Efficacy of Perfusion Computed Tomography (PCT) in Differentiating High-Grade Gliomas from Low Grade Gliomas, Lymphomas, Metastases and Abscess.
Tumoural angioneogenesis and its quantification are important in predicting the tumour grade and in the management with respect to the treatment available and to assess the response to treatment and the prognosis. It also plays major role in the growth and spread of tumours. Hence, a need arises for non-invasive in vivo methods to assess tumour angioneogenesis and tumour grade at the time of presentation and for monitoring the response during treatment and follow up. In this regard Perfusion Computed Tomography (PCT) can be easily added into routine CT studies to obtain such information on lesion physiology along with its morphology. Prospective evaluation of the efficacy of PCT in differentiating high grade gliomas from low grade glioma lymphomas, metastases and abscess. Perfusion CT was performed in 68 patients (17 high-grade gliomas, 10 low-grade gliomas, 7 lymphomas, 27 metastases and 7 abscess). Perfusion parameters which include Cerebral Blood Volume (CBV), Cerebral Blood Flow (CBF), Mean Transit Time (MTT) and Time To Peak (TTP) were derived both from the lesion and the normal parenchyma and were Normalized (n) by obtaining the ratio. Statistical analysis for high grade versus low-grade gliomas, high grade gliomas versus lymphomas, metastases and abscess was performed. Difference in the mean nCBV and nCBF in high grade gliomas were statistically significant from low grade gliomas with cut off of > 3.07 for nCBV and > 2.08 for nCBF yielding good sensitivity and specificity. Difference in the mean nCBV and nMTT in the lymphomas were statistically significant from high grade gliomas (p<0.05) with cut off of <3.40 for nCBV and >1.83 for nMTT yielding good sensitivity and specificity. Difference in the mean nCBV and nMTT in the metastases were statistically significant from high grade gliomas (p<0.05) with cut off of >4.95 for nCBV and >1.88 for nMTT yielding a fair sensitivity and specificity. No statistical significant difference seen among the parameters in differentiating high grade gliomas and abscess. Cerebral PCT greatly adds to the diagnostic accuracy when the diagnosis of a common intra-axial lesion based on morphological characters becomes uncertain.


Systematic review of U.S.-based randomized controlled trials using community health workers.
There is increasing concern about racial and ethnic disparities in health status and health care in the United States (U.S.). Recent recommendations to address these disparities have encouraged the use of community health workers (CHWs) as a promising intervention. The purpose of this review is to provide a systematic examination of randomized controlled trial (RCT) evidence regarding the usefulness of CHWs in the U.S. health care system. We searched electronic databases from January 1, 1990, to June 7, 2007, to identify RCTs using CHWs. Two researchers systematically reviewed all eligible articles. Data were extracted from each eligible study and independently reviewed by both investigators. Twelve studies were eligible for inclusion in this review. Of those 12 studies, 10 demonstrated CHW efficacy in enhancing outcomes. Three of these studies addressed breast cancer screening behaviors and three evaluated Pap smear testing. The review found one study each in the areas of patient enrollment in research, early intervention services, child development, blood pressure reduction and control, and nutritional eating habits. Although significant heterogeneity among studies precluded pooling of data and meta-analyses, the weight of the available RCT evidence suggests positive benefits may be attributable to the use of CHWs interventional strategy in the context of the U.S. health care setting.


The Physiological Bases of Hidden Noise-Induced Hearing Loss: Protocol for a Functional Neuroimaging Study.
Rodent studies indicate that noise exposure can cause permanent damage to synapses between inner hair cells and high-threshold auditory nerve fibers, without permanently altering threshold sensitivity. These demonstrations of what is commonly known as hidden hearing loss have been confirmed in several rodent species, but the implications for human hearing are unclear. Our Medical Research Council-funded program aims to address this unanswered question, by investigating functional consequences of the damage to the human peripheral and central auditory nervous system that results from cumulative lifetime noise exposure. Behavioral and neuroimaging techniques are being used in a series of parallel studies aimed at detecting hidden hearing loss in humans. The planned neuroimaging study aims to (1) identify central auditory biomarkers associated with hidden hearing loss; (2) investigate whether there are any additive contributions from tinnitus or diminished sound tolerance, which are often comorbid with hearing problems; and (3) explore the relation between subcortical functional magnetic resonance imaging (fMRI) measures and the auditory brainstem response (ABR). Individuals aged 25 to 40 years with pure tone hearing thresholds ≤20 dB hearing level over the range 500 Hz to 8 kHz and no contraindications for MRI or signs of ear disease will be recruited into the study. Lifetime noise exposure will be estimated using an in-depth structured interview. Auditory responses throughout the central auditory system will be recorded using ABR and fMRI. Analyses will focus predominantly on correlations between lifetime noise exposure and auditory response characteristics. This paper reports the study protocol. The funding was awarded in July 2013. Enrollment for the study described in this protocol commenced in February 2017 and was completed in December 2017. Results are expected in 2018. This challenging and comprehensive study will have the potential to impact diagnostic procedures for hidden hearing loss, enabling early identification of noise-induced auditory damage via the detection of changes in central auditory processing. Consequently, this will generate the opportunity to give personalized advice regarding provision of ear defense and monitoring of further damage, thus reducing the incidence of noise-induced hearing loss.


ERS statement on respiratory muscle testing at rest and during exercise.
Assessing respiratory mechanics and muscle function is critical for both clinical practice and research purposes. Several methodological developments over the past two decades have enhanced our understanding of respiratory muscle function and responses to interventions across the spectrum of health and disease. They are especially useful in diagnosing, phenotyping and assessing treatment efficacy in patients with respiratory symptoms and neuromuscular diseases. Considerable research has been undertaken over the past 17 years, since the publication of the previous American Thoracic Society (ATS)/European Respiratory Society (ERS) statement on respiratory muscle testing in 2002. Key advances have been made in the field of mechanics of breathing, respiratory muscle neurophysiology (electromyography, electroencephalography and transcranial magnetic stimulation) and on respiratory muscle imaging (ultrasound, optoelectronic plethysmography and structured light plethysmography). Accordingly, this ERS task force reviewed the field of respiratory muscle testing in health and disease, with particular reference to data obtained since the previous ATS/ERS statement. It summarises the most recent scientific and methodological developments regarding respiratory mechanics and respiratory muscle assessment by addressing the validity, precision, reproducibility, prognostic value and responsiveness to interventions of various methods. A particular emphasis is placed on assessment during exercise, which is a useful condition to stress the respiratory system.


[MIII2MII3] n+ trigonal bipyramidal cages based on diamagnetic and paramagnetic metalloligands.
A family of five [MIII2MII3] n+ trigonal bipyramidal cages (MIII = Fe, Cr and Al; MII = Co, Zn and Pd; n = 0 for 1-3 and n = 6 for 4-5) of formulae [Fe2Co3L6Cl6] (1), [Fe2Zn3L6Br6] (2), [Cr2Zn3L6Br6] (3), [Cr2Pd3L6(dppp)3](OTf)6 (4) and [Al2Pd3L6(dppp)3](OTf)6 (5) (where HL is 1-(4-pyridyl)butane-1,3-dione and dppp is 1,3-bis(diphenylphosphino)propane) are reported. Neutral cages 1-3 were synthesised using the tritopic [MIIIL3] metalloligand in combination with the salts CoIICl2 and ZnIIBr2, which both act as tetrahedral linkers. The assembly of the cis-protected [PdII(dppp)(OTf)2] with [MIIIL3] afforded the anionic cages 4-5 of general formula [MIII2PdII3](OTf)6. The metallic skeleton of all cages describes a trigonal bipyramid with the MIII ions occupying the two axial sites and the MII ions sitting in the three equatorial positions. Direct current (DC) magnetic susceptibility, magnetisation and heat capacity measurements on 1 reveal weak antiferromagnetic exchange between the FeIII and CoII ions. EPR spectroscopy demonstrates that the distortion imposed on the {MO6} coordination sphere of [MIIIL3] by complexation in the {MIII2MII3} supramolecules results in a small, but measurable, increase of the zero field splitting at MIII. Complete active space self-consistent field (CASSCF) calculations on the three unique CoII sites of 1 suggest DCo ≈ -14 cm-1 and E/D ≈ 0.1, consistent with the magnetothermal and spectroscopic data.


Strongly nonlinear dynamics of ferroelectric liquid crystals.
Molecular reorientation processes induced in thin ferroelectric liquid crystal systems by strong alternating external electric fields are studied both by solving numerically the equation of reorientation motion of molecules and by measuring the electro-optic response of thin samples. It is shown that the occurrence of a wide band in nonlinear response spectra above the Goldstone-mode frequency is a consequence of complex partially uncorrelated molecular reorientations enforced within smectic layers by sufficiently high fields of high enough frequencies. Such nonlinear reorientational motions of molecules are argued to have a character of weakly chaotic long-lasting transients, related to almost periodic modulations of the amplitude of rotational oscillations performed by molecules with the field frequency. These modulations have been numerically proved to proceed with lower frequencies than the field frequency and with space-dependent depths of temporal changes. The occurrence of the modulations has experimentally been confirmed by registering distinct contributions to electro-optic response spectra at frequencies less than the running frequency of the applied electric field.


Molecular pharmacology of gamma-aminobutyric acid type A receptor agonists and partial agonists in oocytes injected with different alpha, beta, and gamma receptor subunit combinations.
Using systematic combination of alpha 1, alpha 3, and alpha 5 with beta 1, beta 2, and beta 3, together with gamma 1, gamma 2, and gamma 3, we have investigated the contributions of the various alpha, beta, and gamma subunits to the pharmacology of gamma-aminobutyric acid (GABA)A agonists. We have characterized GABA, (RS)-dihydromuscimol, piperidine-4-sulfonic acid, and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol with recombinant human GABAA receptors expressed in Xenopus oocytes. Our observations indicate that the alpha subunit is the major determinant of efficacy for partial GABAA agonists. When alpha 1 and alpha 3 or alpha 1 and alpha 5 are coexpressed, the alpha 1 subunit determines the maximum efficacy, whereas the affinity is determined by the entire combination of subunits. Thus, the results of the present study demonstrate that the pharmacology of GABAA agonists is dependent on the subunit composition of the GABAA receptor complex. Functional GABAA receptors containing two different alpha subunits show pharmacological profiles distinctly different from those of receptors containing a single alpha subtype, indicating that two different alpha subunits can be coexpressed in one functional GABAA receptor complex.


