Monocyte chemoattractant protein-1 and interleukin-8 levels in children with acute poststreptococcal glomerulonephritis.
The infiltration of leukocytes into the glomeruli is a major factor in inflammatory glomerular damage in acute poststreptococcal glomerulonephritis (APSGN). Chemokines participate in leukocyte infiltration. The aim of the present study was to investigate the role of monocyte chemoattractant protein-1 (CCL2/MCP-1) and interleukin-8 (CXL8/IL-8) in APSGN with special emphasis on their role in the clinical course of renal disease. Twenty-one children with APSGN were studied. Serum and urinary CCL2/MCP-1 and CXL8/IL-8 levels were measured by ELISA. The relationships between urinary chemokines and the degree of proteinuria were investigated. Serum and urinary CCL2/MCP-1 levels were significantly higher in the acute phase than in the resolution phase and in controls ( P<0.05). Urinary CCL2/MCP-1 levels in the control group were significantly lower than in both the acute and resolution phases ( P=0.01 and P =0.001, respectively). In the acute phase, urinary CCL2/MCP-1 correlated with the extent of proteinuria ( r=0.58, P =0.006) but not with serum CCL2/MCP-1 levels ( r=0.21, P =0.36). Urinary and serum CXL8/IL-8 levels were significantly elevated in the acute phase compared with the resolution phase and controls ( P<0.05). A consistent increase in urinary CCL2/MCP-1 was found in the acute phase of patients with APSGN, and this correlates with the degree of proteinuria. Our results emphasize the important role of locally produced chemokines in immune-mediated glomerular injury.


The ethics of public policy RCTs: The principle of policy equipoise.
In this article, I ask whether a principle analogous to the principle of clinical equipoise should govern the design and conduct of RCTs evaluating the effectiveness of policy interventions. I answer this question affirmatively, and introduce and defend the principle of policy equipoise. According to this principle, all arms of a policy RCT must be, at minimum, in a state of equipoise with the best proven policy that is also morally and practically attainable and sustainable. For all arms of a policy RCT, policy experts must either (1) reasonably disagree about whether the trial arms are more effective than this policy, or (2) know that they are.


The Discovery of Oropharyngeal Microbiota with Inhibitory Activity against Pathogenic Neisseria gonorrhoeae and Neisseria meningitidis: An In Vitro Study of Clinical Isolates.
With increasing incidence of pathogenic Neisseria infections coupled with emerging resistance to antimicrobials, alternative approaches to limit the spread are sought. We investigated the inhibitory effect of oropharyngeal microbiota on the growth of N. gonorrhoeae and N. meningitidis and the impact of the essential oil-based mouthwash Listerine Cool Mint® (Listerine). Oropharyngeal swabs from 64 men who have sex with men (n = 118) from a previous study (PReGo study) were analysed (ClinicalTrials.gov, NCT03881007). These included 64 baseline and 54 samples following three months of daily use of Listerine. Inhibition was confirmed by agar overlay assay, and inhibitory bacteria isolated using replica plating and identified using MALDI-TOF. The number of inhibitory isolates were compared before and after Listerine use. Thirty-one pharyngeal samples (26%) showed inhibitory activity against N. gonorrhoeae and/or N. meningitidis, and 62 inhibitory isolates were characterised. Fourteen species belonging to the genera Streptococci and Rothia were identified. More inhibitory isolates were observed following Listerine use compared to baseline, although this effect was not statistically significant (p = 0.073). This study isolated and identified inhibitory bacteria against pathogenic Neisseria spp. and established that daily Listerine use did not decrease their prevalence. These findings could provide a new approach for the prevention and treatment of pharyngeal Neisseria infections.


Lymph node calcification in Hodgkin's disease following irradiation.
Calcification at the site of lymph nodes previously affected by Hodgkin's disease and irradiated was found in 8 patients in a series of 481 consecutive cases. The patients were all women, young at the time of diagnosis, and had a long survival. The calcific deposits developed in the anterior mediastinum.


Biochemical and functional characteristics of the plasma membrane of macrophages from BCG-infected mice.
A set of quantitative signs of activation, previously developed in studies of inflammatory peritoneal macrophages, has been applied to the study of immunologically stimulated peritoneal cells. Mice that are infected systemically with Bacillus Calmette Guérin (BCG) and then challenged locally with soluble mycobacterial antigens generate populations of cells that spread rapidly in culture, display an elevated pinocytic rate, ingest IgMC-coated sheep erythrocytes, and have diminished levels of 5'-nucleotidase activity. These effects depend on sensitization with live organisms, require secondary antigenic challenge, and develop on the same schedule as does effective cell-mediated immunity. The challenge is antigen specific and cannot be replaced by a nonspecific inflammatory stimulus. Thus, the characteristics of inflammatory macrophages that were previously defined are applicable to the study of immunologically mediated macrophage activation. Cells sharing this pattern of characteristics, whatever their mode of generation, are proposed to represent a distinct class of differentiated macrophages, as compared with the resident macrophage population.


Prevalence of Prediabetes and Undiagnosed Diabetes in Canada (2007-2011) According to Fasting Plasma Glucose and HbA1c Screening Criteria.
To provide the first population-based estimates of prediabetes and undiagnosed type 2 diabetes prevalence in Canada. We combined two fasting subsamples of the Canadian Health Measures Survey, which were restricted to nonpregnant adults ≥20 years of age (N = 3,494). Undiagnosed diabetes was defined as not having self-reported type 2 diabetes but having blood glucose measures that met Canadian guidelines (i.e., fasting plasma glucose [FPG] level of ≥7.0 mmol/L or hemoglobin A1c [HbA1c] level of ≥6.5% [≥48 mmol/mol]). Prediabetes was defined as an FPG level of ≥6.1 and <7.0 mmol/L or an HbA1c level of ≥6.0% and <6.5% (≥42 and <48 mmol/mol). All estimates were weighted using survey sampling weights. CIs were calculated with the bootstrap method. According to FPG levels, the prevalence of undiagnosed type 2 diabetes in Canadian adults was 1.13% (95% CI 0.79, 1.62), contributing to ∼20% of total type 2 diabetes prevalence (5.62 [95% CI 4.52, 6.95]). Compared with FPG levels, the undiagnosed prevalence was greater using HbA1c level as a criterion (3.09% [95% CI 1.97, 4.81]), ∼41% of the total number of cases of diabetes (7.55 [95% CI 5.98, 9.49]). The HbA1c-only criterion resulted in a threefold increase in prediabetes prevalence overall and a sixfold increase among females (FPG 2.22%, HbA1c 13.31%). Screening based on FPG only identified older undiagnosed case patients, with a mean age of 58.7 years (95% CI 59.9, 63.4). Similarly, using HbA1c identified younger individuals with prediabetes, with reduced BMI and waist circumference compared with FPG levels. In this first study of a nationally representative sample with biospecimen measures, we found that the prevalence of undiagnosed type 2 diabetes and prediabetes was significantly higher using HbA1c levels compared with FPG levels. Further evaluation is needed to fully assess the impact of using the HbA1c criterion.


The flexner report of 1910 and its impact on complementary and alternative medicine and psychiatry in north america in the 20th century.
America experienced a genuinely vast development of biomedical science in the early decades of the twentieth century, which in turn impacted the community of academic psychiatry and changed the way in which clinical and basic research approaches in psychiatry were conceptualized. This development was largely based on the restructuring of research universities in both of the USA and Canada following the influential report of Johns Hopkins-trained science administrator and politician Abraham Flexner (1866-1959). Flexner's report written in commission for the Carnegie Foundation for the Advancement of Teaching in Washington, DC, also had a major influence on complementary and alternative medicine (CAM) in psychiatry throughout the 20th century. This paper explores the lasting impact of Flexner's research published on modern medicine and particularly on what he interpreted as the various forms of health care and psychiatric treatment that appeared to compete with the paradigm of biomedicine. We will particularly draw attention to the serious effects of the closing of so many CAM-oriented hospitals, colleges, and medical teaching programs following to the publication of the Flexner Report in 1910.


Coronary heart disease in Indian Asians.
The Indian Asian population accounts for a fifth of all global deaths from coronary heart disease (CHD). CHD deaths on the Indian subcontinent have doubled since 1990, and are predicted to rise a further 50% by 2030. Reasons underlying the increased CHD mortality among Indian Asians remain unknown. Although conventional cardiovascular risk factors contribute to CHD in Indian Asians as in other populations, these do not account for their increased risk. Type-2 diabetes, insulin resistance and related metabolic disturbances are more prevalent amongst Indian Asians than Europeans, and have been proposed as major determinants of higher CHD risk among Indian Asians. However, this view is not supported by prospective data. Genome-wide association studies have not identified differences in allele frequencies or effect sizes in known loci to explain the increased CHD risk in Indian Asians. Limited knowledge of mechanisms underlying higher CHD risk amongst Indian Asians presents a major obstacle to reducing the burden of CHD in this population. Systems biology approaches such as genomics, epigenomics, metabolomics and transcriptomics, provide a non-biased approach for discovery of novel biomarkers and disease pathways underlying CHD. Incorporation of these 'omic' approaches in prospective Indian Asian cohorts such as the London Life Sciences Population Study (LOLIPOP) provide an exciting opportunity for the identification of new risk factors underlying CHD in this high risk population.


ACR Appropriateness Criteria on Hodgkin's lymphoma: favorable prognosis stage I and II.
The treatment for favorable-prognosis stage I and II Hodgkin's lymphoma has evolved over the past several years. Studies have attempted to reduce long-term treatment-related side effects, such as second malignancies and cardiac toxicity, through reduced chemotherapy or reduced radiotherapy. Randomized trials have compared radiation therapy alone with combined-modality therapy (chemotherapy followed by involved-field radiotherapy). Recent and ongoing trials have evaluated the optimal regimen and number of cycles of chemotherapy and the optimal radiotherapy dose and field size as part of combined-modality therapy, as well as the elimination of radiation therapy. Combined-modality therapy represents the current standard of care for most patients with favorable-prognosis early-stage Hodgkin's lymphoma. Chemotherapy alone could also be an option for selected patients who are at low risk for relapse and high risk for late effects from radiotherapy. This article reviews recent and ongoing studies on treatment for favorable-prognosis early stage Hodgkin's lymphoma. Representative clinical cases are presented, with treatment recommendations from an expert panel of radiation oncologists and medical oncologists.


