NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data.
Cytotoxic T cells are of central importance in the immune system's response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC class I molecules. Peptide binding to MHC molecules is the single most selective step in the Ag-presentation pathway. Therefore, in the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has attracted widespread attention. In the past, predictors of peptide-MHC interactions have primarily been trained on binding affinity data. Recently, an increasing number of MHC-presented peptides identified by mass spectrometry have been reported containing information about peptide-processing steps in the presentation pathway and the length distribution of naturally presented peptides. In this article, we present NetMHCpan-4.0, a method trained on binding affinity and eluted ligand data leveraging the information from both data types. Large-scale benchmarking of the method demonstrates an increase in predictive performance compared with state-of-the-art methods when it comes to identification of naturally processed ligands, cancer neoantigens, and T cell epitopes.


Importance of an M2 depopulating channel for a Kr II metastable state.
An experimental investigation of the radiative lifetime of the metastable 4s24p4(3P)4d4D7/2 level in Kr II shows an unusual situation regarding the importance of an M2 depopulation channel. While the first order M1 and E2 channels are expected to contribute in a dominant way to the decay, the experimental result, obtained using a laser probing technique on a stored ion beam, tau = 0.57+/-0.03 s, is far too short to be due to these channels according to our relativistic multiconfiguration Dirac-Fock calculation. Only if second order contributions to the decay branches (including essentially the M2 contribution) are taken into account in the calculations could the unexpected short lifetime be explained.


Phospholipid membrane encapsulation of nanoparticles for surface-enhanced Raman scattering.
Lipid-encapsulated surface-enhanced Raman scattering (SERS) nanoparticles, with promising applications in biomedical diagnostics, were produced. Gold nanoparticles, 60 nm in diameter, were coated with a ternary mixture of DOPC, sphingomyelin, and cholesterol. The lipid layer is versatile for engineering the chemical and optical properties of the particles. The stability of the lipid-encapsulated particles is demonstrated over a period of weeks. The versatility of the layer is demonstrated by the incorporation of three different Raman-active species using three different strategies. The lipid layer was directly observed by TEM, and the SERS spectrum of the three dye species was confirmed by Raman spectroscopy. UV-vis absorption and dynamic light scattering provide additional evidence of lipid encapsulation. The encapsulation is achieved in aqueous solution, avoiding phase transfer and possible contamination from organic solvents. Furthermore, when fluorescent dye-labeled lipids were employed in the encapsulant, the fluorescence and SERS activity of the particles were controlled by the use of dissolved ions in the preparation solution.


Radiosurgery as primary management for meningiomas extending into the internal auditory canal.
Stereotactic radiosurgery is increasingly utilized as primary management for patients with skull base meningiomas. This study reviews the results of stereotactic radiosurgery for patients with meningiomas extending into the internal auditory canal (IAC) to determine the risk of facial weakness or hearing loss. From 1990 to 2002, 16 patients had radiosurgery for meningiomas extending into the IAC. The median patient age was 63 years. Ten patients had symptoms of vestibulocochlear nerve dysfunction before radiosurgery. The median tumor volume was 5.1 cm3; the median tumor extension into the IAC was 7 mm (range, 3-12). The median tumor margin dose was 15 Gy. The median follow-up was 36 months. Ten meningiomas (63%) decreased in size, and 6 tumors were unchanged. No patient developed facial weakness. One patient (6%) had worsened facial sensation. Three of 14 patients (21%) with either normal hearing clinically (n = 5) or documented Gardner-Robertson class 1-2 before radiosurgery (n = 9) had decreased hearing after radiosurgery. The 1-, 2- and 5-year actuarial incidences of hearing preservation were 93, 84 and 42%, respectively. Three patients (19%) had improved hearing after radiosurgery. One patient with class 2 hearing improved to class 1; 2 patients with no speech discrimination before radiosurgery (class 5) improved to a class 3 status following the procedure. The risk of facial weakness or hearing loss is low after radiosurgery for patients with meningiomas extending into the IAC. Radiosurgery is an excellent alternative to surgical excision for meningiomas in this location, especially if a subtotal resection is likely or a hearing-sacrificing operation such as a translabyrinthine approach is contemplated.


Motor thalamus integration of cortical, cerebellar and basal ganglia information: implications for normal and parkinsonian conditions.
Motor thalamus (Mthal) is implicated in the control of movement because it is strategically located between motor areas of the cerebral cortex and motor-related subcortical structures, such as the cerebellum and basal ganglia (BG). The role of BG and cerebellum in motor control has been extensively studied but how Mthal processes inputs from these two networks is unclear. Specifically, there is considerable debate about the role of BG inputs on Mthal activity. This review summarizes anatomical and physiological knowledge of the Mthal and its afferents and reviews current theories of Mthal function by discussing the impact of cortical, BG and cerebellar inputs on Mthal activity. One view is that Mthal activity in BG and cerebellar-receiving territories is primarily "driven" by glutamatergic inputs from the cortex or cerebellum, respectively, whereas BG inputs are modulatory and do not strongly determine Mthal activity. This theory is steeped in the assumption that the Mthal processes information in the same way as sensory thalamus, through interactions of modulatory inputs with a single driver input. Another view, from BG models, is that BG exert primary control on the BG-receiving Mthal so it effectively relays information from BG to cortex. We propose a new "super-integrator" theory where each Mthal territory processes multiple driver or driver-like inputs (cortex and BG, cortex and cerebellum), which are the result of considerable integrative processing. Thus, BG and cerebellar Mthal territories assimilate motivational and proprioceptive motor information previously integrated in cortico-BG and cortico-cerebellar networks, respectively, to develop sophisticated motor signals that are transmitted in parallel pathways to cortical areas for optimal generation of motor programmes. Finally, we briefly review the pathophysiological changes that occur in the BG in parkinsonism and generate testable hypotheses about how these may affect processing of inputs in the Mthal.


Bradykinin recognizes different molecular forms of the B2 kinin receptor in the presence and absence of guanine nucleotides.
We have previously reported that [3H]bradykinin [( 3H]BK) identifies high- and low-affinity B2 kinin receptor sites in bovine myometrial membranes which are sensitive and insensitive respectively to guanine nucleotides. Here we show that these receptor-binding sites are solubilized by the detergent CHAPS. Equilibrium binding in soluble preparations revealed that [3H]BK identified a maximal number of binding sites (Bmax) of 1119 +/- 160 fmol/mg of protein, with an equilibrium dissociation constant (KD) of 314 +/- 70 pM and with a typical B2 kinin receptor specificity. Dissociation of equilibrium binding was biphasic. In the presence of the GTP analogue guanosine 5'[beta gamma-imido]triphosphate (Gpp[NH]p, [3H]BK bound to the soluble receptors with a KD of 929 +/- 129 pM and a Bmax. of 706 +/- 38 fmol/mg of protein. The Gpp(NH)p-promoted decrease in the apparent affinity and Bmax., which was half-maximal at 0.5 microM, was due at least in part to an increase in the dissociation rate of the slowly dissociating component of the equilibrium binding. Recoveries of guanine-nucleotide-sensitivity and of rapidly and slowly dissociating binding components were essentially identical, whether or not the receptor had been occupied by an agonist before solubilization. Sucrose-density-gradient sedimentation profiles revealed that [3H]BK recognized two different molecular forms of the receptor in the absence or presence of guanine nucleotides. These results provide for the first time direct evidence that guanine nucleotides promote a change in the structure of the B2 kinin-receptor complex. We propose that this structural change is due to dissociation of a guanine-nucleotide-regulatory (G-)protein.


Lack of protection of pre-immunization with saliva of long-term colonized Phlebotomus papatasi against experimental challenge with Leishmania major and saliva of wild-caught P. papatasi.
Immunity to saliva of Phlebotomus papatasi protects against Leishmania major infection as determined by co-inoculation of parasites with salivary gland homogenates (SGHs) of this vector. These results were obtained with long-term colonized female P. papatasi. We investigated the effect of pre-immunization with SGH of long-term colonized P. papatasi against L. major infection co-inoculated with SGH of wild-caught P. papatasi. Our results showed that pre-exposure to SGH of long-term, colonized P. papatasi do not confer protection against infection with L. major co-inoculated with SGH of wild-caught P. papatasi. These preliminary results strongly suggest that the effectiveness of a vector saliva-based vaccine derived from colonized sand fly populations may be affected by inconsistent immune response after natural exposure.


Estimation of π-π Electronic Couplings from Current Measurements.
The π-π interactions between organic molecules are among the most important parameters for optimizing the transport and optical properties of organic transistors, light-emitting diodes, and (bio-) molecular devices. Despite substantial theoretical progress, direct experimental measurement of the π-π electronic coupling energy parameter t has remained an old challenge due to molecular structural variability and the large number of parameters that affect the charge transport. Here, we propose a study of π-π interactions from electrochemical and current measurements on a large array of ferrocene-thiolated gold nanocrystals. We confirm the theoretical prediction that t can be assessed from a statistical analysis of current histograms. The extracted value of t ≈35 meV is in the expected range based on our density functional theory analysis. Furthermore, the t distribution is not necessarily Gaussian and could be used as an ultrasensitive technique to assess intermolecular distance fluctuation at the subangström level. The present work establishes a direct bridge between quantum chemistry, electrochemistry, organic electronics, and mesoscopic physics, all of which were used to discuss results and perspectives in a quantitative manner.


Epilepsy in children with mental retardation: a cohort study.
The cumulative risk of seizures and epilepsy was investigated in a prospectively identified cohort of 221 children with mental retardation (MR) born between 1951 and 1955 in Aberdeen, Scotland. By age 22 years, 33 (15%) had epilepsy. An additional 16 (7%) had had at least one seizure, but did not meet the criteria for epilepsy. The cumulative risk of epilepsy was 9, 11, 13, and 15% at 5, 10, 15, and 22 years, respectively. In children with MR and no associated disabilities, the cumulative risk of epilepsy was only 2.6, 3.2, 3.9, and 5.2% at 5, 10, 15, and 22 years. In children with MR and cerebral palsy (CP), the cumulative risk was 28, 31, and 38% at 5, 10, and 22 years. Children with a postnatal injury associated with MR had a cumulative risk of epilepsy of 53, 66, and 66% at 5, 10, and 15 years after the injury. By age 22 years, 39% had achieved 5-year seizure-free remission, including 56% of children with MR without associated disability, 47% of children with MR and CP, and 11% of children with a postnatal injury. We conclude that, in the absence of associated disability or postnatal injury, the risk of epilepsy in the retarded population is low. Epilepsy in this population also will frequently enter remission in later life.


