Analytical method to determine the orientation of rigid spin labels in DNA.
We demonstrate the ability of pulsed electron double resonance (PELDOR) experiments to determine the orientation of spin labels in biological macromolecules. Thus, the distance information usually obtained from PELDOR data can be complemented by the mutual orientation of macromolecular domains. A method to determine the angle beta between the spin label normal and the interspin axis is proposed and analyzed mathematically. The obtained analytical expression allows extraction of angles beta without a fitting procedure if these angles are equal for both nitroxide of biradical. The method was applied to the experimental data gathered on ten spin-labeled DNA samples. The angles estimated from the PELDOR data are in excellent agreement with literature values.


N-benzoylimido complexes of palladium. Synthesis, structural characterisation and structure-reactivity relationship.
Benzoyl azides, ArC(O)N3, 2, (Ar = phenyl or substituted phenyl), react with [Pd2Cl2(dppm)2], 1, [dppm = bis(diphenylphosphino)methane] with the formation of novel [Pd2Cl2(mu-NC(O)Ar)(dppm)2], 3, benzoylnitrene complexes that were structurally characterised by multinuclear magnetic resonance and IR spectroscopy and, in several instances, by single crystal X-ray diffraction. As shown by crystallographic studies, the C2P4Pd2 rings adopt extended twist-boat conformations with methylene groups bending towards the bridging benzoylimido moieties. X-ray diffraction studies have revealed the chiral nature of the imido complexes, the chiral element being the propeller-like C2P4Pd2 ring. Structural data accumulated on complexes 3 such as short C-N distances (1.32 A), elongated C=O bonds (1.30 A) as well as the outstandingly high barrier to internal rotation around the N-C(O) linkage (88.3 kJ mol(-1)) are in line with extensive ppi-ppi interaction between the bridging nitrogen and the carbonyl carbon atoms. Theoretical calculations indicate an electron shift from the dimer towards the apical nitrogen atom, which, in turn, facilitates the donation of electrons towards the carbonyl moiety. To elucidate the structure-reactivity relationship of benzoyl azides towards 1, crystallographic and solution IR spectroscopic studies were carried out on a series of para-substituted benzoyl azides. The reaction obeys the Hammett equation. The large positive value of the reaction constant indicates that the azides act as electrophiles in the reaction studied. The enhanced reactivity of 2-nitrobenzoyl azide has been attributed to a decreased conjugation of the phenyl and carbonyl moieties in this reagent.


The TP53-Related Signature Predicts Immune Cell Infiltration, Therapeutic Response, and Prognosis in Patients With Esophageal Carcinoma.
TP53 mutation (TP53MUT) is one of the most common gene mutations and frequently occurs in many cancers, especially esophageal carcinoma (ESCA), and it correlates with clinical prognostic outcomes. Nevertheless, the mechanisms by which TP53MUT regulates the correlation between ESCA and prognosis have not been sufficiently studied. Here, in the current research, we constructed a TP53MUT-related signature to predict the prognosis of patients with esophageal cancer and successfully verified this model in patients in the TP53 mutant group, esophageal squamous cell carcinoma group, and adenocarcinoma group. The risk scores proved to be better independent prognostic factors than clinical features, and prognostic features were combined with other clinical features to establish a convincing nomogram to predict overall survival from 1 to 3 years. In addition, we further predicted the tumor immune cell infiltration, chemical drugs, and immunotherapy responses between the high-risk group and low risk group. Finally, the gene expression of the seven-gene signature (AP002478.1, BHLHA15, FFAR2, IGFBP1, KCTD8, PHYHD1, and SLC26A9) can provide personalized prognosis prediction and insights into new treatments.


Abdominal apoplexy associated with the levonorgestrel intrauterine system--case report.
Abdominal apoplexy is defined as intraabdominal haemorrhage without an identifiable pathology. This life-threatening situation is hardly mentioned in the literature. The clinical tableau is non-specific. The onset can be with nausea, mild to severe abdominal pain, a palpable mass in the abdomen or flank and sings of hypovolemic shock. The approach should be resuscitation, look for a likely underlying cause and control the bleeding. The present report will describe a case of abdominal apoplexy in a patient using a levonorgestrel intrauterine system. The management and possible origins of abdominal apoplexy will be discussed.


Identification of dipole disorder in low temperature solution processed oxides: its utility and suppression for transparent high performance solution-processed hybrid electronics.
The ability to deposit high-quality inorganic semiconductors and dielectrics from solution at low process temperatures (∼200 °C) has become a very important research focus. During the course of our investigation, we identify the presence of an induced dipole present in solid state solution processed inorganic oxide insulator layers processed at reduced temperature (200-350 °C) from either molecular precursors, or well-dispersed metal oxide nanoparticles. Chemical composition analysis coupled with electrical measurements shows that the dielectric instability occurs due to proton migration via the Grotthuss mechanism inducing a long lived dipole disorder. Thus we established conditions for suppressing this effect to afford "ideal" high-k dielectric layer. Using this methodology, solution processed all inorganic thin film transistors (TFTs) with charge carrier mobilities exceeding 6 cm2 V-1 s-1 operating at low voltage (5 V) have been achieved. In addition, we show the broad utility of the perovskite high-k dielectric when processed with state of the art polymer and single crystal organic semiconductors yielding mobilities of approx. 7 cm2 V-1 s-1 at only 4 V. These transparent devices demonstrate excellent electrical device stability and a threshold voltage shift of only 0.41 V over 14 h, which is comparable, or better than sputtered oxide films.


An ex vivo method for evaluating the biocompatibility of neural electrodes in rat brain slice cultures.
Failure of neural recording electrodes implanted in the brain is often attributed to the formation of glial scars around the implant. A leading cause of scar formation is the electrode material. Described below is an approach to evaluate the biocompatibility of novel electrode materials in a representative three-dimensional model. The model, brain slice culture, accounts for the response of the neural tissue in the absence of the systemic response. While limitations of any in vitro model exist, brain slice culture provides an indication of the response of neurons and glia in an environment more indicative of the in vivo environment than two-dimensional cell culture of glia or neurons alone. Polybenzylcyclobutene (BCB) electrodes were developed as test materials for flexible electrodes due to ease of processing, low water uptake, and inherent flexibility when formed in thin sheets. Biocompatibilty of the BCB neural electrodes was evaluated using living brain slices derived from the hippocampal regions of 100 g CD rats. Importantly, fewer animals can be used in brain slice culture to evaluate the neural tissue response than when using live animals, since several slices can be obtained per animal. Cellular response to the electrodes was evaluated at 0, 7, and 14 days. At all time points living cells, both neurons and glia, were observed in the vicinity of the electrode. In addition, cells were observed migrating out from the brain slices onto the shank of the BCB electrode. Brain slice culture is shown to be a viable alternative to in vivo evaluation, in that the response of both neurons and glia can be evaluated in a native three-dimensional state, while sacrificing fewer animals. Future in vivo evaluation with BCB will provide definitive answers on the degree of glial scarring in response to this new and biocompatible electrode material.


Relationship between chromosome replication and cell division in a thymineless mutant of Escherichia coli B/r.
The relationship between chromosome replication and cell division was investigated in a thymineless mutant of Escherichia coli B/r. Examination of the changes in average cell mass and DNA content of exponential cultures resulting from changes in the thymine concentration in the growth medium suggested that as the replication time (C) is increased there is a decrease in the period between termination of a round of replication and the subsequent cell division (D). Observations on the pattern of DNA synthesis during the division cycle were consistent with this relationship. Nevertheless, the kinetics of transition of exponential cultures moving between steady states of growth with differing replication velocities provided evidence to support the view that the time of cell division is determined by termination of rounds of replication under steady-state conditions.


A Novel and Simple Modification for Management of Distal Ureter During Laparoscopic Nephroureterectomy Without Patient Repositioning: A Bulldog Clamp Technique and Description of Modified Port Placement.
To describe a novel and pure laparoscopic approach using a custom-made bulldog clamp with modified port placement for management of distal ureter during laparoscopic nephroureterectomy. Between October 2013 and December 2014, 31 patients found to have upper tract urothelial carcinoma were treated using this technique. After finishing a standard laparoscopic transperitoneal nephrectomy in a 45° to 60° recumbent position, an additional 12-mm trocar was inserted at the lower abdomen to allow the surgeon to continue dissecting the ureter caudally toward the bladder wall without repositioning the patient. The intramural ureter was separated from the surrounding detrusor muscle and down to the bladder mucosa, until a tent-shaped bladder cuff and intramural ureter could be formed by retraction in the superior and lateral directions. Then, a custom-made laparoscopic bulldog clamp was placed at the bottom of the tent-shaped structure to prevent urine spillage, and the bladder was closed by two-layer running closure using a barbed suture. All surgeries were completed uneventfully. The mean operative time and estimated blood loss were 146.6 minutes and 47.3 mL, respectively. The median duration of the postoperative hospital stay was 6 days. No complications were noted. There were no positive margins in any specimen. No patients experienced stone formation or local or bladder recurrence during the 10.5-month follow-up period. Our novel technique fully replicates the open excision technique and conforms to the strictest oncologic principles while avoiding patient repositioning and the use of staplers (EndoGIA or Hemolock) to prevent stone formation.


Surface engineering of poly(D,L-lactic acid) by entrapment of soluble eggshell membrane protein.
Soluble eggshell membrane protein (SEP) is used to engineer poly(D,L-lactic acid) (PDL-LA) membrane surface by a physical entrapment method to enhance cytocompatibility. Attenuated total reflection Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and contact angle measurements are used to characterize SEP-modified PDL-LA membrane surface and confirm the formation of an even and stable layer of SEP on PDL-LA membrane surface. NIH3T3 cell lines are used as model cells to evaluate cytocompatibility of the SEP-modified PDL-LA membrane, which is much better than that of virgin PDL-LA membrane. The enhanced cytocompatibility facilitates potential application in tissue engineering.


Hidradenitis suppurativa: a review of current treatment options.
Hidradenitis suppurativa (HS) is a chronic, progressive, debilitating, recurrent inflammatory skin disease characterized by the occurrence of very severe, persistent, painful nodules, abscesses, and fistulas, most commonly found in the skin folds of the axilla, groin, gluteal, and perianal areas. The pathogenesis of HS is still not completely understood; currently, it is considered to be an immune-mediated inflammatory illness (IMID). Due to the significant decrease in the patients' quality of life and a delayed beginning of a treatment, the selection of the appropriate therapy is extremely important in these patients. Regardless of the fact that there are multiple treatment options for HS, no uniformly effective therapy has been found. All the guidelines underline the need for a multidisciplinary approach to the disease, which enables providers to create the right management of HS. This article aims to provide updates on the current treatment options of acne inversa to raise awareness and improve the management of the disease.