A patient with delayed contact dermatitis to coral and she displayed superficial granuloma.
CONTACT WITH CORAL MAY CAUSE A RARE TYPE OF CONTACT DERMATITIS, AND THE RESULTING SKIN REACTION CAN BE DIVIDED INTO DIFFERENT REACTIONS: the acute, delayed and chronic types of coelenterate dermatitis. Granulomas of delayed skin reactions have rarely been reported. Herein, we report on a rare case of a delayed reaction of the skin to coral injury, and the patient displayed superficial granulomas and atypical CD30+ lymphocytes.


Contextual performance prediction for low-level image analysis algorithms.
This paper explores a generic approach to predict the output accuracy of an algorithm without running it, by a careful examination of the local context. Such a performance prediction will allow one to qualify the appropriateness of an algorithm to treat images with given properties (contrast, resolution, noise, richness in details, contours or textures, etc.) resulting either from experimental acquisition conditions or from a specific type of scene. We have to answer the following question: a context c being given at any site, what will be the performance? In our experiments, c is described by three contextual variables: Gabor components, entropy and signal noise ratio. As initially proposed in the related work, the prediction function is determined from training using a logistic regression model. This technique is illustrated on aerial infrared images for two types of algorithm: edge detection and displacement estimation.


Large and rapid local recurrence of clear cell renal cell carcinoma.
After radical nephrectomy, clear cell renal cell carcinoma (ccRCC) recurs locally in <3% of patients. Recurrences typically occur 1-2 years postoperatively and grow at 5-20 mm per year. In contrast, this patient's recurrence was unexpectedly large and swift. A 71-year-old woman was initially found on workup for recurrent urinary tract infections to have a 12 cm left renal tumour. After negative staging scans, she progressed to left open radical nephrectomy. Histology revealed a stage T2b 12 cm ccRCCwith sarcomatoid differentiation, International Society of Urological Pathology (ISUP) grade 4, with clear margins. Only 3 months later, the patient developed left-sided abdominal pain, and CT scans revealed a 15 cm left retroperitoneal local recurrence, as well as widespread peritoneal tumours. In discussion with her treating team, the patient and her family elected not to undergo biopsy or systemic therapy. The patient was palliated and passed away 8 days after re-presentation.


The effect of verapamil on the prevalence and severity of cyclosporine-induced gingival overgrowth in renal allograft recipients.
Cyclosporine A (CsA) and verapamil are two agents used in renal transplantation, both of which are suspected of inducing gingival overgrowth. This study was conducted to investigate the effect of verapamil on the severity and prevalence of CsA-induced gingival overgrowth. Fifty-one (51) renal transplant recipients (total group) of whom 22 were using only CsA (Group A) and 29 of whom were prescribed CsA + verapamil (Group B) were evaluated for various periodontal and pharmacological parameters. No statistically significant differences were found in age, sex, plaque index, gingival index, calculus index, probing depth, CsA oral dose, CsA whole blood level, duration of CsA therapy, azathioprine dose, and prednisolone dose. Although the prevalence of the gingival overgrowth was more pronounced in CsA + verapamil group compared to CsA group (51.72% vs. 40.91%), the difference was not statistically significant. Similarly, the severity of gingival overgrowth, although more manifest in CsA + verapamil group than CsA patients (34.24% vs. 28.91%), was not significantly different. Gingival overgrowth scores in the main group, CsA, and CsA + verapamil groups were found to be positively correlated to periodontal probing depths (r = 0.60, r = 0.70, r = 0.52, respectively) and the gingival index (r = 0.60, r = 0.70, r = 0.54, respectively). CsA oral dose, whole blood level, and duration of CsA therapy were not found to be correlated with the gingival overgrowth in either group. Likewise, the dose of verapamil and the duration of verapamil therapy were not correlated with the gingival overgrowth in Group B. This study indicates that verapamil, when prescribed as the calcium channel blocker in renal transplant patients, has no augmenting effect on the severity and the prevalence of CsA-induced gingival overgrowth.


Modified cryptochrome in vivo absorption in dim photosporulation mutants of Trichoderma.
Mutants of Trichoderma harzianum that are defective in blue-light-induced sporulation were induced by nutritional stresses as an alternative to light. These mutants may be modified in the putative photoreceptor pigment "cryptochrome" or in an early transduction component. dim (dimsighted) mutants induced by a short transient stress were mapped into four complementation groups and were chosen for study of pigment deficiencies by in vivo absorption spectroscopy. Mutants rib(-)10 and lys(-)44 in the dimY complementation group had altered in vivo absorption spectra in the blue region. Difference spectra obtained by subtracting dimY spectra from that of the wild type had difference bands with peaks at 455 and 480 nm. The similarity between the in vivo difference spectra and the action spectrum for sporulation in wild-type Trichoderma suggests that the mutants lack cryptochrome or have a defective cryptochrome. The decrease in photoresponse as well as the modification of the action spectrum near 480 nm in a dimY mutant support these suggestions. Both dimY mutants pleiotropically accumulate a yellow water-soluble pigment absorbing at wavelengths lower than the blue maxima of cryptochrome; this yellow pigment may be related to cryptochrome.


Cardiac calcium channels in planar lipid bilayers. L-type channels and calcium-permeable channels open at negative membrane potentials.
Planar lipid bilayer recordings were used to study Ca channels from bovine cardiac sarcolemmal membranes. Ca channel activity was recorded in the absence of nucleotides or soluble enzymes, over a range of membrane potentials and ionic conditions that cannot be achieved in intact cells. The dihydropyridine-sensitive L-type Ca channel, studied in the presence of Bay K 8644, was identified by a detailed comparison of its properties in artificial membranes and in intact cells. L-type Ca channels in bilayers showed voltage dependence of channel activation and inactivation, open and closed times, and single-channel conductances in Ba2+ and Ca2+ very similar to those found in cell-attached patch recordings. Open channels were blocked by micromolar concentrations of external Cd2+. In this cell-free system, channel activity tended to decrease during the course of an experiment, reminiscent of Ca2+ channel "rundown" in whole-cell and excised-patch recordings. A purely voltage-dependent component of inactivation was observed in the absence of Ca2+ stores or changes in intracellular Ca2+. Millimolar internal Ca2+ reduced unitary Ba2+ influx but did not greatly increase the rate or extent of inactivation or the rate of channel rundown. In symmetrical Ba2+ solutions, unitary conductance saturated as the Ba2+ concentration was increased up to 500 mM. The bilayer recordings also revealed activity of a novel Ca2+-permeable channel, termed "B-type" because it may contribute a steady background current at negative membrane potentials, which is distinct from L-type or T-type Ca channels previously reported. Unlike L-type channels, B-type channels have a small unitary Ba2+ conductance (7 pS), but do not discriminate between Ba2+ and Ca2+, show no obvious sensitivity to Bay K 8644, and do not run down. Unlike either L- or T-type channels, B-type channels did not require a depolarization for activation and displayed mean open times of greater than 100 ms.


Acute Helicobacter pylori infection: clinical features, local and systemic immune response, gastric mucosal histology, and gastric juice ascorbic acid concentrations.
The symptomatology of a case of acute infection with Helicobacter pylori is described, together with the accompanying changes in gastric mucosal histology, local and systemic humoral immune response, and gastric ascorbic acid concentration. The patient was an endoscopist, previously negative for the carbon-14 urea breath test, who had a week of epigastric pain and then became asymptomatic. H pylori was detected by culture of antral biopsy specimens and was still present after 74 days. Five days after infection the histological findings showed acute neutrophilic gastritis; by day 74 changes of chronic gastritis were evident. The patient seroconverted by IgG enzyme linked immunosorbent assay by day 74, but a mucosal IgM and IgA response was evident as early as day 14. Infection was accompanied by a transient hypochlorhydria but a sustained fall in gastric juice ascorbic acid concentration.


Effect of intramolecular charge transfer on fluorescence and singlet oxygen production of phthalocyanine analogues.
Intramolecular charge transfer (ICT) was studied on a series of magnesium, metal-free and zinc complexes of unsymmetrical tetrapyrazinoporphyrazines and tribenzopyrazinoporphyrazines bearing two dialkylamino substituents (donors) and six alkylsulfanyl or aryloxy substituents (non-donors). The dialkylamino substituents were responsible for ICT that deactivated excited states and led to considerable decrease of fluorescence and singlet oxygen quantum yields. Photophysical and photochemical properties were compared to corresponding macrocycles that do not bear any donor centers. The data showed high feasibility of ICT in the tetrapyrazinoporphyrazine macrocycle and significantly lower efficiency of this deactivation process in the tribenzopyrazinoporphyrazine type molecules. Considerable effect of non-donor peripheral substituents on ICT was also described. The results imply that tetrapyrazinoporphyrazines may be more suitable for development of new molecules investigated in applications based on ICT.


Recent hepatitis C virus infections in HIV-infected patients in Taiwan: incidence and risk factors.
Outbreaks of sexually transmitted hepatitis C virus (HCV) infections have been recently reported in HIV-infected men who have sex with men (MSM) in Europe, Australia, and North America. Little is known concerning whether this also occurs in other Asia-Pacific countries. Between 1994 and 2010, a prospective observational cohort study was performed to assess the incidence of recent HCV seroconversion in 892 HIV-infected patients (731 MSM and 161 heterosexuals) who were not injecting drug users. A nested case-control study was conducted to identify associated factors with recent HCV seroconversion, and phylogenetic analysis was performed using NS5B sequences amplified from seroconverters. During a total followup duration of 4,270 person-years (PY), 30 patients (3.36%) had HCV seroconversion, with an overall incidence rate of 7.03 per 1,000 PY. The rate increased from 0 in 1994 to 2000 and 2.29 in 2001 to 2005 to 10.13 per 1,000 PY in 2006 to 2010 (P < 0.05). After adjustment for age and HIV transmission route, recent syphilis remained an independent factor associated with HCV seroconversion (odds ratio, 7.731; 95% confidence interval, 3.131 to 19.086; P < 0.01). In a nested case-control study, seroconverters had higher aminotranferase levels and were more likely to have CD4 ≥ 200 cells/μl and recent syphilis than nonseroconverters (P < 0.05). Among the 21 patients with HCV viremia, phylogenetic analysis revealed 7 HCV transmission clusters or pairs (4 within genotype 1b, 2 within genotype 2a, and 1 within genotype 3a). The incidence of HCV seroconversion that is associated with recent syphilis is increasing among HIV-infected patients in Taiwan.


