Peer Victimization and Suicidal Thoughts and Behaviors in Depressed Adolescents.
Suicide is a leading cause of death among youth worldwide, and depressed adolescents are at a significantly elevated risk to report suicidal ideation, planning, and attempts. Peer victimization is a robust predictor of adolescent suicidal thoughts and behaviors (STBs), but little research has focused on why bullying leads to suicidal thoughts and behaviors. To address this empirical gap, we recruited 340 (246 female) depressed adolescents ages 13-19 (M = 15.59, SD = 1.41) within 48 h of admission for acute psychiatric treatment. At the initial assessment, participants were administered clinical interviews characterizing psychopathology, nonsuicidal self-injury, and STBs (ideation, plans, and attempts). Further, they completed questionnaires assessing 3 forms of victimization (overt, relational, and reputational), recent risky behavior engagement, and psychiatric symptom severity. Controlling for internalizing symptoms and age, overt and reputational bullying were associated with more frequent past month suicide attempts, but not suicide ideation. Past month risky behavior engagement, but not NSSI, mediated the relation between victimization and attempts. However, sex differences revealed that this effect only held for males whereas bullying was directly associated with suicide attempts among females. In contrast, overt and relational bullying were non-linearly associated with suicide plans, and these relations were not mediated by risky behaviors or NSSI. Results highlight the complex network of factors that lead victimized adolescents to engage in STBs and may inform targeted suicide prevention and intervention programs.


Phase stabilization of an octave-spanning Ti:sapphire laser.
We obtain direct stabilization of the carrier-envelope phase for a standard x-folded geometry, octave-spanning, Ti:sapphire laser. The in-loop accumulated carrier-envelope phase error is 0.175 rad (1.65 mHz to 102 kHz). Intracavity continuum generation, which is responsible for the octave bandwidth, is characterized through measurement of the beam parameters.


Classification of Systemic Lupus Erythematosus Using Raman Spectroscopy of Blood and Automated Computational Detection Methods: A Novel Tool for Future Diagnostic Testing.
The aim of this study was to explore the proof of concept for using Raman spectroscopy as a diagnostic platform in the setting of systemic lupus erythematosus (SLE). We sought to identify unique Raman signatures in serum blood samples to successfully segregate SLE patients from healthy controls (HC). In addition, a retrospective audit was undertaken to assess the clinical utility of current testing platforms used to detect anti-double stranded DNA (dsDNA) antibodies (n = 600). We examined 234 Raman spectra to investigate key variances between SLE patients (n = 8) and HC (n = 4). Multi-variant analysis and classification model construction was achieved using principal component analysis (PCA), PCA-linear discriminant analysis and partial least squares-discriminant analysis (PLS-DA). We achieved the successful segregation of Raman spectra from SLE patients and healthy controls (p-value < 0.0001). Classification models built using PLS-DA demonstrated outstanding performance characteristics with 99% accuracy, 100% sensitivity and 99% specificity. Twelve statistically significant (p-value < 0.001) wavenumbers were identified as potential diagnostic spectral markers. Molecular assignments related to proteins and DNA demonstrated significant Raman intensity changes between SLE and HC groups. These wavenumbers may serve as future biomarkers and offer further insight into the pathogenesis of SLE. Our audit confirmed previously reported inconsistencies between two key methodologies used to detect anti-dsDNA, highlighting the need for improved laboratory testing for SLE. Raman spectroscopy has demonstrated powerful performance characteristics in this proof-of-concept study, setting the foundations for future translation into the clinical setting.


Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases.
We report a retrospective clinicopathologic study of 108 primary thyroid gland lymphomas (PTLs), classified using the REAL and proposed WHO classification schemes. The patients included 79 women and 29 men, with an average age of 64.3 years. All patients presented with a thyroid mass. The PTLs were classified as marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) or MZBL (n = 30), diffuse large B-cell lymphoma (DLBCL) with MZBL (n = 36), DLBCL without MZBL (n = 41), and follicle center lymphoma (FCL; n = 1). Excluding the FCL, features of lymphomas of MALT-type were identified in all groups, despite a follicular architecture in 23% of cases. Lymphocytic thyroiditis (LT) was identified in 94%. Ninety-one percent of patients presented with stage IE or IIE disease, whereas 69% had perithyroidal soft tissue infiltration. All patients were treated with surgical excision followed by adjuvant therapy (76%): chemotherapy (15%), radiation (19%), or a combination of radiation and chemotherapy (42%). Disease-specific survival was 82% at last follow up (mean, 82.8 mos) and 79% at 5 years. Statistically, stages greater than IE, presence of DLBCL, rapid clinical growth, abundant apoptosis, presence of vascular invasion, high mitotic rate, and infiltration of the perithyroidal soft tissue were significantly associated with death with disease. No patients with MZBL or stage IE disease died with disease. In summary, PTLs typically occur in middle- to older-aged individuals as a thyroid mass, with a predilection for females. Despite their histologic heterogeneity and frequent simulation of other lymphoma subtypes, virtually all PTLs are lymphomas of MALT-type arising in the setting of LT. Mixed DLBCL and MZBL are common. Overall, PTLs have a favorable outcome with appropriate therapy, but prognosis depends on both clinical stage and histology. MZBL and stage IE tumors have an excellent prognosis, whereas tumors with a large cell component or DLBCL or stage greater than IE have the greatest potential for a poor outcome.


Mannitol-induced acute renal failure.
A 62-year-old man was admitted to the ophthalmologic department for operation of retinal detachment. Mannitol and acetazolamide were prescribed to reduce intraocular pressure. Seven days after operation, gradual onset of drowsy consciousness occurred. The laboratory findings of hypertonic hyponatremia (109 mEq/l), hyperosmolality (341 mosm/kg), metabolic acidosis (pH: 7.17) and acute renal failure (serum creatinine: 8.2 mg/dl) dictated a diagnosis of mannitol-induced acute kidney injury. First, 3% saline was given, but consciousness kept deteriorated with worsened dyspnea and metabolic acidosis. Hemodialysis was then performed subsequently and his consciousness and renal function completely recovered. A special emphasis on the treatment of hypertonic hyponatremia was given.


Risks associated with genetic testing: health insurance discrimination or simply business as usual?
Doctors can test patients for mutations that put them at high risk for hereditary forms of such diseases as breast and ovarian cancer. Even though the opportunities for disease prevention using genetic testing will increase with time, the risks of testing, which include insurance loss and employment discrimination, currently make testing problematic. Some have proposed making use of genetic information in health insurance underwriting illegal. But in the current system of risk-based underwriting, it is hard to imagine that insurance companies will willingly forego access to a growing body of information on risk. If the American public chooses to limit the use of genetic information, a reassessment of current laws or methods of paying for health care will be needed.


Chordoma: diagnosis by fine-needle aspiration biopsy with histologic, immunocytochemical, and ultrastructural confirmation.
Five cases of chordoma, diagnosed by fine-needle aspiration (FNA) biopsy, are presented. Four cases were histologically confirmed, and in one, immunocytochemical and ultrastructural studies were performed on both the aspirate and tissue specimen. Four cases presented as sacral masses, while in the fifth case, a destructive lesion of the clivus extended into the soft tissues of the lateral neck. A spectrum of cytomorphologic features was encountered including the presence of abundant microtissue fragments and cells in a dissociate pattern, often with abundant metachromatic extracellular matrix. Stellate and cuboidal cells often contained intracytoplasmic vacuoles of varying sizes. Intranuclear inclusions, mitotic figures, and anisonucleosis were prominent features of several cases. Immunoperoxidase studies on a single case demonstrated cytoplasmic staining for low- and high-molecular-weight cytokeratins, vimentin, and epithelial membrane antigen, while glial fibrillary acidic protein and carcinoembryonic antigen were negative. Ultrastructural features included the presence of mitochondrial endoplasmic reticulum complexes, occasional desmosome-like junctions, and abundant extracellular matrix adherent to the tumor cells. We believe the cytomorphologic findings are characteristic and, when taken in concert with immunocytochemical and ultrastructural studies, allow differentiation of chordoma from other primary or metastatic neoplasms occurring in bone. As demonstrated in our series, chordoma is often an unsuspected diagnosis. We believe that FNA biopsy of these lesions can lead to a correct preoperative diagnosis and may also be utilized to document recurrence and thus facilitate the evaluation and management of patients with these lesions.


[Importance of uroflowmetry in lower urinary tract symptoms diagnostics].
To summarize the current state of knowledge on the use of uroflowmetry in diagnosis of lower urinary tract dysfunction in women. Review article. Department of Obstetrics and Gynecology, University Hospital Ostrava and Faculty of Medicine, Ostrava University. Literature review. Lower urinary tract dysfunction is associated with debilitating symptoms, which negatively affect the quality of life of a large number of patients, and represent a significant health problem. Inaccurate diagnosis leads to delayed therapy, which could cause disease progression and complications. It has been recently recognized that affected patients express a wide variety of clinical phenotypes. Advancements in diagnostic procedures may allow for individualized treatment and improved treatment outcomes. Diagnostic procedures recommended for patients with suspected lower urinary tract disease include directed medical history, urinalysis, voiding diary, as well as non-invasive and invasive urodynamic methods. Additional diagnostic tests may be used in select cases. Uroflowmetry is a basic urodynamic method used for screening. It represents a standard component used in the diagnostic process for patients with lower urinary tract symptoms. Sonouroflowmetry is a new method, which evaluates the urinary flow and lower urinary tract symptoms in a non-invasive manner by analysing the sound generated by a stream of urine striking the water surface in the toilet bowl.


[Risk factors for arterial hypertension in the adult population of an urban region of Ecuador].
Objectives . To determine the risk factors for arterial hypertension (HTN) in the adult resident population of the city of Cuenca, Ecuador Materials and methods A cross-sectional analytical study of adults selected via multistage random sampling who underwent clinical, anthropometric, and laboratory evaluations. The diagnosis of HTN was defined according to the JNC-7 criteria. A multiple logistic regression model was performed Results A total of 318 persons were included. The prevalence of HTN was 25.8% (males: 27.2% vs. females: 24.7%; p = 0.617). In the multiple logistic regression model, the risk factors for HTN were age > 60 years (OR, 8.68; 95% CI, 3.56-21.14; p < 0.001), obesity according to body mass index (OR, 2.36; 95% CI, 1.04-5.70; p = 0.042), high caloric intake (OR, 2.06; 95% CI, 1.01- 4.53; p = 0.044), and family history of HTN (OR, 1.58; 95% CI, 1.02-2.90; p = 0.040) Conclusions The presence of HTN in this population is associated with both intrinsic and environmental factors, which should be considered in routine evaluations to ensure its early identification and control.