Abatement cost of GHG emissions for wood-based electricity and ethanol at production and consumption levels.
Woody feedstocks will play a critical role in meeting the demand for biomass-based energy products in the US. We developed an integrated model using comparable system boundaries and common set of assumptions to ascertain unit cost and greenhouse gas (GHG) intensity of electricity and ethanol derived from slash pine (Pinus elliottii) at the production and consumption levels by considering existing automobile technologies. We also calculated abatement cost of greenhouse gas (GHG) emissions with respect to comparable energy products derived from fossil fuels. The production cost of electricity derived using wood chips was at least cheaper by 1 ¢ MJ-1 over electricity derived from wood pellets. The production cost of ethanol without any income from cogenerated electricity was costlier by about 0.7 ¢ MJ-1 than ethanol with income from cogenerated electricity. The production cost of electricity derived from wood chips was cheaper by at least 0.7 ¢ MJ-1 than the energy equivalent cost of ethanol produced in presence of cogenerated electricity. The cost of using ethanol as a fuel in a flex-fuel vehicle was at least higher by 6 ¢ km-1 than a comparable electric vehicle. The GHG intensity of per km distance traveled in a flex-fuel vehicle was greater or lower than an electric vehicle running on electricity derived from wood chips depending on presence and absence of GHG credits related with co-generated electricity. A carbon tax of at least $7 Mg CO2e-1 and $30 Mg CO2e-1 is needed to promote wood-based electricity and ethanol production in the US, respectively. The range of abatement cost of GHG emissions is significantly dependent on the harvest age and selected baseline especially for electricity generation.


Ultrasound elastography to determine the layered mechanical properties of articular cartilage and the importance of such structural characteristics under load.
Articular cartilage is an important load bearing surface in joints. Prone to damage and with limited self-repair ability, it is of interest to tissue engineers. Tissue implant design requires full mechanical characterisation of healthy native tissue. A layered organisation of reinforcing collagen fibrils exists in healthy articular cartilage and is believed to be important for correct tissue function. However, the effect of this on the local depth-dependent elasticity is poorly characterised. In this study, quasi-static ultrasound elastography is used both to compare the depth-dependent elastic properties of cartilage structures with two different fibril arrangements and to monitor changes in the elastic properties of engineered samples during development. Results show global and local elastic properties of the native tissues and highlight the differences caused by fibril architecture. At increasing culture periods, results from the engineered tissue demonstrate an increase in elastic stiffness and the time taken to reach equilibrium under a quasi-static displacement. The study suggests suitability of ultrasound elastography for design and monitoring engineered articular cartilage.


Droplet-based bisulfite sequencing for high-throughput profiling of single-cell DNA methylomes.
Genome-wide DNA methylation profile, or DNA methylome, is a critical component of the overall epigenomic landscape that modulates gene activities and cell fate. Single-cell DNA methylomic studies offer unprecedented resolution for detecting and profiling cell subsets based on methylomic features. However, existing single-cell methylomic technologies are all based on use of tubes or well plates and these platforms are not easily scalable for handling a large number of single cells. Here we demonstrate a droplet-based microfluidic technology, Drop-BS, to construct single-cell bisulfite sequencing libraries for DNA methylome profiling. Drop-BS takes advantage of the ultrahigh throughput offered by droplet microfluidics to prepare bisulfite sequencing libraries of up to 10,000 single cells within 2 d. We applied the technology to profile mixed cell lines, mouse and human brain tissues to reveal cell type heterogeneity. Drop-BS will pave the way for single-cell methylomic studies requiring examination of a large cell population.


Caffeinated energy drink use by U.S. adolescents aged 13-17: A national profile.
The present study examined the national prevalence and distribution of adolescent use of caffeinated energy drinks, assessing variations in sociodemographic characteristics, personality traits, lifestyles, and patterns of alcohol and caffeine use. A cross-sectional survey was conducted in May 2014, using a nationally representative sample of 1,032 U.S. early (aged 13-15; n = 602) and middle adolescents (aged 16-17; n = 430). Nearly two thirds of teens reported ever using energy drinks; 41% had done so recently, that is, in the past 3 months. Middle adolescents reported higher prevalences of both lifetime and recent use of energy drinks than early adolescents. Common situational contexts for use (e.g., compensating for lack of sleep or playing sports) differed by both gender and age cohort. In hierarchical logistic regression analyses, gender and geographic region significantly predicted both lifetime and recent use for early adolescents only, whereas age and race were significant predictors only for middle adolescents. For both age cohorts, odds of both lifetime and recent use increased with sensation-seeking score, lifetime alcohol use, and recent caffeinated soft drink use. Among early adolescents, grade point average predicted lifetime use only, whereas coffee and caffeine pill use predicted recent use only. Among middle adolescents, impulsivity and past sports participation predicted lifetime but not recent use. Our findings show that adolescent energy drink use is widespread and varies as a function of demographic, psychosocial, lifestyle, and substance use characteristics. Future research is needed to assess whether differences between early and middle adolescent use patterns are primarily developmental or cohort effects. (PsycINFO Database Record


Acute effects of chundosunbup qi-training on blood concentrations of TSH, calcitonin, PTH and thyroid hormones in elderly subjects.
The present study investigated how the systemic treatment of a programmed exercise, ChunDoSunBup (CDSB) Qi-training, affects the secretion of thyroid and parathyroid hormones in elderly subjects (10 male and 5 female). Plasma concentrations of thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), parathyroid hormone (PTH), ionized calcium, and calcitonin were determined. CDSB Qi-training induces a slight increase in TSH. Both T4 and T3 were increased at the mid-time of CDSB Qi-training (p < 0.05). There were significant correlations only between T3 and T4 at mid-training. This shows that increase in the plasma level of T3 was associated with the secretion of T4. The plasma concentrations of calcitonin and PTH were increased at mid-time and post-time of CDSB Qi-training. But ionized calcium was decreased slightly by CDSB Qi-training. These results suggest that Qi-training modulates the secretion of thyroid hormones, calcium metabolism, and parathyroid hormones in the elderly. However, whether the long-term practice of CDSB Qi-training might change bone metabolism and have longitudinal effects on the thyroid hormone of the elderly need further investigation.


Acquired partial lipodystrophy with C3 hypocomplementemia and antiphospholipid and anticardiolipin antibodies.
Acquired partial lipodystrophy is an extremely rare condition of unknown etiology characterized by progressive loss of fat of the face, neck, trunk, and upper extremities. It usually begins during childhood and is more common in girls. C(3) hypocomplementemia is seen in 70% of patients with acquired partial lipodystrophy. Unlike generalized forms of the disease, no insulin resistance occurs. We present three boys with acquired partial lipodystrophy having C(3) hypocomplementemia. In addition, one of them had antiphospholipid and anticardiolipin antibodies.


Surveillance for waterborne disease and outbreaks associated with recreational water use and other aquatic facility-associated health events--United States, 2005-2006.
Since 1971, CDC, the U.S. Environmental Protection Agency, and the Council of State and Territorial Epidemiologists have collaboratively maintained the Waterborne Disease and Outbreak Surveillance System for collecting and reporting data related to waterborne-disease outbreaks (WBDOs) associated with drinking water. In 1978, WBDOs associated with recreational water (natural and treated water) were added. This system is the primary source of data regarding the scope and effects of disease associated with recreational water in the United States. In addition, data are collected on individual cases of recreational water-associated illnesses and infections and health events occurring at aquatic facilities but not directly related to water exposure. Data presented summarize WBDOs and case reports associated with recreational water use that occurred during January 2005--December 2006 and previously unreported disease reports and outbreaks during 1978--2004. Public health departments in the states, territories, localities, and the Freely Associated States (i.e., the Republic of the Marshall Islands, the Federated States of Micronesia, and the Republic of Palau, formerly parts of the U.S.-administered Trust Territory of the Pacific Islands) have primary responsibility for detecting, investigating, and voluntarily reporting WBDOs to CDC. Although the surveillance system includes data for WBDOs and cases associated with drinking water, recreational water, and water not intended for drinking, only cases and outbreaks associated with recreational water and health events at aquatic facilities are summarized in this report. During 2005--2006, a total of 78 WBDOs associated with recreational water were reported by 31 states. Illness occurred in 4,412 persons, resulting in 116 hospitalizations and five deaths. The median outbreak size was 13 persons (range: 2--2,307 persons). Of the 78 WBDOs, 48 (61.5%) were outbreaks of gastroenteritis that resulted from infectious agents or chemicals; 11 (14.1%) were outbreaks of acute respiratory illness; and 11 (14.1%) were outbreaks of dermatitis or other skin conditions. The remaining eight were outbreaks of leptospirosis (n = two), primary amebic meningoencephalitis (n = one), and mixed or other illnesses (n = five). WBDOs associated with gastroenteritis resulted in 4,015 (91.0%) of 4,412 illnesses. Fifty-eight (74.4%) WBDOs occurred at treated water venues, resulting in 4,167 (94.4%) cases of illness. The etiologic agent was confirmed in 62 (79.5%) of the 78 WBDOs, suspected in 12 (15.4%), and unidentified in four (5.1%). Thirty-four (43.6%) WBDOs had a parasitic etiology; 22 (28.2%), bacterial; four (5.1%), viral; and two (2.6%), chemical or toxin. Among the 48 gastroenteritis outbreaks, Cryptosporidium was confirmed as the causal agent in 31 (64.6%), and all except two of these outbreaks occurred in treated water venues where Cryptosporidium caused 82.9% (29/35) of the gastroenteritis outbreaks. Case reports associated with recreational water exposure that were discussed and analyzed separately from outbreaks include three fatal Naegleria cases and 189 Vibrio illnesses reported to the Cholera and Other Vibrio Illness Surveillance System. For Vibrio reporting, the most commonly reported species were Vibrio vulnificus, V. alginolyticus, and V. parahaemolyticus. V. vulnificus illnesses associated with recreational water exposure had the highest Vibrio illness hospitalization (77.6%) and mortality (22.4%) rates. In addition, 32 aquatic facility-related health events not associated with recreational water use (e.g., pool chemical mixing accidents) that occurred during 1983--2006 were received from New York. These events, which caused illness in 364 persons, are included in this report but analyzed separately. The number of WBDOs summarized in this report and the trends in recreational water-associated disease and outbreaks demonstrate a substantial increase in number of reports from previous years. Outbreaks, especially the largest ones, occurred more frequently in the summer at treated water venues and caused gastrointestinal illness. Deficiencies leading to WBDOs included problems with water-quality, venue design, usage, and maintenance. Case reports of illness associated with recreational water use expand our understanding of the scope of waterborne illness by further underscoring the contribution of less well-recognized swimming venues (e.g., oceans) and illness (e.g., nongastrointestinal illness). Aquatic facilities are also a focus for injuries involving chemicals or equipment used routinely in the operation of swimming venues, thus illustrating the lack of training of some aquatics staff. CDC uses WBDO surveillance data to 1) identify the etiologic agents, types of aquatic venues, water-treatment systems, and deficiencies associated with outbreaks and case reports; 2) evaluate the adequacy of efforts (i.e., regulations and public awareness activities) to provide safe recreational water; 3) expand the scope of understanding about waterborne disease and health events associated with swimming and aquatics facilities; and 4) establish public health prevention priorities, data, and messaging that might lead to improved regulations, guidelines, and prevention measures at the local, state, and federal levels.


