Does the neighborhood food environment contribute to ethnic inequalities in fast-food intake? findings from the ORiEL study.
The neighborhood food environment may contribute to ethnic inequalities in diet. Using data from 1389 participants in the Olympic Regeneration in East London (UK) study we assessed whether ethnic inequalities in neighborhood availability of fast-food restaurants mediated and/or modified ethnic inequalities in fast-food intake in 13-15 year-old adolescents. We compared the proportion of high fast-food consumers across "White UK", "Black", and "South Asian" ethnic categories. We used Poisson regression with robust standard errors to assess direct and indirect effects (mediation analysis) and risk ratios of high fast-food intake by ethnic category and fast-food restaurant availability level (effect measure modification analysis). There were ethnic inequalities in high fast-food intake, with risk ratios in adolescents of Black and South Asian background of 1.53 (95% CI: 1.25, 1.87) and 1.71 (95% CI: 1.41, 2.07) respectively compared to White UK participants. We found no evidence of a mediating effect by fast-food restaurant availability, but found some evidence of effect measure modification: ethnic inequalities in fast-food intake were largest in neighborhoods lacking fast-food restaurants, and narrowed as availability increased. Future research should explore why ethnic minorities are more likely to be high fast-food consumers than the majority ethnic group, especially when fast-food restaurant availability is lowest.


Detection of hepatitis B surface antigen in fixed tissues of patients with cirrhosis and hepatoma.
HBsAg has been sought by light microscopy in liver specimens from patients with cirrhosis (79 cases) and hepatoma (99 cases). The study was carried out on fixed material using orcein staining, immunoperoxidase technique and indirect immunofluorescence. HBsAg was detected in the serum by radio-immunoassay (RIA) using Ausria II-125 in 38 patients with cirrhosis and in 36 with hepatoma. In the 38 seropositive cases of cirrhosis HBsAg-positive cells were observed in 31 (81.6%) by the orcein staining and in 32 (84.2%) by the peroxidase and immunofluorescence staining. Among the 36 seropositive patients with hepatoma, HBsAg was detected in the surrounding non-neoplastic part of the liver, cirrhotic or not, in 30 (83.3%) by orcein staining and in 34 (94.4%) by the immunoperoxidase method and immunofluorescence. Positive solitary-cells were seen occasionally in the tumor tissue in 16 cases using orcein, in 9 using peroxidase and in 7 by fluorescence, out of the 36 seropositive patients with hepatoma. The results of this study do not support the hypothesis of a direct oncogenic effect of HBsAg on the liver cells, since this antigen was detected mainly in the non-neoplastic part of the liver tissue and only occasionally in the tumor cells. Of the 63 cases of seronegative hepatoma, 3 showed some round orcein-positive inclusion bodies in the cytoplasm of the neoplastic and the non-neoplastic cells; these bodies were not stained by the two immunological methods.


Differentiated Instruction as a Viable Framework for Meeting the Needs of Diverse Adult Learners in Health Professions Education.
Health professions education (HPE) instructors are often challenged with simultaneously teaching adult learners of varying educational levels, needs, and backgrounds. With an increased focus on interprofessional education, instructors may be tasked with teaching extremely diverse audiences during a single educational session. While some aspects of differentiated instruction (DI) have been implemented within HPE contexts, the DI framework appears to be relatively unknown in many fields. Evidence from a range of educational fields outside of HPE supports the use of DI as a framework to enhance fairness, diversity and inclusion while meeting core instructional needs. In this Monograph, we explore DI and offer strategies for implementation amenable to many HPE settings.


Drug-induced glaucomas: mechanism and management.
Glaucoma comprises a heterogeneous group of diseases that have in common a characteristic optic neuropathy and visual field defects, for which elevated intraocular pressure is the major risk factor. The level of intraocular pressure within the eye depends on the steady state of formation and drainage of the clear watery fluid, called the aqueous humour, in the anterior chamber of the eye. An obstruction in the circulatory pathway of aqueous humour causes an elevation in intraocular pressure. Because intraocular pressure is the most modifiable parameter, therapeutic measures (medical and surgical) are aimed at reducing the pressure to protect against optic nerve damage. Glaucomatous optic neuropathy results from degeneration of the axonal nerve fibres in the optic nerve and death of their cell bodies, the retinal ganglion cells. Clinical examination of the optic nerve head or disc and the peripapillary nerve fibre layer of the retina reveals specific changes, and the resulting visual field defects can be documented by perimetry. Glaucoma can be classified into four main groups: primary open-angle glaucoma; angle-closure glaucoma; secondary glaucoma; and developmental glaucoma. Drug-induced glaucoma should be considered as a form of secondary glaucoma because it is brought about by specific systemic or topical medications. Although there is a high prevalence of glaucoma worldwide, the incidence of drug-induced glaucoma is uncertain. Drugs that cause or exacerbate open-angle glaucoma are mostly glucocorticoids. Several classes of drugs, including adrenergic agonists, cholinergics, anticholinergics, sulpha-based drugs, selective serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, anticoagulants and histamine H(1) and H(2) receptor antagonists, have been reported to induce or precipitate acute angle-closure glaucoma, especially in individuals predisposed with narrow angles of the anterior chamber. In some instances, bilateral involvement and even blindness have occurred. In this article, the mechanism and management of drug-induced glaucomatous disease of the eye are emphasised. Although the product package insert may mention glaucoma as a contraindication or as an adverse effect, the type of glaucoma is usually not specified. Clinicians should be mindful of the possibility of drug-induced glaucoma, whether or not it is listed as a contraindication and, if in doubt, consult an ophthalmologist.


Subvisual chromatin changes in cervical epithelium measured by texture image analysis and correlated with HPV.
In this study, we are testing the hypothesis that human papillomavirus (HPV) positivity is correlated with chromatin texture in the cell. Interim analyses are important since this study involves 2000 patients and generates 6000 biopsy specimens that will be subjected to quantitative histopathological analysis and correlated to HPV positivity as measured by the Hybrid Capture II test (Digene; Gaithersberg, MD) and both HPV-DNA and mRNA by the polymerase chain reaction (PCR). The studies of optical technologies, from which we derive this sample, use the colposcopically directed and histopathologically classified cervical biopsy as the gold standard. In this report, we describe the results of an interim analysis of quantitative histopathology and chromatin texture as correlates of HPV infection using the cyto-savant system in cytologically and histopathologically negative specimens. A group of 1544 patients entered the optical technology trials, generating 3275 biopsies and 1544 Papanicolaou readings. Two hundred forty-eight patients were cytologically and histopathologically negative. Study pathologists reviewed histologic samples 3 times in a blinded fashion. Non-overlapping, quantitatively stained nuclei were selected from the samples by the pathologists. HPV testing was done using the PCR method and the Hybrid Capture II test. Statistical analysis involved the creation of a classification matrix using a linear discriminant analysis. The matrix was trained on HPV-positive cells by PCR. The analysis included the random creation of both a training set and a validation set that were classified based on the discrimination score obtained by correlating nuclear texture with HPV positivity. The sensitivity of the classification was 52-54% and the specificity was 77-78%. Overall, a 68% predicted accuracy was achieved for both the training set and the test set. The agreement of a test and training set shows that the sets created randomly are indeed similar, and that the discrimination score worked equally well in both sets of cells. Once a cell-by-cell algorithm for HPV positivity was derived, HPV positivity was recalculated on the basis of cell-by-cell texture features. HPV positivity was then recalculated on both a per-biopsy basis and a per-patient basis. For HPV 16 and 18, the positivity rate was 70% on a per-biopsy basis and 73% on a per-patient basis. Although these results are preliminary, they suggest that texture features reflecting chromatin condensation may correlate with HPV positivity. The current sample is histologic, the analysis suggests that in a cytologic sample, HPV positivity could be detected or confirmed by texture features computed as part of an HPV-associated score. Additional biologic markers could be used as needed. While this study was performed on histologic samples, a study of cytologic samples would be more useful. Future studies will examine chromatin texture compared to HPV integration and mRNA HPV expression.