Decreased autonomic modulation of heart rate and altered cardiac sympathovagal balance in patients with Cushing's syndrome: role of endogenous hypercortisolism.
Endogenous Cushing's syndrome is associated with a higher risk of cardiovascular morbidity and mortality. Previous literature suggested multiple possible links by which hypercortisolism may alter the autonomic control of cardiovascular functions. We investigated the impact of chronic endogenous hypercortisolism on the autonomic regulation of cardiac functions by short-term heart rate variability analysis. Eighteen patients with endogenous Cushing's syndrome and 20 age-, gender- and BMI-matched controls participated in the study. ECG signal was acquired in lead II configuration for 5 min and heart rate variability assessment was made in both time and frequency domain using the extracted RR interval data. All time and frequency domain measures of heart rate variability were significantly (p < 0.05) lower in the patient group compared to the control group. The patient group had an altered sympathovagal balance with low frequency/high frequency band ratio significantly higher than the control group [1.857 (0.6747-2.610) vs. 0.8581 (0.4779-1.352); p = 0.0253]. A significant negative correlation was obtained between normalized high frequency power of heart rate variability and basal cortisol levels (r = -0.6594; p = 0.0029). Multiple linear regression analysis identified age, disease duration (in months), basal cortisol levels and systolic blood pressure as independent predictors of normalized high frequency power. Findings of the study clearly portrayed the diminished autonomic modulation of heart rate in endogenous Cushing's syndrome and its possible relationship with hypercortisolism as the main causative factor. Diminished heart rate variability may be an indicator of the increased risk of cardiac mortality in these patients.


Presence of human non-polio enterovirus and parechovirus genotypes in an Amsterdam hospital in 2007 to 2011 compared to national and international published surveillance data: a comprehensive review.
Enteroviruses (EV) and human parechoviruses (HPeV) are endemic worldwide. These infections are a constant cause of hospitalisation and severe disease, predominantly in young children and infants. Coordinated monitoring and surveillance are crucial to control these infections. We have monitored EV and HPeV epidemiology in Amsterdam from 2007 to 2011 with real-time RT-PCR and direct genotyping, facilitating highly sensitive surveillance. Moreover, we conducted a literature survey of existing surveillance data for comparison. Only 14 studies were identified. While HPeV1 was most frequently detected in Amsterdam, EV-B viruses dominated nationally and internationally. Furthermore, the top 10 strains detected differed yearly and per study. However, detection and typing methods were too varied to allow direct comparison and comprehension of the worldwide distribution and circulation patterns of the different genotypes. This limited a direct response to anticipate peaks. Uniform European monitoring programmes are essential to aid prediction of outbreaks and disease management.


Management of annuloaortic ectasia in association with aortic regurgitation.
Annuloaortic ectasia associated with severe aortic regurgitation is usually managed by implanting a composite graft that comprises both valve and conduit. Synthetic valved conduits have been used by most cardiovascular surgeons, with various modifications in the technique. Yet prosthetic valves carry the risks associated with anticoagulation therapy, together with an increased risk of infective endocarditis. We report a case in which a cryopreserved aortic homograft was used for a Bentall procedure in a patient who had annuloaortic ectasia with severe aortic regurgitation. To the best of our knowledge, there are no prior published reports of homograft insertion in treatment of annuloaortic ectasia.


A single exposure to iron oxide nanoparticles attenuates antigen-specific antibody production and T-cell reactivity in ovalbumin-sensitized BALB/c mice.
Superparamagnetic iron oxide nanoparticles have been used in clinical applications as a diagnostic contrasting agent. Previous studies showed that iron oxide nanoparticles deposited in the liver and spleen after systemic administration. The present study investigated the effect of iron oxide nanoparticles on antigen-specific immune responses in mice sensitized with the T cell-dependent antigen ovalbumin (OVA). BALB/c mice were intravenously administered with a single dose of iron oxide nanoparticles (10-60 mg Fe/kg) 1 hour prior to OVA sensitization, and the serum antibody production and splenocyte reactivity were examined 7 days later. The serum levels of OVA-specific IgG(1) and IgG(2a) were significantly attenuated by treatment with iron oxide nanoparticles. The production of interferon-γ and interleukin-4 by splenocytes re-stimulated with OVA in culture was robustly suppressed in mice administered with iron oxide nanoparticles. The viability of OVA-stimulated splenocytes was also attenuated. In contrast, treatment with iron oxide nanoparticles did not affect the viability of splenocytes stimulated with concanavalin A, a T-cell mitogen. Collectively, these data indicate that systemic exposure to a single dose of iron oxide nanoparticles compromises subsequent antigen-specific immune reactions, including the serum production of antigen-specific antibodies, and the functionality of T cells.


Ubiquitin reduces contusion volume after controlled cortical impact injury in rats.
Recent data suggest that ubiquitin has anti-inflammatory properties and therapeutic potential after severe trauma and brain injuries. However, direct evidence for its neuroprotective effects has not yet been provided. We hypothesized that ubiquitin treatment is neuroprotective, and thus reduces brain edema formation and cortical contusion volume after closed traumatic brain injuries. To test this hypothesis, a focal cortical contusion was induced using a controlled cortical impact (CCI) model in Sprague-Dawley rats. Animals (n = 27) were randomized to either 1.5 mg/kg ubiquitin or vehicle (placebo) intravenously within 5 min after CCI. Blood pressure, arterial blood gases (ABG) and intracranial pressure (ICP) were monitored. Ubiquitin serum and cerebrospinal fluid levels were measured by ELISA. Brain water content was quantified gravimetrically after 24 h and cerebral contusion volume was determined in triphenyltetrazolium-chloride stained brains after 7 days. All animals recovered to normal activity. ICP and cerebral perfusion pressures were normal at the end of the observation period. Ubiquitin serum and CSF levels at 24 h and 7 days after CCI were similar in both groups. With ubiquitin brain water content of the injured hemisphere was slightly lower (n = 6/group; 79.97 +/- 0.29% vs. 81.11 +/- 0.52%; p = 0.08). Cortical contusion volume was significantly lower with ubiquitin (n = 7-8/group; 32.88 +/- 2.1 mm(3) vs. 43.96 +/- 4.56 mm(3); p = 0.025). This study shows that ubiquitin treatment after brain injury has direct neuroprotective effects, as demonstrated by improved brain morphology 7 days after brain injury. In connection with its beneficial effects in our previous studies, these data suggest ubiquitin as a promising candidate protein therapeutic for the treatment of brain injuries.


The Effect of COVID-19 Severity, Associated Serum Autoantibodies and Time Interval after the Disease on the Outcomes of Fresh Oocyte ART Cycles in Non-Vaccinated Patients.
It is assumed that SARS-CoV-2- and COVID-19-associated autoimmune processes may affect the outcomes of assisted reproductive technology (ART) cycles. This observational prospective study included 240 infertile patients: 105 patients had no history of COVID-19 (group 1) and 135 patients had experienced COVID-19 (group 2) in a mild (n = 85) or moderate (n = 50) form less than 12 months prior to oocyte retrieval. Using ELISAs, the profiles of their serum autoantibodies were determined, including antiphospholipid antibodies and antibodies to nuclear and thyroid antigens. The parameters of oogenesis and embryogenesis, as well as the pregnancy and childbirth rates, did not differ between groups 1 and 2, and also between the subgroups with different severities of COVID-19. However, when oocyte retrieval was performed less than 180 days after COVID-19, a higher proportion of poor-quality blastocysts was obtained (p = 0.006). A high risk of early miscarriage was found in the patients with moderate COVID-19. In group 2, IgG antibodies to annexin V, phosphatidylethanolamine (PE), and TSHr were detected more often than in group 1 (p = 0.035; p = 0.028; and p = 0.033, respectively), and a weak inverse correlation was revealed between anti-PE IgG and the number of oocytes and zygotes obtained. The results of the study suggest a possible adverse effect of COVID-19 and its associated autoantibodies on the outcomes of fresh oocyte ART cycles and early pregnancy, which depends on the severity of COVID-19 and the time interval after the disease.


A Deep Learning-Based Approach to Estimate Paneth Cell Granule Area in Celiac Disease.
Changes in Paneth cell numbers can be associated with chronic inflammatory diseases of the gastrointestinal tract. So far, no consensus has been achieved on the number of Paneth cells and their relevance to celiac disease (CD). To compare crypt and Paneth cell granule areas between patients with CD and without CD (non-CD) using an artificial intelligence-based solution. Hematoxylin-eosin-stained sections of duodenal biopsies from 349 patients at the McGill University Health Centre were analyzed. Of these, 185 had a history of CD and 164 were controls. Slides were digitized and NoCodeSeg, a code-free workflow using open-source software (QuPath, DeepMIB), was implemented to train deep learning models to segment crypts and Paneth cell granules. The total area of the entire analyzed tissue, epithelium, crypts, and Paneth cell granules was documented for all slides, and comparisons were performed. A mean intersection-over-union score of 88.76% and 91.30% was achieved for crypt areas and Paneth cell granule segmentations, respectively. On normalization to total tissue area, the crypt to total tissue area in CD was increased and Paneth cell granule area to total tissue area decreased when compared to non-CD controls. Crypt hyperplasia was confirmed in CD compared to non-CD controls. The area of Paneth cell granules, an indirect measure of Paneth cell function, decreased with increasing severity of CD. More importantly, our study analyzed complete hematoxylin-eosin slide sections using an efficient and easy to use coding-free artificial intelligence workflow.


Oral administration of 5-methoxypsoralen affects the distribution and metabolism of 2-aminofluorene in Sprague-Dawley rats.
The effects of 5-methoxypsoralen (5-MOP) on the distribution and metabolism of chemical carcinogens such as 2-aminofluorene (AF) has not been previously reported. In this study, the influences of 5-MOP on the metabolism of AF in Sprague-Dawley (SD) rats were investigated. After receiving 5-MOP in 24 hours, AF was introduced into each animal by gastric intubation. After 12, 24, 48 and 72 hours the urine, feces, and cytosol of the liver, kidneys, stomach, colon, bladder and blood of rats were collected and assayed for AF and its metabolites by HPLC. Compared to the control regimen, 5-MOP caused an increase of the metabolites excreted in urine and feces. The largest dose of metabolites were excreted between 48-72 hours. The major metabolite excreted in the urine was 9-hydroxy-AAF (9-OH-AAF) and in the feces was 7-hydroxy-AAF (7-OH-AAF). There was no time-effect for the tissues, and the liver was the main target organ for the AF and its metabolites. The major residual metabolite of AF in the liver, kidneys, stomach, colon and bladder was 7-OH-AAF. In blood it was 9-OH-AAF. The bladder had the lowest metabolic residue in tissues, and blood played the role of transportation but was not the target organ. 5-MOP decreased the concentration of AF and its residual metabolites of liver, stomach, kidneys, bladder and blood at various times. 5-MOP increased the metabolism of AF in order to transform to ring-hydroxylated metabolites and increased excretion of the ring-hydroxylated metabolites, therefore decreasing AF and its residual metabolites in vivo. Although 5-MOP was shown to be an inhibitor of CYP 2A6 and CYP 2B1, somehow it causes an increase of activity in AF metabolism in vivo; it induces more CYPs involved in the metabolism of AF.


