Risk factors of early spontaneous abortions among Japanese: a matched case-control study.
No epidemiological studies have examined risk factors for early spontaneous abortions among Japanese women. In this matched case-control study, we investigated the associations of reproductive, physical, and lifestyle characteristics of women and their husbands with early spontaneous abortion <12 weeks of gestation. Information was collected through medical records for 430 cases of early spontaneous abortion and 860 controls of term delivery. Two controls were individual-matched to one case according to maternal age (± 3 years) and calendar year of events (either early spontaneous abortion or delivery). Multivariable conditional odds ratios (ORs) and 95% confidence interval (CI) were calculated with conditional logistic-regression. The risk of early spontaneous abortions was higher for women with a past history of early spontaneous abortions; OR was 1.98 (95% CI: 1.35, 2.89) for one previous spontaneous abortion, 2.36 (95% CI: 1.47, 3.79) for two, and 8.73 (95% CI: 5.22, 14.62) for three or more. Other factors also influence risk; an OR of 2.39 (95% CI: 1.26, 4.25) was found for women who smoked, and 1.65 (95%CI: 1.17, 2.35) for women working outside the home. Our finding suggests that for Japanese women, smoking and working may be important public health issue targets for the prevention of early spontaneous abortions.


Preclinical Brain Network Abnormalities in Patients with Subjective Cognitive Decline.
Alzheimer's disease (AD) is the most common form of dementia worldwide. Currently there are no disease modifying treatments available. Detecting subjects with increased risk to develop dementia is essential for future clinical trials. Subjective cognitive decline (SCD) is a condition defining individuals who perceive a decrease in their own cognitive functioning in the absence of any detectable deficit on neuropsychological testing. SCD individuals show AD-related biomarkers abnormalities in cerebrospinal fluid. The aim of the present study was to assess brain functional connectivity (FC) changes in SCD individuals. 23 SCD and 33 healthy subjects (HS) underwent an extensive neuropsychological assessment and 3T-MRI scanning including a T1-w volume and resting-state fMRI (RS-fMRI) to assess brain atrophy and brain FC. No between-group differences in grey matter volumes were detected. SCD subjects compared to HS showed both increased and decreased FC in the executive and parietal networks. Associations between cognitive measures, mainly assessing working memory, and FC within brain networks were found both in SCD and HS separately. SCD individuals showed FC abnormalities in networks involving fronto-parietal areas that may account for their lower visuo-spatial working memory performances. Dysfunctions in executive-frontal networks may be responsible for the cognitive decline subjectively experienced by SCD individuals despite the normal scores observed by formal neuropsychological assessment. The present study contributes to consider SCD individuals in an early AD stage with an increased risk of developing the disease in the long term.


[The late results of the surgical treatment of stress urinary incontinence].
The severe stress urinary incontinence is a condition, which traumatize women psychology. Amongst numerous well-known operative techniques for treatment of the stress urinary incontinence authors apply the following ones: suprapubic colpouretherosuspension by Burch, colpouretherosuspension by Ratz, sling operation with synthetic stuff--Ampoxen. The evaluation of late results from the applied operative approaches in 30 patients displaced a long term overcome of stress incontinence. The authors emphasized that during clinical follow up of all cases in the course of 3 years the best results were obtained after application of suprapubic and sling methods. Our conclusion is that the choice of operative approach have to be individual and is in dependence with every clinical case. The postoperative outcome depends on the exactness of the operation.


Bone mineral density assessment using iterative reconstruction compared with quantitative computed tomography as the standard of reference.
This study examines the influence of iterative reconstruction on bone mineral density (BMD) measurement by comparison with standard quantitative computed tomography (QCT; reference) and two other protocols based on filtered back projection. Ten human cadaver specimens of the lumbar spine with a hydroxyapatite calibration phantom underneath, were scanned with 4 protocols: 1. standard QCT, 2. volume scan with FBP, 3. helical scan with FBP, and 4. helical scan with IR (Adaptive Iterative Dose Reduction 3D (AIDR3D)). Radiation doses were recorded as CT dose index (CTDIvol) and BMD, signal-to-noise and contrast-to-noise ratio were calculated. Mean hydroxyapatite concentration (HOA) did not differ significantly between protocols, ranging from 98.58 ± 31.09 mg cm3 (protocol 4) to 100.47 ± 30.82 mg cm3 (protocol 2). Paired sample correlations of HOA values for protocol 4 and protocols 1, 2 and 3 were nearly perfect with coefficients of 0.980, 0.979 and 0.982, respectively (p < 0.004). CTDIvol were 7.50, 5.00, 6.82 (±2.03) and 1.72 (±0.50) mGy for protocols 1, 2, 3 and 4 respectively. Objective image quality was highest for protocol 4. The use of IR for BMD assessment significantly lowers radiation exposure compared to standard QCT and protocols with FBP while not degrading BMD measurement.


Regeneration of corneal epithelium utilizing a collagen vitrigel membrane in rabbit models for corneal stromal wound and limbal stem cell deficiency.
This study was performed to evaluate the potential of a collagen-based membrane, collagen vitrigel (CV), for reconstructing corneal epithelium in the stromal wound and limbal stem cell deficiency (LSCD) models. Three groups of rabbits were used in the stromal wound model: CV affixed using fibrin glue (CV + FG group, n = 9), fibrin glue only (FG group, n = 3) and an untreated control group (n = 3). In the LSCD model, one group received CV containing human limbal epithelial cells (CV + hLEC group, n = 2) and the other was an untreated control (n = 1). Gross observation, including fluorescent staining, pathological examination, immunohistochemistry and electron microscopy, was used to evaluate the effect of CV on the corneal epithelium. In the stromal wound model, fluorescent staining showed that epithelial reconstruction occurred as rapidly in the CV + FG group as it did in the control group. The pathological examination proved that the CV supported a healthy corneal epithelium in the CV + FG group, whereas FG led to hypertrophy and inappropriate differentiation of corneal epithelium in the FG group. In the LSCD model, the corneas in the CV + hLEC group showed sustained tissue transparency with good epithelialization, low inflammatory response and reduced neovascularization. However, the control cornea was translucent and showed high amounts of inflammation and neovascularization. We have demonstrated that CV supports corneal epithelial differentiation and prevents epithelial hypertrophy, in addition to serving as a scaffold for hLEC transplantation, without complications.


Oxidative metabolism of curcumin-glucuronide by peroxidases and isolated human leukocytes.
Conjugation with glucuronic acid is a prevalent metabolic pathway of orally administrated curcumin, the bioactive diphenol of the spice turmeric. The major in vitro degradation reaction of curcumin is autoxidative transformation resulting in oxygenation and cyclization of the heptadienedione chain to form cyclopentadione derivatives. Here we show that curcumin-glucuronide is much more stable than curcumin, degrading about two orders of magnitude slower. Horseradish peroxidase-catalyzed oxidation of curcumin-glucuronide occurred at about 80% of the rate with curcumin, achieving efficient transformation. Using LC-MS and NMR analyses the major products of oxidative transformation were identified as glucuronidated bicyclopentadione diastereomers. Cleavage into vanillin-glucuronide accounted for about 10% of the products. Myeloperoxidase and lactoperoxidase oxidized curcumin-glucuronide whereas tyrosinase and xanthine oxidase were not active. Phorbol ester-activated primary human leukocytes showed increased oxidative transformation of curcumin-glucuronide which was inhibited by the peroxidase inhibitor sodium azide. These studies provide evidence that the glucuronide of curcumin is not an inert product and may undergo further enzymatic and non-enzymatic metabolism. Oxidative transformation by leukocyte myeloperoxidase may represent a novel metabolic pathway of curcumin and its glucuronide conjugate.


Flow injection immunoanalysis based on a magnetoimmunosensor system.
A new immunosensor integrated to a flow system has been developed. It is based on magnetic immunoparticles immobilized on a solid-state transducer using a magnetic field. The described technique renews the immunoparticles reproducibly for each analysis allowing a good measurement precision. The developed experimental approach permits the implementation of an automated immunoassay that is quick (analytical cycle < 30 min) and sensitive in the micromolar concentration range. The system was applied to the determination of rabbit immunoglobulin G as an analyte model.


The Global Programme on Health Promotion Effectiveness (GPHPE): a bold concept with few resources.
This paper describes the past ten years of the International Union for Health Promotion and Education's (IUHPE) flagship programme on health promotion effectiveness. It examines the context in which the programme developed and the organization of the programme to carry out its goals. The paper takes a critical look at the strengths, weaknesses, opportunities and difficulties of conducting such a broad programme within a global membership-based non-governmental organization (NGO). It also discusses how the field of evidence gathering has developed in relationship to the project and what changes have emerged since the early years. Lack of resources, both in terms of contributors and financial support, is identified as the key problem in sustaining an NGO effort to examine effectiveness.


Overview of aristolochic acid nephropathy: an update.
Aristolochic acid nephropathy (AAN) is a rapidly progressive renal interstitial fibrosis caused by medical or environmental exposure to aristolochic acid (AA). Since the outbreak of AAN in Belgium was reported nearly 30 years ago, the safety of herbal remedies has drawn considerable attention, and AAN has become a global public health problem. Breakthroughs have been made to better understand the disease, including the toxicity of AAs, the possible mechanisms of AAN, the disease patterns, and the pathological features; however, some critical problems remain unresolved. Because of the insidious onset of the disease, the incidence of AAN and the prevalence of exposure to AAs are unknown and might be largely underestimated. During the past decades, AA-containing herbs have been strictly administrated in many regions and the occurrence of AAN has declined sharply, yet cases of AAN are still sporadically reported. Despite the progress in the understanding of the disease's pathogenesis, there is no effective treatment for delaying or reversing the renal deterioration caused by AAN. Therefore, the risk of exposure to AAs should be taken seriously by public health workers and clinicians. In this review, we updated the latest data on AAN, summarized the advances throughout these years, and put forward some challenges for future research.