Generating customized transgene landing sites and multi-transgene arrays in Drosophila using phiC31 integrase.
Transgenesis in numerous eukaryotes has been facilitated by the use of site-specific integrases to stably insert transgenes at predefined genomic positions (landing sites). However, the utility of integrase-mediated transgenesis in any system is constrained by the limited number and variable expression properties of available landing sites. By exploiting the nonstandard recombination activity exhibited by a phiC31 integrase mutant, we developed a rapid and inexpensive method for isolating landing sites that exhibit desired expression properties. Additionally, we devised a simple technique for constructing arrays of transgenes at a single landing site, thereby extending the utility of previously characterized landing sites. Using the fruit fly Drosophila melanogaster, we demonstrate the feasibility of these approaches by isolating new landing sites optimized to express transgenes in the nervous system and by building fluorescent reporter arrays at several landing sites. Because these strategies require the activity of only a single exogenous protein, we anticipate that they will be portable to species such as nonmodel organisms, in which genetic manipulation is more challenging, expediting the development of genetic resources in these systems.


Proton Binding Characteristics of Dissolved Organic Matter Extracted from the North Atlantic.
Marine dissolved organic matter (DOM) presents key thermodynamic properties that are not yet fully constrained. Here, we report the distribution of binding sites occupied by protons (i.e., proton affinity spectra) and parametrize the median intrinsic proton binding affinities (log K̅H) and heterogeneities (m), for DOM samples extracted from the North Atlantic. We estimate that 11.4 ± 0.6% of C atoms in the extracted marine DOM have a functional group with a binding site for ionic species. The log K̅H of the most acidic groups was larger (4.01-4.02 ± 0.02) than that observed in DOM from coastal waters (3.82 ± 0.02), while the chemical binding heterogeneity parameter increased with depth to values (m1= 0.666 ± 0.009) ca. 10% higher than those observed in surface open ocean or coastal samples. On the contrary, the log K̅H for the less acidic groups shows a difference between the surface (10.01 ± 0.08) and deep (9.22 ± 0.35) samples. The latter chemical groups were more heterogeneous for marine than for terrestrial DOM, and m2 decreased with depth to values of 0.28 ± 0.03. Binding heterogeneity reflects aromatic carbon compounds' persistence and accumulation in diverse, low-abundance chemical forms, while easily degradable low-affinity groups accumulate more uniformly in the deep ocean.


[Activity of neurons of the motor cortex of the cat during inhibition of a postural change conditioned reflex].
Spike reactions were recorded from motor cortex neurons in cats in the forelimb projection area during external and internal inhibition of the conditioned postural adjustment (transfer of the body weight) of the same limb. Spike responses evoked by external stimulation were of the same character as the responses during conditioned stimulation. As a rule, they were determined by the state of the animal and its habituation to the applied stimulus. Duration of the responses during external stimulation was shorter in trained cats than in untrained ones. Late after-discharges of units and associated conditioned movements disappeared simultaneously during external and internal inhibition. Sometimes the external stimuli were able to depress after-discharges even when the conditioned movements appeared. External stimuli of various modalities inhibited the reflex in different manners. The changes of spike reactions during conditioned posture adjustment resembled those during well learned local conditioned events.


Late outcomes following open and endovascular repair of blunt thoracic aortic injury.
Previous studies have focused on early outcomes of open (descending thoracic aortic repair [DTAR]) and endovascular (thoracic endovascular aneurysm repair [TEVAR]) repair of blunt aortic injury (blunt thoracic aortic injury [BTAI]). Late results remain ill-defined and are the focus of this study. One hundred nine patients (1992-2010) underwent repair for BTAI. Mean age was 39.0 years (73.4% male). DTAR was performed in 90, with left heart bypass (85) or hypothermic arrest (5). TEVAR was used in 19 of 45 patients treated since 2002. A strategy of selective delayed repair has been used since 1997, with 54 of 75 patients treated with delayed repair in this interval. The primary outcome was vital status (100% follow-up; mean, 103.9 months). Mean Injury Severity Score was 39.5. Thirty-day mortality was 4.6% (n = 5). Early morbidity included permanent spinal cord ischemia (SCI, 1.8%), stroke (2.8%), and need for permanent dialysis (1.8%). Independent predictors of a composite outcome of early mortality and these morbidities included age >60 years (odds ratio [OR], 8.4; P = .015), increasing preoperative creatinine (OR, 7.9; P = .017), and occurrence of postoperative sepsis (OR, 9.6; P = .021). Fifteen-year Kaplan-Meier survival was 81.3%. Independent predictors of late mortality included age >60 years (Cox hazard ratio [HR], 4.1; P = .01), increasing creatinine (HR, 9.1; P < .001), or occurrence of postoperative SCI (HR, 20.6; P < .001), but not repair type (P = .73). Endograft collapse occurred in one patient, necessitating reintervention. Freedom from aortic reintervention at 4 years was higher after open repair (DTAR 100% vs TEVAR 94%; P = .03). With careful selection, open or endovascular repair of BTAI has excellent early and late results. Although TEVAR has an increased risk for reintervention, factors other than treatment strategy impact late survival. These data support the growing role of an endoluminal approach for BTAI in anatomically appropriate patients.


[The therapeutic community for recuperation from addiction to alcohol and other drugs in Brasil: in line with or running counter to psychiatric reform?].
In the second half of the last century a revolutionary movement began in the world mental health scenario, namely Psychiatric Reform. At the same juncture, the concept was also put forward for Therapeutic Communities, which would later become the tried and tested model for treatment of addiction to alcohol and other drugs. However, due to the alarming increase of this problem in Brazil, as well as the absence of public policies to address the problem, there was an indiscriminate proliferation of chemical dependency internment locations that, despite calling themselves Therapeutic Communities, in no way resembled the initial model proposed. These places featured inhuman and iatrogenic practices, very similar to those criticized by the Psychiatric Reform movement, which consequently discredited the Therapeutic Community model. This article seeks to demonstrate, through bibliographic research, how the conceptual and methodological bases of Psychiatric Reform closely resemble the Therapeutic Communities movement, having appeared at the same time and for the same reason, and how the lack of control and regulation of chemical dependency internment locations in Brazil has contributed to the current disrepute of this model.


Observation of the narrow state X(3872)-->J/psipi+pi- in pp collisions at sqaure root of s=1.96 TeV.
We report the observation of a narrow state decaying into J/psipi+pi- and produced in 220 pb(-1) of p p-bar collisions at =1.96 Tesqaure root of sV in the CDF II experiment. We observe 730+/-90 decays. The mass is measured to be 3871.3+/-0.7(stat)+/-0.4(syst) MeV/c2, with an observed width consistent with the detector resolution. This is in agreement with the recent observation by the Belle Collaboration of the X(3872) meson.


Cancer Vaccines in Ovarian Cancer: How Can We Improve?
Epithelial ovarian cancer (EOC) is one important cause of gynecologic cancer-related death. Currently, the mainstay of ovarian cancer treatment consists of cytoreductive surgery and platinum-based chemotherapy (introduced 30 years ago) but, as the disease is usually diagnosed at an advanced stage, its prognosis remains very poor. Clearly, there is a critical need for new treatment options, and immunotherapy is one attractive alternative. Prophylactic vaccines for prevention of infectious diseases have led to major achievements, yet therapeutic cancer vaccines have shown consistently low efficacy in the past. However, as they are associated with minimal side effects or invasive procedures, efforts directed to improve their efficacy are being deployed, with Dendritic Cell (DC) vaccination strategies standing as one of the more promising options. On the other hand, recent advances in our understanding of immunological mechanisms have led to the development of successful strategies for the treatment of different cancers, such as immune checkpoint blockade strategies. Combining these strategies with DC vaccination approaches and introducing novel combinatorial designs must also be considered and evaluated. In this review, we will analyze past vaccination methods used in ovarian cancer, and we will provide different suggestions aiming to improve their efficacy in future trials.


[Stereotaxic guidance in open surgery of the brain].
The authors describe the technique used to precisely locate, before surgical ablation, small superficial or deep seated intracerebral lesions. When they are superficial, a burrhole is placed above the lesional site, that is reconstructed by superimposing the CT image onto a plain film radiogram taken during stereotaxy. Deep seated lesions are localized by inserting a guide under stereotaxy, prior to open surgery, which will lead the neurosurgeon without error from the cortex to the lesion. 37 observations are reported where this technique lead to a greatly simplified intervention with minimal cortical damage.


Ophthalmic Research Lecture 2018: DARC as a Potential Surrogate Marker.
Glaucoma is a progressive, neurodegenerative disease that is increasing in prevalence worldwide. There is a need to develop ways in which to diagnose the disease sooner and more reliably in order to prevent irreversible visual loss and meet the growing demands on healthcare services. Research into neuroprotective therapies in glaucoma is lacking a reliable surrogate marker in order to show treatment efficacy in a meaningful and cost-effective manner. The detection of apoptosing retinal cells (DARC) is a new technique that has promise in providing a solution to this unmet clinical need. Multiple animal studies have demonstrated its use as a biomarker in quantifying the effect of retinal neuroprotection methods, and it has recently been translated into humans in phase I and II trials, with phase I demonstrating the visualisation of individual apoptosing retinal cells in healthy and glaucomatous patients, with good safety and tolerability. The future for this technique will now be identifying disease-specific characteristics of human disease that can be used in order to provide us with a much-needed surrogate marker in the field of retinal neurodegeneration.


Pattern Analyses Reveal Separate Experience-Based Fear Memories in the Human Right Amygdala.
Learning fear via the experience of contingencies between a conditioned stimulus (CS) and an aversive unconditioned stimulus (US) is often assumed to be fundamentally different from learning fear via instructions. An open question is whether fear-related brain areas respond differently to experienced CS-US contingencies than to merely instructed CS-US contingencies. Here, we contrasted two experimental conditions where subjects were instructed to expect the same CS-US contingencies while only one condition was characterized by prior experience with the CS-US contingency. Using multivoxel pattern analysis of fMRI data, we found CS-related neural activation patterns in the right amygdala (but not in other fear-related regions) that dissociated between whether a CS-US contingency had been instructed and experienced versus merely instructed. A second experiment further corroborated this finding by showing a category-independent neural response to instructed and experienced, but not merely instructed, CS presentations in the human right amygdala. Together, these findings are in line with previous studies showing that verbal fear instructions have a strong impact on both brain and behavior. However, even in the face of fear instructions, the human right amygdala still shows a separable neural pattern response to experience-based fear contingencies.SIGNIFICANCE STATEMENT In our study, we addressed a fundamental problem of the science of human fear learning and memory, namely whether fear learning via experience in humans relies on a neural pathway that can be separated from fear learning via verbal information. Using two new procedures and recent advances in the analysis of brain imaging data, we localized purely experience-based fear processing and memory in the right amygdala, thereby making a direct link between human and animal research.


