MiR-338 controls BPA-triggered pancreatic islet insulin secretory dysfunction from compensation to decompensation by targeting Pdx-1.
Bisphenol A (BPA) can disrupt glucose homeostasis and impair pancreatic islet function; however, the mechanisms behind these effects are poorly understood. Male mice (4 wk old) were treated with BPA (50 or 500 μg/kg/d) for 8 wk. Whole-body glucose homeostasis, pancreatic islet morphology and function, and miR-338-mediated molecular signal transduction analyses were examined. We showed that BPA treatment led to a disruption of glucose tolerance and a compensatory increase of pancreatic islets insulin secretion and pancreatic and duodenal homeobox 1 (Pdx1) expression in mice. Inhibition of Pdx1 reduced glucose-stimulated insulin secretion and ATP production in the islets of BPA-exposed mice. Based on primary pancreatic islets, we also confirmed that miR-338 regulated Pdx1 and thus contributed to BPA-induced insulin secretory dysfunction from compensation to decompensation. Short-term BPA exposure downregulated miR-338 through activation of G-protein-coupled estrogen receptor 1 (Gpr30), whereas long-term BPA exposure upregulated miR-338 through suppression of glucagon-like peptide 1 receptor (Glp1r). Taken together, our results reveal a molecular mechanism, whereby BPA regulates Gpr30/Glp1r to mediate the expression of miR-338, which acts to control Pdx1-dependent insulin secretion. The Gpr30/Glp1r-miR-338-Pdx1 axis should be represented as a novel mechanism by which BPA induces insulin secretory dysfunction in pancreatic islets.-Wei, J., Ding, D., Wang, T., Liu, Q., Lin, Y. MiR-338 controls BPA-triggered pancreatic islet insulin secretory dysfunction from compensation to decompensation by targeting Pdx-1.


Endovascular management of visceral artery pseudoaneurysms: transcatheter coil embolization using the isolation technique.
To describe our experiences with treatment of visceral artery pseudoaneurysms (VAPA) by transcatheter coil embolization using an isolation technique and to propose indications for treating VAPA with this method. We treated 37 patients with VAPA endovascularly: There were 15 pancreaticoduodenal arcade, 10 hepatic, 5 renal, 3 splenic, and 1 each left gastric, gastroepiploic, adrenal, and superior mesenteric artery pseudoaneurysms. Preprocedure computed tomography (CT) and/or angiographic studies confirmed the presence of VAPA in all 37 patients. Using the isolation technique, we embolized vessels at sites distal and proximal to the pseudoaneurysm. Transcatheter coil embolization with the isolation technique was technically successful in 33 (89%) of 37 patients, and angiogram confirmed the complete disappearance of the VAPA in 32 patients. No major complications occurred during the procedures. In a patient with a pancreaticoduodenal arcade artery pseudoaneurysm, we were unable to control hemorrhage. In 30 of 32 patients who recovered after transcatheter coil embolization using the isolation technique, follow-up CT scan showed no flow in VAPA; they survived without rebleeding. Two of the 32 patients (6%) with confirmed complete disappearance of VAPA on angiogram and CT scan obtained the day after the procedure manifested rebleeding during follow-up. Transcatheter coil embolization using the isolation technique is an effective alternative treatment in patients with VAPA. In combination with coil embolization, the isolation technique is particularly useful in patients whose pseudoaneurysms present surgical difficulties.


Optimisation of culture medium and conditions for alpha-l-Arabinofuranosidase production by the extreme thermophilic eubacterium Rhodothermus marinus.
The culture medium for Rhodothermus marinus was optimised on a shake-flask scale by using statistical factorial designs for enhanced production of a highly thermostable alpha-L-arabinofuranosidase (AFase). The medium containing 3.6 g/l birch wood xylan and 8.2 g/l yeast extract yielded a maximum of 110 nkat/ml AFase activity together with 125 nkat/ml xylanase and 65 nkat/ml beta-xylosidase activity. In addition, low levels of beta-mannanase (30 nkat/ml), alpha-galactosidase (0.2 nkat/ml), beta-galactosidase (0.3 nkat/ml), endoglucanase (5 nkat/ml) and beta-glucosidase (30 nkat/ml) were detected in the culture filtrate. Among the various carbon sources tested, birchwood xylan was most effective for the formation of AFase and xylanase activities, followed by oat spelt and beechwood xylans, and xylan-rich lignocelluoses (e.g., starch-free sugar beet pulp and wheat bran). Constitutive levels of enzyme activities were detected when the bacterium was grown on other polysaccharides and low-molecular-weight carbohydrates. A fermentation in a 5-l fermenter (3-l working volume) using the optimised medium yielded 60 nkat/ml AFase associated with 65 nkat/ml xylanase and 35 nkat/ml beta-xylosidase activities. The crude AFase displayed optimal activity between pH 5.5 and 7 and at 85 degrees C. It had half-lives of 8.3 h at 85 degrees C and 17 min at 90 degrees C. It showed high stability between pH 5 and 9 (24 h at 65 degrees C). The combined use of AFase-rich xylanase and mannanase from R. marinus in the prebleaching of softwood kraft pulp gave a brightness increase of 1.8% ISO. To our knowledge, this is the first report on the production of a high AFase activity by an extreme thermophilic bacterium and this enzyme is the most thermostable AFase reported so far.


Effect of L-type calcium channel blockers on activity of newly formed synapses in mice.
Verapamil (5 microM), nifedipine (10 microM), and ryanodine (10 microM) potentiated rhythmic activity of newly formed synapses, while apamin produced no effect on this potentiation. Ryanodine (1 microM) suppressed synaptic activity, and this effect can be prevented with nifedipine. It was hypothesized that in newly formed synapses Ca2+ entry through L-type channels triggers the release of stored Ca2+, which inhibits secretion of the neurotransmitter.


Estimation of a self-consistent set of radiobiological parameters from hypofractionated versus standard radiation therapy of prostate cancer.
To determine a self-consistent set of radiobiological parameters in prostate cancer. A method to estimate intrinsic radiosensitivity (α), fractionation sensitivity (α/β), repopulation doubling time, number of clonogens, and kick-off time for accelerated repopulation of prostate cancer has been developed. Based on the generalized linear-quadratic model and without assuming the isoeffective hypothesis, the potential applications of the method were investigated using the clinical outcome of biochemical relapse-free survival recently reviewed in the literature. The strengths and limitations of the method, regarding the fitted parameters and 95% confidence intervals (CIs), are also discussed. Our best estimate of α/β is 2.96 Gy (95% CI 2.41-3.53 Gy). The corresponding α value is 0.16 Gy(-1) (95% CI 0.14-0.18 Gy(-1)), which is compatible with a realistic number of clonogens: 6.5 × 10(6) (95% CI 1.5 × 10(6)-2.1 × 10(7)). The estimated cell doubling time is 5.1 days (95% CI 4.2-7.2 days), very low if compared with that reported in the literature. This corresponds to the dose required to offset the repopulation occurring in 1 day of 0.52 Gy/d (95% CI 0.32-0.68 Gy/d). However, a long kick-off time of 31 days (95% CI 22-41 days) from the start of radiation therapy was found. The proposed analytic/graphic method has allowed the fitting of clinical data, providing a self-consistent set of radiobiological parameters for prostate cancer. With our analysis we confirm a low value for α/β with a correspondingly high value of intrinsic radiosensitivity, a realistic average number of clonogens, a long kick-off time for accelerated repopulation, and a surprisingly fast repopulation that suggests the involvement of subpopulations of specifically tumorigenic stem cells during continuing radiation therapy.


Signaling Pathway in Cerebral Vasospasm After Subarachnoid Hemorrhage: News Update.
Subarachnoid hemorrhage (SAH) caused by ruptured intracranial aneurysms is a serious threat to human health and life. Although advances in surgical and anesthetic techniques have improved the prognosis of patients with aneurysms, the rate of death and disability caused by SAH remains high, predominantly due to cerebral vasospasm (CVS) after SAH and early brain damage. In particular, CVS is a common complication after SAH. However, its pathogenesis has not yet been fully elucidated, and clinically effective prevention and treatment measures are still lacking. Spasm of blood vessels can decrease cerebral blood flow, leading to ischemia and hypoxia in brain tissues and ultimately severe neurological dysfunction. Currently, there is no comprehensive theory that can fully explain the mechanisms underlying SAH-caused CVS. However, studies on signal transduction, apoptosis, and glial cell-mediated mechanisms in recent years have shed new light on the treatment of CVS.


Multicentre study of the prognostic impact of preoperative bodyweight on long-term prognosis of hepatocellular carcinoma.
Whether preoperative bodyweight is associated with long-term prognosis in patients after liver resection for hepatocellular carcinoma (HCC) is controversial. This study aimed to investigate the relationship of patient weight with long-term recurrence and overall survival (OS) after curative liver resection for HCC. Data for patients with HCC who underwent curative liver resection between 2000 and 2015 in five centres in China were analysed retrospectively in three groups according to their preoperative BMI: underweight (BMI 18·4 kg/m2 or less), normal weight (BMI 18·5-24·9 kg/m2 ) and overweight (BMI 25·0 kg/m2 or above). Patients' baseline characteristics, operative variables and long-term survival outcomes were compared. Univariable and multivariable Cox regression analyses were performed to identify risk factors for OS and recurrence-free survival (RFS) after resection. Of 1524 patients, 107 (7·0 per cent) were underweight, 891 (58·5 per cent) were of normal weight and 526 (34·5 per cent) were overweight. Univariable analyses showed that underweight and overweight patients had poorer OS (both P < 0·001) and RFS (both P < 0·001) than patients of normal weight. Multivariable Cox regression analysis also identified both underweight and overweight to be independent risk factors for OS (hazard ratio (HR) 1·22, 95 per cent c.i. 1·19 to 1·56, P = 0·019; and HR 1·57, 1·36 to 1·81, P < 0·001, respectively) and RFS (HR 1·28, 1·16 to 1·53, P = 0·028; and HR 1·34, 1·17 to 1·54, P < 0·001). Underweight and overweight patients appear to have a worse prognosis than those of normal weight following liver resection for HCC.


HDL lipids in close relatives of coronary heart disease patients. Environmental and genetic influences.
Female first-degree relatives of CHD patients differed, after the age of forty, from the normal control population by their low HDL cholesterol. Between the ages of 20 and 40 years a slight but significant increase in HDL triglycerides was observed. Except for hormonal contraception which induces significant lowering of HDL cholesterol in the first degree relatives, the observed differences in HDL lipids did not seem related to environmental factors but rather to be genetically determined. In contrast, the low HDL cholesterol observed in the wives of the CHD patients appeared to be related to differences in alcohol intake.