Location of amino acid alterations in mutants of aspartate transcarbamoylase: Structural aspects of interallelic complementation.
Recent genetic studies of the pyrB locus of Escherichia coli resulted in the characterization of 29 mutant strains harboring defects in the structural gene that encodes the catalytic chains of aspartate transcarbamoylase (carbamoylphosphate: L-aspartate carbamoyltransferase, EC 126.96.36.199). Three alleles, pyrB554, pyrB730, and pyrB748, have been cloned, and their nucleotide sequences have been determined along with that of the wild-type pyrBI operon in order to locate the sites of the alterations in the catalytic chains. Missense mutation pyrB554 leads to replacement of serine-52 by phenylalanine, and the inactive mutant enzyme has properties similar to those of wild-type aspartate transcarbamoylase. The amber mutation pyrB730 results in unstable truncated polypeptide chains 27 amino acids shorter than wild-type chains. Deletion mutation pyrB748 causes the removal of 181 amino acids. Combining these results with knowledge of the crystallographic structure of the wild-type enzyme provides a basis for tentative structural mechanisms for the observed complementation behavior of the mutant proteins.


Can Ferroelectricity Improve Organic Solar Cells?
Blends of semiconducting (SC) and ferroelectric (FE) polymers have been proposed for applications in resistive memories and organic photovoltaics (OPV). For OPV, the rationale is that the local electric field associated with the dipoles in a blend could aid exciton dissociation, thus improving power conversion efficiency. However, FE polymers either require solvents or processing steps that are incompatible with those required for SC polymers. To overcome this limitation, SC (poly(3-hexylthiophene)) and FE (poly(vinylidene fluoride-trifluoroethylene)) components are incorporated into a block copolymer and thus a path to a facile fabrication of smooth thin films from suitably chosen solvents is achieved. In this work, the photophysical properties and device performance of organic solar cells containing the aforementioned block copolymer consisting of poly(vinylidene fluoride-trifluoroethylene): P(VDF-TrFE), poly(3-hexylthiophene): P3HT and the electron acceptor phenyl-C61 -butyric acid methyl ester: [60]PCBM are explored. A decrease in photovoltaic performance is observed in blends of the copolymer with P3HT:[60]PCBM, which is attributed to a less favorable nanomorphology upon addition of the copolymer. The role of lithium fluoride (the cathode modification layer) is also clarified in devices containing the copolymer, and it is demonstrated that ferroelectric compensation prevents the ferroelectricity of the copolymer from improving photovoltaic performance in SC-FE blends.


Lynch Syndrome Associated Colon Adenocarcinoma Resembling Lymphoma on Fluoro-Deoxyglucose-Positron Emission Tomography/Computed Tomography.
The patient was a 46-year-old Asian male diagnosed with lynch syndrome associated colon adenocarcinoma in the right ascending colon. A presurgical staging 18-fluoro-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) found increased metabolic activity in the cervical, axillary, mediastinal, supraclavicular, para-aortic and mesenteric lymph nodes. This pattern of metastasis was very unusual for lynch syndrome associated colon adenocarcinoma and the involvement of those lymph nodes resembles the pattern of spread of lymphoma. He underwent right hemicolectomy and he was subsequently treated with 12 cycles of folinic acid (leucovorin), fluorouracil (5-FU), irinotecan. A restaging FDG-PET/CT at the end of the chemotherapy showed interval decrease in size and metabolic activity in the affected lymph nodes. FDG-PET/CT is a useful imaging modality in following-up the treatment response in colon adenocarcinoma.


Traumatic carotid-cavernous fistula in a multiple facial fractures patient: case report and literature review.
Carotid-cavernous fistula (CCF) is a pathologic communication between internal carotid artery (ICA) and cavernous sinus (CS). CCF occurs most commonly in association with craniofacial trauma. Traumatic CCFs are very rare, occurring in 0.17-0.27% of craniomaxillofacial trauma cases. We present a case of the patient treated for multiple facial fractures, who developed symptoms of CCF with several days latency and was successfully treated by endovascular occlusion of ICA. Anatomy of CS, pathophysiology of CCFs and treatment options are concisely reviewed.


Topical corticosteroids knowledge, attitudes, and practices of primary care physicians.
To assess knowledge, attitudes, and practices of primary care physicians (PCPs) toward topical corticosteroids (TCs). Methods: A cross-sectional, 53-item questionnaire based study on TCs was conducted among PCPs in Riyadh, Kingdom of Saudi Arabia between January and March 2015. A maximum score of 30 was calculated for the knowledge portion. Results: Out of 420 PCPs, 336 responded (80%). Most participants (89.6%) reported prescribing TCs. The mean knowledge score was 17.14 (SD=5.48). Only 39% PCPs correctly identified that there are 7 or 4 TCs potency groups (2 different classification systems). The MBBS/MD and diploma-certified physicians scored lower than board-qualified PCPs (p less than 0.05). Family medicine physicians scored higher than general practitioners (GPs) (p less than 0.05). Hospital-based PCPs scored better than private practice PCPs (p less than 0.05). Moreover, those who felt somewhat comfortable (32.5%) in treating dermatology patients were more knowledgeable (p less than 0.05). Lastly, 76.5% of physicians were interested in attending courses on dermatologic therapies. Conclusion: Knowledge of TCs among PCPs was inadequate. Targeted educational interventions delivered by dermatologists are recommended.


Flavanone metabolites decrease monocyte adhesion to TNF-α-activated endothelial cells by modulating expression of atherosclerosis-related genes.
Flavanones are found specifically and abundantly in citrus fruits. Their beneficial effect on vascular function is well documented. However, little is known about their cellular and molecular mechanisms of action in vascular cells. The goal of the present study was to identify the impact of flavanone metabolites on endothelial cells and decipher the underlying molecular mechanisms of action. We investigated the impact of naringenin and hesperetin metabolites at 0·5, 2 and 10 μM on monocyte adhesion to TNF-α-activated human umbilical vein endothelial cells (HUVEC) and on gene expression. Except hesperetin-7-glucuronide and naringenin-7-glucuronide (N7G), when present at 2 μM, flavanone metabolites (hesperetin-3'-sulphate, hesperetin-3'-glucuronide and naringenin-4'-glucuronide (N4'G)) significantly attenuated monocyte adhesion to TNF-α-activated HUVEC. Exposure of both monocytes and HUVEC to N4'G and N7G at 2 μM resulted in a higher inhibitory effect on monocyte adhesion. Gene expression analysis, using TaqMan Low-Density Array, revealed that flavanone metabolites modulated the expression of genes involved in atherogenesis, such as those involved in inflammation, cell adhesion and cytoskeletal organisation. In conclusion, physiologically relevant concentrations of flavanone metabolites reduce monocyte adhesion to TNF-α-stimulated endothelial cells by affecting the expression of related genes. This provides a potential explanation for the vasculoprotective effects of flavanones.


Unfolding of the chromosome of Escherichia coli after treatment with rifampicin.
Until recently it has been assumed that the factors being responsible for the condensation of the DNA in the nucleoid of Escherichia coli are destroyed by rifampicin because it has been impossible to obtain folded chromosomes from cells treated with this inhibitor. In this paper it is shown by viscosity and sedimentation measurements that unfolding of the DNA does not take place during the process of the cell lysis as it should be predicted from this assumption, but is occurring distinctly afterwards. Since the observed unfolding process is too slow to be caused simply by molecular movements it is concluded that it is brought about by the action of salts or detergents of the lysis medium. The structure of the nucleoid is still intact in vivo despite inhibition of RNA synthesis by rifampicin.


Changes in the olfactory response to amino acids in Japanese newts after transfer from an aquatic to a terrestrial habitat.
Amphibians are capable of smelling both volatile and water-soluble (e.g., amino acids) odorants. Adult Japanese newts, Cynops pyrrhogaster, live mostly in water, except during hibernation, but sometimes on land. To examine olfactory responses of the newts to adaptation to a short-term stay on land (land adaptation), we measured the magnitude of the olfactory response at five different time points (land adaptation time: 0, 30, 54, 90, and 114 h after transfer from an aquatic to a terrestrial habitat by using electro-olfactogram (EOG) recordings. Statistical analysis by the weighted linear model (P < 0.05) indicated that the time to land adaptation had a significant effect on the magnitude of the EOG induced by 1 microM and 10 microM amino acid mixtures. Further, the slope estimates of the weighted linear model were significantly positive (P < 0.05). These results indicate that the magnitude of the EOG response to amino acid mixtures (arginine, alanine, proline, and glutamic acid) significantly increases with land adaptation time. On the other hand, we observed no significant relationship between the magnitude of the EOG response induced by an 0.05% volatile odorant mixture (isoamyl acetate, n-amyl acetate, cineole, and limonene) and land adaptation time. Our results indicate that olfactory sensitivity to amino acids significantly increases with land adaptation time in adult Japanese newts.


[Genetic polymorphism of human CYP2E1: new allels detected in exons and exon-intron junctions].
Cytochrome P450-2E1 (CYP2E1) is a major component of the microsomal ethanol-oxidizing system (MEOS) and is also involved in the metabolism of a variety of foreign compounds including carcinogens. It has been shown that there is an interindividual variation in the expression of human hepatic CYP2E1. Gene-environmental interactions have been suggested to account for the difference. In this study, we screened nine exons of the human CYP2E1 gene for detecting allelic variants in genomic DNA samples obtained from 115 Japanese controls, 96 Japanese alcoholics and 124 American control subjects. A novel missense mutation in exon 2 (V72L) was found in Japanese controls, and another missense mutation in exon 8 (D394G) was detected in American Caucasians. In addition, two novel silent mutations in exon 6 (T303T) and exon 8 (F420F) were found in Japanese controls and alcoholics. Especially the silent mutation in exon 8 was highly polymorphic among three population groups. The mutation in exon 2 (V72L) was detected only in Japanese controls, but not in alcoholics although it shows no significant difference. Gene frequency of the silent mutation in exon 8 was significantly higher in Japanese than American Caucasians (34.8% vs 21.0%, p < 0.02). Our data indicated that nucleotide replacement in the open reading frame is no major factor responsible for alcoholism. However, functional significance of the two novel missense mutations remains to be detailed.


Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice.
Cholestasis-induced liver injury during bile duct obstruction causes an acute inflammatory response. To further characterize the mechanisms underlying the neutrophil-induced cell damage in the bile duct ligation (BDL) model, we performed experiments using wild-type (WT) and ICAM-1-deficient mice. After BDL for 3 days, increased ICAM-1 expression was observed along sinusoids, along portal veins, and on hepatocytes in livers of WT animals. Neutrophils accumulated in sinusoids [358 +/- 44 neutrophils/20 high-power fields (HPF)] and >50% extravasated into the parenchymal tissue. Plasma alanine transaminase (ALT) levels increased by 23-fold, and severe liver cell necrosis (47 +/- 11% of total cells) was observed. Chlorotyrosine-protein adducts (a marker for neutrophil-derived hypochlorous acid) and 4-hydroxynonenal adducts (a lipid peroxidation product) were detected in these livers. Neutrophils also accumulated in the portal venules and extravasated into the portal tracts. However, no evidence for chlorotyrosine or 4-hydroxynonenal protein adducts was detected in portal tracts. ICAM-1-deficient mice showed 67% reduction in plasma ALT levels and 83% reduction in necrosis after BDL compared with WT animals. The total number of neutrophils in the liver was reduced (126 +/- 25/20 HPF), and 85% of these leukocytes remained in sinusoids. Moreover, these livers showed minimal staining for chlorotyrosine and 4-hydroxynonenal adducts, indicating a substantially reduced oxidant stress and a diminished cytokine response. Thus neutrophils relevant for the aggravation of acute cholestatic liver injury in BDL mice accumulate in hepatic sinusoids, extravasate into the tissue dependent on ICAM-1, and cause cell damage involving reactive oxygen formation.


Fracture resistance and failure pattern of endodontically treated maxillary premolars restored with transfixed glass fiber post: an in vitro and finite element analysis.
The aims of the study were to determine the effect of different types of endodontic sealers and the presence of a horizontal glass fiber post (HGFP) on the fracture resistance and fracture pattern of mesio-occluso-distal (MOD) restored upper premolars and to analyze the stress distribution. Sixty extracted upper premolars received root canal treatment (RCT) and a MOD cavity preparation. All MOD cavities were restored with the same composite resin (CR). The 60 teeth were divided randomly into 6 groups (n = 10); Group1= AH Plus sealer; Group 2= TotalFill BC sealer; Group 3= BioRoot RCS sealer; Group 4= AH plus sealer + HGFP; Group 5= TotalFill BC sealer + HGFP; and, Group 6= Bio Root RCS sealer + HGFP. All specimens were thermocycled and subjected to cyclic loading. Next, the specimens were subjected to a static load using a universal testing machine. Data were analyzed using two-way ANOVA. Two micro-CTs of the same upper premolar, one without the HGFP and later one with HGFP inserted were made and used to create two finite element (FE) models. For the fracture resistance, two-way ANOVA revealed significant differences for the effect of HGFP (p = 0.029), but no differences for the effect of root canal sealer type (p = 0.561). The HGFP groups showed higher restorable fracture compared to groups without HGFP (p = 0.013). Finite element analysis showed that the inclusion of HGFP reduces stress concentration at the occlusal interface and cervical region. Therefore, it can be concluded that HGFP significantly increased the fracture resistance of endodontically treated upper premolars with MOD cavities and reduced the risk for non-restorable fractures. The FE analysis supports the mechanical test results.


Neural correlates of error awareness.
Error processing results in a number of consequences on multiple levels. The posterior frontomedian cortex (pFMC) is involved in performance monitoring and signalling the need for adjustments, which can be observed as post-error speed-accuracy shifts at the behavioural level. Furthermore autonomic reactions to an error have been reported. The role of conscious error awareness for this processing cascade has received little attention of researchers so far. We examined the neural correlates of conscious error perception in a functional magnetic resonance imaging (fMRI) study. An antisaccade task known to yield sufficient numbers of aware and unaware errors was used. Results from a metaanalysis were used to guide a region of interest (ROI) analysis of the fMRI data. Consistent with previous reports, error-related activity in the rostral cingulate zone (RCZ), the pre-supplementary motor area (pre-SMA) and the insular cortex bilaterally was found. Whereas the RCZ activity did not differentiate between aware and unaware errors, activity in the left anterior inferior insular cortex was stronger for aware as compared to unaware errors. This could be due to increased awareness of the autonomic reaction to an error, or the increased autonomic reaction itself. Furthermore, post-error adjustments were only observed after aware errors and a correlation between post-error slowing and the hemodynamic activity in the RCZ was revealed. The data suggest that the RCZ activity alone is insufficient to drive error awareness. Its signal appears to be useful for post-error speed-accuracy adjustments only when the error is consciously perceived.


Unconventional Activation of IRE1 Enhances TH17 Responses and Promotes Neutrophilic Airway Inflammation.
Treatment-refractory severe asthma manifests a neutrophilic phenotype associated with TH17 responses. Heightened unfolded protein responses (UPRs) are associated with the risk of asthma, including severe asthma. However, how UPRs participate in the deregulation of TH17 cells leading to this type of asthma remains elusive. In this study, we investigated the role of the UPR sensor IRE1 in TH17 cell function and neutrophilic airway inflammation. We found that IRE1 is induced in fungal asthma and is highly expressed in TH17 cells relative to naïve CD4+ T cells. Cytokine (e.g. IL-23) signals induce the IRE1-XBP1s axis in a JAK2-dependent manner. This noncanonical activation of the IRE1-XBP1s pathway promotes UPRs and cytokine secretion by TH17 cells. Ern1 (encoding IRE1)-deficiency decreases the expression of ER stress factors and impairs the differentiation and cytokine secretion of TH17 cells. Genetic ablation of Ern1 leads to alleviated TH17 responses and airway neutrophilia in a Candida albicans asthma model. Consistently, IL-23 activates the JAK2-IRE1-XBP1s pathway in vivo and enhances TH17 responses and neutrophilic infiltration into the airway. Taken together, our data indicate that IRE1, noncanonically activated by cytokine signals, promotes neutrophilic airway inflammation through the UPRmediated secretory function of TH17 cells. The findings provide a novel insight into the fundamental understanding of IRE1 in TH17-biased TH2-low asthma.


Activation of platelet-activating factor receptor in SZ95 sebocytes results in inflammatory cytokine and prostaglandin E2 production.
Platelet-activating factor (PAF) is a group of phosphocholines with various biological effects mediated by the PAF receptor (PAF-R). Activation of the epidermal PAF-R induces the expression of inflammatory mediators, including cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)). The upregulation of COX-2 expression has been shown to be involved in sebocyte proliferation, sebaceous gland inflammation and carcinogenesis. The present study was designed to investigate whether PAF-R activation could induce the expression of COX-2 and production of PGE(2), as well as secretion of the inflammatory cytokine, interleukin-8 (IL-8), in the immortalized sebaceous gland cell line SZ95. Using calcium mobilization studies, we first confirmed that PAF can signal through PAF-R in SZ95 sebocytes. We then found that the production of IL-8 was induced following treatment with PAF-R agonist, however blocked by a specific PAF-R antagonist. Induction of COX-2 expression and increased PGE(2) production were observed in SZ95 sebocytes after PAF-R activation. Finally, it was demonstrated that the production of PGE(2), induced by PAF-R activation and mediated by COX-2 expression, was blocked following PAF-R antagonism in SZ95 sebocytes. These studies suggest that SZ95 sebocytes express functional PAF-Rs and PAF-Rs are involved in regulating the expression of inflammatory mediators, including COX-2, PGE(2) and IL-8.


Reliability of 2 implant stability measuring methods in assessment of various periimplant bone loss: an in vitro study with the Periotest and Osstell Mentor.
The aim of this in vitro study was to evaluate reliability of the Periotest and Osstell Mentor in assessment of periimplant vertical and circular bone loss. Sixteen dental implants were embedded into acrylic resin blocks. The portion of resin around the implant neck was successively removed to mimic periimplant vertical and circular bone loss. Measurement values of 2 devices were compared by assessing the change of Periotest value (PTV) and Implant Stability Quotient (ISQ) values, by calculating correlation analysis and by means of regression analysis referring to increasing bone loss. Both devices were able to discriminate differences of circular bone loss. However, PTVs were not noticeably changed in buccal, buccal-mesial, and buccal-mesial-distal bone loss. The differences in buccal and buccal-mesial bone loss were not discriminated by Osstell Mentor. As the range of bone loss was increased, there was a noticeable correlation of the PTV and ISQ values. The results of this study suggest that both diagnostic devices for implant stability are useful in detecting the circular bone loss. However, the clinical reliability of both devices for detecting the partial vertical bone loss is low.


Predictors of Premature Match Closure in Youth Mentoring Relationships.
Although mentoring is a popular and effective means of intervention with youth, the positive effects of mentoring can be diminished by premature match closure of relationships. Program, mentor, and mentee characteristics were examined as predictors of premature match closure. Secondary data analyses were conducted on a large national database of mentoring programs consisting of match and youth risk information from 170 mentoring programs and 6468 matches from across the U.S. Premature closure was associated with mentee age at match inception and 19 individual mentee characteristics. The set of mentee characteristics were examined as part of a cumulative risk index encompassing seven conceptually combined categories including family background characteristics, school functioning problems, engagement in risky health behaviors, self-regulation difficulties, engagement in illegal or criminal activities, and internalizing and externalizing behavior problems. Both the age of mentees when matched and the cumulative risk index score significantly predicted premature closure. Results are discussed in terms of directions for future research and suggestions for enhancing mentoring program practices.


Palladium/Brønsted-Acid-Catalyzed Diastereoselective Cyclization with Chiral Sulfinamides as Nucleophiles.
This article reports diastereoselective cyclization with chiral sulfinamides as nucleophiles in two reaction pathways: (1) intramolecular allylic substitution and (2) sequential aerobic oxidation with aza-Michael addition. These reactions were enabled by synergistic palladium and Brønsted acid catalysis and produced chiral isoindolines with good yields of 55-92% and high diastereoselectivities of 10:1 to >20:1 dr.


Impact of Altered Airway Pressure on Intracranial Pressure, Perfusion, and Oxygenation: A Narrative Review.
A narrative review of the pathophysiology linking altered airway pressure and intracranial pressure and cerebral oxygenation. Online search of PubMed and manual review of articles (laboratory and patient studies) of the altered airway pressure on intracranial pressure, cerebral perfusion, or cerebral oxygenation. Randomized trials, observational and physiologic studies. Our group determined by consensus which resources would best inform this review. In the normal brain, positive-pressure ventilation does not significantly alter intracranial pressure, cerebral oxygenation, or perfusion. In injured brains, the impact of airway pressure on intracranial pressure is variable and determined by several factors; a cerebral venous Starling resistor explains much of the variability. Negative-pressure ventilation can improve cerebral perfusion and oxygenation and reduce intracranial pressure in experimental models, but data are limited, and mechanisms and clinical benefit remain uncertain. The effects of airway pressure and ventilation on cerebral perfusion and oxygenation are increasingly understood, especially in the setting of brain injury. In the face of competing mechanisms and priorities, multimodal monitoring and individualized titration will increasingly be required to optimize care.