[Rehabilitation of patients with hearing disorders using hearing aids and tactical hearing measures].
After a brief summary of the problems of rehabilitation of hearing-impaired subjects, the optimal conditions for rehabilitation with hearing aids are presented: a) The right timing is crucial. b) Optimal provision of hearing aids must be carried out in close co-operation between the patient, the hearing aid technician and the otolaryngologist. c) Easy handling of the hearing aid and the use of attachments must be guaranteed. d) The hearing-impaired person must be fully informed as to the extent and type of hearing loss. He/she must accept the affliction and know about the possibilities of rehabilitation. The patient's motivation is a pre-requisite for all further steps. e) The patients must learn tactical measures to make optimal use of their hearing ability in relation to their environment. Hearing tactics consist of hearing training and a change in the attitude of the hearing-impaired patients themselves and their attitude towards their surroundings.


Assessing the Dengue Diagnosis Capability Gap in the Military Health System.
Dengue, one of the most widespread infectious diseases, has affected U.S. military readiness throughout history. We explored the dengue diagnosis capability gap by circulating a questionnaire among military end users to determine in what capacity diagnostic test results are needed and how these results would be used at various roles of care in the Military Health System. Results were used to generate target product profiles for potential diagnostic tests. We determined that at far-forward locations, diagnostic tests need to be rugged and easy to use and are primarily needed to inform medical evacuation decisions. In mobile or fixed hospitals, diagnostics can be less portable but must be accurate enough to inform patient care decisions reliably. We then evaluated the suitability of using rapid diagnostic tests and enzyme-linked immunosorbent assays based on published performance characteristics, and we used a model to determine positive and negative predictive values in certain simulated deployments. In far-forward settings, a rapid diagnostic test comprising both antigen- and antibody-based detection can fulfill the capability gap with reasonable accuracy, whereas at higher roles of care immunoglobulin M-enzyme-linked immunosorbent assay was determined to be the most suitable option.


Yttrium-90 transarterial radioembolization and capecitabine in hepatocellular carcinoma with portal vein involvement.
Hepatocellular carcinoma (HCC) with portal vein tumor thrombus is considered an advanced stage disease. Non-surgical local and systemic therapies are the only treatment options available. To analyze the survival and toxicity outcomes of systemic treatment concurrent with yttrium-90 transarterial radioembolization in HCC with liver-limited disease and portal vein involvement with Child-Pugh B liver reserve. The medical records of 22 patients who underwent yttrium-90 transarterial radioembolization concomitant with capecitabine chemotherapy as first-line treatment between 2014 and 2019 were retrospectively reviewed. Twenty-two patients were included in the study. Grade 3 to 4 side effects were evaluated, and hepatic encephalopathy developed in 1 patient after yttrium-90 transarterial radioembolization. In the fourth month of radiological evaluation, 11 patients had a partial response (50%), 5 patients had stable disease (22.7%), and 6 patients (27.3%) developed progressive disease. The median survival time was 21 months. Combined treatment with yttrium-90 transarterial radioembolization and capecitabine may be an effective and safe treatment option. Treatment was associated with a median overall survival of 21 months and a disease control rate of 72.7% at 4 months in patients with inoperable HCC.


Investigation of organic impurity and its occurrence in industrial waste salt produced by physicochemical process.
Industrial waste salt is classified as hazardous waste to the environment. The organic impurity and its occurrence in industrial waste salt affect the salt resource utilization. In this paper, composition quantitative analysis, XRD, TG-DSC, SEM/FIB-SEM coupled with EDS, FTIR, XPS and GC-Ms were chosen to investigate the organic impurity and its occurrence in industrial waste salt. The organic impurities owe small proportion (1.77%) in the specimen and exhibit weak thermal stability within the temperature of 600°C. A clear definition of organic impurity, including 11 kinds of organic compounds, including aldehyde, benzene and its derivatives etc., were detected in the industrial waste salt. These organic impurities, owing (C-O/C-O-C, C-OH/C = O, C-C/CHx/C = C etc.)-containing function group substance, are mainly distributed both on the surface and inside of the salt particles. Meanwhile, the organic substance may combine with metal cations (Ni2+, Mg2+, Cu2+ etc.) through functional groups, such as hydroxide, carbonyl etc., which increases its stability in the industrial waste salt. These findings provide comprehensive information for the resource utilization of industrial waste salt from chemical industry etc.


A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy.
Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24 ng/ml) compared to controls (142.7 ng/ml) or family members non-carriers (82.0 ng/ml) (p-value = 0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.


Isolation of Yersinia enterocolitica and related species from porcine samples obtained from an abattoir.
Swabs of swine carcasses and samples of porcine tongue and trim obtained from an abattoir were examined for the presence of Yersinia enterocolitica and related species (Y. intermedia, Y. kristensenii and Y. frederiksenii). Three enrichment media (phosphate buffered saline, sorbitol-bile salts-phosphate buffered saline, and a modified Rappaport's broth) were compared at 4 degrees C for their efficiency of recovery of Y. enterocolitica and related species. Two secondary enrichment procedures (post-enrichment in modified Rappaport's broth for 2 d at 25 degrees C and treatment with 0.5% KOH in 0.5% NaC1) also were evaluated. The porcine isolates were characterized by biochemical and serological examination, speciation, and biotyping. Eight of 43 samples were positive for Y. enterocolitica and related species. The combination of incubation in sorbitol-bile salts-phosphate buffered saline for 21 d at 4 degrees C followed by post-enrichment in modified Rappaport's broth yielded maximum number of isolates. All isolates, except one, were avirulent as determined by autoagglutination, calcium dependence at 37 degrees C, and HeLa cell invasiveness tests.


Self-organized Learning from Synthetic and Real-World Data for a Humanoid Exercise Robot.
We propose a neural learning approach for a humanoid exercise robot that can automatically analyze and correct physical exercises. Such an exercise robot should be able to train many different human partners over time and thus requires the ability for lifelong learning. To this end, we develop a modified Grow-When-Required (GWR) network with recurrent connections, episodic memory and a novel subnode mechanism for learning spatiotemporal relationships of body movements and poses. Once an exercise is successfully demonstrated, the information of pose and movement per frame is stored in the Subnode-GWR network. For every frame, the current pose and motion pair is compared against a predicted output of the GWR, allowing for feedback not only on the pose but also on the velocity of the motion. Since both the pose and motion depend on a user's body morphology, the exercise demonstration by one individual cannot easily be used as a reference for further users. We allow the GWR to grow online with each further demonstration. The subnode mechanism ensures that exercise information for individual humans is stored and retrieved correctly and is not forgotten over time. In the application scenario, a physical exercise is performed in the presence of an expert like a physiotherapist and then used as a reference for a humanoid robot like Pepper to give feedback on further executions of the same exercise. For evaluation, we developed a new synthetic exercise dataset with virtual avatars. We also test our method on real-world data recorded in an office scenario. Overall, we claim that our novel GWR-based architecture can use a learned exercise reference for different body variations through incremental online learning while preventing catastrophic forgetting, enabling an engaging long-term human-robot experience with a humanoid robot.


The variability of the components of fitness along the menstrual cycle.
This study aims to determine the variability of the components of fitness along the menstrual cycle (MC) of physically active eumenorrheic women. Fifteen subjects were monitored along two consecutive MCs through the calendar-based counting method in combination with a urine luteinizing hormone surge kit. Subjects were tested at the early follicular phase (EFP), pre-ovulatory or late follicular phase (LFP), and post-ovulatory or mid-luteal phase (MLP). In each session, the back squat one-repetition maximum (1-RM), maximum fat oxidation (MFO), maximum oxygen uptake (VO2max) and acute recovery capacity were determined. The results revealed a wide variability among components of fitness and a low to high variability among subjects (acute recovery: 3.6 % [range 1.5 to 9.5%]; back squat 1-RM: 6.1% [range 2.2 to 11%]; VO2max: 6.6% [range 1.1 to 15%]; MFO: 23% [range 4.6 to 35%]). Despite the individual nature, considering the number and magnitude of the responses in each MC phase, the VO2max and the acute recovery capacity tended to be enhanced at the LFP, the MFO at the MLP, and the back squat 1-RM remained stable along the MC. Thus, practitioners are aware of which components are susceptible to change along the MC phase, but an individual monitoring is recommended.


Bottom-up synthesis of chemically precise graphene nanoribbons.
In this article, we describe our chemical approach, developed over the course of a decade, towards the bottom-up synthesis of structurally well-defined graphene nanoribbons (GNRs). GNR synthesis can be achieved through two different methods, one being a solution-phase process based on conventional organic chemistry and the other invoking surface-assisted fabrication, employing modern physics methodologies. In both methods, rationally designed monomers are polymerized to form non-planar polyphenylene precursors, which are "graphitized" and "planarized" by solution-mediated or surface-assisted cyclodehydrogenation. Through these methods, a variety of GNRs have been synthesized with different widths, lengths, edge structures, and degrees of heteroatom doping, featuring varying (opto)electronic properties. The ability to chemically tailor GNRs with tuned properties in a well-defined manner will contribute to the elucidation of the fundamental physics of GNRs, as well as pave the way for the development of GNR-based nanoelectronics and optoelectronics.


Pulmonary Langerhans cell histiocytosis and other pulmonary histiocytic diseases: a review.
Pulmonary Langerhans cell histiocytosis is the most common and best known pulmonary histiocytic lesion; however, the realm of pulmonary histiocytic lesions also includes an assortment of uncommon diseases that may exhibit pulmonary involvement. To review pulmonary Langerhans cell histiocytosis and other pulmonary histiocytoses to better ensure correct diagnosis and optimal assessment of prognosis and treatment. Literature review and primary material from the author's institution. This review discusses the most common pulmonary histiocytosis, pulmonary Langerhans cell histiocytosis, and also reviews the uncommon pulmonary histiocytic lesions, which are distinct from pulmonary Langerhans cell histiocytosis.


Reflection Losses Analysis from Interspacing between the Cells in a Photovoltaic Module Using Novel Encapsulant Materials and Backsheets.
Higher efficiency and output power of a photovoltaic (PV) module can be achieved by minimizing cell-to-module (CTM) power losses. CTM losses are mainly dependent on electrical and optical losses. In this work, reflection losses from interspacing of cells with respect to different encapsulant materials and backsheets are evaluated. Two novel encapsulant materials thermoplastic polyolefin (TPO) and polybutadiene ionomer are used, in addition to conventionally used ethylene vinyl acetate (EVA). Moreover, the effect of using these encapsulant materials separately with Tedlar and Aluminum foil as backsheets is realized. It has been observed that TPO in combination with Tedlar presents minimum reflection losses compared to other encapsulant materials. The reflection losses calculated experimentally with polybutadiene ionomer were 5.4% less than the conventionally used EVA, whereas, the reflection losses calculated experimentally with TPO were 5.9% less than the conventionally used EVA. The experimental results obtained are also validated through simulations.