Variability in the contents of pork meat nutrients and how it may affect food composition databases.
Pork meat is generally recognised as a food with relevant nutritional properties because of its content in high biological value proteins, group B vitamins, minerals especially heme iron, trace elements and other bioactive compounds. But pork meat also contributes to the intake of fat, saturated fatty acids, cholesterol, and other substances that, in inappropriate amounts, may result in negative physiologically effects. However, there are relevant factors affecting the content of many of these substances and somehow such variability should be taken into consideration. So, genetics, age and even type of muscle have a relevant influence on the amount of fat and the contents in heme iron. Also the composition in fatty acids of triacylglycerols is very sensitive to the contents of cereals in the feed; for instance, polyunsaturated fatty acids may range from 10% to 22% in pork meat. The content of other nutrients, like vitamins E and A, are also depending on the type of feed. Some bioactive substances like coenzyme Q10, taurine, glutamine, creatine, creatinine, carnosine and anserine show a large dependence on the type of muscle. This manuscript describes the main factors affecting the composition of pork meat nutrients and how these changes may affect the general food composition databases.


Floating thrombus originating from an almost normal thoracic aorta.
We present a case of floating thrombus originating from an almost normal thoracic aorta in a 54-year-old man who presented with acute arterial occlusion of his left leg. Transesophageal echocardiography (TEE), computed tomography, and magnetic resonance imaging showed two masses in an almost normal aorta after embolectomy for the acute arterial occlusion. Although the embolus was thrombus histologically, malignant tumors could not be ruled out. The masses did not decrease in size after 7 days of anticoagulant therapy, so they were extirpated under cardiopulmonary bypass (CPB) and TEE guidance. Frozen section examination during CPB indicated that there was no evidence of malignancy in the removed mass. TEE played an important role in the diagnosis and surgery of this condition, and it was useful when deciding on a surgical strategy. Because the treatment strategy for this disease remains controversial, further studies are needed.


Diagnostic and therapeutic applications of bentiromide screening test for exocrine pancreatic insufficiency in patients with cystic fibrosis. Comparison with other tests of exocrine pancreatic disease.
The bentiromide test for exocrine pancreatic function was carried out in normal volunteers, patients with cystic fibrosis (CF) without clinical evidence of pancreatic dysfunction, and CF patients with clinically significant exocrine pancreatic insufficiency. The test was performed with and without the concomitant administration of a Lundh test meal. p-Aminobenzoic acid was given on a separate occasion to eliminate false positives due to factors unrelated to pancreatic disease. Correct classification of 25 CF patients with pancreatic insufficiency and 9 CF patients without clinical pancreatic dysfunction was possible by interpreting the results of the above three tests. Isoamylase determinations would have misclassified 20% of the CF patients with pancreatic insufficiency, but were able to detect the CF patients without clinical pancreatic dysfunction on the basis of an elevated pancreatic amylase isoenzyme. The bentiromide test results were normal in CF patients without clinical pancreatic dysfunction despite previous findings of decreased bicarbonate secretion in this group. However, the bentiromide test did appear to be useful in the evaluation of therapeutic intervention with exogenous pancreatic enzymes and other adjunctive therapy.


Using twitter to investigate responses to street reallocation during COVID-19: Findings from the U.S. and Canada.
The COVID-19 pandemic has challenged and encouraged local governments to reallocate street space. The chief purpose of new regimes of street management is to expand spaces for walking and bicycling, and to ease business interactions such as curbside pickup and dining while maintaining social distancing guidelines. We investigated how North Americans on Twitter viewed alternative uses and forms of street reallocation, specifically during the early months of the pandemic from April 1, 2020 to July 1, 2020. Relying on a crowdsourced dataset of government actions (Combs and Pardo 2021), we identified five areas of policy initiative that were broadly representative of government actions: cycling, walking, driving, business, and curbside. First, we identified a corpus of 292,108 geolocated tweets from the U.S. and Canada. Next, we used word vectors, built on this Twitter corpus, to generate similarity scores across the five areas of policy initiative for each tweet. Finally, we selected the top tweets that closely matched ideas contained in the areas of policy initiative, thus creating a finer corpus of 1,537 tweets. Using the five categories as guideposts, we conducted an inductive content analysis to understand opinions expressed on Twitter. Our analysis suggests that renewed use of the curb has opened up possibilities for reimaging this space. Particularly, business uses of the curb for dining and pick up zones have expanded widely, and there is more use of sidewalks; yet both spaces have limited capacity. Planners need to think of expanding these assets while reducing cost burdens for their alternative uses.


Colicin K acts by forming voltage-dependent channels in phospholipid bilayer membranes.
The bactericidal action of colicins K, E1, Ia, and other functionally related colicins involves disruption of active transport and leakage of ions from the cell. We show that a single colicin K molecule can form a voltage-dependent, relatively nonselective, ion-permeable channel of a few picosiemens conductance in a planar phospholipid bilayer membrane. In a membrane containing many of these channels, the ratio of the number of conducting to nonconducting channels changes e-fold per 3.7 mV. We suggest that the physiological effects of colicin K and functionally related colicins result from their ability to form ion-permeable channels in the bacterial plasma membrane.


Thinking big about global health.
The Gates Foundation is funding high-risk research into new ways to improve health in developing countries, but ensuring that the fruits of these studies reach the people who need them most may be the biggest challenge of all.


Acute versus primary care: the health care decision making process for individuals with severe mental illness.
This study's purpose was to determine factors influencing treatment choices of individuals with severe mental illness (SMI). The sample was drawn from admissions to residential crisis programs in San Francisco. Inclusion criteria were an Axis I and Axis III disorder. This qualitative study utilized grounded theory method. Interviews and field notes were coded for recurring themes. Descriptive data were also collected. Participants revealed that the most important influences on treatment decisions were immediate need for care, the belief that their subacute complaints will not be taken seriously by providers, positive reinforcement for emergency service use, and enabling factors such as insurance coverage. Other remarkable findings included: numerous reports of substance induced medical crises, lack of support from family, and unawareness of client's medical conditions in psychiatric facilities. Health care seeking behaviors are learned and learning that will promote the use of outpatient services in SMI must include positive experiences in the delivery of care in the primary care setting. Participants were knowledgeable regarding their illnesses and able to articulate symptoms of illness well. Failure to communicate symptoms appeared to reflect the participant's perception of a lack of response to their reports.


Blue Oleds: High-Efficiency Blue Organic Light-Emitting Diodes Based on Thermally Activated Delayed Fluorescence from Phenoxaphosphine and Phenoxathiin Derivatives (Adv. Mater. 23/2016).
High-performance blue thermally activated delayed fluorescence (TADF) emitters containing a phenoxaphosphine oxide or phenoxathiin dioxide acceptor unit coupled with a dimethylacridan donor unit are developed by T. Yasuda and co-workers, as desribed on page 4626. These emitters can allow efficient up-conversion of triplet excitons into singlet excitons, leading to both photoluminescence and internal electroluminescence quantum efficiencies of up to nearly 100%.


3D-printed photoluminescent bioactive scaffolds with biomimetic elastomeric surface for enhanced bone tissue engineering.
Three dimensional (3D) printed porous bioactive glass nanoparticles scaffolds (BGNS) exhibit excellent bone integration and bone regeneration capacities, but the early rapid ion release, brittle mechanical properties and lack of functions limit their application. In this work, photoluminescent biomimetic elastomeric BGNS were fabricated by directly assembling poly(citrate-siloxane) (PCS) on the surface of BGNS (BGNS@PCS). The morphologies, mechanical behavior, photoluminescent ability, ions release, biomineralization activity, biocompatibility and osteogenic properties of BGNS@PCS were evaluated in detail. The results indicated that BGNS@PCS presented superior elasticity and outstanding compressive strength compared with BGNS. The controlled release of the Si and Ca ions in BGNS@PCS was achieved and enhanced biomineralization ability was also observed. In addition, the modified scaffolds have the photoluminescent ability which has the potential application for bioimaging. BGNS@PCS could significantly promote cells attachment, proliferation and enhance osteogenic differentiation of mouse bone marrow stromal cells (BMSCs). Therefore, the BGNS@PCS with the multifunctional properties including elastomeric surface, enhanced photoluminescent, controlled ions release and biomineralization, reinforced osteogenic activity, would be a promising candidate for bone tissue regeneration. This study probably provides a novel strategy to design biomimetic elastomeric bioceramic scaffolds for hard tissue regeneration.


Selective modulation of endogenous nitric oxide formation in ischemia/reperfusion injury in isolated rat hearts--effects on regional myocardial flow and enzyme release.
The role of nitric oxide (NO) in ischemia/reperfusion injury is controversial. We tested the role of inducible NOS (iNOS) in the ischemia/reperfusion injury in isolated rat hearts using the selective iNOS inhibitor S-methylisothiourea sulfate (SMT) and the non-selective NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). After 15 min of stabilization in Langendorff mode, hearts were perfused either with normal Krebs-Henseleit buffer, buffer containing 100 microM L-NAME, 0.5 microM SMT or 50 microM SMT for 5 min and were subjected to 25 min of ischemia followed by 30 min of reperfusion. Left ventricular developed pressure (LVDP) and total coronary flow (CF) were recorded continuously. After ischemia/reperfusion, a marked expression of iNOS protein was demonstrated by Western blotting, while virtually no iNOS protein was present in hearts without ischemia/reperfusion. Regional myocardial blood flow (RMBF) was measured with colored microspheres. Coronary vasoactive concentration of L-NAME and SMT depressed myocardial function as shown by decreased LVDP, dP/dt(max) and coronary.ow before ischemia. After ischemia the recovery of the total CF was impaired in L-NAME and 50 microM SMT pretreated hearts which was related to homogenous RMBF decrease in the right and left ventricle compared to that in control group. Low concentration SMT (0.5 microM) showed no coronary vasoactive effects before ischemia and attenuated ischemia/reperfusion injury indicated by lower ischemic contracture at 25 min of ischemia and reduced CK and LDH release during reperfusion. Thus, NOS inhibition did not affect blood flow distribution in rat hearts either in the pre-ischemic or reperfusion period. Selective iNOS inhibition reduced ischemic injury by reducing ischemic contracture and CK as well as LDH release during reperfusion.


Structural study of a lead-barium-aluminum phosphate glass by MAS-NMR spectroscopy.
The 31P- and 27Al-MAS-NMR spectra of a lead-barium-aluminum phosphate glass were measured and analyzed, and the short range structure of the glass are discussed. The 31P-MAS-NMR spectrum of the glass studied has a single isotropic peak at -4.76 ppm, indicating that orthophosphate species are the dominant P-sites in the glass. The 27Al-MAS-NMR spectrum of the glass shows that the aluminum ions present in the glass are in 4-, 5-, and 6- fold coordination with oxygen, and that the Al(OP)4 is the dominant moiety for the glass, suggesting the formation of orthophosphate species in the glass.