Improving clinical practice guidelines for practicing cardiologists.
Cardiac-related clinical practice guidelines have become an integral part of the practice of cardiology. Unfortunately, these guidelines are often long, complex, and difficult for practicing cardiologists to use. Guidelines should be condensed and their format upgraded, so that the key messages are easier to comprehend and can be applied more readily by those involved in patient care. After presenting the historical background and describing the guideline structure, we make several recommendations to make clinical practice guidelines more user-friendly for clinical cardiologists. Our most important recommendations are that the clinical cardiology guidelines should focus exclusively on (1) class I recommendations with established benefits that are supported by randomized clinical trials and (2) class III recommendations for diagnostic or therapeutic approaches in which quality studies show no benefit or possible harm. Class II recommendations are not evidence based but reflect expert opinions related to published clinical studies, with potential for personal bias by members of the guideline committee. Class II recommendations should be published separately as "Expert Consensus Statements" or "Task Force Committee Opinions," so that both majority and minority expert opinions can be presented in a less dogmatic form than the way these recommendations currently appear in clinical practice guidelines.


[Subclinical forms of spinal disorders in discogenic lumbar radiculitis].
In patients with discogenic lumbar radiculitis with a unilateral affection of L5 or S1 root motor and central responses of the medial group of plantar muscles were recorded. In S1 root pathology the central response consisted in 25% of the cases in repeated antidromal discharges, which testified to an increased excitability of the corresponding alpha-motoneurons. In patients with L5-radiculitis a predominance of the reflex component in the response was typical. Since this phenomenon was lacking in combined L5 and S1 root lesions, it was interpreted as a sign of a decreasing function of the segmental inhibitory interneurons.


Ochratoxin A induces global DNA hypomethylation and oxidative stress in neuronal cells in vitro.
Recently, it was reported that ochratoxin A (OTA) mycotoxin, produced by a number of Aspergillus and Penicillium fungal species, may cause neuropsychological impairment or mental and emotional disorders but the mechanism of neurotoxicity remains unknown. Adverse effects of OTA in human (SHSY5Y) and mouse (HT22) neuronal cell lines were studied in vitro. OTA was found to be non-cytotoxic in both cell lines at concentrations 2.5-30 μmol/l, which are above the levels reported for human and animal plasma. OTA led to slightly elevated chromosomal instability in HT22 cells at concentrations of 15-30 μmol/l after 48 h, while in SHSY5Y cells, no evidence for genotoxic effects was observed at concentrations of 2.5-30 μmol/l. OTA treatment at 10 μmol/l resulted in elevated levels of unmethylated cytosines in CpG dinucleotides (up to 1.4-fold), elevated levels of intracellular reactive oxygen species (up to 1.6-fold), and in elevated levels of oxidized DNA purines (up to 2.2-fold) in both cell lines. Detected global DNA hypomethylation and oxidative stress were found to be reversible in 96 h and 24-72 h, respectively. In general, the observed pattern of OTA-induced effects in both cell lines was similar, but HT22 cells exhibited higher sensitivity, as well as better repair capacity in response to OTA toxicity. In conclusion, the results suggest that oxidative stress and epigenetic changes are directly involved in OTA-induced neurotoxicity, while cytotoxicity and genotoxicity cannot be considered as primary cause of toxicity in neuronal cells in vitro.


Electrical stimulation for preventing and treating post-stroke shoulder pain.
Shoulder pain after stroke is common and disabling. The optimal management is uncertain, but electrical stimulation (ES) is often used to treat and prevent pain. The objective of this review was to determine the efficacy of any form of surface ES in the prevention and / or treatment of pain around the shoulder at any time after stroke. We searched the Cochrane Stroke Review Group trials register and undertook further searches of MEDLINE, EMBASE and CINAHL. Contact was established with equipment manufacturers and centres that have published on the topic of ES. We considered all randomised trials that assessed any surface ES technique (functional electrical stimulation (FES), transcutaneous electrical nerve stimulation (TENS) or other), applied at any time since stroke for the purpose of prevention or treatment of shoulder pain. Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data. Four trials (a total of 170 subjects) fitted the inclusion criteria. Study design and ES technique varied considerably, often precluding the combination of studies. Population numbers were small. There was no significant change in pain incidence (Odds Ratio (OR) 0.64; 95% CI 0.19 to 2.14) or change in pain intensity (Standardised Mean Difference (SMD) 0.13; 95% CI -1.0 to 1.25) after ES treatment compared to control. There was a significant treatment effect in favour of ES for improvement in pain-free range of passive humeral lateral rotation (Weighted Mean Difference (WMD) 9.17; 95% CI 1.43 to 16.91). In these studies ES reduced the severity of glenohumeral subluxation (SMD -1.13; 95% CI -1.66 to -0.60), but there was no significant effect on upper limb motor recovery (SMD 0.24; 95% CI -0.14 to 0.62) or upper limb spasticity (WMD 0.05; 95% CI -0.28 to 0.37). There did not appear to be any negative effects of electrical stimulation at the shoulder. The evidence from randomised controlled trials so far does not confirm or refute that ES around the shoulder after stroke influences reports of pain, but there do appear to be benefits for passive humeral lateral rotation. A possible mechanism is through the reduction of glenohumeral subluxation. Further studies are required.


Geometric fluctuation theorem for a spin-boson system.
We derive an extended fluctuation theorem for geometric pumping of a spin-boson system under periodic control of environmental temperatures by using a Markovian quantum master equation. We obtain the current distribution, the average current, and the fluctuation in terms of the Monte Carlo simulation. To explain the results of our simulation we derive an extended fluctuation theorem. This fluctuation theorem leads to the fluctuation dissipation relations but the absence of the conventional reciprocal relation.


VALUE OF FRACTAL ANALYSIS OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN VARIOUS STAGES OF DIABETIC RETINOPATHY.
To use fractal dimensional analysis to investigate retinal vascular disease patterns in patients with diabetic retinopathy using spectral domain optical coherence tomography angiography. A retrospective study was conducted which included 49 eyes from 26 control subjects and 58 eyes from 35 patients known to have diabetic retinopathy. Of the 58 eyes with known retinopathy, 31 were categorized as nonproliferative diabetic retinopathy (13 mild, 9 moderate, and 9 severe) and 27 were categorized as proliferative diabetic retinopathy. Optical coherence tomography angiography images were acquired using the RTVue XR Avanti (Optovue, Inc). Automated segmentation was obtained through both the superficial and deep capillary plexuses for each eye. Grayscale optical coherence tomography angiography images were standardized and binarized using ImageJ (National Institutes of Health). Fractal box-counting analyses were conducted using Fractalyse (ThéMA). Fractal dimensions (FDs) and correlation coefficient of the superficial and deep capillary plexuses were compared between control eyes and those in various stages of diabetic retinopathy. The superficial and deep capillary plexuses from diabetic and control eyes were analyzed. The average FD for diabetic eyes was significantly lower than in control eyes in the superficial plexus (P = 2.4 × 10) and in the deep capillary plexus (P = 1.87 × 10 ) with a more statistically significant difference noted in the deep capillary plexus. When analyzing diabetic patients without edema noted on optical coherence tomography, the FD was significantly reduced in the superficial (P = 0.001) and deep (P = 1.49 × 10) plexuses. When analyzing diabetic patients with edema noted on optical coherence tomography, the FD was significantly reduced in the superficial (P = 2.0 × 10) and deep (P = 1.85 × 10) plexuses. The optical coherence tomography angiography FD is significantly lower in both superficial and deep capillary plexuses in eyes with all stages studied of diabetic retinopathy. The results were more often significant for the deep capillary plexus. The use of fractal analysis provides an objective criterion to assess microvascular disease burden in diabetic retinopathy.


Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation.
To examine the relationship between beta carotene plasma concentration and beta carotene supplementation and risk of death from major disease causes. Cohort study of plasma concentrations; randomized, controlled clinical trial of supplementation. Medical school-affiliated dermatology practices. A total of 1188 men and 532 women with mean age of 63.2 years, who had enrolled in a randomized clinical trial of beta carotene supplementation to prevent nonmelanoma skin cancer. Oral beta carotene, 50 mg per day for a median of 4.3 years. All-cause mortality and mortality from cardiovascular disease and cancer. During a median follow-up period of 8.2 years, there were 285 deaths. Persons whose initial plasma beta carotene concentrations were in the highest quartile (>0.52 micromol/L [27.7 microg/dL]) had a lower risk of death from all causes (adjusted relative rate [RR], 0.52; 95% confidence interval [CI] 0.44 to 0.87) and from cardiovascular diseases (adjusted RR, 0.57; 95% CI, 0.34 to 0.95) compared with persons with initial concentrations in the lowest quartile (<0.21 micromol/L [11.2 microg/dL]). Patients randomly assigned to beta carotene supplementation showed no reduction in relative mortality rates from all causes (adjusted RR, 1.03; 95% CI, 0.82 to 1.30) or from cardiovascular disease (adjusted RR, 1.16; 95% CI, 0.82 to 1.64). There was no evidence of lower mortality following supplementation among patients with initial beta carotene concentrations below the median for the study group. These analyses provide no support for a strong effect of supplemental beta carotene in reducing mortality from cardiovascular disease or other causes. Although the possibility exists that beta carotene supplementation produces benefits that are too small or too delayed to have been detected in this study, noncausal explanations should be sought for the association between plasma concentrations of beta carotene and diminished risk of death.


