Detection of new amino acid markers of liver trauma by proton nuclear magnetic resonance spectroscopy.
We examined serum in patients of liver injury to explore the possible clinical application of abnormal micrometabolites as a marker of liver injury and severity in cases of traumatic liver damage. Serum were screened by proton nuclear magnetic resonance spectroscopy in 96 patients with varying degree of liver injury and compared with concentrations in healthy control volunteers. Large quantities of phenylalanine and tyrosine were detected by spectroscopic analysis in patients with liver injury but not in those without liver injury (P < 0.001). Proton nuclear magnetic resonance spectroscopy revealed two unique amino acids, phenylalanine and tyrosine, in the sera of the subjects with liver injury, irrespective of the extent and type of injury gauged by radiology or laparotomy. Phenylalanine spectrum was obtained in all 84 patients with liver injury (100% sensitivity) whereas tyrosine spectrum was present in 83 out of 84 patients (98.8% sensitivity) suggesting that these amino acids were specifically released in the patients of liver injury. Significant correlations were observed between phenylalanine and tyrosine concentrations and total bilirubin levels and albumin levels. Serum phenylalanine and tyrosine concentrations correlated well with imaging and laparotomy findings of liver injury. Phenylanaline and tyrosine appear to be specific and new markers of liver injury.


Effects of theophylline and cyclohexyladenosine on brain injury following normo- and hyperglycemic ischemia: a histopathologic study in the rat.
The present study was designed to determine the effects of theophylline, an adenosine receptor antagonist, and cyclohexyladenosine (CHA), an adenosine receptor agonist, on ischemic brain injury following normo- and hyperglycemic ischemia and reperfusion in fasted male Wistar rats. Moderate hyperglycemia was achieved by administering 17% D-glucose (3 g/kg i.p.), whereas normoglycemic animals received an equal volume of saline. The animals were further divided into two groups: One group was pretreated with either theophylline (0.20 mumol/g i.p.) or an equal volume of saline; the second group received either intraventricular CHA (6.25 nmol) or mock CSF prior to the onset of ischemia. During ischemia, pericranial temperature was maintained at 36 degrees C and EEG was monitored. Cerebral ischemia was induced for 15 min, after which flow was restored and the animals were allowed to recover completely. There were no significant differences in physiologic parameters among the groups studied. Five days following the ischemic episode, the rats were perfused with formalin and the brains subserially sectioned (8 microns) in the coronal plane and stained with celestine blue/acid fuchsin. Histopathologic analysis was performed in a blinded fashion to determine percentage of dead neurons. Hyperglycemic animals had significantly greater ischemic injury in CA1, cortex, and caudate than the normoglycemic group (p < 0.01). Moreover, rats pretreated with theophylline had a significantly (p < 0.01) higher percentage of dead neurons in CA1, cortex, and caudate than corresponding controls.(ABSTRACT TRUNCATED AT 250 WORDS)


Nonlinear mixed effect modeling of the pharmacodynamics of natriuretic peptides in rats.
Natriuretic peptides have not only natriuretic/diuretic but also hypotensive activities, and the decreased renal perfusion caused by the excessive hypotension is known to attenuate the diuretic actions. The present study was designed to examine the relationship between the dosing (intravenous constant infusion) rates and the diuretic actions of alpha-rat atrial natriuretic peptide (alpha-rANP) and rat brain natriuretic peptide (rBNP) in rats, and population (nonlinear mixed effect model) analysis was applied to these complicated diuretic actions. The intrinsic diuretic activities of alpha-rANP and rBNP could be analyzed, and the effects of blood pressure, heart rate, and also inhibition of degradation enzyme on the diuresis of natriuretic peptides were estimated simultaneously. The population analysis was useful for analyzing such pharmacodynamic data for which the individual analysis could not be applied easily.


Laparoscopic conversion of the gastric bypass into a normal anatomy.
Laparoscopic Roux-en-Y gastric bypass (RYGBP) is considered as a non-reversible procedure. We report the laparoscopic conversion of RYGBP into a normal anatomy. In June 2004, a laparoscopic RYGBP was performed in a 46-year-old female sweet-eater with BMI 46 kg/m(2). After 7 months, the patient reported a significant and incapacitating dumping syndrome without postprandial hypoglycemia. She requested conversion to a normal anatomy; hence, a laparoscopic RYGBP reversal was performed. The BMI at the time was 27 kg/m(2). Operative time was 95 minutes and intra-operative blood loss was 150 ml. The patient had an uneventful recovery and was discharged home on the 5th postoperative day. At 6 months follow-up, her BMI was 27 kg/m(2), and barium swallow showed good passage with good gastric motility. After 1 year, the BMI is still unchanged and she is doing well. Restoration of normal anatomy after RYGBP is feasible.


A multicenter randomized controlled clinical pilot study of buccally micro-veneered lithium-disilicate and zirconia crowns supported by titanium base abutments: 1-year outcomes.
To investigate survival rates, technical and biologic outcomes of buccally micro-veneered all-ceramic single implant crowns. Sixty subjects randomly received immediately or early placed implants. Crowns out of lithium-disilicate (n = 30) and zirconia-ceramic (n = 30) were bonded to titanium-base-abutments. Restorations were inspected at baseline (BL) and during follow-up visits (6, 12 months). Technical and biologic parameters were recorded. Data were analysed descriptively. Differences between groups were tested with Student's t-test. Paired T-test was used when comparing data from the same implant or tooth over time. Linear model repeated measures were used to test differences between materials over time. Differences in counts were evaluated using Pearson Chi-square test. The level of significance was at p < .05. After a mean observation time of 13.2 ± 2.4 months, 54 restorations were re-examined. The implant survival rate was 98.3%, and the restoration survival rate was 100%. One early implant failure occurred. Two minor chippings occurred in lithium-disilicate restorations. No chippings or fractures occurred in any zirconia restorations at 1 year (0%). The technical complication rate was 3.7%, with 7.7% complications among the lithium-disilicate restorations and no differences between the two materials (p = .558). At 1-year follow-up, mean Bleeding on Probing (BOP) was higher at implants (0.27 ± 0.3) than adjacent teeth (0.17 ± 0.18) (p = .046) with no differences between materials (p = .36). Differences in pocket probing depth (PPD) between implants and adjacent teeth were significant (p < .01). Jemt Index improved significantly from BL to 1-y-follow-up (p < .001). Preliminary results were good, suggesting that the ceramic type does not impact technical and biologic parameters.


Tetraethylenepentamine-derived carbon dots and tetraethylenepentamine co-immobilized silica stationary phase for hydrophilic interaction chromatography.
In this work, tetraethylenepentamine (TEPA) was used as precursor and reaction medium to prepare tetraethylenepentamine-functionalized carbon dots (TEPACDs), the resultant mixture was subsequently silanized and then grafted on the surface of bare silica. The obtained tetraethylenepentamine-functionalized carbon dots and tetraethylenepentamine co-modified silica stationary phase (Sil-TEPA/CDs) was characterized by multiple ways, such as Fourier transformed infrared spectroscopy (FTIR), elemental analysis and transmission electron microscope, which revealed the successful preparation of the mixed stationary phase and higher density of functional groups on co-modified stationary phase than precursor single-modified stationary phase. The synergistic effect of TEPACDs and TEPA was proved by comparing the separation performance of Sil-TEPA/CDs and Sil-TEPA toward amino acids, nucleosides, and nucleobases, which distinctly enhanced the selectivity of Sil-TEPA/CDs. Thus, 12 nucleosides and nucleobases and 11 amino acids was nicely separated on Sil-TEPA/CDs. By study the influences of the changes of mobile phase composition, mobile phase buffer concentration and buffer pH on the retention behaviors of Sil-TEPA and Sil-TEPA/CDs, it was found that both hydrophilic partitioning and adsorption of analytes on Sil-TEPA/CDs were enhanced benefit from the co-existence of TEPA and TEPACDs, which provided the analytes better separation performance. By comparing the column quality of Sil-TEPA/CDs with four commercially available columns, Sil-TEPA/CDs exhibited the best peak asymmetry of 0.98, and second best column efficiency of 43895 m-1 using guanosine as analyte. The RSD (n = 9) of the retention times of five selected analytes on Sil-TEPA/CDs were within 0.30-0.61% during 40 h of continuously elution, which implied excellent stability of prepared packing material.


Preparation of new bio-based chitosan/Fe2O3/NiFe2O4 as an efficient removal of methyl green from aqueous solution.
Modified chitosan with various functional groups has high potential as an efficient adsorbent in removing water pollution. In this study, new magnetic adsorbent, bio-based chitosan/Fe2O3/NiFe2O4, was successfully prepared by green chemistry route involving mixing of chitosan as core moiety and Fe2O3/NiFe2O4 nanocomposite, and slow evaporation of solvent. Synthesized chitosan/Fe2O3/NiFe2O4 was characterized by FT-IR, TGA, XRD, VSM and FE-SEM. The FT-IR and XRD results confirmed that the successful preparation of chitosan/Fe2O3/NiFe2O4. Uniform dispersion of Fe2O3/NiFe2O4 nanoparticles with low aggregation was confirmed by FE-SEM. The as-prepared magnetic chitosan/Fe2O3/NiFe2O4 was developed as solid phase adsorbent to remove methyl green (MG) dye from aqueous solutions. Several important parameters such as contact time, pH, temperature and adsorbent dosage were investigated systematically. The high and fast MG dye removal (≈ 80%) occurs after 30 min. The optimal conditions for MG removal was recorded at pH = 8, contact time of 60 min, adsorbent dosage of 0.2 g and 25 °C and displayed a high MG dye removal percentage of 96.51% and adsorption capacity of 77.22 mg/g.


Multiple types of sensory neurons respond to irritating volatile organic compounds (VOCs): calcium fluorimetry of trigeminal ganglion neurons.
Many volatile organic compounds (VOCs) are significant environmental irritants that stimulate somatosensory nerve endings to produce pain and irritation. We measured intracellular calcium in cultured trigeminal ganglion neurons to characterize the cellular mechanisms and chemical structural determinants underlying sensitivity to VOCs. Trigeminal neurons responded to homologous series of alcohols (C4-C7) as well as saturated and unsaturated aldehydes in a concentration dependent manner. Ranked in terms of threshold to recruit neurons by compounds of the same carbon chain length, enaldehyde<aldehyde<alcohol. Unlike aldehydes and alcohols that displayed ascending concentration curves, recruitment of neurons by enaldehydes (C4-C7) appeared to saturate, consistent with a mechanism that is restricted in its neural distribution. Using pentanol, pentanal and pentenal as model compounds, we found that many but not all cool/cold-sensitive and capsaicin-sensitive neurons responded with increases in intracellular calcium. These VOCs also stimulated other neurons that were insensitive to cooling and capsaicin. Because not all cooling- and all capsaicin-sensitive neurons responded to the model VOCs, it is highly unlikely that known nociceptive ion channels such as TRPV1 or TRPA1 mediate sensitivity to these compounds. For pentanol, pentanal and pentenal, induced calcium influx was dependent on the presence of extracellular calcium. Responses of all neurons to pentanal and pentenal were also dependent upon extracellular sodium. Responses to pentanol were variably dependent on sodium. The distribution of sensitivity suggests that VOC irritation may be mediated by an as yet unidentified mechanism(s) that is/are distributed across different modalities of neurons.


