were also compared. Seed-based connectivity of the dorsal, middle, and ventral striatum was analyzed in 111 patients using functional MRI. The correlation between connectivity at regions of between-group differences and clinical outcomes was assessed. Patients showed lower striatal connectivity than controls. Connectivity between the middle (associative) striatum and precuneus negatively correlated with executive functions in PD and with memory performance in Alzheimer's disease. PD with cognitive impairment showed decreased connectivity of the dorsal (motor) striatum when compared with early Alzheimer's disease. Striatal connectivity was reduced in patients when compared with controls. Similar compensatory mechanisms were employed to overcome various cognitive deficits in PD and Alzheimer's disease. © 2017 International Parkinson and Movement Disorder Society.


Physical activity and gestational diabetes mellitus among Hispanic women.
Studies in predominantly non-Hispanic white populations have suggested that physical activity during pregnancy is associated with a reduced risk of gestational diabetes mellitus (GDM). There are few such studies in Hispanic women, a group at increased risk for GDM. We conducted a prospective cohort study of household/caregiving, occupational, sports/exercise, and active living habits and the risk of GDM among 1006 Hispanic (predominantly Puerto Rican) prenatal care patients in western Massachusetts from 2000 to 2004. Prepregnancy, early pregnancy, and midpregnancy physical activity was assessed using the Kaiser Physical Activity Survey. A total of 33 women (3.3%) were diagnosed with GDM, and 119 women (11.8%) were diagnosed with abnormal glucose tolerance. There were no significant associations between GDM risk and occupational and active living activities in prepregnancy, early pregnancy, and midpregnancy or with a change in levels of household/caregiving, occupational, and active living activities from prepregnancy to during pregnancy. However, after controlling for age and prepregnancy body mass index (BMI), women in the highest quartile of prepregnancy (OR = 0.2, 95% CI 0.1-0.8, p(trend) = 0.03) and midpregnancy (OR = 0.2, 95% CI 0.1-0.8, p(trend) = 0.004) household/caregiving activities as well as midpregnancy sports/exercise (0.1, 95% CI 0.0-0.7, p(trend) = 0.12) had a reduced risk of GDM compared with women in the lowest quartile. Findings in this Hispanic population, although based on small numbers of cases, are consistent with prior research among predominantly non-Hispanic white populations.


Detection of Multiple Potato Viruses in the Field Suggests Synergistic Interactions among Potato Viruses in Pakistan.
Viral diseases have been a major limiting factor threating sustainable potato (Solanum tuberosum L.) production in Pakistan. Surveys were conducted to serologically quantify the incidence of RNA viruses infecting potato; Potato virus X (PVX), Potato virus Y (PVY), Potato virus S (PVS), Potato virus A (PVA), Potato virus M (PVM) and Potato leaf roll virus (PLRV) in two major potato cultivars (Desiree and Cardinal). The results suggest the prevalence of multiple viruses in all surveyed areas with PVY, PVS and PVX dominantly widespread with infection levels of up to 50% in some regions. Co-infections were detected with the highest incidence (15.5%) for PVX and PVS. Additionally the data showed a positive correlation between co-infecting viruses with significant increase in absorbance value (virus titre) for at least one of the virus in an infected plant and suggested a synergistic interaction. To test this hypothesis, glasshouse grown potato plants were challenged with multiple viruses and analyzed for systemic infections and symptomology studies. The results obtained conclude that multiple viral infections dramatically increase disease epidemics as compared to single infection and an effective resistance strategy in targeting multiple RNA viruses is required to save potato crop.


Rethinking compassion fatigue.
Purpose The purpose of this paper is to argue for a revision of the concept of compassion fatigue in light of both its history and psychodynamics. Design/methodology/approach This paper calls into question conventional interpretations of compassion fatigue and the assumptions underlying them. As an alternative, a psychoanalytic interpretation is offered that sheds light on the phenomenon's unconscious and organizational dynamics. This interpretation also aligns with the concept's historical use in media and politics. Findings In contrast to the assumption that compassion fatigue arises from too much compassion, historical use of the term suggests just the opposite: compassion fatigue is the result of too little compassion. Healthcare literature on compassion fatigue has not only failed to account for this opposing view, but also the underlying psychodynamics at play. By attending to these neglected dimensions, healthcare scholars and practitioners can gain new insights into compassion fatigue and devise more sustainable interventions. Originality/value This paper reveals hidden dimensions to compassion fatigue that call into question conventional interpretations and offer novel perspectives on a core concern of healthcare work.