Molecular identification of the TCA alloantigen as the transferrin receptor on T-cells of a leukemic patient with serum from a monozygotic twin brother.
The transferrin receptor is encoded by a diallelic locus which had been described as the T-cell antigenic system TCA. Using a human lymphoblastoid T-cell line (HSB) which reportedly carries a transferrin receptor and which we showed to be TCA-2 positive by serology, it appeared that only a TCA-2 but not a TCA-1 specific alloantiserum had the capacity to precipitate a protein with a molecular weight of 94,000, which comigrated exactly with the Mr 94,000 protein precipitated by the rabbit anti-HSB and rabbit anti-SB antisera, as well as the transferrin receptor which was precipitated by a transferrin-antitransferrin complex. The positive sera and the latter complex were shown to cross-react in a binding assay. Conversely, a monospecific TCA-1 alloantiserum was shown to react with the Mr 94,000 protein of TCA-1-positive leukocyte suspensions. The allelomorphism of the transferrin receptor may be relevant for the eventual regulatory mechanism controlling cell proliferation, which would be essential at least for those cells that are supposed to play an immunological role like the TCA-positive cells which are described as T-cells probably involved in the process of immunosuppression. In addition, we found increasing amounts of autoantibodies with TCA-1 specificity in serum from a healthy individual (referred to as "donor" in this paper), whose brother at the same time suffered a chronic myeloid leukemia, probably associated with a retrovirus, and whose blood in contrast was shown to contain cytotoxic anti-TCB, from a diallelic locus expressed on theophylline-insensitive T-cells, and anti-B-cell activity.


Diabetes care providers' opinions and working methods after four years of experience with a diabetes patient web portal; a survey among health care providers in general practices and an outpatient clinic.
To gain insight into the opinions and working methods of diabetes care providers after using a diabetes web portal for 4 years in order to understand the role of the provider in patients' web portal use. Survey among physicians and nurses from general practices and an outpatient clinic, correlated with data from the common web portal. One hundred twenty-eight questionnaires were analysed (response rate 56.6%). Responders' mean age was 46.2 ± 9.8 years and 43.8% were physicians. The majority was of opinion that the portal improves patients' diabetes knowledge (90.6%) and quality of care (72.7%). Although uploading glucose diary (93.6%) and patient access to laboratory and clinical notes (91.2 and 71.0%) were considered important, these features were recommended to patients in only 71.8 and 19.5% respectively. 64.8% declared they informed their patients about the portal and 45.3% handed-out the information leaflet and website address. The portal was especially recommended to type 1 diabetes patients (78.3%); those on insulin (84.3%) and patients aged< 65 years (72.4%). Few found it timesaving (21.9%). Diabetes care providers' opinions were not associated with patients' portal use. Providers are positive about patients web portals but still not recommend or encourage the use to all patients. There seems room for improvement in their working methods.


Mutational analysis of the necdin gene in patients with congenital isolated hypogonadotropic hypogonadism.
Necdin activates GNRH gene expression and is fundamental for the development, migration, and axonal extension of murine GNRH neurons. In humans, necdin plays a potential role in the hypogonadotropic hypogonadism phenotype in patients with Prader-Willi syndrome. To investigate necdin gene (NDN) variants in patients with isolated hypogonadotropic hypogonadism (IHH). We studied 160 Brazilian patients with IHH, which includes 92 with Kallmann syndrome and 68 with normosmic IHH. Genomic DNA was extracted and the single NDN exon was amplified and sequenced. To measure GNRH transcriptional activity, luciferase reporter plasmids containing GNRH regulatory regions were transiently transfected into GT1-7 cells in the presence and absence of overexpressed wild-type or mutant necdin. A heterozygous variant of necdin, p.V318A, was identified in a 23-year-old male with Kallmann syndrome. The p.V318A was also present in affected aunt and his father and was absent in 100 Brazilian control subjects. Previous FGFR1 gene analysis revealed a missense mutation (p.P366L) in this family. Functional studies revealed a minor difference in the activation of GNRH transcription by mutant protein compared with wild type in that a significant impairment of the necdin protein activity threshold was observed. A rare variant of necdin (p.V318A) was described in a family with Kallmann syndrome associated with a FGFR1 mutation. Familial segregation and in vitro analysis suggested that this non-synonymous variant did not have a direct causative role in the hypogonadism phenotype. NDN mutations are not a frequent cause of congenital IHH.


The effects of retinoic acid on ciliary function of regenerated sinus mucosa.
Retinoic acid (RA) has been shown to enhance ciliary ultrastructure in regenerated sinus mucosa compared with controls. However, the functional status of the regenerated cilia has not been studied. Our objective was to evaluate the ciliary beat frequency (CBF) of regenerated sinus mucosa treated with topical RA in a rabbit model. Twelve rabbits underwent bilateral surgical stripping of the maxillary sinuses, followed by treatment with RA gel in the right side and an inert gel control in the left side. The rabbits were then killed at either 2 or 4 weeks, and CBF analysis of the regenerated mucosa was performed. Three unoperated rabbits were used to establish normative CBF data. Functional cilia were recovered from 11/12 RA-treated sinuses and 12/12 gel control sinuses. At 2 weeks postoperatively, the RA-treated sinuses showed an average CBF of 19.78 Hz, which was statistically comparable with the normal unoperated controls (p < 0.26). The inert gel-treated mucosa showed a CBF of 29.24 Hz, which was significantly elevated compared with normals (p < 0.05). At 4 weeks, ciliary activity persisted, but both RA-treated sinuses and gel controls showed elevated CBF compared with normals (p < 0.03). Topical RA placed in a demucosalized maxillary sinus yields functional cilia. RA appears to have a normalizing effect on CBF early in the mucosal wound healing process compared with control. This effect appears to be mitigated in later stages of wound healing. RA may be beneficial in enhancing morphological and functional aspects of regenerating cilia.


Association Between Intraoperative Oliguria and Acute Kidney Injury After Major Noncardiac Surgery.
Acute kidney injury (AKI) occurs in 6.1%-22.4% of patients undergoing major noncardiac surgery. Previous studies have shown no association between intraoperative urine output and postoperative acute renal failure. However, these studies used various definitions of acute renal failure. We therefore investigated the association between intraoperative oliguria and postoperative AKI defined by the serum creatinine criteria of the Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) classification. In this single-center, retrospective, observational study, we screened 26,984 patients undergoing elective or emergency surgery during the period September 1, 2008 to October 31, 2011 at a university hospital. Exclusion criteria were age <18 years; duration of anesthesia <120 minutes; hospital stay <2 nights; local anesthesia only; urologic or cardiac surgery; coexisting end-stage kidney disease; and absence of serum creatinine measurement, intraoperative urine output data, or information regarding intraoperative drug use. Multivariable logistic regression analysis was used as the primary analytic method. A total of 5894 patients were analyzed. The incidence of postoperative AKI was 7.3%. By multivariable analysis, ≥120 minutes of oliguria (odds ratio = 2.104, 95% CI, 1.593-2.778; P < .001) was independently associated with the development of postoperative AKI. After propensity-score matching of patients with ≥120 and <120 minutes of oliguria on baseline characteristics, the incidence of AKI in patients with ≥120 minutes of oliguria (n = 827; 10%) was significantly greater than that in those with <120 minutes of oliguria (n = 827; 4.8%; odds ratio = 2.195, 95% CI, 1.806-2.668; P < .001). Contrary to previous studies, we found that intraoperative oliguria is associated with the incidence of AKI after major noncardiac surgery.


The neuropeptide VGF is reduced in human bipolar postmortem brain and contributes to some of the behavioral and molecular effects of lithium.
Recent studies demonstrate that the neuropeptide VGF (nonacronymic) is regulated in the hippocampus by antidepressant therapies and animal models of depression and that acute VGF treatment has antidepressant-like activity in animal paradigms. However, the role of VGF in human psychiatric disorders is unknown. We now demonstrate using in situ hybridization that VGF is downregulated in bipolar disorder in the CA region of the hippocampus and Brodmann's area 9 of the prefrontal cortex. The mechanism of VGF in relation to LiCl was explored. Both LiCl intraperitoneally and VGF intracerebroventricularly reduced latency to drink in novelty-induced hypophagia, and LiCl was not effective in VGF(+/-) mice, suggesting that VGF may contribute to the effects of LiCl in this behavioral procedure that responds to chronic antidepressant treatment. VGF by intrahippocampal injection also had novel activity in an amphetamine-induced hyperlocomotion assay, thus mimicking the actions of LiCl injected intraperitoneally in a system that phenocopies manic-like behavior. Moreover, VGF(+/-) mice exhibited increased locomotion after amphetamine treatment and did not respond to LiCl, suggesting that VGF is required for the effects of LiCl in curbing the response to amphetamine. Finally, VGF delivered intracerebroventricularly in vivo activated the same signaling pathways as LiCl and is necessary for the induction of mitogen-activated protein kinase and Akt by LiCl, thus lending insight into the molecular mechanisms underlying the actions of VGF. The dysregulation of VGF in bipolar disorder as well as the behavioral effects of the neuropeptide similar to LiCl suggests that VGF may underlie the pathophysiology of bipolar disorder.


The Impact of Early Recognition and Treatment of Systemic Hypertension on Reducing Blood Pressure: The Hypertension and Vascular Evaluation Program.
This study aimed to evaluate the effect of an outpatient systemic hypertension program and associated factors with attending recommended follow-up visit. All visits were tracked in the program, 2011 to 2018. We examined patient characteristics by follow-up status and changes in systolic blood pressure (SBP) and the risk of hypertension in follow-up patients using a mixed-effects regression model. Among 310 patients with first visits, 113 patients returned for a follow-up visit. Patients who did not attend a follow-up were older and less likely to have a severe chronic condition or a family history of hypertension than followed-up patients. The risk of hypertension was significantly reduced by the number of follow-up visits (odds ratio = 0.53, 95% confidence interval = 0.31-0.92). Adolescent SBP and body mass index percentiles decreased with more follow-up visits. As the risk of hypertension is significantly reduced with follow-up visits, additional effort should be made to improve the likelihood of follow-up attendance.


On the evolution and population genetics of hybrid-dysgenesis-causing transposable elements in Drosophila.
Much has been learned about transposable genetic elements in Drosophila, but questions still remain, especially concerning their evolutionary significance. Three such questions are considered here. Has the behaviour of transposable elements been most influenced by natural selection at the level of the organism, the population, or the elements themselves? How did the elements originate in the genome of the species? Why are laboratory stocks different from natural populations with respect to their transposable element composition? No final answers to these questions are yet available, but by focusing on the two families of hybrid dysgenesis-causing elements, the P and I factors, we can draw some tentative conclusions.