Response of ammonia oxidizing bacteria and archaea to acute zinc stress and different moisture regimes in soil.
Ammonia oxidation has been intensively studied for its sensitivity to environmental shifts and stresses. However, acute stress effects on the occurrence and composition of ammonia oxidizing bacteria (AOB) and archaea (AOA) based on expression of related molecular markers in complex soil environments have been to an extent overlooked, particularly concerning transient but commonly occurring environmental changes like soil moisture shifts. The present study investigates the responses of AOB and AOA to moisture shifts and high Zn soil content. AmoA gene copies and transcripts of AOB and AOA along with potential nitrification activity were measured in a soil microcosm approach for investigating the referred environmental shifts. Moisture change from 87 to 50 % of the water holding capacity caused a ~99 % reduction of AOB but not of AOA amoA transcripts that did not change significantly. Increasing applied zinc concentrations resulted in a reduction of potential nitrification rates and negatively affected studied gene expressions of both AOB and AOA, with AOB being more responsive. Both 16 S rRNA and amoA transcripts of AOB had an inverse relation to the applied zinc, indicating a gradual loss in total cell activity. Our results suggest the existence of pronounced differences between AOB and AOA concerning ammonia oxidation activity.


Carbohydrates of the Organic Shell Matrix and the Shell-Forming Tissue of the Snail Biomphalaria glabrata (Say).
Sulfated carbohydrates may play a role in the biomineralization of the molluscan shell. The carbohydrates of the extracted water-insoluble organic shell matrix (IM) of the freshwater snail Biomphalaria glabrata were identified as glucose, mannose, galactose, and N-acetyl-glucosamine, whereas the water-soluble organic matrix (SM) additionally contained N-acetyl-galactosamine. A specific lectin binding pattern of the matrix was obtained. One prominent protein of the SM, with a size of 19.6 kDa and a pI of 7.4, was shown to be a glycoprotein with terminal glucosyl or mannosyl moieties. The acidic constitutents of the matrix showed a variety of possible terminal sugars, indicating a heterogenous mixture of proteoglycans or glycosaminoglycans (GAGs) and glycoproteins. At the shell-forming mantle edge, an alcian-blue-positive material was observed in the periostracum groove (PG), the belt, and apically in the cells of the outer mantle epithelium (OME). With the help of lectins, all sugars in question were detected in the PG and the belt, whereas the OME was bound by glucose/mannose- and GlcNac-specific lectins only. Although the complete set of GAGs will be produced in the PG and the belt, a very acidic fraction of GAGs and the 19.6-kDa protein can also be delivered by the OME.


Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma.
Gene-based immunotherapy for cancer is limited by the lack of safe, efficient, reproducible, and titratable delivery methods. Direct injection of DNA into tissue, although safer than viral vectors, suffers from low gene transfer efficiency. In vivo electroporation, in preclinical models, significantly enhances gene transfer efficiency while retaining the safety advantages of plasmid DNA. A phase I dose escalation trial of plasmid interleukin (IL)-12 electroporation was carried out in patients with metastatic melanoma. Patients received electroporation on days 1, 5, and 8 during a single 39-day cycle, into metastatic melanoma lesions with six 100-mus pulses at a 1,300-V/cm electric field through a penetrating six-electrode array immediately after DNA injection. Pre- and post-treatment biopsies were obtained at defined time points for detailed histologic evaluation and determination of IL-12 protein levels. Twenty-four patients were treated at seven dose levels, with minimal systemic toxicity. Transient pain after electroporation was the major adverse effect. Post-treatment biopsies showed plasmid dose proportional increases in IL-12 protein levels as well as marked tumor necrosis and lymphocytic infiltrate. Two (10%) of 19 patients with nonelectroporated distant lesions and no other systemic therapy showed complete regression of all metastases, whereas eight additional patients (42%) showed disease stabilization or partial response. This report describes the first human trial, to our knowledge, of gene transfer utilizing in vivo DNA electroporation. The results indicated this modality to be safe, effective, reproducible, and titratable.


The Incidence of Postoperative Pneumonia in Various Surgical Subspecialties: A Dual Database Analysis.
Pneumonia is the third most common postoperative complication. However, its epidemiology varies widely and is often difficult to assess. For a better understanding, we utilized two national databases to determine the incidence of postoperative pneumonia after various surgical procedures. Specifically, we used the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) and the Nationwide Inpatient Sample (NIS) to determine the incidence and yearly trends of postoperative pneumonia following orthopaedic, urologic, otorhinolaryngologic, cardiothoracic, neurosurgery, and general surgeries. The NIS and NSQIP databases from 2009-2013 were utilized. The Clinical Classification Software (CCS) for International Classification of Diseases, 9th edition (ICD-9) codes provided by the NIS database was used to identify all surgical subspecialty procedures. The incidence of postoperative pneumonia was identified as the total number of cases under each identifying CCS code that also had ICD-9 codes for postoperative pneumonia. In the NSQIP database, the surgical subspecialties were selected using the following identifying string variables provided by NSQIP: 1) "Orthopedics", 2) "Otolaryngology (ENT)", 3) "Urology", 4) "Neurosurgery", 5) "General Surgery", and 6) "Cardiac Surgery" and "Thoracic Surgery". Cardiac and thoracic surgery was merged to create the variable "Cardiothoracic Surgery". Postoperative pneumonia cases were extracted utilizing the available NSQIP nominal variables. All variables were used to isolate the incidences of postoperative pneumonia stratified by surgical specialty. A subsequent trend analysis was conducted to assess the associations between operative year and incidence of postoperative pneumonia. For all NIS surgeries, the incidence of postoperative pneumonia was 0.97% between 2009 and 2013. The incidence was highest among patients who underwent cardiothoracic surgery (3.3%) and urologic surgery (1.73%). Patients who underwent general surgery, neurosurgery, spine surgery, orthopaedic surgery, and ENT surgery had a postoperative pneumonia incidence of 1.1%, 0.6%, 0.5%, 0.5%, and 0.4%, respectively. Overall trend analysis demonstrated a statistically significant decrease in postoperative pneumonia incidence (p <0.001), which paralleled in each specialty as well. In NSQIP, the incidence of postoperative pneumonia for all surgeries that occurred between 2009 and 2013 was 1.3%. The incidences of postoperative pneumonia were highest among patients who underwent cardiothoracic surgery (5.3%), general surgery (1.4%), and neurosurgery (1.4%). The incidences of postoperative pneumonia in patients who underwent ENT surgery, orthopedic surgery, and urologic surgery were 0.7%, respectively. Overall trend analysis demonstrated a statistically significant increase in postoperative pneumonia incidence for patients undergoing cardiothoracic surgery (p <0.001). There were no notable trends for the other surgical subspecialties. The incidence of postoperative pneumonia differs between the two national databases. Furthermore, the incidences differed among the various surgical subspecialties; however, cardiothoracic surgery had the highest incidence in both databases. Furthermore, cardiothoracic surgery appeared to have an increasing trend in incidence. Standardizing and implementing accurate coding methodologies for this complication are needed for a more accurate assessment of this burdensome complication. Future studies should assess interventions, such as oral cleansing and suctioning, incentive spirometry, as well as designated institution-based pneumonia prevention programs and protocols to help prevent and mitigate the occurrence of this complication.


Effect of ischemic post-conditioning on spinal cord ischemic-reperfusion injury in rabbits.
To investigate the potential protective effect of ischemic post-conditioning (Post-con) on ischemia-reperfusion injury of the rabbit spinal cord, and to determine if there is an additive neuroprotective effect when ischemic preconditioning (IPC) and Post-con are combined. Forty New Zealand white rabbits were randomly divided into four groups: group Control (C; n=10), aortic occlusion (AOC; for 30 min; group IPC (n=10) three cycles of three-minute AOC plus three-minute reperfusion before the 30-min AOC; group Post-con (n=10), three cycles of three-minute reperfusion plus three-minute AOC immediately upon reperfusion after 30-min AOC; group IPC+Post-con (n=10), where animals were subjected to both IPC and Post-con. At six hours, 24 hr and 48 hr following reperfusion, neurological function was assessed according to Tarlov scores, and at 48 hr, the spinal cords were procured for the histopathologic evaluation, by comparing the number of intact alpha-motor neurons in the anterior horn. The median count (and quartiles) of intact alpha-motor neurons was greatest in group Post-con 73 (69-76) and group IPC+Post-con 29 (22-42) compared to the numbers of viable alpha-motor neurons in groups C 6 (4-9) and IPC 15 (11-18) (P < 0.001). The numbers of animals who developed paraplegia according to Tarlov criteria were 7/10 in groups Post-con and IPC+Post-con, compared to 9/10 animals in each of groups C and IPC. This laboratory investigation provides histological evidence that Post-con may protect the spinal cord from moderate to severe ischemia reperfusion injury. Ischemic preconditioning conferred no additional benefits in this rabbit model. The results have potential clinical implications for patients undergoing thoracoabdominal aortic reconstructive surgery.


Bronchial reactivity pattern in nonasthmatic parents of asthmatics.
Genetic mechanisms have been proposed to explain the presence of asthma in families. A methacholine challenge can identify individuals with bronchial reactivity (a hallmark of asthma). It may then be possible to determine whether the presence of non-specific bronchial reactivity, as detected by a methacholine response, has potential as a genetic marker. Thirty-one non-asthmatic parent pairs of asthmatic children were selected from asthma (AF) families enrolled in a Natural History of Asthma study. Parent pairs were chosen if both gave negative responses to a modified National Heart, Lung and Blood Institute questionnaire on asthma. The methacholine response of these parents of asthmatic children had a bimodal distribution. These results show that the methacholine response can mark bronchial reactivity without the presence of clinical asthma and that a familial component of bronchial reactivity exists which may be transmitted from one generation to the next.


