An analytical method for the analysis of tulathromycin, an equilibrating triamilide, in bovine and porcine plasma and lung.
Tulathromycin is a novel member of the triamilide class of antibiotics that was developed as a safe and effective single-dose treatment of bovine and porcine respiratory disease. An accurate and precise analytical method was developed for the extraction and measurement of tulathromycin in livestock plasma and lung homogenates. Analytes were solid-phase extracted onto a weak cation exchanger after aqueous dilution of samples and addition of heptadeutero-tulathromycin as an internal standard. Following HPLC with a narrow bore C8 column, quantitative detection of tulathromycin was accomplished by monitoring the transition of a doubly charged precursor ion to a singly charged product ion by tandem mass spectrometry using a triple quadrupole mass spectrometer. Procedures were validated for a dynamic range of 0.1 to 25 ng on column. Observed accuracies were between 90 and 110% of nominal and precision (RSD) varying 7% or less. Response and stability experiments showed that deuterated tulathromycin did not parallel the chemical behavior of tulathromycin. Applicability of the method to livestock studies was tested with plasma and lung samples from cattle and swine dosed with tulathromycin at multiple doses. The results demonstrated that the analytical method performed well in a range of sample concentrations spanning over 3 orders of magnitude and provided dose-exposure relationships for cattle and swine.


A novel postsynaptic density protein: the monocarboxylate transporter MCT2 is co-localized with delta-glutamate receptors in postsynaptic densities of parallel fiber-Purkinje cell synapses.
Confocal immunofluorescence microscopy showed strong monocarboxylate transporter 2 (MCT2) labeling of Purkinje cell bodies and punctate labeling in the molecular layer. By immunogold cytochemistry, it could be demonstrated that the MCT2 immunosignal was concentrated at postsynaptic densities of parallel fiber-Purkinje cell synapses. The distribution of MCT2 transporters within the individual postsynaptic densities mimicked that of the delta2 glutamate receptor, as shown by use of two different gold-particle sizes. The MCT2 distribution was also compared with the distributions of other monocarboxylate transporters (MCT1 and MCT4). The MCT1 immunolabeling was localized in the endothelial cells, while MCT4 immunogold particles were associated with glial profiles, including those abutting the synaptic cleft of the parallel fiber-spine synapses. The postsynaptic density (PSD) molecules identified so far can be divided into five classes: receptors, their anchoring molecules, molecules involved in signal transduction, ion channels, and attachment proteins. Here, we provide evidence that this list of molecules must now be extended to comprise an organic molecule transporter: the monocarboxylate transporter MCT2. The present data suggest that MCT2 has specific transport functions related to the synaptic cleft and that this transporter may allow an influx of lactate derived from perisynaptic glial processes. The expression of MCT2 in synaptic membranes may allow energy supply to be tuned to the excitatory drive.


Independent effects of blood pressure and parathyroid hormone on aortic pulse wave velocity in untreated Chinese patients.
Whether or not calcium-regulating hormones stiffen arteries independent of blood pressure (BP) is uncertain. We investigated the independent associations of carotid-femoral pulse wave velocity (PWV) with 25-hydroxy-vitamin D [25(OH)D], parathyroid hormone (PTH) and 24-h ambulatory BP in untreated Chinese patients. Consecutive untreated patients referred for ambulatory BP monitoring were recruited. PWV was measured with a high-fidelity micromanometer and the SphygmoCor software (AtCor Medical, West Ryde, New South Wales, Australia). Serum 25(OH)D and PTH were determined by electrochemiluminescence immunoassay. Analysis of variance, single and multiple regressions were applied for analyses. In 1052 untreated patients (50.7% women; mean age, 51 years), PWV averaged 7.8 m/s, 24-h SBP/DBP 126.5/81.7 mmHg, serum 25(OH)D and PTH 36.0 nmol/l and 61.6 pg/ml, respectively. In multivariable-adjusted analyses, BP (P < 0.001) and PTH (P = 0.012) increased from less than 25th to at least 75th percentile of the PWV distribution. In continuous analyses, PWV independently increased by 0.40/0.23 m/s per 1-SD increment in SBP/DBP (P < 0.001) and by 0.14 m/s for a doubling of serum PTH (P = 0.029). Associations of PWV with BP were tighter than with PTH (P < 0.001). In pathway analysis, the effect of PTH on PWV did not run via serum or urinary calcium (P = 0.65), but PTH had both a direct (P = 0.026) and a BP-mediated indirect effect (P = 0.043) on PWV. In none of our analyses were PWV associated with serum 25(OH)D. Arterial stiffness, as assessed by PWV, independently increased both with BP and with PTH, but BP remains the main driver of arterial stiffening.


Rise time and formant transition duration in the discrimination of speech sounds: the Ba-Wa distinction in developmental dyslexia.
Across languages, children with developmental dyslexia have a specific difficulty with the neural representation of the sound structure (phonological structure) of speech. One likely cause of their difficulties with phonology is a perceptual difficulty in auditory temporal processing (Tallal, 1980). Tallal (1980) proposed that basic auditory processing of brief, rapidly successive acoustic changes is compromised in dyslexia, thereby affecting phonetic discrimination (e.g. discriminating /b/ from /d/) via impaired discrimination of formant transitions (rapid acoustic changes in frequency and intensity). However, an alternative auditory temporal hypothesis is that the basic auditory processing of the slower amplitude modulation cues in speech is compromised (Goswami et al., 2002). Here, we contrast children's perception of a synthetic speech contrast (ba/wa) when it is based on the speed of the rate of change of frequency information (formant transition duration) versus the speed of the rate of change of amplitude modulation (rise time). We show that children with dyslexia have excellent phonetic discrimination based on formant transition duration, but poor phonetic discrimination based on envelope cues. The results explain why phonetic discrimination may be allophonic in developmental dyslexia (Serniclaes et al., 2004), and suggest new avenues for the remediation of developmental dyslexia.


Improved nondegenerate multiphoton microscopy and axial registration with a reflective objective.
Conventional, degenerate multiphoton microscopy (D-MPM) requires the use of a high-numerical-aperture (NA) objective. Nondegenerate MPM (ND-MPM) imposes the additional demand for precise spatiotemporal overlap of two distinct excitation sources. We demonstrate that the axial focal shift introduced by refractive objective chromatic aberration hinders the spatial requirement of ND-MPM, whereas the use of a reflective objective overcomes this challenge and allows for improved ND excitation efficiency in spite of a lower NA. Moreover, we demonstrate that reflective objective focusing eliminates the axial misregistration of volumetric stacks in traditional D-MPM experiments when multiple excitation wavelengths are used.


Calcium-mediated cyclic AMP inhibition of Na-H exchange in small intestine.
8-Bromo cyclic AMP (cAMP) (10(-4) M) inhibits Na absorption in isolated chicken enterocytes as has been reported previously. Direct measurements of intracellular pH (pHi) using 5,6-carboxyfluorescein diacetate showed that both 8-bromo cAMP and the diuretic amiloride (10(-3) M) stimulated a persistent decrease in pHi of approximately 0.1 pH units, effects that were Na dependent and were not additive when cells were stimulated with both agents. These results suggest inhibition of an amiloride-sensitive Na/H exchange by cAMP. Direct measurements of intracellular Ca [Ca]i were also made using quin 2. 8-Bromo cAMP (10(-4) M) stimulated an immediate and persistent (greater than 10 min) increase in [Ca]i of approximately 20 nM, an effect that was not dependent on extracellular Ca. Pretreatment of cells with the specific calmodulin inhibitor calmidazolium (10(-7) M) and the intracellular Ca-buffering agent MAPTAM blocked cAMP's effects on pH and Na uptake, but did not interfere with amiloride's effects. An increase in [Ca]i stimulated by the Ca ionophore A23187 (10(-6) M) was sufficient by itself to decrease pHi and inhibit amiloride-sensitive Na influx in isolated enterocytes. We conclude that cAMP stimulates the release of endogenous Ca in isolated enterocytes. This increase in [Ca]i appears to be essential for inhibition of amiloride-sensitive Na-H exchange by this cyclic nucleotide.


Gold induced encephalopathy: case report.
We describe a case with neurologic disease manifested as encephalopathy, generalized muscle fasciculations, and peripheral neuropathy occurring in a patient treated with therapeutic doses of gold for presumed rheumatoid arthritis. The illness remitted promptly during chelation therapy with dimercaprol (BAL). A review of the limited experience in the literature with the central nervous system toxicity of gold is given.


[Advances and challenges of nursing in the scientific production on Psoriasis].
The Psoriasis, chronic disease with uncertain cause, affects 1 to 3% of world population, produces great psychological impact and changes in quality of life, a challenging reality. The objective is to analyze the scientific production of nursing on Psoriasis in 1997/2008, examining the approaches and contributions to care. Bibliographic study based on virtual database Medline using the terms "Psoriasis" and "Nursing". Of the 21 articles selected, 19% focus on the pathophysiology and differential diagnosis, 48% treatment, 28% psychological aspects and 42% in nursing care. The rescue of the scientific knowledge increases the challenge of maximizing the scientific production about this subject, bringing significant contributions to advances to a more holistic intervention and higher quality with this clientele.


The effects of lithium on muscle contractile function in humans.
A side effect of lithium (Li+) treatment is fatigue. Li+ decreases inositol triphosphate (IP3) accumulation and IP3 may play a role in excitation-contraction (E-C) coupling in skeletal muscle. Li+ carbonate (600 mg b.i.d. x 6 days) was administered in a randomized, double-blind fashion to 12 males to measure the effect upon muscle contractile function: peak twitch torque (PTT), time to PTT, half-relaxation time, maximal voluntary contraction strength (MVC), percent motor unit activation, M-wave characteristics, and tetanic torque (3 min at 15 and 50 Hz). Li+ resulted in a significant decrease in 15- and 50Hz tetanic torque (P<0.00l), MVC, and resting PTT (P<0.05). There were no effects of Li+ upon any of the other measured variables. Li+ had a negative effect upon E-C coupling and did not affect central motor unit recruitment. Elucidation of the role of IP3 in E-C coupling may help to understand fatigue in some neuromuscular disorders.