Biodegradable polylactide/hydroxyapatite nanocomposite foam scaffolds for bone tissue engineering applications.
Supercritical carbon dioxide processing of poly-L-lactide (PLLA)/hydroxyapatite (nHA) nanocomposites was investigated as a means to prepare foams suitable as scaffolds in bone tissue engineering applications. For given foaming parameters, addition of nHA to the PLLA gave reduced cell sizes and improved homogeneity in the size distribution, but did not significantly affect the degree of crystallinity, which remained of the order of 50 wt% in all the foams. The compressive modulus and strength were primarily influenced by the porosity and there was no significant reinforcement of the matrix by the nHA. The mechanical properties of the foams were nevertheless comparable with those of trabecular bone, and by adjusting the saturation pressure and depressurization rate it was possible to generate porosities of about 85 %, an interconnected morphology and cell diameters in the range 200-400 μm from PLLA containing 4.17 vol% nHA, satisfying established geometrical requirements for bone replacement scaffolds.


Subsequent ipsi- and contralateral femoral fractures after intramedullary nailing of a trochanteric or subtrochanteric fracture: a cohort study on 2012 patients.
The literature is inconclusive as to whether an intramedullary nail changes the distribution of a subsequent ipsi- or contralateral fracture of the femur. We have compared the incidence, localisation, and fracture pattern of subsequent femoral fractures after intramedullary nailing of trochanteric or subtrochanteric fractures in patients without previous implants in either femur at the time of surgery. Retrospective analysis was performed of a two-centre cohort of 2012 patients treated with a short or long intramedullary nail for the management of trochanteric or subtrochanteric fracture between January 2005 and December 2018. Subsequent presentations with ipsi- and contralateral femoral fractures were documented. Only patients with no previous femoral surgery performed, other than the index nailing were followed. Odds ratios (ORs) for subsequent femoral fracture were calculated using robust variance estimates in logistic regression. The mean age of the cohort was 82.4 years and 72.1% were female. The total number of patients presenting with subsequent femoral fractures was 299 (14.9%). The number of patients presenting with subsequent ipsilateral and contralateral femoral fractures was 51 (2.5%) and 248 (12.3%) respectively (OR 5.0; CI 3.7-6.9). Twenty-six (8.7%) of all subsequent femoral fractures occured in the ipsilateral shaft, 14 (4.7%) in the ipsilateral metaphyseal area, one (0.33%) in the contralateral shaft, and three (1.0%) in the contralateral metaphysis (OR 10; CI 3.6-29). An intramedullary nail significantly changes the fracture pattern in the event of a second low-energy trauma, reducing the risk of subsequent proximal ipsilateral femoral fractures and increasing the risk of subsequent ipsilateral femoral fractures in the shaft and distal metaphyseal area compared with the native contralateral femur.


The GroinPain Trial: A Randomized Controlled Trial of Injection Therapy Versus Neurectomy for Postherniorraphy Inguinal Neuralgia.
This study compares tender point infiltration (TPI) and a tailored neurectomy as the preferred treatment for chronic inguinodynia after inguinal herniorraphy. Some 11% of patients develop chronic discomfort after open inguinal herniorraphy. Both TPI and neurectomy have been suggested as treatment options, but evidence is conflicting. Patients with chronic neuropathic pain after primary Lichtenstein repair and >50% pain reduction after a diagnostic TPI were randomized for repeated TPI (combined Lidocaine/corticosteroids /hyaluronic acid injection) or for a neurectomy. Primary outcome was success (>50% pain reduction using Visual Analog Scale, VAS) after 6 months. Cross-over to neurectomy was offered if TPI was unsuccessful. A total of 54 patients were randomized in a single center between January 2006 and October 2013. Baseline VAS was similar (TPI: 55, range 10-98 vs neurectomy: 53, range 18-82, P = 0.86). TPI was successful in 22% (n = 6), but a neurectomy was successful in 71% (n = 17, P = 0.001). After unsuccessful TPI, 19 patients crossed over to neurectomy and their median VAS score dropped from 60 to 14 (P = 0.001). No major complications after surgery were reported. Two-thirds of patients on worker's compensation returned to work. A tailored neurectomy is 3 times more effective than tender point infiltration in chronic inguinodynia after anterior inguinal hernia mesh repair. A step up treatment stratagem starting with tender point infiltration followed by a tailored neurectomy is advised.


The quest for standards in medical imaging.
This article focuses on standards supporting interoperability and system integration in the medical imaging domain. We introduce the basic concepts and actors and we review the most salient achievements in this domain, especially with the DICOM standard, and the definition of IHE integration profiles. We analyze and discuss what was successful, and what could still be more widely adopted by industry. We then sketch out a perspective of what should be done next, based on our vision of new requirements for the next decade. In particular, we discuss the challenges of a more explicit sharing of image and image processing semantics, and we discuss the help that semantic web technologies (and especially ontologies) may bring to achieving this goal.


Song decrystallization in adult zebra finches does not require the song nucleus NIf.
In adult male zebra finches, transecting the vocal nerve causes previously stable (i.e., crystallized) song to slowly degrade, presumably because of the resulting distortion in auditory feedback. How and where distorted feedback interacts with song motor networks to induce this process of song decrystallization remains unknown. The song premotor nucleus HVC is a potential site where auditory feedback signals could interact with song motor commands. Although the forebrain nucleus interface of the nidopallium (NIf) appears to be the primary auditory input to HVC, NIf lesions made in adult zebra finches do not trigger song decrystallization. One possibility is that NIf lesions do not interfere with song maintenance, but do compromise the adult zebra finch's ability to express renewed vocal plasticity in response to feedback perturbations. To test this idea, we bilaterally lesioned NIf and then transected the vocal nerve in adult male zebra finches. We found that bilateral NIf lesions did not prevent nerve section-induced song decrystallization. To test the extent to which the NIf lesions disrupted auditory processing in the song system, we made in vivo extracellular recordings in HVC and a downstream anterior forebrain pathway (AFP) in NIf-lesioned birds. We found strong and selective auditory responses to the playback of the birds' own song persisted in HVC and the AFP following NIf lesions. These findings suggest that auditory inputs to the song system other than NIf, such as the caudal mesopallium, could act as a source of auditory feedback signals to the song motor network.


Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells.
Myeloid-derived suppressor cells (MDSCs) are crucial mediators of tumor-associated immune suppression. Targeting the accumulation and activation of MDSCs has been recognized as a promising approach to enhance the effectiveness of immunotherapies for different types of cancer. The MC38 and B16 tumor-bearing mouse models were established to investigate the role of Fgl2 during tumor progression. Fgl2 and FcγRIIB-deficient mice, adoptive cell transfer, RNA-sequencing and flow cytometry analysis were used to assess the role of Fgl2 on immunosuppressive activity and differentiation of MDSCs. Here, we show that fibrinogen-like protein 2 (Fgl2) regulates the differentiation and immunosuppressive functions of MDSCs. The absence of Fgl2 leads to an increase in antitumor CD8+ T-cell responses and a decrease in granulocytic MDSC accumulation. The regulation mechanism involves Fgl2 modulating cholesterol metabolism, which promotes the accumulation of MDSCs and immunosuppression through the production of reactive oxygen species and activation of XBP1 signaling. Inhibition of Fgl2 or cholesterol metabolism in MDSCs reduces their immunosuppressive activity and enhances differentiation. Targeting Fgl2 could potentially enhance the therapeutic efficacy of anti-PD-1 antibody in immunotherapy. These results suggest that Fgl2 plays a role in promoting immune suppression by modulating cholesterol metabolism and targeting Fgl2 combined with PD-1 checkpoint blockade provides a promising therapeutic strategy for antitumor therapy.


Newly assembled snRNPs associate with coiled bodies before speckles, suggesting a nuclear snRNP maturation pathway.
Small nuclear ribonucleoproteins (snRNPs), which are essential components of the mRNA splicing machinery, comprise small nuclear RNAs, each complexed with a set of proteins. An early event in the maturation of snRNPs is the binding of the core proteins - the Sm proteins - to snRNAs in the cytoplasm followed by nuclear import. Immunolabelling with antibodies against Sm proteins shows that splicing snRNPs have a complex steady-state localisation within the nucleus, the result of the association of snRNPs with several distinct subnuclear structures. These include speckles, coiled bodies and nucleoli, in addition to a diffuse nucleoplasmic compartment. The reasons for snRNP accumulation in these different structures are unclear. When mammalian cells were microinjected with plasmids encoding the Sm proteins B, D1 and E, each tagged with either the green fluorescent protein (GFP) or yellow-shifted GFP (YFP), a pulse of expression of the tagged proteins was observed. In each case, the newly synthesised GFP/YFP-labelled snRNPs accumulated first in coiled bodies and nucleoli, and later in nuclear speckles. Mature snRNPs localised immediately to speckles upon entering the nucleus after cell division. The complex nuclear localisation of splicing snRNPs results, at least in part, from a specific pathway for newly assembled snRNPs. The data demonstrate that the distribution of snRNPs between coiled bodies and speckles is directed and not random.


Vascular hypertrophy-associated hypertension of profilin1 transgenic mouse model leads to functional remodeling of peripheral arteries.
Increased mechanical stress/hypertension in the vessel wall triggers the hypertrophic signaling pathway, resulting in structural remodeling of vasculature. Vascular hypertrophy of resistance vessels leads to reduced compliance and elevation of blood pressure. We showed before that increased expression of profilin1 protein in the medial layer of the aorta induces stress fiber formation, triggering the hypertrophic signaling resulting in vascular hypertrophy and, ultimately, hypertension in older mice. Our hypothesis is that profilin1 induced vascular hypertrophy in resistance vessels, which led to elevation of blood pressure, both of which contributed to the modulation of vascular function. Our results showed significant increases in the expression of alpha(1)- and beta(1)-integrins (280 + or - 6.3 and 325 + or - 7.4%, respectively) and the activation of the Rho/Rho-associated kinase (ROCK) II pathway (260 and 350%, respectively, P < 0.05) in profilin1 mesenteric arteries. The activation of Rho/ROCK led to the inhibition of endothelial nitric oxide synthase expression (39 + or - 5.4%; P < 0.05) and phosphorylation (35 + or - 4.5%; P < 0.05) but also an increase in myosin light chain 20 phosphorylation (372%, P < 0.05). There were also increases in hypertrophic signaling pathways in the mesenteric arteries of profilin1 mice such as phospho-extracellular signal-regulated kinase 1/2 and phospho-c-Jun NH(2)-terminal kinase (312.15 and 232.5%, respectively, P < 0.05). Functional analyses of mesenteric arteries toward the vasoactive drugs were assessed using wire-myograph and showed significant increases in the vascular responses of profilin1 mesenteric arteries toward phenylephrine, but significant decreases in response toward ROCK inhibitor Y-27632, ACh, sodium nitrite, and cytochalasin D. The changes in vascular responses in the mesenteric arteries of profilin1 mice are due to vascular hypertrophy and the elevation of blood pressure in the profilin1 transgenic mice.