Popliteal Angiosarcoma after Bypass with Autologous Saphenous Vein.
Angiosarcoma (AS) is a type of malignancy within sarcomas affecting soft tissue and bone. It presents a very heterogeneous distribution in the human body, and it can appear in multiple locations, from breast to liver or skin. The incidence of this type of tumor is low; however, it is aggressive and requires an early diagnosis to initiate the treatment as soon as possible. In the present article, we report the case of a male patient who was diagnosed with epithelioid AS of popliteal artery after an aneurysm popliteal surgery, as well as its treatment and evolution. This kind of tumors has controversial treatment and poor survival rates in the early years.


Simultaneous flow cytometric measurement of Streptococcus suis phagocytosis by polymorphonuclear and mononuclear blood leukocytes.
A simple flow cytometric method was used to study simultaneously the phagocytosis of Streptococcus suis serotype 2 by polymorphonuclear and mononuclear blood leukocytes from swine and humans. Using this method with a bacteria-to-leukocytes ratio of 10:1 and after 60 min of incubation, 80.2 +/- 2.8% of swine granulocytes and 77.0 +/- 2.8% of swine monocytes were shown to contain FITC-labelled S. suis serotype 2 strain 735. Using the same strain, FITC-labelled bacteria were found in 95.5 +/- 3.2% of human granulocytes and in 92.8 +/- 3.6% of human monocytes. The phagocytosis rates of avirulent and virulent strains of S. suis were not significantly different.


Equine neutrophil myeloperoxidase in plasma: design of a radio-immunoassay and first results in septic pathologies.
The strangulated intestinal pathologies of horses are accompanied by a local activation of the neutrophils, that can be revealed by measuring the tissular enzymatic activity of the granulocytic enzyme myeloperoxidase (MPO). To estimate the possible spreading of this neutrophil activation to the systemic circulation, we designed a radioimmunoassay (RIA) for equine neutrophil myeloperoxidase (MPO) (EC 22.214.171.124) using a specific rabbit antiserum. MPO was labeled with 1 mCi 125I by a technique of self-labeling in the presence of 10(-4) M hydrogen peroxide. The RIA was performed by incubation of 100 microl diluted antiserum, 100 microl labeled MPO (+/-30,000 cpm) and 100 microl of the reference molecule (unlabeled MPO) solution or the unknown sample, at room temperature for 18 h. The antibody-antigen complexes were isolated by double antibody precipitation. The sensitivity of the RIA was 2 ng/ml. The RIA showed good precision and accuracy with intra- and inter-assay coefficients of variation 6% and 8%, respectively, for MPO concentrations ranging from 2 ng/ml to 60 ng/ml. The best sampling technique for MPO measurement in plasma was to collect blood into EDTA, which allowed us to get a plasmatic value stable with time. The mean MPO value in normal horses was 69.5 +/- 19.4 ng/ml in EDTA anticoagulated plasma (n = 48). The stress of transport and anaesthesia did not modify the mean plasmatic value of MPO. No significant increase of plasma MPO was observed in 17 horses submitted to surgery for pathologies without systemic impact. But, in 25 horses with obstructive intestinal pathologies, persistent abnormal MPO concentrations were measured (until 740 ng/ml).


Syringomyelia secondary to tonsillar herniation caused by posterior fossa tumors.
A number of patients diagnosed as having syringomyelia secondary to tonsillar herniation caused by posterior fossa tumors has recently been described, although the backgrounds of the affected patients were not studied. In order to determine the possible causative contribution of the tonsillar herniation, the present cooperative study was carried out. A retrospective study was performed by five cooperating institutes. Magnetic resonance images (MRIs) of patients with posterior fossa tumors were reevaluated with particular attention to the existence of tonsillar herniation and syringomyelia. The total number of patients with posterior fossa tumors whose MRIs were reinvestigated was 164. In 24 out of the 164 patients, tonsillar herniation was apparent in the sagittal plane of the MRI. Syringomyelia was observed in five of the 24 cases with tonsillar herniation being a consistent associated finding. None of the individuals demonstrated any sensory disturbance directly corresponding to the syrinx formation. All but one of the five patients underwent surgical removal of the tumor, but no one required surgical treatment for the syrinx itself. Disappearance or shrinkage of the syrinx could be confirmed by postoperative MRIs in three of them. A simple mechanism of blockage of cerebrospinal fluid flow at the foramen magnum may play an important role in syrinx formation, as evidenced by the unexpectedly high incidence of cervical syrinx along with tonsillar herniation caused by posterior fossa tumors shown in the present study.


Labeling of proteins and oligopeptides with luminescent lanthanide(III) chelates.
Synthesis of a building block that allows introduction of photoluminescent europium(III) and samarium(III) chelates to synthetic oligopeptides on solid phase using standard Fmoc chemistry is described. Upon completion of the oligopeptide synthesis, these conjugates were converted to the corresponding lanthanide(III) chelates by treatment with appropriate lanthanide(III) salt. Also synthesis of a new terpyridine-based europium(III) chelate designed for solution phase protein labeling is demonstrated.


Mechanism of action of methylmercury on in vivo striatal dopamine release. Possible involvement of dopamine transporter.
Methylmercury (MeHg) produces significant increases in the spontaneous output of dopamine (DA) from rat striatal tissue. The mechanism through MeHg produces such increase in the extracellular DA levels could be due to increased DA release or decreased DA uptake into DA terminals. One of the aims of this study was to investigate the role of DA transporter (DAT) in the MeHg-induced DA release. Coinfusion of 400 microM MeHg and nomifensine (50 microM) or amphetamine (50 microM) produced increases in the release of DA similar to those produced by nomifensine and amphetamine alone. In the same way, MeHg-induced DA release was not attenuated under Ca(2+)-free conditions or after pretreatment with reserpine (10 mg/kg i.p.) or tetrodotoxin (TTX), suggesting that the DA release was independent of calcium and vesicular stores, as well as it was not affected by the blockade of voltage sensitive sodium channels. Thus, to investigate whether depolarization of dopaminergic terminal was able to affect MeHg-induced DA release, we infused 75 mM KCl through the dialysis membrane. Our results clearly showed a decrease induced by MeHg in the KCl-evoked DA release. Taken together, these results suggest that MeHg induces release of DA via transporter-dependent, calcium- and vesicular-independent mechanism and it decreases the KCl-evoked DA release.


Determination of cocaine in human hair by gas chromatography/mass spectrometry.
A qualitative method for the determination of cocaine alone without its metabolites in human hair by gas chromatography/mass spectrometry (GC/MS) was developed. The assay used helium as carrier gas, a 30-m bonded phase fused silica OV-1 capillary column, and solid injection at 290 degrees C evaporator temperature. The cocaine concentrations in hair were determined also by radioimmunoassay (RIA). The values obtained are the sum of cocaine and its metabolites. Both GC/MS and RIA meet the requirements for the determination of drug abuse by two different methods in forensic science.


Degradation of oxcarbazepine by UV-activated persulfate oxidation: kinetics, mechanisms, and pathways.
The degradation kinetics and mechanism of the antiepileptic drug oxcarbazepine (OXC) by UV-activated persulfate oxidation were investigated in this study. Results showed that UV/persulfate (UV/PS) process appeared to be more effective in degrading OXC than UV or PS alone. The OXC degradation exhibited a pseudo-first order kinetics pattern and the degradation rate constants (k obs) were affected by initial OXC concentration, PS dosage, initial pH, and humic acid concentration to different degrees. It was found that low initial OXC concentration, high persulfate dosage, and initial pH enhanced the OXC degradation. Additionally, the presence of humic acid in the solution could greatly inhibit the degradation of OXC. Moreover, hydroxyl radical (OH•) and sulfate radical (SO4 (-)••) were identified to be responsible for OXC degradation and SO4 (-)• made the predominant contribution in this study. Finally, major intermediate products were identified and a preliminary degradation pathway was proposed. Results demonstrated that UV/PS system is a potential technology to control the water pollution caused by emerging contaminants such as OXC.


Ameloblastoma: 25 Year Experience at a Single Institution.
Ameloblastoma is a rare, locally aggressive odontogenic neoplasm, accounting for fewer than 1 % of head and neck tumors. Recent literature suggests that the initial surgical approach and histologic growth patterns are the most important prognostic determinants in ameloblastoma. The aim of this study was to compare the clinical presentation, management, and outcomes of patients with ameloblastoma with data reported in the literature; the study spanned 2 decades at a single institution. The institution's database was searched for all patients with pathologically confirmed ameloblastoma, diagnosed between 1990 and 2015. The data collected included sex, age, clinical and imaging findings, management, histologic pattern, clearance of surgical margins, length of follow-up, time to recurrence, and disease-related mortality. The potential risk factors of recurrence were evaluated using log-rank test, proportional hazard model, and Fisher exact test. Review of the database yielded 54 patients with pathologically confirmed ameloblastoma and follow-up. Recurrence was noted in 13 (24 %) patients. Surgical approach was associated with the risk of recurrence (6.1 % following radical resection vs. 52 % following limited surgery, p = 0.002). There were trends toward higher recurrence rate in the group with pathologically documented positive margins (p = 0.054) and in follicular ameloblastoma (p = 0.35). Transformation into ameloblastic carcinoma was identified in two patients. There was no disease-related mortality. Our study confirms the recent data regarding the importance of radical surgical resection in management of ameloblastoma. Surgical approach appears to be the strongest predictor of tumor clearance.


Multi-residue analytical methods using LC-tandem MS for the determination of pharmaceuticals in environmental and wastewater samples: a review.
Multi-residue analytical methodologies are becoming the preferred and required tools against single group analysis, as they provide wider knowledge about the occurrence of pharmaceuticals in the environment necessary for further study of their removal, partition and ultimate fate. However, simultaneous analysis of compounds from different groups with quite different physico-chemical characteristics requires a compromise in the selection of experimental conditions, which in some cases are not the best conditions for all the analytes studied. In this article, an overview of analytical methodologies focusing on the simultaneous determination of acidic, neutral and basic compounds belonging to different therapeutical classes is presented. The state-of-the-art of LC-MS/MS for multi-class analysis is reviewed, highlighting the specific requirements for such analysis.


Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells.
Glucose and the peptide growth factors insulin, IGF-I and IGF-II strongly regulate beta cell mass. Furthermore, beta cell expression of IGF-I receptor (Igf1r) and insulin receptor (Insr) is mandatory for several steps of insulin secretion. We hypothesised that glucose concentration might regulate expression of Igf1r, Insr and insulin receptor-related receptor (Insrr) in islets and beta cells. Moreover, since the ratio of ATP:ADP is the most important intracellular mechanism involved in insulin secretion, and since depletion of ATP leads to AMP accumulation, we evaluated the role of AMP-activated protein kinase (AMPK) in glucose-dependent receptor regulation. In rat islets, high glucose exposure (25 mmol/l) increased gene expression of Igf1r, Insr and Insrr but also of the metabolic glycolysis gene liver-type pyruvate kinase (Pklr) compared with intermediate (6.2 mmol/l) or low glucose concentration (1.6 mmol/l) after 24 h. In rat INS-1E beta cells, only Pklr expression was suppressed by low glucose as in islets, while Insr and Insrr were suppressed by high and increased by low glucose levels. Igf1r expression was suppressed by both high- and low- glucose concentration. Activation of AMPK by 5-amino-imidazolecarboxamide riboside (AICAR, 0.5 mmol/l) suppressed Pklr expression, but strongly stimulated gene expression of Igf1r, Insr and Insrr. Protein expression of IR and IGF-IR reflected glucose and AICAR-regulated mRNA expression of both receptors in INS-1E cells. We conclude that glucose directly interacts with islet and beta cell expression of growth factor receptors that are mandatory for both beta cell growth and insulin secretion. Stimulation of Igf1r and Insr gene expression by the AMPK-activator AICAR might indicate involvement of AMPK in the regulation of Igf1r, Insr and Insrr expression in beta cells.


Development and Validation of a Nomogram Model Affecting the ACT Targeting Rate During Radiofrequency Ablation of Atrial Fibrillation in China.
A nomogram model affecting the activated clotting time (ACT) targeting rate during radiofrequency ablation of atrial fibrillation (RFCA) in China. The aim of this study is to develop and validate a nomogram model for predicting the activated clotting time targeting rate after the initial bolus heparin dosages during the radiofrequency catheter ablation of atrial fibrillation in China. A retrospective observational study was conducted on the data of 465 patients with atrial fibrillation who underwent radiofrequency catheter ablation (RFCA) from October 2019 to June 2022. All patients were randomized into a training cohort (70%; n = 325) and a validation cohort (30%; n = 140). Independent risk factors were identified using univariate and multifactorial logistic regression analysis. The predictive nomogram model was established using R software. The nomogram was developed and evaluated based on differentiation, calibration, and clinical efficacy using concordance statistic (C-statistic), calibration plots, and decision curve analysis (DCA), respectively. The nomogram was established using three variables, including sex (OR 1.01, 95% CI 0.29-1.76, P = 0.007), heparin dose (OR 0.04; 95%CI 0.02-0.05, P < 0.001), and the baseline ACT (OR 0.03; 95%CI 0.02-0.04, P < 0.001). The C-statistic of the nomogram was 0.736 (95%CI 0.675-0.732) in the training cohort and 0.700 (95%CI 0.622-0.721) in the validation cohort. The calibration plots showed good agreement between the predictions and observations in the training and validation cohorts. The clinical decision curve also proves that the map is useful in clinical settings. The nomogram model has good discrimination and accuracy, which can screen attainment groups intuitively and individually, and has a certain predictive value for the probability of ACT reaching the target after the adequate dosage of initial heparin in Chinese patients with atrial fibrillation.


Induced metal redistribution and bioavailability enhancement in contaminated river sediment during in situ biogeochemical remediation.
In situ sediment remediation using Ca(NO3)2 or CaO2 for odor mitigation and acid volatile sulfide (AVS) and organic pollutant (such as TPH and PAHs) removal was reported in many studies and fieldwork. Yet, the associated effects on metal mobilization and potential distortion in bioavailability were not well documented. In this study, contaminated river sediment was treated by Ca(NO3)2 and CaO2 in bench studies. Through the investigation of AVS removal, organic matter removal, the changes in sediment oxidation-reduction potential (ORP), microbial activity, and other indigenous parameters, the effects on metal bioavailability, bioaccessibility, and fraction redistribution in sediment were evaluated. The major mechanisms for sediment treated by Ca(NO3)2 and CaO2 are biostimulation with indigenous denitrifying bacteria and chemical oxidation, respectively. After applying Ca(NO3)2 and CaO2, the decreases of metal concentrations in the treated sediment were insignificant within a 35-day incubation period. However, the [SEMtot-AVS]/f OC increased near to the effective boundary of toxicity (100 μmol g(-1) organic carbon (OC)), indicating that both bioavailability and bioaccessibility of metals (Cu, Zn, and Ni) to benthic organisms are enhanced after remediation. Metals were found redistributed from relatively stable fractions (oxidizable and residual fractions) to weakly bound fractions (exchangeable and reducible fractions), and the results are in line with the enhanced metal bioavailability. Compared with Ca(NO3)2, CaO2 led to higher enhancement in metal bioavailability and bioaccessibility, and more significant metal redistribution, probably due to its stronger chemical reactive capacity to AVS and sediment organic matter. The reactions in CaO2-treated sediment would probably shift from physicochemical to biochemical heterotrophic oxidation for sediment organic matter degradation. Therefore, further investigation on the long-term metal redistribution and associated mobility as well as bioavailability is recommended.


Osteogenic stimulation of osteoprogenitors by putamen ovi peptides and hyaluronic acid.
Eggshell peptides (EP) majorly contribute to rapid bone building in chicks, wherefore this paper investigated their potential for stimulating osteogenesis in vitro. In this study, the effects of EP, also called putamen ovi peptides and a combination of hyaluronic acid with EP in cell culture medium were tested towards proliferation, differentiation, gene expression and mineralization of bovine osteoprogenitors and primary human osteoblasts. The influence of EP at concentrations of 0.005 g/L, 0.5 g/L and 0.5 g/L with 0.25% hyaluronic acid was analyzed using immunocytochemical staining of bone-specific matrix proteins, namely collagen type I, osteonectin, osteopontin and osteocalcin, to prove osteoblastic differentiation. Additionally, Richardson-staining was performed. All tests revealed a superior osteoblastic differentiation with EP at 0.5 g/L after 5 days of cultivation. Hyaluronic acid alone showed controversial results and partially constrained osteoblastic differentiation in combination with EP to a level as low as for pure EP at 0.005 g/L. Of particular interest is the osteoblast-typical mineralization, as an important indicator of bone formation, which was measured indirectly via the calcium concentration after cultivation over 4 weeks. The mineralization showed an increase by a factor of 286 during the cultivation of primary human osteoblasts with hyaluronic acid and EP. Meanwhile, cell cultures treated with EP (0.5 g/L) only showed an 80-fold increase in calcium concentration.The influence of EP (0.5 g/L) on primary human osteoblasts was investigated by gene expression after 2 weeks of cultivation. Microarray and qRT-PCR analysis showed a strongly increased expression of main important genes in bone formation, bone regeneration and the physiological bone remodelling processes. Namely, BMP 2, osteopontin and the matrix metalloproteinases 1 and 9, were present during in vitro osteoprogenitor culture with EP. By explicitly underlining the potential of eggshell peptides for stimulating osteogenesis, as well as emphasizing complex and controversial interaction with hyaluronan, this manuscript is relevant for developing new functionalized biomaterials for bone regeneration.


T wave alternans as a predictor of spontaneous ventricular tachycardia in a canine model of sudden cardiac death.
We recently developed an ambulatory canine model of spontaneous ventricular tachycardia (VT) and sudden cardiac death by creating myocardial infarction, complete AV block, and infusion of nerve growth factor to the left stellate ganglion. Whether or not T wave alternans is associated with the spontaneously occurring episodes of VT in our model was unclear. Through intracardiac electrograms obtained from an implantable cardioverter defibrillator, we manually measured T wave amplitudes prior to VT and while the dogs were at rest (baseline, no VT). Of the 79 VT episodes analyzed, 28 (35.4%) exhibited repolarization alternans. In contrast, only 3 (4.7%) of 64 baseline data cases displayed alternans (P < 0.0001). The magnitude of T wave alternans for dogs that died of sudden cardiac death, dogs that did not die suddenly, and for the total 28 episodes that exhibited repolarization alternans were 4.8 +/- 2.8 mm, 4.9 +/- 3.5 mm, and 4.9 +/- 3.3 mm, respectively (P = NS). We also found the sensitivity, specificity, positive predictive value, negative predictive value, and relative risk of repolarization alternans in predicting VT to be 35.4%, 95.3%, 90.3%, 54.5%, and 1.98, respectively. The ventricular rate prior to VT (65 +/- 11 beats/min) was significantly higher than that at rest (49 +/- 12 beats/min; P < 0.0001). T wave alternans often occurred immediately before the onset of VT in dogs with myocardial infarction, complete AV block, and nerve growth factor infusion to the left stellate ganglion. Increased sympathetic activity might be responsible for the occurrence of the T wave alternans.


Latent phase duration and associated outcomes: a contemporary, population-based observational study.
Little is known about the latent phase of labor, including whether its duration influences subsequent labor processes or birth outcomes. This study aimed to describe the duration of the latent phase of labor from self-report of the onset of painful contractions to a cervical dilation of 5 cm in a large, Swedish population and evaluate the association between the duration of the latent phase of labor and perinatal processes and outcomes that occurred during the active phase of labor, second stage of labor, birth and immediately after delivery, stratified by parity. This was a population-based cohort study of 67,267 pregnancies with deliveries between 2008 and 2020 in the Stockholm-Gotland Regions, Sweden. Nulliparous and parous women without a history of cesarean delivery in spontaneous labor with a term (≥37 weeks of gestation), singleton, live, and vertex fetus without major malformations were included. Imputation was used if the notation of the end of the latent phase of labor (ie, cervical dilation of 5 cm) was missing in the partograph. Multivariable logistic regression was used to estimate the association with adjusted odds ratios and 95% confidence intervals, controlling for potential covariates. Including the time from painful contraction onset to a cervical dilation of 5 cm, the median durations of the latent phase of labor were 16.0 (interquartile range, 10.0-26.6) hours for nulliparous women and 9.4 (interquartile range, 5.9-15.3) hours for multiparous women. The durations of the latent phase of labor beyond the median were associated with increased odds of labor dystocia diagnosis during the first stage active phase or second stage of labor and interventions commonly associated with dystocia (amniotomy, oxytocin augmentation, epidural, and cesarean delivery). The duration of the latent phase of labor of ≥90th percentile vs less than the median in nulliparous women demonstrated an increased risk of adverse neonatal outcomes (Apgar score of <7 at 5 minutes and neonatal intensive care unit admission), chorioamnionitis, and fetal occiput posterior. In multiparous women, longer duration of the latent phase of labor was associated with an increased risk of neonatal intensive care unit admission and chorioamnionitis but was not associated with an Apgar score of <7 at 5 minutes. The duration of the latent phase of labor was not associated with additional markers of maternal risk. The duration of the latent phase of labor in nulliparous women was longer than that of multiparous women at each point of distribution. A longer duration of the latent phase of labor was associated with more frequent dystocia diagnoses and related interventions during the first stage active phase or second stage of labor, including cesarean delivery, nulliparous fetal occiput posterior position, chorioamnionitis, and markers of neonatal morbidity. More research is needed to identify potential mediating paths between the duration of the latent phase of labor and neonatal morbidity.