"Being with a Buddha": A Case Report of Methoxetamine Use in a United States Veteran with PTSD.
Methoxetamine (MXE) is a ketamine analogue with a high affinity for the N-methyl-D-aspartate (NMDA) receptor. MXE is a newly emerging designer drug of abuse and is widely available through on-line sources and is not detected by routine urine drug screens. In this report, we describe a United States (US) veteran with posttraumatic stress disorder (PTSD) and heavy polysubstance use, who injected high dose MXE for its calming effect. Given MXE's structural similarities to ketamine and recent work showing that ketamine reduces PTSD symptoms, we hypothesize that MXE alleviated this veteran's PTSD symptoms through action at the NMDA receptor and via influences on brain-derived neurotrophic factor (BDNF). To our knowledge, this is the first case report of self-reported use of MXE in the US veteran population. More awareness of designer drugs, such as MXE, is an important first step in engaging patients in the treatment of designer drug addiction in both military/veteran settings and civilian settings.


Viral ecology of organic and inorganic particles in aquatic systems: avenues for further research.
Viral abundance and processes in the water column and sediments are well studied for some systems; however, we know relatively little about virus-host interactions on particles and how particles influence these interactions. Here we review virus-prokaryote interactions on inorganic and organic particles in the water column. Profiting from recent methodological progress, we show that confocal laser scanning microscopy in combination with lectin and nucleic acid staining is one of the most powerful methods to visualize the distribution of viruses and their hosts on particles such as organic aggregates. Viral abundance on suspended matter ranges from 105 to 1011 ml-1. The main factors controlling viral abundance are the quality, size and age of aggregates and the exposure time of viruses to aggregates. Other factors such as water residence time likely act indirectly. Overall, aggregates appear to play a role of viral scavengers or reservoirs rather than viral factories. Adsorption of viruses to organic aggregates or inorganic particles can stimulate growth of the free-living prokaryotic community, e.g. by reducing viral lysis. Such mechanisms can affect microbial diversity, food web structure and biogeochemical cycles. Viral lysis of bacterio- and phytoplankton influences the formation and fate of aggregates and can, for example, result in a higher stability of algal flocs. Thus, viruses also influence carbon export; however, it is still not clear whether they short-circuit or prime the biological pump. Throughout this review, emphasis has been placed on defining general problems and knowledge gaps in virus-particle interactions and on providing avenues for further research, particularly those linked to global change.


Effects of aerobic training on psychosocial morbidity and symptoms in patients with asthma: a randomized clinical trial.
Asthma symptoms reduce patients' daily activities, impair their health-related quality of life (HRQoL), and increase their reports of anxiety and depression, all of which seem to be related to a decrease in asthma control. Aerobic exercise training is known to improve aerobic fitness and reduce dyspnea in asthmatics; however, its effect in reducing psychologic distress and symptoms remains poorly understood. We evaluated the role of an aerobic training program in improving HRQoL (primary aim) and reducing psychologic distress and asthma symptoms (secondary aims) for patients with moderate or severe persistent asthma. A total of 101 patients were randomly assigned to either a control group or an aerobic training group and studied during the period between medical consultations. Control group patients (educational program plus breathing exercises) (n = 51) and training group patients (educational program plus breathing exercises plus aerobic training) (n = 50) were followed twice a week during a 3-month period. HRQoL and levels of anxiety and depression were quantified before and after treatment. Asthma symptoms were evaluated monthly. At 3 months, the domains (physical limitations, frequency of symptoms, and psychosocial) and total scores of HRQoL significantly improved only in the training group patients (P < .001); the number of asthma-symptom-free days and anxiety and depression levels also significantly improved in this group (P < .001). In addition, a linear relationship between improvement in aerobic capacity and the days without asthma symptoms was observed (r = 0.47; P < .01). Our results suggest that aerobic training can play an important role in the clinical management of patients with persistent asthma. Further, they may be especially useful for patients with higher degrees of psychosocial distress. clinicaltrials.gov; Identifier: NCT-00989365.