Elevated circulating levels of von Willebrand factor and D-dimer in patients with heart failure and mechanical prosthesis.
To test the hypothesis of association between heart failure and altered haemostatic balance in patients with a mechanical valve prosthesis, comparisons were made between 20 patients with mitral valve replacement and stable chronic heart failure (group A), 20 with the same prosthesis but satisfactory haemodynamics (group B) and 20 age-matched controls (group C). The left ventricular ejection fraction was significantly highest (p < 0.001) in group A. The pulmonary artery systolic pressure was also highest in group A (p < 0.001), without significant difference between groups B and C. Two group A patients had a transient ischaemic attack. The D-dimer plasma concentrations and the antigenic and biologic von Willebrand factor activities were significantly greatest in group A. Significant correlation was found between the plasma concentrations of these activities and pulmonary artery systolic pressure and between D-dimer and ejection fraction. Platelet-activating factor was detected only in six group A patients. The observed relationship between haemostatic factors and heart failure in patients with mechanical heart-valve prosthesis advocates careful evaluation of von Willebrand factor and D-dimer in order to prevent embolic events in such cases.


Multiple sources of sn-1,2-diacylglycerol in platelet-derived-growth-factor-stimulated Swiss 3T3 fibroblasts. Evidence for activation of phosphoinositidase C and phosphatidylcholine-specific phospholipase D.
Platelet-derived growth factor (PDGF) stimulated sn-1,2-diacylglycerol (DAG) mass formation in Swiss 3T3 fibroblasts with a lag time of some 30 s. The response was biphasic, with the second phase being sustained over time. PDGF also stimulated the formation of Ins(1,4,5)P3 with a similar lag time to the DAG response, suggesting that DAG is derived from PtdIns(4,5)P2 hydrolysis at this time point. PDGF-stimulated phosphatidylcholine (PtdCho) hydrolysis in Swiss 3T3 fibroblasts, as measured by the formation of water-soluble choline metabolites and phosphatidylbutanol (PtdBut) accumulation, was by a phospholipase D (PLD)-catalysed pathway which was kinetically downstream of initial PtdIns(4,5)P2 hydrolysis. Accumulation of PtdBut increased up to 15 min, suggesting that PLD activity is not rapidly densitized in response to PDGF. The kinetics of PtdCho hydrolysis closely paralleled the second phase of DAG formation, strongly suggesting that during prolonged stimulation periods PtdCho is a major source of DAG in these cells. However, since PtdIns(4,5)P2 breakdown was also prolonged, PDGF-stimulated DAG may be derived from both phospholipids. Down-regulation of protein kinase C (PKC), by pre-treatment with phorbol 12-myristate 13-acetate, abolished both [3H]choline and [3H]PtdBut formation, suggesting that PLD-catalysed PtdCho hydrolysis may be dependent on PKC activation, supporting its dependence on prior PtdIns(4,5)P2 hydrolysis.


The increasing impact of arthritis on public health.
Age is the most powerful risk factor for osteoarthritis (OA) in the United States. It is estimated that 68% of individuals older than 55 years have radiographic evidence of OA. The US is growing older--the over-65 age group represented only 4% of the population in 1900, but accounted for 12.4% in 1988, and is projected to account for 22% by the year 2030. As the age of our population has increased, so has the prevalence of arthritis. About 43 million individuals (1 in 6) have arthritis, and most are older than 45 years. By the year 2020, 59.4 million persons in the US will be affected by arthritis, thus increasing chronic disability and costs by more than 25%. The annual cost to society in medical care and lost wages is currently estimated to be $65 billion, and is projected to escalate to $95 billion by the year 2000. Physicians who provide care for the increased number of patients with arthritis in the 21st century must be aware of improved therapeutic modalities to reduce arthritis related disabilities, hospitalizations, and complications related to therapy, to minimize the risk of adverse drug reactions, and to preserve function.


How to distinguish between the annihilation and the creation of optical vortices.
Optical vortices are always created or annihilated as vortex dipoles-pairs with opposite topological charge. Here a quantity, consisting of the transverse first and second derivatives of the optical field, is derived with which one can distinguish between vortex dipole annihilation and creation events. Analytical and numerical examples are provided as a demonstration of the method.


Measuring patient satisfaction with vascular access: vascular access questionnaire development and reliability testing.
The primary objective of this study is to measure hemodialysis patients' satisfaction with their vascular access. The secondary objective is to evaluate the measurement tool's psychometric properties to assess patient satisfaction with their vascular access. We generated a comprehensive list of survey items related to patients' views and satisfaction with their vascular access and administered it to participating in-center hemodialysis patients over 4 months. Following a factor analysis, the items were reduced and rescaled to generate the final short-form vascular access questionnaire (SF-VAQ). The SF-VAQ was then administered to a new cohort of hemodialysis patients on two occasions 1 week apart from February 1, 2012, to April 1, 2014. A repeated measures analysis of variance and psychometric evaluation was conducted. The final SF-VAQ with 13 items and four domains was administered to 132 patients (35 fistulas, 14 grafts and 83 catheters). The mean Likert value for overall satisfaction on a scale of 1 (low) to 7 (high) was 5.98, with catheters, fistulas and grafts with values of 5.92, 6.46 and 5.21, respectively. The test-retest reliability for two occasions is 0.92 and the internal consistency for the first administration is high at 0.84. The SF-VAQ is a short, simple to administer vascular access-specific questionnaire with robust psychometric properties that can be used to obtain the patient's views on their vascular access. Based on the newly developed SF-VAQ, patients were the most satisfied with fistulas, scores.


Are Nanoparticles a Threat to Mycorrhizal and Rhizobial Symbioses? A Critical Review.
Soil microorganisms can be exposed to, and affected by, nanoparticles (NPs) that are either purposely released into the environment (e.g., nanoagrochemicals and NP-containing amendments) or reach soil as nanomaterial contaminants. It is crucial to evaluate the potential impact of NPs on key plant-microbe symbioses such as mycorrhizas and rhizobia, which are vital for health, functioning and sustainability of both natural and agricultural ecosystems. Our critical review of the literature indicates that NPs may have neutral, negative, or positive effects on development of mycorrhizal and rhizobial symbioses. The net effect of NPs on mycorrhizal development is driven by various factors including NPs type, speciation, size, concentration, fungal species, and soil physicochemical properties. As expected for potentially toxic substances, NPs concentration was found to be the most critical factor determining the toxicity of NPs against mycorrhizas, as even less toxic NPs such as ZnO NPs can be inhibitory at high concentrations, and highly toxic NPs such as Ag NPs can be stimulatory at low concentrations. Likewise, rhizobia show differential responses to NPs depending on the NPs concentration and the properties of NPs, rhizobia, and growth substrate, however, most rhizobial studies have been conducted in soil-less media, and the documented effects cannot be simply interpreted within soil systems in which complex interactions occur. Overall, most studies indicating adverse effects of NPs on mycorrhizas and rhizobia have been performed using either unrealistically high NP concentrations that are unlikely to occur in soil, or simple soil-less media (e.g., hydroponic cultures) that provide limited information about the processes occurring in the real environment/agrosystems. To safeguard these ecologically paramount associations, along with other ecotoxicological considerations, large-scale application of NPs in farming systems should be preceded by long-term field trials and requires an appropriate application rate and comprehensive (preferably case-specific) assessment of the context parameters i.e., the properties of NPs, microbial symbionts, and soil. Directions and priorities for future research are proposed based on the gaps and experimental restrictions identified.


Creating a database of internet-based clinical trials to support a public-led research programme: A descriptive analysis.
Online trials are rapidly growing in number, offering potential benefits but also methodological, ethical and social challenges. The International Network for Knowledge on Well-being (ThinkWell™) aims to increase public and patient participation in the prioritisation, design and conduct of research through the use of technologies. We aim to provide a baseline understanding of the online trial environment, determining how many trials have used internet-based technologies; how they have been used; and how use has developed over time. We searched a range of bibliographic databases to March 2015, with no date limits, supplemented by citation searching and references provided by experts in the field. Results were screened against inclusion and exclusion criteria, and included studies mapped against a number of key dimensions, with key themes developed iteratively throughout the process. We identified 1992 internet-based trials to March 2015. The number of reported studies increased substantially over the study timeframe. The largest number of trials were conducted in the USA (49.7%), followed by The Netherlands (10.2%); Australia (8.5%); the United Kingdom (5.8%); Sweden (4.6%); Canada (4%); and Germany (2.6%). South Korea (1.5%) has the highest number of reported trials for other continents. There is a predominance of interventions addressing core public health challenges including obesity (8.6%), smoking cessation (5.9%), alcohol abuse (7.7%) and physical activity (10.2%); in mental health issues such as depression (10.9%) and anxiety (5.6%); and conditions where self-management (16.6%) or monitoring (8.1%) is a major feature of care. The results confirm an increase in the use of the internet in trials. Key themes have emerged from the analysis and further research will be undertaken in order to investigate how the data can be used to improve trial design and recruitment, and to build an open access resource to support the public-led research agenda.


Regulation by recombinant interleukin-2 of protective immunity against recurrent herpes simplex virus type 2 genital infection in guinea pigs.
The goal of our study was to determine whether recombinant interleukin-2 (rIL-2) could modify the recurrence pattern of chronic herpes simplex virus type 2 (HSV-2) genital infection in guinea pigs. Animals that developed symptomatic acute HSV-2 infection were distributed at 14 days after viral inoculation into several treatment groups, which were similar with respect to the severity of acute disease. Three rIL-2 dosages administered for 4 weeks in daily subcutaneous injections were tested in this study: 5 X 10(3), 5 X 10(4), and 2.5 X 10(5) U. Daily observations of the animals showed a significant decrease of the incidence of new recurrent lesions with the use of 5 X 10(4) U of rIL-2 (rate of recurrence, 0.08, compared with 0.21 in untreated controls), whereas the other rIL-2 regimens did not affect the overall rate of recurrence. Weekly analysis of recurrences showed that treatment with 5 X 10(4) U of rIL-2 was effective only during the first 3 weeks of use and that 2.5 X 10(5) U of rIL-2 markedly decreased the rate of recurrence in the first week of treatment but not in subsequent weeks. The loss of clinical protection in both groups coincided with the production of neutralizing antibodies to rIL-2. The immune mechanisms possibly involved in the protective effect of rIL-2 in chronic HSV-2 disease were further investigated. Production of gamma interferon correlated well with clinical protection, and circulating levels dropped at the time when neutralizing antibodies to rIL-2 developed. Nonspecific cytotoxicity represented by natural killer cell and lymphokine-activated killer cell activities was also increased in the treated guinea pigs. Antibody titers and lymphocyte proliferation to herpes simplex antigen were similar in rIL-2 and placebo recipients. Finally, we found that the rIL-2-induced immune stimulation was as protective against recurrent HSV-2 disease in guinea pigs as the viral suppression achieved with acyclovir. However, the biological activity of both drugs was not additive when they were coadministered.