Targeting the chemokine receptor CXCR3 and its ligand CXCL10 in the central nervous system: potential therapy for inflammatory demyelinating disease?
Multiple sclerosis is an inflammatory disease of the CNS and a leading cause of disability. Inflammatory mediators play an orchestrating part in lesional development leading to symptoms. Chemokines -- chemoattractant cytokines -- regulate the inflammatory composite of the MS lesion. This review focuses on the present data regarding CXCL10 (previously known as IP-10) and CXRC3 in multiple sclerosis, since consistent data has suggested that this chemokine/chemokine receptor pair has a pivotal role in leukocyte recruitment into the central nervous system (CNS) in multiple sclerosis.


Development of early nuclear antigen in cytomegalovirus infected cells in the presence of RNA and protein synthesis inhibitors.
Human cytomegaloviruses (HCMV) induce nuclear antigens as early as I h after infection as detected by immunofluorescence. Early antigen development occurs in the presence of DNA, RNA, and protein synthesis inhibitors and is dependent on intact viral DNA in the inoculum.


Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies.
Human bone marrow has been shown to contain mesenchymal cells, which fabricate the connective tissue network of the marrow called the stroma. A subset of these marrow-derived mesenchymal cells can be isolated, expanded in culture, and then induced to differentiate into bone-producing osteoblasts and ultimately osteocytes when placed in the proper environment. At present, there are no methods for definitively identifying these cells in human marrow tissue or following their differentiation into osteogenic phenotypes. Therefore, we culture-expanded, marrow-derived mesenchymal cells from human donors and used these cells to immunize cells from human donors and used these cells to immunize mice whose spleens were used to generate hybridoma cell lines, which secrete antibodies to antigens on the cell surface of these culture-expanded mesenchymal cells. Hybridoma culture supernatants were successively screened against highly enriched samples of culture-expanded, marrow-derived mesenchymal cells in cryosections and live cell cultures to identify unique cell surface antigens. Positive clones were then screened against cell suspensions of whole and fractionated marrow to identify hybridomas whose supernatants were nonreactive with marrow hemopoietic cells. Three hybridoma cell lines, SH2, SH3, and SH4, were identified; these hybridomas secrete antibodies that recognize antigens on the cell surface of marrow-derived mesenchymal cells, but fail to react with marrow-derived hemopoietic cells. Additional tissue screening reveals unique tissue distributions for each of the recognized antigens, which suggests different antigen recognition for each antibody. However, all three antibodies fail to react with the cell surface of osteoblasts or osteocytes, suggesting that the antigens recognized by these antibodies are developmentally regulated and specific for primitive or early-stage cells of the osteogenic lineage.


In vitro modulatory effects of Terminalia arjuna, arjunic acid, arjunetin and arjungenin on CYP3A4, CYP2D6 and CYP2C9 enzyme activity in human liver microsomes.
Terminalia arjuna is a tree having an extensive medicinal potential in cardiovascular disorders. Triterpenoids are mainly responsible for cardiovascular properties. Alcoholic and aqueous bark extracts of T. arjuna, arjunic acid, arjunetin and arjungenin were evaluated for their potential to inhibit CYP3A4, CYP2D6 and CYP2C9 enzymes in human liver microsomes. We have demonstrated that alcoholic and aqueous bark extract of T. arjuna showed potent inhibition of all three enzymes in human liver microsomes with IC50 values less than 50 μg/mL. Arjunic acid, arjunetin and arjungenin did not show significant inhibition of CYP enzymes in human liver microsomes. Enzyme kinetics studies suggested that the extracts of arjuna showed reversible non-competitive inhibition of all the three enzymes in human liver microsomes. Our findings suggest strongly that arjuna extracts significantly inhibit the activity of CYP3A4, CYP2D6 and CYP2C9 enzymes, which is likely to cause clinically significant drug-drug interactions mediated via inhibition of the major CYP isozymes.


Cortical circuit activity underlying sleep slow oscillations and spindles.
Slow oscillations and sleep spindles are hallmarks of the EEG during slow-wave sleep (SWS). Both oscillatory events, especially when co-occurring in the constellation of spindles nesting in the slow oscillation upstate, are considered to support memory formation and underlying synaptic plasticity. The regulatory mechanisms of this function at the circuit level are poorly understood. Here, using two-photon imaging in mice, we relate EEG-recorded slow oscillations and spindles to calcium signals recorded from the soma of cortical putative pyramidal-like (Pyr) cells and neighboring parvalbumin-positive interneurons (PV-Ins) or somatostatin-positive interneurons (SOM-Ins). Pyr calcium activity was increased more than threefold when spindles co-occurred with slow oscillation upstates compared with slow oscillations or spindles occurring in isolation. Independent of whether or not a spindle was nested in the slow oscillation upstate, the slow oscillation downstate was preceded by enhanced calcium signal in SOM-Ins that vanished during the upstate, whereas spindles were associated with strongly increased PV-In calcium activity. Additional wide-field calcium imaging of Pyr cells confirmed the enhanced calcium activity and its widespread topography associated with spindles nested in slow oscillation upstates. In conclusion, when spindles are nested in slow oscillation upstates, maximum Pyr activity appears to concur with strong perisomatic inhibition of Pyr cells via PV-Ins and low dendritic inhibition via SOM-Ins (i.e., conditions that might optimize synaptic plasticity within local cortical circuits).


A Unique Genomic Variant of HDR Syndrome in Newborn.
HDR syndrome (also known as Barakat syndrome) is a rare genetic disorder due to deletions/mutations on specific regions of zinc-finger transcription factor (GATA3) gene. A male preterm infant presented with multiple dysmorphic features characterized by small for gestational age, hypognathia and facial abnormalities. Investigations revealed hypocalcemia and low parathyroid hormone levels and bilateral sensorineural deafness. Chromosomal microarray analysis revealed a combination of deletion on chromosome 10p (10p15.3p14) with loss of GATA3 gene and duplication of chromosome 20p (20p13p12.3) as a result of unbalanced 10:20 translocation. Detecting this syndrome at neonatal age is very important because it allows early intervention to minimize future clinical problems.


Synaptic scaling up in medium spiny neurons of aged BACHD mice: A slow-progression model of Huntington's disease.
Huntington's disease (HD) is an autosomal dominant disease that develops in midlife (~ 40 years-old at onset) and then progresses slowly. It is still unclear how striatal medium spiny neurons (MSNs), the most vulnerable neurons in HD, maintain their function for decades despite the chronic expression of mutant huntingtin (mHTT). In this study, we used aged BACHD mice, a HD model expressing the full-length human mHTT gene, to investigate the molecular, morphological and functional properties of striatal MSNs. We report that the density of dendritic spines in MSNs is substantially lower in aged BACHD mice than in wild-type (WT) mice, in the absence of major dendritic changes and neuronal loss. This spine loss is accompanied by changes in transcription, resulting in a low expression of the striatum-specific G protein-coupled receptor 88 (Gpr88) as well as a reorganization of the composition of AMPAR subunits (high Gria1/Gria2 mRNA ratio). We also detected functional changes in BACHD MSNs. Notably, BACHD MSNs were hyperexcitable and the amplitude of AMPAR-mediated synaptic currents was higher than in WT MSNs. Altogether, these data show that both the intrinsic properties and the strength of the remaining synapses are modified in MSNs with low dendritic spine density in aged BACHD mice. These homeostatic mechanisms may compensate for the substantial loss of synaptic inputs and thus alleviate the deleterious effects of mHTT expression on the activity of MSNs and also possibly on the motor phenotype in aged BACHD.


A multimethodological evaluation of arsenic in the Zenne River, Belgium: Sources, distribution, geochemistry, and bioavailability.
The distribution and geochemistry of arsenic (As) in water and sediments of the Zenne River, a small urban river flowing through Brussels (Belgium), were assessed based on the results of 18 sampling campaigns performed between 2010 and 2021. In general, concentrations of As sharply increase between Vilvoorde and Eppegem and are up to 6-8 times higher in the section downstream of Eppegem in comparison to the upstream part of the Zenne. The monitoring surveys in which the grab water samples were taken at a 1-hour sampling frequency revealed that the large temporal variability in As concentrations found in the downstream part of the river is driven by the tidal cycle. The diffusive gradients in thin films (DGT) technique was used to assess the DGT labile As species in surface water and sediment porewater. Three DGT sorbents (Metsorb, Lewatit FO 36, and ZrO2) for the determination of total As were applied to compare their performance, and the 3-mercaptopropyl-functionalized silica (3-MFS) was used for the speciation of As(III) in porewater. Arsenic species are fully labile in surface waters as the DGT time-integrated concentrations of As were in good agreement with the average concentrations calculated from the grab samplings. In sediment porewaters, As is predominantly present as non-DGT labile species (66-93 %), and the DGT labile As fraction is dominated by As(III). Flux calculations evaluating the relative importance of different As sources to the Zenne River revealed the presence of a point source on the tributary Tangebeek, which contributes to 87 % of the As load carried by the Zenne River.


Food allergy: in-vivo diagnostics including challenge.
The diagnosis of food allergy related to IgE-mediated reactions is based on the establishment of the allergic origin of the symptoms and the identification of the causal allergen or allergens. The double-blind, placebo-controlled food challenge remains the 'gold standard' for the in-vivo diagnosis of specific food allergy. Valuable information can be obtained with both in-vitro and in-vivo diagnostic procedures; however, for the accurate prediction and diagnosis of food allergy, these methods must be standardized and correlated with a standardized double-blind, placebo-controlled food challenge procedure.


Dietary calcium supplementation restores pressure natriuresis responses in Dahl-S rats.
Calcium supplementation prevents hypertension in Dahl S (DS) rats. Because abnormal pressure natriuresis may contribute to the development of hypertension, we examined the effect of calcium on pressure natriuresis. DS and Dahl R (DR) rats maintained on a 4% sodium diet containing either 0.5% or 2% calcium for 4 weeks were anesthetized; sodium excretion, renal blood flow, and inulin clearance were determined at perfusion pressures of 100, 125, and 156 mm Hg. Inulin clearance and renal blood flow were not different between groups. Sodium excretion increased with increasing renal perfusion pressure in all groups. The slope of the line relating renal perfusion pressure to sodium excretion was greater (P < .05) in DR rats than in DS rats on normal calcium intakes. High calcium intake normalized the slope of the line relating renal perfusion pressure to sodium excretion in DS rats, but had no effect on DR rats. Thus, dietary calcium supplementation normalizes the blunted pressure natriuresis response in the DS rat and may contribute to the prevention of hypertension.