Linear precoding based on polynomial expansion: reducing complexity in massive MIMO.
Massive multiple-input multiple-output (MIMO) techniques have the potential to bring tremendous improvements in spectral efficiency to future communication systems. Counterintuitively, the practical issues of having uncertain channel knowledge, high propagation losses, and implementing optimal non-linear precoding are solved more or less automatically by enlarging system dimensions. However, the computational precoding complexity grows with the system dimensions. For example, the close-to-optimal and relatively "antenna-efficient" regularized zero-forcing (RZF) precoding is very complicated to implement in practice, since it requires fast inversions of large matrices in every coherence period. Motivated by the high performance of RZF, we propose to replace the matrix inversion and multiplication by a truncated polynomial expansion (TPE), thereby obtaining the new TPE precoding scheme which is more suitable for real-time hardware implementation and significantly reduces the delay to the first transmitted symbol. The degree of the matrix polynomial can be adapted to the available hardware resources and enables smooth transition between simple maximum ratio transmission and more advanced RZF. By deriving new random matrix results, we obtain a deterministic expression for the asymptotic signal-to-interference-and-noise ratio (SINR) achieved by TPE precoding in massive MIMO systems. Furthermore, we provide a closed-form expression for the polynomial coefficients that maximizes this SINR. To maintain a fixed per-user rate loss as compared to RZF, the polynomial degree does not need to scale with the system, but it should be increased with the quality of the channel knowledge and the signal-to-noise ratio.


Transcriptional profiling of embryos lacking the lipoprotein receptor SR-B1 reveals a regulatory circuit governing a neurodevelopmental or metabolic decision during neural tube closure.
The high-density lipoprotein receptor SR-B1 mediates cellular uptake of several lipid species, including cholesterol and vitamin E. During early mouse development, SR-B1 is located in the maternal-fetal interface, where it facilitates vitamin E transport towards the embryo. Consequently, mouse embryos lacking SR-B1 are vitamin E-deficient, and around half of them fail to close the neural tube and show cephalic neural tube defects (NTD). Here, we used transcriptomic profiling to identify the molecular determinants of this phenotypic difference between SR-B1 deficient embryos with normal morphology or with NTD. We used RNA-Seq to compare the transcriptomic profile of three groups of embryos retrieved from SR-B1 heterozygous intercrosses: wild-type E9.5 embryos (WT), embryos lacking SR-B1 that are morphologically normal, without NTD (KO-N) and SR-B1 deficient embryos with this defect (KO-NTD). We identified over 1000 differentially expressed genes: down-regulated genes in KO-NTD embryos were enriched for functions associated to neural development, while up-regulated genes in KO-NTD embryos were enriched for functions related to lipid metabolism. Feeding pregnant dams a vitamin E-enriched diet, which prevents NTD in SR-B1 KO embryos, resulted in mRNA levels for those differentially expressed genes that were more similar to KO-N than to KO-NTD embryos. We used gene regulatory network analysis to identify putative transcriptional regulators driving the different embryonic expression profiles, and identified a regulatory circuit controlled by the androgen receptor that may contribute to this dichotomous expression profile in SR-B1 embryos. Supporting this possibility, the expression level of the androgen receptor correlated strongly with the expression of several genes involved in neural development and lipid metabolism. Our analysis shows that normal and defective embryos lacking SR-B1 have divergent expression profiles, explained by a defined set of transcription factors that may explain their divergent phenotype. We propose that distinct expression profiles may be relevant during early development to support embryonic nutrition and neural tube closure.


Patients' perceptions of nurses' behaviour that influence patient participation in nursing care: a critical incident study.
Patient participation is an important basis for nursing care and medical treatment and is a legal right in many Western countries. Studies have established that patients consider participation to be both obvious and important, but there are also findings showing the opposite and patients often prefer a passive recipient role. Knowledge of what may influence patients' participation is thus of great importance. The aim was to identify incidents and nurses' behaviours that influence patients' participation in nursing care based on patients' experiences from inpatient somatic care. The Critical Incident Technique (CIT) was employed. Interviews were performed with patients (n = 17), recruited from somatic inpatient care at an internal medical clinic in West Sweden. This study provided a picture of incidents, nurses' behaviours that stimulate or inhibit patients' participation, and patient reactions on nurses' behaviours. Incidents took place during medical ward round, nursing ward round, information session, nursing documentation, drug administration, and meal.


Quantitative characterization of the relationship between levels of extended corticosteroid use and related adverse events in a US population.
This retrospective study assessed the incidence and timing of adverse events (AEs) among patients prescribed varying dose levels of corticosteroids in the US. Patients with selected autoimmune or inflammatory disease diagnoses between 2006 and 2015 were identified from a privately insured administrative database. Patients were stratified into treatment cohorts based on dosage and length of corticosteroid use: intermittent use with duration <60 days, and three extended use cohorts with duration ≥60 days at low (≤7.5 mg/day), medium (>7.5-≤15 mg/day) or high (>15 mg/day) prednisone-equivalent dosage. The incidence of and time to corticosteroid-related AEs were assessed by cohort. A total of 78,704 patients met the selection criteria, of whom 9.5%, 11.0% and 8.6% were classified into the high-, medium-, and low-dose extended corticosteroid use cohorts, respectively. Corticosteroid exposure varied across study conditions, from 34% of dermatomyositis/polymyositis to 6% of psoriatic arthritis patients prescribed extended high dose. Hypertension, pneumonia and osteoporosis were the AEs with the highest incidence rates (41.9, 27.4 and 19.8 cases respectively per 1000 patient-months for the high-dose cohort). For most AEs, all levels of extended corticosteroid use exhibited significant risks of increased incidence compared to intermittent use. Some AEs had dose relationships, with higher dose correlated with higher incidence; other AEs had duration relationships with longer duration correlated with higher incidence regardless of dose. Average time to AE onset was relatively short, occurring at 2.3-6.7 months after corticosteroid initiation. Through a rigorous quantitative characterization, extended steroid exposure was associated with increased incidence and earlier onset of AEs among privately insured adults in the US.


Chiropractic treatment of coccygodynia via instrumental adjusting procedures using activator methods chiropractic technique.
To discuss a case of coccygodynia that responded favorably to conservative chiropractic adjusting procedures with the Activator Methods Chiropractic Technique (AMCT) and the Activator II Adjusting Instrument (AAI II). A 29-year-old woman had unremitting coccygeal pain of 3 weeks' duration. The problem began after she had moved heavy boxes while at work. The pain was characterized by a continual dull ache in the coccygeal region, accompanied by intermittent sharp pain, particularly upon sitting or rising from a seated position. She had been taking self-prescribed over-the-counter analgesics (aspirin and ibuprofen) for 3 weeks without obtaining relief. Treatment consisted of mechanical force, manually assisted, short-lever (MFMA) chiropractic adjusting procedures to the coccygeal area, primarily the sacrococcygeal ligament. The AAI II was used to deliver the adjustment according to diagnostic and treatment protocol specified for AMCT. The patient experienced first treatment. Chiropractic coccygeal manipulation may be effectively delivered via instrumental adjustment in certain cases of coccygodynia. The use of an AAI II in administering the coccygeal adjustment has the benefit of being a gentle, noninvasive procedure, as well as being comfortably tolerated by the patient. This method of coccygeal adjustment may bear consideration in certain cases of coccygodynia.


Bicomponent β-sheet assembly of dipeptide fluorophores of opposite polarity and sensitive detection of nitro-explosives.
Fluorescent hydrogels of two dipeptide-pyrene amphiphiles of opposite polarity are developed via bicomponent antiparallel β-sheet co-assembly. The helical molecular assembly resulted in the formation of fluorescent nanofibers. The sandwich-like interaction of nitroaromatics within the hydrogel matrix enabled selective and sensitive detection of toxic nitro-explosives.


Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial.
We tested whether the concurrence of food intake and elevated concentrations of endogenous melatonin, as occurs with late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes-associated G allele in the melatonin receptor-1B gene (MTNR1B). In a Spanish natural late-eating population, a randomized, crossover study was performed. Each participant (n = 845) underwent two evening 2-h 75-g oral glucose tolerance tests following an 8-h fast: an early condition scheduled 4 h prior to habitual bedtime ("early dinner timing") and a late condition scheduled 1 h prior to habitual bedtime ("late dinner timing"), simulating an early and a late dinner timing, respectively. Differences in postprandial glucose and insulin responses between early and late dinner timing were determined using incremental area under the curve (AUC) calculated by the trapezoidal method. Melatonin serum levels were 3.5-fold higher in the late versus early condition, with late dinner timing resulting in 6.7% lower insulin AUC and 8.3% higher glucose AUC. The effect of late eating impairing glucose tolerance was stronger in the MTNR1B G-allele carriers than in noncarriers. Genotype differences in glucose tolerance were attributed to reductions in β-cell function (P for interaction, Pint glucose area under the curve = 0.009, Pint corrected insulin response = 0.022, and Pint disposition index = 0.018). Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impairs glucose tolerance, especially in MTNR1B G-risk allele carriers, attributable to insulin secretion defects.


Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1.
We tested the hypothesis that ex vivo hepatocyte gene therapy can correct the metabolic disorder in fumarylacetoacetate hydrolase-deficient (Fah(-/-)) pigs, a large animal model of hereditary tyrosinemia type 1 (HT1). Recipient Fah(-/-) pigs underwent partial liver resection and hepatocyte isolation by collagenase digestion. Hepatocytes were transduced with one or both of the lentiviral vectors expressing the therapeutic Fah and the reporter sodium-iodide symporter (Nis) genes under control of the thyroxine-binding globulin promoter. Pigs received autologous transplants of hepatocytes by portal vein infusion. After transplantation, the protective drug 2-(2-nitro-4-trifluoromethylbenzyol)-1,3 cyclohexanedione (NTBC) was withheld from recipient pigs to provide a selective advantage for expansion of corrected FAH(+) cells. Proliferation of transplanted cells, assessed by both immunohistochemistry and noninvasive positron emission tomography imaging of NIS-labeled cells, demonstrated near-complete liver repopulation by gene-corrected cells. Tyrosine and succinylacetone levels improved to within normal range, demonstrating complete correction of tyrosine metabolism. In addition, repopulation of the Fah(-/-) liver with transplanted cells inhibited the onset of severe fibrosis, a characteristic of nontransplanted Fah(-/-) pigs. This study demonstrates correction of disease in a pig model of metabolic liver disease by ex vivo gene therapy. To date, ex vivo gene therapy has only been successful in small animal models. We conclude that further exploration of ex vivo hepatocyte genetic correction is warranted for clinical use.


Association Between Optic Disc Hemorrhage and Renal Function in South Korea.
The purpose of this article is to investigate the relationship between renal function and disc hemorrhage (DH). This retrospective cross-sectional survey was conducted at Kangbuk Samsung Hospital Health Screening Center between August 2012 and July 2013, and a total of 168,044 participants at least 20 years of age who voluntarily visited the health screening center for systemic and ophthalmologic examinations, including fundus photography, were enrolled. All subjects underwent a physical examination and provided samples for laboratory analysis. Digital fundus photographs of both eyes were taken and reviewed. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine concentration using the Modification of Diet in Renal Disease (MDRD) formula and Cockcroft-Gault (CG) formula. Subjects were stratified by eGFR into quartiles. Among participants, 220 (0.1%) showed DH, and 2376 (1.6%) showed glaucomatous retinal nerve fiber layer defects. The DH group showed higher creatinine and lower eGFR than the non-DH group. A significant trend was observed among higher creatinine, decreased eGFR as obtained by the MDRD and CG formulas, and the prevalence of DH (P for trend ≤0.003, logistic regression analysis). A multiple logistic regression model adjusted for age, sex, hypertension, diabetes, and hyperlipidemia showed that the lowest eGFR quartiles estimated by MDRD and CG were significantly associated with DH compared with the highest eGFR quartile (adjusted odds ratio, 1.96; 95% confidence interval, 1.22-3.14 by CG, 1.86; 95% confidence interval, 1.17-2.96 by MDRD). Renal function impairment was independently associated with a higher prevalence of DH in a South Korean population.


Do cytogenetic abnormalities precede morphologic abnormalities in a developing malignant condition?
Cytogenetic evaluation of bone marrow and neoplastic tissues plays a critical role in determining patient management and prognosis. Here, we highlight two cases in which the cytogenetic studies challenge the common practice of using hematologic and morphologic changes as key factors in malignant disease management. The first case is that of a lymph node sample from a 40-yr-old non-Hodgkin's lymphoma (NHL) patient sent for determination of disease progress. Hematologic studies showed no evidence of transformation to high-grade NHL (>15% blasts with rare mitotic figures). Cytogenetic studies of lymph node showed multiple clonal abnormalities, most notably a der(18) from a t(14;18) which is associated with high-grade NHL. After two cycles of chemotherapy with fludarabine, the patient did not show any clinical response, suggesting possible progression to high-grade lymphoma. The second case is of a patient with a history of human immunodeficiency virus and blastic natural killer leukemia/lymphoma. Hematologic studies of ascitic fluid classified the patient as having pleural effusion lymphoma whereas bone marrow analysis showed no malignancy. Bone marrow cytogenetic studies showed multiple clonal abnormalities including a t(8;14), which is commonly associated with Burkitt's lymphoma (BL). To our knowledge, this is the first case wherein a morphologically normal bone marrow showed presence of clonal abnormalities consistent with BL or Pleural effusion lymphoma. After two cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy, the patient's general condition and ascitis improved and she was discharged. These studies clearly demonstrate that genetic changes often precede morphologic changes in a developing malignant condition. Therefore, the critical information needed for care of patients with malignant disorders may be incomplete or inaccurate if cytogenetic evaluation is overlooked.


Extended treatment of venous thromboembolism: a systematic review and network meta-analysis.
To evaluate efficacy and safety of oral anticoagulant regimens and aspirin for extended venous thromboembolism (VTE) treatment. We searched MEDLINE, Embase, CENTRAL and conference proceedings for randomised controlled trials studying vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or aspirin for secondary prevention of VTE beyond 3 months. ORs (95% credible intervals) between treatments were estimated using random-effects Bayesian network meta-analysis. Sixteen studies, totaling more than 22 000 patients, were included. Compared with placebo or observation and with aspirin, respectively, the risk of recurrent VTE was lower with standard-intensity VKAs (0.15 (0.08 to 0.24) and 0.23 (0.09 to 0.54)), low-dose factor Xa inhibitors (0.16 (0.06 to 0.38) and 0.25 (0.09 to 0.66)), standard-dose factor Xa inhibitors (0.17 (0.08 to 0.33) and 0.27 (0.11 to 0.65)) and the direct thrombin inhibitor (0.15 (0.04 to 0.37) and 0.23 (0.06 to 0.74)) although the risk of major bleeding was higher with standard-intensity VKAs (4.42 (1.99 to 12.24) and 4.14 (1.17 to 18.86)). Effect estimates were consistent in male patients and those with index pulmonary embolism or with unprovoked VTE and in sensitivity analyses. In addition, compared with placebo or observation, the risk of all-cause mortality was reduced with standard-intensity VKAs (0.44 (0.20 to 0.87)) and low-dose factor Xa inhibitors (0.38 (0.12 to 0.995)). Standard-intensity VKAs and DOACs are more efficacious than aspirin for extended VTE treatment. Despite a higher risk of major bleeding, standard-intensity VKAs was associated with a lower risk of all-cause mortality. Since overall efficacy and safety of standard-intensity VKAs and DOACs are in equipoise, patient factors, costs and patient preferences should be considered when recommending extending anticoagulation treatment.


Synergism between NMDA and domoic acid in a murine model of behavioural neurotoxicity.
We have examined the behavioural neurotoxicity of domoic acid (DOM) and kainic acid (KA) in mice following administration of ligands active at the N-methyl-d-aspartate (NMDA) receptor. Groups of female CD-1 mice (n=4) were injected i.p. with saline or one of three doses of either DOM or KA. Doses of DOM and KA were selected from the steep portion of the respective dose response curves and were equitoxic when compared between the two ligands. Toxicity was recorded as both total cumulative toxicity over 60 min according to a previously validated 7 point rating scale, and as the latency to the onset of tremors and/or convulsions. Five minutes prior to administration of either agonist mice were injected with either saline, NMDA (40 mg/kg) or a combination of NMDA and 15 mg/kg CPP (3-[2-carboxypiperazine-4-yl]propyl-1-phosphonic acid). Neither NMDA nor CPP at these doses produced significant changes from baseline responding when injected prior to saline. Injection of NMDA prior to DOM, however, resulted in significantly increased cumulative toxicity and significantly reduced latencies to seizures at the two highest doses of DOM (3.75 and 5.0 mg/kg). NMDA-induced potentiation of DOM toxicity was completely antagonized by co-administration of CPP. In contrast, injection of NMDA prior to KA did not result in significant changes in KA toxicity at any of the doses tested using either index of behavioural toxicity. These results confirm previous reports of synergism between DOM and ligands acting at the NMDA receptor in isolated neurons, and provide further evidence of pharmacological dissociation of the actions of DOM and KA in vivo.


Expression of epidermal growth factor receptor changes in the hypothalamus during the onset of female puberty.
Recent findings have led to the concept that transforming growth factor alpha (TGF alpha) contributes to the neuroendocrine regulation of female puberty by stimulating the release of luteinizing hormone-releasing hormone (LHRH), the neurohormone controlling sexual development. It was postulated that this effect is mediated by epidermal growth factor receptors (EGFR) and that EGFR may not be located on LHRH neurons, so that TGF alpha-induced LHRH release would require an intermediate cell-to-cell interaction, presumably of glial-neuronal nature. The present study was undertaken to characterize the presence of EGFR in rat hypothalamus and to determine if changes in EGFR gene expression and EGFR protein occur at the time of puberty. RNA blot hybridization demonstrated that the hypothalamus expresses all mRNA species known to encode EGFR. RNase protection assays revealed that alternative splicing of the EGFR primary mRNA transcript occurs in the hypothalamus and produces a predominant transcript encoding the full-length EGFR and a much less abundant, shorter mRNA encoding a truncated, and presumably secreted form of EGFR. EGFR-like immunoreactive material was found in several hypothalamic regions including the organum vasculosum of the lamina terminalis, supraoptic, suprachiasmatic, and paraventricular nuclei, ependymal cells lining the third ventricle, some astrocytes associated with blood vessels, astrocytes of the pial surface, and tanycytes and glial cells of the median eminence (ME). Low levels of EGFR mRNA were detected by hybridization histochemistry in cells of the same areas containing EGFR-like immunoreactivity. Double-immunohistochemistry revealed that even though LHRH neurons are in close proximity to EGFR-positive cells, they do not contain EGFR. In the ME, EGFR-immunonegative LHRH nerve terminals tightly coexist with EGFR-positive cells, presumably tanycytes and glial astrocytes. EGFR mRNA levels measured by quantitative reverse transcription-polymerase chain reaction assay (RT-PCR) in the ME-arcuate nucleus region at the time of puberty decreased in the morning of the first proestrus, i.e., preceding the first preovulatory surge of gonadotropins, and rebounded at the time of the surge. Functional EGFR protein levels, detected by the ability of the receptor to autophosphorylate in response to ligand or divalent antibody-induced activation, changed in a similar manner at the time of puberty. No such changes were observed in the cerebellum, a brain region irrelevant to neuroendocrine reproductive control. These results demonstrate the existence of EGF receptors in the prepubertal female rat hypothalamus and suggest that changes in EGFR gene expression and biologically active EGFR protein contributes to the neuroendocrine process underlying the first preovulatory surge of gonadotropins.(ABSTRACT TRUNCATED AT 250 WORDS)


Titania nanobundle networks as dye-sensitized solar cell photoanodes.
Quasi-one-dimensional (1D) titania nanobundles were synthesized via a hydrothermal method and used to print random network nanostructured films. These films are shown to be ideally suited for application as photoanodes in dye-sensitized solar cells (DSCs) as they have a higher porosity compared to the traditional 1D nanostructured TiO2 materials. Devices constructed using the N719 dye and iodide/triiodide as the redox mediator in the electrolyte yielded energy conversion efficiencies (η = 6.1 ± 0.2%), which were marginally lower than for devices made with the commonly used P25 titania films (η = 6.3 ± 0.1%) under one sun simulated solar radiation. Application of an electrolyte based on the [Co(bpy)3](2+/3+) redox couple and the MK2 organic sensitizer resulted in higher efficiencies (η = 7.70 ± 0.1%) than for the P25 devices (η = 6.3 ± 0.3%). Each performance parameter (short circuit current density, open circuit voltage and fill factor) was higher for the TiO2 nanobundle devices than those for the P25-based devices. The results of electrochemical impedance spectroscopy (EIS), intensity-modulated photovoltage spectroscopy (IMVS), and dye-loading measurements indicated that the better performance of TiO2 nanobundle devices with cobalt electrolytes correlates with higher porosity, relatively fast electron transport and more efficient suppression of electron recombination. A faster rate of diffusion of the cobalt complexes through the highly porous TiO2 nanobundle network is proposed to contribute to the enhanced device efficiency.