Neck dissection findings in primary head and neck high-grade adenocarcinoma.
Primary salivary adenocarcinoma of the head and neck is rare. In cases where cervical metastases are evident or suspected, neck dissection is likely to play a role in management. However, there is little data in the literature regarding the findings and outcome of neck dissection in these patients. The present study comprised a review of 12 patients with high-grade salivary adenocarcinoma (salivary ductal carcinoma or adenocarcinoma, not otherwise specified (NOS). Eight underwent neck dissection (four modified radical, four selective). Histological examination showed evidence of cervical metastases in five. The prevalence of occult metastases in the N(0) neck was 40 per cent. Computed tomography (CT) and magnetic resonance imaging (MRI) were not useful in detecting occult neck disease. Five patients had no evidence of disease at the most recent follow up. Neck dissection is indicated in patients with high-grade salivary adenocarcinoma, and may provide information for planning adjuvant treatment.


What can be learned from fishers' perceptions for fishery management planning? Case study insights from Sainte-Marie, Madagascar.
Local support is critical to the success and longevity of fishery management initiatives. Previous research suggests that how resource users perceive ecological changes, explain them, and cope with them, influences local support. The objectives of this study were two-fold. First, we collated local fishers' knowledge to characterize the long-term socio-ecological dynamics of the small-scale fishery of Sainte-Marie Island, in Madagascar. Second, we empirically assessed the individual- and site-level factors influencing support for fishery restrictions. Our results indicate that fishers observed a decline in fish abundance and catch sizes, especially in nearshore areas; many also perceived a reduction in fish sizes and the local disappearance of species. To maintain their catches, most fishers adapted by fishing harder and further offshore. Accordingly, fishers identified increased fishing effort (number of fishers and gear evolution) as the main cause of fishery changes. Collectively, our results highlight that the transition from a subsistence to commercial fishery, and resulting changes in the relationship between people and the fisheries, was an underlying driver of fishery changes. Additionally, we found that gender, membership to local associations, coping mechanisms, and perceptions of ecological health, were all interlinked and significantly associated with conservation-oriented attitudes. Conservation-oriented attitudes, however, were not associated with fishers' willingness to decrease fishing. In the short-term, area-based restrictions could contribute to building support for conservation. In the long-term, addressing the underlying causes of the decline will necessitate collaborations among the various groups involved to progressively build livelihood flexibility. Collectively, our study provides additional insights on the individual- and site-level factors influencing support for fishery restrictions. It also highlights the importance of dialoguing with fishers to ensure that fishery management plans are adapted to the local context.


[Interaction of negative (CytT) and positive (cAMP-CRP) regulation in the promoter region of the uridine phosphorylase (udp) gene in Escherichia coli K-12].
Interaction of negative (CytR) and positive (cAMP-CRP) control in the promoter region of the uridine phosphorylase (udp) gene of Escherichia coli has been studied by using udp-lac operon fusions in which the structural lacZ gene is expressed from the wild type promoter udpP+ or from mutant promoters udpP1 and udpP18. The specific activity of beta-galactosidase was examined in these fusions in cytR+ and cytR- backgrounds after introduction of specific mutations in crp locus, crp* and crp(a) altering interaction of CRP protein with catabolite-sensitive promoters. The data obtained using crp* mutation confirm the proposed model of the udp gene regulation, according to which CytR repressor protein interferes with CRP binding site in the promoter-operator region of the udp gene and thereby prevents the positive action of cAMP-CRP complex on the udp expression. Additional data in favor of this model were obtained using crp(a) mutation which most probably alters the structure of CRP protein in such a way that it exhibits more high affinity to the udp promoter, as compared to the CytR repressor protein. Indeed, taken by itself, the crp(a) mutation did not lead to any increase in the expression of udpP+-lac fusion under the conditions of cAMP limitation (on glucose-grown cells), in spite of whether or not the CytR repressor was present. However, when combined with the ptsG mutation or when cells were grown on succinate medium, complete constitutive expression of udpP+-lac fusion is observed, even in the presence of the cytR gene product. The effect of the crp(a) mutation was virtually the same in strains harboring udpP1-lac fusion. These data are in accordance with suggestion that udpP1 is a mutation in the site of the promoter-operator region that responds to the cytR gene product, while the corresponding binding site for CRP protein is still unaltered in this mutant. On the other hand, the crp(a) mutation causes only slight alteration in the expression of udpP18-lac fusion, providing additional evidence that udpP18 mutation seems to comprise a modification of the promoter-operator region, where binding sites for CRP and CytR proteins overlap.


Supplying nitrate before bud break induces pronounced changes in nitrogen nutrition and growth of young poplars.
Tree nutrient research concentrated on endogenous C and N remobilisation in spring has neglected to acknowledge the possibilities of significant effects of N uptake before bud break, especially on the quality of regrowth and N reserve remobilisation. To investigate this subject, experimental studies were performed on young poplars (Populus tremula×Populus alba, clone INRA 717-1B4) grown with a controlled nutrient supply: (i) without N, 'control'; (ii) N supplied throughout the course of the experiment, 'N-supply'; and (iii) N supplied only before bud break, 'N-pulse'. Results confirm the hypothesis that poplar scions can significantly take up nitrate before bud break, amounting to ~34% of the total N stored the previous year. After bud break, emerging leaves restart the sap flow, which increased nitrate uptake to support the regrowth. N-pulse and N-supply treatments were found to have significant effects shortly after a growth period, i.e. by increasing N content of all tissues (e.g. 37 and 81% in new shoots respectively), leaf area (18 and 29%) and specific leaf area (20 and 35%). Therefore, results confirm the hypothesis that early N supply plays a significant role in the N status and N remobilisation involved in the spring regrowth of young trees.


Acid precipitation and sulfate deposition in Florida.
The acidity of rainfall in Florida has increased markedly in the past 25 years, and the average sulfate and nitrate concentrations have increased by factors of 1.6 and 4.5, respectively, over the period. Annual average pH values below 4.7 now occur over the northern three quarters of the state. Summer rainfall has average pH values 0.2 to 0.3 unit lower than winter rainfall, and sulfate concentrations at most sites are higher in summer. The annual deposition of H(+) (about 300 to 500 equivalents per hectare) in northern Florida is a third to a half of the deposition in the heavily impacted northeastern United States; comparable figures for excess sulfate (derived from sulfur dioxide) are 7 to 11 kilograms of sulfur per hectare or 50 to 90 percent of the sulfate deposition rates at Hubbard Brook, New Hampshire.


Expression of cannabinoid receptor 2 and its inhibitory effects on synovial fibroblasts in rheumatoid arthritis.
Recent studies have suggested immunomodulatory and anti-inflammatory effects of cannabinoid receptor 2 (CB2R) activation, which shows no psychoactivity. However, it is still unclear whether CB2R is expressed in fibroblast-like synoviocytes (FLS) of RA. In this study we investigated whether CB2R is expressed in FLS of RA, and whether CB2R activation modulates the function of RA-FLS. Expression of CB2R in synovial tissue and FLS was studied by immunohistochemistry, western blotting and RT-PCR. mRNA expression levels of CB2R, IL-6 and MMPs were analysed by quantitative real-time RT-PCR. The protein concentrations of IL-6 and MMPs in culture supernatants were determined by ELISA. The protein levels of signal transducing molecules were assayed by western blotting. Both mRNA and protein expression of CB2R were found in synovial tissue and cultured FLS with slightly higher levels in RA patients than in OA patients. In cultured RA-FLS, the expression level of CB2R was up-regulated by stimulation with IL-1β, TNF-α or lipopolysaccharide. In vitro, HU-308, a selective CB2R agonist, inhibited IL-1β-induced proliferation of RA-FLS as well as IL-1β-induced production of MMP-3, MMP-13 and IL-6 in RA-FLS in a dose-dependent manner. HU-308 also suppressed IL-1β-induced activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in FLS. In RA-FLS, proinflammatory mediators up-regulate the expression of CB2R, which negatively regulates the production of proinflammatory cytokines and MMPs. These data suggest that CB2R may be a potential therapeutic target of RA.


The ERCC1 and ERCC4 (XPF) genes and gene products.
The ERCC1 and ERCC4 genes encode the two subunits of the ERCC1-XPF nuclease. This enzyme plays an important role in repair of DNA damage and in maintaining genomic stability. ERCC1-XPF nuclease nicks DNA specifically at junctions between double-stranded and single-stranded DNA, when the single-strand is oriented 5' to 3' away from a junction. ERCC1-XPF is a core component of nucleotide excision repair and also plays a role in interstrand crosslink repair, some pathways of double-strand break repair by homologous recombination and end-joining, as a backup enzyme in base excision repair, and in telomere length regulation. In many of these activities, ERCC1-XPF complex cleaves the 3' tails of DNA intermediates in preparation for further processing. ERCC1-XPF interacts with other proteins including XPA, RPA, SLX4 and TRF2 to perform its functions. Disruption of these interactions or direct targeting of ERCC1-XPF to decrease its DNA repair function might be a useful strategy to increase the sensitivity of cancer cells to some DNA damaging agents. Complete deletion of either ERCC1 or ERCC4 is not compatible with viability in mice or humans. However, mutations in the ERCC1 or ERCC4 genes cause a remarkable array of rare inherited human disorders. These include specific forms of xeroderma pigmentosum, Cockayne syndrome, Fanconi anemia, XFE progeria and cerebro-oculo-facio-skeletal syndrome.


Extended interval between enzyme therapy infusions for adult patients with Gaucher's disease type 1.
Enzyme replacement therapy (ERT) for Gaucher's disease with alglucerase or imiglucerase is efficacious, well-tolerated and safe. However, cost considerations, visits to medical facilities, potentially duration of theray for life, are issues of major concern to a proportion of treated patients and has, in some cases, led to the withdrawal of therapy. To elucidate whether an extension of the interval between enzyme infusions to once every three weeks is as effective in maintaining the clinical responses achieved with the bi-monthly regimen. Four patients with an optimal response to ERT (at 30 units/kg every two weeks for an average of 27 months), were subjected to enzyme dose/frequency changes that essentially constituted a reduction in cumulative dose over the treatment period. Patients were assessed every 6 months for alterations in haematological parameters, plasma chitotriosidase levels, liver and spleen size, and bone symptoms. All patients had to resume the previous infusion schedule of once every two weeks; one because of new bone marrow infiltrates, two because of visceral enlargement, and the fourth due to progressive anaemia. This limited experience suggests that a reduction in enzyme dose associated with an extended interval between infusions may lead to variable disease control, and underscores the need for individualization of enzyme therapy.