[Menstrual status as risk factors of endometriosis: a case-control study].
A case-control study, involving 203 cases of pelvic endometriosis and 406 randomly selected and age-matched community controls, was conducted. The results showed that women characterized by earlier menarche (< or = 12 years) and longer period (> 7 days) were associated with an elevated risk. Longer cycle (> 35 days) seemed to have a protective effect. There are a tendency to increasing risk for endometriosis associated with primary dysmenorrhea and energetic physical activities during menstruation. The results indicate that intensive treatment of primary dysmenorrhea and avoidance of strenuous exercise during menstruation may prevent pelvic endometriosis.


Taiwanese female vegetarians have lower lipoprotein-associated phospholipase A2 compared with omnivores.
Many studies supported that vegetarians have a lower risk of cardiac diseases and mortality, partly due to better blood pressure and serum cholesterol profiles. However, the inflammatory markers, especially lipoprotein-associated phospholipase A2 (Lp-PLA2), have not been well-studied. This study aimed to compare inflammatory markers and conventional risk factors between vegetarians and omnivores. One hundred and seventy-three vegetarians and 190 omnivores were studied. Fasting blood samples were obtained to compare levels of glucose, total cholesterol, triacylglycerol, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, homocysteine, Lp-PLA2 activity, and high-sensitivity C-reactive protein (hs-CRP). Vegetarians had higher serum levels of the following markers: hs-CRP (1.8 ± 3.4 vs. 1.2 1.8 mg/L, respectively; p = 0.05), homocysteine (9.39 ± 3.22 vs. 7.62 ± 2.41 μmol/L, respectively; p < 0.01), and triacylglycerol (96.91 ± 59.56 vs. 84.66 ± 43.24 mg/dL, respectively; p < 0.05). Vegetarians also had lower levels of Lp-PLA2 (18.32 ± 7.19 10-3 μmol/min/mL vs. 20.22 8.13 10-3 μmol/min/mL; p < 0.05), total cholesterol (180.62 ± 36.55 mg/dL vs. 192.73 ± 36.57 mg/dL; p < 0.01), LDL cholesterol (118.15 ± 32.8 vs. 126.41 ± 34.28 mg/dL; p < 0.05), and HDL cholesterol (55.59 ± 13.30 vs. 62.09 ± 14.52 mg/dL, p < 0.01). Multivariate analyses demonstrated that a vegetarian diet increases the chances for high serum hs-CRP and low Lp-PLA2 activity. In addition to lower total cholesterol, LDL-cholesterol, and HDL-cholesterol, Taiwanese female vegetarians have lower serum Lp-PLA2 activity but higher levels of hs-CRP, homocysteine, and triacylglyerol. It might be due to geographic differences of vegetarian diets, and further studies are needed.


The K-Ras effector p38γ MAPK confers intrinsic resistance to tyrosine kinase inhibitors by stimulating EGFR transcription and EGFR dephosphorylation.
Mutations in K-Ras and epidermal growth factor receptor (EGFR) are mutually exclusive, but it is not known how K-Ras activation inactivates EGFR, leading to resistance of cancer cells to anti-EGFR therapy. Here, we report that the K-Ras effector p38γ MAPK confers intrinsic resistance to small molecular tyrosine kinase inhibitors (TKIs) by concurrently stimulating EGFR gene transcription and protein dephosphorylation. We found that p38γ increases EGFR transcription by c-Jun-mediated promoter binding and stimulates EGFR dephosphorylation via activation of protein-tyrosine phosphatase H1 (PTPH1). Silencing the p38γ/c-Jun/PTPH1 signaling network increased sensitivities to TKIs in K-Ras mutant cells in which EGFR knockdown inhibited growth. Similar results were obtained with the p38γ-specific pharmacological inhibitor pirfenidone. These results indicate that in K-Ras mutant cancers, EGFR activity is regulated by the p38γ/c-Jun/PTPH1 signaling network, whose disruption may be a novel strategy to restore the sensitivity to TKIs.


Transcriptome Landscape Analyses of the Regulatory Network for Zygotic Embryo Development in Paeonia ostii.
Paeonia ostii is a worldwide ornamental flower and an emerging oil crop. Zyotic embryogenesis is a critical process during seed development, and it can provide a basis for improving the efficiency of somatic embryogenesis (SE). In this study, transcriptome sequencing of embryo development was performed to investigate gene expression profiling in P. ostii and identified Differentially expressed genes (DEGs) related to transcription factors, plant hormones, and antioxidant enzymes. The results indicated that IAA (Indole-3-acetic acid), GA (Gibberellin), BR (Brassinosteroid) and ETH (Ethylene) were beneficial to early embryonic morphogenesis, while CTK (Cytokinin) and ABA (Abscisic Acid) promoted embryo morphogenesis and maturation. The antioxidant enzymes' activity was the highest in early embryos and an important participant in embryo formation. The high expression of the genes encoding fatty acid desaturase was beneficial to fast oil accumulation. Representative DEGs were selected and validated using qRT-PCR. Protein-protein interaction network (PPI) was predicted, and six central node proteins, including AUX1, PIN1, ARF6, LAX3, ABCB19, PIF3, and PIF4, were screened. Our results provided new insights into the formation of embryo development and even somatic embryo development in tree peonies.


The Integrin Binding Peptide, ATN-161, as a Novel Therapy for SARS-CoV-2 Infection.
Many efforts to design and screen therapeutics for severe acute respiratory syndrome coronavirus (SARS-CoV-2) have focused on inhibiting viral cell entry by disrupting ACE2 binding with the SARS-CoV-2 spike protein. This work focuses on inhibiting SARS-CoV-2 entry through a hypothesized α5β1 integrin-based mechanism, and indicates that inhibiting the spike protein interaction with α5β1 integrin (+/- ACE2), and the interaction between α5β1 integrin and ACE2 using a molecule ATN-161 represents a promising approach to treat COVID-19.


Supplementation of a restricted maternal diet with protein or carbohydrate alone prevents a reduction in fetal muscle fibre number in the guinea-pig.
A 60% reduction in maternal feed intake is known to cause a reduction of approximately 20% in biceps brachii fibre number in the guinea-pig fetus. This investigation was designed to isolate the dietary component responsible by reducing all dietary components to 60% of the ad lib. level and supplementing the protein, carbohydrate or fat component to the level of the ad lib. intake. Fetal muscles were examined at 50 d gestation to determine numbers of primary and secondary fibres, and at term to determine total fibre number. Fetal and neonatal weights were reduced in all restricted groups (P < 0.05) when compared with ad lib. controls. At term this reduction was significantly less (P < 0.05) in the protein-supplemented group (20%) than in the 60%-restricted and fat-supplemented groups (43%) and the carbohydrate-supplemented group (34%). Biceps brachii fibre numbers were reduced in the 60%-restricted fat-supplemented groups by 14-16%, but fibre numbers were similar in control, protein-supplemented and carbohydrate-supplemented groups. Any reduction in fibre number was in the secondary fibre component of total fibre number. Therefore, biceps brachii fibre numbers were reduced only when maternal diets were deficient in both protein and carbohydrate.


Unraveling the mechanism of high altitude pulmonary edema.
During the last decade, major advances in the understanding of the mechanism of high altitude pulmonary edema (HAPE) have supplemented the landmark work done in the previous 30 years. A brief review of the earlier studies will be described, which will then be followed by a more complete treatise on the subsequent research, which has elucidated the role of accentuated pulmonary hypertension in the development of HAPE. Vasoactive mediators, such as nitric oxide (NO) and endothelin-1, have played a major role in this understanding and have led to preventive and therapeutic interventions. Additionally, the role of the alveolar epithelium and the Na-K ATPase pump in alveolar fluid clearance has also more recently been understood. Direction for future work will be given as well.


Genotypic association analysis using discordant-relative-pairs.
In practice, family-based design has been widely used in disease-gene association analysis. The major advantage of such design is that it is not subject to spurious association due to population structure such as population stratification (PS) and admixture. A disadvantage is that parental genotypes are hard to obtain if the disease is late onset for which a discordant-relative-pair design is useful. Designs of such kind include full-sib-pair, half-sib-pair, first-cousin-pair, and so on. The closer the relatedness of the pair, the less possible that they are subject to population stratification. On the other hand, the association test using close relative-pairs may be less powerful due to over-matching. Trade-off between these two factors (population structure and over-matching) is the major concern of this study. Some tests, namely McNemar's test, matched Cochran-Armitage trend tests (CATTs), matched maximum efficient robust test (MERT), and Bhapkar's test, are used for testing disease-gene association based on relative-pair designs. These tests are shown to be valid in the presence of PS but not admixture. Numerical studies show that the McNemar's test, additive CATT, MERT, and Bhapkar's test are robust in power, but none of them is uniformly more powerful than the others. In most simulations, the power of any of the tests increases as the pair is more distant. The proposed methods are applied to two real examples.


Meta-analysis of the effects of respiratory rehabilitation programmes on exercise capacity in accordance with programme characteristics.
This study was performed to investigate the effects of respiratory rehabilitation programmes on exercise capacity in terms of the programme type, the protocol used and other programme characteristics. As the suitable rehabilitation programmes have not been specified, diverse programmes are provided in clinics. Meta-analysis of the primary study results. A computerized search through MEDLINE and CINHAL in addition to tracking down references cited in bibliographies of primarily searched studies were performed to obtain sample studies. Finally 19 research reports were examined. The results of meta-regression showed that the combined effect size of the programmes on exercise capacity was unaffected by forced expiratory volume (in one second), age, the duration and frequency of the programme, or study quality. In addition, the results of meta-anova indicated that the combined effect size was not affected by (i) whether a programme was hospital based or not, (ii) whether a programme was lower-extremity or combined low- and upper-extremity exercise training, (iii) measurement time, and (iv) exercise intensity. The effects of programmes on exercise capacity were not differed in terms of the places where rehabilitation programmes were applied, programme content, measurement time, exercise target sites of body, and the duration and frequency of the programme. The results of the present study can provide objective data when constructed or applied on a respiratory rehabilitation programme in clinics.