Positron emission tomographic studies of aging and Alzheimer disease.
In this study the positron emission tomographic (PET)-18F-2-deoxy-2-fluoro-D-glucose (FDG) technique was used to study both normal aging and senile dementia. The results derived from 15 young normal subjects (mean age, 26 +/- 5 years) and 22 elderly normal subjects (mean age, 66 +/- 7 years) failed to indicate significant metabolic changes associated with age. A group of 24 patients with senile dementia (mean age, 73 +/- 7 years) showed consistent diminutions in regional glucose use relative to the elderly normals. Across all brain regions the diminutions were 17%-24%. There were also significant correlations between the measures of glucose use and the measures of cognitive functioning. Discriminant function classification analysis results indicate that better than 80% classification accuracy can be achieved for individual PET measures. These data suggest a possible future diagnostic use of PET in senile dementia.


Fulminant encephalopathy with basal ganglia hyperintensities in HIV-infected drug users.
To define a clinical syndrome associated with active drug abuse in HIV-infected individuals. We performed a retrospective review to identify individuals treated at the Johns Hopkins Hospital from 1993 to 2008 who were HIV-infected and were actively abusing drugs and had bilateral basal ganglia lesions on MRI. They were identified using a key word search in the radiology database, autopsy database, and the Moore HIV clinic database. Clinical, laboratory, and radiographic findings were correlated to define the syndrome. Ten individuals were identified who presented with a change in mental status or seizures, used cocaine or cocaine with heroin, had uncontrolled HIV infection (>190,000 copies/mL of plasma), elevated CSF protein (63-313 mg/dL), and diffuse hyperintense bilateral basal ganglia lesions on imaging. The majority of patients (8/10) had renal failure and despite supportive therapy most (7/9) ultimately died (median survival 21 days). Postmortem examination in one individual showed the presence of overwhelming microglial activation in the basal ganglia. The 2 surviving individuals were started on combined antiretroviral therapy (CART) during hospitalization. We describe a unique clinical syndrome of a fulminant encephalopathy associated with primarily basal ganglia involvement in HIV-infected drug abusers. This syndrome is a rare but serious condition that is associated with a high mortality rate. Early CART institution may be useful and neuroprotective in this disorder, although this requires further investigation.


Essential-oil variability of Juniperus deltoides R.P.Adams along the east Adriatic coast - how many chemotypes are there?
The composition of the essential oils isolated from twigs of ten Juniperus deltoides R.P. Adams populations from the east Adriatic coast was determined by GC-FID and GC/MS analyses. Altogether, 169 compounds were identified, representing 95.6-98.4% of the total oil composition. The oils were dominated by monoterpenes (average content of 61.6%), which are characteristic oil components of species of the Juniperus section. Two monoterpenes, α-pinene and limonene, were the dominant constituents, comprising on average 46.78% of the essential oils. Statistical methods were deployed to determine the diversity of the terpene classes and the common terpenes between the investigated populations. These statistical analyses revealed the existence of three chemotypes within all populations, i.e., a α-pinene, limonene, and limonene/α-pinene type.


Single-dose pharmacokinetics of imipenem-cilastatin in neonates.
The single-dose pharmacokinetics of imipenem (N-formimidoyl thienamycin), a beta-lactam antibiotic, used in combination with cilastatin, a renal dehydropeptidase I inhibitor, were evaluated in 10 neonates 1 to 8 days of age. The imipenem-cilastatin combination was given intravenously over a 15-min period at a dose of 15 or 25 mg/kg. Drug concentrations in serum, urine, and cerebrospinal fluid (when available) were determined by high-pressure liquid chromatography, and plasma disposition of the drugs was described by a two-compartment open model. The mean peak plasma levels of imipenem 30 min postinfusion were 55.4 and 27.2 micrograms/ml, and the mean t1/2 beta values were 2.1 and 1.8 h at doses of 25 and 15 mg/kg, respectively. The calculated volume of distribution was 0.41 liters/kg. In two patients from whom cerebrospinal fluid was obtained 1.5 h postinfusion, imipenem levels were 5.6 and 1.1 micrograms/ml at doses of 25 and 15 mg/kg, respectively, representing 10 and 4% of the 1-h serum levels. No side effects attributable to a single dose of imipenem-cilastatin were noted.


A Novel Nomogram for Early Identification and Intervention in Colorectal Cancer Patients at Risk for Malnutrition.
Malnutrition is under-recognized in cancer patients and can lead to poor treatment outcomes. We aim to develop an outpatient-focused score based on the Malnutrition Screening Tool (MST) to help identify colorectal cancer (CRC) profiles at high risk for malnutrition. 506 CRC patients during initial outpatient oncology consultation at our tertiary referral outpatient oncology clinic completed the MST. Objective and subjective data were collected through chart review. Data gathered are as follows: demographics, anthropometrics, laboratory values, patient-reported symptoms, MST score, cancer history, performance status, socioeconomic status, and Charlson Comorbidity. Predictors of malnutrition were identified by logistic regression. Receiver operating curve (ROC), area under the curve (AUC), and our model's predictability were determined. Significant predictors of malnutrition are as follows: younger age (20-39 vs >40 years) (P = .007), normal-to-low body mass index at presentation (P = .019), Eastern Cooperative Oncology Group classification 2-3 (P = .012), metastatic disease (P = .046), albumin <3.0 g/dL (P = .033), fatigue (P < .001), and change in stool/bowel habits (P = .002). In our derived malnutrition score, risk of malnutrition increased from 11% for score 0, to 100% for scores 9-10. Receiver operating curve showed AUC .745 (95% CI, .697-.793). An outpatient clinic-derived malnutrition score obtained from objective and patient-reported variables may facilitate identification of CRC patients at highest risk for malnutrition. Rapid identification and intervention in high-risk patients may improve treatment recovery, therapy tolerance, and quality of life. Our tool requires external validation before application in clinical practice.


Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 delta32.
Individuals who are homozygous for the 32-bp deletion in the gene coding for the chemokine receptor and major human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 (CCR5 -/-) lack functional cell surface CCR5 molecules and are relatively resistant to HIV-1 infection. HIV-1 infection in CCR5 -/- individuals, although rare, has been increasingly documented. We now report that the viral quasispecies from one such individual throughout disease is homogenous, T cell line tropic, and phenotypically syncytium inducing (SI); exclusively uses CXCR4; and replicates well in CCR5 -/- primary T cells. The recently discovered coreceptors BOB and Bonzo are not used. Although early and persistent SI variants have been described in longitudinal studies, this is the first demonstration of exclusive and persistent CXCR4 usage. With the caveat that the earliest viruses available from this subject were from approximately 4 years following primary infection, these data suggest that HIV-1 infection can be mediated and persistently maintained by viruses which exclusively utilize CXCR4. The lack of evolution toward the available minor coreceptors in this subject underscores the dominant biological roles of the major coreceptors CCR5 and CXCR4. This and two similar subjects (R. Biti, R. Ffrench, J. Young, B. Bennetts, G. Stewart, and T. Liang, Nat. Med. 3:252-253, 1997; I. Theodoreu, L. Meyer, M. Magierowska, C. Katlama, and C. Rouzioux, Lancet 349:1219-1220, 1997) showed relatively rapid CD4+ T-cell declines despite average or low initial viral RNA load. Since viruses which use CXCR4 exclusively cannot infect macrophages, these data have implications for the relative infection of the T-cell compartment versus the macrophage compartment in vivo and for the development of CCR5-based therapeutics.


The anxious wait: assessing the impact of patient accessible EHRs for breast cancer patients.
Personal health records (PHRs) provide patients with access to personal health information (PHI) and targeted education. The use of PHRs has the potential to improve a wide range of outcomes, including empowering patients to be more active participants in their care. There are a number of widespread barriers to adoption, including privacy and security considerations. In addition, there are clinical concerns that patients could become anxious or distressed when accessing complex medical information. This study assesses the implementation of a PHR, and its impact on anxiety levels and perceptions of self-efficacy in a sample of breast cancer patients. A quasi-experimental pre-test/post-test design was used to collect data from participants to evaluate the use of the PHR. Study participants completed background and pre-assessment questionnaires and were then registered into the portal. By entering an activation key, participants were then able to review their lab results and diagnostic imaging reports. After six weeks, participants completed post-assessment questionnaires and usability heuristics. All data were collected using an online survey tool. Data were cleaned and analyzed using SAS v9.1. A total of 311 breast cancer patients completed demographic and pre-assessment questionnaires, 250 registered to use the online intervention, and 125 participants completed all required study elements. Matching the pre- and post-anxiety scores demonstrated a decrease in mean anxiety scores (-2.2, p = 0.03); the chemotherapy sub-group had a statistically insignificant mean increase (1.8, p = .14). There was no mean change in self-efficacy scores. Participants generally found the portal easy to use; however, the perceived value of improved participation was not detected in the self-efficacy scores. Having access to personal health information did not increase anxiety levels. While these results suggest that the use of this PHR may be of benefit for informing patients, further research is required to investigate the impact on the patients experiences, their participation in their care, their relationships with the health care team, and their health outcomes.


Study of circulating IgG antibodies to peptide antigens derived from BIRC5 and MYC in cervical cancer.
The present study was undertaken to detect circulating IgG antibodies to peptide antigens derived from baculoviral IAP repeat-containing protein 5 isoform 2 (BIRC5) and myc proto-oncogene protein (MYC) in cervical cancer. A total of 107 female patients with cervical cancer of stages I and II, and 130 healthy female subjects were recruited for analysis of circulating IgG antibodies to BIRC5 and MYC. Student's t-test showed significant differences in circulating levels of anti-BIRC5 IgG (t = -4.27, df = 235, P < 0.0001) and anti-MYC IgG (t = 3.51, df = 232, P = 0.0005) between the patient group and the control group. Receiver operating characteristic (ROC) analysis showed an area under the ROC curve (AUC) of 0.67 with sensitivity of 23.4% against specificity of 90% for the anti-BIRC5 IgG assay and an AUC of 0.66 with sensitivity of 9.4% against specificity of 90.6% for the anti-MYC IgG assay. Analysis of quality control samples gave an inter-assay deviation of 8.9% in the anti-BIRC5 IgG assay and 9.0% in the anti-MYC IgG assay. This work suggests that anti-BIRC5 IgG could serve as a biomarker for early diagnosis of cervical cancer although a panel of such tumor-associated antigens is needed to develop a highly sensitive test.