Characterization and genetic analysis of an EIN4-like sequence (CaETR-1) located in QTL(AR1) implicated in ascochyta blight resistance in chickpea.
Two alleles of a chickpea (Cicer arietinum L.) ethylene receptor-like sequence (CaETR-1) were sequence-characterized using synteny analysis with genome sequences of Medicago truncatula L. The full length of the sequence obtained in the accession FLIP84-92C resistant to ascochyta blight (CaETR-1a) span 4,428 bp, including the polyadenylation signal in the 3'-untranslated region (UTR), whereas it has a 730 bp deletion in the 3'-UTR region in the susceptible accession PI359075 (CaETR-1b). The deduced protein belongs to subfamily II of the ethylene receptors and contains all the domains that define EIN4 homologs in Arabidopsis. The EIN4-like sequence (CaETR-1) has been mapped using a recombinant inbred line (RIL) population derived from an intraspecific cross between ILC3279 and WR315, resistant and susceptible to blight, respectively. The locus was located in LGIVa of the genetic map, flanked by markers NCPGR91 and GAA47 (at distances of 11.3 and 17.9 cM, respectively). This is the first potentially functional sequence identified under a QTL peak for ascochyta blight resistance in chickpea (QTL(AR1)). This EIN4-like (CaETR-1) sequence explained up to 33.8% of the total phenotypic variation. This sequence could be directly related to blight resistance, together with other QTLs that have been found to be involved in resistance to this major chickpea disease.


PVB chemotherapy in patients with recurrent or advanced dysgerminoma: a Phase II study of the EORTC Gynaecological Cancer Cooperative Group.
Dysgerminoma accounts for 1% of all ovarian cancers and for 50% of all ovarian germ cell malignancies. Low stage patients (50%) can be cured with local treatment. The aim of this trial was to study the objective tumour response rate and toxicity of PVB (cisplatin, vinblastine, bleomycin) chemotherapy in patients with pure advanced or recurrent dysgerminoma. Eighteen eligible patients with advanced dysgerminoma were entered into this study. Three patients had local bulky recurrence only; all the others also had metastatic disease. The median age at entry was 27 years (range 1348). Seventeen patients had had prior surgery and one had undergone prior radiotherapy. The WHO performance status was 0 in 12 patients, 1 in three patients, and 2 in three patients. The treatment consisted of: intravenous or intramuscular bleomycin 30 mg on days 2, 9 and 16, intravenous vinblastine 0.15 mg/kg on days 1 and 2, and intravenous cisplatin 20 mg/m2 on days 1-5. This regimen was given at 3-week intervals for a total of four cycles. Twelve patients obtained a complete response (66%), five a partial response (28%), and one could not be evaluated because radiotherapy was administered immediately after chemotherapy. After a median follow-up of 76 months (range 4-132), 14 (78%) patients were alive and well. Two died of disease progression, one of neutropenic septicaemia and one of lung fibrosis. No unusual toxicity was reported. Alopecia, as well as nausea and vomiting, were common. Leucopenia (78%), thrombocytopenia (17%) and infection (11%) were the other severe (grade 3-4) side effects. The PVB chemotherapy regimen is highly effective in patients with advanced ovarian dysgerminoma. However, the BEP (bleomycin, etoposide, cisplatin) regimen, which is equally as potent and less toxic, is preferred.


Computer modelling reveals new conformers of the ATP binding loop of Na+/K+-ATPase involved in the transphosphorylation process of the sodium pump.
Hydrolysis of ATP by Na+/K+-ATPase, a P-Type ATPase, catalyzing active Na+ and K+ transport through cellular membranes leads transiently to a phosphorylation of its catalytical α-subunit. Surprisingly, three-dimensional molecular structure analysis of P-type ATPases reveals that binding of ATP to the N-domain connected by a hinge to the P-domain is much too far away from the Asp369 to allow the transfer of ATP's terminal phosphate to its aspartyl-phosphorylation site. In order to get information for how the transfer of the γ-phosphate group of ATP to the Asp369 is achieved, analogous molecular modeling of the M4-M5 loop of ATPase was performed using the crystal data of Na+/K+-ATPase of different species. Analogous molecular modeling of the cytoplasmic loop between Thr338 and Ile760 of the α2-subunit of Na+/K+-ATPase and the analysis of distances between the ATP binding site and phosphorylation site revealed the existence of two ATP binding sites in the open conformation; the first one close to Phe475 in the N-domain, the other one close to Asp369 in the P-domain. However, binding of Mg2+•ATP to any of these sites in the "open conformation" may not lead to phosphorylation of Asp369. Additional conformations of the cytoplasmic loop were found wobbling between "open conformation" <==> "semi-open conformation <==> "closed conformation" in the absence of 2Mg2+•ATP. The cytoplasmic loop's conformational change to the "semi-open conformation"-characterized by a hydrogen bond between Arg543 and Asp611-triggers by binding of 2Mg2+•ATP to a single ATP site and conversion to the "closed conformation" the phosphorylation of Asp369 in the P-domain, and hence the start of Na+/K+-activated ATP hydrolysis.


Long-term effect of inducible silent ischaemia on left ventricular systolic function.
Silent myocardial ischaemia is readily detected by exercise radionuclide ventriculography in patients with coronary artery disease. In those who remain asymptomatic and event-free, it is not known whether silent ischaemia which is inducible despite anti-ischaemic medication exerts an insidious detrimental effect on left ventricular function. To study this, 34 medically treated patients (mean age 57; 26 men) underwent prospective measurement of left ventricular ejection fraction (LVEF) during rest and exercise radionuclide ventriculography without interruption of anti-ischaemic medication at baseline and 12 months later. There was no significant mean (standard deviation, 95% confidence interval) deterioration from baseline to 12 months in LVEF at rest (50% v 49%, SD 5; 95% CI = -3 to +1), peak exercise (44% v 45%, SD 8; 95% CI = -1 to +4) and the change in LVEF from rest to exercise (-6% v -4%, SD 7; 95% CI = -1 to +5). Thus, in coronary artery disease patients who remain asymptomatic and event-free on medical therapy, silent myocardial ischaemia which is readily inducible at baseline despite medication does not lead per se to deterioration of left ventricular systolic function at rest or exercise over 12 months.


Binding specificity and presynaptic action of anaphylatoxin C5a in rat brain.
Human anaphylatoxin C5a injected directly to the perifornical hypothalamus (PFH) of the rat elicits food intake in sated rats, an effect which mimics that of norepinephrine (NE) at the PFH. The ability of C5a to induce food intake is selectively blocked by the alpha-adrenergic antagonist phentolamine, confirming that C5a exerts its effects via an alpha-adrenergic receptor system. In this study specific C5a binding sites on rat brain slices were detected using 125I-C5a at 2.4 nM in the presence of unlabeled noncompeting C3a and competing C5a at 0.5 microM. To determine whether the in vivo activity of C5a was due to direct stimulation of an alpha-adrenergic receptor system or to indirect modulation via a specific C5a receptor, rats were pretreated at the PFH with C5ai, the "inactive" 74-desarginated derivative of C5a. C5ai blocked stimulation of feeding by C5a but had no effect on food intake elicited by NE, suggesting a presynaptic site for C5a activity. To determine whether C5a anaphylatoxin acts at presynaptic or postsynaptic sites, the ability of C5a and of NE to induce food intake in sated rats was compared before and after injection of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT) to the PFH. AMPT would produce focal depletion of endogenous catecholamines by inhibition of catecholamine biosynthesis. Rats treated with AMPT failed to respond to C5a but ate excessively following NE, suggesting that C5a acts presynaptically, possibly to release NE. We propose that C5a acts at a specific C5a/C5ai receptor to modulate catecholamine activity at the brain site.


The modified Belt-Fuqua procedure using an asymmetric "furisode" sleeve for proximal hypospadias with severe curvature.
Proximal hypospadias repair is a challenge in the pediatric urology field. Although the previous reports showed that the Belt-Fuqua staged procedure is reliable with a low complication rate for midshaft hypospadias, this procedure has not been generally applied to more proximal hypospadias with severe ventral curvature due to technical limitations. To solve these technical limitations, we developed a modified Belt-Fuqua procedure using an asymmetric long skin sleeve looking like a Japanese long-sleeved Kimono called a "furisode". The aim of this study was to evaluate the outcomes of this new modification of the Belt-Fuqua procedure for the repair of proximal hypospadias with severe curvature in children. The study retrospectively reviewed consecutive patients with proximal hypospadias with severe curvature underwent this new technique. The major modifications included are proximal degloving beyond the urethral meatus, asymmetrical ventral transposition of dorsal preputial skin like a furisode sleeve, and circumferential proximal anastomosis of preputial skin to native meatus in the first stage. Hypospadias severity was evaluated objectively in two ways: preoperatively by the Glans-Urethral Meatus-Shaft score and intraoperative direct measurement of ventral curvature. The primary outcome was urethroplasty complications. A total of 66 patients completed both stages of the furisode technique. The median Glans-Urethral Meatus-Shaft score was 11. Overall, 60 (91%) patients showed ventral curvature greater than 60 degrees after degloving, and 35 (53%) underwent ventral grafting with a dermal graft in the first stage. Median urethral length constructed at the second stage was 41.5 mm. The median follow-up period was 25 months. Complications occurred in 9 patients (14%); 7 had urethral diverticula, 1 showed a fistula and 1 had a urethral stricture. Neither glans dehiscence nor meatal stenosis occurred. There are a couple of advantages of this furisode technique to other tunneled flap techniques like the Ulaanbaatar procedure. The first is the ease of glans reshaping with a Firlit collar at the first stage because of no urethra in the glans. The second is that a long neourethra could be made by the same skin flap with one anastomosis to the native urethra.The weakness of this procedure was that urethral diverticula were prone to occur less than one year after urethroplasty. The furisode technique, a new modification of the Belt-Fuqua procedure, provides an alternative staged repair of proximal hypospadias. This technique was easily applied for hypospadias with severe curvature requiring ventral grafting.