The effect of isoferritins on granulopoiesis.
The evidence for a regulatory role of acidic isoferritins on hemopoiesis is not entirely consistent with our knowledge of ferritin biochemistry, and no clear picture of this phenomeonon has emerged. In the present study, we have been unable to confirm a consistent effect of purified heart (acidic), spleen (basic), or serum (glycosylated) isoferritins on CFU-GM colony formation in vitro. Inhibition of colony formation by cell extracts or conditioned media does not relate to the presence of acidic isoferritins, nor is this effect neutralized by a monoclonal antibody to acidic isoferritins. The composition of ferritin preparations previously described as inhibitory to CFU-GM colony growth could not be confirmed, and they were not found to be predominantly acidic in nature. Our data do not support a role for acidic isoferritins as inhibitors of granulopoiesis.


Helicobacter pylori stool antigen test.
Helicobacter pylori ( H.pylori ) infection is usually acquired in early childhood. Invasive techniques used for diagnosis of H.pylori infection require endoscopic examination which is expensive and inconvenient and may cause complications. The aim of this study was to evaluate the performance of a new noninvasive diagnostic method, stool antigen test for H.pylori in untreated children with recurrent abdominal pain. Eighty children (35 female, 45 male) who have undergone upper gastrointestinal endoscopy due to recurrent abdominal pain were included in the study. The H.pylori stool antigen test (HpSA) is based on a sandwich enzyme immunoassay with antigen detection. HpSA sensitivity, specificity, and positive and negative predictive values were determined with reference to the results of both histology and rapid urease test as a gold standard ( H. pylori status). While 49 of the 80 children (61%) tested were positive for H.pylori according to the results of both histology and rapid urease test, 28 children had negative H.pylori status. Among those 49 children, 48 were found to be positive by HpSA. Of 28 patients with negative H.pylori status, 28 were H.pylori -negative also in the stool test. The sensitivity, specificity, and positive and negative predictive values of HpSA were found to be 98%, 100%, 100%, and 96.5%, respectively. These findings have demonstrated that HpSA as a relatively simple, inexpensive and time saving noninvasive test is a reliable method for detection of H.pylori infections in children.


Functional cohesion of gene sets determined by latent semantic indexing of PubMed abstracts.
High-throughput genomic technologies enable researchers to identify genes that are co-regulated with respect to specific experimental conditions. Numerous statistical approaches have been developed to identify differentially expressed genes. Because each approach can produce distinct gene sets, it is difficult for biologists to determine which statistical approach yields biologically relevant gene sets and is appropriate for their study. To address this issue, we implemented Latent Semantic Indexing (LSI) to determine the functional coherence of gene sets. An LSI model was built using over 1 million Medline abstracts for over 20,000 mouse and human genes annotated in Entrez Gene. The gene-to-gene LSI-derived similarities were used to calculate a literature cohesion p-value (LPv) for a given gene set using a Fisher's exact test. We tested this method against genes in more than 6,000 functional pathways annotated in Gene Ontology (GO) and found that approximately 75% of gene sets in GO biological process category and 90% of the gene sets in GO molecular function and cellular component categories were functionally cohesive (LPv<0.05). These results indicate that the LPv methodology is both robust and accurate. Application of this method to previously published microarray datasets demonstrated that LPv can be helpful in selecting the appropriate feature extraction methods. To enable real-time calculation of LPv for mouse or human gene sets, we developed a web tool called Gene-set Cohesion Analysis Tool (GCAT). GCAT can complement other gene set enrichment approaches by determining the overall functional cohesion of data sets, taking into account both explicit and implicit gene interactions reported in the biomedical literature. GCAT is freely available at http://binf1.memphis.edu/gcat.


A primer on arrhythmias in patients with hypertrophic cardiomyopathy.
Patients with hypertrophic cardiomyopathy are at risk of atrial and ventricular arrhythmias, yet treatment options for these patients are made almost solely by extrapolation from patients with other diseases. Heart block may be seen spontaneously but is especially prevalent following septal reduction strategies. Atrial fibrillation is the most common arrhythmia in patients with hypertrophic cardiomyopathy. The onset of atrial fibrillation often represents a turning point clinically for patients, marked by substantial functional deterioration and morbidity. Sudden cardiac death is the most common cause of death in the young patient, but still contributes to mortality in older patients. Major risk factors for sudden cardiac death include resuscitated sudden cardiac death, marked hypertrophy, syncope, and family history of sudden cardiac death due to hypertrophic cardiomyopathy. Minor risk factors for sudden cardiac death include nonsustained ventricular tachycardia, and hypotensive response to exercise. Emerging possible risk factors include atrial fibrillation, myocardial ischemia, left ventricular outflow tract obstruction, genetic mutations, left ventricular apical aneurysms, myocardial fibrosis, and end stage disease.


Towards the optimization of botanical insecticides research: Aedes aegypti larvicidal natural products in French Guiana.
Natural products have proven to be an immeasurable source of bioactive compounds. The exceptional biodiversity encountered in Amazonia, alongside a rich entomofauna and frequent interactions with various herbivores is the crucible of a promising chemodiversity. This prompted us to search for novel botanical insecticides in French Guiana. As this French overseas department faces severe issues linked to insects, notably the strong incidence of vector-borne infectious diseases, we decided to focus our research on products able to control the mosquito Aedes aegypti. We tested 452 extracts obtained from 85 species originating from 36 botanical families and collected in contrasted environments against an Ae. aegypti laboratory strain susceptible to all insecticides, and a natural population resistant to both pyrethroid and organophosphate insecticides collected in Cayenne for the most active of them. Eight species (Maytenus oblongata Reissek, Celastraceae; Costus erythrothyrsus Loes., Costaceae; Humiria balsamifera Aubl., Humiriaceae; Sextonia rubra (Mez) van der Werff, Lauraceae; Piper hispidum Sw., Piperaceae; Laetia procera (Poepp.) Eichl., Salicaceae; Matayba arborescens (Aubl.) Radlk., Sapindaceae; and Cupania scrobitulata Rich., Sapindaceae) led to extracts exhibiting more than 50% larval mortality after 48 h of exposition at 100 µg/mL against the natural population and were considered active. Selectivity and phytochemistry of these extracts were therefore investigated and discussed, and some active compounds highlighted. Multivariate analysis highlighted that solvents, plant tissues, plant family and location had a significant effect on mortality while light, available resources and vegetation type did not. Through this case study we highlighted that plant defensive chemistry mechanisms are crucial while searching for novel insecticidal products.


Central projections of identified Drosophila sensory neurons in relation to their time of development.
Eight sensory structures (campaniform sensilla), appearing identical in the light and scanning electron microscopes, are found in specific locations on the wings of Drosophila. Their axons enter one of 2 central tracts, a medial one or a lateral one. The topographic arrangement of the sensilla on the wing is not reflected in this central projection pattern. There is, however, a strict correlation between the time when a sensillum develops and the path its axon follows: The 4 sensilla whose axons form the medial projection are born and differentiate early during the development of the wing, while the other 4 sensilla, all of which project laterally, arise during a second wave of differentiation. This time-related projection pattern remains stable in the face of a variety of genetically induced alterations in the precise number and location of sensilla.


Obtaining Hartree-Fock and density functional theory doubly excited states with Car-Parrinello density matrix search.
The calculation of doubly excited states is one of the major problems plaguing the modern day excited state workhorse methodology of linear response time dependent Hartree-Fock (TDHF) and density function theory (TDDFT). We have previously shown that the use of a resonantly tuned field within real-time TDHF and TDDFT is able to simultaneously excite both the alpha and beta electrons to achieve the two-electron excited states of minimal basis H(2) and HeH(+) [C. M. Isborn and X. Li, J. Chem. Phys. 129, 204107 (2008)]. We now extend this method to many electron systems with the use of our Car-Parrinello density matrix search (CP-DMS) with a first-principles fictitious mass method for wave function optimization [X. Li, C. L. Moss, W. Liang, and Y. Feng, J. Chem. Phys. 130, 234115 (2009)]. Real-time TDHF/TDDFT is used during the application of the laser field perturbation, driving the electron density toward the doubly excited state. The CP-DMS method then converges the density to the nearest stationary state. We present these stationary state doubly excited state energies and properties at the HF and DFT levels for H(2), HeH(+), lithium hydride, ethylene, and butadiene.


Thymol, a dietary monoterpene phenol abrogates mitochondrial dysfunction in β-adrenergic agonist induced myocardial infarcted rats by inhibiting oxidative stress.
Mitochondrial dysfunction has been suggested to be one of the important pathological events in isoproterenol (ISO), a synthetic catecholamine and β-adrenergic agonist induced myocardial infarction (MI). In this context, we have evaluated the impact of thymol against ISO induced oxidative stress and calcium uniporter malfunction involved in the pathology of mitochondrial dysfunction in rats. Male albino Wistar rats were pre and co-treated with thymol (7.5 mg/kg body weight) daily for 7 days. Isoproterenol (100 mg/kg body weight) was subcutaneously injected into rats on 6th and 7th day to induce MI. To explore the extent of cardiac mitochondrial damage, the activities/levels of cardiac marker enzymes, mitochondrial lipid peroxidation products, antioxidants, lipids, calcium, adenosine triphosphate and multi marker enzymes were evaluated. Isoproterenol induced myocardial infarcted rats showed a significant increase in the activities of cardiac diagnostic markers, heart mitochondrial lipid peroxidation, lipids, calcium, and a significant decrease in the activities/levels of heart mitochondrial superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, isocitrate, malate, α-ketoglutarate and NADH-dehydrogenases, cytochrome-C-oxidase, and adenosine triphosphate. Thymol pre and co-treatment showed near normalized effects on all the biochemical parameters studied. Transmission electron microscopic findings and mitochondrial swelling studies confirmed our biochemical findings. The in vitro study also revealed the potent free-radical scavenging activity of thymol. Thus, thymol attenuates the involvement of ISO against oxidative stress and calcium uniporter malfunction associated with mitochondrial dysfunction in rats.