Properties and latencies of potentials evoked in postganglionic sympathetic nerves by electrical stimulation of aortic, sinus and hypoglossal nerves in cats.
The properties and latencies of potentials evoked in cardiac (CN) and renal (RN) sympathetic nerves by electrical stimulation of the sinus, aortic and hypoglossal nerves were studied in cats. Electrical stimulation of the sinus nerve evoked only excitatory responses in the sympathetic nerves. Electrical stimulation of the aortic nerve fibers evoked excitatory or inhibitory responses in sympathetic nerves. It was possible to evoke 4-5 Hz oscillations in CN and RN after electrical stimulation of the aortic and sinus nerve.-It is suggested that electrical stimulation of the baroafferents is partially responsible for "post-excitatory inhibition" in CN and RN. The central transmission time was the same for the aortic and sinus chemoreceptor reflex and for the somatosympathetic reflex. This period was shorter than the central transmission time of the aortic nerve baroreceptor reflex.


Exceptional response of skin symptoms to secukinumab treatment in a patient with SAPHO syndrome: Case report and literature review.
SAPHO syndrome is a rare clinical entity characterized by a wide range of dermatological and musculoskeletal manifestations. Treatment strategies are not standardized. Palmoplantar pustulosis (PPP) is the most common rash in patients with SAPHO syndrome. A 24-year-old Chinese woman with no relevant medical or familial history had a 1-year history of cutaneous lesions with PPP and pain in the sternoclavicular joint. Based on the diagnostic criteria for SAPHO syndrome proposed by Nguyen et al in 2012, we diagnosed SAPHO syndrome with severe PPP as the predominant manifestation. Due to the limited therapeutic efficacy of methotrexate and cyclosporin, we started therapy with subcutaneous secukinumab 150 mg weekly for the first month, then 150 mg monthly thereafter. After 4 weeks of secukinumab administration, the patient showed significant remission of pustular skin lesions, with almost no joint pain and no adverse reaction. Complete remission of skin symptoms was achieved after 3 months. Joint pain and adverse events have not reoccurred in follow-up thus far. In patients with SAPHO syndrome, we recommend personalized treatment, which may have excellent therapeutic efficacy in those with PPP or severe skin symptoms. Although data related to the use of IL-17 blockers for SAPHO syndrome are very limited, secukinumab provides a novel therapeutic option, especially for patients with PPP and severe skin lesions. Further prospective studies are needed to support our findings.


Down-regulation of survivin by antisense oligonucleotides increases apoptosis, inhibits cytokinesis and anchorage-independent growth.
Survivin, a member of the inhibitor of apoptosis protein (IAP) family, is detected in most common human cancers but not in adjacent normal cells. Previous studies suggest that survivin associates with the mitotic spindle and directly inhibits caspase activity. To further investigate the function of survivin, we used a survivin antisense (AS) oligonucleotide to downregulate survivin expression in normal and cancer cells. We found that inhibition of survivin expression increased apoptosis and polyploidy while decreasing colony formation in soft agar. Immunohistochemistry showed that cells without survivin can initiate the cleavage furrow and contractile ring, but cannot complete cytokinesis, thus resulting in multinucleated cells. These findings indicate that survivin plays important roles in a late stage of cytokinesis, as well as in apoptosis.


Occurrence, distribution, and environmental risk of pharmaceutical residues in Mombasa peri-urban creeks, Kenya.
The information on pharmaceutical compounds' distribution and their possible risks in marine ecosystems along the Kenya coast is limited especially in the peri-urban creeks. Hence, this study aimed to determine pharmaceutical residue levels and distribution in selected peri-urban creeks in Mombasa and Gazi bay. The target compounds were analgesic (acetaminophen), antibiotics (trimethoprim and sulfamethoxazole), antiepileptic (carbamazepine), and antiretroviral (nevirapine). Pharmaceutical residues in grab surface seawater in wet and dry seasons ranged from below detection limit (BDL)-1065.6 μg L-1 and BDL-71.3 μg L-1, respectively. The concentration of the pharmaceutical residues was high in Tudor creek in the dry and wet seasons with a mean concentration of 63.3 μg L-1 and 233.1 μg L-1 respectively compared to Makupa creek (dry season, 54.2 μg L-1; wet season 16.2 μg L), and Mtwapa creek (dry season, 43.1 μg L-1; wet season, 15.0 μg L-1). Gazi Bay being used as a control site had a mean concentration of 21.3 μg L-1 and 3.1 μg L-1 during the dry season and wet season respectively. Acetaminophen and nevirapine were the most ubiquitous compounds in seawater since they were found in all seawater samples collected. Risk quotients (RQ) for invertebrates and algae based on the mean concentrations of the analytes were estimated to provide a preliminary environmental risk assessment. The results suggest that the studied acetaminophen, trimethoprim, sulfamethoxazole, and carbamazepine in seawater pose low (0.01 ≤ RQ < 0.1) to medium (0.1 ≤ RQ < 1) ecological risk whereas nevirapine poses medium to high (RQ ≥ 1) ecological risk to the ecosystems of Mombasa periurban creeks and Gazi bay. Further research, however, is encouraged on the distribution of pharmaceuticals in the marine environment and the long-term synergistic effects of mixtures of these compounds on marine biota.


Hepatic insulin gene therapy prevents diabetic enteropathy in STZ-treated CD-1 mice.
Depending on the population examined, from 6 to 83% of people with diabetes mellitus exhibit symptoms of altered gut motility, manifesting as dysphagia, reflux, early satiety, nausea, abdominal pain, diarrhea, or constipation. Hyperglycemia-induced cell loss within the enteric nervous system has been demonstrated in both diabetic rodents and patients with diabetes. Glycemic control is recommended to prevent diabetic gastroenteropathy but is often difficult to achieve with current treatment modalities. We asked if hepatic insulin gene therapy (HIGT) could inhibit the development of diabetic gastroenteropathy in mice. Bowel length, bowel transit, colonic muscle relaxation, and the numbers of both stimulatory and inhibitory neurons in the colonic myenteric plexus were compared in groups of diabetic mice (DM), control nondiabetic mice (Con), and diabetic mice treated with HIGT (HIGT). Delivery of a metabolically responsive insulin transgene to the liver of STZ-diabetic mice with an adeno-associated virus, sero-type 8 (AAV8) produced near-normal blood sugars for over 1 month and prevented anatomic, functional, and neurohistologic changes observed in diabetic mice. We conclude that in addition to normalizing oxidative metabolism in diabetic rodents, HIGT is sufficient to prevent the development of diabetic gastroenteropathy.


Chemometric applications to assess quality and critical parameters of virgin and extra-virgin olive oil. A review.
Today virgin and extra-virgin olive oil (VOO and EVOO) are food with a large number of analytical tests planned to ensure its quality and genuineness. Almost all official methods demand high use of reagents and manpower. Because of that, analytical development in this area is continuously evolving. Therefore, this review focuses on analytical methods for EVOO/VOO which use fast and smart approaches based on chemometric techniques in order to reduce time of analysis, reagent consumption, high cost equipment and manpower. Experimental approaches of chemometrics coupled with fast analytical techniques such as UV-Vis spectroscopy, fluorescence, vibrational spectroscopies (NIR, MIR and Raman fluorescence), NMR spectroscopy, and other more complex techniques like chromatography, calorimetry and electrochemical techniques applied to EVOO/VOO production and analysis have been discussed throughout this work. The advantages and drawbacks of this association have also been highlighted. Chemometrics has been evidenced as a powerful tool for the oil industry. In fact, it has been shown how chemometrics can be implemented all along the different steps of EVOO/VOO production: raw material input control, monitoring during process and quality control of final product.


Texture analysis of ultrahigh field T2*-weighted MR images of the brain: application to Huntington's disease.
To develop a framework for quantitative detection of between-group textural differences in ultrahigh field T2*-weighted MR images of the brain. MR images were acquired using a three-dimensional (3D) T2*-weighted gradient echo sequence on a 7 Tesla MRI system. The phase images were high-pass filtered to remove phase wraps. Thirteen textural features were computed for both the magnitude and phase images of a region of interest based on 3D Gray-Level Co-occurrence Matrix, and subsequently evaluated to detect between-group differences using a Mann-Whitney U-test. We applied the framework to study textural differences in subcortical structures between premanifest Huntington's disease (HD), manifest HD patients, and controls. In premanifest HD, four phase-based features showed a difference in the caudate nucleus. In manifest HD, 7 magnitude-based features showed a difference in the pallidum, 6 phase-based features in the caudate nucleus, and 10 phase-based features in the putamen. After multiple comparison correction, significant differences were shown in the putamen in manifest HD by two phase-based features (both adjusted P values=0.04). This study provides the first evidence of textural heterogeneity of subcortical structures in HD. Texture analysis of ultrahigh field T2*-weighted MR images can be useful for noninvasive monitoring of neurodegenerative diseases.


miR-942-5p prevents sepsis-induced acute lung injury via targeting TRIM37.
MicroRNAs (miRNAs) have been demonstrated to play pivotal roles in the pathogenesis of sepsis-induced acute lung injury (ALI). In this work, we aimed to clarify the potential role and the underlying mechanism of miR-942-5p in a lipopolysaccharide (LPS)-induced A549 cell injury model. The cell injury was evaluated by CCK-8 assay, flow cytometry and enzyme-linked immunosorbent assay (ELISA). The expression levels of miR-942-5p and tripartite motif-containing protein 37 (TRIM37) were measured by real-time PCR and Western blot, and their association was then validated by bioinformatics, luciferase reporter assay and RNA pull-down assay. We found that the expression of miR-942-5p was decreased in LPS-treated A549 cells. Furthermore, LPS treatment suppressed A549 cell viability, promoted apoptosis and increased the levels of inflammatory cytokines. Conversely, overexpression of miR-942-5p increased cell viability, reduced apoptosis and alleviated inflammatory cytokine secretion in the presence of LPS. Moreover, miR-942-5p directly targeted TRIM37 by binding to the 3'-UTR of TRIM37 mRNA. Upregulation of TRIM37 effectively reversed the anti-apoptotic and anti-inflammatory effects of miR-942-5p in LPS-induced A549 cells. Our findings suggested that miR-942-5p protected against LPS-induced cell injury through inhibiting apoptosis and inflammation in A549 cells by negatively regulating TRIM37.