On biometric systems: electrocardiogram Gaussianity and data synthesis.
Electrocardiogram is a slow signal to acquire, and it is prone to noise. It can be inconvenient to collect large number of ECG heartbeats in order to train a reliable biometric system; hence, this issue might result in a small sample size phenomenon which occurs when the number of samples is much smaller than the number of observations to model. In this paper, we study ECG heartbeat Gaussianity and we generate synthesized data to increase the number of observations. Data synthesis, in this paper, is based on our hypothesis, which we support, that ECG heartbeats exhibit a multivariate normal distribution; therefore, one can generate ECG heartbeats from such distribution. This distribution is deviated from Gaussianity due to internal and external factors that change ECG morphology such as noise, diet, physical and psychological changes, and other factors, but we attempt to capture the underlying Gaussianity of the heartbeats. When this method was implemented for a biometric system and was examined on the University of Toronto database of 1012 subjects, an equal error rate (EER) of 6.71% was achieved in comparison to 9.35% to the same system but without data synthesis. Dimensionality reduction is widely examined in the problem of small sample size; however, our results suggest that using the proposed data synthesis outperformed several dimensionality reduction techniques by at least 3.21% in EER. With small sample size, classifier instability becomes a bigger issue and we used a parallel classifier scheme to reduce it. Each classifier in the parallel classifier is trained with the same genuine dataset but different imposter datasets. The parallel classifier has reduced predictors' true acceptance rate instability from 6.52% standard deviation to 1.94% standard deviation.


The definition of life: a brief history of an elusive scientific endeavor.
In spite of the spectacular developments in our understanding of the molecular basis that underlies biological phenomena, we still lack a generally agreed-upon definition of life, but this is not for want of trying. Life is an empirical concept; and, as suggested by the many unsuccessful efforts to define it, this task is likely to remain, at best, a work in progress. Although phenomenological characterizations of life are feasible, a precise definition of life remains an elusive intellectual endeavor. This is not surprising: as Nietszche once wrote, there are concepts that can be defined, whereas others only have a history. The purpose of this essay is to discuss some of the manifold (and often unsatisfactory) definitions of life that have been attempted from different intellectual and scientific perspectives and reflect, at least in part, the key role that historical frameworks play. Although some efforts have been more fruitful, the lack of an all-embracing, generally agreed-upon definition of life sometimes gives the impression that what is meant by life's origin is defined in somewhat imprecise terms and that several entirely different questions are often confused. The many attempts made to reduce the nature of living systems to a single living compound imply that life can be so well defined that the exact point at which it started can be established with the sudden appearance of the first replicating molecule. On the other hand, if the emergence of life is seen as the stepwise (but not necessarily slow) evolutionary transition between the non-living and the living, then it may be meaningless to draw a strict line between them.


Scleromyxedema myopathy: case report and review of the literature.
We describe a patient who had scleromyxedema associated with proximal myopathy. The histopathologic and electron microscopic features are presented. In addition, we review the clinical and pathologic features of all 9 previously reported patients with documented scleromyxedema and myopathy. Proximal (pharyngeal) or distal dysphagia (7 of 7 patients), elevated creatine kinase (5 of 8), elevated aldolase (3 of 3), and electromyographically demonstrated myopathy (7 of 7) were usual features. Four patients had muscle biopsies that showed myofibril vacuolar changes, but inflammation was infrequent (2 cases). Our patient responded to oral prednisone and weekly intravenous methotrexate with improvement of the erythroderma, papular rash, and muscle strength.


Pathogenesis of preeclampsia: a comprehensive model.
The objective of this review was to provide a comprehensive and practical concept on the pathogenesis of preeclampsia on the basis of the currently available scientific evidence. A MEDLINE search was performed of English-language articles published between 1966 and 1997, supplemented with references cited in relevant research articles. Using our data sources, we developed a scheme describing the sequence of events between implantation and the time of manifest clinical disease characterized by generalized endothelial cell dysfunction. A yet unidentified toxic circulating factor released by the ischemic placenta, is held responsible for the impaired endothelial cell function. Particularly, epidemiological studies point to a concept in which immune maladaptation to the fetal allograft plays a key role in causing defective placentation leading to placental ischaemia. The incidence of preeclampsia in sisters and daughters of women who had had preeclampsia is raised. Disease states with vascular involvement, like chronic hypertension and diabetes mellites, are associated with an increased risk for preeclampsia. Recently subclinical abnormalities in hemostasis, metabolism and volume homeostasis have been described in patients with a history of preeclampsia. Placental ischemia secondary to defective placentation, a prerequisite for the development of preeclampsia, has a multifactorial origin consisting of three major components: immune maladaptation, genetic predisposition, and vascular mediated factors. Probably, a summation of these factors will determine whether a pregnant woman is to develop the syndrome. The recently described subclinical abnormalities in hemostasis, metabolism, and vascular function in patients with a history of preeclampsia might give the clinician the opportunity to reduce the recurrence risk by pharmacotherapeutic intervention.


Lipocortins are major substrates for protein kinase C in extracts of human neutrophils.
We have identified two major proteins in human neutrophils that are phosphorylated in vitro by protein kinase C (PKC) as lipocortins III and a fragment of a lipocortin-like 68-kDa protein. In electroporated cells, the 68-kDa protein was phosphorylated during stimulation of the cells with either FMLP or PMA. Lipocortins are of interest because of their Ca2(+)- and phospholipid-dependent actin binding properties and ability to inhibit phospholipase A2. Two crude fractions of enzymes and proteins exposed to [gamma-32]PATP in the presence of Ca2+, Mg2+, phosphatidylserine and 1,2-oleoyl-acetyl-rac-glycerol were analyzed by gel electrophoresis and autoradiography. A number of proteins in a detergent-free fraction, including proteins at 36 and 32 kDa, were phosphorylated in the presence of these cofactors. In contrast, only two major proteins (35 and 32 kDa) were phosphorylated in a detergent-extracted fraction. Phosphorylation of the 36, 35, and 32 kDa proteins required the presence of Ca2+, Mg2+, and phosphatidylserine in our soluble fraction and detergent extract, indicating PKC-dependent phosphorylation. The 32-kDa protein phosphorylated in both the soluble fraction and detergent extract was identified as lipocortin III by immunoprecipitation with a cross-reactive antibody that recognized lipocortin I and comparison of cyanogen bromide (CNBr) cleavage patterns of this protein with a lipocortin III standard. The 68-kDa protein was identified as a lipocortin VI-like protein by immunoprecipitation with anti-calelectrin. Additionally, the CNBr cleavage pattern of the 68-kDa protein was similar to that of the 36-kDa protein phosphorylated in our soluble fraction. Autoradiograms of the 68- and 36-kDa fragments immunoprecipitated from our soluble fraction with anticalelectrin and cleaved with CNBr showed that both of these proteins were phosphorylated in this sample. Because phosphorylation is known to change the functional characteristics of the lipocortins, the potential exists to link PKC and lipocortins in neutrophils to regulation of granulemembrane interactions or mediation of inflammation.


Impact of Hypertension and Subclinical Organ Damage on the Incidence of Cardiovascular Disease Among Japanese Residents at the Population and Individual Levels - The Circulatory Risk in Communities Study (CIRCS).
In Japan, a community-based screening program for cardiovascular disease (CVD) has been effective in preventing stroke and coronary artery disease (CAD). The present study aimed to clarify which risk factors assessed at the screening examinations affect the incidence of CVD and the magnitude of the association after the late 1990 s.Methods and Results:We conducted a 12.5-year prospective study of 10,612 Japanese residents aged 40-74 years between 1995 and 2000, initially free of CVD and who underwent the screening examinations. During the follow-up, 364 cases of stroke and 137 cases of CAD were identified. The population attributable fraction of stroke was the largest for hypertension (HT; 46%), while the relative risk of stroke was the highest for atrial fibrillation (multivariable hazard ratio, 4.9; 95% confidence interval, 2.9-8.3). The population attributable fraction of CAD was relatively large for HT, current smoking, and high non-high-density lipoprotein cholesterol (20-29%). A dose-response relationship was found between the incidence of these cardiovascular events and the number of comorbid hypertensive subclinical organ damage markers: funduscopic changes, ST-T changes on ECG at rest, proteinuria and low estimated glomerular filtration rate. HT and hypertensive subclinical organ damage are significantly associated with incident stroke and CAD at the population level, suggesting that management of HT and assessment of subclinical organ damage in hypertensive subjects at a screening program are still beneficial for community-based CVD prevention.


Effect of Pycnogenol® on attention-deficit hyperactivity disorder (ADHD): study protocol for a randomised controlled trial.
Methylphenidate (MPH), the first choice medication for attention-deficit hyperactivity disorder (ADHD), is associated with serious adverse effects like arrhythmia. Evidence on the association of ADHD with immune and oxidant-antioxidant imbalances offers potential for antioxidant and/or immunomodulatory nutritional supplements as ADHD therapy. One small randomised trial in ADHD suggests, despite various limitations, therapeutic benefit from Pycnogenol®, a herbal, polyphenol-rich extract. This phase III trial is a 10-week, randomised, double-blind, placebo and active treatment controlled multicentre trial with three parallel treatment arms to compare the effect of Pycnogenol® to MPH and placebo on the behaviour of 144 paediatric ADHD and attention-deficit disorder (ADD) patients. Evaluations of behaviour (measured by the ADHD-Rating Scale (primary endpoint) and the Social-emotional Questionnaire (SEQ)), immunity (plasma cytokine and antibody levels, white blood cell counts and faecal microbial composition), oxidative stress (erythrocyte glutathione, plasma lipid-soluble vitamins and malondialdehyde and urinary 8-OHdG levels, as well as antioxidant enzyme activity and gene expression), serum zinc and neuropeptide Y level, urinary catecholamines and physical complaints (Physical Complaints Questionnaire) will be performed in week 10 and compared to baseline. Acceptability evaluations will be based on adherence, dropouts and reports of adverse events. Dietary habits will be taken into account. This trial takes into account comorbid behavioural and physical symptoms, as well as a broad range of innovative immune and oxidative biomarkers, expected to provide fundamental knowledge on ADHD aetiology and therapy. Research on microbiota in ADHD is novel. Moreover, the active control arm is rather unseen in research on nutritional supplements, but of great importance, as patients and parents are often concerned with the side effects of MPH. Clinicaltrials.gov number: NCT02700685 . Registered on 18 January 2016. EudraCT 2016-000215-32 . Registered on 4 October 2016.