Role of alpha v integrins in mesangial cell adhesion to vitronectin and von Willebrand factor.
This study demonstrates (by flow cytometry and immunoprecipitation after cell surface radiolabeling and by using monoclonal antibodies to alpha v, beta 3, and alpha v beta 3 and alpha v beta 5 complexes) that alpha v beta 3, the vitronectin receptor, and alpha v beta 5 are expressed in vitro on cultured human mesangial cells (HMC) of the 5th to 8th passages. Antibodies to alpha v, beta 3 and alpha v beta 3 respectively precipitated an alpha beta heterodimer with molecular weights of 140 and 97 kDa. We analyzed the role of the various integrins in HMC interactions with vitronectin, and with fibronectin and von Willebrand factor (vWf), which are synthetized respectively by mesangial and endothelial cells. Cell adhesion increased in a dose dependent manner with the concentration of plastic-coated matrix protein and vWf. Inhibition of cell attachment with monoclonal antibodies to integrins indicated that HMC adhesion to vWf primarily involves alpha v beta 3, and that alpha v beta 5 may also contribute to cell binding to vWf. Adhesion to vitronectin involves both alpha v beta 3 and alpha v beta 5 complexes. In contrast, adhesion to fibronectin was not affected by monoclonal antibodies to alpha v beta 3 and alpha v beta 5 complexes. We propose that integrins alpha v beta 3 and alpha v beta 5, present on HMC, could mediate an interaction between mesangial and endothelial cells by binding to vWf, released at the basal site of endothelial cells.


A clinical study on the role of Akshi Tarpana with Jeevantyadi Ghrita in Timira (Myopia).
Myopia is a major public health problem pertaining to eye that entails substantial societal, personal, educational, and economical impact. Various surveys in India have found the prevalence of myopia ranging from 6.9% to 19.7%. Myopia progression is irreversible and methods for the correction of myopia are not without complications. Myopia closely resembles Timira involving first and second Patala in terms of symptoms, anatomical structures involved, and the pathogenesis of the disease. The study is aimed at evaluating the efficacy of the Akshi-Tarpana procedure with Jeevantyadi Ghrita in fresh and old myopes. A total of 54 patients (108 eyes) having myopia ≥-6 D were registered for the study and divided into two groups (Group A, Akshi-Tarpana with Jeevantyadi Ghrita, and Group B, Akshi-Tarpana with plain Go Ghrita), by stratified sampling. The procedure was done in 5 sittings of 5 days each with an equal interval of 5 days between each sitting. A total of 22 patients in Group A and 18 in Group B completed the treatment. Obtained data were statistically analyzed using a t-test and the study reveals that objectively, 09.30% and 05.55% eyes were cured, 16.28% and 02.78% markedly improved, and 34.88% and 11.11% moderately improved in Group A and B, respectively.


Unmet Health Care Needs among Children Exposed to Parental Incarceration.
Objectives The incarceration rate in the United States has increased rapidly since the mid-1970s and, accordingly, a large number of children are exposed to parental incarceration. Research finds that parental incarceration is associated with deleterious physical and mental health outcomes among children, but little is known about these children's health care access. Methods I used data from the 2011-2012 National Survey of Children's Health (N = 95,531), a population-based and nationally representative survey of non-institutionalized children ages 0-17 in the United States, to estimate the association between exposure to parental incarceration and children's unmet health care needs. Results In logistic regression models that adjust for an array of demographic and socioeconomic characteristics, children exposed to parental incarceration, compared to their counterparts, have 1.26 (95% CI 1.02-1.54) times the odds of having any unmet health care need. Analyses that disaggregate by type of unmet health care need (mental, dental, vision, mental health, or other) suggest this association is driven by a greater likelihood of unmet mental health care needs (OR 1.60; 95% CI 1.04-2.46). Conclusions Children exposed to parental incarceration, a vulnerable group especially at risk of physical and mental health problems, face challenges to health care access, especially mental health care access. Given that parental incarceration is concentrated among those children most in need of health care, parental incarceration may exacerbate existing inequalities in unmet health care needs.


The use of alpha-adrenoceptor antagonists in the pharmacological management of benign prostatic hypertrophy: an overview.
Benign prostatic hypertrophy (BPH) produces symptomatic urethral obstruction in a significant percentage of older men. Since the incidence of BPH is age related, the clinical and economic impact of this disease will continue to progress as average lifespan increases. BPH is associated with growth of both glandular and stromal elements of the prostate gland. Glandular hyperplasia can be partially reversed by withdrawal of androgenic tone with androgen receptor antagonists or steroid-5-alpha-reductase inhibitors. However, the reduction in prostatic size produced by these agents has little effect on the dynamic tone induced by nerve mediated contraction of stromal smooth muscle. This tone is mediated by activation of alpha-adrenoceptors. Therefore the alpha-adrenoceptor antagonists represent a useful pharmacological approach to the treatment of BPH. Studies in isolated strips of human prostate show that either exogenous alpha-adrenoceptor agonists or electrical field stimulation will induce contraction. Studies with selective antagonists such as prazosin show that this response is mediated by the alpha 1-adrenoceptor, even though radioligand binding studies show the presence of alpha 1 and alpha 2 adrenoceptor subtypes in approximately equal density. Following the cloning of multiple alpha 1-adrenoceptors, the contractile response in human prostate has been assigned to the alpha 1A adrenoceptor. However, recent data would suggest a functional role for another subtype, which has not yet been cloned, and designated as alpha 1L based on a relatively low affinity for prazosin. Clinical trials have shown efficacy of a variety of alpha-adrenoceptor antagonists in BPH, including non-selective agents such as phenoxybenzamine, as well as a variety of selective alpha 1-adrenoceptor antagonists, most structurally related to prazosin. The agents most commonly employed at the present time include the prazosin analogs terazosin, doxazosin and alfuzosin, as well as the structurally unrelated indoramin and tamsulosin. The design of new alpha 1-antagonists for BPH has concentrated on agents producing preferential blockage of urogenital vis-á-vis vascular alpha 1-adrenoceptors, based either on selectivity for the alpha 1A-adrenoceptor subtype or on functional uroselectivity in animal models. While these newer agents offer the prospect of reducing the incidence of the cardiovascular side effects associated with current therapy their superiority over nonselective alpha 1-adrenoceptor antagonists remains to be demonstrated in the clinical setting.


Pathogenetic mechanisms in B27 associated diseases.
Various aspects of pathogenesis, or more broadly, aetiopathogenesis, in the field of B27 related disorders are considered. The main conclusions can be expressed as follows: Genetic factors are involved in the causation of the spondarthritides, although there is still controversy within individual disorders concerning the precise mode of inheritance. For instance, in some conditions evidence appears stronger for a Mendelian mechanism, in others for a multifactorial process. The mode of the HLA-B27-receptor interaction is not yet fully established, but there is strong support for the one gene cross-tolerance theory, in ankylosing spondylitis at least. It is likely that environmental factors 'collaborate' with genetic factors in causing spondarthritic disease. The factors in the environment have yet to be proved, but there is some evidence that micro-organisms such as Klebsiella and Yersinia are involved (e.g. ankylosing spondylitis, Reiter's disease, reactive arthritis). Of noninfective environmental factors, trauma could play a part, as suggested by the mode of onset and pattern of development of some examples of ankylosing spondylitis and psoriatic arthritis.


Nonlinear amplitude dynamics in flagellar beating.
The physical basis of flagellar and ciliary beating is a major problem in biology which is still far from completely understood. The fundamental cytoskeleton structure of cilia and flagella is the axoneme, a cylindrical array of microtubule doublets connected by passive cross-linkers and dynein motor proteins. The complex interplay of these elements leads to the generation of self-organized bending waves. Although many mathematical models have been proposed to understand this process, few attempts have been made to assess the role of dyneins on the nonlinear nature of the axoneme. Here, we investigate the nonlinear dynamics of flagella by considering an axonemal sliding control mechanism for dynein activity. This approach unveils the nonlinear selection of the oscillation amplitudes, which are typically either missed or prescribed in mathematical models. The explicit set of nonlinear equations are derived and solved numerically. Our analysis reveals the spatio-temporal dynamics of dynein populations and flagellum shape for different regimes of motor activity, medium viscosity and flagellum elasticity. Unstable modes saturate via the coupling of dynein kinetics and flagellum shape without the need of invoking a nonlinear axonemal response. Hence, our work reveals a novel mechanism for the saturation of unstable modes in axonemal beating.


Non-invasive evaluation of bladder outlet obstruction in men suspected of benign prostatic hyperplasia: usefulness of the d index.
To compare a new index of voiding dysfunction (D) based purely on free uroflow vs. Abrams-Griffiths (A-G) number obtained from intubated flow, for classification of bladder outlet obstruction in men. Urodynamic tracings of 60 non-neurological patients (30 before transurethral resection of the prostate and of 30 men suspected of benign prostatic hyperplasia included in a medical therapy trial) were retrospectively analyzed. The Valentini-Besson-Nelson model was used to evaluate the value of the D index. A-G was obtained from intubated flows. Obstruction was defined as D > 32.5 cm H2O (translation of A-G criterion). D showed 82.05% sensitivity with 66.66% specificity; the positive predictive value was 82.05% and the negative predictive value 66.66% for the whole population, 83.3 vs. 80.9% sensitivity with 58.3 vs. 77.7% specificity for pre- transurethral resection of the prostate vs. medical therapy group. D index which can be obtained from a free uroflow appears as a valuable alternative to invasive urodynamic investigations when the diagnosis of bladder outlet obstruction needs to be more solidly established before a treatment decision or in men suspected of benign prostatic hyperplasia who elect for watchful waiting.