[French doctors working in Great Britain: a study of their characteristics and motivations for migration].
As member states in the European Union now recognize the national qualifications of other member states, doctors will be able to move more freely within Europe according to the opportunities on offer and the constraints imposed by the different health-care systems. The aim of this study is to understand the reasons why French doctors choose to work in Great Britain. A self-completed questionnaire was used to conduct a survey among French doctors registered with the British Medical Council in 2005 who had done their studies in France and for whom the address was correct. The response rate, which was difficult to assess (impossible to distinguish between incorrect addresses and absence of response), was about 37%. The results show that doctors move to Britain for various reasons. In most cases (59%), the decision to emigrate is made for both professional and personal reasons. The second most common profile (29%), including essentially women, comprises those who emigrate to join a spouse. The third profile (12%) concerns those who emigrate for purely professional reasons: this group is made up of men who, for the most part, are disappointed with conditions in the French-hospital system: lack of recognition, poor pay and limited career prospects. Doctors who are dissatisfied with working conditions and low revenues in France seem to find that the National Health Service provides a better environment. Whatever the original reasons for expatriation, doctors particularly appreciate the salaried status, organization of working hours and teamwork, as well as more recognition of the work done. Because of uncertainties in the representativity of the returned questionnaires, the results of our study cannot be generalized to the whole population of French doctors currently working in Britain, but it does bring to light the principal reasons for their move to Britain. Though few doctors emigrate, the trend testifies to the dissatisfaction felt by certain doctors in the French health-care system. The study also underlines the dependence of the NHS on the immigration of health-care professionals.


A systematic review of modern metal-on-metal total hip resurfacing vs standard total hip arthroplasty in active young patients.
This systematic review compared 2 treatments for hip disease in active young patients: modern metal-on-metal total hip resurfacing and standard total hip arthroplasty. We conducted a literature search to identify relevant randomized and clinical controlled trials and included 968 patients from 4 trials in our analysis. Our results indicated increased rates of revision, femoral neck fractures, and component loosening among patients who received modern metal-on-metal hip resurfacing. No significant differences in the rates of mortality, dislocation, or deep hip joint infection were found between treatment groups. Hip function scores were similar between the 2 groups, but the resurfacing group showed higher activity levels. These results have provided insufficient evidence to determine whether modern metal-on-metal total hip resurfacing offers clinical advantages over standard total hip arthroplasty.


Evaluation of anterior chamber angle by van Herick grading and ultrasound biomicroscopy in light and dark conditions for finding appositional angle closure and plateau iris configuration.
To evaluate association of the van Herick (VH) grades with the ultrasound biomicroscopic (UBM) parameters, appositional irido-trabecular contact (A-ITC) and plateau iris (PI) in a randomly sampled population. A 10% random sample of all residents aged 40 or older of the Kumejima study underwent UBM under dark and light conditions in the four quadrants of right eyes. Of 301 right eyes with eligible UBM images, 101 (33.6%) and 200 (66.4%) were classified as VH ≤ 2 and VH ≥ 3, respectively. The UBM parameters on angle width and ciliary body configuration were significantly different between VH ≤ 2 and VH ≥ 3 eyes (p < 0.001). A-ITC was found in at least one quadrant in 54.5% and 75.2% of VH ≤ 2 eyes under light and dark conditions, respectively; and 20.5% and 45.5% of VH ≥ 3 eyes. When 'VH ≤ 2' was used to screen eyes with A-ITC in three or more quadrants, the sensitivity and specificity were 74.1% and 75.3%, respectively. A-ITC was significantly associated with shallower anterior chamber (p = 0.018) and higher intraocular pressure (p = 0.044) in VH ≥ 3 eyes. Plateau iris (PI) was found in 15.8% and 6.0% of VH ≤ 2 and VH ≥ 3 eyes, respectively. Plateau iris (PI) was significantly associated with the UBM parameters on angle width and ciliary body configuration. When 'VH ≤ 2' was used to screen eyes with PI, the sensitivity and specificity were 57.1% and 68.9%, respectively. The VH grade of ≤2 and ≥3 showed significant association with UBM angle width and ciliary body configuration parameters. The VH ≤ 2 criterion should be useful for screening of A-ITC and PI.


Failure to Rescue in Emergency General Surgery: Impact of Fragmentation of Care.
Compare EGS patient outcomes after index and nonindex hospital readmissions, and explore predictive factors for nonindex readmission. Readmission to a different hospital leads to fragmentation of care. The impact of nonindex readmission on patient outcomes after EGS is not well established. The Nationwide Readmissions Database (2017) was queried for adult patients readmitted after an EGS procedure. Patients were stratified and propensity-matched according to readmission destination: index versus nonindex hospital. Outcomes were failure to rescue (FTR), mortality, number of subsequent readmissions, overall hospital length of stay, and total costs. Hierarchical logistic regression was performed to account for clustering effect within hospitals and adjusting for patient- and hospital-level potential confounding factors. A total of 471,570 EGS patients were identified, of which 79,127 (16.8%) were readmitted within 30 days: index hospital (61,472; 77.7%) versus nonindex hospital (17,655; 22.3%). After 1:1 propensity matching, patients with nonindex readmission had higher rates of FTR (5.6% vs 4.3%; P < 0.001), mortality (2.7% vs 2.1%; P < 0.001), and overall hospital costs [in $1000; 37 (27-64) vs 28 (21-48); P < 0.001]. Nonindex readmission was independently associated with higher odds of FTR [adjusted odds ratio 1.18 (1.03-1.36); P < 0.001]. Predictors of nonindex readmission included top quartile for zip code median household income [1.35 (1.08-1.69); P < 0.001], fringe county residence [1.08 (1.01-1.16); P = 0.049], discharge to a skilled nursing facility [1.28 (1.20-1.36); P < 0.001], and leaving against medical advice [2.32 (1.81-2.98); P < 0.001]. One in 5 readmissions after EGS occur at a different hospital. Nonindex readmission carries a heightened risk of FTR. Level III Prognostic. Prognostic.


2-(2-Nitro-anilino)benzoic acid.
In the title compound, C(13)H(10)N(2)O(4), the nitro N atom deviates by 0.031 (2) Å from the plane of the benzene ring to which it is attached. The aromatic rings are oriented at a dihedral angle of 50.6 (1)°. An intra-molecular N-H⋯O hydrogen bond occurs. In the crystal, inversion dimers are formed by pairs of O-H⋯O inter-actions.


A novel nomogram for predicting cancer-specific survival in women with uterine sarcoma: a large population-based study.
Uterine sarcoma (US) is a rare malignant uterine tumor with aggressive behavior and rapid progression. The purpose of this study was to constructa comprehensive nomogram to predict cancer-specific survival (CSS) of patients with US-based on the Surveillance, Epidemiology, and End Results (SEER) database. A retrospective population-based study was conducted using data from patients with US between 2010 and 2015 from the SEER database. They were randomly divided into a training cohort and a validation cohort ata 7-to-3 ratio. Multivariate Cox analysis was performed to identify independent prognostic factors. Subsequently, a nomogram was established to predict patient CSS. The discrimination and calibration of the nomogram were evaluated by the concordance index (C-index) and the area under the curve (AUC). Finally, net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration plotting, and decision-curve analysis (DCA) were used to evaluate the benefits of the new prediction model. A total of 3861 patients with US were included in our study. As revealed in multivariate Cox analysis, age at diagnosis, race, marital status, insurance record, tumor size, pathology grade, histological type, SEER stage, AJCC stage, surgery status, radiotherapy status, and chemotherapy status were found to be independent prognostic factors. In our nomogram, pathology grade had strongest correlation with CSS, followed by age at diagnosis and surgery status. Compared to the AJCC staging system, the new nomogram showed better predictive discrimination with a higher C-index in the training and validation cohorts (0.796 and 0.767 vs. 0.706 and 0.713, respectively). Furthermore, the AUC value, calibration plotting, NRI, IDI, and DCA also demonstrated better performance than the traditional system. Our study validated the first comprehensive nomogram for US, which could provide more accurate and individualized survival predictions for US patients in clinical practice.


[Effect of plasmapheresis on myocardial functional activity and blood circulation in the thyroid in thyrotoxicosis patients].
The results are examined of plasmapheresis use for preoperative preparation of 55 thyrotoxic patients. Myocardial function was studied by polycardiography and thyroid circulation by means of rheography. It was concluded that myocardial function and thyroid circulation return to normal under plasmapheresis effect.


Sleep apneas are increased in mice lacking monoamine oxidase A.
Alterations in the serotonin (5-HT) system have been suggested as a mechanism of sleep apnea in humans and rodents. The objective is to evaluate the contribution of 5-HT to this disorder. We studied sleep and breathing (whole-body plethysmography) in mutant mice that lack monoamine oxidase A (MAOA) and have increased concentrations of monoamines, including 5-HT. Compared to wild-type mice, the mutants showed similar amounts of slow wave sleep (SWS) and rapid eye movement sleep (REMS), but exhibited a 3-fold increase in SWS and REMS apnea indices. Acute administration of the MAOA inhibitor clorgyline decreased REMS amounts and increased the apnea index in wild-type but not mutant mice. Parachlorophenylalanine, a 5-HT synthesis inhibitor, reduced whole brain concentrations of 5-HT in both strains, and induced a decrease in apnea index in mutant but not wild-type mice. Our results show that MAOA deficiency is associated with increased sleep apnea in mice and suggest that an acute or chronic excess of 5-HT contributes to this phenotype.


Multimodal hippocampal and amygdala subfield volumetry in polygenic risk for Alzheimer's disease.
Preclinical models of Alzheimer's disease (AD) suggest that volumetric reductions in medial temporal lobe (MTL) structures manifest before clinical onset. AD polygenic risk scores (PRSs) are further linked to reduced MTL volumes (the hippocampus/amygdala); however, the relationship between the PRS and specific subregions remains unclear. We determine the relationship between the AD-PRSs and MTL subregions in a large sample of young participants (N = 730, aged 22-35 years) using a multimodal (T1w/T2w) approach. We first demonstrate that the PRSs for the hippocampus/amygdala predict their respective volumes and specific hippocampal subregions (pFDR < 0.05). We further observe negative relationships between the AD-PRSs and whole hippocampal/amygdala volumes. Critically, we demonstrate novel associations between the AD-PRSs and specific hippocampal subfields such as CA1 (β = -0.096, pFDR = 0.045) and the fissure (β = -0.101, pFDR = 0.041). We provide evidence that the AD-PRS is linked to specific MTL subfields decades before AD onset. This may help inform preclinical models of AD risk, providing additional specificity for intervention and further insight into mechanisms by which common AD variants confer susceptibility.