[Clinical, humoral and scintigraphic assessment of a bisphosphonate as potential treatment of diaphyseal dysplasia: Ribbing and Cammurati-Engelmann diseases].
Cammurati-Engelmann's Disease or Progressive Diaphyseal Dysplasia (PDD), is a rare autosomal dominant disorder, sometimes non hereditable, which begins in childhood, and is characterized by symmetrical excess of osseous apposition in diaphysis and metaphysis of long bones. In severe cases skull and vertebrae could be involved. Clinically, patients refer limb pain, muscular weakness and atrophy, easy fatigability and waddling gait. Later on S. Ribbing described an illness that he thought was a separate entity with sclerosis and enlargement of diaphysis of femora and tibiae, which begins after puberty, is less extensive, not always symmetric and without gait or neurological involvement. Some authors think it may be an adult form of the PDD. As no specific treatments are available we report one case of each entity, treated with the bisphosphonate pamidronate, by the oral route. A white female, 69 years old, with clinic and radiology of Ribbing's Disease, had positive scintigraphy in the affected areas and elevated bone biochemical markers: Serum alkaline phosphatase (SAP): 57 UKA. Total urinary hydroxyproline (THP): 60 mg/24 h. Bone Gla protein (BGP): 40 ng/ml. Considering the high bone turnover treatment with oral pamidronate, 400 mg/day plus Calcium 1g/day was started, dose was then progressively reduced. After two months pain almost disappeared, and THP became normal: 14 mg/24 h; with normalization of BGP values: 8 ng/ml, and a decrease of SAP: 21 UKA, 99mTc MDP uptake by affected bones decreased after 1 year of treatment. Because of these results we decided to begin treatment in a white female 17 years old, 32 kg weight, 1.47 m height with PDD characteristics and also a high bone turnover (THP: 95 mg/24 h. SAP: 32 UKA). After six months of Calcium 1 g/day, given with meals, and oral pamidronate 100 mg/day, she became painless with normal strength and gait, almost normalization of THP (48 mg/24 h). Although a small decrease of SAP, and no charges in scintigraphy. These results obtained with pamidronate suggest that it may be useful to treat dysplasias with high bone turnover.


Computational simulations of respiratory-laryngeal interactions and their effects on lung volume termination during phonation: Considerations for hyperfunctional voice disorders.
Glottal resistance plays an important role in airflow conservation, especially in the context of high vocal demands. However, it remains unclear if laryngeal strategies most effective in controlling airflow during phonation are consistent with clinical manifestations of vocal hyperfunction. This study used a previously validated three-dimensional computational model of the vocal folds coupled with a respiratory model to investigate which laryngeal strategies were the best predictors of lung volume termination (LVT) and how these strategies' effects were modulated by respiratory parameters. Results indicated that the initial glottal angle and vertical thickness of the vocal folds were the best predictors of LVT regardless of subglottal pressure, lung volume initiation, and breath group duration. The effect of vertical thickness on LVT increased with the subglottal pressure-highlighting the importance of monitoring loudness during voice therapy to avoid laryngeal compensation-and decreased with increasing vocal fold stiffness. A positive initial glottal angle required an increase in vertical thickness to complete a target utterance, especially when the respiratory system was taxed. Overall, findings support the hypothesis that laryngeal strategies consistent with hyperfunctional voice disorders are effective in increasing LVT, and that conservation of airflow and respiratory effort may represent underlying mechanisms in those disorders.


NaoXinTong Inhibits the Advanced Atherosclerosis and Enhances the Plaque Stability in Apolipoprotein E Deficient Mice.
Buchang NaoXinTong (NXT), a Chinese medicine, has been widely used to treat patients with coronary heart disease in China. However, the underlying mechanisms need more elucidations. In this study, we investigated if NXT can inhibit the progression of the established lesions while stabilizing plaques. Apolipoprotein E deficient (apoE(-/-)) mice in 3 groups received following treatment: group 1 was fed a high-fat diet (HFD) for 18 weeks; group 2 was prefed HFD for 12 weeks followed by HFD containing NXT for additional 6 weeks; group 3 was prefed HFD for 8 weeks followed by HFD containing NXT for additional 10 weeks. After treatment, serum and aorta samples were collected and determined lipid profiles, lesions, collagen content, mineralization, and macrophage accumulation in aortic root, respectively. NXT had slight effect on serum lipid profiles but significantly reduced progression of the advanced lesions. In aortic wall, NXT increased smooth muscle cell/collagen content in lesion cap while reducing buried fibrous caps, mineralization, and macrophage accumulation within lesions, which suggests that NXT can stabilize plaques. In addition, NXT increased expression of smooth muscle 22α mRNA while inhibiting expression of matrix metalloproteinase-2 and tumor necrosis factor α mRNA in aortas. Our study demonstrates that NXT can reduce advanced atherosclerosis and enhance the plaque stability in apoE(-/-) mice.


Effect of nicardipine on angiotensin II platelet content.
We evaluated the effect of nicardipine treatment on platelet angiotensin II content in 18 essential hypertensive patients. Nicardipine induced a decrease in platelet angiotensin II content in all patients (-14%), but particularly in 10 (P less than 0.05; -20.5%). No other differences were found between these patients and the others. Further investigations are required to determine whether platelet angiotensin II content reduction contributes to the prophylactic and therapeutic effects of calcium antagonists on atherosclerosis.


Four new species and one new subspecies of Arctiinae (Lepidoptera: Erebidae) from the Tambopata river, Madre de Dios, Peru.
Four new species and one new subspecies of Arctiinae (Lepidoptera: Erebidae) are described. Aphyle niedmandi sp. nov., Evius ocassus sp. nov., Paranerita maculata sandeepani ssp. nov., Paranerita kotolnuki sp. nov. and Baritius flexuosus sp. nov. were collected in the Tambopata River region, Madre de Dios (Peru), as part of a Citizen Science Project, in mutual collaboration between the Natural History Museum (Lima-Peru) and Rainforest Expeditions. External morphological descriptions, morphology of male genitalia, and geographic distributions in Peru are given for all taxa as well as their barcoding.


A double-blind evaluation of amlodipine in patients with chronic, stable angina: sustained efficacy and lack of "withdrawal phenomenon" upon abrupt discontinuation.
To date, the clinical utility of first-generation, shortacting calcium antagonists has not been optimal due to their multiple dosing requirements. This has led to poor compliance in some patients. In this study, the safety and efficacy of a new generation dihydropyridine calcium antagonist, amlodipine (5-10 mg once daily) were evaluated in patients with chronic, stable angina pectoris. Amlodipine monotherapy was given to 226 patients over an 8-week, single-blind period, and the responders (> or = 7% improvement in exercise time) then underwent a randomized, placebo-controlled, double-blind withdrawal phase, lasting for a further 4 weeks. Amlodipine was shown to be both effective and well-tolerated in patients with chronic, stable angina pectoris. There was no evidence for the development of tolerance to amlodipine over a total of 3 months and there did not appear to be any significant problems (of the type noted with abrupt beta-blocker cessation) associated with its withdrawal.


Bacterial AsmA-Like Proteins: Bridging the Gap in Intermembrane Phospholipid Transport.
In eukaryotic cells, nonvesicular lipid transport between organelles is mediated by lipid-transfer proteins. Recently, a new class of these lipid transporters has been described to facilitate the bulk of inter-organelle lipid transport at contact sites by forming bridge-like structures with a hydrophobic groove through which lipids travel. Because their predicted structure is composed of repeating β-groove (RBG) domains, they have been named the RBG protein superfamily. Early studies on RBG proteins VPS13 and ATG2 recognized the resemblance of their predicted structures to that of the bacterial Lpt system, which transports newly synthesized lipopolysaccharides (LPS) between the inner and the outer membranes (IMs and OMs) of Gram-negative bacteria. In these didermic bacteria, the IMs and OMs are separated by an aqueous periplasmic compartment that is traversed by a bridge-like structure built with β-jelly roll domains from several Lpt proteins that provides a hydrophobic groove for LPS molecules to travel across the periplasm. Despite structural and functional similarities between RBG proteins and the Lpt system, the bacterial AsmA-like protein family has recently emerged as the likely ancestor of RBG proteins and long sought-after transporters that facilitate the transfer of phospholipids from the IM to the OM. Here, we review our current understanding of the structure and function of bacterial AsmA-like proteins, mainly focusing on recent studies that have led to the proposal that AsmA-like proteins mediate the bulk of phospholipid transfer between the IMs and OMs.


Novel Method to Predict In Vivo Liver-to-Plasma Kpuu for OATP Substrates Using Suspension Hepatocytes.
The ability to predict human liver-to-plasma unbound partition coefficient (Kpuu) is of great importance to estimate unbound liver concentration, develop PK/PD relationships, predict efficacy and toxicity in the liver, and model the drug-drug interaction potential for drugs that are asymmetrically distributed into the liver. A novel in vitro method has been developed to predict in vivo Kpuu with good accuracy using cryopreserved suspension hepatocytes in InVitroGRO HI media with 4% BSA. Validation was performed using six OATP substrates with rat in vivo Kpuu data from i.v. infusion studies where a steady state was achieved. Good in vitro-in vivo correlation (IVIVE) was observed as the in vitro Kpuu values were mostly within 2-fold of in vivo Kpuu Good Kpuu IVIVE in human was also observed with in vivo Kpuu data of dehydropravastatin from positron emission tomography and in vivo Kpuu data from PK/PD modeling for pravastatin and rosuvastatin. Under the specific Kpuu assay conditions, the drug-metabolizing enzymes and influx/efflux transporters appear to function at physiologic levels. No scaling factors are necessary to predict in vivo Kpuu from in vitro data. The novel in vitro Kpuu method provides a useful tool in drug discovery to project in vivo Kpuu.


Bilateral Glaucomatous Optic Neuropathy Caused by Eye Rubbing.
In this report, we describe a particular condition of a 52-year-old man who showed advanced bilateral glaucomatous-like optic disc damage, even though the intraocular pressure resulted normal during all examinations performed. Visual field test, steady-state pattern electroretinogram, retinal nerve fiber layer and retinal tomographic evaluations were performed to evaluate the optic disc damage. Over a 4-year observational period, his visual acuity decreased to 12/20 in the right eye and counting fingers in the left eye. Visual fields were severely compromised, and intraocular pressure values were not superior to 14 mm Hg during routine examinations. An accurate anamnesis and the suspicion of this disease represent a crucial aspect to establish the correct diagnosis. In fact, our patient strongly rubbed his eyes for more than 10 h per day. Recurrent and continuous eye rubbing can induce progressive optic neuropathy, causing severe visual field damage similar to the pathology of advanced glaucoma.