Case Report: Refractory Cryptosporidiosis after CAR T-Cell Therapy for Lymphoma.
Cryptosporidial diarrhea is uncommon in immunocompetent individuals, more often seen in severely immunocompromised patients. Severe refractory cases have been described in patients with HIV/AIDS before the advent of modern antiretroviral therapy due to an inability to mount an adequate cellular immune response. We describe an 85-year-old patient post-chimeric antigen receptor T-cell therapy relapsed lymphoma who developed refractory Cryptosporidium spp. diarrhea in the setting of persistent CD4+ cytopenia. Despite receiving multiple antiparasitic agents, including failure of a prolonged course of nitazoxanide, the patient experienced persistent symptoms for 9 months with repeatedly positivity stool Cryptosporidium spp. direct fluorescent antibody (DFA) test. We highlight this case of refractory Cryptosporidium spp. and the importance of recognizing the pathogen in a non-HIV-infected immunosuppressed host.


[Ion concentration in the cerebrospinal fluid in multiple sclerosis].
The concentrations of electrolytes Na, K, Ca, Mg, and Cl and trace elements Cu and Zn were determined in the lumbar cerebrospinal fluids of forty patients with multiple sclerosis. Metal ion concentrations were measured using atomic absorption spectroscopy and flame photometry, respectively. Compared with corresponding values obtained from a control group, statistically significant increases in concentration of Na, Cl, Ca, and Zn have been found. Also reported are the results of determinations of ion concentrations in cerebrospinal fluids obtained from patients suffering from diseases other than multiple sclerosis. Possible causes of deviations from the norm are discussed.


Advocacy, policies and practicalities of preventive chemotherapy campaigns for African children with schistosomiasis.
Preventive chemotherapy campaigns against schistosomiasis have progressively scaled-up during the last decade, administering single standard dose praziquantel (40 mg/kg) treatments to millions of African children. Steps taken in securing international advocacy and national level implementation are traced to highlight an international treatment platform set for further expansion, including surveillance of schistosomiasis, school-level targeting with better on-site drug administration and annual reporting of programmatic indicators (i.e., treatment coverage), potentially in real-time. Several shortcomings in need of resolution are identified and efficacy of praziquantel is assessed by a systematic review. If WHO predictions in reduction of schistosomiasis are to be realized, careful international harmonization and tailoring of national resources are required. Maintaining an effective drug distribution system and regularly checking drug efficacy are paramount.


Nonequilibrium transition and pattern formation in a linear reaction-diffusion system with self-regulated kinetics.
We consider a reaction-diffusion system with linear, stochastic activator-inhibitor kinetics where the time evolution of concentration of a species at any spatial location depends on the relative average concentration of its neighbors. This self-regulating nature of kinetics brings in spatial correlation between the activator and the inhibitor. An interplay of this correlation in kinetics and disparity of diffusivities of the two species leads to symmetry breaking non-equilibrium transition resulting in stationary pattern formation. The role of initial noise strength and the linear reaction terms has been analyzed for pattern selection.


Association Between Erectile Dysfunction and Carotid Subclinical Atherosclerosis in HIV-Infected Patients.
Erectile dysfunction (ED) is frequent in HIV-infected patients, and it can be associated with atherosclerosis and cardiovascular events. So, the objective was to evaluate whether the presence of moderate-severe ED was a marker of subclinical atherosclerosis (SCA) in HIV-infected patients. A cross-sectional study was conducted in a cohort of HIV-infected patients. The presence of ED was assessed using the International Index of Erectile Function (IIEF-5) questionnaire. The presence of SCA was determined by calculating the mean carotid intima-media thickness with Doppler ultrasound. A logistic regression analysis was performed to check the variables associated with SCA. One hundred thirty-nine men of 45 (10) years of age were included, of which 130 (94.9%) received antiretroviral therapy. In 30 (22%) patients, the Framingham score was higher than 10%. In 36 (25.9%) patients, ED was detected in a moderate-severe degree and in 53 (38.1%), SCA was detected. In the multivariate analysis, variables independently associated with the presence of SCA were as follows: older age [odds ratio (OR) = 1.22, confidence interval (CI) 95%: 1.1 to 1.35, P < 0.001] and moderate-severe ED (OR = 4.68, CI 95%: 1.18 to 18.5; P = 0.028). Variables associated with moderate-severe ED were as follows: age (OR = 1.107, CI 95%: 1.041 to 1.17, P < 0.001) and having antibodies for hepatitis C virus (OR = 5.12, CI 95%: 1.54 to 17.03, P < 0.001). HIV-Infected patients often have moderate-severe ED, especially the elderly and coinfected patients with hepatitis C virus. ED can be an early clinical manifestation of incipient atherosclerosis, so its presence should involve a deep control of cardiovascular risk factors and using a regimen with a better atherogenic profile.