Improving results for coronary artery bypass graft surgery in the elderly.
The proportion of elderly patients undergoing isolated coronary artery bypass grafting (CABG) surgery has steadily increased. We have evaluated temporal trends in hospital outcomes of patients who were 75 years and older undergoing CABG (1990-2010) at our institution. Data were collected prospectively for 3483 consecutive patients who were 75 years and older (median 78 years; range 75-94) undergoing isolated CABG at our institution over three time cohorts: 1990-96 (n = 817), 1997-2003 (n = 1534) and 2004-10 (n = 1132). Overall mortality declined from 6.0% (49/817) in the earliest era (1990-96) to 1.9% (22/1132) in the most recent era (2003-10; P < 0.001). Mortality in low-risk patients (elective, primary surgery with the ejection fraction >40%) was 5.9% (13/220), 0.8% (4/514) and 0% (0/411) in the first, second and third eras, respectively (P < 0.001). Despite the overall increase in comorbidities in our elderly patients, the prevalences of certain risk factors such as poor LV function, urgency of surgery and reoperation have all declined with time. The independent risk factors for mortality in our population were congestive heart failure, left main disease, earlier year of operation, reoperation, preoperative myocardial infarction, cardiopulmonary bypass time, emergent/urgent surgery and peripheral vascular disease. Of these, earlier year of operation (OR: 3.0; 95% CI: 1.8-5.2) was the most significant predictor. Also, age >80 did not predict mortality. The principle finding from this analysis is a contemporary low operative mortality for CABG in an elderly patient cohort. Risk of death is particularly low in a low-risk subset of elderly patients with reasonable LV function undergoing elective, primary CABG.


Apocrine carcinoma of the skin. A clinicopathologic, immunocytochemical, and ultrastructural study.
Apocrine carcinomas of the skin are rare and incompletely studied neoplasms. An immunohistochemical and ultrastructural study is reported of specimens from six patients with apocrine skin carcinoma in various body sites. Three tumors were in the axilla; one, the eyelid; one, the ear; and one, the scalp. There were three local recurrences and three regional lymph node metastases, but no patient died of cancer (follow-up, 2-10 years). The most reliable histopathologic criteria for identifying apocrine skin carcinoma appear to be decapitation secretion, periodic acid-Schiff-positive diastase-resistant material in the cells or lumen, and immunoreactivity with gross cystic disease fluid protein 15. All specimens expressed common epithelial antigens (cytokeratins, carcinoembryonic antigen, and epithelial membrane antigen) and histiocytic-secretive antigens (Leu-M1, lysozyme, LN5, alpha-1-antitrypsin, and alpha-1-antichymotrypsin). S-100 protein was found in the three nonaxillary tumors. Ultrastructurally, the primary tumors, and especially the secondary lesions, were dedifferentiated compared with normal apocrine glands. Apocrine differentiation in skin tumors does not indicate an exclusive origin from the apocrine sweat glands; these neoplasms usually have an indolent clinical course.


The reliability of personal and family medical histories in the identification of hepatitis B carriers.
Blood specimens were obtained from 300 patients and were tested for the five hepatitis B virus (HBV) serum markers: HBsAg, HbeAg, anti-HBs, anti-HBe and anti-HBc. Medical histories were checked to determine any previous experience of HBV infection in the patients or their families. Serum markers showed that 54.3% of the group had evidence of earlier HBV infection, 10% were HBsAg carriers, and 3% were HBeAg-positive. The patients' own histories correctly identified carriers in 23.1% of those giving a positive HBV history (p less than 0.05). Family histories were found to be an unreliable means of detecting HBV carriers. HBeAg carriers were twice as likely to be identified by their histories than HBsAg carriers. Blood donation refusal was the most frequent indicator of previous HBV infection.


Deep diagnostic agent forest (DDAF): A deep learning pathogen recognition system for pneumonia based on CT.
Even though antibiotics agents are widely used, pneumonia is still one of the most common causes of death around the world. Some severe, fast-spreading pneumonia can even cause huge influence on global economy and life security. In order to give optimal medication regimens and prevent infectious pneumonia's spreading, recognition of pathogens is important. In this single-institution retrospective study, 2,353 patients with their CT volumes are included, each of whom was infected by one of 12 known kinds of pathogens. We propose Deep Diagnostic Agent Forest (DDAF) to recognize the pathogen of a patient based on ones' CT volume, which is a challenging multiclass classification problem, with large intraclass variations and small interclass variations and very imbalanced data. The model achieves 0.899 ± 0.004 multi-way area under curves of receiver (AUC) for level-I pathogen recognition, which are five rough groups of pathogens, and 0.851 ± 0.003 AUC for level-II recognition, which are 12 fine-level pathogens. The model also outperforms the average result of seven human readers in level-I recognition and outperforms all readers in level-II recognition, who can only reach an average result of 7.71 ± 4.10% accuracy. Deep learning model can help in recognition pathogens using CTs only, which might help accelerate the process of etiological diagnosis.


Physicians' implementation of dietitians' recommendations: a study of the effectiveness of dietitians.
To determine how often dietitians' recommendations were implemented by physicians and to identify workplace and demographic factors that correlated with successful implementation of recommendations. A cohort of hospitals was surveyed by mail. Dietitians recorded recommendations written in five consecutive medical record entries and sent them to the chief clinical dietitian. Seventy-two hours later, physicians' order sheets were reviewed to assess implementation. Dietitians completed demographic questionnaires. Forty-four general hospitals in Philadelphia and the surrounding area were surveyed. To ensure similar standards of nutrition care, only hospitals approved by the Joint Commission on Accreditation of Healthcare Organizations were selected. chi 2, Fisher's exact test, and the Kruskall-Wallis test were used to correlate demographic variables with implementation rate. Implementation of the dietitians' recommendations by physicians' orders. Responses were obtained from 35 of the 44 hospitals and 98 (70%) of the clinical dietitians. Of the 865 recommendations, 42% were implemented. Significantly higher implementation rates were noted for recommendations solicited by (50%) or discussed with the physician (65%). Dietitians were more successful in teaching hospitals and when they reported to a hospital-operated foodservice rather than a contract foodservice. Success correlated with a lower workload when measured by the ratio of admissions to staff but not when measured by the ratio of beds to staff. Dietitians could have a greater effect on nutrition care by discussing recommendations with physicians. Further research is needed about staffing formulas and methods to improve the effectiveness of dietitians.


Dopamine-induced increase in atrioventricular conduction in atrial fibrillation-flutter.
We report a patient with controlled atrial fibrillation-flutter (AFF) and mitral stenosis who developed a marked increase in atrioventricular conduction during an infusion of low dose dopamine with development of hemodynamic compromise. This side effect has not been previously described in humans. Dopamine infusion should be used with caution in patients with AFF.


An evaluation of mercury levels in Louisiana fish: trends and public health issues.
To characterize statewide fish tissue mercury levels in edible finfish the first comprehensive analysis of Louisiana's fish tissue mercury database was conducted. Analyses were based on fifteen years of fish tissue mercury data collected from 368 waterbodies between 1994 and 2008 (n=14,344). The overall objectives of this study were to establish baseline fish tissue mercury levels; and evaluate species-specific temporal and spatial trends in fish tissue mercury levels. Fish tissue mercury levels ranged from 0.001 ppm (the detection limit) to 5.904 ppm for king mackerel; with an overall geometric mean of 0.218 ppm. Ninety-five percent of samples had mercury levels below the FDA's action level of 1.0 ppm for methylmercury in commercial food. Forty-four percent of all samples had mercury levels above the U.S. EPA's methylmercury fish tissue criterion of 0.3 ppm for sportfish. Species of potential concern include cobia, king mackerel, blackfin tuna, greater amberjack, spotted bass, bowfin, largemouth bass and freshwater drum. There was a significant but small decline in statewide length-adjusted largemouth bass mercury levels between 1994-1999 to 2003-2008 (p<0.05). The highest fish mercury levels were observed in Pearl, Calcasieu, Mermentau, Ouachita, Pontchartrain and Sabine basins. Length-adjusted largemouth bass mercury levels were significantly higher in wetlands and rivers/streams vs. lakes; and in wetlands vs. estuaries (p<0.05). Data were analyzed from a public health perspective to make recommendations for optimizing monitoring and outreach.


Evaluation of patient-held carbapenemase-producing Enterobacteriaceae (CPE) alert card.
Public Health England recommends patient-held cards for those colonized with carbapenemase-producing Enterobacteriaceae (CPE). Alert cards were provided to 104 CPE-positive inpatients, with follow-up at six months. Excluding those who died, the response rate was 39%. Sixteen patients (46%) recalled receiving the card; 13 (81%) of these retained it, most (64%) of whom reported using it. This is the first evaluation of a patient-held alert card for any antimicrobial-resistant (AMR) bacteria in the UK. This study demonstrated that, when retained, CPE alert cards can be an effective communication tool. Further work is required to evaluate effectiveness and improve retention.


Amino acid sequence of two new milk-clotting proteases from the macroalga Gracilaria edulis.
This study is aimed at identifying and characterising the proteases we previously extracted from the red seaweed Gracilaria edulis with the potential as milk-clotting enzymes. The protease extract was first analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and zymography. Two protease bands with a molecular weight of 44 and 108 kDa were identified, and analysed using in-gel digestion and liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS). Eight peptides from the LC-MS/MS analysis matched those in existing protein databases but they were not related to any protease of the genera Gracilaria and Hydropuntia. Further analysis revealed that more than 80% of the peptide sequence of the algal proteases matched with those from members of the bacteria kingdom, including Gallaecimonas and Alteromonas. Among these, twelve matching homolog proteases were identified as metalloprotease and serine protease. The results indicated that the algal proteases have a close relationship with both algae and bacteria, and suggest that the proteases might have resulted from past bacterial colonisation of the algae and subsequent horizontal gene transfer between bacteria and algae.


Extrachromosomal and integrated genetic elements in Clostridium difficile.
Clostridium difficile is a major nosocomial pathogen, causing gastrointestinal disease in patients undergoing antibiotic therapy. This bacterium contains many extrachromosomal and integrated genetic elements, with recent genomic work giving new insights into their variability and distribution. This review summarises research conducted in this area over the last 30 years and includes a discussion on the functional contributions of these elements to host cell phenotypes, as well as encompassing recent genome sequencing studies that have contributed to our understanding of their evolution and dissemination. Importantly, we also include a review of antibiotic resistance determinants associated with mobile genetic elements since antibiotic use and the spread of antibiotic resistance are currently of significant global clinical importance.