Lymphoscintigraphy in cutaneous melanoma: a total body atlas of sentinel node mapping.
Lymphoscintigraphy of malignant melanoma has been a reliable method of identifying regional lymph nodes at risk for metastases and is now considered part of the standard of care in patients with melanoma. The status of the sentinel lymph node (SLN) is predictive of the metastatic status of the corresponding regional lymph node group. Lymphatic channel mapping allows identification of the SLN, thereby making selective lymph node sampling possible. Consequently, SLN identification with lymphoscintigraphy results in both less extensive surgery and more efficient pathologic examination of the lymph node specimens. Therefore, it is imperative that radiologists and nuclear medicine physicians know which radiopharmaceuticals to use, recognize different lymphatic drainage patterns from various primary tumor sites throughout the body, use proper imaging techniques, and recognize potential pitfalls in image interpretation.


Synthesis of undoped and manganese-doped hgte nanoparticles using [Hg(TeCH2CH2NMe2)2] as a single source precursor.
The Reaction of [HgCl2(tmeda)] with NaTeCH2CH2NMe2 gave a mercury tellurolate, [Hg(TeCH2CH2. NMe2)2] (1) as a yellow crystalline solid, which was characterized by elemental analysis, UV-vis, mass and NMR (1H, 13C, 125Te, 199Hg) spectroscopy. Thermolysis of 1 in hexadecylamine (HDA) at 90 degrees C in the absence and presence of Mn(OAc)2.4H2O gave undoped and Mn-doped HgTe nanoparticles which were characterized by XRD, EDAX, TEM, EPR and magnetic measurements. These particles could be synthesized with mean particle size of 6-7 nm (from TEM). Manganese substitution at Hg site in HgTe lead to a linear decrease in lattice parameter with increasing concentration of Mn. Magnetization measurements showed ferromagnetic ordering at room temperature with very small coercive field (Hc, 50 Oe) for Hg0.973 Mn0.027 Te sample. This sample also exhibited distinct ferromagnetic resonance (FMR) in the EPR spectrum.


Overexpression of acylglycerol kinase is associated with poorer prognosis and lymph node metastasis in nasopharyngeal carcinoma.
Acylglycerol kinase (AGK) has been reported to promote a malignant phenotype and enhance the development of cancer stem cells. However, the clinical value of AGK in cancer remains unclear. This study aimed to investigate the expression and clinicopathological significance of AGK in nasopharyngeal carcinoma (NPC). AGK was significantly upregulated in NPC cell lines and clinical specimens as indicated by real-time PCR and Western blotting. Among the AGK-positive cases, 52/114 (45.6 %) of the archived human NPC specimens expressed high levels of AGK. High expression of AGK was associated with significantly shorter overall and disease-free survival (P < 0.001 and P = 0.002; log-rank test) and was an independent prognostic factor for overall survival (P = 0.041; multivariate Cox analysis). High AGK expression was associated with lymph node metastasis (P < 0.001; chi-squared test) and was an independent predicted factor for lymph node metastasis in NPC (P = 0.032; multivariate logistic analysis). AGK is overexpressed and associated with disease progression and lymph node metastasis in NPC. AGK has potential as a novel prognostic factor for overall survival in NPC.


A Multi-Class Tactile Brain-Computer Interface Based on Stimulus-Induced Oscillatory Dynamics.
We proposed a multi-class tactile brain-computer interface that utilizes stimulus-induced oscillatory dynamics. It was hypothesized that somatosensory attention can modulate tactile-induced oscillation changes, which can decode different sensation attention tasks. Subjects performed four tactile attention tasks, prompted by cues presented in random order and while both wrists were simultaneously stimulated: 1) selective sensation on left hand (SS-L); 2) selective sensation on right hand (SS-R); 3) bilateral selective sensation; and 4) selective sensation suppressed or idle state (SS-S). The classification accuracy between SS-L and SS-R (79.9 ± 8.7%) was comparable with that of a previous tactile BCI system based on selective sensation. Moreover, the accuracy could be improved to an average of 90.3 ± 4.9% by optimal class-pair and frequency-band selection. Three-class discrimination had an accuracy of 75.2 ± 8.3%, with the best discrimination reached for the classes SS-L, SS-R, and SS-S. Finally, four classes were classified with an accuracy of 59.4 ± 7.3%. These results show that the proposed system is a promising new paradigm for multi-class BCI.


Mechanism of the tissue-specific action of the selective androgen receptor modulator S-101479.
Selective androgen receptor modulators (SARMs) comprise a new class of molecules that induce anabolic effects with fewer side effects than those of other anabolic agents. We previously reported that the novel SARM S-101479 had a tissue-selective bone anabolic effect with diminished side effects in female animals. However, the mechanism of its tissue selectivity is not well known. In this report, we show that S-101479 increased alkaline phosphatase activity and androgen receptor (AR) transcriptional activity in osteoblastic cell lines in the same manner as the natural androgen ligand dihydrotestosterone (DHT); conversely, stimulation of AR dimerization was very low compared with that of DHT (34.4%). S-101479 increased bone mineral content in ovariectomized rats without promoting endometrial proliferation. Yeast two-hybrid interaction assays revealed that DHT promoted recruitment of numerous cofactors to AR such as TIF2, SRC1, β-catenin, NCoA3, gelsolin and PROX1 in a dose-dependent manner. SARMs induced recruitment of fewer cofactors than DHT; in particular, S-101479 failed to induce recruitment of canonical p160 coactivators such as SRC1, TIF2 and notably NCoA3 but only stimulated binding of AR to gelsolin and PROX1. The results suggest that a full capability of the AR to dimerize and to effectively and unselectively recruit all canonical cofactors is not a prerequisite for transcriptional activity in osteoblastic cells and resulting anabolic effects in bone tissues. Instead, few relevant cofactors might be sufficient to promote AR activity in these tissues.


Effects of Lexical and Somatosensory Feedback on Long-Term Improvements in Intelligibility of Dysarthric Speech.
Intelligibility improvements immediately following perceptual training with dysarthric speech using lexical feedback are comparable to those observed when training uses somatosensory feedback (Borrie & Schäfer, 2015). In this study, we investigated if these lexical and somatosensory guided improvements in listener intelligibility of dysarthric speech remain comparable and stable over the course of 1 month. Following an intelligibility pretest, 60 participants were trained with dysarthric speech stimuli under one of three conditions: lexical feedback, somatosensory feedback, or no training (control). Participants then completed a series of intelligibility posttests, which took place immediately (immediate posttest), 1 week (1-week posttest) following training, and 1 month (1-month posttest) following training. As per our previous study, intelligibility improvements at immediate posttest were equivalent between lexical and somatosensory feedback conditions. Condition differences, however, emerged over time. Improvements guided by lexical feedback deteriorated over the month whereas those guided by somatosensory feedback remained robust. Somatosensory feedback, internally generated by vocal imitation, may be required to affect long-term perceptual gain in processing dysarthric speech. Findings are discussed in relation to underlying learning mechanisms and offer insight into how externally and internally generated feedback may differentially affect perceptual learning of disordered speech.


[Prevention of colibacillosis in pigs with CA-80 polyvalent vaccine].
A live polyvalent Escherichia coli vaccine, CA-80, has been produced and adopted into practice in this country. It contains a definite amount of immunogenic agents, such as the K 88 antigen, the LT and ST toxins, the K 99 antigen, and an enteroinvasive strain. Laboratory and field experiments have shown that the immunization of sows with newborn sucking pigs leads to the drop of mortality rate from 8.48 to 1.84 per cent as well as to the rise of the average liveweight by 400 to 600 g on the 30th day following birth. Besides, the live vaccine has been shown to act protectively both against the homologous and heterologous enterotoxigenic strains of Escherichia coli and against E. coli strains with a K 99 antigen.


Self-assembly of SiO2/Gd-DTPA-polyethylenimine nanocomposites as magnetic resonance imaging probes.
Controlled self-assembly of organic/inorganic magnetic hybrid materials have important applications in magnetic resonance imaging (MRI). In this study, a widely used polycation polyethylenimine was conjugated with gadopentetic acid (Gd-DTPA) as a gadolinium bearing polyelectrolyte (Gd-DTPA-PEI). Next, multilayers of Gd-DTPA-PEI were coated on silica nanoparticles through layer-by-layer (LbL) self-assembly with polyanions as monitored by dynamic light scattering, zeta-potential, and scanning electron microscopy. The thickness of the multilayer film was estimated from quartz crystal microbalance based on counting frequency change of each adsorbed layer. The magnetic relaxation of SiO2/(Gd-DTPA-PEl/polyanion), core-shell nanocomposite was tested at 1.5 T magnetic field in a clinical MRI scanner, and a 3-fold increase in T1 relaxivity to 15.1 Gd mM(-1)s(-1) was noticed comparing to Gd-DTPA small molecules. Dextran sulfate was coated as the outermost layer on the nanocomposite for better biocompatibility as verified by in vitro cytotoxicity studies. This formulation provides good signal intensity enhancement of mouse liver in vivo with only 1/25 dose of clinical standard at 30 and 60 minutes after intravenous injection. This sensitive imaging probe with unique core-shell structures may find broad applications in cellular and molecular imaging.


Complications in preserving the airway in intensive care unit patients.
Maintaining the airway in patients in intensive care unit (ICU) is often a vitally important issue for successful treatment of patients. The aim of the study was to identify the complications as the most common causes of difficult ventilation in ICU patients. This retrospective study included 12 patients with difficult pulmonary ventilation, aged 12-70 years, 8 male and 4 female. All patients were intubated for a period of 7-14 days on mechanical ventilation. Due to the need of prolonged mechanical ventilation, the patients underwent surgical tracheotomy and tracheal cannula was placed in five patients. Patients with unilateral atelectasis of the lung underwent bronchoscopy and airway lavage. All patients underwent regular intensive clinical observation and diagnosis, x-ray, CT and MRI. They all were administered antibiotic therapy as well as symptomatic and supportive therapy. Five patients underwent tracheotomy. In one patient with Down syndrome, tracheal rupture occurred two hours after general anesthesia. He developed massive pleural, mediastinal and subcutaneous emphysema. Seven patients with unilateral atelectasis of the lung underwent bronchoscopy and airway lavage. In two patients, therapeutic bronchoscopy with lavage was repeated twice, and in one patient bronchoscopy was repeated 4 times over a 6-month period. Eight patients died and four patients survived. Of the patients with polytrauma, two were in vigil coma, one survived for 6 months, while the other died from respiratory failure. In conclusion, it is important to promptly recognize and appropriately treat complications while maintaining airway in ICU patients, especially those with multiple trauma or conditions after extensive surgery. Preventing hypoxemia as a result of hypoxia has a far-reaching significance for the clinical course and success of patient treatment.