Ammonium recovery from reject water combined with hydrogen production in a bioelectrochemical reactor.
In this study, a bioelectrochemical reactor was investigated for simultaneous hydrogen production and ammonium recovery from reject water, which is an ammonium-rich side-stream produced from sludge treatment processes at wastewater treatment plants. In the anode chamber of the reactor, microorganisms converted organic material into electrical current. The electrical current was used to generate hydrogen gas at the cathode with 96±6% efficiency. Real or synthetic reject water was fed to the cathode chamber where proton reduction into hydrogen gas resulted in a pH increase which led to ammonium being converted into volatile ammonia. The ammonia could be stripped from the solution and recovered in acid. Overall, ammonium recovery efficiencies reached 94% with synthetic reject water and 79% with real reject water. This process could potentially be used to make wastewater treatment plants more resource-efficient and further research is warranted.


in Situ X-ray Photoelectron Spectroscopic and Electrochemical Studies of the Bromide Anions Dissolved in 1-Ethyl-3-Methyl Imidazolium Tetrafluoroborate.
Influence of electrode potential on the electrochemical behavior of a 1-ethyl-3-methylimidazolium tetrafluoroborate (EMImBF₄) solution containing 5 wt % 1-ethyl-3-methylimidazolium bromide (EMImBr) has been investigated using electrochemical and synchrotron-initiated high-resolution in situ X-ray photoelectron spectroscopy (XPS) methods. Observation of the Br 3d5/2 in situ XPS signal, collected in a 5 wt % EMImBr solution at an EMImBF₄⁻vacuum interface, enabled the detection of the start of the electrooxidation process of the Br⁻ anion to Br₃⁻ anion and thereafter to the Br₂ at the micro-mesoporous carbon electrode, polarized continuously at the high fixed positive potentials. A new photoelectron peak, corresponding to B⁻O bond formation in the B 1s in situ XPS spectra at E ≤ ⁻1.17 V, parallel to the start of the electroreduction of the residual water at the micro-mesoporous carbon electrode, was observed and is discussed. The electroreduction of the residual water caused a reduction in the absolute value of binding energy vs. potential plot slope twice to ca. dBE dE-1 = ⁻0.5 eV V-1 at E ≤ ⁻1.17 V for C 1s, N 1s, B 1s, F 1s, and Br 3d5/2 photoelectrons.


Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation.
There are seven well-known lysosomal storage diseases that produce angiokeratoma corporis diffusum clinically. beta-Mannosidosis (MANB1; OMIM248510), first reported in humans in 1986, is a rare hereditary lysosomal storage disease caused by a deficiency of the enzyme beta-mannosidase. Since then, 13 cases of beta-mannosidase deficiency in ten families have been described. A human beta-mannosidase mutation has been reported only by Alkhayat et al. in 1998. To clarify its pathogenesis we did electron microscopic, biochemical and molecular biological investigations of a Japanese patient with beta-mannosidosis. Ultrastructural analyses, enzyme assays, cell culture and mRNA and genomic DNA were sequenced to find mutations in the beta-mannosidase gene. Electron microscopy of skin biopsy specimens from the patient showed cytoplasmic vacuolation of lysosomes in blood and lymph vessels, endothelial cells, fibroblasts, secretory portions of eccrine sweat glands, neural cells and basal keratinocytes in the epidermis. This vacuolation was also observed in cultured keratinocytes and fibroblasts. Assays of seven enzyme activities in plasma and cultured skin fibroblasts showed a marked decrease of beta-mannosidase activity. Sequencing the beta-mannosidase cDNA revealed a four-base (ATAA) insertion between exons 7 and 8, resulting in a frameshift at codon 321 and termination at codon 325. Analysis of the patient's genomic DNA revealed a novel homozygous A(+1)-->G splice site mutation in intron 7. To our knowledge, this is the first case of beta-mannosidosis reported in Japan and the second report in which a gene mutation is identified. The biological importance of beta-mannose moieties in glycoproteins in basal keratinocytes is suggested.


The biocompatibility of compressed collagen foam plugs.
The tissue reaction to reexpanded, purified bovine collagen sponge placed percutaneously into the lung, pleural space, liver, kidney, and muscle was studied in dogs and rabbits. In addition, the biocompatibility and radiopacity of tantalum-treated collagen foam plugs was examined. No adverse effects were found. We believe that collagen plugs may be of use in occluding needle tracts from biopsy sites to prevent complications such as bleeding or pneumothoraces.


Identification of Atuveciclib (BAY 1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer.
Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.


The nuclear pore and plant development.
All macromolecules that traffic between the nucleus and the cytoplasm traverse the nuclear pore. While yeast and mammalian nuclear pore structure and function have recently been substantially refined, our understanding of the plant nuclear pore is still far from comprehensive. Nevertheless, a number of nuclear pore and nucleocytoplasmic trafficking components have recently been identified as required for diverse developmental and signaling pathways. In addition, some aspects of the nuclear pore composition itself now appear under developmental control and nuclear pore components have recently surfaced as novel players in plant cytokinesis. Here, we review these new findings in context and attempt to correlate molecular functions with developmental processes.


Spirometry in 5-year-olds--validation of current guidelines and the relation with asthma.
Spirometry is more frequently measured in younger children. Our primary aim was to validate 2005 ATS-ERS Task Force standards for spirometry in adults and older children among a population of 5-year-old children. Our secondary aim was to relate spirometry to asthma symptoms. Children were participants in a longitudinal cohort study where asthma symptoms and spirometry were assessed. Of the 827 children assessed, spirometry was obtained in 638 (85 with wheeze). A back-extrapolated volume/FVC ratio of <5% was achieved in 99% of children, the best two FVC were < or =150 ml of each other in 89% and three efforts were obtained within six attempts in 88%. The best two FVC were within 10% of each other in 82% of children. Only 13% achieved a forced expiratory time (FET) of > or =3 sec, whereas 80% had an FET of > or =1 sec. All criteria (including FET > or =1 s and FVC < or =10%) were met in 400 (65%) of the 638 children. Most spirometric indices were reduced in association with current wheeze and a history of asthma; children with current wheeze had a mean reduction of 0.65 FEV(1) z score compared to healthy children, P < 0.001. An FEV(1) z score of -1.0 had 82% sensitivity but only 50% specificity for current wheeze, the corresponding numbers for an FEF(50) z score of -1.0 being 79% and 71%. The standards for spirometry are mostly achieved in this age group but are not necessarily valid and require revision. Reliable spirometry is feasible in 5-year-old children where reduced measurements are associated with asthma symptoms and in whom FEF(50) appears to be the most discriminatory variable.


[Sensitivity and specificity of prick skin test with two concentrations of standardized extract of Culex quinquefasciatus in allergic children].
Diagnostic options for immune reactions to mosquito bites are limited. In Cuba, IgE-mediated reactions are frequently related to Culex quinquefasciatus bite. To determine the sensitivity and specificity of skin prick test with two doses of standardized extract in nitrogen protein units (PNU of Culex quinquefasciatus (BIOCEN, Cuba). An analytical study was conducted on 100 children between 2 and 15 years old. Fifty atopic patients with a history of allergy to mosquito bite and positive specific serum IgE Culex quinquefasciatus and fifty atopic patients without a history of allergy to mosquito bite and negative specific serum IgE to Culex quinquefasciatus. Skin prick tests (SPT) were performed by duplicates on the forearms of the patients. Investigated doses were 100 PNU/mL and 10 PNU/mL. SPT with the highest concentration obtained a mean wheal size of 22.09 mm2 and for lower doses of 8.09 mm2, a statistically significant difference (p=0.001, Student's t test). Positive skin test correlated in 100% of patients with the presence of specific IgE. Testing with both doses showed a 94% of specificity and 88% of sensitivity. The diagnostic accuracy of SPT using both doses of standardized extract was similar, which justifies its use for diagnosis of sensitization to Culex quinquefasciatus in patients with symptoms of allergy to mosquito bite.


Drug interference in immunogenicity assays depends on valency.
Direct comparison of immunogenicity data is hampered by differential drug interference in different assay formats. In this paper we identify a drug-related factor that influences the extent of drug interference. We systematically investigated the influence of drug valency of different antibody-derived biologicals on the drug interference, using mono- and bivalent formats of adalimumab as a model system. Our results indicate that compared to regular bivalent antibodies, antibody-derived drugs that are monovalent result in less drug interference. Two real-life examples were examined: natalizumab, an IgG4 antibody that becomes effectively monovalent in vivo due to Fab arm exchange, and certolizumab pegol, a pegylated Fab fragment. For both drugs it was demonstrated that drug interference is less pronounced in an antigen-binding test compared to similar assays for other therapeutic antibodies. When comparing immunogenicity data obtained for different biologicals this phenomenon should be taken into account.


Multisensory temporal processing in early deaf.
Navigating the world relies on understanding progressive sequences of multisensory events across time. Early deaf (ED) individuals are more precise in visual detection of space and motion than their normal hearing (NH) counterparts. However, whether ED individuals show altered multisensory temporal processing abilities is less clear. According to the connectome model, brain development depends on experience, and therefore the lack of audition may affect how the brain responds to remaining senses and how they are functionally connected. We used a temporal order judgment (TOJ) task to examine multisensory (visuotactile) temporal processing in ED and NH groups. We quantified BOLD responses and functional connectivity (FC) in both groups. ED and NH groups performed similarly for the visuotactile TOJ task. Bilateral posterior superior temporal sulcus (pSTS) BOLD responses during the TOJ task were significantly larger in the ED group than in NH. Using anatomically defined pSTS seeds, our FC analysis revealed stronger somatomotor and weaker visual regional connections in the ED group than in NH during the TOJ task. These results suggest that a lack of auditory input might alter the balance of tactile and visual area FC with pSTS when a multisensory temporal task is involved.


Effects of acid and cleansing agents on shear bond strength and marginal microleakage of glass-ionomer cements.
The aims of the present study were to evaluate the effects of various dentin chemical pretreatments (a) on the shear bond strength of five glass-ionomer cements (GICs) and (b) on marginal microleakage of the five GICs used in association with resin composites in Class V restorations. The dentin treatments were: three acid agents (polyacrylic acid, tannic acid, orthophosphoric acid), three cleansing agents (Tubulicid blue solution, hydrogen peroxide, and sodium hypochlorite), and an aqueous solution as control. After dentin treatment, the test specimens were stored in water at 37 degrees C for 24 hr. Shear bond strength was determined with a universal testing machine at a cross-head speed of 0.5 cm/min. Sodium hypochlorite and polyacrylic acid significantly improved the adhesion of GICs to a different degree in the various materials. Regarding microleakage tests, 320 non-retentive cavities were prepared at the cementum-enamel junction in freshly extracted human teeth. The teeth were thermocycled, immersed in dye solution, and serial-sectioned longitudinally at three sites. Treatment with sodium hypochlorite was the most effective in reducing marginal leakage. The present results suggest that dentin treatment is an important step in all resin composite/GIC restorations.