Comparative Study of the Pathogenesis of Rhinopneumonitis Induced by Intranasal Inoculation of Hamsters with Equine Herpesvirus-9, Equine Herpesvirus-1 strain Ab4p and Zebra-borne Equine Herpesvirus-1.
Equine herpesvirus-9 (EHV-9), equine herpesvirus-1 (EHV-1) and zebra-borne EHV-1 are members of the family Herpesviridae and cause encephalitis and rhinopneumonitis in a range of animal species. The aim of this study was to characterize and compare the rhinopneumonitis induced by experimental intranasal inoculation of groups of hamsters with EHV-9, EHV-1 strain Ab4p or zebra-borne EHV-1 viruses. Animals inoculated with EHV-9 had earlier and more severe neurological and respiratory signs than those inoculated with EHV-1 strain Ab4p or zebra-borne EHV-1. At 4-5 days post inoculation (dpi), hamsters inoculated with EHV-9 had significantly increased expression of open reading fame (ORF) 30, the viral gene encoding the DNA polymerase, in lung tissue. ORF 30 expression at these time points was higher in the hamsters infected with EHV-9 than in those inoculated with the other two viruses. Severe, mild or very mild rhinitis was seen in animals inoculated with EHV-1 strain Ab4p, EHV-9 and zebra-borne EHV-1, respectively. Viral antigen was detected in olfactory receptor neurons, inflammatory cells and desquamated epithelial cells in animals in all groups until 5 dpi. Tracheitis was also seen in all three virus-infected groups with viral antigen detected in tracheal epithelium. Inoculated hamsters developed interstitial pneumonia of increasing severity over the course of the experiment. Bronchopneumonia and vasculitis were also seen in all three infected groups. These results confirm that, in addition to their neurotropism, EHV-9 and zebra-borne EHV-1 are pneumotropic viruses. EHV-1 strain Ab4p caused more severe upper respiratory tract disease, but no significant differences were detected in the severity of pneumonia induced by each virus.


The nucleotide sequence of five ribosomal protein genes from the cyanelles of Cyanophora paradoxa: implications concerning the phylogenetic relationship between cyanelles and chloroplasts.
The nucleotide sequences of the ribosomal protein genes rps18, rps19, rpl2, rpl33, and partial sequence of rpl22 from cyanelles, the photosynthetic organelles of the protist Cyanophora paradoxa, have been determined. These genes form two clusters oriented in opposite and divergent directions. One cluster contains the rpl33 and rps18 genes; the other contains the rpl2, rps19, and rpl22 genes, in that order. Phylogenetic trees were constructed from both the DNA sequences and the deduced protein sequences of cyanelles, Euglena gracilis and land plant chloroplasts, and Escherichia coli, using parsimony or maximum likelihood methods. In addition, a phylogenetic tree was built from a distance matrix comparing the number of nucleotide substitutions per site. The phylogeny inferred from all these methods suggests that cyanelles fall within the chloroplast line of evolution and that the evolutionary distances between cyanelles and land plant chloroplasts are shorter than between E. gracilis chloroplasts and land plant chloroplasts.


Co-culture of fibroblasts and hepatic parenchymal cells induces metabolic changes and formation of a three-dimensional structure.
Co-culturing of tendon fibroblasts and liver parenchymal cells in Williams' medium E supplemented with fetal bovine serum, hormones, and L-ascorbic acid 2-phosphate, a long acting vitamin C derivative, resulted in formation of three-dimensional structure. Both growth of fibroblasts and their production of collagen were inhibited, however production of albumin by the hepatocytes was much better preserved than when individual cells were cultured separately, indicating epithelial-mesenchymal interactions stimulate reorganization of the liver-like tissue from isolated cells.


Characterization of the BM88 promoter and identification of an 88 bp fragment sufficient to drive neurone-specific expression.
BM88 is a neurone-specific protein implicated in cell cycle exit and differentiation of neuronal precursors. It is widely expressed in terminally differentiated neurones but also in neuronal progenitors, albeit in lower levels. Thus BM88 expression shows a tight correlation with the progression of progenitor cells towards neuronal differentiation. Here we report the genomic organization and proximal promoter characterization of the human and mouse BM88 genes. Both promoters lie in a CpG island, are TATA-less and have multiple transcription start sites. Deletion analysis performed on the human BM88 gene revealed an 88 bp minimal promoter fragment that is preferentially active in neural cells. Importantly, this minimal promoter is sufficient to confer specific transcriptional activity in primary neurones, but not in glial cells. Within the promoter region there are four functional Sp1-binding sites. Simultaneous mutations to all four Sp1 sites results in complete loss of promoter activity. Transactivation experiments revealed that Sp1 directly activates the BM88 promoter while activation also occurs in the presence of neurogenin-1. Characterization of the promoter elements that control neurone-specific and developmental expression of BM88 should contribute to the elucidation of the transcriptional networks that regulate the transition from a proliferative neural progenitor to a post-mitotic neurone.


Left pulmonary isomerism with normal arrangement of the heart and abdominal organs. Computed tomography of two adults.
The computed tomography and the three-dimensional reformatting of the thorax of two adults with left pulmonary isomerism demonstrated: two right-sided and two left-sided pulmonary lobes, bilateral hyparterial upper lobe bronchi, symmetrical main bronchi in one and slightly longer left in the other, normal atrial arrangement as identified by a broader right atrial appendage and the coronary sinus on computed tomograms. The arrangement of the heart and abdominal organs was normal. Computed tomography could be a direct non-invasive approach in identification of the arrangement of the heart and organs.


Degradation of various insecticides in cooked eggs during in vitro human digestion.
The objective of this study was to determine the effects of cooking and in vitro human digestion on the changes of five insecticides-fipronil, bifenthrin, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD), and 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (DDE)-in egg whites and yolks. Each insecticide was applied to egg whites and yolks at a concentration of 1000 μg/g. After cooking the egg whites and yolks, concentrations of bifenthrin, DDD, and DDE decreased (P < 0.05), whereas those of fipronil and DDT were unchanged (P > 0.05) in both egg whites and yolks. Next, an in vitro human digestion model that simulates all the steps of human digestion was employed. Until digestion in the small intestine, the concentrations of fipronil and DDT in the cooked egg whites and yolks were unchanged (P > 0.05), whereas those of bifenthrin, DDD, and DDE decreased (P < 0.05) at each digestion step. In the large intestinal digestion step with Escherichia coli and Lactobacillus sakei as enterobacteria, the concentrations of all the insecticides decreased (P < 0.05) in the cooked egg whites and yolks. Among the insecticides, bifenthrin showed the lowest concentration (P < 0.05). In conclusion, the use of bifenthrin as an insecticide would be comparatively less toxic than other insecticides in terms of environmental pollution and human health, because of its easy degradation.


Defensive components in insect eggs: are anthraquinones produced during egg development?
Eggs of several insect species are protected against natural enemies by noxious components. However, almost nothing is known about the fate of these defensive substances during egg development nor their site of biosynthesis. The eggs of several leaf beetle species of the taxon Galerucini contain components that are unusual in insects: 1,8-dihydroxylated anthraquinones and anthrones that deter predators such as ants and birds. These components, i.e., the anthrones dithranol and chrysarobin, and the anthraquinones chrysazin and chrysophanol, are not sequestered from host plants. We asked whether the amounts of these components in the overwintering eggs of Galeruca tanaceti change from deposition to larval hatching. Gas chromatography-mass spectroscopy (GC-MS) analyses of eggs revealed a significant decrease in total amounts of dithranol and chrysophanol from egg deposition in autumn to the next spring 5 months later. Thus, these results do not provide any hint of active anthraquinone biosynthesis within eggs. Instead, the anthrones and anthraquinones that must be incorporated by the female into the eggs seem to be degraded to some extent either by the embryo or endosymbionts. GC-MS analyses showed that parasitization of eggs had some effects on the quantities of anthrones and anthraquinones.