Tracking human position and lower body parts using Kalman and particle filters constrained by human biomechanics.
In this paper, a novel framework for visual tracking of human body parts is introduced. The approach presented demonstrates the feasibility of recovering human poses with data from a single uncalibrated camera by using a limb-tracking system based on a 2-D articulated model and a double-tracking strategy. Its key contribution is that the 2-D model is only constrained by biomechanical knowledge about human bipedal motion, instead of relying on constraints that are linked to a specific activity or camera view. These characteristics make our approach suitable for real visual surveillance applications. Experiments on a set of indoor and outdoor sequences demonstrate the effectiveness of our method on tracking human lower body parts. Moreover, a detail comparison with current tracking methods is presented.


Ethnic disparities in outcome from posttransplant infections.
Black transplant recipients have decreased graft survival and increased rejection rates compared with whites. Because increased rejection rates may lead to more immunosuppression in black recipients, ethnic differences may exist for outcomes of posttransplant infectious complications. All episodes of infection between December 1996 and October 1998 on the transplant services at the University of Virginia Health Sciences Center were prospectively evaluated. Parameters recorded included self-designated ethnicity, demographics, APACHE II scores, laboratory and microbiologic data, immunosuppression, episodes of rejection, and outcome measures. Evaluation of 303 episodes of infection demonstrated an increased mortality rate for white compared with black recipients (19% vs. 3%, P = 0.0006) despite having a similar severity of illness (APACHE II score). Among renal transplant recipients, episodes of infection occurring in black recipients (n = 46) were also associated with a decreased mortality rate versus whites (n = 89) (0% vs. 15%, P = 0.006) and shorter mean length of stay (12 +/- 2 vs. 25 +/- 4 days, P = 0.002) despite similar severity of illness and rejection rates. For posttransplant infections in liver transplant recipients, blacks (n = 23) demonstrated a trend toward decreased mortality (9% vs. 26%, P = 0.07) but equal lengths of stay despite similar APACHE II scores, rejection rates, and age. White liver transplant recipients had an increased incidence of viral infections (15% vs. 0%, P = 0.03). All other infecting organisms were similar. The unexpected finding of a significantly decreased rate of mortality associated with posttransplant infections in black recipients remains largely unexplained but may be related to subtle differences in immune response between racial or ethnic groups.


Living with Hepatitis C Virus: A Systematic Review and Narrative Synthesis of Qualitative Literature.
Background and Aims. The lived experience of HCV has not been well documented in the literature. The aim of this systematic review was to understand the experiences of living with Hepatitis C Virus (HCV). Methods. Five databases were searched from inception until January 19, 2015. Studies were included if they focused on adults diagnosed with HCV; reported experience living with HCV; and described original research. Results. 46 studies were included. Studies found that participants had reduced quality of life due to physical symptoms. Due to physical symptoms and discrimination, many participants switched to part-time work or quit their jobs. Many individuals reported negative experiences with the healthcare system; themes of feeling unsupported, not having adequate information, and not feeling involved in decisions were reported. Stigma significantly impacted those living with HCV. Conclusions. Published literature indicates that those with HCV often feel stigmatized and unsupported in their care, relationships, and work environments, while simultaneously coping with physical and psychological symptoms. This synthesis points to areas where greater education, compassion, and patient-centered healthcare could improve the experience of people living with HCV.


Human Extracellular-Matrix Functionalization of 3D hiPSC-Based Cardiac Tissues Improves Cardiomyocyte Maturation.
Human induced pluripotent stem cells (hiPSC) possess significant therapeutic potential due to their high self-renewal capability and potential to differentiate into specialized cells such as cardiomyocytes. However, generated hiPSC-derived cardiomyocytes (hiPSC-CM) are still immature, with phenotypic and functional features resembling the fetal rather than their adult counterparts, which limits their application in cell-based therapies, in vitro cardiac disease modeling, and drug cardiotoxicity screening. Recent discoveries have demonstrated the potential of the extracellular matrix (ECM) as a critical regulator in development, homeostasis, and injury of the cardiac microenvironment. Within this context, this work aimed to assess the impact of human cardiac ECM in the phenotype and maturation features of hiPSC-CM. Human ECM was isolated from myocardium tissue through a physical decellularization approach. The cardiac tissue decellularization process reduced DNA content significantly while maintaining ECM composition in terms of sulfated glycosaminoglycans (s-GAG) and collagen content. These ECM particles were successfully incorporated in three-dimensional (3D) hiPSC-CM aggregates (CM+ECM) with no impact on viability and metabolic activity throughout 20 days in 3D culture conditions. Also, CM+ECM aggregates displayed organized and longer sarcomeres, with improved calcium handling when compared to hiPSC-CM aggregates. This study shows that human cardiac ECM functionalization of hiPSC-based cardiac tissues improves cardiomyocyte maturation. The knowledge generated herein provides essential insights to streamline the application of ECM in the development of hiPSC-based therapies targeting cardiac diseases.


Pdots, a new type of nanoparticle, bind to mTHPC via their lipid modified surface and exhibit very high FRET efficiency between the core and the sensitizer.
Pdots are a new type of nanoparticle which exhibit strong potential for future applications in biophysics and cell biology. They are composed of organic chromophoric polymers, whose surfaces can be modified with different amphiphilic polymers, such as PEGylated lipids to make them very stable as colloids in water. We demonstrate in this manuscript that the lipid nano-coating around the Pdot can bind very efficiently to amphiphilic molecules, such as photosensitizers e.g. meso-tetrahydroxyphenylchlorin (mTHPC). As a result the sensitizer is brought into very close contact with the cores of the Pdots, and resonance energy transfer from the core to the sensitizer is very efficient; in some cases it is close to 1. We show the spectroscopic properties of two types of Pdots; their sizes, which are in the 13-47 nm range, depend on the kind of polymer and the length of the PEGylated lipid chains that wrap it. We measured the efficiency of FRET by investigating the decrease in donor intensity or its lifetime upon binding with mTHPC. We also show the relative yields of singlet oxygen that are obtained via two pathways: by exciting the Pdots which transfer the energy to the attached sensitizer, or by exciting the sensitizer directly. This methodology could be used to enhance the use of a photosensitizer by employing both pathways in parallel.


A Dynamic Efficient Sensory Encoding Approach to Adaptive Tuning in Neural Models of Optic Flow Processing.
This paper introduces a self-tuning mechanism for capturing rapid adaptation to changing visual stimuli by a population of neurons. Building upon the principles of efficient sensory encoding, we show how neural tuning curve parameters can be continually updated to optimally encode a time-varying distribution of recently detected stimulus values. We implemented this mechanism in a neural model that produces human-like estimates of self-motion direction (i.e., heading) based on optic flow. The parameters of speed-sensitive units were dynamically tuned in accordance with efficient sensory encoding such that the network remained sensitive as the distribution of optic flow speeds varied. In two simulation experiments, we found that model performance with dynamic tuning yielded more accurate, shorter latency heading estimates compared to the model with static tuning. We conclude that dynamic efficient sensory encoding offers a plausible approach for capturing adaptation to varying visual environments in biological visual systems and neural models alike.


Association between experimental pain biomarkers and serologic markers in patients with different degrees of painful knee osteoarthritis.
To assess the association between pain mechanisms (sensitization) and biochemical markers for cartilage, bone, and inflammation in patients with knee pain. The study group comprised 281 patients with different degrees of knee pain intensity and radiographic findings (using the Kellgren/Lawrence [K/L] scale). The following structurally related serologic biomarkers were measured in serum: high-sensitivity C-reactive protein (hsCRP), matrix metalloproteinase (MMP)-mediated breakdown of CRP (CRPM), MMP-mediated degradation of type I collagen (C1M), C2M, and C3M. Pressure-pain thresholds (PPT) (peripheral and spreading sensitization), temporal summation of pain, and conditioning pain modulation (CPM) (with the latter 2 biomarkers representing generalized sensitization) were assessed. For each pain parameter, the patients were categorized as most sensitized or least sensitized. Correlations were observed between the pain biomarkers PPT, temporal summation, and CPM and maximal pain intensity during the last 24 hours. Significant associations between most of the serologic biomarkers were observed. A high CRPM level was associated with centralized sensitization (temporal summation and CPM). None of the serologic markers correlated with the intensity or duration of knee pain, and only hsCRP correlated with the K/L grade. The most-sensitized group contained more women than men, and the least-sensitized group contained more men than women. A platform of mechanistic pain biomarkers in combination with structure-related serologic biomarkers provides new possibilities for understanding how osteoarthritis-related structural features may be associated with pain and pain sensitization. This study showed significant correlations between central pain sensitization and CRPM as a possible measure for chronic inflammation. Future pain association studies should include biomarkers representing the local joint environment more specifically.


Effect of hypergravity stimulus on XTH gene expression in Arabidopsis thaliana.
Hypergravity stimulus suppresses plant shoot growth by making the cell wall rigid. Xyloglucan endotransglucosylase/hydrolase (XTH) is involved in determining the rigidity of cell walls. We demonstrated that hypergravity influenced the expression of some XTH genes in shoots of Arabidopsis thaliana L.; in response to hypergravity stimulus of 300 g, the expression of AtXTH22 was up-regulated, while that of AtXTH15 was down-regulated. The effect of hypergravity on the expression of these genes was nullified by lanthanum chloride at 0.1 mM, suggesting that the expression of these XTH genes in Arabidopsis is under the control of the mechanoreceptor.


Iterative diffraction calculations of transverse mode distributions in confocal unstable laser resonators.
A theoretical investigation has been undertaken to study the transverse modes of two-dimensional positive branch, confocal unstable resonators. Mode amplitude and phase information is obtained from a numerical-iterative type calculation that uses the Fresnel integral for propagating the cavity radiation back and forth between resonator mirrors. Near- and far-field distributions for empty cavity resonators are presented for various resonator Fresnel numbers and magnifications, along with results of resonator mode stability and diffraction losses when cavity perturbations such as mirror misalignment and/or a uniformly saturable gain medium are included. In addition, the diffractive calculations are compared with results obtained from geometric models.