Advancements in infrared imaging platforms: complementary imaging systems and contrast agents.
Recent advancements in the infrared (IR) imaging system design as well as the co-development of compatible contrast agents have facilitated the potential application of fluorescence imaging systems for deep tissue diagnostics and real-time vasculature visualization for intraoperative surgical guidance. Compared to conventional imaging techniques that achieve superior tissue penetration depth through the use of high energy or ionizing radiation sources, complementary chemical compounds, also known as imaging probes or contrast agents, are required to enable enhancement of the imaging sensitivity required for improved image quality in the IR fluorescence imaging technique. Therefore, using a systems-level approach to plan research efforts where the requirements of the imaging setup are considered at the start of the contrast agent design to effectively improve detection sensitivity would reduce the technical entry barrier for the adoption of new technologies. In this paper, we highlight (1) the recent advancements and key operating differences in the reported IR imaging systems, and (2) the recent progress in creating biocompatible IR-emitting contrast agents as well as improving detection sensitivity using targeting agents. The ability to maximize the full benefits and performance of any IR imaging platform is highly reliant on the thorough understanding of the requirements of each imaging platform and the physical characteristics of the complementary contrast agents.


Effects of high glucose on cellular proliferation and fibronectin production by cultured human mesangial cells.
Diabetic glomerulosclerosis is characterized by the accumulation of the matrix protein fibronectin in the glomerular mesangium and could result from increased mesangial cell fibronectin synthesis induced by hyperglycemia. To test this hypothesis, we cultured human mesangial cells for up to 14 days in media containing normal (5 mM) or high glucose (20 to 115 mM) concentrations and assessed cellular proliferation and fibronectin synthesis. When compared to 5 mM glucose, high glucose levels significantly inhibited cellular proliferation in a dose dependent fashion, as assessed by direct cell counting and thymidine incorporation. After eight days in culture, tissue culture supernatant fibronectin levels, as assessed by ELISA, were significantly higher from cells cultured under high glucose conditions than cells exposed to normal glucose levels. After 14 days and when compared to 5 mM glucose, matrix fibronectin levels and fibronectin mRNA expression (by Northern analysis) were also increased by 20 mM glucose. To control for the osmotic effects of high glucose, mesangial cells were also cultured in the presence of 20 mM or 50 mM mannitol. Mannitol had no effect on cellular proliferation but significantly increased tissue culture supernatant fibronectin levels and fibronectin gene expression. These studies demonstrate that, in vitro, high glucose suppresses human mesangial cell proliferation and stimulates fibronectin synthesis. The increase in fibronectin synthesis may in part result from changes in osmolality induced by high glucose. These data suggest that increased mesangial cell fibronectin synthesis may play a role in the accumulation of glomerular fibronectin common to diabetic glomerulosclerosis.


The effect of pre-exercise carbohydrate feedings on the intensity that elicits maximal fat oxidation.
The aim of the present study was to examine the effect of ingesting 75 g of glucose 45 min before the start of a graded exercise test to exhaustion on the determination of the intensity that elicits maximal fat oxidation (Fatmax). Eleven moderately trained individuals (VO2max: 58.9 +/- 1.0 ml x kg(-1) x min(-1); mean +/- sx), who had fasted overnight, performed two graded exercise tests to exhaustion, one 45 min after ingesting a placebo drink and one 45 min after ingesting 75 g of carbohydrate in the form of glucose. The tests started at 95 W and the workload was increased by 35 W every 3 min. Gas exchange measures and heart rate were recorded throughout exercise. Fat oxidation rates were calculated using stoichiometric equations. Blood samples were collected at rest and at the end of each stage of the test. Maximal fat oxidation rates decreased from 0.46 +/- 0.06 to 0.33 +/- 0.06 g min(-1) when carbohydrate was ingested before the start of exercise (P < 0.01). There was also a decrease in the intensity which elicited maximal fat oxidation (60.1 +/- 1.9% vs 52.0+3.4% VO2max) after carbohydrate ingestion (P < 0.05). Maximal power output was higher in the carbohydrate than in the placebo trial (346 +/- 12 vs 332 +/- 12 W) (P < 0.05). In conclusion, the ingestion of 75 g of carbohydrate 45 min before the onset of exercise decreased Fatmax by 14%, while the maximal rate of fat oxidation decreased by 28%.


Distribution and phenotype of Epstein-Barr virus-infected cells in inflammatory bowel disease.
Little is known about Epstein-Barr virus (EBV) infection of colon mucosa, particularly in inflammatory bowel diseases. Crohn's disease and ulcerative colitis are thought to differ in T-helper lymphocyte composition and cytokine secretion patterns. Some of the implicated cytokines are growth factors for EBV-infected cells. We examined colon mucosa for differences in the distribution and phenotype of EBV-infected cells. Colon tissues with Crohn's disease (n = 31) or ulcerative colitis (n = 25) and controls (n = 60) were characterized by in situ hybridization and immunohistology for six EBV gene products as indicators of latent and replicative EBV infection. The cells were additionally phenotyped by combined detection of the EBV transcripts and B- or T-cell antigens. B lymphocytes predominated as the site of latent EBV infection in the colon and were most numerous in ulcerative colitis. In active ulcerative colitis, EBV-positive lymphocytes accumulated under and within the epithelium and displayed evidence for replicative infection. The patterns of mucosal EBV gene expression indicate local impairment of virus-specific T-cell responses in active ulcerative colitis. Detection of EBV may help to discriminate between active ulcerative colitis and other inflammatory bowel diseases. Colon mucosa is a potential site of EBV replication and may be relevant for EBV transmission.


Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.
Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.


Gamma-hydroxybutyric acid in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol.
Gamma-hydroxybutyric acid has been proposed as a pharmacotherapy for alcoholism in part based on similar discriminative stimulus effects as ethanol. To date, drug discrimination studies with gamma-hydroxybutyric acid and ethanol have exclusively used rodents or pigeons as subjects. To evaluate possible differences between species, sex, and route of administration, this study investigated the substitution of gamma-hydroxybutyric acid (intragastrically or intramuscularly) for ethanol 30 or 60 min after administration in male (n=6) and female (n=7) cynomolgus monkeys trained to discriminate 1.0 and 2.0 g/kg ethanol. At least one dose of gamma-hydroxybutyric acid completely or partially substituted for ethanol in three of the 13 monkeys tested, with each case occurring in female monkeys. Ethanol-appropriate responding did not increase with gamma-hydroxybutyric acid dose. Monkeys were more sensitive to the response rate decreasing effects of gamma-hydroxybutyric acid administered intramuscularly compared with intragastrically. The lack of gamma-hydroxybutyric acid substitution for ethanol suggests that these drugs have different receptor bases for discrimination. Furthermore, the data do not strongly support shared discriminative stimulus effects as the rationale for gamma-hydroxybutyric acid pharmacotherapy for alcoholism.


A case of Hashimoto's encephalopathy presenting with seizures and psychosis.
Hashimoto's encephalopathy (HE) is a rare, poorly understood, autoimmune disease characterized by symptoms of acute or subacute encephalopathy associated with increased anti-thyroid antibody levels. Here, we report a case of a 14-year-old girl with HE and briefly review the literature. The patient presented with acute mental changes and seizures, but no evidence of infectious encephalitis. In the acute stage, the seizures did not respond to conventional antiepileptic drugs, including valproic acid, phenytoin, and topiramate. The clinical course was complicated by the development of acute psychosis, including bipolar mood, insomnia, agitation, and hallucinations. The diagnosis of HE was supported by positive results for antithyroperoxidase and antithyroglobulin antibodies. Treatment with methylprednisolone was effective; her psychosis improved and the number of seizures decreased. HE is a serious but curable, condition, which might be underdiagnosed if not suspected. Anti-thyroid antibodies must be measured for the diagnosis. HE should be considered in patients with diverse neuropsychiatric manifestations.


Psychosocial intervention development for the prevention and treatment of depression: promoting innovation and increasing access.
Great strides have been made in developing psychosocial interventions for the treatment of depression and bipolar disorder over the last three decades, but more remains to be done. The National Institute of Mental Health Psychosocial Intervention Development Workgroup recommends three priorities for future innovation: 1) development of new and more effective interventions that address both symptom change and functional capacity, 2) development of interventions that prevent onset and recurrence of clinical episodes in at-risk populations, and 3) development of user-friendly interventions and nontraditional delivery methods to increase access to evidence-based interventions. In each of these areas, the Workgroup recommends systematic study of the mediating mechanisms that drive the process of change and the moderators that influence their effects. This information will highlight the elements of psychosocial interventions that most contribute to the prevention and treatment of mood disorders across diagnostic groups, populations served, and community settings. The process of developing innovative interventions should have as its goal a mental health service delivery system that prevents the onset and recurrence of the mood disorders, furnishes increasingly effective treatment for those who seek it, and provides access to evidence-based psychosocial interventions via all feasible means.