Urinary bladder endometriosis: a report of two cases.
Endometriosis of the urinary tract is uncommon, and the most common site of involvement is urinary bladder. Two cases of endometriosis of urinary bladder are presented. The first patient, a 39-year-old woman, complained of dysuria during menstruation and the other 37-year-old woman suffered from intermittent gross hematuria. Pre-operative examinations included ultrasonography, computed tomography and cystoscopic biopsy. Case 1 was in premenopausal status, but the serum estrogen level of case 2 was in postmenopausal status because she was given no exogenous estrogen after previous bilateral salpingo-oophorectomy. Endometriosis of urinary bladder rarely occurs in postmenopausal woman without exogenous estrogen replacement. Case 1 received danazole treatment after transurethral resection of bladder tumor and case 2 received partial cystectomy after transurethral resection of bladder tumor. The patients were followed 36 and 4 months, respectively, and the symptoms kept improving during this period.


The Role of Temperament in the Etiopathogenesis of Bipolar Spectrum Illness.
Bipolar disorder constitutes a challenge for clinicians in everyday clinical practice. Our knowledge concerning this clinical entity is incomplete, and contemporary classification systems are unable to reflect the complexity of this disorder. The concept of temperament, which was first described in antiquity, provides a helpful framework for synthesizing our knowledge on how the human body works and what determines human behavior. Although the concept of temperament originally included philosophical and sociocultural approaches, the biomedical model is dominant today. It is possible that specific temperaments might constitute vulnerability factors, determine the clinical picture, or modify the course of illness. Temperaments might even act as a bridge between genes and clinical manifestations, thus giving rise to the concept of the bipolar spectrum, with major implications for mental health research and treatment. More specifically, it has been reported that the hyperthymic and the depressive temperaments are related to the more "classic" bipolar disorder, whereas cyclothymic, anxious, and irritable temperaments are related to more complex manifestations and might predict poor response to treatment, violent or suicidal behavior, and high comorbidity. Incorporating of the concept of temperament and the bipolar spectrum into the standard training of psychiatric residents might well result in an improvement of everyday clinical practice.


Mouse T lymphoma cells contain a transmembrane glycoprotein (GP85) that binds ankyrin.
In this study we have used complementary biochemical and immunological techniques to establish that the lymphoma GP85 membrane glycoprotein is a transmembrane protein with a cytoplasmic domain that binds directly to ankyrin, a molecule known to link the membrane to the cytoskeleton. The evidence supporting our conclusion that the GP85 is a transmembrane glycoprotein is as follows: (a) GP85 can be surface-labeled with Na 125I and contains wheat germ agglutinin-binding sites, indicating that it has an extracellular domain; (b) GP85 can be phosphorylated by intracellular kinases, indicating that it has an intracellular domain; and (c) GP85 can be successfully incorporated into phospholipid vesicles, indicating the existence of a hydrophobic domain in the molecule. Further studies show that GP85 displays immunological cross-reactivity with the lymphocyte Pgp-1 (differentiation-specific) membrane glycoprotein, and with the erythrocyte anion transport membrane protein, band 3. Immunocytochemical studies indicate that an ankyrin-like protein accumulates underneath the lymphoma GP85 cap structure, suggesting an association of the ankyrin-like protein and GP85. This relationship has been further confirmed by the following results of binding and reconstitution experiments: (a) purified GP85 binds directly to an ankyrin-Sepharose column; (b) purified GP85 inserts into phospholipid vesicles in both the normal (right side out) and reversed (inside out) orientation (and with only the reversed configuration permits binding of ankyrin to GP85); and (c) cleavage of GP85 with trypsin yields a 40-kD peptide fragment that is part of the cytoplasmic domain and contains the ankyrin binding site(s). Based on these findings, we suggest that the lymphoma GP85 transmembrane glycoprotein contains a cytoplasmic domain that is directly involved in linking ankyrin to the cytoskeleton. This transmembrane linkage may play a pivotal role in receptor capping and cell activation in lymphocytes.


[Changes of the EEG capacity observed in certain pathologies of the central nervous system and in pain].
Published data on changing spectra of electroencephalograms (EEG), as observed in different pathological hypoxic conditions (hypoxia, ischemia of the brain, aging) were analyzed; changing EEG spectra were experimentally studied in pain. The EEG changes were found to be identical in all cases. At the very beginning of a pathological factor onset, there was an increasing dominating peak of the EEG spectrum (or, the beta2-frequency range was going up--stage I). Then, the spectral distribution began to shift gradually to the low-frequency region: the frequency-predominant rhythm was slowing down; the slow-wave region was increasing and the fast-wave EEG part (II, III) was decreasing. Affections in pain fit the limits of I and II and, sometimes, III stages. In hypoxia and ischemia, a new stage of changes (IV) developed later: there emerged, in EEG, a peculiar high-amplitude rhythmic "burst-type" activity, which preconditioned a specific pattern of the EEG spectrum (the discussed stage is hard to detect in aging). The above stage is critical for the body. The total EEG capacity sharply dropped after its onset in hypoxia, ischemia and aging and the bioelectric activity was made up only of scanty slow waves (V). The described changing EEG spectra develop at an increasing total spectrum capacity (hypoxia), at capacity decrease (ischemia and aging) or it does not change altogether (pain). The homogeneous changes of EEG spectra in the above pathophysiological conditions make it possible to conclude that they denote a gradual progression of a change in brain functioning. It was suggested that such change is related with a slowing general velocity in brain functioning.


Home telecare system using cable television plants--an experimental field trial.
To solve the inconvenience of routine transportation of chronically ill and handicapped patients, this paper proposes a platform based on a hybrid fiber coaxial (HFC) network in Taiwan designed to make a home telecare system feasible. The aim of this home telecare system is to combine biomedical data, including three-channel electrocardiogram (ECG) and blood pressure (BP), video, and audio into a National Television Standard Committee (NTSC) channel for communication between the patient and healthcare provider. Digitized biomedical data and output from medical devices can be further modulated to a second audio program (SAP) subchannel which can be used for second-language audio in NTSC television signals. For long-distance transmission, we translate the digital biomedical data into the frequency domain using frequency shift key (FSK) technology and insert this signal into an SAP band. The whole system has been implemented and tested. The results obtained using this system clearly demonstrated that real-time video, audio, and biomedical data transmission are very clear with a carrier-to-noise ratio up to 43 dB.


cDNA clone coding for part of a mouse H-2d major histocompatibility antigen.
mRNA coding for mouse major transplantation antigens of the d haplotype was partially purified, copied into double-stranded cDNA, and cloned in Escherichia coli. Clones were selected by their ability to hybridize specifically with mRNA coding for H-2K, D, or L antigens. One of these clones, pH-2d-1, carries a 1200-base-pair insert, comprising the noncoding region, including poly(A) at the 3' end and part of the coding region. A partial sequence of the latter region showed extensive homology with the known amino acid sequences of H-2Kb,Kk, and HLA-B7 antigens. From this comparison, it appears that the coding region extends from amino acid 133 in the second domain, through the third domain, to the cytoplasmic COOH-terminal region. A stretch of 24 hydrophobic or uncharged residues, located 31 amino acids from the COOH-terminal end, could represent the segment that spans the membrane. This is followed on the cytoplasmic side of the membrane by a cluster of basic amino acids and a possible phosphorylation site on a threonine residue.


Examining the role of MEDLINE as a patient care information resource: an analysis of data from the Value of Libraries study.
This study analyzed data from a study on the value of libraries to understand the specific role that the MEDLINE database plays in relation to other information resources that are available to health care providers and its role in positively impacting patient care. A previous study on the use of health information resources for patient care obtained 16,122 responses from health care providers in 56 hospitals about how providers make decisions affecting patient care and the role of information resources in that process. Respondents indicated resources used in answering a specific clinical question from a list of 19 possible resources, including MEDLINE. Study data were examined using descriptive statistics and regression analysis to determine the number of information resources used and how they were used in combination with one another. Health care professionals used 3.5 resources, on average, to aid in patient care. The 2 most frequently used resources were journals (print and online) and the MEDLINE database. Using a higher number of information resources was significantly associated with a higher probability of making changes to patient care and avoiding adverse events. MEDLINE was the most likely to be among consulted resources compared to any other information resource other than journals. MEDLINE is a critical clinical care tool that health care professionals use to avoid adverse events, make changes to patient care, and answer clinical questions.


Estimating the contributions of NMDA and non-NMDA currents to EPSPs in retinal ganglion cells.
Whole-cell recordings were obtained from retinal ganglion cells of the tiger salamander (Ambystoma tigrinum) in a superfused slice preparation to evaluate contributions of NMDA (N-methyl-D-aspartate) and KA/AMPA (kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid) receptors to excitatory postsynaptic potentials (EPSPs) of retinal ganglion cells. Synaptic activation of retinal ganglion cells was achieved through the use of a brief pressure pulse of hyperosmotic Ringer (Ringer + sucrose) delivered through a microelectrode visually placed in the inner plexiform layer while whole-cell recordings were obtained from adjacent cells in the ganglion cell layer. Separation of NMDA and KA/AMPA excitatory postsynaptic currents (EPSCs) was achieved through the application of the antagonists NBQX and D-AP7, while inhibitory currents were blocked by strychnine and picrotoxin. Simple addition of the two independent EPSCs showed, most often, that the sum of the KA/AMPA and NMDA currents was less than the control response, but in some cases the sum of the two currents exceeded the magnitude of the control response. Neither result was consistent with expectations based on voltage-clamp principles and the assumption that the two currents were independent; for this reason, we considered the possibility of nonlinear interactions between KA/AMPA and NMDA receptors. Computer simulations were carried out to evaluate the summation experiments. We used both an equivalent cylinder model and a more realistic, compartmental model of a ganglion cell constrained by a passive leakage conductance, a linear KA/AMPA synaptic current, and a nonlinear NMDA current based on the well-known, voltage-sensitive Mg2+ block. Computer simulation studies suggest that the hypo- and hyper-summation of NMDA and KA/AMPA currents, observed physiologically, can be accounted for by a failure to adequately space clamp the neuron. Clamp failure leads to enhanced NMDA currents as the ion channels are relieved of the Mg2+ block; their contribution is thus exaggerated depending on the magnitude of the conductance change and the spatial location of the synaptic input.