Genomic imprinting and allelic exclusion.
In diploid cells, allelic exclusion reduces genes to functional haploidy, because only one of two alleles is active. It is best known in cells producing immunoglobulins, but other examples also exist. X-chromosome inactivation in female mammals is related to allelic exclusion, but in this case the dosage compensation mechanism extends to the whole chromosome. Functional hemizygosity in some mammalian cell lines is probably also due to allelic exclusion, where one autosomal allele is active and the other is methylated and inactive. In early development, it may be important to have only one functional copy of specific regulatory genes. If one considers the possible mechanisms whereby genes are switched from an active to an inactive form, or vice versa, complications arise if the same type of switch operates in two homologous chromosomes segregating independently at mitosis. This complication is avoided if one of the genes is totally inactive. It is therefore suggested that important regulatory gene are subject to allelic exclusion and that this provides a basis for genomic imprinting. Male or female gametes complement in the zygote, because they may have different inactive genes, and the active allele in each case is then functionally haploid in the zygote and developing embryo. These haploid genes would be those involved in critical switches of gene activity during the developmental process. Allelic exclusion imposed by imprinting might be based on the heritable DNA methylation of the regulatory regions of silent genes.


Continuous glucose monitoring: A review of the technology and clinical use.
Continuous glucose monitoring (CGM) is an increasingly adopted technology for insulin-requiring patients that provides insights into glycemic fluctuations. CGM can assist patients in managing their diabetes with lifestyle and medication adjustments. This article provides an overview of the technical and clinical features of CGM based on a review of articles in PubMed on CGM from 1999 through January 31, 2017. A detailed description is presented of three professional (retrospective), three personal (real-time) continuous glucose monitors, and three sensor integrated pumps (consisting of a sensor and pump that communicate with each other to determine an optimal insulin dose and adjust the delivery of insulin) that are currently available in United States. We have reviewed outpatient CGM outcomes, focusing on hemoglobin A1c (A1C), hypoglycemia, and quality of life. Issues affecting accuracy, detection of glycemic variability, strategies for optimal use, as well as cybersecurity and future directions for sensor design and use are discussed. In conclusion, CGM is an important tool for monitoring diabetes that has been shown to improve outcomes in patients with type 1 diabetes mellitus. Given currently available data and technological developments, we believe that with appropriate patient education, CGM can also be considered for other patient populations.


Venous effects of oral contraceptives.
In a five-year analysis of an oral contraceptive trial by the Council for the Investigation of Fertility Control venous effects were the third most troublesome group of side-effects with both combined and sequential therapy. Vein complaints, leg cramps, and thrombophlebitis were significantly more frequent with the combined preparations that contained a relatively low dose of progestogen and a high dose of oestrogen than with the other groups tested. No cases of thrombophlebitis occurred in women taking the strongly oestrogenic sequential groups.Histological examination of uterine curettings showed that most progestogenic combined preparations were associated with a high incidence of dilated endometrial sinusoids, while the oestrogenic sequential regimens and low-dose progestogen-only regimens had a low incidence. The incidence of stromal condensation round the sinusoids correlated with the incidence of leg cramps, and these effects appeared to be specific for each preparation tested.


Transforming growth factor-β and smooth muscle differentiation.
Transforming growth factor (TGF)-β family members are multifunctional cytokines regulating diverse cellular functions such as growth, adhesion, migration, apoptosis, and differentiation. TGF-βs elicit their effects via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knockout mouse models for the different components of the TGF-β signaling pathway have revealed their critical roles in smooth muscle cell (SMC) differentiation. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular disorders such as aorta aneurysm and congenital heart diseases due to SMC defects. In this review, the current understanding of TGF-β function in SMC differentiation is highlighted, and the role of TGF-β signaling in SMC-related diseases is discussed.


Identification of COL6A1 as a differentially expressed gene in human astrocytomas.
Diffuse infiltrating gliomas are the most common tumors of the central nervous system. Gliomas are classified by the WHO according to their histopathological and clinical characteristics into four classes: grade I (pilocytic astrocytoma), grade II (diffuse astrocytoma), grade III (anaplastic astrocytoma), and grade IV (glioblastoma multiforme). Several genes have already been correlated with astrocytomas, but many others are yet to be uncovered. By analyzing the public SAGE data from 21 patients, comprising low malignant grade astrocytomas and glioblastomas, we found COL6A1 to be differentially expressed, confirming this finding by real time RT-PCR in 66 surgical samples. To the best of our knowledge, COL6A1 has never been described in gliomas. The expression of this gene has significantly different means when normal glia is compared with low-grade astrocytomas (grades I and II) and high-grade astrocytomas (grades III and IV), with a tendency to be greater in higher grade samples, thus rendering it a powerful tumor marker.


Morphometric and microsatellite-based comparative genetic diversity analysis in Bubalus bubalis from North India.
To understand the similarities and dissimilarities of a breed structure among different buffalo breeds of North India, it is essential to capture their morphometric variation, genetic diversity, and effective population size. In the present study, diversity among three important breeds, namely, Murrah, Nili-Ravi and Gojri were studied using a parallel approach of morphometric characterization and molecular diversity. Morphology was characterized using 13 biometric traits, and molecular diversity through a panel of 22 microsatellite DNA markers recommended by FAO, Advisory Group on Animal Genetic Diversity, for diversity studies in buffaloes. Canonical discriminate analysis of biometric traits revealed different clusters suggesting distinct genetic entities among the three studied populations. Analysis of molecular variance revealed 81.8% of genetic variance was found within breeds, while 18.2% of the genetic variation was found between breeds. Effective population sizes estimated based on linkage disequilibrium were 142, 75 and 556 in Gojri, Nili-Ravi and Murrah populations, respectively, indicated the presence of sufficient genetic variation and absence of intense selection among three breeds. The Bayesian approach of STRUCTURE analysis (at K = 3) assigned all populations into three clusters with a degree of genetic admixture in the Murrah and Nili-Ravi buffalo populations. Admixture analysis reveals introgression among Murrah and Nili-Ravi breeds while identified the Gojri as unique buffalo germplasm, indicating that there might be a common origin of Murrah and Nili-Ravi buffaloes. The study provides important insights on buffalo breeds of North India that could be utilized in designing an effective breeding strategy, with an appropriate choice of breeds for upgrading local non-descript buffaloes along with conservation of unique germplasm.


Characterization of the alpha-1 adrenergic receptors in the thoracic aorta of control and aldosterone hypertensive rats: correlation of radioligand binding with potassium efflux and contraction.
Pharmacologic analysis of functional and radioligand binding studies were used to determine whether alterations in adrenergic receptors contribute to the catecholamine supersensitivity observed in the thoracic aorta of aldosterone hypertensive rats (AHR). Adrenergic function was evaluated using receptor-mediated contraction and rate of 42K efflux. The pA2 for phentolamine was the same in AHR (7.9 +/- 0.1 and 8.0 +/- 0.1) and control (7.9 +/- 0.2 and 8.1 +/- 0.1) rats whether measured by contraction or 42K efflux. The pA2 value for the selective alpha-1 antagonist prazosin (9.8 +/- 0.1 to 10.7 +/- 0.2) and the alpha-2 antagonist yohimbine (6.6 +/- 0.2 to 7.4 +/- 0.2) was similar in AHR and control groups using both norepinephrine and phenylephrine as agonists. The rank order of potency was prazosin greater than phentolamine greater than yohimbine in both groups. The KD for [3H]prazosin binding to AHR (26 +/- 3 pM) and control tissue (34 +/- 6 pM) agreed with the prazosin KB obtained by measurements of contraction and 42K efflux. The alpha-1 receptor density was also unaltered: 39 +/- 1 fmol/mg in AHR and 44 +/- 3 fmol/mg in control. Assessment of the NE dissociation constant (Ka) by method of fractional receptor inactivation indicated that the Ka was 4.8 X 10(-7) M in both AHR and control tissues. However, at the same receptor occupancy, the NE-induced increase in 42K efflux was elevated markedly in aorta from AHR. We conclude that alteration in adrenergic receptor density, affinity or type is not the cause of catecholamine supersensitivity in the aorta from AHR and that postreceptor events mediate this phenomenon.


Single-Cell Transcriptome Analyses Reveal Endothelial Cell Heterogeneity in Tumors and Changes following Antiangiogenic Treatment.
Angiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here, we characterized by single-cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling. We classified tumor endothelial cells into three subpopulations that appeared to correspond with tip-like, transition, and stalk-like cells. Previously identified markers for tip and stalk cells were confirmed and several novel ones discovered. Blockade of VEGF rapidly inhibited cell-cycle genes and strongly reduced the proportion of endothelial tip cells in tumors. In contrast, blockade of Dll4 promoted endothelial proliferation as well as tip cell markers; blockade of both pathways inhibited endothelial proliferation but preserved some tip cells. We also phenotypically classified other tumor stromal cells and found that tumor-associated fibroblasts responded to antiangiogenic drug treatments by upregulating hypoxia-associated genes and producing secreted factors involved in angiogenesis. Overall, our findings better define the heterogeneity of tumor endothelial and other stromal cells and reveal the roles of VEGF and Dll4-Notch in specifying tumor endothelial phenotype, highlighting the response of stromal cells to antiangiogenic therapies.Significance: These findings provide a framework for defining subpopulations of endothelial cells and tumor-associated fibroblasts and their rapid changes in gene expression following antiangiogenic treatment. Cancer Res; 78(9); 2370-82. ©2018 AACR.


Direct observation of molecular preorganization for chirality transfer on a catalyst surface.
The chemisorption of specific optically active compounds on metal surfaces can create catalytically active chirality transfer sites. However, the mechanism through which these sites bias the stereoselectivity of reactions (typically hydrogenations) is generally assumed to be so complex that continued progress in the area is uncertain. We show that the investigation of heterogeneous asymmetric induction with single-site resolution sufficient to distinguish stereochemical conformations at the submolecular level is finally accessible. A combination of scanning tunneling microscopy and density functional theory calculations reveals the stereodirecting forces governing preorganization into precise chiral modifier-substrate bimolecular surface complexes. The study shows that the chiral modifier induces prochiral switching on the surface and that different prochiral ratios prevail at different submolecular binding sites on the modifier at the reaction temperature.