Two novel mutations in ABHD12: expansion of the mutation spectrum in PHARC and assessment of their functional effects.
PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts) is a recently described autosomal-recessive neurodegenerative disease caused by mutations in the α-β-hydrolase domain-containing 12 gene (ABHD12). Only five homozygous ABHD12 mutations have been reported and the pathogenesis of PHARC remains unclear. We evaluated a woman who manifested short stature as well as the typical features of PHARC. Sequence analysis of ABHD12 revealed a novel heterozygous c.1129A>T (p.Lys377*) mutation. Targeted comparative genomic hybridization detected a 59-kb deletion that encompasses exon 1 of ABHD12 and exons 1-4 of an adjacent gene, GINS1, and includes the promoters of both genes. The heterozygous deletion was also carried by the patient's asymptomatic mother. Quantitative reverse transcription-PCR demonstrated ∼50% decreased expression of ABHD12 RNA in lymphoblastoid cell lines from both individuals. Activity-based protein profiling of serine hydrolases revealed absence of ABHD12 hydrolase activity in the patient and 50% reduction in her mother. This is the first report of compound heterozygosity in PHARC and the first study to describe how a mutation might affect ABHD12 expression and function. The possible involvement of haploinsufficiency for GINS1, a DNA replication complex protein, in the short stature of the patient and her mother requires further studies.


Thermal stability of Li2B12H12 and its role in the decomposition of LiBH4.
The purpose of this study is to compare the thermal and structural stability of single phase Li2B12H12 with the decomposition process of LiBH4. We have utilized differential thermal analysis/thermogravimetry (DTA/TGA) and temperature programmed desorption-mass spectroscopy (TPD-MS) in combination with X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy to study the decomposition products of both LiBH4 and Li2B12H12 up to 600 °C, under both vacuum and hydrogen (H2) backpressure. We have synthesized highly pure single phase crystalline anhydrous Li2B12H12 (Pa-3 structure type) and studied its sensitivity to water and the process of deliquescence. Under either vacuum or H2 backpressure, after 250 °C, anhydrous Li2B12H12 begins to decompose to a substoichiometric Li2B12H12-x composition, which displays a very broad diffraction halo in the d-spacing range 5.85-7.00 Å, dependent on the amount of H released. Aging Pa-3 Li2B12H12 under 450 °C/125 bar H2 pressure for 24 h produces a previously unobserved well-crystallized β-Li2B12H12 polymorph, and a nanocrystalline γ-Li2B12H12 polymorph. The isothermal release of hydrogen pressure from LiBH4 along the plateau and above the melting point (Tm = 280 °C) initially results in the formation of LiH and γ-Li2B12H12. The γ-Li2B12H12 polymorph then decomposes to a substoichiometric Li2B12H(12-x) composition. The Pa-3 Li2B12H12 phase is not observed during LiBH4 decomposition. Decomposition of LiBH4 under vacuum to 600 °C produces LiH and amorphous B with some Li dissolved within it. The lack of an obvious B-Li-B or B-H-B bridging band in the FTIR data for Li2B12H(12-x) suggests the H poor B12H(12-x) pseudo-icosahedra remain isolated and are not polymerized. Li2B12H(12-x) is persistent to at least 600 °C under vacuum, with no LiH formation observable and only a ca. d = 7.00 Å halo remaining. By 650 °C, Li2B12H(12-x) is finally decomposed, and amorphous B can be observed, with no LiH reflections. Further studies are required to clarify the structural symmetry of the β- and γ-Li2B12H12 polymorphs and substoichiometric Li2B12H(12-x).


Teledermatology in the UK: lessons in service innovation.
Teledermatology has the potential to revolutionize the delivery of dermatology services by facilitating access to specialist services at a distance. In the U.K. over the previous decade there have been numerous attempts at introducing and using teledermatology; however, the development of teledermatology as routine service provision remains limited. To identify factors that promote successful use of teledermatology as a part of routine service provision. A longitudinal qualitative study of teledermatology, drawing on data from in-depth semistructured interviews; observations of systems in practice; and public meetings. Data were analysed collectively by the research team using established qualitative analytical techniques to identify key thematic categories. The sample consisted of teledermatology services within the U.K. (n = 12) studied over 8 years (1997-2005). Individual participants (n = 68 interviews) were consultant dermatologists, researchers, teledermatology nurses, administrators, patient advocates, general practitioners and technologists. The analysis compared services that did or did not become part of routine healthcare practice to identify features that supported the normalization of teledermatology. Requirements for using and integrating teledermatology into practice included: political support; perceived benefit and relative commitment that outweighs effort; pragmatic approaches to proving efficacy and safety; perception of risk as being 'manageable' on the basis of professional judgement; high levels of flexibility in practice (in terms of individuals, technology and organization); and reconceptualizing professional roles. Successful implementation of teledermatology as a routine service requires greater understanding of and attention to the interplay between social and technical aspects of teledermatology, and how this is accommodated both by healthcare professionals and the organizations in which they work.


The seductive allure of neuroscience explanations.
Explanations of psychological phenomena seem to generate more public interest when they contain neuroscientific information. Even irrelevant neuroscience information in an explanation of a psychological phenomenon may interfere with people's abilities to critically consider the underlying logic of this explanation. We tested this hypothesis by giving naïve adults, students in a neuroscience course, and neuroscience experts brief descriptions of psychological phenomena followed by one of four types of explanation, according to a 2 (good explanation vs. bad explanation) x 2 (without neuroscience vs. with neuroscience) design. Crucially, the neuroscience information was irrelevant to the logic of the explanation, as confirmed by the expert subjects. Subjects in all three groups judged good explanations as more satisfying than bad ones. But subjects in the two nonexpert groups additionally judged that explanations with logically irrelevant neuroscience information were more satisfying than explanations without. The neuroscience information had a particularly striking effect on nonexperts' judgments of bad explanations, masking otherwise salient problems in these explanations.


Periodically changing morphology of the growth interface in Si, Ge, and GaP nanowires.
Nanowire growth in the standard <111> direction is assumed to occur at a planar catalyst-nanowire interface, but recent reports contradict this picture. Here we show that a nonplanar growth interface is, in fact, a general phenomenon. Both III-V and group IV nanowires show a distinct region at the trijunction with a different orientation whose size oscillates during growth, synchronized with step flow. We develop an explicit model for this structure that agrees well with experiment and shows that the oscillations provide a direct visualization of catalyst supersaturation. We discuss the implications for wire growth and structure.


Lower reinforcing strength of the phenyltropane cocaine analogs RTI-336 and RTI-177 compared to cocaine in nonhuman primates.
Drugs that inhibit brain dopamine transporters (DAT) have been developed as potential agonist medications for cocaine abuse and dependence. Because the mechanism of action of such drugs is similar to cocaine, one concern regarding their use is the abuse potential of the medications themselves. The present study compared the reinforcing strength of cocaine (0.003-0.3mg/kg) and two 3-phenyltropane analogs of cocaine, RTI-336 (3beta-(4-chlorophenyl)-2beta-[3-(4'-methylphenyl)isoxazol-5-yl]tropane hydrochloride; 0.003-0.1mg/kg) and RTI-177 (3beta-(4-chlorophenyl)-2beta-[3-phenylisoxazol-5-yl]tropane hydrochloride; 0.003-0.1mg/kg), using a progressive-ratio (PR) schedule in rhesus monkeys (n=4). PR schedules of reinforcement are frequently used to measure reinforcing strength of drugs. Earlier research using limited-access conditions reported that cocaine was a stronger reinforcer than either RTI-336 or RTI-177. Because the 3-phenyltropanes have longer durations of action, one purpose of the present study was to examine reinforcing strength using longer experimental sessions. Under these conditions, cocaine functioned as a reinforcer in all monkeys, and RTI-336 and RTI-177 functioned as a reinforcer in three of four subjects. Consistent with their documented slower onset of neurochemical and pharmacological effects, RTI-336 and RTI-177 were weaker reinforcers, resulting in fewer injections than cocaine. On average, the potencies of the two RTI compounds were not different than that of cocaine. These results support the view that slow-onset DA-selective uptake inhibitors have lower abuse liability than cocaine. In addition, the present findings suggest that changes in PR session length can influence potency comparisons between drugs, but not measures of reinforcing strength.


Coffee Consumption and the Risk of Thyroid Cancer: A Systematic Review and Meta-Analysis.
An inverse association has been reported between coffee consumption and the risk of several cancers. However, the association between coffee and thyroid cancer is controversial. Thus, this study aimed to evaluate the association between coffee consumption and the risk of thyroid cancer through a systematic review and meta-analysis. Published studies were examined from PubMed, Embase, Cochrane Central, and the reference lists of the retrieved articles. The summary odds ratio (OR) for the association between coffee consumption was categorized as highest versus lowest consumption, and thyroid cancer risk was calculated using a fixed effects model. Subgroup analyses by study design, geographic location, source of controls, and adjusted variables were performed. A total of 1039 thyroid cancer cases and 220,816 controls were identified from five case-control studies and two cohort studies. The summary OR for the association between coffee consumption and thyroid cancer risk was 0.88 (95% confidence interval (CI) = 0.71-1.07). There was no significant heterogeneity among the study results (I² = 0%, p = 0.79). However, the beneficial effect of coffee consumption on thyroid cancer was found only in hospital-based case-control studies (OR= 0.59, 95% CI= 0.37-0.93). There was no significant association between coffee consumption and thyroid cancer risk according to our meta-analysis results. These findings should be interpreted with caution because of potential biases and confounding variables. Further prospective studies with a larger number of cases are encouraged to confirm these results.