Dietary exposure of acrylamide from the fifth Chinese Total Diet Study.
The levels of acrylamide in 240 food composite samples from the 5th Chinese Total Diet Study (TDS) were measured using an LC-MS/MS method and the exposure estimates for the general population were evaluated. The samples were collected from 20 provinces in China, covering about two thirds of the Chinese population. Acrylamide was detected in 40.0% of composite samples with the concentrations ranged from 0.8 to 211.8 μg/kg. The average dietary intakes from the 5th Chinese TDS were 0.319 μg kg(-1) bw day(-1) and an increase with about 70% was observed from the 3rd Chinese TDS in 2000 to the 5th Chinese TDS between 2009 and 2012. The main food group contributors to acrylamide exposure were vegetables (35.2%), cereals (34.3%) and potatoes (15.7%). Based on the benchmark dose lower confidence limit at 10% risk (BMDL10) of 0.31 mg kg(-1) bw day(-1) for the induction of mammary tumors in rats and 0.18 mg kg(-1) bw day(-1) for Harderian gland tumors in mice, the margins of exposure (MOEs) were 973 and 565 for Chinese general population, respectively. These MOEs indicate a human health concern.


Anesthetic Techniques in Endoscopic Sinus and Skull Base Surgery.
Endoscopic sinus approach has become one of the most common surgical techniques for endoscopic sinus and skull base surgery. Anesthetic management has an important impact on the overall patient management, from the preoperative assessment and management to the quality of the surgical field and the postoperative recovery. Hemostasis is critical for adequate anatomical endoscopic visualization. Mild controlled hypotension seems to improve the visibility of the surgical field. Reduction of intraoperative bleeding should be considered during the treatment planning. Preoperative preparations include the optimization of comorbidities and cessation of drugs that may inhibit coagulation.


Prevalence of metabolic syndrome in Iranian professional drivers: results from a population based study of 12,138 men.
It is evident that professional driving is associated with substantial changes in lifestyle habits. Professional drivers are prone to metabolic syndrome (MetS) and its complications because their working environment is characterized by numerous stress factors such as lack of physical activity due to working in a fixed position, disruption in diet, and irregular sleep habits. The aim of the present study was to estimate the prevalence of MetS among long distance drivers residing in West Azerbaijan province in Iran. To assess the prevalence of metabolic syndrome among professional long distance drivers, 12138 participants were enrolled in this cross sectional study. The MetS was defined using International Diabetes Federation criteria. Among 12138 participants, 3697 subjects found to be MetS. The crude and age-adjusted rates of MetS were 30.5% and 32.4% respectively. Based on Body mass index (BMI), 5027 subjects (41.4%) were overweight (BMI ≥ 25.01-30 kg/m2), and 2592 (21.3%) were obese (BMI ≥ 30.01 kg/m2). The presence of central obesity was more common than other components. The associations of MetS with BMI, pack-year smoking, age, weekly driving duration and driving experiences were significant in the logistic regression. By increasing BMI, pack-year smoking, age, weekly driving duration and driving experiences, odds ratio of MetS was increased. The study suggests that MetS has become a noteworthy health problem among Iranian long distance drivers. This might be due to the following facts: sitting in a fixed position for long hours while working, cigarette smoking, job stress, unhealthy diet and lack of physical activity. Educational programs should be established for promoting healthy lifestyle and also for early detection and appropriate interventions.


The particular usefulness of radioisotope methods in some benign bone diseases.
The authors have performed radioisotope examinations in 271 patients with various non-neoplastic bone diseases. According to their opinion, early diagnosis and follow-up of therapeutic results are the main characteristics which allow radioisotopes to play an important and irreplaceable role. They particularly emphasize the usefulness of radioisotope methods in femoral aseptic necrosis and Paget's disease.


Competition for bumblebee visitation between Melampyrum pratense and Viscaria vulgaris with healthy and Ustilago-infected flowers.
We studied bumblebee foraging on two sympatrically and simultaneously flowering species, Melampyrum pratense (Scrophulariaceae) and Viscaria vulgaris (Caryophyllaceae) during the flowering season of Viscaria in south-west Sweden. We distinguished between healthy and Ustilago-infected Viscaria plants. Both species shared the main insect visitor, queens of Bombus hortorum, which collected nectar from both species but pollen from Melampyrum only. The pattern of visitation changed over the season: bumblebees preferred Viscaria early on, but changed to Melampyrum later in the season, probably because of the higher sugar content of Melampyrum nectar and the possibility of collecting both nectar and pollen from the same flower. Pollen collecting is probably of increasing importance since the need of pollen for the developing larvae will increase with time. Flowers of Viscaria received fewer visits in plots with other species than in pure Viscaria plots during one year and received more visits early than late in the season during both years. Melampyrum flowers received similar amounts of visits in mixed and pure environments. They also received more visits early than late, although this was probably a result of pollinator satiation since Melampyrum became very abundant with time. Ustilago-infected plants received far fewer visits but because of its long flowering time the proportion of open flowers receiving visits was still high. Viscaria flowers received significantly more visits than flowers of other species when bumblebees made heterospecific flower visits from Ustilago-infected plants; thus Ustilago spores were probably effectively dispersed from infected to healthy plants by the pollinators. The mechanism behind competition for pollination in this system was competition through pollinator preference, since the visitation rate to Viscaria actually decreased, but also competition through improper pollen transfer (grains of both species were found on the bodies of bumblebees) since the incidence of switching between the two species increased, probably resulting in an increased misplacement of conspecific pollen grains with time.


A novel non-peptide endothelin antagonist isolated from bayberry, Myrica cerifera.
A potent non-peptide ET receptor antagonist, myriceron caffeoyl ester (50-235), was isolated from the bayberry, Myrica cerifera. This compound selectively antagonized specific binding of [125I]ET-1, but not of [125I]ET-3, to rat cardiac membranes, ET-1-induced increase in the intracellular free calcium concentration in Swiss 3T3 fibroblasts, and ET-1-induced contraction of rat aortic strips. Thus, 50-235 is the first non-peptide ET(A) receptor antagonist. This compound can be useful for studying the physiological role of endothelin and exploring its role in various diseases.


Olfactory receptor 78 is expressed in hypothalamic vasopressin/oxytocin neurons, parenchymal microglia and choroidal macrophages in mice.
Olfactory receptors have been detected in extraolfactory organs. Olfactory receptor 78 (Olfr78), proposed to respond to small organic acids, is widely expressed in the kidney, arterioles, colon, and prostate. However, its expression patterns in the brain remain largely unknown. Using immunohistochemistry, we revealed that Olfr78 was densely expressed in the hypothalamus and choroid plexus and sparsely expressed throughout the parenchyma. By costaining with cellular markers, we further found that Olfr78 was expressed in the somata and axons of vasopressin/oxytocin neurons in the hypothalamic paraventricular/supraoptic nuclei. Olfr78 was also strongly expressed in macrophages in the choroid plexus and moderately expressed in microglia near the parenchymal vasculature. Considering that these brain regions should communicate with cerebral blood flow, Olfr78 could contribute to sensing the humoral conditions surrounding the cerebrovascular system.