Patterns of insertions and their covariation with substitutions in the rat, mouse, and human genomes.
The rates at which human genomic DNA changes by neutral substitution and insertion of certain families of transposable elements covary in large, megabase-sized segments. We used the rat, mouse, and human genomic DNA sequences to examine these processes in more detail in comparisons over both shorter (rat-mouse) and longer (rodent-primate) times, and demonstrated the generality of the covariation. Different families of transposable elements show distinctive insertion preferences and patterns of variation with substitution rates. SINEs are more abundant in GC-rich DNA, but the regional GC preference for insertion (monitored in young SINEs) differs between rodents and humans. In contrast, insertions in the rodent genomes are predominantly LINEs, which prefer to insert into AT-rich DNA in all three mammals. The insertion frequency of repeats other than SINEs correlates strongly positively with the frequency of substitutions in all species. However, correlations with SINEs show the opposite effects. The correlations are explained only in part by the GC content, indicating that other factors also contribute to the inherent tendency of DNA segments to change over evolutionary time.


Influence of soya antigen levels in milk replacers on the disruption of intestinal motility patterns in calves sensitive to soya.
An experiment was designed to determine the soya antigen levels in milk replacers above which gastrointestinal disorders appeared in preruminant calves previously sensitized to antigenic soya by feeding a soya-based milk replacer for 3 months. These calves were then equipped with wire electrodes on the duodenum and the mid-jejunum. The sensitization was visualized using direct skin testing, plasma anti-soya antibody determination and intestinal myoelectric activity recording. After sensitization, the calves were occasionally fed liquid test meals containing various proportions of antigenic soya and whey. The soya-fed calves displayed larger 24 h skin reactions to beta-conglycinin and higher plasma anti-soya antibody titres than the controls maintained on a skim-milk based milk replacer. Disturbances of the myoelectric activity patterns were recorded on the duodenum and mid-jejunum after feeding antigenic soya, but not non-antigenic soya or milk protein, in the soya-sensitized calves. When the level of antigens was varied, disorders in the jejunal motility patterns appeared when antigenic soya provided one-third or more of the dietary protein in the test meals, although some abnormalities were evident at lower incorporation rates. The major change was a reduction in the mean duration of the jejunal migrating motor complexes which was essentially accounted for by a decrease in the mean duration of the phase I (quiescence). This level of antigens corresponded approximately to 14 and 12 mg of immunoreactive glycinin and beta-conglycinin respectively, per gram of protein intake, i.e. 80 and 70 mg/kg0.75 per test meal.


Pixel-Level Clustering of Hematoxylin-Eosin-Stained Sections of Mouse and Human Biliary Tract Cancer.
We previously established mouse models of biliary tract cancer (BTC) based on the injection of cells with biliary epithelial stem cell properties derived from KRAS(G12V)-expressing organoids into syngeneic mice. The resulting mouse tumors appeared to recapitulate the pathological features of human BTC. Here we analyzed images of hematoxylin and eosin (H&E) staining for both the mouse tumor tissue and human cholangiocarcinoma tissue by pixel-level clustering with machine learning. A pixel-clustering model that was established via training with mouse images revealed homologies of tissue structure between the mouse and human tumors, suggesting similarities in tumor characteristics independent of animal species. Analysis of the human cholangiocarcinoma tissue samples with the model also revealed that the entropy distribution of cancer regions was higher than that of noncancer regions, with the entropy of pixels thus allowing discrimination between these two types of regions. Histograms of entropy tended to be broader for noncancer regions of late-stage human cholangiocarcinoma. These analyses indicate that our mouse BTC models are appropriate for investigation of BTC carcinogenesis and may support the development of new therapeutic strategies. In addition, our pixel-level clustering model is highly versatile and may contribute to the development of a new BTC diagnostic tool.


Usage of C-Reactive Protein Testing in the Diagnosis and Monitoring of Psoriatic Arthritis (PsA): Results from a Real-World Survey in the USA and Europe.
C-reactive protein (CRP) is an important non-specific marker of both acute and chronic inflammation and can be elevated in patients with psoriatic arthritis (PsA). However, the use of CRP testing in the management of PsA can vary. This study investigated how CRP testing is implemented in real-world clinical practice for disease management of PsA. A point-in-time survey of rheumatologists and dermatologists and their next six consulting patients with PsA was conducted in France, Germany, Italy, Spain, UK (EU5), and the USA between June and August 2018. Use of CRP testing was obtained by asking the physician to state (yes/no) whether CRP was used to aid PsA diagnosis and/or to monitor the patient's disease activity. The number of CRP tests conducted in the last 12 months for each patient enrolled was provided. Data were collected for 2270 patients (USA, n = 595; EU5, n = 1675). In the EU5, CRP testing was conducted to aid diagnosis in 78.7% of patients (vs. 43.4% in USA) and CRP was used to monitor disease activity in 72.0% (vs. 34.6% in USA). The majority (80.9%) of patients in the EU5 had at least one CRP test in the last 12 months compared to 42.9% in the USA. Patients treated by rheumatologists (vs. dermatologists) were at least 50% more likely to have CRP tested for monitoring purposes, this difference being most pronounced in the USA. In the EU5, CRP testing was conducted a mean ± standard deviation of 2.7 ± 1.7 times during the last 12 months, versus 2.0 ± 1.4 in the USA. CRP was more commonly used for the diagnosis and monitoring of PsA in Europe compared to the USA and was more commonly ordered by rheumatologists than dermatologists. In the absence of a better serum biomarker of inflammation, more data are needed to understand how CRP testing should be used in the diagnosis and management PsA.


Epidemiological differentiation of Serratia marcescens: typing by bacteriocin production.
A new method for comparing and differentiating strains of S. marcescens is described which has proved useful in determining the epidemiology of hospital infections. Strains were grown in Trypticase soy broth, and bacteriocin production was induced with mitomycin C for 5 hr. The bacteriocin lysates were then spotted onto nine standard indicator strains, which were chosen with the aid of computer analysis from the 118 indicators tested. After 24 hr at 37 C, zones of inhibition due to bacteriocins were recorded. One hundred twentynine strains were differentiated into 72 different bacteriocin production patterns, but 11 strains were nontypable. None of the 45 other strains of Enterobacteriaceae produced bacteriocins. Bacteriocin production was a stable epidemiological marker. Colonial mutants always had identical patterns, as did the same strain which has passed from patient to patient through cross-infection. The new technique does not require any specialized equipment and can be used in laboratories with limited budgets. The applications of the new method in cross-infection studies and as a supplement to serological typing are discussed.


[Determining the parameters for receptor-ligand interaction by serial dilution method for the case when the ligand and receptor are in a pre-existing mixture].
New methods of determining the binding parameters for ligand-receptor interaction are considered. The considered approaches are based on the earlier suggested method of serial dilution and application of so-called coordinates of dilution. It was shown that the suggested methods allow to evaluate affinity constant and ligand concentration even for the case, when the receptor and corresponding ligand of unknown concentration are in a mixture and their separation from each other is impossible. In this connection the suggested methods are especially useful for studying the ligand-receptor interaction if the receptor is very liable and its purification from the ligand would cause drastic changes of its binding properties.


Recessive TTN truncating mutations define novel forms of core myopathy with heart disease.
Core myopathies (CM), the main non-dystrophic myopathies in childhood, remain genetically unexplained in many cases. Heart disease is not considered part of the typical CM spectrum. No congenital heart defect has been reported, and childhood-onset cardiomyopathy has been documented in only two CM families with homozygous mutations of the TTN gene. TTN encodes titin, a giant protein of striated muscles. Recently, heterozygous TTN truncating mutations have also been reported as a major cause of dominant dilated cardiomyopathy. However, relatively few TTN mutations and phenotypes are known, and titin pathophysiological role in cardiac and skeletal muscle conditions is incompletely understood. We analyzed a series of 23 families with congenital CM and primary heart disease using TTN M-line-targeted sequencing followed in selected patients by whole-exome sequencing and functional studies. We identified seven novel homozygous or compound heterozygous TTN mutations (five in the M-line, five truncating) in 17% patients. Heterozygous parents were healthy. Phenotype analysis identified four novel titinopathies, including cardiac septal defects, left ventricular non-compaction, Emery-Dreifuss muscular dystrophy or arthrogryposis. Additionally, in vitro studies documented the first-reported absence of a functional titin kinase domain in humans, leading to a severe antenatal phenotype. We establish that CM are associated with a large range of heart conditions of which TTN mutations are a major cause, thereby expanding the TTN mutational and phenotypic spectrum. Additionally, our results suggest titin kinase implication in cardiac morphogenesis and demonstrate that heterozygous TTN truncating mutations may not manifest unless associated with a second mutation, reassessing the paradigm of their dominant expression.


Rapid modification of the insect elicitor N-linolenoyl-glutamate via a lipoxygenase-mediated mechanism on Nicotiana attenuata leaves.
Some plants distinguish mechanical wounding from herbivore attack by recognizing specific constituents of larval oral secretions (OS) which are introduced into plant wounds during feeding. Fatty acid-amino acid conjugates (FACs) are major constituents of Manduca sexta OS and strong elicitors of herbivore-induced defense responses in Nicotiana attenuata plants. The metabolism of one of the major FACs in M. sexta OS, N-linolenoyl-glutamic acid (18:3-Glu), was analyzed on N. attenuata wounded leaf surfaces. Between 50 to 70% of the 18:3-Glu in the OS or of synthetic 18:3-Glu were metabolized within 30 seconds of application to leaf wounds. This heat-labile process did not result in free alpha-linolenic acid (18:3) and glutamate but in the biogenesis of metabolites both more and less polar than 18:3-Glu. Identification of the major modified forms of this FAC showed that they corresponded to 13-hydroxy-18:3-Glu, 13-hydroperoxy-18:3-Glu and 13-oxo-13:2-Glu. The formation of these metabolites occurred on the wounded leaf surface and it was dependent on lipoxygenase (LOX) activity; plants silenced in the expression of NaLOX2 and NaLOX3 genes showed more than 50% reduced rates of 18:3-Glu conversion and accumulated smaller amounts of the oxygenated derivatives compared to wild-type plants. Similar to 18:3-Glu, 13-oxo-13:2-Glu activated the enhanced accumulation of jasmonic acid (JA) in N. attenuata leaves whereas 13-hydroxy-18:3-Glu did not. Moreover, compared to 18:3-Glu elicitation, 13-oxo-13:2-Glu induced the differential emission of two monoterpene volatiles (beta-pinene and an unidentified monoterpene) in irlox2 plants. The metabolism of one of the major elicitors of herbivore-specific responses in N. attenuata plants, 18:3-Glu, results in the formation of oxidized forms of this FAC by a LOX-dependent mechanism. One of these derivatives, 13-oxo-13:2-Glu, is an active elicitor of JA biosynthesis and differential monoterpene emission.