Innovative low-cost biosorption process of Cr6+ by Pseudomonas alcaliphila NEWG-2.
Chromium is one of the heavy metal pollutants that causing risky health issues when discharged into the aquatic ecosystems. The current investigation focused on the bioremoval of Cr6+ depending on the bacterial sorption process by using Pseudomonas sp. NEWG-2 which was identified on the basis of morphological, cultural characteristics, 16S rRNA sequencing and phylogenetic analysis as Pseudomonas alcaliphila strain NEWG-2. It is clear from the FCCD experiments that the bacterium can grow normally and remove 96.60% of 200 mg/l of Cr6+ using yeast extract (5.6 g/l), glucose (4.9 g/l), pH (7) for 48 h incubation period. SEM and EDS analyses proved that the Cr6+ was biosorbed by P. alcaliphila NEWG-2. FTIR spectra indicated that the phenolic, carbonyl ester, acetyl, carboxylate, alkanes and carbonyl were the main groups involved in the chromium biosorption. Of the equilibrium isotherms models, the Langmuir model was more obedient, with a maximum uptake (qmax) of 10 mg/g (bacterial-alginate beads), than the Freundlich one. The findings reveal the efficiency of P. alcaliphila NEWG-2 in Cr6+ biosorption, with feasibility in the treatment of chromium-contaminated water as a green-technology tool. Interestingly, to the best of our knowledge, this is the first report on Cr6+ biosorption process by P. alcaliphila.


Lactoquinomycin C and D, two new medermycin derivatives from the marine-derived Streptomyces sp. SS17A.
Lactoquinomycin C (1) and Lactoquinomycin D (2), two new medermycin derivatives together with six known compounds (3-8) were isolated from the rice solid fermentation of the marine-derived Streptomyces sp. SS17A. The intriguing structural features of the Lactoquinomycin D (2) which contains 5,14-epoxidation is relatively rare in medermycin derivatives. Compounds 1 and 2 exhibited no cytotoxicity against PC-3 and HCT-116 cancer cell lines, whereas compound 3 showed stronger cytotoxicity with IC50 values of 0.02 and 0.04 μM, respectively. A structure-activity relationship was observed for the cytotoxicity of the medermycin derivatives with a γ-lactone unit is required for significant cytotoxicity based on compounds 1-3.


[Acute spinal amyotrophy in toxoplasmosis].
A 19 year-old man developed an acute syndrome of the anterior horn of cervical spinal cord during a primo-infection with toxoplasma. The neurological syndrome was completely regressive after treatment with 1 600 mg/day of trimethoprim-sulfamethoxazole for three months.


Automating genomic data mining via a sequence-based matrix format and associative rule set.
There is an enormous amount of information encoded in each genome--enough to create living, responsive and adaptive organisms. Raw sequence data alone is not enough to understand function, mechanisms or interactions. Changes in a single base pair can lead to disease, such as sickle-cell anemia, while some large megabase deletions have no apparent phenotypic effect. Genomic features are varied in their data types and annotation of these features is spread across multiple databases. Herein, we develop a method to automate exploration of genomes by iteratively exploring sequence data for correlations and building upon them. First, to integrate and compare different annotation sources, a sequence matrix (SM) is developed to contain position-dependant information. Second, a classification tree is developed for matrix row types, specifying how each data type is to be treated with respect to other data types for analysis purposes. Third, correlative analyses are developed to analyze features of each matrix row in terms of the other rows, guided by the classification tree as to which analyses are appropriate. A prototype was developed and successful in detecting coinciding genomic features among genes, exons, repetitive elements and CpG islands.


Transmembrane helices before, during, and after insertion.
The transmembrane (TM) helix is the fundamental structural unit of helix-bundle membrane proteins. Recent biophysical studies provide new insights into the interactions of TM helices with each other and with membrane lipid bilayers. The biological process of helix insertion is carried out by translocon complexes acting in concert with ribosomes. An electron cryo-microscopic reconstruction of these complexes reveals their architecture in new detail, and shows that the complex is constructed from four SecY/Sec61 heterotrimers and two TRAP complexes. A disulfide bridge study shows that elongating polypeptide chains pass through the pore previously identified in the X-ray structure of an archaeal SecY heterotrimer. The fundamental code used by the translocon to select polypeptide segments for insertion as TM helices has been broken. A detailed analysis of the TM amino acid distributions of helix-bundle membrane proteins of known structure recapitulates this code.


Psychometric properties of the Chinese Mandarin version of the Borderline Symptom List, short form (BSL-23) in suicidal adolescents.
The short form of the Borderline Symptom List (BSL-23) is a self-rated instrument developed from the initial 95-item German version of the Borderline Symptom List (BSL-95). It is widely used among Chinese adults, but its applicability, factor structure and validity remain uncertain in adolescents. This study aimed to evaluate the psychometric properties of the Chinese Mandarin version of the BSL-23 in a sample of suicidal adolescents. The Chinese Mandarin BSL-23 was given to 279 outpatient adolescents with self-injurious thoughts or behaviors. The factor structure, reliability, convergent validity, criterion-related validity and cut-off value were investigated. The Chinese Mandarin version of the BSL-23 demonstrated a one-factor structure and replicated the original version. The scale had high reliability and good test-retest stability. The Chinese Mandarin BSL-23 was correlated with depression, hopelessness, impulsivity, emotional dysregulation, self-esteem, loneliness, childhood trauma and parental bonding patterns evaluated with a variety of scales. The measure showed good criterion-related validity and predictive accuracy (AUC = 0.87) for self-injurious and suicidal adolescents with borderline personality disorder (BPD) at a cut-off point of 60/61 (mean score 2.60/2.65), with a sensitivity of 0.76 and specificity of 0.83. The Chinese Mandarin version of the BSL-23 is a reliable and valid self-reported instrument to assess BPD symptomatology among suicidal adolescents.


Comments on "SVD-based modeling for image texture classification using wavelet transform".
This correspondence points out that in [1] there are some errors in two important formulas and the performance of the proposed singular value decomposition (SVD) feature is severely overestimated. It also presents a modified SVD feature which competes with the Gabor feature.


Predicting stroke and mortality in mitral stenosis with atrial flutter: A machine learning approach.
Our study hypothesized that an intelligent gradient boosting machine (GBM) model can predict cerebrovascular events and all-cause mortality in mitral stenosis (MS) with atrial flutter (AFL) by recognizing comorbidities, electrocardiographic and echocardiographic parameters. The machine learning model was used as a statistical analyzer in recognizing the key risk factors and high-risk features with either outcome of cerebrovascular events or mortality. A total of 2184 patients with their chart data and imaging studies were included and the GBM analysis demonstrated mitral valve area (MVA), right ventricular systolic pressure, pulmonary artery pressure (PAP), left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) class, and surgery as the most significant predictors of transient ischemic attack (TIA/stroke). MVA, PAP, LVEF, creatinine, hemoglobin, and diastolic blood pressure were predictors for all-cause mortality. The GBM model assimilates clinical data from all diagnostic modalities and significantly improves risk prediction performance and identification of key variables for the outcome of MS with AFL.


First report of a bite by the mottled rock rattlesnake (Crotalus lepidus lepidus).
Bites by the mottled rock rattlesnake (Crotalus lepidus lepidus) are rare. There appear to be no reports of bites by this subspecies in the literature. This is a case report of a bite by a captive specimen of this diminutive pit viper, and includes a review of what is known regarding its venom.


Engineered Jurkat Cells for Targeting Prostate-Specific Membrane Antigen on Prostate Cancer Cells by Nanobody-Based Chimeric Antigen Receptor
Recently, modification of T cells with chimeric antigen receptor (CAR) has been an attractive approach for adoptive immunotherapy of cancers. Typically, CARs contain a single-chain variable domain fragment (scFv). Most often, scfvs are derived from a monoclonal antibody of murine origin and may be a trigger for host immune system that leads to the T-cell clearance. Nanobody is a specific antigen-binding fragment derived from camelid that has great homology to human VH and low immunogenic potential. Therefore, in this study, nanobody was employed instead of scFv in CAR construct. In this study, a CAR was constructed based on a nanobody against PSMA (NBPII-CAR). At first, Jurkat cells were electroporated with NBPII-CAR, and then flow cytometry was performed for NBPII-CAR expression. For functional analysis, CAR T cells were co-cultured with prostate cancer cells and analyzed for IL-2 secretion, CD25 expression, and cell proliferation. Flow cytometry results confirmed the expression of NBPII-CAR on the transfected Jurkat cells. Our data showed the specificity of engineered Jurkat cells against prostate cancer cells by not only increasing the IL-2 cytokine (about 370 pg/ml) but also expressing the T-cell activation marker CD25 (about 30%). In addition, proliferation of engineered Jurkat cells increased nearly 60% when co-cultured with LNCaP (PSMA+), as compared with DU145 (PSMA-). Here, we describe the ability of nanobody-based CAR to recognize PSMA that leads to the activation of Jurkat cells. This construct might be used as a promising candidate for clinical applications in prostate cancer therapy.


The crystal structures of the enzyme hydroxymethylbilane synthase, also known as porphobilinogen deaminase.
The enzyme hydroxymethylbilane synthase (HMBS; EC 22.214.171.124), also known as porphobilinogen deaminase, catalyses the stepwise addition of four molecules of porphobilinogen to form the linear tetrapyrrole 1-hydroxymethylbilane. Thirty years of crystal structures are surveyed in this topical review. These crystal structures aim at the elucidation of the structural basis of the complex reaction mechanism involving the formation of tetrapyrrole from individual porphobilinogen units. The consistency between the various structures is assessed. This includes an evaluation of the precision of each molecular model and what was not modelled. A survey is also made of the crystallization conditions used in the context of the operational pH of the enzyme. The combination of 3D structural techniques, seeking accuracy, has also been a feature of this research effort. Thus, SAXS, NMR and computational molecular dynamics have also been applied. The general framework is also a considerable chemistry research effort to understand the function of the enzyme and its medical pathologies in acute intermittent porphyria (AIP). Mutational studies and their impact on the catalytic reaction provide insight into the basis of AIP and are also invaluable for guiding the understanding of the crystal structure results. Future directions for research on HMBS are described, including the need to determine the protonation states of key amino-acid residues identified as being catalytically important. The question remains - what is the molecular engine for this complex reaction? Thermal fluctuations are the only suggestion thus far.