A Pitfall in Prenatal Ultrasonic Detection of Submucous Cleft Palate.
We present a case with prenatal diagnosis of submucous cleft palate (SMCP) which was described using 2- and 3-dimensional (3D) ultrasonography in utero. A 25-year-old pregnant woman was referred to our department for fetal ultrasound screening. After the detection of cardiac and spinal malformations of fetal, further detailed examination detected SMCP, which showed a gap within the hard palate on axial transversal view with the soft palate visible on sagittal view. The imaging of a defective hard palate in prenatal 3D ultrasonography is similar to that in postmortem 3D computed tomography reconstruction. A gap within the hard palate and verification of the visibility of the soft palate should be key points in the prenatal diagnosis of SMCP. Three-dimensional ultrasonic imaging is helpful for displaying the shape and extent of the bony defect in SMCP.


Cryosurgery in prostate carcinoma: clinical evidence of immunostimulation of host versus tumor.
Results of cryosurgery in the manipulation of prostate cancer in a rabbit animal model is discussed. Clinical application of cryosurgery in the treatment of prostate cancer in man and its effect on metastases is presented.


New advances in the diagnosis of canine and feline liver and pancreatic disease.
The diagnosis of liver and pancreatic disorders in dogs and cats present their own set of challenges. However, as new diagnostic tests are developed and the optimal ways in which to use existing tests are determined, the ability of the veterinary profession to make these diagnoses continues to improve. Histopathological assessment is considered to be the reference standard for the diagnosis of many hepatic and pancreatic diseases, but it has some inherent limitations. New classes of diagnostic tests for liver disease that are currently being studied include direct and indirect serum markers of hepatic fibrosis, such as hyaluronic acid; novel markers of hepatocellular injury, such as circulating microRNAs; and quantitative tests of hepatic microsomal function. Assays for pancreas-specific lipase have greatly improved the ability of practitioners to diagnose pancreatitis in dogs and cats. However, further research is needed to fully understand the characteristics of these assays, especially in patients with concurrent non-pancreatic disease. The more common use and refinement of CT and MRI to assess the hepatobiliary system and pancreas of dogs and cats also have huge potential to improve diagnostic capabilities.


Variability of human fasted venous plasma metabolomic profiles with tourniquet induced hemostasis.
Venous plasma metabolomics is a potent and highly sensitive tool for identifying and measuring metabolites of interest in human health and disease. Accurate and reproducible insights from such metabolomic studies require extreme care in removing preanalytical confounders; one of these is the duration of tourniquet application when drawing the venous blood sample. Using an untargeted plasma metabolomics approach, we evaluated the effect of varying durations of tourniquet application on the variability in plasma metabolite concentrations in five healthy female subjects. Tourniquet application introduced appreciable variation in the metabolite abundances: 73% of the identified metabolites had higher temporal variation compared to interindividual variation [Intra-Class Correlation (ICC) > 0.50]. As such, we recommend tourniquet application for minimal duration and to wait for 5 min with the needle in situ after removing the tourniquet, to reduce hemostasis-induced variability and false flags in interpretation.


Barbiturate inhibition of endothelium-dependent dilatation of blood- and Krebs-perfused rat tail arteries.
Rat tail artery segments were cannulated both ends, immersed in an organ bath filled with Krebs solution, and perfused at a constant 3 ml/min with Krebs solution from a reservoir or arterial blood from a donor conscious rat. Donor rats had chronic indwelling exteriorized silastic cannulas in a carotid artery and jugular vein. Blood withdrawn from the carotid artery returned to the donor rat via the jugular vein cannula after perfusing the tail artery segment. Arteries were constricted and perfusion pressure increased by infusing noradrenaline into the perfusate. In Krebs perfused arteries vasodilator responses were obtained to acetylcholine (ACh) and sodium nitroprusside (NP) infused for 1 min at 10(-6) M. The addition of the barbiturates, 'Inactin' (5-ethyl-5-(1-methylpropyl)-2-thiobarbiturate) and pentobarbitone, at 10, 30 and 100 micrograms/ml progressively inhibited responses to ACh but not to NP. Pentobarbitone 30 micrograms/ml also significantly inhibited responses to 3 X 10(-7) M of the calcium ionophore A23187, shifted the dose-response curve for ACh to the right and suppressed the maximum ACh response. Vasoconstrictor responses were also obtained by periarterial stimulation of the sympathetic nerves at 5 Hz for 5 s every 2 min. These responses were markedly inhibited by ACh (10(-5) M) and this inhibition was not affected by Inactin 100 micrograms/ml. In arterial segments perfused with blood from a donor conscious rat, ACh infused for 1 min at a rate calculated to produce a concentration of 10(-4) M in the blood perfusate at the site of infusion, decreased tail artery perfusion pressure.(ABSTRACT TRUNCATED AT 250 WORDS)


Preventing Oral Disease: Alternative Providers and Places to Address This Commonplace Condition.
Oral health disease in young children has not decreased, despite adequate modalities for treatment and prevention. Because many children may not see a dentist before oral disease has begun, disease progression can be expected, affecting short-term and long-term oral health. However, most children are seen by other health professionals frequently in their youngest years, providing a unique opportunity to help weave a safety net of oral health care until they are established in a dental home. This article details ways primary care providers can promote oral health, including ways to integrate ancillary dental professionals into the primary care home.


Can cell morphology in monolayer reveal its behaviour in aggregates?
The morphology of HeLa cells was altered to stellate shape by 0.2-1.0 mM butyric acid. At similar concentrations butyric acid did not alter the ability of HeLa cells to aggregate, but did inhibit the remodelling of the aggregates. Papaverine at 10 micrometers, on the other hand, had no effect on cells in monolayer, but severely inhibited the ability of cells to aggregate and the remodelling of the aggregates. Our results show that the effect of a drug on the morphology of HeLa cells in monolayer does not predict its effect in aggregates of cells which more faithfully approximate the behaviour of cells in tissue than the monolayer.


Pregnancy-associated changes in the endocrine pancreas of normoglycaemic streptozotocin-treated Wistar rats.
The effect of pregnancy on pancreatic insulin content and relative B-cell volume has been studied in normoglycaemic Wistar rats treated with streptozotocin 14 days before mating. A single intravenous injection of streptozotocin (30 mg/kg body weight) caused a significant reduction of pancreatic insulin content and B-cell volume. The islet insulin content was 60% of control values. However, pregnancy-associated adaptation was preserved in these streptozotocin-treated animals. Plasma insulin levels, pancreatic insulin and B-cell volume were significantly enhanced compared with non-pregnant rats investigated on the same date. The incorporation of [3H]-thymidine into islets from pregnant rats (day 10.5) was higher than that in islets isolated from non-pregnant animals. After delivery insulin content and B-cell volume returned to pre-pregnant values. Also during a longer period after streptozotocin treatment (156 days), no measurable enhancement of B-cell volume and pancreatic insulin content was observed indicating the unresponsiveness of residual B cells to compensate spontaneously for the loss despite persisting normoglycaemia.


Detection of singlet oxygen production by ESR.
SINGLET molecular oxygen is a very powerful oxidant. Its action is important in a variety of chemical and biological processes(1-4), for examples dye-sensitised photooxidation of lipids, proteins and nucleic acids(4), photodynamic inactivation of viruses(5) and cells(4), phototherapy of cancer(6,7), carcinogenesis(8), haemolysis of erythocytes(9), sensitisation of the human skin(4) and degradation of food(4). The methods used to detect singlet oxygen are unspecific, of low sensitivity or laborious. Photooxidation of 1,3-diphenylisobenzofuran seems to be the most widely used diagnostic test for (1)O(2). However, in the absence of additional control experiments this test does not prove the intermediacy of (1)O(2) (ref. 4) and 1,3-diphenylisobenzofuran has very low solubility and dimerises in aqueous solutions. Lion et al.(10) have proposed a new method to detect (1)O(2) involving the generation of stable nitroxide radicals when (1)O(2) reacts with the sterically hindered amine 2,2,6,6,-tetramethylpiperidin. When using this method to detect (1)O(2) in neutral aqueous solutions, we found no radical production. We report here our investigation of this problem, as it is biologically important to be able to detect (1)O(2) production in such solutions.