Profile of dual tobacco users in India: an analysis from Global Adult Tobacco Survey, 2009-10.
Individuals who use both smoked and smokeless tobacco products (dual tobacco users) form a special group about which little is known. This group is especially relevant to India, where smokeless tobacco use is very common. The aim of this study was to characterise the profile of dual users, study their pattern of initiation to the second product, their attitudes toward quittingas well as their cessation profile. The GATS dataset for India was analyzed using SPSS; . In India, dual tobacco users (42.3 million; 5.3% of all adults; 15.4% of all tobacco users) have a profile similar to that of smokers. Some 52.6% of dual users started both practices within 2 years. The most prevalent product combination was bidi-khaini (1.79%) followed by bidi-gutka (1.50%), cigarette-khaini (1.28%), and cigarette-gutka (1.22%). Among daily users, the correlation between the daily frequencies of the use of each product was very high for most product combinations. While 36.7% of dual users were interested in quitting, only 5.0% of dual users could do so. The prevalence of ex-dual users was 0.4%. Dual users constitute a large, high-risk group that requires special attention.


Glucose and arterial blood pressure variability in Obstructive Sleep Apnea Syndrome.
Current evidence supports an association between Obstructive Sleep Apnea Syndrome (OSAS), insulin resistance, type 2 diabetes mellitus (DM) and cardiovascular disorders. The relationship is complex and still remains poorly understood. The aim of this study was to examine the potential correlation of sleep characteristics with glucose and arterial pressure values variability in non - diabetic, non-hypertensive patients with OSAS. We examined 22 subjects, 11 men and 11 women (mean age 54 ± 14,5 years), recently diagnosed with OSAS (Apnea - Hypopnea Index (AHI) ≥ 5 apneas/hypopneas per hour of sleep) by full night polysomnography (PSG). Fasting and postprandial after a 2 hour oral glucose tolerance test (OGTT) glucose and insulin levels were measured, and homeostatic model assessment of insulin resistance (HOMA(IR)) index profile as well as Matsuda insulin sensitivity index (ISI) were calculated. A 24 hour glucose monitoring with subcutaneous measurements every 5 minutes and a 24-hour arterial blood pressure (ABP) monitoring (Holter monitoring) were evaluated. AHI, a widely accepted marker of the severity of OSAS, was correlated with HOMA and Matsuda index (p = 0.016 and p = 0.022, respectively), Standard Deviation (SD) of glucose measurements (p = 0.05) and mean diastolic blood pressure (p = 0.007). Percentage of sleep time with saturation of hemoglobin with oxygen, as measured by pulse oximetry, (SpO2) < 90% was also correlated with HOMA and Matsuda index (p = 0.014 and p = 0.012, respectively), coefficient of variation (CV) of glucose measurements (p = 0.009) and SD of 24-hour systolic blood pressure. Moreover, minimum SpO2 was correlated with glucose levels (p = 0.018), Matsuda index (p = 0.30) and SD of 24-hour diastolic and systolic blood pressure (p = 0.005 and p = 0.022, respectively). Glucose and arterial pressure variability were associated with markers of OSAS severity (AHI, % sleep time with SpO2 < 90%, min SpO2), among nondiabetic patients. Thus, glucose and arterial pressure variability in OSAS may be an additional marker of cardiovascular risk as well as of future diabetes in these subjects. Nevertheless, the clinical significance of our observations remains to be confirmed by prospective studies.


Evaluation of true kinetic parameters for reversible immobilized enzyme reactions.
For a reversible one-substrate reaction system that follows the Haldane reaction mechanism, a new and effective method has been proposed to extract true or intrinsic kinetic parameters of immobilized enzymes from diffusion limited rate data. The method utilizes the effectiveness factors correlated in terms of the general modulus defined by Aris and Bischoff, and a new modulus defined in the present study. It requires a trial-and-error calculation, but only a few data points. Furthermore, it provides a saving of materials such as substrates and enzymes, and takes less time for experiments compared to the initial rate methods. The usefulness of the method is demonstrated by determining the kinetic parameters for membrane bound fumarase which catalyzes the reaction of the conversion of fumarate to L-malate, for which the equilibrium constant is ca. 4.


Treatment of lower urinary tract symptoms in multiple sclerosis patients: Review of the literature and current guidelines.
Multiple sclerosis (MS) is a unique neurological disease with a broad spectrum of clinical presentations that are time- and disease course-related. Lower urinary tract symptoms (LUTS) are highly prevalent in this patient population, with approximately 90% showing some degree of voiding dysfunction and/or incontinence 6-8 years after the initial MS diagnosis. Major therapeutic goals include quality of life improvement and the avoidance of urological complications Owing to the wide divergence of clinical symptoms and disease course, evaluation and treatment differ between patients. Treatment must be customized for each patient based on disease phase, patient independence, manual dexterity, social support, and other medical- or MS-related issues. Ablative or irreversible therapies are indicated only when the disease course is stable. In most cases of "safe" bladder, behavioural treatment is considered first-line defense. Antimuscarinic drugs, alone or in combination with intermittent self-catheterization, are currently the mainstay of conservative treatment, and several other medications may help in specific disease conditions. Second-line treatment includes botulinum toxin A injection, neuromodulation, indwelling catheters, and surgery in well-selected cases.


Next-generation sequencing and comparative analysis of Pyrrhocorax pyrrhocorax and Pyrrhocorax graculus (Passeriformes: Corvidae) mitochondrial genomes.
The complete mitochondrial genomes of Red-billed Chough (Pyrrhocorax pyrrhocorax) and Yellow-billed Chough (Pyrrhocorax graculus) were sequenced using the Ion Torrent PGM platform. These mitogenomes contain 16,889 bp (Red-billed Chough) and 16,905 bp (Yellow-billed Chough), including 13 protein-coding genes (PCGs), two ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and a control region (D-loop). The gene content, orientation, and structure are similar to a wide range of other vertebrate species and the nucleotide composition is very similar to other Passeriformes. All PCGs start with ATG, except for COX1 that starts with GTG, and four stop codons and one incomplete stop codon are used (TAA, TAG, AGG, AGA, and T-). The size of PCGs is the same in both mitogenomes, except for ND6 that has one codon less in the Yellow-billed Chough. All the tRNAs can fold into a typical cloverleaf secondary structure. These mitogenomic data can be of great value in complementing forthcoming approaches on molecular ecology, comparative and functional genomics.


Noncompliance with the law prohibiting the sale of cigarettes to minors in Brazil: an inconvenient truth.
To draw up an up-to-date scenario of compliance with the law prohibiting the sale of cigarettes to minors. We used data about youth access to cigarette purchase that were obtained through a nationwide survey conducted in 2015 among students aged 13-17 years. We estimated simple proportions of attempts to buy cigarettes, success of attempts, purchase of cigarettes on a regular basis, and purchase of cigarettes on a regular basis in a store or bar. All estimates were stratified by gender, age group, and Brazilian macro-region. Crude absolute difference and adjusted absolute difference in the proportion of smokers in each category by variable of interest were analyzed by a generalized linear model with binomial distribution and identity link function. Approximately 7 in every 10 adolescent smokers attempted to buy cigarettes at least once in the 30 days prior to the survey. Of those, approximately 9 in every 10 were successful, and individuals aged 16-17 years (vs. those aged 13-15 years) were less often prevented from buying cigarettes (adjusted absolute difference, 8.1%; p ≤ 0.05). Approximately 45% of all smokers aged 13-17 years in Brazil reported buying their own cigarettes on a regular basis without being prevented from doing so, and, of those, 80% reported buying them in a store or bar (vs. from a street vendor). Our findings raise an important public health concern and may contribute to supporting educational and surveillance measures to enforce compliance with existing anti-tobacco laws in Brazil, which have been disregarded.


Larvicidal activity of the essential oil from Tetradium glabrifolium fruits and its constituents against Aedes albopictus.
In our screening programme for new agrochemicals from wild plants, the essential oil of Tetradium glabrifolium (Champ. ex Benth.) T.G. Hartley fruits was found to possess strong larvicidal activity against the Asian tiger mosquito, Aedes albopictus L. The essential oil was extracted via hydrodistillation, and the constituents were determined by GC-MS analysis. The active compounds were isolated and identified by bioassay-directed fractionation. GC-MS analyses revealed the presence of 19 components with 2-tridecanone (43.38%), 2-undecanone (24.09%), D-limonene (13.01%), caryophyllene (5.04%) and β-elemene (4.07%) being the major constituents. Bioactivity-directed chromatographic separation of the oil led to the isolation of 2-tridecanone, 2-undecanone and D-limonene as active compounds. The essential oil of T. glabrifolium exhibited larvicidal activity against the early fourth-instar larvae of A. albopictus, with an LC50 value of 8.20 µg mL(-1). The isolated constituent compounds, 2-tridecanone, 2-undecanone and D-limonene, possessed strong larvicidal activity against the early fourth-instar larvae of A. albopictus, with LC50 values of 2.86, 9.95 and 41.75 µg mL(-1) respectively. The findings indicated that the essential oil of T. glabrifolium fruits and the three constituents have an excellent potential for use in control of A. albopictus larvae and could be useful in the search for newer, safer and more effective natural compounds as larvicides.


[Autism and Autism-associated Metabolites].
Gene-microbiota interactions are now proposed to be a special case of gene-environmental interaction. Preclinical and clinical data summarized in this article reveal that a specific serum metabolite, associated with alterations in gut microbiome composition, might have an emerging role in the onset and pathogenesis of autism. Altered level of this specified metabolite may induce perturbations in the epigenome and modulate the expression of key disease susceptible genes in neurons and their associated cells during critical periods of neurodevelopment. The gut microbiota itself is now regarded as a reservoir for environmental epigenetic factors.


Neurobrucellosis: clinical and diagnostic features.
We describe the neurological involvement in brucellosis and revisited diagnostic criteria for neurobrucellosis. Patients with laboratory-confirmed brucellosis who were consequently hospitalized were observed prospectively in a brucellosis-endemic region. The neurobrucellosis was diagnosed by any one of the following criteria: (1) symptoms and signs consistent with neurobrucellosis; (2) isolation of Brucella species from cerebrospinal fluid (CSF) and/or presence of anti-Brucella antibodies in CSF; (3) the presence of lymphocytosis, increased protein, and decreased glucose levels in CSF; or (4) diagnostic findings in cranial magnetic resonance imaging or CT. Lumbar puncture was performed in 128 laboratory-confirmed brucellosis cases who had neurological symptoms and signs, and 48 (37.5%) were diagnosed as neurobrucellosis. The sensitivity of tube agglutination (TA) in CSF was 0.94, specificity 0.96, positive predictive value 0.94, and negative predictive value 0.96. Brucella bacteria were isolated from CSF in 7 of 48 patients (15%). The mean age of 48 neurobrucellosis patients was 42 years (SD, 19 years), and 16 (33%) were female. The most common neurological findings were agitation (25%), behavioral disorders (25%), muscle weakness (23%), disorientation (21%), and neck rigidity (17%). Cranial nerves were involved in 9 of 48 patients (19%). One patient was left with a sequela of peripheral facial paralysis and 2 patients with sensorineural hearing loss. Patients with severe and persistent headache and other neurologic symptoms and signs should be considered for neurobrucellosis in endemic regions and to possibly receive longer therapy than 6 weeks. Brucella TA with Coombs test in CSF is sensitive and specific by using a cutoff of ≥1:8.