Fluorescence measurement of calcium transients in perfused rabbit heart using rhod 2.
Surface fluorescence spectroscopy of the beating heart to measure cytosolic calcium has been limited by the need to use ultraviolet excitation light for many of the commonly used calcium indicators. Ultraviolet light in the heart produces a high level of background fluorescence and is highly absorbed, limiting tissue penetration. Visible wave-length fluorescence dyes such as rhod 2 are available; however, the lack of spectral shift with calcium binding precludes the use of ratio techniques to account for changes in cytosolic dye concentration. We have developed a method for in vivo quantitation of cytosolic rhod 2 concentration that in conjunction with calcium-dependent fluorescence measurements permits estimation of cytosolic calcium levels in perfused rabbit hearts. Reflective absorbance of excitation light by rhod 2 loaded into myocardium was used as an index of dye concentration and the ratio of fluorescence intensity to absorbance as a measure of cytosolic calcium concentration. Endothelial cell loading of rhod 2 was found to be minimal (< 5%), and dye leak rate out of the cytosol was slow, with approximately 5% loss of dye fluorescence occurring between 10 and 30 min after dye loading. Rhod 2 loading into subcellular compartments, determined by manganese quenching, was also minimal (< 5%). The dissociation constant of rhod 2 for calcium was measured in vitro to be 500 nM, and this value increased to 710 nM in the presence of 0.5 mM myoglobin. On the basis of this value and in vivo fluorescence measurements, cytosolic calcium concentration in the rabbit heart was found to be 229 +/- 90 nM at end diastole and 930 +/- 130 nM at peak systole, with peak fluorescence preceding peak ventricular pressure by approximately 40 ms. This technique should facilitate detailed analysis of calcium transients from the whole heart.


A systematic examination of a random sampling strategy for source apportionment calculations.
Estimating the relative contributions from multiple potential sources of a specific component in a mixed environmental matrix is a general challenge in diverse fields such as atmospheric, environmental and earth sciences. Perhaps the most common strategy for tackling such problems is by setting up a system of linear equations for the fractional influence of different sources. Even though an algebraic solution of this approach is possible for the common situation with N+1 sources and N source markers, such methodology introduces a bias, since it is implicitly assumed that the calculated fractions and the corresponding uncertainties are independent of the variability of the source distributions. Here, a random sampling (RS) strategy for accounting for such statistical bias is examined by investigating rationally designed synthetic data sets. This random sampling methodology is found to be robust and accurate with respect to reproducibility and predictability. This method is also compared to a numerical integration solution for a two-source situation where source variability also is included. A general observation from this examination is that the variability of the source profiles not only affects the calculated precision but also the mean/median source contributions.


Global suppression of protein folding defects and inclusion body formation.
Amino acid substitutions at a site in the center of the bacteriophage protein P22 tailspike polypeptide chain suppress temperature-sensitive folding mutations at many sites throughout the chain. Characterization of the intracellular folding and chain assembly process reveals that the suppressors act in the folding pathway, inhibiting the aggregation of an early folding intermediate into the kinetically trapped inclusion body state. The suppressors alone increase the folding efficiency of the otherwise wild-type polypeptide chain without altering the stability or activity of the native state. These amino acid substitutions identify an unexpected aspect of the protein folding grammar--sequences within the chain that carry information inhibiting unproductive off-pathway conformations. Such mutations may serve to increase the recovery of protein products of cloned genes.


[Role of various types of serotonin reception in the hypothalamic modulation of the release of luteinizing hormone].
Ciproheptadin was found to depress the activating effect of serotonin in the preoptic brain area and in the hypothalamic arquate nuclei. Blockade of the type II serotonin receptors increased the content of luteinizing hormone in the blood in dioestrus-2 stage and in the morning during pro-estrus. Microiontophoretic administration of serotonin into the thalamic arquate nuclei during the blockade decreased the luteinizing hormone level in the blood in dioestrus-2 stage and in the morning during pro-estrus. Administration of serotonin into the preoptic area under the same conditions invariably decreased the hormone level in the blood. A significant negative correlation was found between the luteinizing hormone contents in the blood and hypophysis.


National registry-based case-control study: comorbidity and stroke in young adults.
Stroke is overrepresented in cohorts of young adults with chronic diseases. The prevalence and impact of comorbidity among young stroke patients have not been compared with individuals without stroke. Our aim was to investigate the association between comorbidity and stroke in young adults. A nationwide cohort of patients (aged 15-44 years), registered in the Swedish Stroke Register, (Riksstroke) 2001-2009, was identified. Age- and sex-matched controls were randomly selected from the Population Register of Sweden. Discharge diagnoses were retrieved from the National Patient Register and grouped by chapter in the International Classification of Diseases 10th revision. Associations between ICD-10 chapters and stroke were stratified (age, sex, and stroke type) and analyzed by multivariable logistic regression. In 2599 stroke patients analyzed, the prevalence of vascular risk factors (hypertension 25.3%, dyslipidemia 13.0%, diabetes 9.7%, heart failure 3.2%, and atrial fibrillation 2.8%), all ICD-10 chapters (except pregnancy) and prestroke hospitalizations were more frequent among cases than controls. Independent associations were found between stroke and eight ICD-10 chapters: neoplasms (odds ratios (OR) 1.53, 95% CI 1.15-2.05), blood (OR 1.61, 1.11-2.34), endocrine (OR 2.28, 1.77-2.93), psychiatric (OR 1.50, 1.24-1.81), nervous (OR 1.91, 1.46-2.50), eye (OR 1.67, 1.05-2.64), circulatory (OR 3.05, 2.45-3.80), and symptoms (OR 1.31, 1.13-1.52). The risk of stroke increased by 26% per ICD-10 chapter diagnosed. In addition to vascular risk factors, comorbidity (represented by ICD-10 chapters) was associated with increased risk of stroke in young individuals. The risk of stroke was further increased with the number of diagnosed ICD-10 chapters.


Improving Real-Time Lower Limb Motor Imagery Detection Using tDCS and an Exoskeleton.
The aim of this work was to test if a novel transcranial direct current stimulation (tDCS) montage boosts the accuracy of lower limb motor imagery (MI) detection by using a real-time brain-machine interface (BMI) based on electroencephalographic (EEG) signals. The tDCS montage designed was composed of two anodes and one cathode: one anode over the right cerebrocerebellum, the other over the motor cortex in Cz, and the cathode over FC2 (using the International 10-10 system). The BMI was designed to detect two MI states: relax and gait MI; and was based on finding the power at the frequency which attained the maximum power difference between the two mental states at each selected EEG electrode. Two different single-blind experiments were conducted, E1 and a pilot test E2. E1 was based on visual cues and feedback and E2 was based on auditory cues and a lower limb exoskeleton as feedback. Twelve subjects participated in E1, while four did so in E2. For both experiments, subjects were separated into two equally-sized groups: sham and active tDCS. The active tDCS group achieved 12.6 and 8.2% higher detection accuracy than the sham group in E1 and E2, respectively, reaching 65 and 81.6% mean detection accuracy in each experiment. The limited results suggest that the exoskeleton (E2) enhanced the detection of the MI tasks with respect to the visual feedback (E1), increasing the accuracy obtained in 16.7 and 21.2% for the active tDCS and sham groups, respectively. Thus, the small pilot study E2 indicates that using an exoskeleton in real-time has the potential of improving the rehabilitation process of cerebrovascular accident (CVA) patients, but larger studies are needed in order to further confirm this claim.


Threat of an influenza pandemic: family physicians in the front line.
The chance of an influenza pandemic is real and clinicians should keep themselves informed about the rationale and science behind preventive and therapeutic principles relating to an (impending) influenza pandemic. Vaccination is considered the best prevention in case of a pandemic threat and first choice to contain the impact of a pandemic. Pending the availability of an effective pandemic vaccine, antivirals are likely the only effective agents for prevention and treatment. When an influenza pandemic is impending, all interventions aim to prevent people becoming infected and to suppress replication and transmission of the virus as much as possible. Antivirals will be prescribed to patients with laboratory confirmed pre-pandemic influenza as well as to their contacts (post-exposure prophylaxis) which may delay development of or even prevent a pandemic. During a manifest influenza pandemic, however, there is large-scale spreading of the influenza virus. Therefore, preventive use of antivirals is less efficient to prevent transmission. Delaying the pandemic is then important in order to prevent exhausting public health resources and disruption of society. Thus, during a manifest pandemic everyone with influenza symptoms should receive antivirals as quickly as possible, regardless of virological confirmation. To ensure optimal effectiveness of antivirals and to minimize development of drug resistant viral strains, the use of antivirals for annual influenza should be restrictive. The crucial position of family physicians during an (impending) influenza pandemic necessitates the development of primary health care guidelines on this topic for all countries. Family physicians will play a key role in assessing and treating victims of a new influenza virus, and in reassuring the worried well. We outline various possible interventions in the event of an impending and a manifest influenza pandemic, such as non-medial measures, prescription of antivirals, and vaccination, and emphasize the need for pandemic influenza preparedness.


Multi-View Design Patterns and Responsive Visualization for Genomics Data.
A series of recent studies has focused on designing cross-resolution and cross-device visualizations, i.e., responsive visualization, a concept adopted from responsive web design. However, these studies mainly focused on visualizations with a single view to a small number of views, and there are still unresolved questions about how to design responsive multi-view visualizations. In this paper, we present a reusable and generalizable framework for designing responsive multi-view visualizations focused on genomics data. To gain a better understanding of existing design challenges, we review web-based genomics visualization tools in the wild. By characterizing tools based on a taxonomy of responsive designs, we find that responsiveness is rarely supported in existing tools. To distill insights from the survey results in a systematic way, we classify typical view composition patterns, such as "vertically long," "horizontally wide," "circular," and "cross-shaped" compositions. We then identify their usability issues in different resolutions that stem from the composition patterns, as well as discussing approaches to address the issues and to make genomics visualizations responsive. By extending the Gosling visualization grammar to support responsive constructs, we show how these approaches can be supported. A valuable follow-up study would be taking different input modalities into account, such as mouse and touch interactions, which was not considered in our study.


Probe for simultaneous membrane and nucleus labeling in living cells and in vivo bioimaging using a two-photon absorption water-soluble Zn(ii) terpyridine complex with a reduced π-conjugation system.
Small, biocompatible and water-soluble molecules with high two-photon absorption (2PA) cross-section values (δ) are in high demand for specific bioimaging applications. Here, two novel terpyridine derivative ligands with donor-acceptor (D-A) (L1) and donor-π-acceptor (D-π-A) (L2) models, and their corresponding Zn(ii) complexes are designed and characterized. It was found that the two-photon absorption cross section values (δ) in the near-infrared region (NIR, about 800 nm) are significantly enhanced for complexes 1 and 2 compared to their free D-A type ligand L1, while those of complexes 3 and 4 were greatly decreased relative to their free ligand L2, thus confirming that the smaller ligand (D-A type) displays a suitable Turn-ON fluorescence pair for two-photon fluorescence microscopy (2PFM). Firstly, the potential of simultaneously labeling a live cell plasma membrane and nucleus using complex 1 is demonstrated. In addition, live larval and adult zebrafish incubated with an optimal concentration of 1 demonstrated clear brain uptake. Lastly and importantly, using such a probe to visualize the blood-brain-barrier (BBB) capillary endothelial cells and penetrate the BBB into the central nervous system (CNS) intravenously in a mouse model is also explored.