Chlordecone-induced potentiation of carbon tetrachloride hepatotoxicity: a morphometric and biochemical study.
The present study, conducted over a time course of 36 hr after CCl4 administration, describes sequential morphometric and biochemical changes which occur in livers of rats exposed to a combination of low levels of chlordecone (10 ppm for 15 days) and a single ip injection of CCl4 (0.1 ml/kg). Those changes were compared to hepatic alterations which occur in rats that received the same dose of chlordecone or CCl4 alone. Biochemical studies showed only trivial increases in levels of glutamic-pyruvic transaminase (GPT), glutamic-oxalacetic transaminase (GOT), and moderate but temporary increases in isocitrate dehydrogenase (ICD) after CCl4 alone. The combination of chlordecone and CCl4 resulted in significantly greater elevations of all three serum enzymes at all time intervals examined. Morphometric data showed no difference between normal diet controls and animals exposed to chlordecone alone as far as numerical density of hepatocytes or volume densities of hepatocytes with glycogen, lipid, dilated rough endoplasmic reticulum (RER), pyknosis, or mitoses. Morphometric analysis of livers from animals that received CCl4 alone showed decreases in numerical density, temporary decrease in percentage of hepatocytes containing glycogen, an increase in hepatocytes containing lipid, temporary increase in hepatocytes with dilated RER, and temporary increases in pyknotic nuclei. Soon after the initial hepatic injury was histologically evident between 4 and 6 hr, the number of mitoses increased dramatically and this progressed until complete recovery from CCl4 damage. From all indices of damage, complete recovery was evident by 36 hr after CCl4 administration.(ABSTRACT TRUNCATED AT 250 WORDS)


Discussion: 'Ovarian epithelial carcinoma with pelvic endometriosis,' by Wang et al.
In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Wang S, Qui L, Lang JH, et al. Clinical analysis of ovarian epithelial carcinoma with coexisting pelvic endometriosis.


Frontline Science: ATF3 is responsible for the inhibition of TNF-α release and the impaired migration of acute ethanol-exposed monocytes and macrophages.
Binge drinking represses host innate immunity and leads to a high risk of infection. Acute EtOH-pretreated macrophages exhibit a decreased production of proinflammatory mediators in response to LPS. ATF3 is induced and counter-regulates the LPS/TLR4 inflammatory cascade. Here, we investigated the potential role of ATF3 in LPS tolerance in acute ethanol-pretreated macrophages. We found that there was an inverse correlation between ATF3 and LPS-induced TNF-α production in acute ethanol-pretreated murine monocytes and macrophages. The knockdown of ATF3 attenuated the inhibitory effects of acute ethanol treatment on LPS-induced TNF-α production. Furthermore, ChIP assays and co-IP demonstrated that ATF3, together with HDAC1, negatively modulated the transcription of TNF-α. In binge-drinking mice challenged with LPS, an up-regulation of ATF3 and HDAC1 and a concomitant decrease in TNF-α were observed. Given that HDAC1 was concomitantly induced in acute ethanol-exposed monocytes and macrophages, we used the HDACi TSA or silenced HDAC1 to explore the role of HDAC1 in acute ethanol-treated macrophages. Our results revealed that TSA treatment and HDAC1 knockdown prevented acute ethanol-induced ATF3 expression and the inhibition of TNF-α transcription. These data indicated a dual role for HDAC1 in acute ethanol-induced LPS tolerance. Furthermore, we showed that the induction of ATF3 led to the impaired migration of BM monocytes and macrophages. Overall, we present a novel role for ATF3 in the inhibition of LPS-induced TNF-α and in the impairment of monocyte and macrophage migration.


Multiplanar analysis for pulmonary nodule classification in CT images using deep convolutional neural network and generative adversarial networks.
Early detection and treatment of lung cancer holds great importance. However, pulmonary-nodule classification using CT images alone is difficult to realize. To address this concern, a method for pulmonary-nodule classification based on a deep convolutional neural network (DCNN) and generative adversarial networks (GAN) has previously been proposed by the authors. In that method, the said classification was performed exclusively using axial cross sections of pulmonary nodules. During actual medical-examination procedures, however, a comprehensive judgment can only be made via observation of various pulmonary-nodule cross sections. In the present study, a comprehensive analysis was performed by extending the application of the previously proposed DCNN- and GAN-based automatic classification method to multiple cross sections of pulmonary nodules. Using the proposed method, CT images of 60 cases with confirmed pathological diagnosis by biopsy are analyzed. Firstly, multiplanar images of the pulmonary nodule are generated. Classification training was performed for three DCNNs. A certain pretraining was initially performed using GAN-generated nodule images. This was followed by fine-tuning of each pretrained DCNN using original nodule images provided as input. As a result of the evaluation, the specificity was 77.8% and the sensitivity was 93.9%. Additionally, the specificity was observed to have improved by 11.1% without any reduction in the sensitivity, compared to our previous report. This study reports development of a comprehensive analysis method to classify pulmonary nodules at multiple sections using GAN and DCNN. The effectiveness of the proposed discrimination method based on use of multiplanar images has been demonstrated to be improved compared to that realized in a previous study reported by the authors. In addition, the possibility of enhancing classification accuracy via application of GAN-generated images, instead of data augmentation, for pretraining even for medical datasets that contain relatively few images has also been demonstrated.


Panobinostat inhibits breast cancer progression via Vps34-mediated exosomal pathway.
Exosomes play crucial roles in intercellular communication, including tumor metastasis. Panobinostat (LBH589), a histone deacetylases (HDAC) inhibitor, is an emerging anti-tumor drug with promising efficacy in cancer therapy. This study was set out from recent evidence that exosome was a mechanism of intercellular drug transfer with significant pharmacological consequences. It enlightened us LBH589 might regulate tumor growth through exosomal secretion. Here we demonstrated LBH589 induced autophagy and facilitated secretory autophagy. Furthermore, LBH589 dose- and time-dependently stimulated exosomal release mediated by Vps34/Rab5C pathway, documented by the ablation of Vps34 and/or Rab5C in breast cancer cells. Additionally, the findings also presented LBH589 inhibited breast cancer progression via exosomes. Altogether, we revealed a novel mechanism of LBH589 in exosome-mediated anti-tumor effects in breast cancer. The schematic diagram of signaling pathways involved in the suppression of breast cancer progression by LBH589 via exosomes.


Differential gene expression during sporulation in Bacillus subtilis: structure and regulation of the spoIIID gene.
The gene spoIIID, which is essential for spore formation in Bacillus subtilis, was cloned and sequenced. It consists of one open reading frame which would encode a 93-amino-acid protein with a classic helix-turn-helix motif, characteristic of sequence-specific DNA-binding proteins. SpoIIID protein is a previously identified transcription factor, capable of altering the specificity of RNA polymerase containing sigma K in vitro (Kroos et al., 1989). The spoIIID83 mutation (by which the locus was originally identified), was sequenced and found to be a single base substitution in the ribosome binding site upstream of the spoIIID open reading frame. A transcriptional fusion to lacZ was constructed and used to examine the regulation of spoIIID. Expression of spoIIID occurred only during sporulation, beginning 1.5 to 2 hours after the initiation of sporulation. The dependence of spoIIID expression on other spo loci suggests that it is mother-cell-specific, and that it is transcribed by sigma E-containing RNA polymerase.