Determining an approximate minimum toxic dosage of diphacinone in horses and corresponding serum, blood, and liver diphacinone concentrations: a pilot study.
Poisoning of nontarget species is a major concern with the use of anticoagulant rodenticides (ARs). At postmortem examination, differentiating toxicosis from incidental exposure is sometimes difficult. Clotting profiles cannot be performed on postmortem samples, and clinically significant serum, blood, and liver AR concentrations are not well-established in most species. We chose diphacinone for our study because, at the time, it was the publicly available AR most commonly detected in samples analyzed at the University of Kentucky Veterinary Diagnostic Laboratory. We determined an approximate minimum toxic dosage (MTD) of oral diphacinone in 3 horses and measured corresponding serum, blood, and liver diphacinone concentrations. Diphacinone was administered orally to healthy horses. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and serum and blood diphacinone concentrations were measured daily. At the study endpoint, the horses were euthanized, and diphacinone concentration was measured in each liver lobe. The horse that received 0.2 mg/kg diphacinone developed prolonged (>1.5× baseline) PT and aPTT; the horse that received 0.1 mg/kg did not. This suggests an approximate oral MTD in horses of 0.2 mg/kg diphacinone. Median liver diphacinone concentration at this dosage was 1,780 (range: 1,590-2,000) ppb wet weight. Marginal (model-adjusted) mean diphacinone concentrations of liver lobes were not significantly different from one another (p = NS). Diphacinone was present in similar concentrations in both serum and blood at each time after administration, indicating that both matrices are suitable for detection of diphacinone exposure in horses.


[On the 150th anniversary of the introduction of anesthesia in Spain: the role of dentists].
We first discuss the circumstances that were influential in the role played by dentists during the early stages of anesthesia. We then study the positions of several Spanish dentists on the new technique for eliminating pain. Two opposing groups are found: on the one hand physician-dentists were cautions and prudent, and on the other, professionals with lesser qualifications such as surgeon-dentists, healers and bloodletters were clearly and boldly in favor of the new technique.


Detection of telomerase activity in exfoliated cells in urine from patients with bladder cancer.
Telomeres are specific structures located at the ends of chromosomes that help maintain chromosome stability. In most tissues, telomeres become shorter as cells divide, a phenomenon thought to be associated with limitations on normal cell proliferation. Almost all types of cancer cells, including bladder cancer cells, express the enzyme telomerase, which can maintain or extend telomere length. We examined telomerase activity in tumor specimens from a cohort of patients with bladder cancer and determined whether telomerase could be detected in exfoliated cancer cells present in urine from these patients. Spontaneously voided urine specimens and bladder-washing fluids (obtained by propelling normal saline into the bladder through a catheter and then withdrawing the liquid contents) were taken from 45 patients before they underwent surgery. Telomerase activity was examined by means of the TRAP (telomeric repeat amplification protocol) assay on extracts of tumor samples from 42 patients and extracts of exfoliated cells in urine and bladder-washing fluid from 42 and 43 patients, respectively. Standard cytologic examination (Pap staining) of urine specimens was also used to detect exfoliated cancer cells. Telomerase activity was found in 41 (98%; 95% confidence interval [CI] = 87%-100%) of the 42 tumor samples examined. In contrast, it was not detected in normal bladder tissue from two autopsied individuals who were free of bladder cancer and five of six individuals who had bladder cancer. Telomerase was detected in exfoliated cells in 23 (55%; 95% CI = 39%-70%) of the 42 spontaneously voided urine specimens and in 36 (84%; 95% CI = 69%-93%) of the 43 bladder-washing fluids examined. Considering voided urine specimens and bladder-washing fluids together, telomerase was detected in exfoliated cells from 40 (89%; 95% CI = 76%-96%) of the 45 patients. Telomerase activity was not detected in bladder-washing fluids from 12 cancer-free individuals. Cancer cells were detected by means of standard cytologic examination in the urine of 19 (42%; 95% CI = 28%-58%) of the 45 patients. Urine cytologic examination detected cancer cells in one (8%; 95% CI = 0%-38%) of 12 patients with grade 1 tumors and in 13 (46%; 95% CI = 28%-66%) of 28 patients with grade 2 tumors. In contrast, telomerase activity was detected in exfoliated cells (in voided urine or bladder-washing fluids) from nine (75%; 95% CI = 43%-95%) of 12 patients with grade 1 tumors and from 27 (96%; 95% CI = 82%-100%) of 28 patients with grade 2 tumors. Telomerase activity can be detected in exfoliated cells in urine from patients with bladder cancer, and measurement of this activity appears to be more sensitive in detecting the presence of cancer than standard urine cytologic examination. These findings suggest that measuring telomerase activity in exfoliated cells would be useful in the diagnosis and follow-up of patients with bladder cancer, a possibility that warrants further study.


Metagenomic Survey of the Highly Polyphagous Anastrepha ludens Developing in Ancestral and Exotic Hosts Reveals the Lack of a Stable Microbiota in Larvae and the Strong Influence of Metamorphosis on Adult Gut Microbiota.
We studied the microbiota of a highly polyphagous insect, Anastrepha ludens (Diptera: Tephritidae), developing in six of its hosts, including two ancestral (Casimiroa edulis and C. greggii), three exotic (Mangifera indica cv. Ataulfo, Prunus persica cv. Criollo, and Citrus x aurantium) and one occasional host (Capsicum pubescens cv. Manzano), that is only used when extreme drought conditions limit fruiting by the common hosts. One of the exotic hosts ("criollo" peach) is rife with polyphenols and the occasional host with capsaicinoids exerting high fitness costs on the larvae. We pursued the following questions: (1) How is the microbial composition of the larval food related to the composition of the larval and adult microbiota, and what does this tell us about transience and stability of this species' gut microbiota? (2) How does metamorphosis affect the adult microbiota? We surveyed the microbiota of the pulp of each host fruit, as well as the gut microbiota of larvae and adult flies and found that the gut of A. ludens larvae lacks a stable microbiota, since it was invariably associated with the composition of the pulp microbiota of the host plant species studied and was also different from the microbiota of adult flies indicating that metamorphosis filters out much of the microbiota present in larvae. The microbiota of adult males and females was similar between them, independent of host plant and was dominated by bacteria within the Enterobacteriaceae. We found that in the case of the "toxic" occasional host C. pubescens the microbiota is enriched in potentially deleterious genera that were much less abundant in the other hosts. In contrast, the pulp of the ancestral host C. edulis is enriched in several bacterial groups that can be beneficial for larval development. We also report for the first time the presence of bacteria within the Arcobacteraceae family in the gut microbiota of A. ludens stemming from C. edulis. Based on our findings, we conclude that changes in the food-associated microbiota dictate major changes in the larval microbiota, suggesting that most larval gut microbiota is originated from the food.


Transformation in the pharmaceutical industry--a systematic analysis of operational evidence.
Through systematic collection and trending of pharmaceutical data, operational evidence to verify existence of 14 factors affecting the ongoing pharmaceutical transformation has been compiled. These 14 factors are termed transformation triggers. The theoretical evidence in support of these triggers is carried forward from a systematic review of the literature that was conducted previously. Trends in operational evidence and the associated theoretical evidence were compared to identify areas of similarity and contrast. Areas of strong correlation between theoretical evidence and operational evidence included four transformation triggers: a fully integrated pharma network, personalized medicine, translational research, and pervasive computing. Key areas of contrast included three transformation triggers-namely, healthcare management focus, adaptive trials, and regulatory enforcement-for which the operational evidence was stronger than the theoretical evidence. The intent of this paper is to provide proof to demonstrate if there is any operational evidence that supports the 14 transformation triggers previously identified during the theoretical part of this research. The theoretical evidence for these triggers was carried forward to this paper for study from an operational perspective. The practical evidence established in this paper was compared with the corresponding theoretical evidence to identify areas of similarity and difference. This resulted in four triggers that had strong relationship between operational and theoretical evidence; they are a fully integrated pharma network, personalized medicine, translational research, and pervasive computing. The areas of difference included three transformation triggers for which the operational evidence was stronger than the theoretical evidence. These were healthcare management focus, adaptive trials, and regulatory enforcement.


Cardiac Ultrasound under Speckle Tracking Technology Based Analysis of Efficacy of Respiratory Rehabilitation on Chronic Obstructive Pulmonary Disease.
The study shined spotlight on the effect of respiratory rehabilitation training on chronic obstructive pulmonary disease (COPD), which was evaluated using speckle ultrasound algorithm-based cardiac ultrasound. Then, 90 patients with stable COPD, who were admitted to the hospital from January 2018 to December 2019, were randomly rolled into three groups, namely, the fast inhalation and slow exhalation (A) group, abdominal breathing (B) group, and control (C) group. For group A, on the basis of the conventional treatment, the method of rapid inhalation and slow exhalation was adopted. The group B (n = 30) adopted the abdominal breathing method besides the conventional treatment. In addition, the group C (n = 30) received only conventional treatment. Finally, the efficacy and parameters of the three treatment methods were compared. The echocardiographic parameters and echocardiographic images were calculated and processed by the speckle tracking method. Three kinds of operators were used to track the myocardial spots successfully, and the corresponding points in the image were obtained and calculated. It was found that there was no significant difference in the degree of dyspnea, exercise endurance, lung function, respiratory muscle function, and quality of life (QOL) before treatment (P > 0.05). After treatment, in contrast with group C, the previously mentioned indicators in groups A and B were obviously better (P < 0.05). Further, both the echocardiographic images and echocardiographic parameters of groups A and B were obviously improved, and there was no obvious difference between groups A and B. Hence, some degree of respiratory rehabilitation was very effective in the diagnosis of patients with chronic pulmonary obstruction. In conclusion, the speckle tracking algorithm-based cardiac ultrasound improves the image quality. At the same time, respiratory rehabilitation training is effective on COPD and worthy of clinical promotion.