High-density SNP genotyping to define beta-globin locus haplotypes.
Five major beta-globin locus haplotypes have been established in individuals with sickle cell disease (SCD) from the Benin, Bantu, Senegal, Cameroon, and Arab-Indian populations. Historically, beta-haplotypes were established using restriction fragment length polymorphism (RFLP) analysis across the beta-locus, which consists of five functional beta-like globin genes located on chromosome 11. Previous attempts to correlate these haplotypes as robust predictors of clinical phenotypes observed in SCD have not been successful. We speculate that the coverage and distribution of the RFLP sites located proximal to or within the globin genes are not sufficiently dense to accurately reflect the complexity of this region. To test our hypothesis, we performed RFLP analysis and high-density single nucleotide polymorphism (SNP) genotyping across the beta-locus using DNA samples from healthy African Americans with either normal hemoglobin A (HbAA) or individuals with homozygous SS (HbSS) disease. Using the genotyping data from 88 SNPs and Haploview analysis, we generated a greater number of haplotypes than that observed with RFLP analysis alone. Furthermore, a unique pattern of long-range linkage disequilibrium between the locus control region and the beta-like globin genes was observed in the HbSS group. Interestingly, we observed multiple SNPs within the HindIII restriction site located in the Ggamma-globin intervening sequence II which produced the same RFLP pattern. These findings illustrated the inability of RFLP analysis to decipher the complexity of sequence variations that impacts genomic structure in this region. Our data suggest that high-density SNP mapping may be required to accurately define beta-haplotypes that correlate with the different clinical phenotypes observed in SCD.


Reliable Next-Generation Sequencing of Formalin-Fixed, Paraffin-Embedded Tissue Using Single Molecule Tags.
Sequencing of tumor DNA to detect genetic aberrations is becoming increasingly important, not only to refine cancer diagnoses but also to predict response to targeted treatments. Next-generation sequencing is widely adopted in diagnostics for the analyses of DNA extracted from routinely processed formalin-fixed, paraffin-embedded tissue, fine-needle aspirates, or cytologic smears. PCR-based enrichment strategies are usually required to obtain sufficient read depth for reliable detection of genetic aberrations. However, although the read depth relates to sensitivity and specificity, PCR duplicates generated during target enrichment may result in overestimation of library complexity, which may result in false-negative results. Here, we report the validation of a 23-gene panel covering 41 hotspot regions using single-molecule tagging of DNA molecules by single-molecule molecular inversion probes (smMIPs), allowing assessment of library complexity. The smMIP approach outperforms Sanger and Ampliseq-Personal Genome Machine-based sequencing in our clinical diagnostic setting. Furthermore, single-molecule tags allow consensus sequence read formation, allowing detection to 1% allele frequency and reliable exclusion of variants to 3%. The number of false-positive calls is also markedly reduced (>10-fold), and our panel design allows for distinction between true mutations and deamination artifacts. Not only is this technique superior, smMIP-based library preparation is also scalable, easy to automate, and flexible. We have thus implemented this approach for sequence analysis of clinical samples in our routine diagnostic workflow.


Phonon bottleneck in graphene-based Josephson junctions at millikelvin temperatures.
We examine the nature of the transitions between the normal and superconducting branches in superconductor-graphene-superconductor Josephson junctions. We attribute the hysteresis between the switching (superconducting to normal) and retrapping (normal to superconducting) transitions to electron overheating. In particular, we demonstrate that the retrapping current corresponds to the critical current at an elevated temperature, where the heating is caused by the retrapping current itself. The superconducting gap in the leads suppresses the hot electron outflow, allowing us to further study electron thermalization by phonons at low temperatures (T≲1 K). The relationship between the applied power and the electron temperature was found to be P∝T3, which we argue is consistent with cooling due to electron-phonon interactions.


Evidence for involvement of non-biliary excretion into the intestines in the formation of methylsulphonyl-containing metabolites of 2-chloro-N-isopropylacetanilide (propachlor) by swine and rats.
1. Radiolabelled metabolites excreted in the urine of swine after an oral dose of 14C-propachlor were similar to those previously reported with rats and included methylsulphonyl (CH3SO2-)-containing metabolites. 2. A bile-duct-cannulated pig dosed orally with 14C-propachlor excreted 7.6% dose in the bile compared with approx. 75% dose with rats. Although enterohepatic circulation had been prevented with the bile-duct-cannulated pig. CH3SO3 metabolites of propachlor were excreted in the urine. Enterohepatic circulation had been reported to be necessary for formation of CH3SO2 metabolites of propachlor with rats. 3. Germ-free pigs dosed orally with 14-C-propachlor did not excrete urinary CH3SO2 metabolites, indicating involvement of the enteric flora in the production of these metabolites as shown previously with rats. 4. A g.l.c.-mass spectrometric specific ion monitoring technique indicated that trace amounts of CH3SO2 metabolites were present in the urine and bile of bile-duct-cannulated rats dosed orally with 14C-propachlor. This was confirmed by isolation and mass-spectral analyses. 5. It is concluded that after oral administration of propachlor to rats and swine, glutathione (GSH) conjugation and cysteine conjugate beta-lyase activity in the enteric flora are involved in formation of CH3SO2 metabolites. Presumably, the GSH conjugate is formed in mammalian tissue and must be returned to the lumen of the gut to be acted upon by the gut microflora. In rats this is accomplished primarily by biliary excretion, whereas in swine a non-biliary mechanism is much more important.


Effect of combined alcohol and tobacco exposure on risk of cancer of the hypopharynx.
The effect of moderate to heavy exposure to alcohol and tobacco on the risk of cancer of the hypopharynx is estimated in a case-control study. All incident hypopharyngeal cancer patients in Denmark who were under 75 years of age were compared with incident cases of laryngeal cancer and population sampled controls. The ascertainment of cases and controls took place during March 1980 to March 1982. Thirty-two patients with cancer of the hypopharynx, 321 patients with cancer of the larynx, and 1141 population sampled controls participated in the study. The effect of combined exposure to alcohol and tobacco seemed to be multiplicative rather than additive, a finding which is similar to that in laryngeal cancer patients. However, as there were only small numbers, only major deviations from the additive or multiplicative model for interaction would be detectable.


[Renal scintigraphy using technetium dimercaptosuccinic acid in the diagnosis of pyelonephritis in children: study of 17 cases]
OBJECTIVE: To determine whether the presence of abnormal results in DMSA renal scintigraphy indicates pyelonephritis. METHODS: We performed the washout test in 17 children with urinary tract infection, as a criterion standard, to locate the infection site. All the children underwent DMSA renal scintigraphy in the acute phase of the disease. The results were analyzed by the chi-square test or Fisher test. RESULTS: DMSA renal scintigraphy revealed changes in all five cases of pyelonephritis, suggesting acute kidney involvement. On the other hand, only one child with cystitis (total = 12 cases) had abnormal results in renal scintigraphy. Sensitivity and specificity were 100% and 92%, respectively. CONCLUSION: DMSA renal scintigraphy is a sensitive method for the diagnosis of pyelonephritis in children.


Regulation of fumonisin B(1) biosynthesis and conidiation in Fusarium verticillioides by a cyclin-like (C-type) gene, FCC1.
Fumonisins are a group of mycotoxins produced in corn kernels by the plant-pathogenic fungus Fusarium verticillioides. A mutant of the fungus, FT536, carrying a disrupted gene named FCC1 (for Fusarium cyclin C1) resulting in altered fumonisin B(1) biosynthesis was generated. FCC1 contains an open reading frame of 1,018 bp, with one intron, and encodes a putative 319-amino-acid polypeptide. This protein is similar to UME3 (also called SRB11 or SSN8), a cyclin C of Saccharomyces cerevisiae, and contains three conserved motifs: a cyclin box, a PEST-rich region, and a destruction box. Also similar to the case for C-type cyclins, FCC1 was constitutively expressed during growth. When strain FT536 was grown on corn kernels or on defined minimal medium at pH 6, conidiation was reduced and FUM5, the polyketide synthase gene involved in fumonisin B(1) biosynthesis, was not expressed. However, when the mutant was grown on a defined minimal medium at pH 3, conidiation was restored, and the blocks in expression of FUM5 and fumonisin B(1) production were suppressed. Our data suggest that FCC1 plays an important role in signal transduction regulating secondary metabolism (fumonisin biosynthesis) and fungal development (conidiation) in F. verticillioides.


Echolucent carotid plaque is associated with restenosis after carotid endarterectomy.
The mechanism of carotid endarterectomy (CEA) restenosis remains unclear. Our research aimed to investigate the relationship between the carotid plaque grayscale median (GSM) value and restenosis after CEA. Between January 2010 and January 2018, 1280 consecutive patients underwent CEA at our institution; 32 patients were diagnosed with restenosis by ultrasound at 1 year after CEA. The correlations between plaque GSM, plaque echogenicity, clinical manifestations, shunting, and restenosis were analyzed. In total, 829 patients were ultimately enrolled; 32 (4%) presented diagnoses of restenosis (mean age 67.3 ± 8.0 years, 81.2% men). The GSM value was lower in the restenosis group (68.1 ± 19.9 vs 59.9 ± 14.7, p = 0.02). After multiple logistic regression analysis, the GSM value was found to be an independent risk factor for restenosis (OR 0.976, 95% CI 0.957-0.995). Shunting was another significant independent risk factor for restenosis (OR 2.39, 95% CI 1.07-5.34). The GSM cutoff value for predicting restenosis was 75 (sensitivity 0.38, specificity 0.84, area under the curve 0.62). We separated the patients into 2 groups by GSM (GSM ≤ 75 and GSM > 75 subgroups). Comparison of the 2 groups indicated that symptomatic manifestation was related to restenosis in the subgroup with GSM ≤ 75, indicating predominantly echolucent plaques, but not in the subgroup with GSM > 75, indicating predominantly echogenic plaques. Predominantly echolucent carotid plaques, as measured by GSM, had a higher restenosis risk at 1 year than echogenic plaques.


Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.
In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine6 and D-ornithine6 or N epsilon-(2,3-diaminopropionyl)-D-lysine and N delta-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding affinities of peptides containing two cytotoxic side chains were lower. Antagonistic carriers [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,D-Lys6,D-Ala10] LH-RH [where Nal(2) is 3-(2-naphthyl)alanine], [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,N epsilon-(2,3-diaminopropionyl)-D-Lys6,D-Ala10]LH-RH, and their D-Pal(3)3 homologs [Pal(3) is 3-(3-pyridyl)alanine] as well as [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,Tyr5,N epsilon-(2,3-diamino-propionyl)-D-Lys6,D-Ala10]LH-RH were linked to cytotoxic compounds. The hybrid molecules inhibited ovulation in rats at doses of 10 micrograms and suppressed LH release in vitro. The receptor binding of cytotoxic analogues was decreased compared to the precursor peptides, although analogues with 2-(hydroxymethyl)anthraquinone hemiglutarate had high affinities. All of the cytotoxic analogues tested inhibited [3H]thymidine incorporation into DNA in cultures of human breast and prostate cancer cell lines. Some cytotoxic analogues also significantly suppressed the growth of mammary and prostate cancers in vivo in animal models.


Comparison of gastroesophageal reflux disease symptoms and proton pump inhibitor response using gastroesophageal reflux disease impact scale questionnaire.
To compare gastroesophageal reflux disease (GERD) symptoms and response to proton pump inhibitor (PPI) in patients with erosive esophagitis (EE), non-erosive reflux disease (NERD) or functional heartburn (FH) using GERD impact scale (GIS) questionnaire. Total 126 patients with GERD symptoms were diagnosed as EE (n = 62), NERD (n = 34) and FH (n = 30) by endoscopy, 24-hour esophageal pH testing and Bernstein test, prospectively. Analysis of risk factors and GIS questionnaire for GERD symptoms and quality of life were performed before and 8 weeks after PPI treatment. EE group had a higher proportion of men, frequent alcohol consumption, smoking, hiatal hernia, body mass index ≥ 25 kg/m(2) and triglyceride levels (≥ 150 mg/dL) than the other groups (all P < 0.05). On the other hand, both psychiatric treatment and psychopharmacotherapy were more frequent in patients with FH than in those with EE and NERD (both P < 0.05). Among GERD symptoms, chest pain was more frequent in FH group than in EE and NERD groups (P < 0.05). Eating problems and limitation of productive daily activities occurred frequently in FH group and NERD group, respectively. GIS after 8 week PPI treatment showed improvement in all of the GERD symptoms in EE (all P < 0.05) and in acid regurgitation, epigastric pain and hoarseness in NERD group (all P < 0.05). In terms of quality of life, PPI treatment improved sleep disturbance in EE (P = 0.031) and limitation of productive activity in the NERD group (P = 0.001). GIS questionnaire showed that different characteristics and symptoms improved after PPI therapy among patients with EE, NERD and FH, demonstrating the usefulness of the GIS questionnaire.


Enteric pathogen-plant interactions: molecular connections leading to colonization and growth and implications for food safety.
Leafy green vegetables have been identified as a source of foodborne illnesses worldwide over the past decade. Human enteric pathogens, such as Escherichia coli O157:H7 and Salmonella, have been implicated in numerous food poisoning outbreaks associated with the consumption of fresh produce. An understanding of the mechanisms responsible for the establishment of pathogenic bacteria in or on vegetable plants is critical for understanding and ameliorating this problem as well as ensuring the safety of our food supply. While previous studies have described the growth and survival of enteric pathogens in the environment and also the risk factors associated with the contamination of vegetables, the molecular events involved in the colonization of fresh produce by enteric pathogens are just beginning to be elucidated. This review summarizes recent findings on the interactions of several bacterial pathogens with leafy green vegetables. Changes in gene expression linked to the bacterial attachment and colonization of plant structures are discussed in light of their relevance to plant-microbe interactions. We propose a mechanism for the establishment and association of enteric pathogens with plants and discuss potential strategies to address the problem of foodborne illness linked to the consumption of leafy green vegetables.


[Conduction disorders in aortic valve diseases].
Among 304 cases of aortic valvulopathies studied for surgical selection, the authors have found a high incidence of conduction disturbances (16% in aortic stenosis and 18,4% in aortic regurgitation). The conduction defects are mostly intraventricular among stenosis isolated or associated to regurgitation and mostly atrio-ventricular among pure aortic insufficiencies. The highest incidence (30%) being found in patients with bacterial endocarditis acute or healed. The incidence of conduction disturbances increases with age, with the presence of valvular calcifications, of left ventricular strain or failure, of coronary insufficiency and angina... practically with the duration and the severity of the valvular disease. Surgical risk is heavier and natural prognosis poorer in valvulopathies with conduction disturbances. But these disturbances never contraindicates surgery : it is sometimes necessary to insert a pacemaker with or without valvular replacement mostly in aortic stenosis with infrahisian conduction defects. During hemodynamic investigation of such cases one must be ready to stimulate the heart, particularly during right heart catheterization of patients with complete left bundle branch block.


Influence of substituent type and position on the adsorption mechanism of phenylboronic acids: infrared, Raman, and surface-enhanced Raman spectroscopy studies.
This paper shows systematic spectroscopic studies using Fourier-transform infrared absorption (FT-IR), Fourier-transform Raman (FT-Raman), and surface-enhanced Raman (SERS) in an aqueous silver sol of fluoro and formyl analogues of phenylboronic acids: 2-fluorophenylboronic acid (2-F-PhB(OH)2), 3-fluorophenylboronic acid (3-F-PhB(OH)2), 4-fluorophenylboronic acid (4-F-PhB(OH)2), 2-formylphenylboronic acid (2-CHO-PhB(OH)2), 3-formylphenylboronic acid (3-CHO-PhB(OH)2), and 4-formylphenylboronic acid (4-CHO-PhB(OH)2). To produce an extensive table of vibrational spectra, density functional theory (DFT) calculations with the B3LYP method at the 6-311++G(d,p) level of theory were performed for the ground state geometry of the most stable species, dimers in cis-trans conformation. On the basis of the SERS spectral profile, the adsorption modes of the phenylboronic acid isomers were proposed. The type of substituent and its position in the phenyl ring have a strong influence on the geometry of isomers on the silver nanoparticle's surface. This effect was especially evident in the case of 4-CH-PhB(OH)2, for which dearomatization of the phenyl ring took place upon adsorption.


An inhibitor of spleen tyrosine kinase suppresses experimental crescentic glomerulonephritis.
Non-selective inhibitors of spleen tyrosine kinase (SYK) efficiently suppress disease in T cell-dependent models of crescentic glomerulonephritis. However, the therapeutic potential of selective SYK inhibitors in this disease has not been established. In addition, we lack knowledge regarding SYK expression in non-myeloid cells in glomerulonephritis. We addressed these two issues in a rat model of nephrotoxic serum nephritis (NTN) using a SYK inhibitor, GS-492429. Disease was induced in Sprague-Dawley rats (Study 1) or Wistar-Kyoto (WKY) rats (Study 2) by immunization with sheep IgG and administration of sheep anti-rat nephrotoxic serum. Animals were untreated or received GS-492429 (30 mg/kg/bid) or vehicle treatment from 2 h before nephrotoxic serum injection until being killed 3 or 24 h later (Study 1) or 14 days later (Study 2). Two-colour confocal microscopy found that SYK expression in NTN kidney was restricted to myeloid cells and platelets, with no evidence of SYK expression by T cells, mesangial cells, podocytes or tubular epithelial cells. In Study 1, GS-492429 treatment significantly reduced glomerular neutrophil and macrophage infiltration, with protection from glomerular thrombosis and proteinuria. In Study 2, GS-492429 treatment reduced glomerular crescent formation by 70% on day 14 NTN in conjunction with reduced glomerular thrombosis, glomerulosclerosis and tubular damage. This was accompanied by a marked reduction in markers of inflammation (CCL2, TNF-α, NOS2, MMP-12). Importantly, the protective effects of GS-492429 were independent of T cell infiltration and activation and independent of JAK/STAT3 signalling. In conclusion, this study demonstrates that a SYK inhibitor can suppress the development of crescentic glomerulonephritis through effects upon myeloid cells and platelets.


Home oxygen therapy is an acknowledged treatment for patients suffering from chronic hypoxaemia, due to pulmonary or cardiac disease, and may have positive effects on survival and quality of life. The risks and side effects of the treatment are usually mild, and the equipment has developed to become relatively affordable, accessible and easy to transport. Adjustments in the oxygen settings can be necessary when travelling by airplane or during physical effort or sleep. Prescription and follow-ups are usually best maintained by hospital departments with expertise in pulmonary medicine, as argued in this review.


Nucleoside-nucleotide free diet protects rat colonic mucosa from damage induced by trinitrobenzene sulphonic acid.
Growing evidence suggests that intestinal recovery from injury induced by radiation, endotoxin, and protein deficiency is improved by the ingestion of nucleosides and nucleotides. This study examined the effect of dietary nucleosides and nucleotides supplementation on trinitrobenzene sulphonic acid induced colonic damage in experimental colitis. Sprague-Dawley rats were randomised into two groups and fed nucleic acid free 20% casein diet (control) or this diet supplemented with 0.5% nucleoside-nucleotide mixture for four weeks. On the second week, colonic inflammation was induced in rats by intracolonic administration of 0.25 ml of 50% ethanol containing 25 mg of trinitrobenzene sulphonic acid. Additionally, other sets of rats were treated with 0.25 ml of 50% ethanol, 25 mg of trinitrobenzene sulphonic acid in 0.25 ml saline, or 0.25 ml of 0.9% saline. After two weeks, colon weight, macroscopic and microscopic damage scores, were significantly greater (p < 0.05) in the nucleoside-nucleotide supplemented group compared with the non-supplemented control groups. The same variables seen in the trinitrobenzene sulphonic acid-ethanol group fed nucleoside-nucleotide free diet were greater (p < 0.05) than in the rest of the groups fed nucleoside-nucleotide free diet and treated with ethanol, trinitrobenzene sulphonic acid in saline, or saline. Histologically, segmental ulceration and inflammation associated with significantly increased infiltration of polymorphonuclear leucocytes, macrophages, lymphocytes, fibroblasts were observed in the supplemented group compared with the controls. In the nucleoside-nucleotide supplemented group the epithelial damage, mucosal erosion, oedema, and coagulative necrosis of the muscularis propria was more extensive in comparison to the non-supplemented control groups. This study suggests that dietary nucleosides and nucleotides may aggravate colonic damage and inflammation in chemically induced experimental colitis in rats; and that nucleoside-nucleotide free diet combined with other pharmacological agents may offer a better response.