Sex-Stratified Polygenic Risk Score Identifies Individuals at Increased Risk of Basal Cell Carcinoma.
The incidence of basal cell carcinoma (BCC) is higher among men than women. Susceptibility loci for BCC have been identified through genome-wide association studies, and two previous studies have found polygenic risk scores (PRS) to be significantly associated with the risk of BCC. However, to our knowledge, sex-stratified PRS analyses examining the genetic contribution to BCC risk among men and women have not been previously reported. To quantify the contribution of genetic variability on the BCC risk by sex, we derived a polygenic risk score and estimated the genetic relative risk distribution for men and women. Using 29 published single nucleotide polymorphisms, we found that the estimated relative risk of BCC increases with higher percentiles of the polygenic risk score. For men, the estimated risk of BCC is twice the average population risk at the 88th percentile, while for women, this occurs at the 99th percentile. Our findings indicate that there is a significant impact of genetic variation on the risk of developing BCC and that this impact may be greater for men than for women. Polygenic risk scores may be clinically useful tools for risk stratification, particularly in combination with other known risk factors for BCC development.


Stimulus specificity in the habituation of the startle response in the rat.
A series of experiments evaluated whether the habituation of the startle response of the rat to tactile and auditory cues is stimulus specific. Experiment 1 showed stimulus specificity of a short-term habituation effect, whereby the startle to the second of a pair of stimuli was significantly less when the initial stimulus involved the same rather than the different modality. Experiments 2 and 3 focused on the more persistent decrement in startle that is a result of repeated stimulation, and demonstrated that such long-term habituation to the tactile and auditory stimuli contained a stimulus specific component in addition to a generalized component. The generalized habituation observed between the tactile and auditory stimuli in the three experiments may be due to an auditory accompaniment of the tactile stimulus employed. Discussion emphasized the utility of investigating habituation in a preparation with robust specificity.


Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer.
To standardize the pathological analysis of total mesorectal excision specimens of rectal cancer following neoadjuvant chemoradiotherapy for locally advanced disease (T3/T4), including tumour regression. Standardized dissection and reporting was used for 60 patients who underwent total mesorectal excision following long-course chemoradiotherapy. Tumour regression was scored by two pathologists (K.S., D.G.) using both an established 5-point tumour regression grade (TRG), and a novel 3-point grade. Both scores were evaluated for interobserver variability. A complete or near-complete pathological response (3-point TRG 1) was found in 10 patients (17%). Using the 5-point TRG, there was good agreement between both pathologists (kappa = 0.64). Using the 3-point grade, agreement was excellent (kappa = 0.84). No disease recurrence has been reported in patients with a complete, or near complete pathological response (3-point TRG 1), after a mean follow-up of 22 months. Tumour regression grade is a useful method of scoring tumour response to chemoradiotherapy in rectal cancer. TRG 1 and 2 can be regarded as a complete pathological response (ypT0). A modified 3-point grade has the advantage of better reproducibility, with similar prognostic significance.


Multiple cerebral infarction diagnosed as Eosinophilic Granulomatosis with Polyangiitis by autopsy.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis of unknown cause involving the brain and accompanied by prominent eosinophilia. Intracardiac thrombosis is a major cardiac complication of EGPA that may cause thromboembolism. A 53-year-old man presenting with abulia (consciousness disturbance) and left upper limb paralysis was admitted to our hospital. His case was complicated by penetrating branches, small vessel infarcts, and endocardial thrombosis in the right and left ventricle. Cardiomyopathy was also observed. Sixteen days after admission, the patient died from intracranial hemorrhage. Brain autopsy revealed two major findings: 1) large hemorrhagic infarction caused by cardiac embolism; and 2) granuloma and eosinophil infiltration. Vasculitis was accompanied by eosinophil infiltration in the cortical blood vessels and granuloma. In this case study, we report autopsy findings of brain infarction in a patient with EGPA and endocardial thrombosis. The brain infarction was caused by the cardiac embolisms and vasculitis.


The correlation between the subsets of tumor infiltrating memory T cells and the expression of indoleamine 2,3-dioxygenase in gastric cancer.
Although many researchers have concentrated on the mechanism of T cell anergy resulting from over-expression of Indoleamine 2,3-dioxygenase (IDO), it remains unclear what alterations will developed in memory T cells (Tm) under over-expression of IDO. Immunohistochemical staining for IDO expression in gastric cancer tissues (n=50) was carried out. Tumor-infiltrating memory Tm cells were counted by flow cytometry. The association between IDO expression and the subsets of tumor infiltrating Tm are discussed. The higher IDO expressions were significantly associated with deeper invasion (P=0.016) and higher frequencies (P=0.038) of lymph node metastasis. The lower tumor-infiltrating CD4+Tm were significantly associated with the advanced clinical stage (P=0.026) and lymph node metastasis (P=0.016). The lower percentages of CD8+Tm were significantly related to undifferentiated histological type (P=0.042) and lymph node metastasis (P=0.037). However, the lower percentage of CD8+Tem was significantly correlated to differentiated histological type (P=0.017), lower frequencies of lymph node metastasis (P=0.014), and earlier clinical stage (P=0.008). The higher IDO expression patients had significantly lower percentages of CD4+Tm (P=0.012) and CD8+Tm (P=0.033). Nevertheless, it was confirmed that the higher level of IDO expression correlated with higher percentages of CD8+Tm cells in univariate and multivariate analysis (P=0.011). IDO over-expression and Tm in tumor microenvironments were correlated with the disease stage and histological type of gastric cancer. Higher IDO expression was related to the lower percentage of CD4+Tm and CD8+Tm, whereas the higher level of IDO expression related with a higher percentage of CD8+Tem.


Effects of leukocidin from Fusobacterium necrophorum on bovine peripheral leukocytes in vitro.
Partially purified leukocidin from Fusobacterium necrophorum damaged bovine peripheral leukocytes as demonstrated by trypan blue staining. Granulocytes were most and T-lymphocytes least sensitive to the leukocidin. Heating for 30 min at 60 degrees C completely inactivated the leukocidin. The cytotoxicity of the leukocidin could be neutralized by homologous anti-leukocidin. Scanning electron microscopy of the exposed cells revealed an apparent destruction of the cell membranes, loss of the microvilli and smoothing of the cell surfaces.


Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis.
Glutamate toxicity on PC12 cells is mediated by oxidative stress as a consequence of the inhibition of a cystine uptake system with depletion of GSH. In this study we report that glutamate decreases PC12 cell viability, inhibiting the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). This decrease was prevented by the antioxidants vitamin E, idebenone and L-deprenyl, which were also shown to be effective in reducing the accumulation of reactive oxygen species (ROS) in cells exposed to glutamate, decreasing the fluorescence of 2',7'-dichlorofluorescein (DCF). Incubation of PC12 cells with high glutamate concentrations induced mitochondrial dysfunction, leading to the loss of mitochondrial transmembrane potential, evaluated as a decrease in rhodamine 123 (Rh123) retention by mitochondria, and to the decrease of intracellular ATP levels. The mitochondrial dysfunction, induced by glutamate, can be involved in the observed increase of [Ca2+]i. The elevation of [Ca2+]i occurred after GSH depletion, suggesting that oxidative stress is involved in the disturbances of intracellular calcium homeostasis. In conclusion, our data indicate that glutamate, at concentrations which block cystine uptake in PC12 cells leading to GSH depletion and inducing oxidative stress, increases ROS accumulation and decreases cell survival by a mechanism involving mitochondrial dysfunction and impairment of Ca2+ homeostasis.