Fermented Viola mandshurica inhibits melanogenesis in B16 melanoma cells.
We assessed the effects of chloroform extract of fermented Viola mandshurica (CEFV) on melanogenesis B16 melanoma cells. CEFV treatment significantly decreased melanin content and tyrosinase activity in dose-dependent manners. To elucidate the mechanism of the inhibitory effects of CEFV on melanogenesis, we performed RT-PCR and Western blotting for melanogenesis-related genes such as tyrosinase, tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF). CEFV strongly inhibited mRNA as well as the protein expression of tyrosinase and MITF, but had no significant effect on TRP-1 or TRP-2 expressions. It markedly decreased the phosphorylation of cAMP responsive element binding protein (CREB), and induced the duration of extracellular signal-regulated kinase (ERK) activation, leading to reduction of MITF expression and subsequently that of tyrosinase. Therefore, we suggest that CEFV induces downregulation of melanogenesis through decreased CREB phosphorylation and ERK activation.


Prevention and treatment of osteoporosis with natural products: Regulatory mechanism based on cell ferroptosis.
With the development of society, the number of patients with osteoporosis is increasing. The prevention and control of osteoporosis has become a serious and urgent issue. With the continuous progress of biomedical research, ferroptosis has attracted increased attention. However, the pathophysiology and mechanisms of ferroptosis and osteoporosis still need further study. Natural products are widely used in East Asian countries for osteoporosis prevention and treatment. In this paper, we will discuss the basic mechanisms of ferroptosis, the relationship between ferroptosis and osteoclasts and osteoblasts, and in vitro and in vivo studies of natural products to prevent osteoporosis by interfering with ferroptosis. This article takes ferroptosis, natural products, osteoporosis, osteoblasts and osteoclast as key words. Retrieve literature from 2012 to 2023 indexed in databases such as PubMed Central, PubMed, Web of Science, Scopus and ISI. Ferroptosis has many regulatory mechanisms, including the system XC -/GSH/GPX4, p62/Keap1/Nrf2, FSP1/NAD (P) H/CoQ10, P53/SAT1/ALOX15 axes etc. Interestingly, we found that natural products, such as Artemisinin, Biochanin A and Quercetin, can play a role in treating osteoporosis by promoting ferroptosis of osteoclast and inhibiting ferroptosis of osteoblasts. Natural products have great potential to regulate OBs and OCs by mediating ferroptosis to prevent and treat osteoporosis, and it is worthwhile to explore and discover more natural products that can prevent and treat osteoporosis.


Identification of Semantically Similar Sentences in Clinical Notes: Iterative Intermediate Training Using Multi-Task Learning.
Although electronic health records (EHRs) have been widely adopted in health care, effective use of EHR data is often limited because of redundant information in clinical notes introduced by the use of templates and copy-paste during note generation. Thus, it is imperative to develop solutions that can condense information while retaining its value. A step in this direction is measuring the semantic similarity between clinical text snippets. To address this problem, we participated in the 2019 National NLP Clinical Challenges (n2c2)/Open Health Natural Language Processing Consortium (OHNLP) clinical semantic textual similarity (ClinicalSTS) shared task. This study aims to improve the performance and robustness of semantic textual similarity in the clinical domain by leveraging manually labeled data from related tasks and contextualized embeddings from pretrained transformer-based language models. The ClinicalSTS data set consists of 1642 pairs of deidentified clinical text snippets annotated in a continuous scale of 0-5, indicating degrees of semantic similarity. We developed an iterative intermediate training approach using multi-task learning (IIT-MTL), a multi-task training approach that employs iterative data set selection. We applied this process to bidirectional encoder representations from transformers on clinical text mining (ClinicalBERT), a pretrained domain-specific transformer-based language model, and fine-tuned the resulting model on the target ClinicalSTS task. We incrementally ensembled the output from applying IIT-MTL on ClinicalBERT with the output of other language models (bidirectional encoder representations from transformers for biomedical text mining [BioBERT], multi-task deep neural networks [MT-DNN], and robustly optimized BERT approach [RoBERTa]) and handcrafted features using regression-based learning algorithms. On the basis of these experiments, we adopted the top-performing configurations as our official submissions. Our system ranked first out of 87 submitted systems in the 2019 n2c2/OHNLP ClinicalSTS challenge, achieving state-of-the-art results with a Pearson correlation coefficient of 0.9010. This winning system was an ensembled model leveraging the output of IIT-MTL on ClinicalBERT with BioBERT, MT-DNN, and handcrafted medication features. This study demonstrates that IIT-MTL is an effective way to leverage annotated data from related tasks to improve performance on a target task with a limited data set. This contribution opens new avenues of exploration for optimized data set selection to generate more robust and universal contextual representations of text in the clinical domain.


Effect of high ambient temperature on feed digestibility in broilers.
The effect of chronic heat exposure on feed digestibility of broilers was investigated. Eighty 4-wk-old male chickens were brooded in individual battery cages in two controlled-environment rooms at a constant ambient temperature (22 or 32 C) until 6 wk of age. They were equally distributed into three treatments: 22 C, ad libitum feed consumption (22AL); 32 C, ad libitum feed consumption (32AL), and 22 C, pair-feeding on the daily feed intake of heat-exposed chickens (22PF). Broilers were fed either a standard corn-soybean meal diet (control diet) or a practical seasonal diet containing several ingredients including wheat, spring pea, and animal fat (summer diet). Digestibility of energy, dry matter, protein, fat, starch, and nitrogen, and total mineral balances were measured between 38 and 42 d of age. Apparent metabolizable energy content of summer diet was significantly decreased in 32AL compared to 22AL, whereas AME of the control diet did not change. Nitrogen retention was significantly reduced in 32AL birds compared to 22AL and 22PF birds, irrespective of the diet. Taking into account these differences in nitrogen balance, AMEn was reduced under hot exposure: -72 and -155 kcal for control and summer diets respectively, in 32AL compared to 22PF chickens. This reduction could be explained by a significant decrease of nutrient digestibility:protein: -4.2 percentage units irrespective of the diet, fat: -1.7 and -5.2 percentage units for control and summer diets respectively, and starch: -4.2 percentage units for summer diet. It thus appears worthwhile to take into account such reduction in digestibility to formulate practical diets for brooding under hot conditions. High quality oil and protein sources should also be used instead of low quality feedstuffs, like animal sources, in such conditions.


Evolutionary history versus current causal role in the definition of disorder: reply to McNally.
The harmful dysfunction (HD) analysis (Wakefield, American Psychologist 47 (1992a) 373) asserts that "disorder" means "harmful dysfunction", where "harm" is a value concept anchored in social values and "dysfunction" is a factual concept referring to failure of a mechanism to perform a natural function. Additionally, the HD analysis claims that a mechanism's natural functions are its naturally selected effects. McNally (Behaviour Research and Therapy (2000) pp. 309-314) argues to the contrary that "dysfunction" is a value concept referring to negative failures of function, that "function" refers to current causal roles and not evolutionarily designed causal roles, and that "disorder" consequently means "harmful failure of a mechanism to perform a valued current causal role." I reply by showing that McNally's proposals lack the HD analysis's power to explain common judgments about function, dysfunction, and disorder. "Dysfunction" cannot be a negative value concept because many dysfunctions are positive or neutral; "function" cannot refer to current causal roles because many current causal roles are not functions and some functions are not current causal roles; and "disorder" cannot refer to harmful failures of current causal roles because that definition allows almost any negative condition whatever to be a disorder and thus fails to explain the distinctions we make between disorder and non-disorder.


Towards cardiac MRI based risk stratification in idiopathic dilated cardiomyopathy.
Sudden cardiac death (SCD) secondary to arrhythmia remains a risk in those with dilated cardiomyopathy (DCM), an implantable cardiac defibrillator (ICD) is an effective strategy to prevent SCD. Current guidelines recommend selection for ICD based on ejection fraction (EF) less than 35%, however, most SCD occurs in those with EF>35%. Although meta-analysis has demonstrated a survival benefit for primary prevention ICD in DCM, no randomised trial has shown a significant reduction in overall mortality including the most recent 'Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heat Failure on Mortality' study. Clearly, a more sophisticated selection strategy is required. Cardiac MRI (CMR) is an ideal non-invasive imaging technique which allows calculation of EF as well as tissue characterisation with gadolinium contrast, parametric mapping and feature tracking. Late gadolinium enhancement detects mid-wall fibrosis in approximately 30% of those with DCM, three meta-analyses have demonstrated an association between fibrosis in DCM and SCD, and those without fibrosis are at low risk of SCD. T1 mapping and extracellular volume (ECV) calculation are methods of demonstrating diffuse fibrosis in the myocardium. Raised ECV and native T1 have been associated with worse outcomes but the relationship to SCD has not been well studied. Undoubtedly, more research is required but CMR has several tools which offer incremental value above EF to improve risk stratification and consequent outcomes and resource utilisation in those with DCM.