Priapism induced by chlorpromazine and trazodone: mechanism of action.
To investigate the mechanism of drug-induced priapism, we gave the antipsychotic agent chlorpromazine and the antidepressant trazodone to 14 dogs by intravenous and intracorporeal injection. Bilateral intracorporeal pressure, blood flow within the internal pudendal artery, and systemic blood pressure were monitored. Venous outflow restriction was evaluated by continuous saline infusion of the corpus cavernosum with the infrarenal aorta clamped. When delivered by intracorporeal injection, both drugs induced erection in a manner similar to that of intracorporeal injection of papaverine. Internal pudendal arterial flow increased slightly at the beginning of tumescence, and excellent venous restriction occurred. Intravenous injection, however, could neither induce an erection nor facilitate an erection after sub-threshold neurostimulation. We believe that the alpha-adrenergic antagonist properties of chlorpromazine and trazodone probably cause priapism by local action.


Surgical treatment of class II dento-facial deformity during adolescence: Long-term follow-up.
The purpose of this study is to evaluate the long-term stability of patients operated during adolescence on the base of clinical measurements and cephalometric analysis. Although, the potential benefits of early orthognathic surgery are known to be a reduction in treatment times and a greater healing potential leading to a better adaptation and stability of the occlusion, muscles, bones and joints, no consensus can be found in literature on the minimum age for surgical correction. In this study, thirty patients (age ≤ 15) with a class II dento-skeletal malocclusion were selected, of which 11 having a hyperdivergent (II,1) and 19 a hypodivergent (II,2) growth pattern, representing 2 distinct groups with a different treatment plan and long-term behavior. Observing the performance of all parameters over-time, it is seen that subjects belonging to division II,2 have a modification of the growth vectors maintaining the harmonious development between the jaws and the facial aesthetics. Less predictable is the trend in hyperdivergent patients, which are more prone to relapse in the long-term. Early surgery in these patients should be considered in the light of the degree of deformity and its influence felt by the patient on his development of self-image and interpersonal relationship.


Is precipitation a predictor of mortality in Bangladesh? A multi-stratified analysis in a South Asian monsoon climate.
While numerous studies have assessed the association between temperature and mortality in various locations, few have addressed the relationship between precipitation and mortality. Given the high amounts of rainfall in many tropical monsoon areas and the often seasonally pronounced differences, there might be a potentially strong impact on health outcomes and death. In this study, we investigated the association between precipitation and daily death counts in Bangladesh from 2003 to 2007 using regression models with a quasipoisson distribution adjusting for long-term time and seasonal trends, day of the month, age and perceived temperature. Effects were assessed for all ages, the elderly and by gender. During the dry season a sharp increase in death risk was found at very high precipitation amounts which are most likely to be cyclone-related. This cyclone effect was most pronounced for females at the immediate day with an increase of 18.7% (3.8-35.6%) in non-external cause mortality per mm precipitation above 5mm. At longer lags we found a negative association between precipitation and mortality indicating some kind of dry effect which was more pronounced for the elderly with a mortality increase of 4.4% (2.6-6.2%) per mm decrease in precipitation. During the rainy season, we observed a protective effect of rainfall which was strongest during periods of seasonally high equivalent temperatures with a decrease in mortality of 4.0% (2.3-5.6%) per mm increase in precipitation on the immediate day. The observed associations between precipitation and mortality differed by season, age and gender. Generally, a strong short-term increase in mortality was associated with cyclonic activity during the dry season, while ongoing low rainfall seemed to have an adverse impact at higher lags. During the rainy season, precipitation seemed to mitigate heat effects.


Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor.
Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that has a major role in sensory neurotransmission. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) class B G-protein-coupled receptor and a type 1 transmembrane domain protein, receptor activity-modifying protein 1 (RAMP1). Here we report the structure of the human CGRP receptor in complex with CGRP and the Gs-protein heterotrimer at 3.3 Å global resolution, determined by Volta phase-plate cryo-electron microscopy. The receptor activity-modifying protein transmembrane domain sits at the interface between transmembrane domains 3, 4 and 5 of CLR, and stabilizes CLR extracellular loop 2. RAMP1 makes only limited direct contact with CGRP, consistent with its function in allosteric modulation of CLR. Molecular dynamics simulations indicate that RAMP1 provides stability to the receptor complex, particularly in the positioning of the extracellular domain of CLR. This work provides insights into the control of G-protein-coupled receptor function.


Thorotrast induced hepatic cholangiocarcinoma and angiosarcoma.
A 49 year old woman developed hepatic cholangiocarcinoma and angiosarcoma 22 years after the administration of Thorotrast. The etiologic association between Thorotrast and a variety of malignant hepatic neoplasms is well known, but the simultaneous occurrence of two different hepatic neoplasms has not been previously reported.


Murine erythroid 5-aminolevulinate synthase: Adenosyl-binding site Lys221 modulates substrate binding and catalysis.
5-Aminolevulinate synthase (ALAS) catalyzes the initial step of mammalian heme biosynthesis, the condensation between glycine and succinyl-CoA to produce CoA, CO2, and 5-aminolevulinate. The crystal structure of Rhodobacter capsulatus ALAS indicates that the adenosyl moiety of succinyl-CoA is positioned in a mainly hydrophobic pocket, where the ribose group forms a putative hydrogen bond with Lys156. Loss-of-function mutations in the analogous lysine of human erythroid ALAS (ALAS2) cause X-linked sideroblastic anemia. To characterize the contribution of this residue toward catalysis, the equivalent lysine in murine ALAS2 was substituted with valine, eliminating the possibility of a hydrogen bond. The K221V substitution produced a 23-fold increase in the [Formula: see text] and a 97% decrease in [Formula: see text]. This reduction in the specificity constant does not stem from lower affinity toward succinyl-CoA, since the [Formula: see text] of K221V is lower than that of wild-type ALAS. For both enzymes, the [Formula: see text] value is significantly different from the [Formula: see text]. That K221V has stronger binding affinity for succinyl-CoA was further deduced from substrate protection studies, as K221V achieved maximal protection at lower succinyl-CoA concentration than wild-type ALAS. Moreover, it is the CoA, rather than the succinyl moiety, that facilitates binding of succinyl-CoA to wild-type ALAS, as evident from identical [Formula: see text] and [Formula: see text] values. Transient kinetic analyses of the K221V-catalyzed reaction revealed that the mutation reduced the rates of quinonoid intermediate II formation and decay. Altogether, the results imply that the adenosyl-binding site Lys221 contributes to binding and orientation of succinyl-CoA for effective catalysis.


A case of sinonasal teratocarcinosarcoma treated with surgery and post-operative intensity-modulated radiotherapy (IMRT).
Sinonasal teratocarcinosarcoma (SNTCS) is a rare and aggressive malignant neoplasm, which has poor prognosis. SNTCS is histologically characterized by the combination of one or more epithelial elements and mesenchymal components. We report a 59-year-old man with SNTCS involving right maxillary and ethmoid sinuses. He complained of numbness of the right cheek for 1 month. Computed tomography and magnetic resonance imaging revealed soft tissue filling the right maxillary and ethmoid sinuses, protruding into the nasal cavity. Tumor was removed with Denker rhinotomy, and post-operative intensity-modulated radiation therapy (IMRT: 64Gy in 32 fractions) was performed. Follow-up examination for 2 years after the IMRT has shown no evidence of recurrence or metastasis. IMRT is a new type of conformal radiotherapy that is based on the use of non-uniform radiation beam intensities. IMRT can achieve optimal dose distributions and may improve the clinical outcomes dramatically with minimal complications. This report describes this patient's clinical course, etiology, diagnosis and management of SNTCS, and the advantage of IMRT in the treatment of SNTCS.


Structure of cDNA clones coding for the entire prepro alpha 1 (III) chain of human type III procollagen. Differences in protein structure from type I procollagen and conservation of codon preferences.
Two overlapping cDNA clones that cover the complete length of the mRNA for human type III procollagen were characterized. The data provided about 2500 base pairs of sequence not previously defined for human type III procollagen. Two tripeptide sequences of -Gly-Xaa-Yaa- were identified that were not detected previously by amino acid sequencing of human type III collagen. The two additional tripeptide units, together with three previously detected, establish that the alpha 1 (III) chain is 15 amino acids longer than either the alpha 1 (I) or alpha 2 (I) chains of type I collagen. The additional tripeptide units made hydropathy plots of the N-terminal and C-terminal regions of type III collagen distinctly different from those of type I collagen. The data also demonstrated that human type III procollagen has the same third base preference in codons for glycine, proline and alanine that was previously found with human and chick type I procollagen. In addition, comparison of two cDNA clones from the same individual revealed a variation in structure in that the codon for amino acid 880 of the alpha 1 (III) chain was -CTT- for leucine in one clone and -TTT- for phenylalanine in the other.


MicroRNA-29b-3p suppresses oral squamous cell carcinoma cell migration and invasion via IL32/AKT signalling pathway.
Oral squamous cell carcinoma (OSCC) is aggressive accompanied with poor prognosis. We previously isolated the most invasive cells resembling the invasive tumour front by microfluidic technology and explored their differentially expressed microRNAs (miRNAs) in our previous work. Here, we verified the miR-29b-3p as a guarder that suppressed migration and invasion of OSCC cells and was down-regulated in the most invasive cells. Besides that, the invasion suppression role of miR-29b-3p was achieved through the IL32/AKT pathway. Thus, miR-29b-3p and IL32 might serve as therapeutic targets for blocking the progression and improving the outcome of OSCC.


Agreement and predictive power of six fall risk assessment methods in community-dwelling older adults.
A large number of fall risk assessment methods are available with a variety of performances for screening the risk of falling in older adults, but their agreement for assessing the risk of falling remains unknown. This observational prospective cohort study describes the agreement and predictive power of methods to classify the risk of falling in older adults using prospective data and published cut-off values. Fifty-two participants aged 74 years (interquartile range 69-80) were assessed using the Berg Balance Scale, polypharmacy, Falls Risk Assessment Score, Fall Risk Assessment Tool, Fall Efficiency Scale, and Posturography. Nine participants (17 %) reported at least one fall after six months. Cochran's test showed different proportions of participants classified as at high risk of falling among all methods (Q = 69.560, p < 0.001). A slightly better-then-chance agreement was estimated between all FRA methods (Light's κ = 0.074, 95%CI [0.021; 0.142]). We found both global and pairwise agreement levels that question the agreement among fall risk assessment methods for screening community-dwelling older adults.