Chronic cervical radiculopathic pain is associated with increased excitability and hyperpolarization-activated current ( Ih) in large-diameter dorsal root ganglion neurons.
Cervical radiculopathic pain is a very common symptom that may occur with cervical spondylosis. Mechanical allodynia is often associated with cervical radiculopathic pain and is inadequately treated with current therapies. However, the precise mechanisms underlying cervical radiculopathic pain-associated mechanical allodynia have remained elusive. Compelling evidence from animal models suggests a role of large-diameter dorsal root ganglion neurons and plasticity of spinal circuitry attached with Aβ fibers in mediating neuropathic pain. Whether cervical radiculopathic pain condition induces plastic changes of large-diameter dorsal root ganglion neurons and what mechanisms underlie these changes are yet to be known. With combination of patch-clamp recording, immunohistochemical staining, as well as behavioral surveys, we demonstrated that upon chronic compression of C7/8 dorsal root ganglions, large-diameter cervical dorsal root ganglion neurons exhibited frequent spontaneous firing together with hyperexcitability. Quantitative analysis of hyperpolarization-activated cation current ( Ih) revealed that Ih was greatly upregulated in large dorsal root ganglion neurons from cervical radiculopathic pain rats. This increased Ih was supported by the enhanced expression of hyperpolarization-activated, cyclic nucleotide-modulated channels subunit 3 in large dorsal root ganglion neurons. Blockade of Ih with selective antagonist, ZD7288 was able to eliminate the mechanical allodynia associated with cervical radiculopathic pain. This study sheds new light on the functional plasticity of a specific subset of large-diameter dorsal root ganglion neurons and reveals a novel mechanism that could underlie the mechanical allodynia associated with cervical radiculopathy.


Laser Interstitial Thermal Therapy for Epilepsy.
MRI-guided laser interstitial thermal therapy (MgLiTT) uses a narrow diameter cannula to stereotactically target and heat deeper cerebral structures. This technique produces a precise lesion in the brain with great reliability because the localized tissue temperature change is monitored in real time. Because MgLiTT minimizes injury to surrounding brain, it appears to have a lower risk of affecting normal neurological function, and because it is done through a burr hole, there is less operative risk, less discomfort, and shorter hospitalizations. It is FDA approved for soft tissue ablation and is being increasingly applied to the surgical treatment of epilepsy, especially when seizures arise from deeper structures such as the hippocampus, amygdala, or discrete dysplastic tissue such as hypothalamic hamartomas. Mesial temporal epilepsy is the most frequently encountered surgically remedial epilepsy suitable for MgLiTT, particularly when there is unilateral hippocampal sclerosis. There is emerging evidence that it can be effective for eliminating seizures in this type of epilepsy, and that it has a lower risk of cognitive deficits than anterior temporal lobectomy.


Hyperdense basilar artery sign diagnoses acute posterior circulation stroke and predicts short-term outcome.
It is well established that the hyperdense middle cerebral artery sign is a specific marker for early ischemia in anterior circulation. However, little is known about the hyperdense basilar artery sign (HDBA) in posterior circulation. Our aim was to determine whether the HDBA sign has utility in early diagnosis of acute posterior circulation stroke and prediction of short-term outcome. Three-blinded readers examined unenhanced computed tomography scans for the HDBA sign, and materials were classified into two groups according to this sign. Vascular risk factors, admission and discharge National Institute of Health Stroke Scale (NIHSS) scores, short-term outcome, and radiological findings between the two groups were compared. One hundred and twenty-six cases of acute posterior circulation stroke (PCS) were included in the study. No statistically significant differences were found in risk factors of ischemic stroke, except atrial fibrillation (P=0.025). Admission and discharge NIHSS scores for the positive HDBA group were significantly higher than scores for the negative HDBA group (P=0.001, 0.002, respectively). The infarction territory for the positive HDBA group was mainly multi-region in nature (51.6%, P<0.001), while the negative HDBA group showed mainly middle territory infarction. Significant independent predictors of short-term outcome included the HDBA sign (P<0.001) and admission NIHSS scores (P<0.001). Approximately half of the HDBA patients showed multi-region infarction and a serious neurological symptom. Based on our results, this sign might not only be helpful in early diagnosis of acute PCS but also be able to correlate with a poor short-term outcome.