[Paroxysmal EEG disorders in various forms of schizophrenia among children and adolescents].
A comparative study of the frequency of EEG paroxysmal disturbances in healthy and schizophrenic children and adolescents was carried out. The study has enabled the authors to reveal a greater occurrence of bilateral outbreaks of relatively high-amplitude slow waves in the picture of the cortical rhythms in patients with paroxysmal schizophrenia, as well as in a group of patients with psychopathy-like disorder taking the form of persistent pathological cravings. The intensification of the paroxysmal outbreaks on the EEGs of the patients with paroxysmal schizophrenia can be regarded as an indication of incidental rises of the excitability of the brain systems synchronizing the cortical rhythms, these rises creating conditions favouring the transition from one functional state of the patients to another. On the other hand, marked paroxysmal outbreaks in patients suffering from continuous schizophrenia with prevalence of psychopathic heboid-type disorders in the clinical picture can be associated with pronounced signs of retardation and distortion of the age regularities of the development.


BingleSeq: a user-friendly R package for bulk and single-cell RNA-Seq data analysis.
RNA sequencing is an indispensable research tool used in a broad range of transcriptome analysis studies. The most common application of RNA Sequencing is differential expression analysis and it is used to determine genetic loci with distinct expression across different conditions. An emerging field called single-cell RNA sequencing is used for transcriptome profiling at the individual cell level. The standard protocols for both of these approaches include the processing of sequencing libraries and result in the generation of count matrices. An obstacle to these analyses and the acquisition of meaningful results is that they require programing expertise. Although some effort has been directed toward the development of user-friendly RNA-Seq analysis analysis tools, few have the flexibility to explore both Bulk and single-cell RNA sequencing. BingleSeq was developed as an intuitive application that provides a user-friendly solution for the analysis of count matrices produced by both Bulk and Single-cell RNA-Seq experiments. This was achieved by building an interactive dashboard-like user interface which incorporates three state-of-the-art software packages for each type of the aforementioned analyses. Furthermore, BingleSeq includes additional features such as visualization techniques, extensive functional annotation analysis and rank-based consensus for differential gene analysis results. As a result, BingleSeq puts some of the best reviewed and most widely used packages and tools for RNA-Seq analyses at the fingertips of biologists with no programing experience. BingleSeq is as an easy-to-install R package available on GitHub at https://github.com/dbdimitrov/BingleSeq/.


Effect of doping in carbon nanotubes on the viability of biomimetic chitosan-carbon nanotubes-hydroxyapatite scaffolds.
This work describes the preparation and characterization of biomimetic chitosan/multiwall carbon nanotubes/nano-hydroxyapatite (CTS/MWCNT/nHAp) scaffolds and their viability for bone tissue engineering applications. The cryogenic process ice segregation-induced self-assembly (ISISA) was used to fabricate 3D biomimetic CTS scaffolds. Proper combination of cryogenics, freeze-drying, nature and molecular ratio of solutes give rise to 3D porous interconnected scaffolds with clusters of nHAp distributed along the scaffold surface. The effect of doping in CNT (e.g. with oxygen and nitrogen atoms) on cell viability was tested. Under the same processing conditions, pore size was in the range of 20-150 μm and irrespective on the type of CNT. Studies on cell viability with scaffolds were carried out using human cells from periosteum biopsy. Prior to cell seeding, the immunophenotype of mesenchymal periosteum or periosteum-derived stem cells (MSCs-PCs) was characterized by flow cytometric analysis using fluorescence-activated and characteristic cell surface markers for MSCs-PCs. The characterized MSCs-PCs maintained their periosteal potential in cell cultures until the 2nd passage from primary cell culture. Thus, the biomimetic CTS/MWCNT/nHAp scaffolds demonstrated good biocompatibility and cell viability in all cases such that it can be considered as promising biomaterials for bone tissue engineering.


Current status of prenatal diagnosis by DNA analysis.
In 1989 we are continuing to move gene diagnosis over to the direct detection mode. We have sickle cell anemia, alpha-thalassemia, beta-thalassemia, Duchenne muscular dystrophy, Becker muscular dystrophy and cystic fibrosis moved to direct detection with hemophilia B and alpha-1-antitrypsin deficiency soon to be there. For indirect detection, we still have hemophilia A, and a comment on the genetics of hemophilia A is important. Remember that sickle cell anemia is caused by one mutation, while beta-thalassemia and cystic fibrosis have a finite number of alleles. Duchenne muscular dystrophy results from a different mutation for every affected individual, but most of these are deletions and can be directly detected. Hemophilia A is another X-linked disorder with almost every affected individual having a different mutation. That means that there probably are 100 ways to get beta-thalassemia and about 10,000 ways to get hemophilia A, so we need some really good novel techniques to detect these directly, and we are working hard on such techniques. I would not be surprised if hemophilia A moved into the direct detection category in the next year or so. We need to find the Huntington disease gene, and then it will move into the direct detection column. Neurofibromatosis is still in the indirect detection group but also may move very soon. Polycystic kidney disease is also still in the indirect detection column. This summarizes where prenatal and presymptomatic gene diagnosis stands in late 1989.


Multiplex CRISPR/Cas9 system impairs HCMV replication by excising an essential viral gene.
Anti-HCMV treatments used in immunosuppressed patients reduce viral replication, but resistant viral strains can emerge. Moreover, these drugs do not target latently infected cells. We designed two anti-viral CRISPR/Cas9 strategies to target the UL122/123 gene, a key regulator of lytic replication and reactivation from latency. The singleplex strategy contains one gRNA to target the start codon. The multiplex strategy contains three gRNAs to excise the complete UL122/123 gene. Primary fibroblasts and U-251 MG cells were transduced with lentiviral vectors encoding Cas9 and one or three gRNAs. Both strategies induced mutations in the target gene and a concomitant reduction of immediate early (IE) protein expression in primary fibroblasts. Further detailed analysis in U-251 MG cells showed that the singleplex strategy induced 50% of indels in the viral genome, leading to a reduction in IE protein expression. The multiplex strategy excised the IE gene in 90% of all viral genomes and thus led to the inhibition of IE protein expression. Consequently, viral genome replication and late protein expression were reduced by 90%. Finally, the production of new viral particles was nearly abrogated. In conclusion, the multiplex anti-UL122/123 CRISPR/Cas9 system can target the viral genome efficiently enough to significantly prevent viral replication.


[Antagonists of the type 3 serotonin receptor (5 -HT3) in IBS].
Irritable bowel syndrome (IBS) is a common chronic gastrointestinal (GI) disorder, but its pathophysiology remains unknown. 5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter involved in the brain-gut connection. Alosetron, a 5-HT3 receptor antagonist, has been demonstrated in randomized, placebo-controlled trials (RCT) to be effective in diarrhea-predominant IBS(IBS-D). Constipation is the most common adverse event. Alosetron improved abdominal pain and discomfort and stool consistency in both female and male patients, but it did not improve other symptoms (sense of urgency, stool frequency and bloating) in male patients. Although less is known about the gender differences in therapeutic benefit, a new 5-HT3 antagonist, cilansetron, has demonstrated effectiveness in male and female IBS-D patients and is currently under clinical trials.


[The extracellular matrix of peripheral lung cancer in the scar and of pneumosclerosis of different origins (the immunohistochemistry and electron microscopy of the collagens)].
Collagen types and ultrastructural features of the stroma and scar extracellular matrix in the peripheral lung carcinoma, post-tuberculosis and post-pneumonia pneumosclerosis foci, fibrosing alveolitis interstitium were studied on the material of operational and transbronchial lung biopsies. It is established that by the collagen composition the scars in the peripheral carcinoma are identical to the pneumosclerosis foci and are distinguished from the carcinoma stroma by a higher concentration of type IV and V collagens (p less than 0.05). Accumulation of type III collagen in the lung carcinoma stroma reflects anaplasia of the tumour as the domination of type III collagen is characteristic of the embryonal tissue. The decrease of collagen type IV in the cancer stroma correlates with an increase of its malignancy. Pneumosclerosis in the fibrosing alveolitis is distinct from the focal forms of pneumosclerosis by a higher content of collagen I and a lower content of collagen V this being probably due to the character of sclerosis morphogenesis in this disease.


NO Releasing and Anticancer Properties of Octahedral Ruthenium-Nitrosyl Complexes with Equatorial 1 H-Indazole Ligands.
With the aim of enhancing the biological activity of ruthenium-nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind)4(NO)]Cl2·H2O ([3]Cl2·H2O) and trans-[RuOH(Hind)4(NO)]Cl2·H2O ([4]Cl2·H2O), have been prepared from trans-[Ru(NO2)2(Hind)4] ([2]). When the pH-dependent solution behavior of [3]Cl2·H2O and [4]Cl2·H2O was studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind)2(Hind)2(NO)] ([5]) and [RuOH(ind)2(Hind)2(NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV-vis, 1H NMR) techniques. Compound [2], as well as [3]Cl2·2(CH3)2CO, [4]Cl2·2(CH3)2CO, and [5]·0.8CH2Cl2, the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl2 and [4]Cl2 was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3-6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump-probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl2 and [4]Cl2 showed considerable antiproliferative activity in human cancer cell lines with IC50 values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru-NO complexes [3]Cl2 and [4]Cl2 was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO.


Mucosa-associated bacteria in the human gastrointestinal tract are uniformly distributed along the colon and differ from the community recovered from feces.
The human gastrointestinal (GI) tract harbors a complex community of bacterial cells in the mucosa, lumen, and feces. Since most attention has been focused on bacteria present in feces, knowledge about the mucosa-associated bacterial communities in different parts of the colon is limited. In this study, the bacterial communities in feces and biopsy samples from the ascending, transverse, and descending colons of 10 individuals were analyzed by using a 16S rRNA approach. Flow cytometric analysis indicated that 10(5) to 10(6) bacteria were present in the biopsy samples. To visualize the diversity of the predominant and the Lactobacillus group community, denaturing gradient gel electrophoresis (DGGE) analysis of 16S rRNA gene amplicons was performed. DGGE analysis and similarity index comparisons demonstrated that the predominant mucosa-associated bacterial community was host specific and uniformly distributed along the colon but significantly different from the fecal community (P < 0.01). The Lactobacillus group-specific profiles were less complex than the profiles reflecting the predominant community. For 6 of the 10 individuals the community of Lactobacillus-like bacteria in the biopsy samples was similar to that in the feces. Amplicons having 99% sequence similarity to the 16S ribosomal DNA of Lactobacillus gasseri were detected in the biopsy samples of nine individuals. No significant differences were observed between healthy and diseased individuals. The observed host-specific DGGE profiles of the mucosa-associated bacterial community in the colon support the hypothesis that host-related factors are involved in the determination of the GI tract microbial community.