Gabapentin acutely increases the apnea-hypopnea index in older men: data from a randomized, double-blind, placebo-controlled study.
Although drugs with sedative properties may increase the risk of airway collapse during sleep, their acute effects on the apnea-hypopnea index in older adults are under-reported. We investigated the acute effects of gabapentin (GABA) on sleep breathing in older men without sleep apnea. A double-blind, randomized, placebo-controlled cross-over pilot study using a bedtime dose of gabapentin 300 mg was conducted in eight non-obese older men. Polysomnography measured the effects of the intervention. The apnea-hypopnea index was higher in the gabapentin arm than in the placebo arm (22.4 ± 6.1 versus 12.2 ± 4.3, P ≤ 0.05, d: 0.67), as was the oxygen desaturation index (20.6 ± 5.8 versus 10.8 ± 3.9, P ≤ 0.05, d: 0.68). The number needed to harm was four. A subset analysis demonstrated that differences in sleep respiratory parameters were present only during non-rapid eye movement sleep, as well as only in the supine position. No adverse events were reported. Hence, gabapentin worsened sleep breathing acutely compared with placebo. Long-term clinical trials are warranted to elucidate the clinical relevance of these findings for the safety profile of GABAergic agents.


Tracking the interplay between bound peptide and the lid domain of DnaK, using molecular dynamics.
Hsp70 chaperones consist of two functional domains: the 44 kDa Nucleotide Binding Domain (NBD), that binds and hydrolyses ATP, and the 26 kDa Substrate Binding Domain (SBD), which binds unfolded proteins and reactivates them, utilizing energy obtained from nucleotide hydrolysis. The structure of the SBD of the bacterial Hsp70, DnaK, consists of two sub-domains: A β-sandwich part containing the hydrophobic cavity to which the hepta-peptide NRLLLTG (NR) is bound, and a segment made of 5 α-helices, called the "lid" that caps the top of the β-sandwich domain. In the present study we used the Escherichia coli Hsp70, DnaK, as a model for Hsp70 proteins, focusing on its SBD domain, examining the changes in the lid conformation. We deliberately decoupled the NBD from the SBD, limiting the study to the structure of the SBD section, with an emphasis on the interaction between the charges of the peptide with the residues located in the lid. Molecular dynamics simulations of the complex revealed significant mobility within the lid structure; as the structure was released from the forces operating during the crystallization process, the two terminal helices established a contact with the positive charge at the tip of the peptide. This contact is manifested only in the presence of electrostatic attraction. The observed internal motions within the lid provide a molecular role for the function of this sub-domain during the reaction cycle of Hsp 70 chaperones.


The ringlike pattern in vulvar melanosis: a new dermoscopic clue for diagnosis.
Vulvar melanosis is a benign pigmented lesion that may clinically mimic melanoma. Whereas the dermoscopic features of other pigmented skin lesions have been extensively described, little is known about vulvar melanosis. A retrospective dermoscopic study was conducted on 87 lesions with histopathologically proved melanosis. We describe and define, for the first time to our knowledge, a ringlike pattern, found in 28 of 87 melanotic lesions (32%), characterized by multiple round to oval structures, white to tan, with dark brown, well-defined regular borders. The structureless and globularlike patterns were observed in 18 of 87 lesions (21%), the parallel pattern in 15 (17%), and the cobblestonelike and reticularlike patterns in 4 (5%). A significant association was found between the distribution of multifocal lesions showing a ringlike vs a nonringlike pattern (82% vs 52%; P = .008), whereas a weak association was found between anatomical site and the different patterns (P = .55). The ringlike pattern was frequently combined with multifocality and simultaneous occurrence at the labia majora and the labia minora. Dermoscopy can be useful for the clinical detection of vulvar melanosis, and the ringlike pattern may represent a new dermoscopic clue for the diagnosis of this lesion.


Equation or algorithm: differences and choosing between them.
The issue of whether formal reasoning or a computing-intensive approach is the most efficient manner to address scientific questions is the subject of some considerable debate and pertains not only to the nature of the phenomena and processes investigated by scientists, but also the nature of the equation and algorithm objects they use. Although algorithms and equations both rely on a common background of mathematical language and logic, they nevertheless possess some critical differences. They do not refer to the same level of symbolization, as equations are based on integrated concepts in a denotational manner, while algorithms specifically break down a complex problem into more elementary operations, in an operational manner. They may therefore be considered as suited to the representation of different phenomena. Specifically, algorithms are by nature sufficient to represent weak emergent phenomena, but not strong emergent patterns, while equations can do both. Finally, the choice between equations and algorithms are by nature sufficient to represent weak emergent phenomena, but not strong emergent patterns, while equations behave conversely. We propose a simplified classification of scientific issues for which both equation- and/or algorithm-based approaches can be envisaged, and discuss their respective pros and cons. We further discuss the complementary and sometimes conflicting uses of equations and algorithms in a context of ecological theory of metapopulation dynamics. We finally propose both conceptual and practical guidelines for choosing between the alternative approaches.


Headache due to spontaneous spinal cerebrospinal fluid leak secondary to cerebrospinal fluid-venous fistula: Case series.
Cerebrospinal fluid-venous fistula is an uncommon cause of spontaneous spinal cerebrospinal fluid leak (SSCSFL). We aim to describe the clinical presentation, imaging evaluation, treatment and outcome of SSCSFL secondary to cerebrospinal fluid-venous fistula. A retrospective review was undertaken of SSCSFL cases secondary to cerebrospinal fluid-venous fistula confirmed radiologically or intraoperatively, seen at our institution from January 1994 to March 2019. Cases with undetermined SSCSFL etiology, alternative etiology or unconfirmed fistula were excluded. Forty-four of 156 patients met the inclusion criteria (31 women, 13 men). Mean age of symptom onset was 52.6 years (SD 8.7, range 33-71 years). Headache was the presenting symptom in almost all, typically daily (69%), and most often in occipital/suboccipital regions. Headache character was most commonly pressure (38%), followed by throbbing/pulsing (21.4%). Orthostatic headache worsening occurred in 69% and an even greater percentage of patients (88%) reported Valsalva-induced headache exacerbation or precipitation. Headache occurred in isolation to Valsalva maneuvers in 12%. Of 37 patients with documented cerebrospinal fluid opening pressure, 13% were <6 cmH2O; 84%, 7-20 cmH2O; and one, 25 cmH2O. Fistulas were almost exclusively thoracic (95.5%). Only one patient responded definitively to epidural blood patch (EBP). Forty-two patients underwent surgery. Most improved following surgery; 48.7% were completely headache free and 26.8% had at least 50% improvement. In our series, cerebrospinal fluid-venous fistula was associated with a greater occurrence of Valsalva-induced headache exacerbation or precipitation than orthostatic headache and did not respond to EBP. Surgery provided significant improvement. Cerebrospinal fluid-venous fistula should be considered early in the differential diagnosis of Valsalva-induced ("cough") headache.


[Medicinal plants in phytotherapy].
Plant kingdom has a wider biochemical diversity than animals and at least four-fifths of secondary metabolites come from vegetable world. This is probably due to the link between soil and plants, therefore these have to develop numerous adaptation mechanisms. To date, about 40% of modern monomolecular drugs derives directly or indirectly from plants. The phytotherapy today constitutes the most popular medical practice of complementary medicine, and in many countries its increase is continuous. Some vegetable preparations are marked as pharmaceutical regulation. However in the most cases, in absence of clinical tests, the empiric experience matured in a long period can be considered acceptable testimony of their efficacy. The vegetable products, that are used to cure smaller indications, are based on the Directive 2004/24/EC of March 2004.


Total chemically available (free and intrachain) lysine and furosine in pea, bean, and lentil sprouts.
The effect of the germination of peas, beans, and lentils under differing conditions of illumination for different times on parameters linked to the Maillard reaction (chemically available free and intrachain lysine, lysine availability, and furosine) was evaluated. The chemically available free lysine content in the raw seeds of the three legumes was quite small compared to the chemically available intrachain lysine content, and furosine was detectable only in the beans and the lentils. The effect of germination was to increase lysine availability compared with levels in the raw seeds in all of the germinated samples, the smallest increase taking place in the lentils. In addition, furosine became detectable in all of the germinated samples. Quantities varied depending on the germination conditions but in all cases were higher than the quantities observed in the raw seeds. Linear correlations were observed to exist between some of the parameters considered in the three legumes tested.


[Ischemic testicular necrosis following vasectomy: rare and typical complications of an outpatient procedure].
Taking the clinical case of a patient who developed unilateral testicular necrosis following vasectomy as a starting point, the early and late complications of this procedure are described based on a literature review.In the USA 7% of all men undergo vasectomy, as compared to 2% in Germany. Early postoperative complications include bleeding/hematoma (0.5-18%), infection (0.3-32.9%), epididymitis (0.4-6.1%), granuloma (0.07-90%), and rare complications such as vas deferens abscess, vesicular gland abscess, vasovenous fistula, testicular necrosis, arteriovenous fistula, pulmonary embolism, endocarditis, scrotal skin necrosis and Fournier's disease which mostly have been reported in the form of case reports. Late complications are chronic pain (0.5-18%), pain during sex (2.9%), hydrocele (0-4%) as well as spermatocele (1.6%). There is a failure rate of 4.3-16% as concluded from the number of patients with nonmotile sperm in the post-vasectomy semen analysis. The postoperative paternity rate is 0-4%.Bilateral vasectomy is a secure way of contraception; perioperative and late complications are on an average rare, however, with a range up to 90%. In individual cases severe complications occur, which should be detected at an early stage. Therefore a close follow-up should be maintained after this outpatient procedure. One should ask for risk factors of endocarditis or thrombosis preoperatively. The patient should be informed of the possible loss of a testicle because of the severity of this complication. Postoperative semen analysis is obligatory.


Genetic variants in the apelin system and blood pressure responses to dietary sodium interventions: a family-based association study.
We examined the association between genetic variants in the apelin system and blood pressure (BP) responses to low-sodium and high-sodium interventions in the GenSalt Study. A 7-day low-sodium intervention (51.3 mmol sodium per day) followed by a 7-day high-sodium intervention (307.8 mmol sodium per day) was conducted among 1906 participants from 637 Han Chinese families. BP measurements were obtained at baseline and following each intervention using a random-zero sphygmomanometer. Twenty-three single nucleotide polymorphisms (SNPs), including both tag and functional SNPs, were selected from three candidate genes (APLN, APLNR, and ACE2). Single marker and haplotype analyses were conducted using the Family Based Association Test program. The false discovery rate method was used to correct for multiple testing. SNPs rs2282623 and rs746886 of the APLNR gene were significantly associated with DBP (both P = 0.002) and mean arterial pressure (MAP) (P = 0.001 and 0.005, respectively) responses to low-sodium intervention. Six SNPs of the ACE2 gene were significantly associated with SBP, DBP, or MAP responses to low-sodium intervention. Three of them, rs1514283, rs1514282, and rs4646176, were also significantly associated with MAP response to high-sodium intervention (all P <or= 0.006). Haplotype analysis indicated the A-T-T haplotype of APLNR SNPs rs721608-rs2282623-rs746886 was associated with decreased DBP and MAP responses to low-sodium intervention (P = 0.001 and 0.003, respectively), whereas G-C-C was associated with increased SBP and MAP responses to high-sodium intervention (P = 0.004 and 0.01, respectively). This large family-based study indicates that genetic variants in the APLNR and ACE2 genes are significantly associated with BP responses to dietary sodium intervention.