Hesperidin attenuates brain biochemical changes of irradiated rats.
The purpose of this study was to evaluate the efficacy of hesperidin (HES), a citrus flavonoid, against the severity of biochemical disorders in the cerebral hemispheres of irradiated rats. Hesperidin (50 mg/kg body weight) was administered to male albino rats via gavages during 10 successive days before whole body exposure to gamma rays (5 Gy) and during 14 days after irradiation. The animals were sacrificed on the 14th day post-irradiation. The results demonstrated a significant increase of the levels of thiobarbituric acid reactive substances (TBARS), protein carbonyls (CO), and advanced oxidation protein products (AOPP), associated to significant decreases of total superoxide dismutase (tSOD) and catalase (CAT) activities, and reduced thiols content in the cerebral hemispheres of irradiated rats indicating oxidative stress. A significant decrease of the serotonin (5-HT), dopamine (DA), norepinephrine (NE) and epinephrine (EPI) contents and a significant increase of the activity of monoamine oxidase (MAO) were recorded, also, indicating alterations in the metabolism of monoamines. Moreover, a significant decrease of the activities of glutamate dehydrogenase (GDH) and creatine phophokinase (CPK), and a significant increase of calcium ions (Ca (+2)) levels were recorded in the mitochondria. Hesperidin treatment has significantly attenuated oxidative stress, monoamines alterations and mitochondrial damage in the cerebral hemispheres of irradiated rats. It could be concluded that hesperidin might attenuate the severity of radiation-induced biochemical disorders in brain tissues.


Clinical use of fetal measurements to determine the whelping day in German shepherd breed bitches.
The aim of this work was to use a linear regression model previously developed in a pilot study to calculate days before parturition (DbP) using inner chorionic cavity (ICC), biparietal diameter (BPD), crown-rump length (CRL), body diameter (BD) and deep portion of telencephalic vesicle (DPTV) in German shepherd dogs (GSD) with known ovulation day and then to test that model in bitches with unknown ovulation day. In our current study, a model for GSD bitches published in a previous report, proved satisfactory for ICC [DbP=44.76-(4.34×ICC)] and BPD [DbP=38.65-(12.86×BPD)]. We therefore used their model, but developed a new one for CRL, BD and DPTV. For ICC and BPD, we tested accuracy for more than 35days before parturition (ICC) and more than 15days before parturition (BPD). Measurements were taken on at least two fetuses during each ultrasound recording (US) of 22 GSD bitches with known (n=16) and unknown (n=6) ovulation days. The accuracy of the above model was 77-100% for ICC and 83-96% for BPD with a precision of ±1 and ±2days, respectively. Accuracy increased significantly when US was performed more than 35days before parturition for ICC and more than 15days before parturition for BPD. BD and CRL were the most accurate parameters (R2=0.95 and 0.85). In bitches with unknown ovulation day, BD accuracy was 71.4-100% with a precision of ±1day and ±2days, respectively. CRL and DPTV were less accurate (±1day, 60%; ±2days, 80% accuracy).


Atherosclerotic plaque burden, plaque vulnerability and arterial remodeling: the role of inflammation.
Atherosclerotic narrowing of the arterial lumen is caused by gradual plaque growth and arterial remodeling. Expansive remodeling retards and constrictive remodeling accelerates narrowing of the lumen by plaque accumulation. In the acute phase luminal narrowing may be accelerated by rupture of a vulnerable plaque and subsequent thrombus formation. Inflammatory cells are key players in all these determinants of atherosclerotic luminal narrowing. Inflammatory cells are present in both early and advanced stages of atherosclerosis. Chronic infections have been suggested as trigger of arterial inflammation, but no causal relationship has yet been proved. Systemic markers of inflammation, like C-reactive protein, are predictors for the occurrence of future adverse cardiovascular events, confirming the role of inflammatory responses in arterial occlusive disease. In this review the central role of inflammation in atherosclerotic luminal narrowing will be discussed.


Shiga toxin 1 causes direct renal injury in rats.
Infection with Shiga toxin (Stx)-producing Escherichia coli has been implicated to cause hemolytic uremic syndrome, which is characterized by histological abnormalities such as microvascular thrombi and tubular cell damage in the kidney. Although Stx is known to be the major virulence factor of the pathogen, it is still unclear whether Stx directly impairs renal cells in vivo to cause such histological changes and deterioration of renal function. To assess the consequence of the direct action of Stx on renal cells, left kidneys of rats were perfused with Stx1 from the renal artery through the renal vein and then revascularized. Kidneys of control animals were perfused with the vehicle alone. On day 1, apoptosis and induction of tumor necrosis factor alpha gene expression were noticed to occur in the medulla of the Stx1-perfused kidneys. On day 3, extensive tubular injuries were observed by light microscopy: aggregated platelets and monocytic infiltrates in both glomeruli and the medullary interstitium were detected by immunostaining. Tubular changes were more extensive on day 9, with areas of infarction seen in the cortex and medulla. These changes were not found to occur in the sham-operated kidneys. No obvious glomerular changes were detected by light microscopy at any time point. When nonperfused right kidneys were removed after the Stx1 perfusion of the left kidneys, the serum creatinine and blood urea nitrogen levels were increased from day 2, and acute renal failure followed on day 3. These results indicate that Stx1 caused glomerular platelet aggregation, tubular damage, and acute deterioration of renal function by acting directly on renal cells.


The legendary Rome halo displays.
The two Rome halo displays of 1629 and 1630 are prominent in the early halo literature, and the 1629 display is still cited today for having contained a 28 degrees circular halo. We have examined seventeenth century correspondence and publications in order to learn as much as possible about the existing documentation of the two displays. We find the documentation to be too weak to support a definitive interpretation of either display, and we see little evidence for a 28 degrees halo or for other rare halos. The two displays remain important for their role in initiating modern halo science.


Non-convulsive seizures and non-convulsive status epilepticus in neuro-intensive care unit.
Most seizures in critical ill patients are non-convulsive, and some patients may develop non-convulsive status epilepticus (NCSE), a state of continuous or repetitive seizures without convulsions. With the growing use of continuous electroencephalogram (EEG) monitoring in neuro-intensive care units, non-convulsive seizure (NCS) and NCSE are increasingly diagnosed in patients with impaired consciousness, and progress has been made in identifying various EEG characteristics of NCS/NCSE. Epidemiological studies have contributed to a better understanding of etiologies and risk factors for NCS and NCSE. However, sufficient clinical trials about the treatment of NCS and NCSE are still lacking. The appropriate level of aggressiveness in the treatment of NCSE is still debated, particularly with regard to the use of anesthetics in patients with refractory NCSE. In this review, we summarize the EEG, clinical, epidemiological, diagnostic and therapeutic knowledge of NCS and NCSE in the neuro-intensive care setting in detail.


The role of imaging in the preoperative assessment of children with inflammatory colitis.
Accurate diagnosis of Crohn's disease or ulcerative colitis is essential for surgical planning. This study compared the accuracy, safety, and utility of small bowel follow-through (SBFT) and magnetic resonance enterography (MRE) for detecting small bowel (SB) involvement preoperatively. A retrospective review of children who underwent colectomy for inflammatory bowel disease (2000-2014) was performed. Preoperative SBFT and MRE were independently reviewed by two radiologists blinded to clinical data. Gold standard for diagnosis was surgical pathology. 68 patients (36 female) were included. 45 patients had SBFT prior to colectomy, 17 patients had MRE, and 6 both. Interrater reliability for radiologic interpretation was 90% (SBFT) and 91% (MRE). Mean study durations were 190min (SBFT) and 59min (MRE). Median effective dose for SBFT was 1.5mSv, while MRE involved no ionizing radiation. Specificities for diagnosing SB involvement were 87.5% (SBFT) and 94% (MRE). 54 patients underwent subtotal colectomy and ileostomy, 12 restorative proctocolectomy, and 2 colectomy with ileorectal anastomosis. Preoperative imaging correlated with surgical pathology in 83% (SBFT) and 90% (MRE). MRE is at least as effective as SBFT for assessing SB disease in children with colitis prior to colectomy. MRE requires less time and does not expose children to ionizing radiation. Retrospective Case Series, Level 4 Evidence.


Rationally designed multifunctional nanoparticles as GSH-responsive anticancer drug delivery systems based on host-guest polymers derived from dextran and β-cyclodextrin.
Tumor proliferation and metastasis rely on energy provided by mitochondria. The hexokinase inhibitor lonidamine (LND) could suppress the activities in mitochondria, being a potential antitumor drug. However, limited water-solubility of LND may hinder its biomedical applications. Besides, the cancer-killing effect of LND is compromised by the high level of glutathione (GSH) in cancer cells. Therefore, it is urgent to find a proper method to simultaneously deliver LND and deplete GSH as well as monitor GSH level in cancer cells. Herein, a host polymer β-cyclodextrin-polyethylenimine (β-CD-PEI) and a guest polymer dextran-5-dithio-(2-nitrobenzoic acid) (Dextran-SS-TNB) were synthesized and allowed to form LND-loaded GSH-responsive nanoparticles through host-guest inclusion complexation between β-CD and TNB as host and guest molecular moieties, respectively, which functioned as a system for simultaneous delivery of LND and -SS-TNB species into cancer cells. As a result, the delivery system could deplete GSH and elevate reactive oxygen species (ROS) level in cancer cells, further induce LND-based mitochondrial dysfunction and ROS-based immunogenic cell death (ICD), leading to a synergistic and efficient anticancer effect. In addition, -SS-TNB reacted with GSH to release TNB2-, which could be a probe with visible light absorption at 410 nm for monitoring the GSH level in the cells.


Financial Decision-Making Capacity and Patient-Centered Discharge.
An ethically sound discharge from the hospital can be impeded by a number of factors, including a lack of payor for a patient's care, a lack of appropriate discharge options, and a lack of authority to sign a patient into a long-term facility. In some cases, the primary barrier involves the patient's lack of financial decision-making capacity. When a patient's income comes primarily from government assistance, financial decision making is connected to both the individual's well-being and to fair allocation of resources. Taking away another person's financial independence is a substantial intrusion on autonomy and should not be considered lightly. However, poor management of funds can lead to homelessness, medical noncompliance, vulnerability to financial exploitation, and other threats to human flourishing. As with medical decision-making capacity, poor decisions alone do not invalidate an individual's right to self-determination. And as with medical decision-making capacity, such determinations should not be made ad hoc or be capricious, but should rely on sound assessment criteria. When there are justified concerns that a patient may be vulnerable due to limited financial decision-making capacity, an evaluation should be completed and a surrogate payee be sought, when appropriate.