Prehospital intubation in patients with isolated severe traumatic brain injury: a 4-year observational study.
Objectives. To study the effect of prehospital intubation (PHI) on survival of patients with isolated severe traumatic brain injury (ISTBI). Method. Retrospective analyses of all intubated patients with ISTBI between 2008 and 2011 were studied. Comparison was made between those who were intubated in the PHI versus in the trauma resuscitation unit (TRU). Results. Among 1665 TBI patients, 160 met the inclusion criteria (105 underwent PHI, and 55 patients were intubated in TRU). PHI group was younger in age and had lower median scene motor GCS (P = 0.001). Ventilator days and hospital length of stay (P = 0.01 and 0.006, resp.) were higher in TRUI group. Mean ISS, length of stay, initial blood pressure, pneumonia, and ARDS were comparable among the two groups. Mortality rate was higher in the PHI group (54% versus 31%, P = 0.005). On multivariate regression analysis, scene motor GCS (OR 0.55; 95% CI 0.41-0.73) was an independent predictor for mortality. Conclusion. PHI did not offer survival benefit in our group of patients with ISTBI based on the head AIS and the scene motor GCS. However, more studies are warranted to prove this finding and identify patients who may benefit from this intervention.


Effect of vitrification on the microRNA transcriptome in mouse blastocysts.
Vitrification is commonly used in the cryopreservation of mammalian blastocysts to overcome the temporal and spatial limitations of embryo transfer. Previous studies have shown that the implantation ability of vitrified blastocysts is impaired and that microRNAs (miRNAs) regulate the critical genes for embryo implantation. However, little information is available about the effect of vitrification on the miRNA transcriptome in blastocysts. In the present study, the miRNA transcriptomes in fresh and vitrified mouse blastocysts were analyzed by miRNA Taqman assay based method, and the results were validated using quantitative real-time PCR (qRT-PCR). Then, the differentially expressed miRNAs were assessed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Overall, 760 known mouse miRNAs were detected in the vitrified and fresh mouse blastocysts. Of these, the expression levels of five miRNAs differed significantly: in the vitrified blastocysts, four miRNAs (mmu-miR-199a-5p, mmu-miR-329-3p, mmu-miR-136-5p and mmu-miR-16-1-3p) were upregulated, and one (mmu-miR-212-3p) was downregulated. The expression levels of all miRNAs measured by the miRNA Taqman assay based method and qRT-PCR were consistent. The four upregulated miRNAs were predicted to regulate 877 candidate target genes, and the downregulated miRNA was predicted to regulate 231 genes. The biological analysis further showed that the differentially expressed miRNAs mainly regulated the implantation of embryos. In conclusion, the results of our study showed that vitrification significantly altered the miRNA transcriptome in mouse blastocysts, which may decrease the implantation potential of vitrified blastocysts.


Fertility after unilateral orchidectomy and radiotherapy for patients with malignant tumours of the testis.
The results of treatment for patients with seminoma of the testis by orchidectomy and irradiation are so satisfactory that retroperitoneal lymph node dissection is no longer practised. However, this operation is still used routinely in some centres for patients with testicular teratomas despite the lack of evidence that it gives better results than those obtained with irradiation followed by removal of lymphographically demonstrable residual tumour and in the face of the high incidence of ejaculatory impotence which follows. On grounds of preservation of sexual function and fertility there is a great advantage to be gained from the latter form of treatment. Thirty-four of our patients between the ages of 25 and 45 years treated by irradiation to the para-aortic and iliac nodes for testicular tumours fathered 52 children to term after their treatment.


Neurophysiological Effects of Whole Coffee Cherry Extract in Older Adults with Subjective Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Pilot Study.
Bioactive plant-based compounds have shown promise as protective agents across multiple domains including improvements in neurological and psychological measures. Methodological challenges have limited our understanding of the neurophysiological changes associated with polyphenol-rich supplements such as whole coffee cherry extract (WCCE). In the current study, we (1) compared 100 mg of WCCE to a placebo using an acute, randomized, double-blind, within-subject, cross-over design, and we (2) conducted a phytochemical analysis of WCCE. The primary objective of the study was to determine the neurophysiological and behavioral changes that resulted from the acute administration of WCCE. We hypothesized that WCCE would increase brain-derived neurotrophic factor (BDNF) and glutamate levels while also increasing neurofunctional measures in cognitive brain regions. Furthermore, we expected there to be increased behavioral performance associated with WCCE, as measured by reaction time and accuracy. Participants underwent four neuroimaging scans (pre- and post-WCCE and placebo) to assess neurofunctional/metabolic outcomes using functional magnetic resonance imaging and magnetic resonance spectroscopy. The results suggest that polyphenol-rich WCCE is associated with decreased reaction time and may protect against cognitive errors on tasks of working memory and response inhibition. Behavioral findings were concomitant with neurofunctional changes in structures involved in decision-making and attention. Specifically, we found increased functional connectivity between the anterior cingulate and regions involved in sensory and decision-making networks. Additionally, we observed increased BDNF and an increased glutamate/gamma-aminobutyric acid (GABA) ratio following WCCE administration. These results suggest that WCCE is associated with acute neurophysiological changes supportive of faster reaction times and increased, sustained attention.


The effect of alcohol consumption on periodontitis in older Danes.
To examine the association of alcohol consumption measured at different points in time and periodontitis at 20 years follow-up and to investigate whether long-term alcohol consumption is related to periodontitis in old age. Participants aged 65 years or older in 2003, from the longitudinal study Copenhagen City Heart Study (CCHS), were invited to participate in the Copenhagen Oral Health Senior Study. Clinical periodontal attachment loss was calculated to determine the progress of periodontitis. Alcohol consumption was measured at CCHS follow-ups in 1981-1983, 1991-1994 and 2001-2003, using a standard questionnaire. Alcohol consumption was defined as light, moderate and heavy drinking and used individually for each follow-up. The three follow-ups were summarized into long-term alcohol consumption. Logistic regression analysis was used to estimate the relation between alcohol consumption measured at different points in time and periodontitis and to assess the effect of long-term alcohol consumption on periodontitis. The results show that heavy drinkers in 1981-1983 had a higher odds ratio for having periodontitis compared to light drinkers (OR = 4.64 95% CI = [1.1; 19.42]). Early consumption of alcohol may increase the odds of having periodontitis 20 years later. There is a need for further studies including larger populations to investigate both alcohol consumption measured at different points in time, and long-term alcohol consumption and periodontitis progression over time.


MRI Sequences in Head & Neck Radiology - State of the Art.
Background Magnetic resonance imaging (MRI) has become an essential imaging modality for the evaluation of head & neck pathologies. However, the diagnostic power of MRI is strongly related to the appropriate selection and interpretation of imaging protocols and sequences. The aim of this article is to review state-of-the-art sequences for the clinical routine in head & neck MRI and to describe the evidence for which medical question these sequences and techniques are useful. Method Literature review of state-of-the-art sequences in head & neck MRI. Results and Conclusion Basic sequences (T1w, T2w, T1wC+) and fat suppression techniques (TIRM/STIR, Dixon, Spectral Fat sat) are important tools in the diagnostic workup of inflammation, congenital lesions and tumors including staging. Additional sequences (SSFP (CISS, FIESTA), SPACE, VISTA, 3D-FLAIR) are used for pathologies of the cranial nerves, labyrinth and evaluation of endolymphatic hydrops in Menière's disease. Vessel and perfusion sequences (3D-TOF, TWIST/TRICKS angiography, DCE) are used in vascular contact syndromes, vascular malformations and analysis of microvascular parameters of tissue perfusion. Diffusion-weighted imaging (EPI-DWI, non-EPI-DWI, RESOLVE) is helpful in cholesteatoma imaging, estimation of malignancy, and evaluation of treatment response and posttreatment recurrence in head & neck cancer. Understanding of MRI sequences and close collaboration with referring physicians improves the diagnostic confidence of MRI in the daily routine and drives further research in this fascinating image modality. Key Points: · Understanding of MRI sequences is essential for the correct and reliable interpretation of MRI findings.. · MRI protocols have to be carefully selected based on relevant clinical information.. · Close collaboration with referring physicians improves the output obtained from the diagnostic possibilities of MRI.. Citation Format · Widmann G, Henninger B, Kremser C et al. MRI Sequences in Head & Neck Radiology - State of the Art. Fortschr Röntgenstr 2017; 189: 413 - 422.


The treatment of burns in children.
As a cause of accidental death in childhood, burns are exceeded only by motor car injuries and drownings. The mortality has been reduced substantially in recent years, but very many children must still carry scars both physical and emotional for the rest of their lives from burning accidents, many of which were preventable.


Ultrasound-mediated targeted drug delivery with a novel cyclodextrin-based drug carrier by mechanical and thermal mechanisms.
Various mechanisms for ultrasound-mediated targeted drug delivery have been investigated in the past several decades. Cyclodextrins are already known for their ability to encapsulate various drugs in their lipophilic cavity; this paper reports evaluation of the potential of a cyclodextrin-based nanocarrier as a drug delivery vehicle, using cell monolayers in vitro in conjunction with ultrasound as the release mechanism. The application of ultrasound to the cell monolayers results in both thermal and mechanical effects; a current challenge is to differentiate between these effects. In this study, the cell uptake routes of doxorubicin encapsulated in the cyclodextrin-based carrier were investigated, examining individually the thermal and the mechanical effects of focused ultrasound for drug release. Exploiting mechanical effects, the uptake of encapsulated doxorubicin into cancer cells was increased by a factor of up to 5.5 when ultrasound was applied. Thermal application of FUS increased the cellular uptake of encapsulated doxorubicin by a factor of up to 9.6. Hyperthermia without focused ultrasound resulted in an increase by a factor of up to 5.7.