Linderae Radix Ameliorates Cognitive Dysfunction by Inhibiting Neuroinflammation and Synaptic Damage in Alzheimer's Disease Models.
Neuroinflammation and synaptic damage are important etiologies associated with the progression of Alzheimer's disease (AD). Linderae Radix (LR) has antioxidant and anti-inflammatory properties. This study investigated whether LR attenuates microglia activation-mediated neuroinflammation and synaptic degeneration and improves AD pathological phenotypes induced by amyloid beta oligomers (AβO) or lipopolysaccharide (LPS) toxicity. For in vitro studies, we treated LR to AβO-stimulated HT22 cells or LR LPS-stimulated BV2 cells. For in vivo studies, we administered LR to mice and AβO was injected by stereotaxic to induce cognitive impairment, neuroinflammation, and synaptic loss. We found that LR increased the cell viability reduced by AβO. Moreover, LR inhibited pro-inflammatory mediators such as nitric oxide (NO), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2), and downregulated p38 mitogen-activated protein kinase (MAPK) signaling in BV2 cells. Behavioral assessments demonstrated that LR administration significantly improved cognitive decline induced by AβO-injection. Furthermore, we found that microglia activation increased, and the expression of synaptic proteins decreased in the hippocampus of the AβO-injected group, which was alleviated in the LR-treated group. These findings suggest that LR may be a potential candidate for protection against neuroinflammation and synaptic loss, and may prevent or delay AD progression.


Adsorption of metadiiodobenzene on Cu(110): a theoretical study.
In this work, we have computationally modeled the adsorption of 1,3-diiodobenzene (meta-diiodobenzene or m-DIB) on Cu(1 1 0) by means of density functional theory including van der Waals interaction using Grimme's method. We have compared the adsorption energies and structures of 23 possible configurations of the physisorbed molecule. Furthermore, we have simulated STM images for the four most stable configurations using the Tersoff-Hamann approach at different bias voltages. We find that all the adsorption orientations have comparable energy, and we discuss the relative probabilities of experimental observation. We find that the adsorption induces small distortions in the molecular structure of the adsorbate and in some cases an adsorption-induced symmetry breakdown occurs. We also find evidence that the most stable arrangement is actually a bistable system with interesting symmetry properties.


Rectal plasmablastic lymphoma in Ebstein Barr virus positive and human immunodeficiency virus negative subject after external radiation therapy for prostatic cancer.
Plasmablastic lymphoma (PBL) represents a rare and aggressive subtype of diffuse large B cells lymphoma (DLBCL) most associated with the human immunodeficiency virus (HIV). Prognosis remains poor despite various treatment approaches. We describe an evolution at six months of HIV negative PBL and Ebstein Barr virus (EBV) positive PBL with chemotherapy. Role of radiotherapy is still unclear.


A Survey of Cardiothoracic Surgical Training in the United Kingdom: Realities of a 6-Year Integrated Training Program.
In recent years, cardiothoracic (CT) surgical training has faced several challenges, including a reduction in working hours and trainees favoring shorter training programs. We carried out a national survey in the United Kingdom (UK) to assess the CT 6-year training program. All CT trainees in the UK (n = 121) were sent an online survey. This was combined with a debate at the Society for CT Surgery of Great Britain and Ireland. Ninety-one (75.2%) of all trainees responded. Despite 56 (68.1%) being rostered for more than a 48-hour week, 31 (34.1%) of all trainees work an extra 10 hours. The majority (56, 61.5%) thought that on-calls and night duty are useful. Just over half of the trainees (47, 51.6%) spend at least 2 full days in the operating room, but 79 (86.8%) thought that this is too little and would spend voluntary time operating. Simulation of operations is thought to be useful; however, few thought that this should take more precedence in their training program. The majority of trainees thought that the current assessment of surgical training is suboptimal and does not examine surgical skill. Similarly, the majority thought that a defined number of operations is required before qualification. Trainees remain committed to their profession and are willing to dedicate more time perfecting their art. They believe that despite wanting extra operating experience, they will be ready for independent practice at the completion of their training. It rests with training bodies to find alternative assessments for surgical ability and to define experience at the exit point of training.


Inhibition of the dorsomedial striatal direct pathway is essential for the execution of action sequences.
Contrary to the previous notion that the dorsomedial striatum (DMS) is crucial for acquiring new learning, accumulated evidence has suggested that the DMS also plays a role in the execution of already learned action sequences. Here, we examined how the direct and indirect pathways in the DMS regulate action sequences using a task that requires animals to press a lever consecutively. Cell-type-specific bulk Ca2+ recording revealed that the direct pathway was inhibited at the time of sequence execution. The sequence-related response was blunted in trials where the sequential behaviors were disrupted. Optogenetic activation at the sequence start caused distraction of action sequences without affecting motor function or memory of the task structure. By contrast with the direct pathway, the indirect pathway was slightly activated at the start of the sequence, but the optogenetic suppression of such sequence-related signaling did not impact the behaviors. These results suggest that the inhibition of the DMS direct pathway promotes sequence execution potentially by suppressing the formation of a new association.


Protein binding in vivo to OP2 promoter of the Pseudomonas putida TOL plasmid.
The transcription of OP2 encoding enzymes for m-toluate catabolism on the Pseudomonas putida TOL plasmid is activated by basal-level XylS protein in the presence of m-toluate or by overproduced XylS protein in the absence of m-toluate. In this study, in vivo dimethyl sulfate (DMS) footprinting was performed to understand the mechanism of transcriptional regulation of OP2 promoter by XylS. In the presence of overproduced XylS without m-toluate, several protected nucleotides were observed, indicating the binding of RNA polymerase to DNA. However, the protection was canceled upon addition of m-toluate. These results suggest that RNA polymerase is retained by XylS on the OP2 promoter in the absence of inducer, and is released by m-toluate binding to XylS, concomitant with transcription.


SARS-CoV-2-specific CD4+ T cell longevity correlates with Th17-like phenotype.
Determinants of memory T cell longevity following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain unknown. In addition, phenotypes associated with memory T cell longevity, antibody titers, and disease severity are incompletely understood. Here, we longitudinally analyzed SARS-CoV-2-specific T cell and antibody responses of a unique cohort with similar numbers of mild, moderate, and severe coronavirus disease 2019 cases. The half-lives of CD4+ and CD8+ T cells were longer than those of antibody titers and showed no clear correlation with disease severity. When CD4+ T cells were divided into Th1-, Th2-, Th17-, and Tfh-like subsets, the Th17-like subset showed a longer half-life than other subsets, indicating that Th17-like cells are most closely correlated with T cell longevity. In contrast, Th2- and Tfh-like T cells were more closely correlated with antibody titers than other subsets. These results suggest that distinct CD4+ T cell subsets are associated with longevity and antibody responses.


Low molecular weight constituents of male mouse urine mediate the pregnancy block effect and convey information about the identity of the mating male.
Mouse urine contains a complex mixture of chemosignals including a variety of small volatile molecules that are bound to major urinary proteins. In addition to signalling maleness, male urine also conveys information about individuality, which allows recently mated female mice to distinguish the urinary chemosignals of the mating male from those of an unfamiliar male. The highly polymorphic nature of the major urinary proteins makes them a likely candidate for conveying individuality information in the context of the pregnancy block effect. This was investigated by comparing the pregnancy-blocking effectiveness of a high molecular weight urinary fraction, containing major urinary proteins, with that of a low molecular weight fraction containing volatile ligands. Not only was the high molecular weight fraction ineffective in blocking pregnancy, but it also appeared to be less important in signalling individuality than the low molecular fraction. The high molecular weight fraction was ineffective in inducing expression of the immediate early gene product egr-1 in the accessory olfactory bulb. In contrast, the low molecular weight fraction induced egr-1 expression in the mitral/tufted neurons in the anterior subregion of the accessory olfactory bulb, suggesting that they activate the V1R class of vomeronasal receptor neuron.