Hospital admissions for severe infections in people with chronic kidney disease in relation to renal disease severity and diabetes status.
Immunosuppressive agents are being investigated for the treatment of chronic kidney disease (CKD) but may increase risk of infection. This was a retrospective observational study intended to evaluate the risk of hospitalized infection in patients with CKD, by estimated glomerular filtration rate (eGFR) and proteinuria status, aiming to identify the most appropriate disease stage for immunosuppressive intervention. Routine UK primary-care and linked secondary-care data were extracted from the Clinical Practice Research Datalink. Patients with a record of CKD were identified and grouped into type 2, type 1 and nondiabetes cohorts. Time-dependent, Cox proportional hazard models were used to determine the likelihood of hospitalized infection. We identified 97 839 patients with a record of CKD, of these 11 719 (12%) had type 2 diabetes. In these latter patients, the adjusted hazard ratios (aHR) were 1.00 (95% CI: 0.80-1.25), 1.00, 1.03 (95% CI: 0.92-1.15), 1.36 (95% CI: 0.20-1.54), 1.82 (95% CI: 1.54-2.15) and 2.41 (95% CI: 1.60-3.63) at eGFR stages G1, G2 (reference), G3a, G3b, G4 and G5, respectively; and 1.00, 1.45 (95% CI: 1.29-1.63) and 1.91 (95% CI: 1.67-2.20) at proteinuria stages A1 (reference), A2 and A3, respectively. All aHRs (except G1 and G3a) were significant, with similar patterns observed within the non-DM and overall cohorts. eGFR and degree of albuminuria were independent markers of hospitalized infection in both patients with and without diabetes. The same patterns of hazard ratios of eGFR and proteinuria were seen in CKD patients regardless of diabetes status, with the risk of each outcome increasing with a decreasing eGFR and increasing proteinuria. Infection risk increased significantly from eGFR stage G3b and proteinuria stage A2 in type 2 diabetes. Treating type 2 DM patients with CKD at eGFR stages G1-G3a with immunosuppressive therapy may therefore provide a favourable risk-benefit ratio (G1-G3a in type 2 diabetes; G1-G2 in nondiabetes and overall cohorts) although the degree of proteinuria needs to be considered.


A novel method to assess copy number variation in melanoma: Droplet digital PCR for precise quantitation of the RREB1 gene in formalin-fixed, paraffin-embedded melanocytic neoplasms, a proof-of-concept study.
Melanocytic neoplasms can be challenging to diagnose. One well-established diagnostic aid is the detection of copy number variation (CNV) in a few key genetic loci using conventional methods such as fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA). Droplet digital polymerase chain reaction (ddPCR) is a novel, cost-effective, rapid, and automated method to detect CNV. We perform the first investigation of ddPCR to assay Ras-responsive element-binding protein-1 (RREB1), the most common CNV in melanoma using formalin-fixed, paraffin-embedded (FFPE) melanocytic lesion samples; CMA data are used as the gold standard. Archival samples from 2013 to 2021 were analyzed, including 153 data points from 39 FFPE samples representing 34 patients. Benign, borderline, malignant, and metastatic melanocytic neoplasms were examined. ddPCR showed a sensitivity and specificity of 93.8% and 95.7% using one reference gene, and 87.5% and 100% using a different reference gene for RREB1 gain detection. Here we show that ddPCR can provide inexpensive, rapid, and robust data on the commonest copy number alteration in melanoma. Future development and validation could provide a useful ancillary tool in the diagnosis of challenging melanocytic lesions.


Two new species of the Clubionacorticalis-group from Yunnan Province, China (Araneae, Clubionidae).
The present paper describes two new Clubionacorticalis-group species collected from Xishuangbanna, Yunnan Province of China: Clubionasubmoralis sp. n. (♀♂) and Clubionapollicaris sp. n. (♀♂).


Sulfate and phosphate analysis in glycoproteins and other biologic compounds using ion chromatography. Application to glycoprotein hormones and sugar esters.
An ion chromatography procedure was devised for the simultaneous determination of phosphate and sulfate in the same sample. In order to eliminate interference from zwitterionic compounds (particularly amino acids and peptides) generated during hydrolysis of the phosphate- or sulfate-containing compounds a pretreatment step with a cation-exchange column was required. The detection of sulfate is approximately twice as sensitive as phosphate on a molar basis. The useful working range for sulfate was 200 pmole to 35 nmole with the ion chromatography employed; the range for phosphate was 400 pmole to 65 nmole. Linearity in this range was very satisfactory. Representative analyses are presented for hydrolyzates of several glycoprotein hormones and sugar sulfates and phosphate esters. Replicate analyses were +/- 3.0% or better. The glycoprotein hormone analyses for sulfate did not indicate whole integers per mole, suggesting mixtures of isohormones as has been found by others using chromatofocusing or isoelectric focussing and immunoassay.


Protective effect of Rumenic acid rich cow's milk against colitis is associated with the activation of Nrf2 pathway in a murine model.
Dietary supplementation with pure cis9, trans11 isomer of Conjugated Linoleic Acid -known as Rumenic Acid (RA)- improves cytoprotective defenses downstream through the activation of nuclear factor-E2-related factor-2(Nrf2). This capability, when Rumenic Acid is consumed in the form of foods, is still unknown. The ability of standard (St) or cow milk naturally-enriched in RA (En) to activate Nrf2 pathway and its impact on dextran sodium sulfate (DSS)-induced colitis was comparatively evaluated. Activity of Nrf2 pathway was investigated in colonic tissue of BALB/c mice, receiving 4-week supplement with skimmed milk (SK), St or St reinforced with pure RA (RSt) providing increasing RA dose (0, 124 or 404mg RA/kg-1 b.w, respectively). Next, the anti-oxidant/ anti-inflammatory effect produced by St or En treatment (383mg RA/kg-1 b.w.) was explored. Finally, macroscopic and histomorphologic features of colitis were evaluated in animals challenged with 5% (w/v) DSS, at the end of St or En treatment. Significant activation of Nrf2 pathway is associated with RSt and En intake (P<0.05), but not with SK or En treatment. En pre-treatment offers better protection, in comparison with St, against pro-oxidant, pro-inflammatory signs (P<0.01) and macroscopic signs triggered by DSS. It can be concluded that Nrf2 activation by higher RA amount contained in En is, at least in part, responsible for the improved protection associated with En intake against DSS-induced colitis.


Imaginative processes in children are not particularly imaginative.
The authors argue that children prefer fictions with imaginary worlds. But evidence from the developmental literature challenges this claim. Children's choices of stories and story events show that they often prefer realism. Further, work on the imagination's relation to counterfactual reasoning suggests that an attraction to unrealistic fiction would undermine the imagination's role in helping children understand reality.


Clinical inertia: viewpoints of general practitioners and diabetologists.
Large clinical studies have enabled best practice guidelines to be issued. Intended to serve practitioners in their daily practice, the guidelines are also excellent tools for assessing physician performance. It was therefore demonstrated that despite the observation of insufficient glycaemic control, physicians did not systematically increase drug treatments. As a result, they have been accused of clinical inertia! In this journal, we first try to reveal what is behind this concept and to differentiate true inertia from pseudo inertia. Secondly, we consider how general practitioners and diabetologists, through their respective positions, can develop a synergy that is able to fight against inertia but that can especially, improve the glycaemic control of our patients.


Relationship of Red Cell Distribution Width to Adverse Outcomes in Adults With Congenital Heart Disease (from the Boston Adult Congenital Heart Biobank).
Red cell distribution width (RDW), a measure of variability in red cell size, predicts adverse outcomes in acquired causes of heart failure. We examined the relation of RDW and outcomes in adults with congenital heart disease. We performed a prospective cohort study on 696 ambulatory patients ≥18years old enrolled in the Boston Adult Congenital Heart Disease Biobank between 2012 and 2016 (mean age 38.7 ± 13.5 years; 49.9% women). The combined outcome was all-cause mortality or nonelective cardiovascular hospitalization. Most patients had moderately or severely complex congenital heart disease (42.5% and 38.5%, respectively). Mean RDW was 14.0 ± 1.3%. RDW >15% was present in 81 patients (11.6%). After median 767days of follow-up, 115 patients sustained the primary combined outcome, including 31 who died. Higher RDW predicted both the combined outcome (hazard ratio [HR] for RDW >15% = 4.5, 95% confidence interval [CI] 3.0 to 6.6; HR per + 1SD RDW = 1.8, 95% CI 1.6 to 2.0, both p <0.0001) and death alone (HR for RDW >15% = 7.1, 95% CI 3.5 to 14.4; HR per + 1SD RDW = 1.8, 95% CI 1.6 to 2.0, both p <0.0001). RDW remained an independent predictor of the combined outcome after adjusting for age, cyanosis, congenital heart disease complexity, ventricular systolic function, New York Heart Association functional class, hemoglobin concentration, mean corpuscular volume, high-sensitivity C-reactive protein and estimated glomerular filtration rate (HR per + 1SD RDW = 1.5, 95% CI 1.2 to 1.9, p <0.0001). RDW also remained an independent predictor of mortality alone after adjustment for age plus each variable individually. In conclusion, elevated RDW is an independent predictor of all-cause mortality or nonelective cardiovascular hospitalization in adults with congenital heart disease. This simple clinical biomarker identifies increased risk for adverse events even among patients with preserved functional status.


Optic nerve sheath fenestration for an isolated optic nerve glioma.
The treatment modalities for neurofibromatosis type 1-associated optic gliomas include chemotherapy, radiation therapy, and surgical excision. The current recommendation is to consider treatment for an optic nerve glioma only if there is clear evidence of either ophthalmologic or radiographic progression with significant visual dysfunction. We report a case of a child with neurofibromatosis type 1 and an isolated optic nerve glioma with documented progression and visual loss in which clinical signs improved and visual deterioration stabilized after optic nerve sheath fenestration.


Pulmonary artery partition: new method for correction of interrupted aortic arch.
We have successfully corrected interrupted aortic arch with ventricular septal defect by employing deep hypothermia and circulatory arrest, a median sternotomy incision, and a pulmonary arteriotomy. This simplified technique has the advantage of an abbreviated period of cerebral ischemia, with a relatively simple partitioning of the pulmonary artery.


Myocardial uptake of radiotechnetium in two cases of ventricular aneurysm after infarction.
Two very similar cases of persistent positive myocardial scintigraphy with radiotechnetium are described and, in view of agreement of other medical, electrocardiographic, apexcardiographic and radiographic data, this can be ascribed to the presence of a parietal ventricular aneurysm after myocardial infarction.