Monolayer Graphene Radiation Sensor with Backend RF Ring Oscillator Transducer.
This paper proposes a new graphene gamma- and beta-radiation sensor with a backend RF ring oscillator transducer employed to convert the change in the graphene resistivity due to ionizing irradiation into a frequency output. The sensor consists of a CVD monolayer of graphene grown on a copper substrate, with an RF ring oscillator readout circuit in which the percentage change in frequency is captured versus the change in radiation dose. The novel integration of the RF oscillator transducer with the graphene monolayer results in high average sensitivity to gamma irradiation up to 3.82 kΩ/kGy, which corresponds to a percentage change in frequency of 7.86% kGy-1 in response to cumulative gamma irradiation ranging from 0 to 1 kGy. The new approach helps to minimize background environmental effects (e.g., due to light and temperature), leading to an insignificant error in the output change in frequency of the order of 0.46% when operated in light versus dark conditions. The uncertainty in readings due to background light was analyzed, and the error in the resistance was found to be of the order of 1.34 Ω, which confirms the high stability and selectivity of the proposed sensor under different background effects. Furthermore, the evolution of the graphene's lattice defect density due to radiation was observed using Raman spectroscopy and SEM, indicating a lattice defect density of up to 1.780 × 1011/cm2 at 1 kGy gamma radiation, confirming the increase in the graphene resistance and proving the graphene's sensitivity. In contrast, the graphene's defect density in response to beta radiation was 0.683 × 1011/cm2 at 3 kGy beta radiation, which is significantly lower than the gamma effects. This can be attributed to the lower p-doping effect caused by beta irradiation in ambient conditions, compared with that caused by gamma irradiation. Morphological analysis was used to verify the evolution of the microstructural defects caused by ionizing irradiation. The proposed sensor monitors the low-to-medium cumulative range of ionizing radiations ranging from 0 to 1 kGy for gamma radiation and 0 to 9 kGy for beta radiation, with high resolution and selectivity, filling the research gap in the study of graphene-based radiation sensors at low-to-medium ionizing radiation doses. This range is essential for the pharmaceutical and food industries, as it spans the minimum range for affecting human health, causing cancer and DNA damage.


Mesosecrin: a secreted glycoprotein produced in abundance by human mesothelial, endothelial, and kidney epithelial cells in culture.
Human mesothelial cells, endothelial cells, and type II kidney epithelial cells growing in culture devote approximately 3% of their total protein synthesis to the production of an Mr approximately 46-kD, pI 7.1, secreted glycoprotein (designated Sp46). Fibroblasts make about 1/10th as much Sp46 as these cell types, and their synthesis is dependent upon hydrocortisone. Keratinocytes, urothelial cells, conjunctival epithelial cells, and mammary epithelial cells do not make detectable amounts of Sp46. Mesothelial cells secrete Sp46 onto the substratum, and from there it is subsequently released into the medium. Immunofluorescence analysis using specific antisera discloses that Sp46 is deposited beneath cells as a fine coating on the substratum. In sparse cultures, Sp46 is detected in trails behind motile cells. In contrast, secreted fibronectin coalesces into fibers, most of which remain in contact with and on top of the cells; thus Sp46 does not preferentially bind to fibronectin. About 6 kD of the mass of human Sp46 is N-linked oligosaccharide, which is terminally sialated before secretion. Sp46 has a low glycine content, indicating that it is not a collagenlike protein. Its NH2-terminal sequence over the first 40 amino acids does not resemble any protein for which sequence information is available. Sp46 appears to be a novel extracellular glycoprotein, high-level constitutive expression of which is restricted to mesoderm-derived epithelial and endothelial cells. We therefore propose for it the name "mesosecrin."


Aldehyde dehydrogenase 1 a1 regulates energy metabolism in adipocytes from different species.
Survival and longevity of xenotransplants depend on immune function and ability to integrate energy metabolism between cells from different species. However, mechanisms for interspecies cross talk in energy metabolism are not well understood. White adipose tissue stores energy and is capable of mobilization and dissipation of energy as heat (thermogenesis) by adipocytes expressing uncoupling protein 1 (Ucp1). Both pathways are under the control of vitamin A metabolizing enzymes. Deficient retinoic acid production in aldehyde dehydrogenase 1 A1 (Aldh1a1) knockout adipocytes (KO) inhibits adipogenesis and increases thermogenesis. Here we test the role Aldh1a1 in regulation of lipid metabolism in xenocultures. Murine wide-type (WT) and KO pre-adipocytes were encapsulated into a poly-L-lysine polymer that allows exchange of humoral factors <32kD via nanopores. Encapsulated murine adipocytes were co-incubated with primary differentiated canine adipocytes. Then, expression of adipogenic and thermogenic genes in differentiated canine adipocytes was detected by real-time polymerase chain reaction (PCR). The regulatory factors in WT and KO cells were identified by comparison of secretome using proteomics and in transcriptome by gene microarray. Co-culture of encapsulated mouse KO vs WT adipocytes increased expression of peroxisome proliferator-activated receptor gamma (Pparg), but reduced expression of its target genes fatty acid binding protein 4 (Fabp4), and adipose triglyceride lipase (Atgl) in canine adipocytes, suggesting inhibition of PPARγ activation. Co-culture with KO adipocytes also induced expression of Ucp1 in canine adipocytes compared to expression in WT adipocytes. Cumulatively, murine KO compared to WT adipocytes decreased lipid accumulation in canine adipocytes. Comparative proteomics revealed significantly higher levels of vitamin A carriers, retinol binding protein 4 (RBP4), and lipokalin 2 (LCN2) in KO vs WT adipocytes. Our data demonstrate the functional exchange of regulatory factors between adipocytes from different species for regulation of energy balance. RBP4 and LCN2 appear to be involved in the transport of retinoids for regulation of lipid accumulation and thermogenesis in xenocultures. While the rarity of thermogenic adipocytes in humans and dogs precludes their use for autologous transplantation, our study demonstrates that xenotransplantation of engineered cells could be a potential solution for the reduction in obesity in dogs and a strategy for translation to patients.


Combined total hip and knee arthroplasty during the same hospital admission: is it safe?.
The purpose of this study was to compare outcomes of combined total joint arthroplasty (TJA) (total hip arthroplasty (THA) and total knee arthroplasty (TKA) performed during the same admission) versus bilateral THA, bilateral TKA, single THA, and single TKA. Combined TJAs performed on the same day were compared with those staged within the same admission episode. Data from the National (Nationwide) Inpatient Sample recorded between 2005 and 2014 were used for this retrospective cohort study. Postoperative in-hospital complications, total costs, and discharge destination were reviewed. Logistic and linear regression were used to perform the statistical analyses. p-values less than 0.05 were considered statistically significant. Combined TJA was associated with increased risk of deep vein thrombosis, prosthetic joint infection, irrigation and debridement procedures, revision arthroplasty, length of stay (LOS), and in-hospital costs compared with bilateral THA, bilateral TKA, single THA, and single TKA. Combined TJA performed on separate days of the same admission showed no statistically significant differences when compared with same-day combined TJA, but trended towards decreased total costs and total complications despite increased LOS. Combined TJA is associated with increased in-hospital complications, LOS, and costs. We do not recommend performing combined TJA during the same hospital stay. Cite this article: Bone Joint J 2019;101-B:573-581.


Failed Intrauterine Pregnancy: What Is a Failed Pregnancy, What Is Not?
Pregnancy failure is defined as a lack of sonographic evidence of current or expected viability. Technologic advances in ultrasound imaging continue to redefine diagnostic criteria of pregnancy failure or success. When evaluating a pregnancy, the first step is an assessment of maternal risk factors for failure. Imaging clues such as an empty gestational sac measuring ≥25 mm or an embryo ≥7 mm without cardiac activity are reliable signs of pregnancy failure, whereas embryonic growth <1 mm/d is not. Combinations of sonographic findings can be used for a more accurate prediction of pregnancy success or failure.


Chemodiversity of Ladder-Frame Prymnesin Polyethers in Prymnesium parvum.
Blooms of the microalga Prymnesium parvum cause devastating fish kills worldwide, which are suspected to be caused by the supersized ladder-frame polyether toxins prymnesin-1 and -2. These toxins have, however, only been detected from P. parvum in rare cases since they were originally described two decades ago. Here, we report the isolation and characterization of a novel B-type prymnesin, based on extensive analysis of 2D- and 3D-NMR data of natural as well as 90% (13)C enriched material. B-type prymnesins lack a complete 1,6-dioxadecalin core unit, which is replaced by a short acyclic C2 linkage compared to the structure of the original prymnesins. Comparison of the bioactivity of prymnesin-2 with prymnesin-B1 in an RTgill-W1 cell line assay identified both compounds as toxic in the low nanomolar range. Chemical investigations by liquid chromatography high-resolution mass spectrometry (LC-HRMS) of 10 strains of P. parvum collected worldwide showed that only one strain produced the original prymnesin-1 and -2, whereas four strains produced the novel B-type prymnesin. In total 13 further prymnesin analogues differing in their core backbone and chlorination and glycosylation patterns could be tentatively detected by LC-MS/HRMS, including a likely C-type prymnesin in five strains. Altogether, our work indicates that evolution of prymnesins has yielded a diverse family of fish-killing toxins that occurs around the globe and has significant ecological and economic impact.


Analysis of the comprehensibility of chemical hazard communication tools at the industrial workplace.
Chemical classification and labelling systems may be roughly similar from one country to another but there are significant differences too. In order to harmonize various chemical classification systems and ultimately provide consistent chemical hazard communication tools worldwide, the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) was endorsed by the United Nations Economic and Social Council (ECOSOC). Several countries, including Japan, Taiwan, Korea and Malaysia, are now in the process of implementing GHS. It is essential to ascertain the comprehensibility of chemical hazard communication tools that are described in the GHS documents, namely the chemical labels and Safety Data Sheets (SDS). Comprehensibility Testing (CT) was carried out with a mixed group of industrial workers in Malaysia (n=150) and factors that influence the comprehensibility were analysed using one-way ANOVA. The ability of the respondents to retrieve information from the SDS was also tested in this study. The findings show that almost all the GHS pictograms meet the ISO comprehension criteria and it is concluded that the underlying core elements that enhance comprehension of GHS pictograms and which are also essential in developing competent persons in the use of SDS are training and education.