Vitislactone, a non-canonical strigolactone exudated by grapevine rootstocks in response to nitrogen starvation.
Strigolactones are compounds produced by plant roots in response to nutrient deficiency, acting both as local and systemic signals to control development and nutrition. Strigolactones are exuded in the rhizosphere to positively influence interactions with beneficial microbes. LC-MS/MS analysis shows that two genetically distinct grapevine rootstocks exudate one or two non-canonical strigolactones when subjected to low nitrogen conditions. Gene expression profiles and orobanche seed germination assays confirm that the biosynthesis and exudation of non-canonical compounds is the preferred pathway. The first compound, corresponding to heliolactone or 6-epi-heliolactone, is only exuded by the rootstock showing lower shoot branching and a higher level of mycorrhization with arbuscular mycorrhizal fungi. The structure of the second compound exuded by both rootstocks was identified by NMR and LC-MS/MS analysis. It is a non-canonical strigolactone, which has never been identified in another species. This first identification of a natural compound with the potential to stimulate beneficial root-microbe interactions in grapevines opens new perspectives in viticulture.


The nodal neck level of sentinel lymph nodes in mucosal head and neck cancer.
Sentinel node biopsy is emerging as a successful means of identifying subclinical lymph node disease in mucosal head and neck cancer. Sentinel node studies in melanoma and breast cancer have identified sentinel nodes at unusual sites and the technique is redefining our understanding of dynamic lymphatic flow. In this study, the sentinel nodes in mucosal head and neck malignancies were mapped according to their site within the neck and this was correlated with tumour site within the oral cavity. Fifty-two necks were explored for sentinel nodes from tumours located in the tongue (23 cases), floor of mouth (12 cases), palate (six cases), retromolar trigone (five cases), alveolus (three cases), buccal mucosa (two cases), tonsil (two cases) and lip (one case). In total, 124 sentinel nodes were found in levels I-V. Two hot spots were found in the tonsils and were not excised, two nodes were located in level IIB, four nodes were found in level IV, three in the contralateral neck and one in level V. The sentinel nodes located at unusual sites would not have been excised in a supraomohyoid neck dissection and the study has improved our understanding of dynamic lymph flow from tumours.


Impact of liberal use of mediolateral episiotomy on the incidence of obstetric anal sphincter tear.
To assess the impact of liberal compared with restrictive use of mediolateral episiotomy on the incidence of obstetric anal sphincter tear (OAST). Data between the years 1999-2001 (era 1) when liberal mediolateral episiotomy was applied were compared with the years 2004-2008 (era 2) when restricted mediolateral episiotomy was implemented. Liberal mediolateral episiotomy was done for fetal or maternal indications, while restrictive mediolateral episiotomy was done when a tear was imminent. Primary outcome was the incidence of OAST. A total of 25,170 women who delivered vaginally were included. After adjusting for potential confounders, the incidence of OAST was found to be significantly higher in era 2 (0.4 %) compared to era 1 (0.1 %), (p = 0.02; adjusted OR 2.23; 95 % CI, 1.16-4.29). Among primiparous women, the incidence of mediolateral episiotomy was 71.8 and 27.1 % in eras 1 and 2, respectively (p < 0.001), and the incidence of OAST was 0.2 and 1 % in eras 1 and 2, respectively (p = 0.009; adjusted OR 4.15; 95 % CI, 1.42-12.10). Among multiparous women, the incidence of OAST did not differ significantly (p = 0.52). Returning to the liberal policy among primiparous women only, 124 deliveries are needed to prevent one OAST. Liberal compared to restrictive use of mediolateral episiotomy may be a sphincter-saving procedure among primiparous women.


Cost-Effectiveness Evaluation of Collaborative Care for Diabetes and Depression in Primary Care.
Information is limited on the cost effectiveness of strategies to improve depressive symptoms in patients with Type 2 diabetes in primary care outside of the U.S. Using patient data from a 12-month controlled implementation trial, outcomes and healthcare costs determined through administrative database linkages were compared for a strategy of family physician notification and follow-up ("enhanced care") versus collaborative care. Two measures of effectiveness were used: depression-free days (DFDs) based on Patient Health Questionnaire, and quality-adjusted life years (QALYs) based on EQ-5D. Data were collected November 2010 to January 2013 with analyses completed in May 2015. Incremental cost-effectiveness ratios were also compared against true usual care patients. Among 227 patients, mean age was 58 years, 55% were female, and mean diabetes duration was 12 years. Compared with total 12-month cost per usual care patient (C$5,889), the incremental cost was C$450 for patients in enhanced care and C$1,021 for collaborative care. Both enhanced and collaborative care strategies improved outcomes compared with usual care, with incremental DFDs of 65.9 and 117.6, and incremental QALYs of 0.006 and 0.042, respectively. Compared with enhanced care, collaborative care yielded incremental cost-effectiveness ratios of C$11/DFD and C$15,861/QALY. Compared with usual care, the incremental cost-effectiveness ratios were C$7/DFD or C$76,271/QALY for enhanced care and C$9/DFD or C$24,368/QALY for collaborative care. In primary care patients with Type 2 diabetes who screened positive for depression, physician notification and follow-up was a clinically effective strategy compared with usual care, but investing more resources in collaborative care yielded the most cost-effective strategy.


Artificial neural network model to distinguish pleomorphic adenoma from adenoid cystic carcinoma on fine needle aspiration cytology.
To differentiate pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) on fine needle aspiration cytology (FNAC) is often challenging to cytologists. In the present study, we tried to make an artificial neural network (ANN) model from the FNAC smears to differentiate PA from ACC. The detailed cytomorphological features were analysed on the FNAC of histopathology proven cases of PA (n = 35) and ACC (n = 33) and enumerated semi-quantitatively by two independent observers. These data were used to make an ANN model to distinguish PA from ACC on FNAC material. We used neuro-intelligence software to build the ANN model. The network architecture was 10-2-1. The heuristic search engine was applied to have this model. We used backpropagation neural network to teach ANN. At least 500 iterations were done to train the model. The efficacy of this ANN model was assessed with the help of the confusion matrix and receiver operating characteristic curve. The data were separated automatically by the software as a training set (n = 48), validation set (n = 10) and test set (n = 10). The ANN model was able to differentiate every case (10/10) of PA and ACC in the final test set. The area under the receiver operating characteristic curve was 1. The currently built ANN model is competent to identify PA and ACC cases on FNAC. Additional parameters and new cases can be incorporated into this open-ended ANN model to make it more robust.


Under fire: gun violence is not just an urban problem.
Gun violence continues to be a source of trauma patient morbidity and mortality annually in the United States. We sought to characterize gun violence in the combined suburban and rural county of Lancaster, PA, and compare it with gun violence results obtained in urban areas. All gunshot wound (GSW) admissions from January 2000-December 2013 were queried from trauma registry. Patients sustaining ball bearing/ball bullet (BB) or pellet gun injury were excluded. Data collected included mortality, injury severity score (ISS), number of GSW per patient, and cost data. Linear trend tests assessed the change in mortality, patients with three or more GSWs, and patients with an ISS ≥15 and ISS ≥25 over the study period. Statistical significance was defined as P < 0.05. A total of 478 patients met our inclusion criteria. Linear trend tests revealed no significant changes in percent mortality (P = 0.973), percent of patients with three or more GSWs (P = 0.692), percent of patients with an ISS ≥15 (P = 0.545), and percent of patients with an ISS ≥25 (P = 0.343) over the 14-y study period. No significant change in cost per case was observed over the study period (P = 0.246); however, percent reimbursement significantly increased (P = 0.012). In the relatively affluent suburban and rural community of Lancaster, PA, there is a low-level pattern of gunshot violence and subsequent mortality that has not changed over time. This continuing pattern of gunshot violence speaks to the need for development of innovative preventative measures, as well as continuing efforts against gunshot violence by health care and law-enforcement personnel in suburban and urban centers alike.


Animal farms are hot spots for airborne antimicrobial resistance.
Animal farms are known reservoirs for environmental antimicrobial resistance (AMR). However, knowledge of AMR burden in the air around animal farms remains disproportionately limited. In this study, we characterized the airborne AMR based on the quantitative information of 30 antimicrobial resistance genes (ARGs), four mobile genetic elements (MGEs), and four human pathogenic bacteria (HPBs) involving four animal species from 20 farms. By comparing these genes with those in animal feces, the distinguishing features of airborne AMR were revealed, which included high enrichment of ARGs and their potential mobility to host HPBs. We found that depending on the antimicrobial class, the mean concentration of airborne ARGs in the animal farms ranged from 102 to 104 copies/m3 and was accompanied by a considerable intensity of MGEs and HPBs (approximately 103 copies/m3). Although significant correlations were observed between the ARGs and bacterial communities of air and fecal samples, the abundance of target genes was generally high in fine inhalable particles (PM2.5), with an enrichment ratio of up to 102 in swine and cattle farms. The potential transferability of airborne ARGs was universally strengthened, embodied by a pronounced co-occurrence of ARGs-MGEs in air compared with that in feces. Exposure analysis showed that animal farmworkers may inhale approximately 104 copies of human pathogenic bacteria-associated genera per day potentially carrying highly transferable ARGs, including multidrug resistant Staphylococcus aureus. Moreover, PM2.5 inhalation posed higher human daily intake burdens of some ARGs than those associated with drinking water intake. Overall, our findings highlight the severity of animal-related airborne AMR and the subsequent inhalation exposure, thus improving our understanding of the airborne flow of AMR genes from animals to humans. These findings could help develop strategies to mitigate the human exposure and dissemination of ARGs across different media.


Reduction in the Cesarean Delivery Rate After Obstetric Care Consensus Guideline Implementation.
To evaluate the rate of primary cesarean delivery after adopting labor management guidelines. This is a before-after retrospective cohort study at a single academic center. This center adopted guidelines from the Consensus for the Prevention of the Primary Cesarean Delivery. Nulliparous women attempting vaginal delivery with viable, singleton, vertex fetuses were included. For the primary outcome of cesarean delivery rate among induced or augmented patients, 200 consecutive women managed before guideline adoption were compared with 200 similar patients afterward. Secondary outcomes of overall cesarean delivery rate, maternal morbidity, neonatal outcomes, and labor management practices were analyzed with inclusion of intervening spontaneously laboring women. Between September 13, 2013, and September 28, 2014, 275 women preguideline and 292 postguideline were identified to include 200 deliveries after induction or augmentation each. Among women delivering after induction or augmentation, the cesarean delivery rate decreased from 35.5% to 24.5% (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.38-0.91). The overall cesarean delivery rate decreased from 26.9% to 18.8% (adjusted OR 0.59, CI 0.38-0.92). Composite maternal morbidity was reduced (adjusted OR 0.66, CI 0.46-0.94). The frequency of cesarean delivery documenting arrest of dilation at less than 6 cm decreased from 7.1% to 1.1% postguideline (n=182 and 176 preguideline and postguideline, respectively, P=.006) with no change in other indications. Postguideline, the cesarean delivery rate among nulliparous women attempting vaginal delivery was substantially reduced in association with decreased frequency in the diagnosis of arrest of dilation at less than 6 cm.