Aggregative growth in the size-controlled growth of monodispersed gold nanoparticles.
This article describes the findings of an investigation of the aggregative growth mechanism for the formation of gold nanoparticles in aqueous solutions under ambient conditions with high monodispersity (2% RSD) over a wide range of particle sizes (10-100 nm). The utilization of the gold nanoparticles synthesized by this simple, reproducible growth mechanism has recently been demonstrated for establishing the size correlation for the surface plasmon resonance optical and surface-enhanced Raman scattering spectroscopic properties. The particle size, morphology, and optical properties of the nanoparticles produced at different stages of the growth processes were determined as a function of control parameters such as the reaction time and seed/precursor concentrations. The results have allowed us to establish a quantitative correlation between the growth size and the seed/precursor concentrations for the precise control of nanoparticle sizes. The kinetic measurements have demonstrated a polycrystalline character for the grown particles, a bimodal size distribution in the early stage of growth, sigmoidal kinetic behavior for the growth, and a correlation of the nucleation parameters with the particle size and distribution. These findings provided important indicators for the operation of an aggregative growth mechanism in the particle size growth and have important implications in understanding interparticle aggregation and coalescence in nanoparticle formation and growth under similar conditions.


Cyclin D1 G870A polymorphism and risk of colorectal cancer: a case control study.
The present study aimed to analyse the role of cyclin D1 A870G polymorphism in modulating the susceptibility to colorectal cancer (CRC) in the Kashmiri population. The genotype distribution of the cyclin D1 gene in 130 CRC cases in comparison with 160 healthy controls was investigated. No direct significant association between cyclin D1 genotypes and CRC was observed; however, the AG and AA genotypes were found to be associated with an increased risk of CRC compared to the GG genotype, with an almost 2-fold increase in OR. This study suggests that the cyclin D1 polymorphism is associated with an increased risk of CRC in the Kashmiri population.


Outdoor characterization of radio frequency electromagnetic fields in a Spanish birth cohort.
There is considerable public concern in many countries about the possible adverse effects of exposure to non-ionizing radiation electromagnetic fields, especially in vulnerable populations such as children. The aim of this study was to characterize environmental exposure profiles within the frequency range 100kHz-6GHz in the immediate surrounds of the dwellings of 123 families from the INMA-Granada birth cohort in Southern Spain, using spot measurements. The arithmetic mean root mean-square electric field (ERMS) and power density (SRMS) values were, respectively, 195.79mV/m (42.3% of data were above this mean) and 799.01µW/m(2) (30% of values were above this mean); median values were 148.80mV/m and 285.94µW/m(2), respectively. Exposure levels below the quantification limit were assigned a value of 0.01V/m. Incident field strength levels varied widely among different areas or towns/villages, demonstrating spatial variability in the distribution of exposure values related to the surface area population size and also among seasons. Although recorded values were well below International Commission for Non-Ionizing Radiation Protection reference levels, there is a particular need to characterize incident field strength levels in vulnerable populations (e.g., children) because of their chronic and ever-increasing exposure. The effects of incident field strength have not been fully elucidated; however, it may be appropriate to apply the precautionary principle in order to reduce exposure in susceptible groups.


Improving Outpatient Provider Communication for High-Risk Discharges From the Hospitalist Service.
Patients are at risk for adverse events during inpatient-to-outpatient transitions of care. Previous improvement work has been targeted at this care transition, but gaps in discharge communication still exist. We aimed to increase documentation of 2-way communication between hospitalists and primary care providers (PCPs) for high-risk discharges from pediatric hospital medicine (PHM) services from 7% to 60% within 30 months. A3 improvement methodology was used. A list of high-risk discharge communication criteria was developed through engagement of PCPs and hospitalists. A driver diagram guided interventions. The outcome measure was documentation of successful 2-way communication with the PCP. Any documented 2-way discharge communication attempt was the process measure. Via a survey, hospitalist satisfaction with the discharge communication expectation served as the balancing measure. All patients discharged from PHM services meeting ≥1 high-risk criterion were included. Statistical process control charts were used to assess changes over time. There were 3241 high-risk discharges (442 baseline: November 2017 to January 2018; 2799 intervention and sustain: February 2018 to June 2020). The outcome measure displayed iterative special cause variation from a mean baseline of 7% to peak of 39% but regressed and was sustained at 27%. The process measure displayed iterative special cause variation from a 13% baseline mean to a 64% peak, with regression to 41%. The balancing measure worsened from baseline of 5% dissatisfaction to 13%. Interventions temporally related to special cause improvements were education, division-level performance feedback, standardization of documentation, and offloading the task of communication coordination from hospitalists to support staff. Improvement methodology resulted in modestly sustained improvements in PCP communication for high-risk discharges from the PHM services.


Metabolic and distribution studies with radiolabeled 5-fluorouracil.
5-Fluorouracil (5-FU) is an effective anti-tumor drug, which has been used both as a single agent and in combination with other chemotherapeutic agents for the treatment of tumors such as breast and colorectal carcinoma. We synthesized 5-FU with trace amounts of 18F-5-FU and administered the compounds intravenously to 6 cancer patients. The patients were scanned at 2 hr intervals for 12 hrs and their urine collected whenever possible. We also injected 5-FU with the tracer 18F-5-FU, at pharmacological doses, into non-tumored rats, and sampled their bile and blood for 95 mins post-injection. For comparison, 2-14C-5-FU was injected into non-tumored rats and their bile and blood sampled at the same intervals. Minute quantities of rat bile and serum were analyzed chromatographically by high-performance TLC. 5-FU and two of its metabolites (FBAL and FUPA) were identified and quantified by this technique. Both percentage and absolute amounts of 5-FU in the bile follow comparative kinetic patterns. While the liver and the urinary bladder were clearly observable in all 16 patients, the detectability of the gall-bladder was correlated to the inverse of the alkaline phosphatase level in the blood. This work suggests that the diversity of the 5-FU metabolism in cancer patients may allow the use of 18F-5-FU as a probe for understanding those individual variabilities in clinical situations.


An investigation into E-cigarette cytotoxicity in-vitro using a novel 3D differentiated co-culture model of human airways.
Currently there is a lack of consensus on the possible adverse health effects of E-cigarettes (ECs). Important factors including cell model employed and exposure method determine the physiological relevance of EC studies. The present study aimed to evaluate EC cytotoxicity using a physiologically relevant in-vitro multicellular model of human airways. Human bronchial epithelial cells (CALU-3) and pulmonary fibroblasts (MRC-5) were co-cultured at air-liquid-interface for 11-14 days post which they were exposed to whole cigarette smoke (WCS) or EC vapour (ECV) at standard ISO-3308 regime for 7 m using a bespoke aerosol delivery system. ECV effects were further investigated at higher exposure times (1 h-6 h). Results showed that while WCS significantly reduced cell viability after 7 m, ECV decreased cell viability only at exposure times higher than 3 h. Furthermore, ECV caused elevated IL-6 and IL-8 production despite reduced cell viability. ECV exposure also produced a marked increase in oxidative stress. Finally, WCS but not ECV exposure induced caspase 3/7 activation, suggesting a caspase independent death of ECV exposed cells. Overall, our results indicate that prolonged ECV exposure (≥3 h) has a significant impact on pro-inflammatory mediators' production, oxidative stress and cell viability but not caspase 3/7 activity.


Effects of antenatal uteroplacental hypoperfusion on neonatal microvascularisation and excitotoxin sensitivity in mice.
Vascular intrauterine growth restriction (IUGR) occurs in about 5% of pregnancies and may reduce the incidence of periventricular leukomalacia in preterm newborns. We evaluated neonatal excitotoxicity in a murine model of vascular IUGR involving unilateral uterine ligation on embryonic day (E)13.5. Birth weight was significantly decreased in the ligation group compared with the sham group (p < 0.001). VEGFs, VEGF receptors (VEGFRs), and NMDA receptor subunit mRNAs in brain extracts were assayed using quantitative RT-PCR. Ligation was associated with increased mRNAs for the vascular marker PECAM-1 on postnatal day (PD)2 and VEGFR-3 on PD2 and PD10, contrasting with decreased VEGFA and VEGFC on PD10. Microvessel density was increased on PD7. Ligated and sham pups received intracerebral ibotenate (NMDA agonist) on PD2 or PD10. Cortical and white matter (WM) lesions after 5 d were reduced in ligated versus sham pups injected on PD2 (p < 0.001 and p < 0.01, respectively); this effect persisted on PD42 (p < 0.01 and p < 0.05, respectively). With ibotenate on PD10, lesions were exacerbated after 5 d in the ligated group in the cortex (p < 0.05) and WM (p < 0.05) and on PD42 in the cortex (p < 0.05). In conclusion, vascular IUGR offered only transient protection against neonatal excitotoxic lesions, possibly via angiogenesis.


Non-syndromic language delay in a child with disruption in the Protocadherin11X/Y gene pair.
Protocadherin11 is located on both the X and Y chromosomes in Homo sapiens but only on the X chromosome in other hominid species. The pairing of PCDH11Y with PCDH11X arose following a duplicative 3.5 Mb translocation from the ancestral X chromosome to the Y chromosome several million years ago. The genes are highly expressed in fetal brain and spinal cord. The evolutionary consequence of this duplication has been proposed to include the sexual dimorphism of cerebral asymmetry and the hominid specific transition to the capacity for language. We report a case of a male child referred for genetic investigation of severe language delay. Microarray analysis indicated the presence of a 220 Kb intragenic deletion at Xq21.31 involving the PCDH11X gene. Fluorescence in situ hybridization using a BAC probe mapping to intron 2 of the Protocadherin11X/Y gene pair confirmed loss of the locus on both the X and Y chromosomes. The X chromosome deletion was maternally inherited, but the Y chromosome deletion was found to be a de novo occurrence in this child. This finding lends support to the hypothesis that the Protocadherin11X/Y gene plays a role in language development in humans and that rare copy number variation is a possible mechanism for communication disorders.


An Unusual Type of Localized Hypertrophic Cardiomyopathy With Wolf Parkinson White Syndrome Presenting With Pulmonary Edema.
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease that is the most common genetic cardiac disorder. The disease is characterized by excessive thickening of the left ventricular myocardium. The anterior portion of the interventricular ventricular septum is often involved. Asymmetric hypertrophy of apical site, left ventricular free wall, and right ventricle are less common in hypertrophic cardiomyopathy that occur in 1% cases. We report a case of a patient with an unusual type of hypertrophic cardiomyopathy and Wolf Parkinson White (WPW) presenting with pulmonary edema.