Decreased sensitivity to thermal stimuli in adolescents with autism spectrum disorder: relation to symptomatology and cognitive ability.
Social communication deficits and repetitive behaviors are established characteristics of autism spectrum disorder (ASD) and the focus of considerable study. Alterations in pain sensitivity have been widely noted clinically but remain understudied and poorly understood. The ASD population may be at greater risk for having their pain undermanaged, especially in children with impaired cognitive ability and limited language skills, which may affect their ability to express pain. Given that sensitivity to noxious stimuli in adolescents with ASD has not been systematically assessed, here we measured warm and cool detection thresholds and heat and cold pain thresholds in 20 high-functioning adolescents with ASD and 55 typically developing adolescents using a method-of-limits quantitative sensory testing protocol. Adolescents with ASD had a loss of sensory function for thermal detection (P < .001, both warm and cool detection thresholds) but not pain threshold (P > .05, both heat and cold pain thresholds) in comparison to controls, with no evidence for significant age or sex effects (P > .05). Intelligence quotients and symptomatology were significantly correlated with a loss of some types of thermal perception in the ASD population (ie, warm detection threshold, cool detection threshold, and heat pain threshold; P < .05). Decreased thermal sensitivity in adolescents with ASD may be associated with cognitive impairments relating to attentional deficits. Our findings are consistent with previous literature indicating an association between thermal perception and cortical thickness in brain regions involved in somatosensation, cognition, and salience detection. Further brain-imaging research is needed to determine the neural mechanisms underlying thermal perceptual deficits in adolescents with ASD. We report quantitative evidence for altered thermal thresholds in adolescents with ASD. Reduced sensitivity to warmth, coolness, and heat pain was related to impaired cognitive ability. Caregivers and clinicians should consider cognitive ability when assessing and managing pain in adolescents with ASD.


Graphene-based neuron encapsulation with controlled axonal outgrowth.
Neuronal constructs with tuneable 3D geometry can contribute greatly to the construction of brain-like functional tissues for transplantable grafts and robust experimental models. In this study, we propose a self-folding graphene/polymer bilayer film that forms a micro-roll for neuron encapsulation, and highlight the importance of employing pores on the micro-roll to allow neurons to interact with their surroundings. The micro-patterns and varied thicknesses of the bilayer provide control over the 3D geometries of the micro-roll. The pores facilitate the diffusion of reagents, resulting in the adequate loading of probes for imaging and the successful stimulation of the encapsulated neurons. Moreover, the encapsulated neurons inside the micro-roll are functionally integrated into surrounding neuronal networks by extending their axons through the pores. Thus, our method for encapsulating neurons with a porous graphene-laden film allows the construction of precisely shaped neuronal tissues that interact with their surroundings. We believe that the method will open a new avenue for the reconstruction of functional neuronal tissues and is potentially applicable to other self-folding bilayers.


Wave energy extraction by coupled resonant absorbers.
In this article, a range of problems and theories will be introduced that will build towards a new wave energy converter (WEC) concept, with the acronym 'ROTA' standing for resonant over-topping absorber. First, classical results for wave power absorption for WECs constrained to operate in a single degree of freedom will be reviewed and the role of resonance in their operation highlighted. Emphasis will then be placed on how the introduction of further resonances can improve power take-off characteristics by extending the range of frequencies over which the efficiency is close to a theoretical maximum. Methods for doing this in different types of WECs will be demonstrated. Coupled resonant absorbers achieve this by connecting a WEC device equipped with its own resonance (determined from a hydrodynamic analysis) to a new system having separate mass/spring/damper characteristics. It is shown that a coupled resonant effect can be realized by inserting a water tank into a WEC, and this idea forms the basis of the ROTA device. In essence, the idea is to exploit the coupling between the natural sloshing frequencies of the water in the internal tank and the natural resonance of a submerged buoyant circular cylinder device that is tethered to the sea floor, allowing a rotary motion about its axis of attachment.


Mechanism of glia-neuron cell-fate switch in the Drosophila thoracic neuroblast 6-4 lineage.
During development of the Drosophila central nervous system, neuroblast 6-4 in the thoracic segment (NB6-4T) divides asymmetrically into a medially located glial precursor cell and a laterally located neuronal precursor cell. In this study, to understand the molecular basis for this glia-neuron cell-fate decision, we examined the effects of some known mutations on the NB6-4T lineage. First, we found that prospero (pros) mutations led to a loss of expression of Glial cells missing, which is essential to trigger glial differentiation, in the NB6-4T lineage. In wild-type embryos, Pros protein was localized at the medial cell cortex of dividing NB6-4T and segregated to the nucleus of the glial precursor cell. miranda and inscuteable mutations altered the behavior of Pros, resulting in failure to correctly switch the glial and neuronal fates. Our results suggested that NB6-4T used the same molecular machinery in the asymmetric cell division as other neuroblasts in cell divisions producing ganglion mother cells. Furthermore, we showed that outside the NB6-4T lineage most glial cells appeared independently of Pros.


Antibiotic suseptibility of bacteria isolated from oral infections.
Exudates from bacterial infections of oral soft tissues were cultured and tested for antiobiotic susceptibility. Of 74 specimens tested, 68 were cultivable on blood agar; 56 of the cultivable exudates were pure cultures and 12 were mixed cultures. Strepococci and staphylococci accounted for 57% and 34%, respectively, of the pure cultures. Anaerobic bacteria were found in nearly 15% of the pure culture exudates. Gramnegative organisms accounted for about 4% of the pure cultures. Virtually all of the pure and mixed streptococcal cultures were sensitive or moderately susceptible to ampicillin, cephalothin, and penicillin; however, approximately 50% of the streptococal and staphylocococcal isolates were resistant to demeclocycline hydrochloride and erythromycin.


Maternal vitamin D and neonatal anthropometrics and markers of neonatal glycaemia: Belfast Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study.
Vitamin D deficiency is a common occurrence globally, and particularly so in pregnancy. There is conflicting evidence regarding the role of vitamin D during pregnancy in non-skeletal health outcomes for both the mother and the neonate. The aim of this study was to investigate the associations of maternal total 25-hydroxy vitamin D (25OHD) with neonatal anthropometrics and markers of neonatal glycaemia in the Belfast centre of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. Serological samples (n 1585) were obtained from pregnant women in the Royal Jubilee Maternity Hospital, Belfast, Northern Ireland, between 24 and 32 weeks' gestation as part of the HAPO study. 25OHD concentrations were measured by liquid chromatography tandem-MS. Cord blood and neonatal anthropometric measurements were obtained within 72 h of birth. Statistical analysis was performed. After adjustment for confounders, birth weight standard deviation scores (SDS) and birth length SDS were significantly associated with maternal total 25OHD. A doubling of maternal 25OHD at 28 weeks' gestation was associated with mean birth weight SDS and mean birth length SDS higher by 0·05 and 0·07, respectively (both, P=0·03). There were no significant associations with maternal 25OHD and other measures of neonatal anthropometrics or markers of neonatal glycaemia. In conclusion, maternal total 25OHD during pregnancy was independently associated with several neonatal anthropometric measurements; however, this association was relatively weak.


A Promising Three-Step Heat Treatment Process for Preparing CuO Films for Photocatalytic Hydrogen Evolution from Water.
Copper (II) oxide (CuO) nanostructures were prepared on fluorine-doped tin oxide (FTO) using a three-step heat treatment process in a sol-gel dip-coating method. The precursor used for the dip-coating process was prepared using copper acetate, propan-2-ol, diethanolamine, and polyethylene glycol 400. Dip-coated films in layers of 2, 4, 6, 8, and 10 were prepared by drying each layer at 110 and 250 °C for 10 and 5 min, respectively, followed by calcination at 550 °C for 1 h. The films were applied toward photocatalytic hydrogen evolution from water. The X-ray diffraction (XRD) pattern of the films confirmed the tenorite phase of pure CuO. Raman spectroscopy revealed the 1Ag and 2Bg phonon modes of CuO, confirming the high purity of the films produced. The CuO films absorb significant photons in the visible spectrum due to their low optical band gap of 1.25-1.33 eV. The highest photocurrent of -2.0 mA/cm2 at 0.45 V vs reversible hydrogen electrode (RHE) was recorded for CuO films consisting of six layers under 1 sun illumination. A more porous surface, low charge transfer resistance, and high double-layer capacitance at the CuO/electrolyte interface observed for the films consisting of six layers contributed to the high photocurrent density attained by the films. CuO films consisting of six layers prepared using the conventional two-step heat treatment process for comparative purposes yielded 65.0% less photocurrent at 0.45 V vs RHE compared to similar films fabricated via the three-step heating method. The photocurrent response of the CuO nanostructures prepared using the three-step heat treatment process is promising and can be employed for making CuO for photovoltaic and optoelectronic applications.


No Difference in Functional Outcomes When Lateral Extra-Articular Tenodesis Is Added to Anterior Cruciate Ligament Reconstruction in Young Active Patients: The Stability Study.
To assess the functional outcomes of patients included in the Stability Study randomized controlled trial comparing anterior cruciate ligament reconstruction (ACLR) alone with ACLR with lateral extra-articular tenodesis (LET) at 6, 12, and 24 months postoperatively. Six hundred eighteen patients undergoing ACLR, all under the age of 25 years either returning to contact pivoting sport or displaying signs of high-grade rotatory laxity or generalized ligamentous laxity, were randomly assigned to receive ACLR alone or ACLR plus LET. A total of 356 of these patients were randomized at centers participating in the functional assessments. Our primary outcome was Limb Symmetry Index, calculated using a series of 4-hop tests at 6, 12, and 24 months postoperatively. Secondary outcome measures included pain, patient-reported function, and isokinetic strength testing. We found no statistically significant difference in the proportion of patients either unwilling or unfit to complete the hop testing in the ACLR alone or ACLR with LET group at 6 months (40 vs 40 respectively; P = 1.00), 12 months (25 vs 27; P = .76), and 24 months (21 vs 23; P = .87). Of those who completed hop testing, there were no statistically significant differences between groups in Limb Symmetry Index at 6, 12, or 24 months. Self-reported function (Lower Extremity Functional Score) significantly favored the ACLR alone group at 3 (P = .01) and 6 months (P = .02) postoperative but was similar by 12 months postoperative. Pain scores (P4) also showed a statistically significant difference in favor of the ACL alone group, but this also resolved by 6 months. Quadriceps peak torque (P = .03) and average power (P = .01) were also significantly different in favor of the ACLR alone group at 6 months postoperative; however, these were similar between groups by 12 months postoperative (P = .11 and P = .32, respectively). The addition of a LET to ACLR results in slightly increased pain, a mild reduction in quadriceps strength, and reduced subjective functional recovery up to 6 months postoperatively. However, these differences do not have any impact on objective function as measured by hop test limb symmetry index. I, Randomized Controlled Trial.