Selective alveolo-bronchographic findings in type B chronic obstructive lung disease patients with particular reference to lesions in small airways.
Selective alveolo-bronchography (SAB) was performed in 14 patients with type B chronic obstructive lung disease to evaluate the morphologic changes of their "small airways". The distance from the branching portion of the segmental bronchus (B9) to the end of the conducting airway was divided into three equal parts (central, middle and peripheral). In the peripheral part, interruption of the airway with a rounded or tapering end was noted at a high incidence (9 cases). Dilatation of the bronchus, irregular outline of the bronchial wall and increased angle of branching were also conspicuous in this part. Inadequate lateral branchings of airways were often observed in the middle and the peripheral part, particularly in the latter (10 cases). Generalized narrowing of an airway and narrowing especially at a branching point were observed in about one half of the cases. Fringes and/or spikes were most often seen in the central part of the airway (9 cases). These pathological appearances are considered to reflect morphologic changes in "small airway disease", and thus SAB can serve as a useful method for detecting lesions of the small airways.


Greater renal vascular involvement in the black patient with essential hypertension. A comparison of systemic and renal hemodynamics in black and white patients.
Systemic, splanchnic, and renal hemodynamic data were derived from 60 male and female, black and white, untreated and uncomplicated patients with essential hypertension. The systemic hemodynamic data confirmed our previous findings that at any level of arterial pressure, when black and white patients are matched for age, sex, and mean arterial pressure, cardiac index and total peripheral resistance were similar. This suggests that hypertensive vascular disease is no more severe in the black. This concept was supported further with respect to the splanchnic vasculature; however, renal blood flow was less and renal vascular resistance was higher at any level of mean arterial pressure (or total peripheral resistance) in the black. These physiological findings lend credence to those reports suggesting that at any level of pressure, hypertensive disease and morbidity (e.g., renal impairment) are more severe in the black patient. In addition, these data underscore the importance of understanding regional circulatory characteristics and they do not necessarily follow pari passu measured indices of systemic hemodynamics.


Bivalent vaccines effectively protect mice against influenza A and respiratory syncytial viruses.
Influenza and Respiratory Syncytial virus (RSV) infections together contribute significantly to the burden of acute lower respiratory tract infections. Despite the disease burden, no approved RSV vaccine is available. While approved vaccines are available for influenza, seasonal vaccination is required to maintain protection. In addition to both being respiratory viruses, they follow a common seasonality, which warrants the necessity for a concerted vaccination approach. Here, we designed bivalent vaccines by utilizing highly conserved sequences, targeting both influenza A and RSV, as either a chimeric antigen or individual antigens separated by a ribosome skipping sequence. These vaccines were found to be effective in protecting the animals from challenge by either virus, with mechanisms of protection being substantially interrogated in this communication.


Transfer of Stress Resilient QTLs and Panicle Traits into the Rice Variety, Reeta through Classical and Marker-Assisted Breeding Approaches.
Reeta is a popular late-maturing high-yielding rice variety recommended for cultivation in the eastern Indian states. The cultivar is highly sensitive to submergence stress. Phosphorus deficiency is an additional constraint for realizing high yield. The quantitative trait loci (QTLs), Sub1, for submergence and Pup1 for low phosphorus stress tolerance along with narrow-grained trait, GW5 were introgressed into the variety from the donor parent, Swarna-Sub1 through marker-assisted breeding. In addition, phenotypic selections for higher panicle weight, grain number, and spikelet fertility were performed in each segregating generation. Foreground selection detected the 3 target QTLs in 9, 8 and 7 progenies in the BC1F1, BC2F1, and BC3F1 generation, respectively. Recurrent parent's genome recovery was analyzed using 168 SSR polymorphic markers. The foreground analysis in 452 BC3F2 progenies showed five pyramided lines in homozygous condition for the target QTLs. No donor fragment drag was noticed in the Sub1 and GW5 QTLs carrier while a segmentwas observed in the Pup1 carrier chromosome. The developed lines were higher yielding, had submergence, and had low phosphorus stress-tolerance alongwith similar to the recipient parent in the studied morpho-quality traits. A promising pyramided line is released in the name of Reeta-Panidhan (CR Dhan 413) for the flood-prone areas of Odisha state.


Genetics and paediatric nursing.
In response to major research initiatives in genetics, the government has invested significantly in new programmes of research and development for NHS staff (Department of Health (DH) 2003. Nurses may feel that these programmes have not yet impacted on their area of practice and are unlikely to for some time. Other priorities may be felt to be more important. This article considers the impact of genetics on the work of nurses who care for children and young people. It introduces a short questionnaire which we are using to identify and fill any gaps in knowledge, training and resources for nurses to prepare them to 'realise the potential of genetics' (DH 2003) in their practice.


Did Kettlewell commit fraud? Re-examining the evidence.
H.B.D. Kettlewell is famous for several investigations conducted in the early 1950s on the phenomenon of industrial melanism, which are widely regarded as the classic demonstration of natural selection. In a recent (2002) book-length popularization of this episode in the history of the science, science writer Judith Hooper draws attention to what she interprets as discrepancies in the results reported by Kettlewell in his first scientific papers on the subject. On the basis of correspondence among Kettlewell and his associates, a survey of scientific publications that mention outstanding questions surrounding the phenomenon, as well as interviews with his son, surviving colleagues, and scientists who have worked on industrial melanims, Hooper all but explicitly concludes that Kettlewell committed fraud. The following essay critically examines her evidence in support of this allegation, including her discussion of his character, the alleged motives, and whether fraud was even committed. None of Hooper's arguments is found to withstand careful scrutiny. The concluding section draws several conclusions about how history of science should be depicted to the public.


Composition and antibacterial activity of the essential oils from Zanthoxylum rhoifolium.
The essential oils from the aerial parts of leaves, fruits and flowers of Zanthoxylum rhoifolium of Southern Brazil (Rio Grande do Sul), were analysed by GC, GC/MS, and chiral phase gas chromatography (CPGC). Forty-eight compounds were identified from the essential oils. The major constituents of the essential oil of the leaves were germacrene D (34 %) and bicyclogermacrene (23 %) and of the fruits, menth-2-en-1-ol (46.2 %), beta-myrcene (30.2 %), (-)-linalool (15 %) and (-)-alpha-terpineol (8.45 %). beta-Myrcene (65 %) and menth-2-en-1-ol (5.4 %) dominate the essential oil of the flowers. The oils of the leaves and fruits were bioactive with antibacterial activity against Staphylococcus aureus (Gram positive), and Klebsiella pneumoniae and Salmonella setubal bacteria (Gram negative) microorganisms, while the essential oil of the flowers was inactive.


Productivity of Senior Dental Students Engaged in Comprehensive Care: A Seven-Year Follow-Up Study.
The aims of this study were to determine the trend of senior dental students' rate of production of clinical procedures performed in the comprehensive care clinic at one U.S. dental school and to compare that trend to what was reported immediately following inception of that clinic. In addition, total clinic revenues collected were recorded and compared. The periods used for comparisons were 2005 and 2006 combined, the last years before introduction of comprehensive care (called "pre-comp care"); 2007 and 2008 combined, the first two years of comprehensive care (called "post-comp care"); and subsequent years through 2014. The number of procedures and total charges were tracked in the electronic health record, and the total number of student-hours was calculated by multiplying the number of students in the class by the total number of available clinic hours. The rate calculated in this way was then multiplied by a factor of 1,000 for ease of interpretation. The results showed a generally upward trend and a significant increase from post-comp care to 2014 for all procedures combined and for indirect restorations. There was a generally downward trend and a significant decrease from post-comp care to 2014 for direct restorations, extractions, and root planing. There was some up and down fluctuation but no significant change from post-comp care to 2014 for exams. In terms of all procedures, the rate per student/1,000 clinic hours increased from approximately 227 to 419, an 85% increase over seven years. These results show that implementation of the comprehensive care clinic model of clinical education has increased the total clinical productivity of senior dental students at this dental school. Additional studies are indicated to determine the proper balance between a quality education and the financial capabilities of the institution.


Microsurgical reconstruction of wide simple and compound foot defects.
A mutilated foot as a result of traumas or resection for tumours or ulcers, is a serious physical and social handicap for the patient, because it impairs deambulation and affects his selfgovernment. The evolution of microsurgical techniques has allowed us to utilize such methods to reconstruct wide simple and composite losses of substance of the foot, usually treated conservatively or radically with amputation and prosthesization. Functional, cosmetic and social outcome has been evaluated. We evaluated 23 patients affected by cutaneous (19) and osteocutaneous (4) losses of substance of the foot (11 of rearfoot, 5 of forefoot, 4 of the sole, 1 of middlefoot, 1 of the dorsum, and 1 of the malleolus). We performed 23 microsurgical reconstructions harvesting 24 free flaps (14 radial flaps, 4 latissimus dorsi, 3 fibula, 1 scapular flap, 1 lateral arm, 1 iliac crest). Cutaneous and muscular flaps healed in 3 weeks, while osteocutaneous flaps healed in 10 to 12 weeks. Deambulation was restored in all patients but 1, within 6 months from surgery, and all patients went back to their work and social life. We observed in the early follow-up 2 cases of partial skin necrosis, which solved spontaneously and 1 case of total necrosis (overall complication = 4.3%). Donor area morbidity was rated as fair. Overall success rate was 95.7% at a mean follow-up of 3 years. Free microsurgical transfers allowed us to obtain a satisfactory and long-lasting morpho-functional restoration of wide superficial and deep losses of substance of the foot, guaranteeing the patient a fast psycho-physical and social rehabilitation.


Electrophysiological simulation of tinnitus.
The auditory brainstem response to clicks of 60 dB sensation level was recorded with superimposed pure tones at six frequencies and four sensation levels in an attempt to simulate the effects of tinnitus on the auditory brainstem response. Changes in responses were assessed by subtracting the auditory brainstem response obtained to the click-plus-tone from the auditory brainstem response obtained to the immediately preceding click alone. The dyssynchrony created by exogenously produced pure tones was considerable and probably reflected adaptation of individual single units; however, the auditory brainstem response to clicks alone changed markedly from the beginning to the end of the experiment and confounded a simple interpretation of the results.