Heredity and age-related macular degeneration. Observations in monozygotic twins.
To determine the concordance of age-related macular degenerative changes in monozygotic twins. Between 1984 and 1993, we examined a total of nine pairs of monozygotic twins with substantial age-related macular degenerative changes in at least one member of the pair, ranging from extensive large drusen to advanced atrophic and/or disciform scarring. Eight pairs were female and one pair was male. Ages ranged from 62 to 88 years. Monozygosity was confirmed by genetic testing in each of the seven twin pairs on whom it was performed. In eight of the nine twin pairs, the fundus appearance and the incidence of visual impairment were similar. In the ninth pair, one twin had advanced exudative age-related macular degeneration with vision loss in one eye, while the other had large, confluent drusen and good visual function in both eyes. Environmental factor, including diet, geographic background, and medical history, were essentially similar in the twin pairs. Although selection factors and similar environmental influences might impact our findings, the markedly similar incidence of macular degenerative changes in these monozygotic twins suggests that a substantial genetic component may exist in a potentially large proportion of patients with age-related macular degeneration. Further studies are warranted to define this hereditary influence.


The role of specialist and general nurses working with people with multiple sclerosis.
To describe the perceived role of nurses and other carers of people with multiple sclerosis from the perspective of different stakeholders (people with multiple sclerosis, non-specialist nurses, specialist nurses and other health care professionals). Multiple sclerosis is one of the commonest causes of disability in young adults. People with multiple sclerosis require supportive care during the disease trajectory. The role of different health and social care providers has not been reported previously. Survey. Questionnaire data collected in 2002 during the first phase of scale development (health professionals n = 459; people with multiple sclerosis n = 65; total response rate 59.4%). The data were reanalysed to compare responses across sample groups. There was consensus that neurologists and specialist nurses were the most appropriate professionals in the provision of specialist care with specialist nurses also being identified as key providers of emotional support. However, there were also significant differences in nominations reflecting the different perspectives of the stakeholder groups and a self-report bias. Each stakeholder group frequently emphasised their own perceived contribution to care. The different perspective of people with multiple sclerosis was also noteworthy with their greater emphasis on social care and lay support. The findings indicate a dissonance in the views of different stakeholders within the care system. The division of labour associated with nursing care requires further exploration. The contrasting paradigms of health care professionals and people with multiple sclerosis regarding models of disability were highlighted. Multiple sclerosis, like other chronic illnesses, requires substantial nursing care. There is a growing number of specialist nurses in the workforce, however, little is known how their role interfaces with other nurses.


Phenotype flexibility in wild fish: Dolly Varden regulate assimilative capacity to capitalize on annual pulsed subsidies.
1. Large digestive organs increase rates of energy gain when food is plentiful but are costly to maintain and increase rates of energy loss when food is scarce. The physiological adaptations to this trade-off differ depending on the scale and predictability of variation in food abundance. 2. Currently, there is little understanding of how animals balance trade-offs between the cost and capacity of the digestive system in response to resource pulses: rare, ephemeral periods of resource superabundance. We investigated the physiological and behavioural tactics of the fish Dolly Varden (Salvelinus malma) that rear in watersheds with low in situ productivity, but experience annual resource pulses from the spawning migrations of Pacific salmon. The eggs of Pacific salmon provide high-energy food for Dolly Varden. 3. Dolly Varden sampled 6 weeks prior to the resource pulse exhibited atrophy of the stomach, pyloric caeca, intestine and liver. Throughout the portion of the growing season prior to the resource pulse, fish exhibited empty stomachs, low indices of energy condition and muscle isotope signatures reflecting the previous resource pulse. 4. During the resource pulse, Dolly Varden exhibited large digestive machinery, gorged on salmon eggs and rapidly stored energy in fat reserves, somatic growth and gonad development. Dolly Varden appeared to achieve nearly their entire annual energy surplus during the ∼ 5-week period when sockeye salmon spawn. 5. Digestive flexibility provides Dolly Varden the energy efficiency required to survive and reproduce when resource abundance is concentrated into an annual pulse that is predictable, yet highly ephemeral. Although fish are known to incur extremely variable energy budgets, our study is one of the first to document digestive flexibility in wild fish. Our study emphasizes that fish can rely heavily on rare, high-magnitude foraging opportunities. Human actions that attenuate spikes in food abundance may have stronger than anticipated effects on consumer energy budgets.


Safety to drive after common limb fractures.
One hundred Orthopaedic Consultants in the UK were randomly selected and asked to complete a postal questionnaire indicating when they felt patients with treated, pain free, common limb fractures could return to driving. Seventy-two questionnaires were returned. Six were not completed leaving 66 completed questionnaires. Analysis revealed a clear mandate to allow or prevent driving in patients with certain treatment modalities and stages of union. In the lower limb there was majority agreement of suitability to drive in 61% of the 28 presented scenarios. Opinion was more divided for the upper limb, with only 43% of the scenarios having majority agreement. Our results show that while for some common limb fractures there is a clear body of opinion supporting safety to drive, for other common fractures opinion is less clear cut. This has important financial, medico-legal and legal implications that could be resolved by formal testing.


Targeted DNA sequencing for assessing clonality in multiple lung tumors: A new approach to an old dilemma.
The differential diagnosis between multiple primary lung cancer (MPLC) and advanced lung cancer has traditionally relied on conventional radiology and pathology. However, the outcomes of traditional diagnostic workup are often limited, and staging is uncertain. Increasing evidence suggests that next-generation sequencing (NGS) techniques offer the possibility of comparing multiple tumors on a genomic level. The objective of this study is to assess the clinical impact utility of targeted sequencing in patients presenting with multiple synchronous or metachronous lung tumors. We describe the diagnostic workup conducted in a patient with three lung tumors, where we used a targeted 50-gene DNA sequencing panel (Ion AmpliSeq TM Cancer Hotspot Panel v2) to assess clonality and establish an accurate lung adenocarcinoma stage. Positive results were confirmed by pyrosequencing or Sanger sequencing. Three surgically resected lung tumors were submitted for targeted sequencing. The tumor from the upper right lobe was positive for a TP53 c.659A > G mutation and native for KRAS. The tumor from the upper left lobe was positive for TP53 c.725G > T and KRAS c.35G > T mutations. The tumor from the lower left lobe was positive for TP53 c.1024C > T and KRAS C.34G > T mutations. Results and reviewed literature in the field support the diagnosis of MPLC instead of a single advanced lung cancer. Targeted DNA sequencing significantly increases diagnostic accuracy in patients with multiple lung tumors. NGS panels should be available for patients presenting with multiple lung tumors.


Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes.
The forkhead box M1 (FoxM1) transcription factor regulates expression of cell cycle genes essential for DNA replication and mitosis during organ repair and cancer progression. Here, we demonstrate that FoxM1-deficient (-/-) mouse embryonic fibroblasts and osteosarcoma U2OS cells depleted in FoxM1 levels by small interfering RNA transfection display increased DNA breaks, as evidenced by immunofluorescence focus staining for phosphospecific histone H2AX. FoxM1-deficient cells also exhibit stimulation of p53 transcriptional activity, as evidenced by increased expression of the p21(cip1) gene. FoxM1-deficient cells display reduced expression of the base excision repair factor X-ray cross-complementing group 1 (XRCC1) and breast cancer-associated gene 2 (BRCA2), the latter of which is involved in homologous recombination repair of DNA double-strand breaks. Furthermore, FoxM1 protein is phosphorylated by checkpoint kinase 2 (Chk2) in response to DNA damage. This phosphorylation of FoxM1 on serine residue 361 caused increased stability of the FoxM1 protein with corresponding increased transcription of XRCC1 and BRCA2 genes, both of which are required for repair of DNA damage. These results identify a novel role for FoxM1 in the transcriptional response during DNA damage/checkpoint signaling and show a novel mechanism by which Chk2 protein regulates expression of DNA repair enzymes.


Concentrations of betaxolol in ocular tissues of patients with glaucoma and normal monkeys after 1 month of topical ocular administration.
To measure the concentration of betaxolol in tissues of humans with glaucoma and normal monkeys after topical administration. Enucleated eyes (n = 7) of patients with glaucoma (age range, 27-79 years), without apparent anatomic disruption that would be likely to influence betaxolol absorption and intraocular distribution (exceptions: one pseudophakic, one aphakic) or other disease, were analyzed for betaxolol concentrations after self-administration of 0.25% betaxolol twice daily for 28 days or longer. The last instillation was made within 6 hours of surgery. Cynomolgus monkeys (n = 3) received 0.25% betaxolol twice daily unilaterally for 30 days. Betaxolol was measured by HPLC and tandem mass spectrometry (MS/MS) in plasma and ocular tissues. In humans, mean betaxolol concentrations (excluding the aphakic patient) were 71.4 +/- 41.8 ng/g in the retina, 31.2 +/- 14.8 ng/g in the optic nerve head, and 1290 +/- 1170 ng/g in the choroid. Mean concentrations in the iris and ciliary body were 73,200 +/- 89,600 and 4,250 +/- 3,020 ng/g, respectively. Betaxolol concentration was higher in all ocular tissues than in the plasma (0.59 +/- 0.32 ng/mL). In the monkeys the concentrations in the posterior tissues of the treated eyes were higher than in the untreated eyes, with mean differences in the retina and optic nerve head of 121 and 130 ng/g, respectively. Topically applied betaxolol was bioavailable to posterior ocular tissues, including the retina and optic nerve head, of patients with glaucoma and of normal cynomolgus monkeys. The higher betaxolol levels in the treated versus untreated monkey eyes are consistent with betaxolol's reaching posterior tissues by local absorption and distribution.


ES&T in the 21st Century: A Data-Driven Analysis of Research Topics, Interconnections, And Trends in the Past 20 Years.
Environmental Science & Technology (ES&T) has served a leadership role in reporting advanced and significant research findings for decades and accumulated tremendous amount of high-quality literature. In this study, we developed tailored text mining methods and analyzed 29 188 papers published in ES&T from 2000 to 2019, and we performed data-driven analyses to reveal some critical information and guidance on what has been published, what topical changes have evolved, and what are the areas that deserve additional attention. While top research keywords remained stable (water, sorption, soil, emiss, oxid, exposur), the trending up and emerging keywords showed clear shift over the years. Keywords related to nanobased materials (nanoparticl, nanomateri, carbon nanotub), climate and energy (climat, ch4, greenhouse gas emiss, mitig, energi), and health (exposur, health, ingest) demonstrated the strongest uptrend in the past 10 years, while plastics and PFAS were among clear emerging topics in the past 5 years. Co-occurrence analysis showed distinct associations between media (water, soil, air, sediment), chemicals (pcb, humic subst, particulate matt), processes (sorption, remov, degrad), and properties (kinet, mechan, speciat). Furthermore, a rule-based classification deciphered trends, distributions, and interconnections of articles based on either monodomains (air, soil, solid waste, water, and wastewater) or multidomains. It found water and wastewater cross-discipline articles tended to have higher citation values, while air domain tended to stand alone. Water and air monodomains consistently increased their shares in publications (together 56.3% in 2019), while shares of soil studies gradually declined. This study provides new data-driven methods on literature mining and offers unique insights on environmental research landscape and opportunities.