[Testing cross-calibration between positron emission tomographs and their peripheral devices].
The aim of this study was to evaluate the cross-calibration of positron emission tomographs and their peripheral devices prior to a multicenter study. The instrumentation of 22 sites (including 24 dedicated PET scanners), including 21 that could be operated in 2D mode and 20 in 3D mode, was investigated according to standardized acquisition and reconstruction protocols, and the cross-calibration was checked against the dose calibrators (22 instruments) and the sample changer (20 instruments). The deviation of the cross-calibration to the dose calibrators was below 5% for 10 of 21 PET scanners (2D mode) and 6 of 20 (3D mode). For 6 (2D mode) and 6 (3D mode) scanners, the corresponding error was up to 10%. In turn, the deviation between dose calibrator and standard was less than 8% for 19 devices, and even less than 5% for 14 devices. In most of the well counters evaluated, the cross-calibration error was less than 10%. Although required in general, the cross-calibration between positron emission tomographs and their peripheral devices becomes even more critical when pooling data in the framework of quantitative clinical multicenter studies.


Colonic dysmotility and morphological abnormality frequently detected in Japanese patients with irritable bowel syndrome.
Colonoscopy and computed tomography (CT) are used primarily to exclude organic diseases in patients with irritable bowel syndrome (IBS), rather than to assess the pathophysiology of IBS. We aimed to evaluate colonic dysmotility and morphology in Japanese patients with IBS. One hundred eighty-four patients with IBS and 49 asymptomatic controls who underwent colonoscopy in combination with CT colonography or barium enema were retrospectively reviewed between 2008 and 2012. Water-aided colonoscopy was performed without sedation by a single endoscopist. The duration and pattern of colonic movement and cecal intubation time were recorded. To assess colonic morphology, barium enema or CT colonography were performed immediately after colonoscopy. Colonic dysmotility was more frequent in the IBS group (28.8% vs. 2.0% in controls, P<0.001), especially in cases of IBS with diarrhea (IBS-D) (IBS with constipation [IBS-C] 28.8% vs. IBS-D 60.0% vs. mixed IBS [IBS-M] 5.1%, P<0.001). Colonic morphological abnormality was more frequent in the IBS group than in the control group (77.7% vs. 24.5%, P<0.001), especially in IBS-M and IBS-C groups (IBS-C 77.5% vs. IBS-D 48.9% vs. IBS-M 100%, P<0.001). Most patients with IBS with colonic dysmotility had experienced stress related to their symptoms. Cecal intubation time was significantly longer in the IBS group than in the control group (12.1±6.9 minutes vs. 4.6±1.9 minutes, P<0.001). Unsedated colonoscopy, combined with radiographic findings, can detect colonic dysmotility and morphological abnormality. Technical difficulties observed during cecal intubation may partially explain the pathophysiology of IBS.


Neuropeptide Y suppresses absence seizures in a genetic rat model primarily through effects on Y receptors.
Neuropeptide Y (NPY) potently suppresses absence seizures in a model of genetic generalized epilepsy, genetic absence epilepsy rats of Strasbourg (GAERS). Here we investigated the Y-receptor subtype(s) on which NPY exerts this anti-absence effect. A dual in vivo approach was used: the cumulative duration of seizures was quantified in adult male GAERS in 90-min electroencephalogram recordings following intracerebroventricular (i.c.v.) injection of: (i) subtype-selective agonists of Y1 ([Leu31Pro34]NPY, 2.5 nmol), Y2 (Ac[Leu(28,31)]NPY24-36, 3 nmol), Y5 receptors [hPP1(-17),Ala31,Aib32]NPY, 4 nmol), NPY (3 nmol) or vehicle; and following (ii) i.c.v. injection of antagonists of Y1 (BIBP3226, 20 nmol), Y2 (BIIE0246, 20 nmol) and Y5 (NPY5RA972, 20 nmol) receptors or vehicle, followed by NPY (3 nmol). Injection of the Y1- and Y5-selective agonists resulted in significantly less mean seizure suppression (37.4% and 53.9%, respectively) than NPY (83.2%; P < 0.05), while the Y2 agonist had similar effects to NPY (62.3% suppression, P = 0.57). Food intake was not increased following injection of the Y2 agonist, while significant increases in food intake were seen following NPY and the other Y-subtype agonists. Compared with vehicle, NPY injection suppressed seizures following the Y1 and Y5 antagonists (45.3% and 80.1%, respectively, P < 0.05), but not following the Y2 antagonist (5.1% suppression, P = 0.46). We conclude that NPY Y2 receptors are more important than Y1 and Y5 receptors in mediating the effect of NPY to suppress absence seizures in a genetic rat model. Y2 receptor agonists may represent targets for novel drugs against genetic generalized epilepsies without resulting in appetite stimulation.


Interaction of Rhei Rhizoma extract with cytochrome P450 3A and efflux transporters in rats.
Traditional Chinese herbal medicines are frequently prescribed in pharmacotherapy in Japan. In the present study, we evaluated the possible interaction of several herbal extracts including Rhei Rhizoma extract with cytochrome P450 (CYP) 3A and efflux transporters such as P-glycoprotein and multidrug resistance-associated protein (MRP) 2. Rhei Rhizoma extract (100 microg/ml) significantly suppressed the CYP3A-mediated 6beta-hydroxylation of testosterone in hepatic microsomes, and increased the extent of bioavailability of midazolam, a typical CYP3A substrate, in rats. Also, Rhei Rhizoma extract (300 microg/ml) significantly suppressed P-glycoprotein-mediated efflux transport of rhodamine 123 (Rho123) in rat everted intestine. In an in-vivo study, Rhei Rhizoma extract added to intestinal perfusate at a concentration of 300 microg/ml significantly suppressed the intestinal exsorption of Rho123, though it exerted no effect on the biliary excretion of Rho123. Furthermore, the in-vitro and in-vivo MRP2-mediated intestinal efflux of 2,4-dinitrophenyl-S-glutathione was significantly suppressed by Rhei Rhizoma extract (1000 microg/ml). In conclusion, Rhei Rhizoma extract, which is taken orally at doses of 0.5-1 g each or 1-3 g daily in clinical practice, may cause pharmacokinetic herb-drug interactions in the process of the intestinal and/or hepatic CYP3A-mediated drug metabolism and P-glycoprotein- and/or MRP2-mediated efflux transport in the intestine.


Patients and professionals in collaborative testing of a web-based tool for integrated care: an evaluation study.
Since 2001, patients in Norway with long-term, complex needs for care have had a legal right to an "individual care plan", intended to increase efficiency and quality in health and social services, as well as patient involvement. Commonly, a responsible group is established to manage the planning process. A web-based application was developed and tested for three years in groups including both patients and professionals. Data were collected through questionnaires, interviews, project documentation and field notes. The findings showed that iterative testing improved usability. Participants expressed confidence in the online access and their enhanced control of planning and documentation. Testing in real-life environments added valuable and unforeseen information. It also showed that technical and organizational aspects influenced each other, and should not be considered separately. Despite the successful testing and improvement of the application, some participants and groups did not feel comfortable using it. Further research will be undertaken to address barriers to participation.


Immunoelectron microscopy of cell populations in regional and central lymph of sheep.
The immunoreactivity and the ultrastructural localization of monoclonal anti-sheep lymphocyte antibodies conjugated with colloidal gold particles were examined in free-floating cells of sheep central lymph from the thoracic duct, postnodal lymph draining either the popliteal nodes or the mesenteric nodes, and prenodal lymph draining the pregnant uterus. The monoclonal antibodies used in this study were SBU-T1 (CD5), SBU-T4 (CD4), SBU-T8 (CD8), SBU-II (anti DR antibody), and E53 which are reported to be sheep homologues of human T1, T4, T8, HLA-DR, and pan B cell antibodies, respectively. Colloidal gold particles were evenly distributed or segmentally aggregated on the surfaces of lymphocytes and macrophages incubated with monoclonal antibodies and in vesicles in the cytoplasm of anti DR antibody labeled macrophages. Not only did CD5 labeled cells show a high percentage in each regional lymph examined, but the percentage of CD4 labeled cells was consistently higher than that of CD8 labeled cells. Moreover, the immunoreactivity of CD8 labeled cells was specific among lymph from the different regions. The sum of the percentages of CD4 and CD8 labeled cells was less than the percentage of CD5 labeled cells, indicating the presence of a minor T cell subpopulation which was CD5+, CD4-, and CD8-. A characteristic finding was a high percentage of CD8 labeled cells and many abnormal eosinophils in uterine prenodal lymph in pregnant sheep. Taken together the results showed that variously labeled immunoreactive cells are distributed somewhat differently in lymph derived from different organ sites.


The clinical efficacy of paremyd with and without dapiprazole in subjects with light and dark brown irides.
Paremyd, a mydriatic formulation of 0.25% tropicamide and 1.0% hydroxyamphetamine hydrobromide provides adequate dilation for binocular indirect ophthalmoscopy in young Caucasians. We studied the clinical effectiveness of Paremyd in dilating heavily pigmented eyes by comparing its mydriatic efficacy in Blacks, Asians and Caucasians with light and dark brown irides. We also evaluated the efficacy of one drop of dapiprazole (Rev-Eyes) in reversing Paremyd-induced mydriasis in our subject sample. In a masked, randomized, controlled experimental design, several visual functions which included pupillary dilation, near visual acuity, amplitude of accommodation, ocular hyperemia, and discomfort glare were measured at 30-min intervals, for a total of 300 min, in subjects dilated with a single drop of Paremyd in each eye. Ease of binocular indirect ophthalmoscopy was also assessed. A 3-way analysis of variance was used to assess changes in these measures as function of irides color/pigmentation (designated as light or dark brown iris color), presence or absence of dapiprazole, and test time interval. We found that subjects in our light brown irides group (mainly Caucasians) dilated faster than subjects in our dark brown irides group (mainly Blacks). Dapiprazole increased the speed of recovery from pupillary dilation for all subjects, but more so for those with light rather than dark brown irides. Similarly, subjects with light rather than dark brown irides recovered accommodative function more quickly. Although neither the use of dapiprazole nor the degree of iris color/pigmentation was significantly related to visual acuity or glare discomfort, there was a clear trend that these visual measures were affected to a greater degree in subjects with dark brown (primarily Blacks) rather than light brown irides. Overall, Paremyd provided adequate dilation for binocular indirect ophthalmoscopy in all subjects irrespective of iris color/pigmentation. Our data indicate that a single drop of Paremyd provides adequate mydriasis, without significant side effects, for routine fundus examination of all subjects, independent of iris color/pigmentation. Furthermore, a single drop of dapiprazole was effective in speeding the return of pupillary dilation in most subjects, but had no significant effect on accommodation, near visual acuity or glare discomfort. Side effects such as stinging upon instillation, conjunctival hyperemia, and a few instances of ptosis, with possible additional cost to patients, appear to lessen its overall clinical benefit.