HIV type 1 and cytomegalovirus coinfection in the female genital tract.
The relationship between human immunodeficiency virus (HIV) type 1 and human cytomegalovirus (CMV) was studied in blood, saliva, and cervicovaginal lavage (CVL) specimens from 33 HIV-1-infected women. An association between HIV-1 RNA and CMV DNA was found in the CVL specimens, which also were tested for cytokine levels. Women with detectable CMV DNA in CVL specimens were more likely to have higher interleukin (IL)-1 beta and IL-8 levels than were women with undetectable CMV DNA in CVL specimens. More than 1 strain of CMV was detected in specimens from 2 patients. These results suggest mechanisms by which CMV coinfection could affect HIV-1 disease progression.


Potential molecular mechanisms of myrtenal against colon cancer: A systematic review.
Colon cancer is a serious health problem across the globe with various dietary lifestyle modifications. It arises as an inflammation mediated crypts in the colon epithelial cells and undergoes uncontrolled cell division and proliferation. Bacterial enzymes contribute to a major outbreak in colon cancer development upon the release of toxic metabolites from the gut microflora. Pathogen associated molecular patterns and damage associated molecular patterns triggers the NLPR3 inflammasome pathways that releases pro-inflammatory cytokines to induce cancer of the colon. Contributing to this, specific chemokines and receptor complexes attribute to cellular proliferation and metastasis. Bacterial enzymes synergistically attack the colon mucosa and degenerate the cellular integrity causing lysosomal discharge. These factors further instigate the Tol like receptors (TLRs) and Nod like receptors (NLRs) to promote angiogenesis and supply nutrients for the cancer cells. Myrtenal, a monoterpene, is gaining more importance in recent times and it is being widely utilized against many diseases such as cancers, neurodegenerative diseases and diabetes. Based on the research data's, the reviews focus on the anticancer property of myrtenal by emphasizing its therapeutic properties which downregulate the inflammasome pathways and other signalling pathways. Combination therapy is gaining more importance as they can target every variant in the cellular stress condition. Clinical studies with compounds like myrtenal of the monoterpenes family is provided with positive results which might open an effective anticancer drug therapy. This review highlights myrtenal and its biological potency as a cost effective drug for prevention and treatment of colon cancer.


Staining and embedding of human chromosomes for 3-d serial block-face scanning electron microscopy.
The high-order structure of human chromosomes is an important biological question that is still under investigation. Studies have been done on imaging human mitotic chromosomes using mostly 2-D microscopy methods. To image micron-sized human chromosomes in 3-D, we developed a procedure for preparing samples for serial block-face scanning electron microscopy (SBFSEM). Polyamine chromosomes are first separated using a simple filtration method and then stained with heavy metal. We show that the DNA-specific platinum blue provides higher contrast than osmium tetroxide. A two-step procedure for embedding chromosomes in resin is then used to concentrate the chromosome samples. After stacking the SBFSEM images, a familiar X-shaped chromosome was observed in 3-D.


Reading the dyslexic brain: multiple dysfunctional routes revealed by a new meta-analysis of PET and fMRI activation studies.
Developmental dyslexia has been the focus of much functional anatomical research. The main trust of this work is that typical developmental dyslexics have a dysfunction of the phonological and orthography to phonology conversion systems, in which the left occipito-temporal cortex has a crucial role. It remains to be seen whether there is a systematic co-occurrence of dysfunctional patterns of different functional systems perhaps converging on the same brain regions associated with the reading deficit. Such evidence would be relevant for theories like, for example, the magnocellular/attentional or the motor/cerebellar ones, which postulate a more basic and anatomically distributed disorder in dyslexia. We addressed this issue with a meta-analysis of all the imaging literature published until September 2013 using a combination of hierarchical clustering and activation likelihood estimation methods. The clustering analysis on 2360 peaks identified 193 clusters, 92 of which proved spatially significant. Following binomial tests on the clusters, we found left hemispheric network specific for normal controls (i.e., of reduced involvement in dyslexics) including the left inferior frontal, premotor, supramarginal cortices and the left infero-temporal and fusiform regions: these were preferentially associated with reading and the visual-to-phonology processes. There was also a more dorsal left fronto-parietal network: these clusters included peaks from tasks involving phonological manipulation, but also motoric or visuo-spatial perception/attention. No cluster was identified in area V5 for no task, nor cerebellar clusters showed a reduced association with dyslexics. We conclude that the examined literature demonstrates a specific lack of activation of the left occipito-temporal cortex in dyslexia particularly for reading and reading-like behaviors and for visuo-phonological tasks. Additional deficits of motor and attentional systems relevant for reading may be associated with altered functionality of dorsal left fronto-parietal cortex.


Measuring functional impairment associated with pain: psychometric analysis of an exploratory scoring protocol for activity pattern indicators.
Behavioral science theorists who study pain have advocated the development of measures designed to assess aspects of behavior. Recently, Diller , Fordyce , Jacobs, and Brown developed a 64-item self-report activity measure. Assessment of functional impairment associated with pain is a potentially appropriate application for the Activity Pattern Indicators (API). The API provides a description of actual functioning; frequency of behavior is the unit of measurement. Currently, no agreed upon scoring protocol is available for this measure. We propose to design, in accordance with measurement theory, a psychometrically sound yet practical scoring protocol. The API data presented allow an acceptable degree of reliability and sensitivity to group differences. Results of the present study support continued psychometric exploration of: the current scoring protocol, alternative scoring protocols, and the Activity Pattern Indicators.


[A case of systemic scleroderma complicating pulmonary hypertension].
The patient was a 7-year-old girl. At the age of 6, deposits of pigment had appeared on the skin of her face and limbs, the skin had become sclerosed, and she had developed dyspnea on exertion. Her previous physician had hospitalized her. She was diagnosed as systemic scleroderma that accompanied pulmonary hypertension by her symptoms and laboratory findings. She was referred to our hospital at 7 years of age, and she was hospitalized. At that time, the entire skin showed deposition of brown pigment, the skin of the limbs was sclerotic. And the face was mask-like, flexion of the joints of the fingers and knees was limited, and the fingertips were ulcerated. Raynaud's phenomenon was present. She was positive for antinuclear antibodies, and negative for other autoantibodies. Echocardiography revealed pulmonary hypertension. After admission, steroid pulse therapy and cyclophosphamide (CY) pulse therapy were initiated, and for aftercare, 15 mg/day of prednisolone (PSL) and mizolibin (MZB) were administered orally. After several months, the sclerosis of the skin improved and the restriction of limb flexion was almost eliminated. The pulmonary hypertension advanced temporarily (maximum: 70 mmHg), but after oral administration of a PGI2 preparation and low-flow supplemental oxygen therapy and the initiation of anticoagulant therapy, the systolic pressure of the pulmonary artery improved to 34 mmHg. The CY pulse therapy was terminated after two years, and internal use of PSL and MZB was continued. The patient's condition is now stable. This case was treated from an early stage with steroid pulse therapy and CY pulse therapy, accompanied with oral administration of a PGI2 preparation for the pulmonary hypertension. The dermal symptoms improved, and it was possible to maintain a state of remission.


Goldfish as a model for studying the effect of hypernatremia on blood plasma lipoproteins.
To evaluate the effect of hypernatremia on the organization of blood plasma high density lipoproteins (HDL) in goldfish; to compare the state of hypernatremia in fish and humans; to assess the possible risks and consequences of the effect of hypernatremia on human plasma lipoproteins. The fish were acclimated for 20 days at a critical salinity of 11.5 g/L; after that the salt water was gradually "desalinated". The concentration of Na+ and the content of total water were determined in tissues, cells, and body fluids. The HDL organization was assessed by the number of apolipoprotein molecules per particle. The methods of flame spectrophotometry, electrophoresis and MALDI were used. In fresh water, the state of normonatremia was maintained in the fish body; at critical water salinity, the state of hypernatremia. Against the background of hypernatremia, the initial signs of muscle and erythrocyte dehydration appeared in fish, the total water content in the plasma did not change, and HDL disintegrated into small particles, which, upon restoration of normonatremia, were combined into the original large forms. In goldfish at the state of normonatremia, large forms of HDL are stable while at the state of hypernatremia, the small forms of HDL are stable. Under conditions of a hypertonic environment and plasma hypernatremia, the breakdown of HDL prevents the loss of water from the fish organism and reduces the threat of their dehydration. Human hypernatremia is characterized by plasma sodium levels comparable to that in goldfish, however accompanied by life-threatening metabolic changes. The results of this study may be useful for assessing the risks of HDL breakdown at hypernatremia and for the development of protocols for the treatment of pathological conditions in humans (Fig. 4, Ref. 45).


Bias in artificial intelligence in vascular surgery.
Application of artificial intelligence (AI) has revolutionized the utilization of big data, especially in patient care. The potential of deep learning models to learn without a priori assumption, or without prior learning, to connect seemingly unrelated information mixes excitement alongside hesitation to fully understand AI's limitations. Bias, ranging from data collection and input to algorithm development to finally human review of algorithm output affects AI's application to clinical patient presents unique challenges that differ significantly from biases in traditional analyses. Algorithm fairness, a new field of research within AI, aims to mitigate bias by evaluating the data at the preprocessing stage, optimizing during algorithm development, and evaluating algorithm output at the postprocessing stage. As the field continues to develop, being cognizant of the inherent biases and limitations related to black box decision making, biased data sets agnostic to patient-level disparities, wide variation of present methodologies, and lack of common reporting standards will require ongoing research to provide transparency to AI and its applications.


Acute unilateral post-operative submandibular sialadenitis following posterior cranial fossa surgery.
Extreme degree of rotation and flexion of the head during posterior fossa surgeries can lead to acute post-operative submandibular sialadenitis that can cause respiratory compromise. Identification of this problem is vital to prevent deterioration in the early post-operative period. This condition responds well to conservative management provided airway obstruction is taken care of. We discuss a case of a 63-year-old female, with a left side vestibular schwannoma who developed airway obstruction in post-operative period due to swelling of right submandibular gland. Various possible mechanisms leading to this condition and related literature are briefy reviewed.