[Thyroid papillary cancer using TPO staining].
Immunostaining for TPO (MoAb47) has been used to predict the risk of thyroid cancer in thyroid adenomas without uptake in thyroid 99m pertechnetate scintigraphy. This case describes a 16-year-old girl with thyroid papillary cancer staining 95% positive using TPO staining. The case indicates that TPO staining can not be used as the only parameter in the evaluation of the risk of cancer in the thyroid gland.


Morphological and molecular characterization of an Elaeis oleifera (H.B.K) Cortes germplasm collection located in Ucayali, Peru.
The African oil palm (Elaeis guineensis Jacq) is a crop that is widely distributed in tropical regions around the world; however, this crop is subject to limitations such as rapid trunk growth and susceptibility to bud rot and red ring diseases particularly in South America. To overcome these limitations, national breeding and conservation programs have been established, and there is a need to identify parental palms from natural populations of the American oil palm (E. oleifera H.B.K. Cortes) with desirable yield and morphological traits (i.e., yield production and bunch number) and with high genetic diversity. However, in Peru the morphological and genetic data related to this important crop is limited. In this study, we characterized the morphological and yield and estimated the genetic diversity using 12 neutral microsatellite markers (simple sequence repeats, SSRs) across 72 oil palm individuals belonging to the E. oleifera germplasm collection located in the tropical region of Ucayali, Peru. Our results showed that morphological and yield traits explained approximately 40.39% of the variability within the Peruvian germplasm. Furthermore, Yield Production was highly correlated with two yield traits: Bunch Number (0.67) and Average weight per bunch (0.78). Based on the yield and morphological traits, a clustering analysis was performed and three phenotypic groups were identified (1, 2 and 3) in which groups 1 and 3 showed high scores associated primarily with yield traits. Microsatellite markers revealed 143 alleles, 11.92 ± 4.72 alleles per locus (A) and an expected heterozygosity (He) of 0.69 ± 0.045. A structural analysis identified three populations (k = 3), that were not related to the phenotypic groups. Interestingly, a multiple allele background was identified within the groups using multilocus and phylogenetic relationship analyses. This is the first Peruvian report regarding E. oleifera that shows preliminary data of the morphological and yield traits and genetic data, and highlight the importance of this information to set up future steps to national breeding strategies and improve the conservation of genetic material of E. oleifera. Overall, these novel findings could contribute to the development of the local oil palm industry in Peru.


Introducing a novel experimental model of bladder transplantation in mice.
Bladder dysfunction is a common clinical problem attributed to various conditions such as posterior urethral valves, neurogenic bladder, ureteral ectopy, or bladder exstrophy. Currently, the main therapeutic option for these dysfunctions is neobladder reconstruction with gastrointestinal tract segments. However, the latter was associated with significant long-term complications. To provide a new candidate of possible surgical solution for bladder dysfunction, we propose a novel orthotropic mouse bladder transplantation model. The donor bladder with abdominal aorta and inferior vena cava was isolated and orthotopically sutured to the recipient, whose bladder above the ureteral opening level was removed. The recipient mice showed more than 80% 6-month survival rate and comparable body weight to control mice. At both 1 month and 6 months posttransplant, the urine voiding behavior of recipient mice and control mice was monitored by cystometry. We found that the recipient mice displayed similar bladder pressure and urine secretion ability compared to control mice especially at 6 months posttransplant. Similarity of bladder structure between recipient and control mice was confirmed by histology. As a proof of principle, we tested our model in an allogeneic setting. Early acute rejection was noted after day 5 that was histologically more profound by day 10 posttransplant. These results indicate that the mouse bladder transplant is able to provide normal bladder function.


The next generation of CRISPR-Cas technologies and applications.
The prokaryote-derived CRISPR-Cas genome editing systems have transformed our ability to manipulate, detect, image and annotate specific DNA and RNA sequences in living cells of diverse species. The ease of use and robustness of this technology have revolutionized genome editing for research ranging from fundamental science to translational medicine. Initial successes have inspired efforts to discover new systems for targeting and manipulating nucleic acids, including those from Cas9, Cas12, Cascade and Cas13 orthologues. Genome editing by CRISPR-Cas can utilize non-homologous end joining and homology-directed repair for DNA repair, as well as single-base editing enzymes. In addition to targeting DNA, CRISPR-Cas-based RNA-targeting tools are being developed for research, medicine and diagnostics. Nuclease-inactive and RNA-targeting Cas proteins have been fused to a plethora of effector proteins to regulate gene expression, epigenetic modifications and chromatin interactions. Collectively, the new advances are considerably improving our understanding of biological processes and are propelling CRISPR-Cas-based tools towards clinical use in gene and cell therapies.


Method of error analysis for phase-measuring algorithms applied to photoelasticity.
We present a method of error analysis that can be applied for phase-measuring algorithms applied to photoelasticity. We calculate the contributions to the measurement error of the different elements of a circular polariscope as perturbations of the Jones matrices associated with each element. The Jones matrix of the real polariscope can then be calculated as a sum of the nominal matrix and a series of contributions that depend on the errors associated with each element separately. We apply this method to the analysis of phase-measuring algorithms for the determination of isoclinics and isochromatics, including comparisons with real measurements.


Trend analysis of leprosy in Morocco between 2000 and 2017: Evidence on the single dose rifampicin chemoprophylaxis.
Morocco has achieved the goal of leprosy elimination as a public health problem several years ago (less than 1 case/ 10 000 habitant). The aim of this study was to analyze trends of leprosy detection during the last 17 years taking into consideration the implementation of single dose rifampicin chemoprophylaxis (SDRC) started in 2012. Time series of leprosy cases detected at national level between 2000 and 2017. Variable collected for each year were leprosy per 100000 H, age category, gender, origin, regions, grade of disabilities and clinical forms. The detection time series was assessed by Joinpoint Regression Analysis. Annual percentage changes (APCs) were estimated to identify the years (joinpoint) when significant changes occurred in the trend. We therefore examined trends in leprosy detection according to epidemiological variables. Joinpoint regression showed a reduction in the detection rate between 2000 and 2017. The APC for the period 2012-2017 (-16.83, 95% CI: -29.2 to -2.3, p <0.05) was more pronounced than that of the previous period 2000-2012 (- 4.68, 95% CI: -7.3 to -2.0, p <0.05); with a significant break in the same joinpoint year SDRC implementation. In stratified analysis, case detection decreased, but not significantly, after the joinpoint years in men, children, multi-bacillary cases, grade 0-1 disabilities, rural and urban cases and in ten regions. Leprosy detection was declining over years with a significant reduction by 16% per year from 2012 to 2017. SDRC may reduce leprosy detection over the years following its administration.


[Comorbidity in cardiac pathology: clinical-organizational and epidemiological problems].
Scientific (analytical) approach directs researcher to the study of nosology in isolated native view. The phenomenon under consideration- comorbidity becomes significant and to a substantial degree is able to affect all aspects of the process of medical care. This is shown in this review along such directions as frequency of overt or concealed comorbidity or real state of the problem; magnitude of intracardiac and extracardiac comorbidity; difficulties of diagnostics and treatment arising with comorbidity; problems of validity of statistical (and epidemiological) side of the matter; value of social and organizational aspects of patients care in situations when comorbidity is present.


Fibroblast Growth Factor 23 Predicts Mortality and End-Stage Renal Disease in a Canadian Asian Population with Chronic Kidney Disease.
Chronic kidney disease (CKD) is a leading cause of morbidity and mortality. Biomarkers that predict end-stage renal disease (ESRD) and/or mortality could usher in new therapeutics to halt this onslaught. While fibroblast growth factor (FGF)23 can predict both ESRD and mortality, it has not been studied in North American CKD patients of Asian ethnicity. This is a prospective investigation about the role of FGF23 in 998 Canadian patients of Asian descent with CKD defined by an estimated glomerular filtration rate (eGFR) <60 mL/min/m2 and followed up for 3 years. The mean age of patients was 68.9 years and 68.3% were males. The mean (range) eGFR, and median FGF23 were 40.2 (11.0-59.0) mL/min and 154.1 (7.0-7,823.0) RU/mL, respectively. Over the 3 years, higher values of FGF23 levels at baseline were associated with higher risk of ESRD (hazard ratio [HR] for log[Fgf23] = 2.16 [95% CI 1.20-3.89]). Despite the short follow-up, 42 patients died due to cardiovascular diseases (38.8%), cancer (14.9%), and infections (12.7%). Log-FGF23 levels were independently associated with death, HR 1.94, 95% CI 1.24-3.03. Mortality risk increased in FGF23 subgroups from <100 to >400 RU/mL. In a time-changing covariate analysis, serial log-FGF23 levels over the 3 years predicted mortality with a HR of 2.66 (95% CI 1. 79-3.95). In a Canadian Asian population with CKD, FGF23 levels obtained at 6-monthly intervals for 3 years predicted ESRD and mortality suggesting that it is also a risk marker in Asians.


Suppression of the tumorigenic phenotype by chromosome 18 transfer into pancreatic cancer cell lines.
A number of lines of evidence have suggested that the long arm of chromosome 18 apart from SMAD4 may carry a tumor-suppressor gene(s) that plays a role in the early stage of pancreatic ductal carcinogenesis. Thus, adenovirus-mediated introduction of SMAD4 does not suppress in vitro growth in cells with completely inactivated SMAD4, and frequent loss of 18q at the SMAD4 locus is observed in pancreatic cancers but no abnormalities of the normal SMAD4 homolog have been detected. In this study, we introduced a normal copy of chromosome 18 into some pancreatic ductal carcinoma cells with and without a complete inactivation of SMAD4. Both anchorage-dependent and -independent proliferation as well as invasiveness were significantly suppressed in the hybrid clones compared with that of their parental cells. Moreover, significant suppression of tumorigenesis was observed after inoculation in nude mice, irrespective of the SMAD4 status. Our present study provides the first functional evidence of the existence of an additional tumor-suppressor gene(s), other than SMAD4 and DCC, that is responsible for the pathogenesis in the early stage of pancreatic ductal carcinogenesis.