Preoperative parathyroid localization: prospective evaluation of technetium 99m sestamibi.
The utility of preoperative parathyroid localization remains controversial. The gold standard for identification of abnormal parathyroid glands is exploration of the neck by an experienced surgeon. However, both for the experienced and less experienced surgeon, it may be desirable to localize the abnormality before surgery. Such a study would not only direct the surgeon to the site of the lesion but also would help reduce unnecessary dissection, the number of negative explorations, and operative anesthesia time. Unfortunately, currently used noninvasive techniques including ultrasonography, thallium-technetium subtraction, computed tomography scan, and magnetic resonance imaging have had only limited success (35% to 78%) in demonstrating abnormal parathyroid glands. Thirty patients with proven hyperparathyroidism were enrolled to compare a new imaging agent, technetium 99m sestamibi, as an alternative to thallium 201 for subtraction scintigraphy with technetium 99m pertechnetate. Only 14 of 30 patients operated on at George Washington University underwent an identical surgical approach (exploration of all four glands) and had complete preoperative calcium and parathormone levels, postoperative calcium levels, and total time of surgical procedures to formulate the basis of this report. The remaining 16 had their surgeries at other institutions. A surgical approach different from that used at George Washington University and unavailability of postoperative calcium levels and times of surgical procedures from these institutions necessitated deletion of these 16 patients from this report. Technetium 99m sestamibi-technetium 99m subtraction scans accurately localized the abnormal parathyroid gland in 13 of 14 patients, as compared with only 9 of 14 thallium 201-technetium 99m pertechnetate subtraction scans. These results support technetium 99m sestamibi scanning as the superior modality for preoperative parathyroid localization.


Cancer after spinal fusion: the role of bone morphogenetic protein.
Bone morphogenetic protein (BMP) is used in tens of thousands of spinal fusions each year. A trial evaluating a high-dose BMP formulation demonstrated that its use may be associated with an increased risk of cancer. To evaluate whether BMP, as commonly used today, is associated with an increased risk of cancer or benign tumors. We performed a retrospective study using the Thomson Reuter MarketScan database. We retained all patients who had no previous diagnosis of cancer or benign tumor and had at least 2 years of uninterrupted enrollment in the database before and after their operations. A propensity score--matched cohort was created to ensure greater covariate balance between treatment groups. Within the propensity score--matched cohort (n = 4698), BMP-exposed patients had a nonsignificant increase in the rate of cancer diagnosis (9.37% vs 7.92%; P = .08). After adjustment for covariates, BMP exposure was associated with a 31% increased risk of benign tumor diagnosis (odds ratio, 1.31; 95% confidence interval, 1.02-1.68; P < .05). When the benign tumor diagnoses were stratified by organ type, BMP patients had significantly more diagnoses of benign nervous system tumors (0.81% vs 0.34%; P = .03), and within this group, benign tumors of the spinal meninges were much more common in the BMP-treated group (0.13% vs 0.02%; P = .002). The results of this large, independent, propensity-matched study suggest that the use of BMP in lumbar fusions is associated with a significantly higher rate of benign neoplasms but not malignancies.


Delineation of a cross-reactive idiotype on human autoantibodies with antibody against a synthetic peptide.
Antibody against a cross-reactive idiotype (CRI) on human IgM-rheumatoid factor (RF) antibodies was induced by immunization of rabbits with a synthetic peptide ( PSL2 ) corresponding to the second complementarity-determining region (CDR), and adjacent amino acid residues of the kappa light chain of the IgM-RF Sie . The anti-peptide antibody bound efficiently to IgM-RF proteins known to share a cross-reactive idiotype, and to their isolated kappa chains. The anti-CRI was absorbed by, and eluted from, a peptide-Sepharose affinity column. The antibody activity was inhibited by the free peptide in solution. The anti-peptide antibody thus identifies a public idiotype on human IgM-RF, that is largely dependent on the primary sequence of the second CDR of the light chain. Such peptide-induced antiidiotypes of predefined specificity may facilitate studies of the molecular basis of idiotypic cross-reactions, the inheritance and somatic diversification of antibody molecules, and the regulation of the idiotype network.


The intervals method: a new approach to analyse finite element outputs using multivariate statistics.
In this paper, we propose a new method, named the intervals' method, to analyse data from finite element models in a comparative multivariate framework. As a case study, several armadillo mandibles are analysed, showing that the proposed method is useful to distinguish and characterise biomechanical differences related to diet/ecomorphology. The intervals' method consists of generating a set of variables, each one defined by an interval of stress values. Each variable is expressed as a percentage of the area of the mandible occupied by those stress values. Afterwards these newly generated variables can be analysed using multivariate methods. Applying this novel method to the biological case study of whether armadillo mandibles differ according to dietary groups, we show that the intervals' method is a powerful tool to characterize biomechanical performance and how this relates to different diets. This allows us to positively discriminate between specialist and generalist species. We show that the proposed approach is a useful methodology not affected by the characteristics of the finite element mesh. Additionally, the positive discriminating results obtained when analysing a difficult case study suggest that the proposed method could be a very useful tool for comparative studies in finite element analysis using multivariate statistical approaches.


In vivo gene transfer into testis and sperm: developments and future application.
Despite significant advances in the treatment of infertility via assisted reproductive technology (ART), the underlying causes of idiopathic male infertility still remain unclear. Accumulating evidence suggests that disorders associated with testicular gene expression may play an important role in male infertility. To be able to fully study the molecular mechanisms underlying spermatogenesis and fertilization, it is necessary to manipulate gene expression in male germ cells. Since there is still no reliable method of recapitulating spermatogenesis culture, the development of alternative transgenic approaches is paramount in the study of gene function in testis and sperm. Established methods of creating transgenic animals rely heavily upon injection of DNA into the pronucleus or the injection of transfected embryonic stem cells into blastocysts to form chimeras. Despite the success of these two approaches for making transgenic and knockout animals, concerns remain over costs and the efficiency of transgene integration. Consequently, efforts are in hand to evaluate alternative methodologies. At present, there is much interest in developing approaches that utilize spermatozoa as vectors for gene transfer. These approaches, including testis mediated gene transfer (TMGT) and sperm mediated gene transfer (SMGT), have great potential as tools for infertility research and in the creation of transgenic animals. The aim of this short review is to briefly describe developments in this field and discuss how these gene transfer methods might be used effectively in future research and clinical arenas.


Inhibition of steroid sulphatase activity by steroidal methylthiophosphonates: potential therapeutic agents in breast cancer.
The hydrolysis of steroid sulphates, by steroid sulphatase, is an important source of oestrogenic steroids (oestrone, oestradiol and 5-androstene-3 beta,17 beta-diol) which are found in tumours. In the present study, we have examined the effect of dehydroepiandrosterone-3-O-methylthiophosphonate (DHA-3-MTP), pregnenolone-3-O-methylthiophosphonate (pregnenolone-3-MTP) and cholesterol-3-O-methylthiophosphonate (cholesterol-3-MTP) on the inhibition of oestrone sulphatase as well as DHA sulphatase activities in intact MCF-7 breast cancer cells and in placental microsomes. All three methylthiophosphonates significantly (P < 0.01) inhibited the hydrolysis of oestrone sulphate (E1 S) in intact MCF-7 cells (31-85% inhibition at 1 microM and 53-97% inhibition at 10 microM). Significant inhibition of DHA sulphatase was also achieved. At a concentration of 50 microM, all three compounds inhibited the hydrolysis of dehydroepiandrosterone sulphate (DHAS) by > 95%. Using human placental microsomes, the Km and Vmax of E1S were determined to be 8.1 microM and 43 nmol/h/mg protein. The corresponding Ki values for DHA-3-MTP, pregnenolone-3-MTP and cholesterol-3-MTP were found to be 4.5, 1.4 and 6.2 microM, respectively. Such inhibitors which are resistant to metabolism may have considerable potential as therapeutic agents and may have additional advantage over aromatase inhibitors in also reducing tumour concentrations of the oestrogenic steroid, 5-androstene-3 beta,17 beta-diol, by inhibiting the hydrolysis of DHAS.


Religious struggle and religious comfort in response to illness: health outcomes among stem cell transplant patients.
Growing interest has focused on relationships between health and religious coping among cancer patients. However, little is known about the health correlates of negative or conflicted religious responses. The current study examined general religiousness and two modes of cancer-specific religious coping, drawing closer to faith (positive) and struggling with faith (negative), among 213 multiple myeloma patients evaluated at the same point in treatment, during their initial work-up for autologous stem cell transplantation. The outcomes assessed included standardized measures and clinician ratings of depression, general distress, physical functioning, mental health functioning, pain, and fatigue. Results indicated that, after adjusting for relevant control variables, negative religious coping was associated with significantly poorer functioning on all outcomes but one: depression, distress, mental health, pain, and fatigue. Neither general religiousness nor positive religious coping was significantly related to any of the outcomes measured. Results highlight the role of negative or ambivalent religious responses to illness.