Putative nociceptive modulatory neurons in the dorsolateral pontomesencephalic reticular formation.
The present study was undertaken to confirm the dorsolateral pontomesencephalic reticular formation (an area that includes the nucleus cuneiformis (NCF) and nucleus parabrachialis (NPB)) as a sensitive site for stimulation-produced antinociception and to investigate the possibility that there are cells in this region that show a change in activity that can be correlated with the occurrence of a nocifensive reflex (the tail-flick withdrawal response from noxious heat (TF)). Such cells have been previously demonstrated in the rostral ventromedial medulla (RVM). Extracellular single unit recording studies were made at sites from which it was possible to inhibit the TF with currents of 10 microA or less. Cellular response to 3 TF trials at 5 min intervals, and spontaneous activity over a 10 min period, were monitored for each unit. Of the cells encountered, 17% displayed an increase (on-cells) and 4% a decrease (off-cells) in activity that preceded the TF. The remaining cells were unaffected by the TF (neutral cells). On- and off-cells were found throughout the region from which TF suppression was observed but were most concentrated in the areas of the NCF and NPB. The presence of on- and off-cells in the NCF/NPB region as well as the RVM suggests that the input to RVM from NCF/NPB may be important in descending nociceptive modulation.


Prevalence of Escherichia coli O157 in lambs at slaughter in Rome, central Italy.
A study on the prevalence of the faecal carriage of Escherichia coli O157 in lambs was performed in the major slaughterhouse in Rome, central Italy, during 2002. A total of 643 animals, consisting of 378 weaned and 265 suckling lambs, were assayed for the presence of E. coli O157. Five O157-agglutinating E. coli strains were isolated (0.8%, 95% CI 0.3-1.9). Only one was positive to PCR specific for the eae gene and produced verocytotoxin VT2, with a VTEC O157 overall prevalence of 0.2% (95% CI 0.0-1.0), whereas one strain possessed the eae gene only. All the other isolates were negative for the presence of all the virulence genes considered. The animals were either from local farms or imported from Eastern Europe. The results suggest an age-specific difference since the microorganism was isolated only from 0.3% (95% CI 0.0-1.7) of weaned lambs, while all samples from suckling lambs tested negative. From this study, the overall risk of human exposure to pathogenic E. coli O157 from lamb meat consumption derived from the major slaughterhouse in Rome can be considered reasonably low, particularly when suckling lamb meat is considered.


Synthesis of highly substituted benzene ring systems through three-component coupling of enyne imines, Fischer carbene complexes, and electron-deficient alkynes.
Three-component coupling of Fischer carbene complexes, enyne aldehyde hydrazones, and electron-deficient alkynes leads to simple benzoate derivatives in a process involving the formation of an N-aminopyrrole derivative, Diels-Alder reaction, and nitrene extrusion. The products are readily converted into isoquinolones through reaction with primary amines. The reaction proceeds best with highly substituted and electron-rich pyrroles even though these are the sterically least favorable substrates, and this reactivity trend is supported by a computational study.


Radiosurgery for Glioblastoma.
Glioblastoma (GBM) is infiltrative neoplasm with limited treatment options and poor overall survival. Stereotactic radiosurgery (SRS) allows spatially precise and conformal delivery of high doses of radiation. Salvage SRS for locally recurrent GBM was shown to improve patient survival and have more favorable safety profile than repeated surgical resection. Boost SRS after fractionated radiation therapy is sometimes attempted; however, Radiation Therapy Oncology Group 93-05 randomized clinical trial did not demonstrate benefits of upfront SRS that was administered before fractionated radiation. Administration of bevacizumab with SRS is associated with improved survival and can allow SRS dose escalation.


Direct and indirect presynaptic control of dopamine release by excitatory amino acids.
Dopamine (DA) release from nerve terminals of the nigrostriatal DA neurons not only depends on the activity of nigral DA cells but also on presynaptic regulation. Glutamatergic neurons of cortical origin play a prominent role in these presynaptic regulations. The direct glutamatergic presynaptic control of DA release is mediated by N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA) receptors, located on DA nerve terminals. In addition, by acting on striatal target cells, these glutamatergic neurons contribute also to indirect regulations of DA release involving several transmitters such as GABA, acetylcholine and neuropeptides. Diffusible messengers such as nitric oxide (NO) or arachidonic acid (AA) which are particularly formed under the stimulation of NMDA receptors may also participate to the regulation of DA release. In the present study, it will be shown that the co-application of NMDA and carbachol synergistically increases the release of [3H]-DA and that this effect is reduced by mepacrine or 4-bromophenacylbromide (10(-7) M), two inhibitors of PLA2. Therefore endogenously released AA induced by the co-stimulation of NMDA and cholinergic receptors seems to be involved, at least partly, in the release of DA.


Laser interferometric measurements on the dynamic behaviour of the cupula in the fish lateral line.
The motion of the cupula in the supra-orbital lateral line canal of the ruff in response to sinusoidal water movements was measured in vivo by means of a novel laser interferometer microscope. The interferometer utilized the laser light scattered back from a small bead (phi approximately equal to 1 micron) which was positioned under visual control on a selected location inside the cupula. The displacement of the cupula was measured in the range of 0.3 to 300 nm. The stimulus-response relation is found to be linear in this range. The frequency response of the cupula measured at the top is identical to that measured at the base near the sensory hair bundles. From this result it is concluded that the cupula is sliding over the sensory epithelium during motion in the physiological displacement range. A hydrodynamical model of cupular motion which incorporates a frequency dependent boundary layer around the cupula is presented. The model accurately describes the experimental data.


Relationship between lactate accumulation, LDH activity, LDH isozyme and fibre type distribution in human skeletal muscle.
Lactate concentration, total LDH activity and muscle-specific LDH isozymes were determined in pools of the two main types of human skeletal muscle fibres. Analyses were made from biopsy specimens obtained after intense dynamic exercise lasting approximately 30 s. Lactate concentration, total LDH activity and muscle-specific LDH activity displayed higher average values for FT (fast twitch) fibres than for ST (slow twitch) fibres. In addition, positive correlations were found both between the individual percentage of FT fibres and muscle lactate concentration and between lactate concentration and total LDH activity and muscle-specific LDH activity respectively.


Emergence of carbapenem resistant Escherichia coli isolates producing blaNDM and blaOXA-48-like carried on IncA/C and IncL/M plasmids at two Iranian university hospitals.
The emergence of carbapenem resistance among Escherichia coli is a serious threat to public health. The objective of this study was to investigate resistance genes and clonality of carbapenem resistant E. coli in Iran. Between February 2015 and July 2016, a total of 32 non-duplicate E. coli isolates that were ertapenem resistant or intermediate (R/I-ETP) were collected from patient clinical or surveillance cultures (rectal swabs) at two university hospitals. Resistance genes were identified by PCR and sequencing. Conjugation experiments, PCR-based replicon typing, PFGE and multilocus sequence typing (MLST) were performed. PCR assays showed, among the 32 isolates, twenty-nine strains produced carbapenemase genes. The predominant carbapenemase was blaOXA-48 (82.8%), followed by blaNDM-1 (31%), blaNDM-7 (6.9%) and blaOXA-181 (3.4%). Seven of the blaNDM positive isolates co-harbored blaOXA-48 carbapenemases. The blaNDM and blaOXA-48 were found in IncA/C and IncL/M conjugative plasmids, respectively. The blaCTX-M-15, qnrA and intI1 genes were also present in most isolates. The PFGE revealed genetic diversity among the 28 E. coli isolates, which belonged to six minor PFGE clusters and 14 isolates were singletons. The 26 isolates were distributed into 18 STs, of which two were dominant (ST648 and ST167). We identified one blaNDM-1-positive ST131 E. coli isolates that harbor the blaCTX-M-15 and blaTEM genes. Horizontal transfer of IncA/C and IncL/M plasmids has likely facilitated the spread of the blaOXA-48 and blaNDM genes among E. coli. Their clonal diversity and the presence of faecal carriers in isolates suggest an endemic spread of OXA-48 and NDM. Therefore, it emphasizes the critical importance of monitoring and controlling the spread of carbapenem resistant E. coli.


Impact of Fluorescence in Situ Hybridization in the Detection of Cryptic Fusion Transcript PML/RARA and A Complex t(5;15;17) in a Case of Acute Promyelocytic Leukemia.
Genetic aspects of a 28 year-old female patient with typical morphological and clinical features of acute promyelocytic leukemia is presented. Pml/rara fusion transcript and a complex translocation involving chromosomes 5, 15 and 17 were detected by fluorescence in situ hybridization (FISH) technique which was applied as in adjunct to conventional cytogenetics. The patient deceased soon in spite of the immediate ATRA and cytostatic therapy.


Correction: Interactive Effects of Black-Tailed Prairie Dogs and Cattle on Shrub Encroachment in a Desert Grassland Ecosystem.
[This corrects the article DOI: 10.1371/journal.pone.0154748.].


The short-chain alcohol dehydrogenase superfamily: variations on a common theme.
Multiple alignment of members of the short-chain alcohol dehydrogenase (SCAD) superfamily, according to the conserved domains A-F, has revealed a number of important relationships. It can be shown that the 17 beta-hydroxysteroid dehydrogenase type 2 enzyme is more closely related to D-beta-hydroxybutyrate dehydrogenase than it is to 17 beta-hydroxysteroid dehydrogenase type 1. Carbonyl reductase, previously considered to be a member of the aldo-keto reductase superfamily, displayed high homology in the conserved domains and is clearly part of the SCAD superfamily despite the insertion of a large peptide between conserved domains. Alignment of the product of the Leishmania methotrexate resistance gene HMTX showed that an internal, highly conserved domain can be substituted by an unrelated sequence without loss of biological activity. Furthermore, comparisons of the chimeric trifunctional enzyme enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase/3-hydroxyacyl-CoA epimerase with other family members suggests that the region between the conserved B and C domains is the last to diverge between closely related enzymes and that the F domain appears to evolve with a different evolutionary clock to the rest of the protein. Finally, a highly conserved pattern of serine and threonine residues in the active site of SCAD enzymes indicates that these residues may play an important role in catalysis. These observations should facilitate alignment of future members of the SCAD superfamily.


The in vivo TRPV6 protein starts at a non-AUG triplet, decoded as methionine, upstream of canonical initiation at AUG.
TRPV6 channels function as epithelial Ca(2+) entry pathways in the epididymis, prostate, and placenta. However, the identity of the endogenous TRPV6 protein relies on predicted gene coding regions and is only known to a certain level of approximation. We show that in vivo the TRPV6 protein has an extended N terminus. Translation initiates at a non-AUG codon, at ACG, which is decoded by methionine and which is upstream of the annotated AUG, which is not used for initiation. The in vitro properties of channels formed by the extended full-length TRPV6 proteins and the so-far annotated and smaller TRPV6 are similar, but the extended N terminus increases trafficking to the plasma membrane and represents an additional scaffold for channel assembly. The increased translation of the smaller TRPV6 cDNA version may overestimate the in vivo situation where translation efficiency may represent an additional mechanism to tightly control the TRPV6-mediated Ca(2+) entry to prevent deleterious Ca(2+) overload.