The paraphilias, obsessive compulsive spectrum disorder, and the treatment of sexually deviant behaviour.
The paraphilias have been mostly ignored by psychiatry, even though psychiatrists are ideally suited to treat and diagnose these disorders by virtue of their medical and psychological training. The sexual deviations require an understanding of both biological and psychological causation and skills in psychological and pharmacological treatments. More recently the Supreme Court of the United States in Kansas v Hendricks (1997) upheld the constitutionality of the civil commitment of sexually deviant individuals for psychiatric treatment. As the various states adopt statutes based on Hendricks, psychiatry will be forced to take an active interest in the diagnosis and the management of the paraphilias. This paper outlines briefly where the field is in the understanding of the natural history, diagnosis, and treatment of the paraphilias.


Multigene Panel Testing in a Large Cohort of Adults With Epilepsy: Diagnostic Yield and Clinically Actionable Genetic Findings.
Although genetic testing among children with epilepsy has demonstrated clinical utility and become a part of routine testing, studies in adults are limited. This study reports the diagnostic yield of genetic testing in adults with epilepsy. Unrelated individuals aged 18 years and older who underwent diagnostic genetic testing for epilepsy using a comprehensive, next-generation sequencing-based, targeted gene panel (range 89-189 genes) were included in this cross-sectional study. Clinical information, provided at the discretion of the ordering clinician, was reviewed and analyzed. Diagnostic yield was calculated for all individuals including by age at seizure onset and comorbidities based on clinician-reported information. The proportion of individuals with clinically actionable genetic findings, including instances when a specific treatment would be indicated or contraindicated due to a diagnostic finding, was calculated. Among 2,008 individuals, a diagnostic finding was returned for 218 adults (10.9%), with clinically actionable findings in 55.5% of diagnoses. The highest diagnostic yield was in adults with seizure onset during infancy (29.6%, 0-1 year), followed by in early childhood (13.6%, 2-4 years), late childhood (7.0%, 5-10 years), adolescence (2.4%, 11-17 years), and adulthood (3.7%, ≥18 years). Comorbid intellectual disability (ID) or developmental delay resulted in a high diagnostic yield (16.0%), most notably for females (19.6% in females vs 12.3% in males). Among individuals with pharmacoresistant epilepsy, 13.5% had a diagnostic finding, and of these, 57.4% were clinically actionable genetic findings. These data reinforce the utility of genetic testing for adults with epilepsy, particularly for those with childhood-onset seizures, ID, and pharmacoresistance. This is an important consideration due to longer survival and the complexity of the transition from pediatric to adult care. In addition, more than half of diagnostic findings in this study were considered clinically actionable, suggesting that genetic testing could have a direct impact on clinical management and outcomes.


Operative treatment of post-traumatic proximal radioulnar synostosis.
The results of operative resection of a post-traumatic proximal radioulnar synostosis performed by one surgeon in eighteen limbs of seventeen consecutive patients during an eight-year period were reviewed retrospectively. The resection was performed an average of nineteen months after the injury; eight limbs had the resection less than twelve months after the injury. A free fat graft was used in the first eight patients. No adjuvant non-steroidal anti-inflammatory medication or low-dose radiation was used postoperatively as prophylaxis against heterotopic ossification. We classified the proximal radioulnar synostoses into three subgroups: A indicated a synostosis at or distal to the bicipital tuberosity (four limbs), B indicated a synostosis involving the radial head and the proximal radioulnar joint (seven limbs), and C indicated a synostosis that was contiguous with bone extending across the elbow to the distal aspect of the humerus (seven limbs). The patients were followed for an average of thirty-four months (range, twenty-four to sixty months). The synostosis recurred in one patient, the only patient in the series who had sustained a closed head injury at the time of the initial injury. Additional complications included a fracture of the ulna, a broken pin on a hinged elbow distractor, and dislodgment of a free nonvascularized fat graft in one patient each. The seventeen limbs that did not have a recurrence regained an average of 139 degrees of rotation of the forearm. With the number of patients available, we could not detect a significant relationship between subsequent rotation of the forearm and the size of the synostosis, the use of interpositional fat, or the concomitant use of a hinged elbow distractor. The eight limbs that had resection of the synostosis less than twelve months after the injury regained an average of 144 degrees of rotation compared with 134 degrees in the nine limbs that had resection at least twelve months after the injury. This difference could not be shown to be significant. In this series, operative resection of a post-traumatic proximal radioulnar synostosis led to good results despite the lack of adjuvant radiation therapy or anti-inflammatory medication.


Effect of prolactin on urinary excretion and renal haemodynamics in conscious rats.
1. Conscious rats received a saline infusion (5.8 ml . hr-1) via a tail vein, for a 6 hr period. For the final 2 hr of this infusion period, prolactin (7.1 microgram (100 g body wt.)-1 . hr-1) was incorporated in the infusate. A control group of animals continued to receive saline alone. 2. In the first hour of prolactin administration (in comparison with the control group), urine flow, sodium output and osmolal output were all significantly reduced (P less than 0.02); there was also a reduction (P less than 0.05) in renal plasma flow (p-amino-hippurate clearance), but the filtration fraction did not alter. The changes in urinary excretion, and in renal haemodynamics, did not persist for the second hour of prolactin administration, but there was a sustained increase in body fluid volume. 3. It is possible that altered renal haemodynamics are responsible for the reduced urinary water and solute excretion which occurs during acute prolactin administration.


Effects of sea water and stanniectomy on branchial Ca(2+) handling and drinking rate in eel (Anguilla anguilla L.).
We examined the effects of seawater adaptation and extirpation of the Stannius corpuscles on branchial Ca(2+) flows, gill plasma membrane Ca(2+) transporters and drinking rate of European eels, Anguilla anguilla. Transepithelial Ca(2+) inflow in the gills increased 2 weeks after transfer of the eels from fresh water to sea water and after stanniectomy. Neither of these treatments changed the membrane density or the affinity of the Ca(2+)-extrusion mechanisms (Ca(2+)-ATPase and Na(+)/Ca(2+)-exchanger) in the gill cells, as measured in basolateral plasma membrane vesicles. We conclude that the increase in the Ca(2+)-transporting capacity observed in the gills of fish exposed to the larger transepithelial Ca(2+) fluxes, resulting from exposure to sea water or stanniectomy, involves an increase in number and/or size of the Ca(2+)-transporting cells, but not in the membrane density of Ca(2+) transporters. Branchial Ca(2+) outflow was higher in stanniectomised than in sham-operated fish. Changes in electrochemical driving forces as well as plasma stanniocalcin or teleocalcin levels may be the basis for the observed differences. Stanniectomy enhanced drinking in stanniectomised eels. Drinking was not further affected by transfer to sea water. These observations suggest that the corpuscles of Stannius are involved in the water balance.


Criminalising research fraud.
The incidence of research fraud has reached troubling levels. Too often peer review has failed to prevent it. The harm caused by such conduct extends to patients, co-authors, supervisors, employing institutions, funders, journals, publishers, and importantly the area and direction of the research itself and its potential influence are tarnished. A number of commentators have raised the option of criminal charges being preferred against those responsible for such fraud. This has occurred in the United States, in particular, but also in the United Kingdom, Korea and Australia in high-profile cases. There is much to be said for this form of prosecutorial response to the phenomenon of research fraud given its multi-level ramifications, the considered nature of the conduct, and the fact that it is engaged in by persons well positioned to appreciate the harm that their deceit may cause. The involvement of the criminal law enhances the potential for deterrence from yielding to the temptation and opportunity to engage in research fraud.


A triad of bovine inherited diseases (abstract).
Three inherited diseases of cattle seen in the past 2 years were described. Familial acantholysis of Angus cattle was seen in 9/54 calves born to cows inadvertently mated to a full sibling bull. Sloughing skin from the joints, nose and palate were seen at 1 day of age, confirmed as suprabasilar clefts on histopathology. A 2-year-old Charolais steer was noted at ante-mortem slaughter inspection with a whole body tremor and nystagmus. Histopathologically, eosinophilic plaques expanded white matter throughout the brain, consistent with a syndrome of 'progressive ataxia' of Charolais cattle. Two calves born from Red Devon cattle had marked hyperkeratosis, microtia and periocular reddening with deep fissuring of the keratin, characteristic of congenital ichthyosis.


Sirenomelia and cyclopia cluster in Cali, Colombia.
Sirenomelia and cyclopia share etiologic and pathogenic characteristics. A cluster of these two patterns of malformation in the city of Cali, Colombia, is described. Four sirenomelia and four cyclopia cases were born within a 165 days period in one hospital in Cali. The lapse between conception dates of first and last cases was shorter for sirenomelia (53 days) than for cyclopia (231 days). Based on ECLAMC (Latin American Collaborative Study of Congenital Malformations) published data, the observed/expected ratio (5.7) for both defects is statistically significant (P < 0.001). Mother's residence during the first trimester of pregnancy is concentrated in a same city quarter for four of the eight cases, close to a know polluting active landfill, and the other four cases, along the Cauca river, downstream from this landfill. Birth prevalence rates for two sentinel anomalies, that is, anal and esophageal atresia for sirenomelia and oral clefts for DeMyer holoprosencephaly spectra, were not higher in Cali than in the rest of ECLAMC material. The Computer Assisted Telephone Interviewing was applied to mothers of the 8 patients, and 32 matched controls. Seven of 295 variables were associated with sirenomelia, 3 of them related to house tap water, one to exposure to street drugs, one to physical injury, and 2 secondary to abnormal pregnancy outcome. None was associated with cyclopia. Results from hair dosage of heavy metals in the 8 patient's mothers were inconsistent. The time-space cluster is nonrandom for sirenomelia, and possibly random for cyclopia. The polluting landfill remains as a possible etiological factor.