Double-Poling Biomechanics of Elite Cross-country Skiers: Flat versus Uphill Terrain.
In light of the recent revolutionary change in the use of the double-poling (DP) technique in cross-country skiing, our purpose was to compare the associated kinetics and kinematics on flat (DPflat) and uphill terrain (DPup), as well as to identify factors that determine performance. Thirteen elite male cross-country skiers completed two incremental speed tests (Vpeak) involving roller skiing with the DP technique at moderate (13 and 24 km·h) and high speed (15 and 28.5 km·h) on a treadmill that was flat (1°) or tilted uphill (7°). Pole forces and three-dimensional whole-body kinematics were monitored simultaneously. In comparison to DPflat, during DPup, swing times were much shorter (-48%) and peak pole forces greater (+13%) and generated later during the poling phase (+68%), with higher impulses for all force components (+87%-123%). Furthermore, pole forces were 18% more effectively oriented for propulsion. During DPup, the skiers demonstrated more flexed elbows, as well as shoulder angles that were less flexed in the forward direction and less abducted throughout the poling phase, together with more highly flexed knee and ankle joints, a more upright thorax, less flexed hips, and a shortened backward swing after pole off. With DPup, the skiers raised their center of mass 25% more, attaining maximal heel raise and maximal vertical position at a timepoint closer to pole plant compared with flat. On the uphill incline, the magnitude of Vpeak was positively related to body mass, relative pole length (% body height), and magnitude of heel raise. The present findings provide novel insights into the coordination, kinetics and kinematics of elite skiers while DP on flat and uphill terrain.


Droplet Breakup Dynamics in Bi-Layer Bifurcating Microchannel.
Breakup of droplets at bi-layer bifurcating junction in polydimethylsiloxane (PDMS) microchannel has been investigated by experiments and numerical simulation. The pressure drop in bi-layer bifurcating channel was investigated and compared with single-layer bifurcating channel. Daughter droplet size variation generated in bi-layer bifurcating microchannel was analyzed. The correlation was proposed to predict the transition between breakup and non-breakup conditions of droplets in bi-layer bifurcating channel using a phase diagram. In the non-breakup regime, droplets exiting port can be switched via tuning flow resistance by controlling radius of curvature, and or channel height ratio. Compared with single-layer bifurcating junction, 3-D cutting in diagonal direction from bi-layer bifurcating junction induces asymmetric fission to form daughter droplets with distinct sizes while each size has good monodispersity. Lower pressure drop is required in the new microsystem. The understanding of the droplet fission in the novel microstructure will enable more versatile control over the emulsion formation, fission and sorting. The model system can be developed to investigate the encapsulation and release kinetics of emulsion templated particles such as drug encapsulated microcapsules as they flow through complex porous media structures, such as blood capillaries or the porous tissue structures, which feature with bifurcating junctions.


Crystal structure of bacterial cytotoxic necrotizing factor CNFY reveals molecular building blocks for intoxication.
Cytotoxic necrotizing factors (CNFs) are bacterial single-chain exotoxins that modulate cytokinetic/oncogenic and inflammatory processes through activation of host cell Rho GTPases. To achieve this, they are secreted, bind surface receptors to induce endocytosis and translocate a catalytic unit into the cytosol to intoxicate host cells. A three-dimensional structure that provides insight into the underlying mechanisms is still lacking. Here, we determined the crystal structure of full-length Yersinia pseudotuberculosis CNFY . CNFY consists of five domains (D1-D5), and by integrating structural and functional data, we demonstrate that D1-3 act as export and translocation module for the catalytic unit (D4-5) and for a fused β-lactamase reporter protein. We further found that D4, which possesses structural similarity to ADP-ribosyl transferases, but had no equivalent catalytic activity, changed its position to interact extensively with D5 in the crystal structure of the free D4-5 fragment. This liberates D5 from a semi-blocked conformation in full-length CNFY , leading to higher deamidation activity. Finally, we identify CNF translocation modules in several uncharacterized fusion proteins, which suggests their usability as a broad-specificity protein delivery tool.


Maternal Fructose Consumption Disrupts Brain Development of Offspring in a Murine Model of Autism Spectrum Disorder.
Objective The objective of this study was to localize by neuroimaging the altered structural brain development of these offspring using an autism model of transgenic mice lacking contactin-associated protein-like 2 (Cntnap2). Materials and Methods Pregnant dams were randomly allocated to fructose solution (10% W/V) as only drinking fluid or water. Cntnap2 heterozygous (+/-) offspring from each group were euthanized at 6 months of age and their whole brains evaluated by magnetic resonance imaging. T2-weighted images were acquired to evaluate the volumes of 29 regions of interest involved in autism spectrum disorder (ASD) pathogenesis. Whole brains were washed and processed for Nissl staining. Mann-Whitney U test and one-way analysis of variance were used for statistical analysis (significance: p < 0.05). Results The corpus callosum, anterior commissure, and caudate putamen were significantly smaller in Cntnap2 (+/-) male offspring exposed to fructose. No brain alterations were found in the female counterparts. Nissl staining of the caudate putamen revealed higher neuronal cell count in the male fructose offspring. Female group revealed an increase in caudate putamen neuronal cell count. Conclusion Metabolic dysregulation in pregnancy alters fetal brain development in genetically predisposed offspring. This is consistent with findings in human studies and supports the role of intrauterine factors in the etiology of autism.


Expression of HLA system antigens on placenta.
The levels of HLA-A and -B antigens expressed by placenta have been assessed relative to parental and other A and B antigen types that were not shared by the foetus. A purified preparation of placenta plasma membrane was used to estimate the antigen activities. The results indicate that maternally and paternally inherited A and B antigen activities and beta2-microglobulin are expressed to similar extents but at much lower levels than in spleen lymphocytes (less than 5%). The possibility that the amounts detected were caused by contamination with blood or maternal tissue was ruled out. The low levels of A and B antigens may account for the lack of a cellular immune response to the other polymorphic cell surface antigens of the trophoblast. No evidence was obtained for the expression of a significant level of Ia antigens.


Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder.
Declarative memory impairments are common in patients with bipolar illness, suggesting underlying hippocampal pathology. However, hippocampal volume deficits are rarely observed in bipolar disorder. Here we used surface-based anatomic mapping to examine hippocampal anatomy in bipolar patients treated with lithium relative to matched control subjects and unmedicated patients with bipolar disorder. High-resolution brain magnetic resonance images were acquired from 33 patients with bipolar disorder (21 treated with lithium and 12 unmedicated), and 62 demographically matched healthy control subjects. Three-dimensional parametric mesh models were created from manual tracings of the hippocampal formation. Total hippocampal volume was significantly larger in lithium-treated bipolar patients compared with healthy controls (by 10.3%; p=0.001) and unmedicated bipolar patients (by 13.9%; p=0.003). Statistical mapping results, confirmed by permutation testing, revealed localized deficits in the right hippocampus, in regions corresponding primarily to cornu ammonis 1 subfields, in unmedicated bipolar patients, as compared to both normal controls (p=0.01), and in lithium-treated bipolar patients (p=0.03). These findings demonstrate the sensitivity of these anatomic mapping methods for detecting subtle alterations in hippocampal structure in bipolar disorder. The observed reduction in subregions of the hippocampus in unmedicated bipolar patients suggests a possible neural correlate for memory deficits frequently reported in this illness. Moreover, increased hippocampal volume in lithium-treated bipolar patients may reflect postulated neurotrophic effects of this agent, a possibility warranting further study in longitudinal investigations.


Undersized mitral annuloplasty alters left ventricular shape during acute ischemic mitral regurgitation.
Underlying left ventricular (LV) dysfunction contributes to poor survival after operation to correct ischemic mitral regurgitation (IMR). Many surgeons do not appreciate that a key component of the Bolling undersized mitral ring annuloplasty concept is to decrease LV wall stress by altering LV shape, but precise 3-dimensional (3-D) geometric data do not exist substantiating this effect. We tested the hypothesis that annular reduction decreases regional circumferential LV radius of curvature (ROC) in a model of acute IMR. Eight adult sheep underwent insertion of an adjustable Paneth-type annuloplasty suture and radiopaque markers on the LV and mitral annulus. The animals were studied with biplane videofluoroscopy during baseline conditions, then before and after tightening the annuloplasty suture during proximal left circumflex occlusion. End-systolic circumferential regional LV ROC and mitral annular area were computed. Acute IMR was eliminated (MR grade 2.1+/-0.4 to 0.4+/-0.4, mean+/-SD, P<0.05) by tightening the Paneth annuloplasty suture. Paneth suture tightening during circumflex occlusion also decreased end-systolic regional circumferential radii of curvature at the basal (anterior, 3.40+/-0.16 to 3.34+/-0.14 cm; posterior, 3.31+/-0.23 to 3.24+/-0.26 cm; P<0.05) and equatorial levels (anterior, 2.99+/-0.21 to 2.89+/-0.29 cm; posterior, 2.86+/-0.38 to 2.81+/-0.41 cm; P<0.05). Acute proximal circumflex occlusion caused IMR and increased end-systolic LV radii of curvature in this experimental preparation. Annular reduction sufficient to abolish IMR also decreased end-systolic anterior and posterior LV ROC, which would be expected to reduce LV wall stress and oxygen consumption in these regions, both potentially beneficial effects. The long-term effects of undersized annuloplasty on LV remodeling and function, however, will require further study in chronic animal preparations or patients with chronic IMR.


Reduced fertility among overweight and obese men.
Overweight and obese men have been reported to have lower sperm counts and hormonal changes, but data are lacking regarding effects on couple fertility. We examined the relationship between male body mass index (BMI) and infertility in couples enrolled in the Agricultural Health Study in the United States. The analysis sample was limited to couples (wife <40 years old) with an attempt at pregnancy in the last 4 years based on pregnancy and fertility data provided by wives. Infertility was defined as not conceiving a pregnancy after at least 12 months of unprotected intercourse regardless of whether or not a pregnancy ultimately occurred. Self-reported weight and height were used to calculate BMI (kg/m). Adjusted odds ratios (aORs) for infertility associated with increases in male BMI were calculated with logistic regression. Adjusting for potential confounders, a 3-unit increase in male BMI was associated with infertility (aOR = 1.12; 95% confidence interval = 1.01-1.25; n = 1329). There was a dose-response relationship, and the BMI effect was stronger when the data were limited to couples with the highest-quality infertility data. The association between BMI and infertility was similar for older and younger men, suggesting that erectile dysfunction in older men does not explain the association. This report of lower fertility in overweight and obese men needs replication. If the findings are robust, programs to prevent obesity may improve men's reproductive health and save medical costs for infertility treatment.