Langerhans cells and NK cells cooperate in the inhibition of chemical skin carcinogenesis.
Tissue immunosurveillance is an important mechanism to prevent cancer. Skin treatment with the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), followed by the tumor promoter 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), is an established murine model for squamous cell carcinoma (SCC). However, the innate immunological events occurring during the initiation of chemical carcinogenesis with DMBA remain elusive. Here, we discovered that natural killer (NK) cells and Langerhans cells (LC) cooperate to impair this oncogenic process in murine skin. The depletion of NK cells or LC caused an accumulation of DNA-damaged, natural killer group 2D-ligand (NKG2D-L) expressing keratinocytes and accelerated tumor growth. Notably, the secretion of TNFα mainly by LC promoted the recruitment of NK cells into the epidermis. Indeed, the TNFα-induced chemokines CCL2 and CXCL10 directed NK cells to DMBA-treated epidermis. Our findings reveal a novel mechanism how innate immune cells cooperate in the inhibition of cutaneous chemical carcinogenesis.


The clinical features of tick bite.
The clinical features of bites by the Australian scrub tick, Ixodes holocyclus, are reviewed. Eight cases of tick bite are summarized, including six new cases of tick paralysis in children. In almost all cases neuroparalysis became worse transiently, after the tick had been removed. One child with life-threatening respiratory and bulbar palsy received canine antitick antivenene, with rapid reversal of clinical signs. The differential diagnosis of tick bite includes all acute childhood diseases which can affect the motor units; the importance of including the possibility of tick envenomation in the differential diagnosis of acute weakness or paralysis in children is illustrated. The clinical features of neuromuscular paralysis are described, together with a review of the tick's local effects at the bite site.


Novel ITGB6 mutation in autosomal recessive amelogenesis imperfecta.
Hereditary defects in tooth enamel formation, amelogenesis imperfecta (AI), can be non-syndromic or syndromic phenotype. Integrins are signaling proteins that mediate cell-cell and cell-extracellular matrix communication, and their involvement in tooth development is well known. The purposes of this study were to identify genetic cause of an AI family and molecular pathogenesis underlying defective enamel formation. We recruited a Turkish family with isolated AI and performed mutational analyses to clarify the underlying molecular genetic etiology. Autozygosity mapping and exome sequencing identified a novel homozygous ITGB6 transversion mutation in exon 4 (c.517G>C, p.Gly173Arg). The glycine at this position in the middle of the βI-domain is conserved among a wide range of vertebrate orthologs and human paralogs. Clinically, the enamel was generally thin and pitted with pigmentation. Thicker enamel was noted at the cervical area of the molars. In this study, we identified a novel homozygous ITGB6 mutation causing isolated AI, and this advances the understanding of normal and pathologic enamel development.


A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis and all-trans isomers of retinoic acid.
Retinoids are potent regulators of cell proliferation, cell differentiation, and morphogenesis and are important therapeutic agents in oncology and dermatology. The gene regulatory activity of endogenous retinoids is effected primarily by retinoic acid isomers (all-trans and 9-cis) that are synthesized from retinaldehyde precursors in a broad range of tissues and act as ligands for nuclear retinoic acid receptors. The catabolism of all-trans-retinoic acid (atRA) is an important mechanism of controlling RA levels in cell and tissues. We have previously identified two cytochrome P450s, P450RAI-1 and P450RAI-2 (herein named CYP26A1 and CYP26B1), which were shown to be responsible for catabolism of atRA both in the embryo and the adult. In this report, we describe the identification, molecular cloning, and substrate characterization of a third member of the CYP26 family, named CYP26C1. Transiently transfected cells expressing CYP26C1 convert atRA to polar water-soluble metabolites similar to those generated by CYP26A1 and -B1. Competition studies with all-trans, 13-cis, and 9-cis isomers of retinoic acid demonstrated that atRA was the preferred substrate for CYP26C1. Although CYP26C1 shares extensive sequence similarity with CYP26A1 and CYP26B1, its catalytic activity appears distinct from those of other CYP26 family members. Specifically, CYP26C1 can also recognize and metabolize 9-cis-RA and is much less sensitive than the other CYP26 family members to the inhibitory effects of ketoconazole. CYP26C1 is not widely expressed in the adult but is inducible by RA in HPK1a, transformed human keratinocyte cell lines. This third CYP26 member may play a specific role in catabolizing both all-trans and 9-cis isomers of RA.