Toll-like receptor 7 mRNA is reduced in hepatitis C-based liver cirrhosis and hepatocellular carcinoma, out-performs alpha-fetoprotein levels, and with age and serum aspartate aminotransferase is a new diagnostic index.
Hepatitis B and C viruses are leading causes of liver cirrhosis and hepatocellular carcinoma (HCC). Toll-like receptor 7 (TLR-7) has been implicated in the pathogenesis of HCC linked to hepatitis B. We hypothesised a role of leukocyte TLR-7 mRNA in hepatitis C related liver cirrhosis and HCC, using alpha-fetoprotein (AFP) and liver function tests as comparators. We recruited 102 patients with HCV-related HCC, 97 with HCV-related liver cirrhosis and 60 healthy controls. Quantification of TLR-7 mRNA was performed using real-time PCR, AFP and routine LFTs by standard techniques. TLR-7 mRNA levels were significantly lower in HCC patients compared to cirrhotic patients and lower again in healthy controls (p < 0.001 for trend). In multivariate analysis, age, aspartate transaminase (AST), AFP, and TLR-7 mRNA were significant predictors of HCC. The ROCC/AUC for age, AST and TLR-7 mRNA were all between 0.64 and 0.78 (all P < 0.01), but for AFP was 0.57 (95% CI 0.48-0.65, P = 0.09). We derived an index score using age, AST and TLR-7 mRNA for the diagnosis of HCC. The ROCC/AUC for the index was superior to all three root indices in the prediction of HCC. The index linked significantly with the Tokyo and Vienna liver cancer staging systems, but not with those of the CLIP and Okuda systems, in distinguishing HCC from liver cirrhosis. The combination of TLR-7 mRNA levels with age and AST improves the performance of TLR-7 in HCC diagnosis, out-performs alpha-fetoprotein and predicts early HCC.


Meakin adjuvant regimen in premenopausal patients with breast cancer.
A 10-year experience using ovarian ablation and prednisolone as adjuvant therapy for premenopausal patients with breast carcinoma, emphasizing tolerability and morbidity is reported. Thirty patients (15 aged less than 45 years, 15 aged greater than or equal to 45 years; range 28-54 years) underwent mastectomy/lumpectomy with axillary clearance (with or without local irradiation) followed by ovarian irradiation and prednisolone therapy (2.5 mg three times daily for 5 years). Patients were reviewed every 3 months for the first 3 years and every 6 months thereafter. Follow-up was between 1.5 and 10 years (median 5 years). Twenty-four patients are still alive. Three patients stopped therapy because of side-effects. There was a mean(s.e.m.) weight gain of 8.46(1.69) per cent on therapy. Nineteen patients have been weaned off prednisolone over a period of 0.5-7.5 months (median 2 months) and the median length of time off steroids is now 3 years (range 0.5-5 years). This regimen appears to be associated with an acceptable level of patient tolerability and a low chronic morbidity rate and should be considered as an alternative to adjuvant systemic cytotoxic therapy.


The effects of myofascial trigger point injections are naloxone reversible.
Ten patients with myofascial trigger point pain were entered into a double-blind cross-over study of the reversibility of myofascial trigger point injection (TPI) effects with naloxone versus placebo in order to test the hypothesis that the benefits of TPI are mediated, at least in part, through activation of an endogenous opioid system. Injection of trigger points with 0.25% bupivacaine decreased pain in all subjects and increased range of motion in subjects who, on initial assessment, demonstrated limitations of movement of the affected part(s). Allodynia and palpable bands preceding TPI when present also showed reduction after TPI. All improvements afforded by TPI were significantly reversed with intravenous naloxone (10 mg) compared to intravenous placebo. These results demonstrate a naloxone-reversible mechanism in TPI therapy. This suggests an endogenous opioid system as a mediator for the decreased pain and improved physical findings following injection of myofascial trigger points with local anesthetic.


Promoting Counter-Cyclical Fiscal Policy: Fiscal Rules Versus Institutions.
We explore under different exchange rate regimes how fiscal rules and institutions can reduce the procyclical stance of fiscal policy (i.e. how government spending responds to GDP fluctuations). We construct a fiscal rules index which is a composite index measuring the overall strength of fiscal rules in a country at a given time. We use it in a dynamic model with a GMM estimator, for a panel of 153 countries over the period 1993-2015. We find that under fixed exchange rate regimes, while better institutions can reduce procyclicality, rules increase it or do not affect it. This result suggests that under fixed exchange rate regimes, a focus should be put on stronger institutional quality rather than on the adoption of fiscal rules. However, under flexible exchange rate regimes, we find that institutions and rules are complementary in reducing procyclicality. Rules help reduce procyclicality and are more effective, in particular, when institutions are stronger. Our results are robust to different specifications as well as to the use of alternative variables of institutional quality.


Non-radical-dominated catalytic degradation of methylene blue by magnetic CoMoO4/CoFe2O4 composite peroxymonosulfate activators.
In this study, magnetic CoMoO4/CoFe2O4 (CMO/CFO) nanospheres with a core-shell structure were synthesized via two-step hydrothermal methods. The obtained particles were employed as catalysts to activate peroxymonosulfate (PMS) and degrade methylene blue (MB). The physico-chemical characterizations of the synthesized CMO/CFO showed that the CMO shell contributed to the enhancement of redox conversion and the increase in the concentration of oxygen vacancies (OVs). By examining reactive oxygen species (ROS) in the CMO/CFO/PMS system, the MB degradation was dominated by a non-radical pathway, and 1O2 was identified as the most abundant ROS. Besides, the CMO/CFO exhibited faster reaction kinetics than the pristine CFO. Moreover, the magnetic properties guaranteed the recycling and reuse of CMO/CFO, and the removal rate of MB was maintained at ∼94% after continuous use five times. Both the tolerance to SO42-and the wide pH range where the material is applicable make it a promising catalyst for dyeing wastewater treatment.


Disagreement between students and preceptors regarding the value of teaching behaviors for ambulatory care settings.
Medical students and preceptors commonly disagree on methods of clinical instruction in ambulatory care, although the extent of the problem is not documented. The purpose is to identify disagreement and concordance between students and preceptors for teaching behaviors in ambulatory care. We surveyed students and preceptors at 4 U.S. schools. Respondents rated 58 behaviors on two scales. Disagreement was recognized when the percentage of students and preceptors who recommended a behavior and rated it important differed by over 15% (p < .01). Disagreement was identified for 8 behaviors (14%). Six were valued less by students, including "watch the student perform critical tasks in history taking and other communication" (59% compared with 82%). Two behaviors were valued more by students, including "delegate responsibility to the student for the wrap up discussion with the patient" (82% compared with 61%). Students and preceptors disagree regarding the value of a minority of teaching behaviors. Because some are potentially important, however, early negotiation regarding their use may enhance teaching effectiveness and mutual satisfaction with learning.


[Concept of functional therapy exemplified by fresh closed humeral fracture].
The method of functional treatment of closed humerus fractures has gained an established position of success. A good outcome has proved to depend not only on correct indication, but it also depends decisively on physiotherapeutic exercises. The challenge to the physiotherapist has grown, and a standardised concept is now required. The authors' own approach is described in some detail. Excellent success was obtained from 80 in 82 cases, with average periods of treatment being shortened by something between two and four weeks.


The Transdiagnostic Nature of Social Anhedonia: Historical and Current Perspectives.
In this chapter, we trace the historical roots of the social anhedonia (SoA) construct to current conceptualizations. We first describe the aspects of SoA that distinguish it from anhedonia in general. We summarize evidence that SoA is a transdiagnostic symptom and risk factor. Although several forms of psychopathology are associated with elevated rates of self-reported SoA, one unresolved issue is whether the processes and mechanisms underlying SoA in one disorder are the same as the processes and mechanisms underlying SoA seen in another disorder. We assert that there may be different causal factors underlying SoA across disorders. Considering both the principles of equifinality and multifinality, we offer an integrative model for social reward processing. This conceptualization considers roles for the following: attention; social cognition, including, but not limited to, social skills; reward learning and valuation; working memory; anticipation, prediction, and remembering; and motivation and effort. We conclude that SoA may be caused by multiple underlying impairments, all of which may serve as targets for intervention. This conceptualization is provided as an impetus for further research in the area.


Asymmetric interactions in semiaquatic insects.
Interspecific interactions were studied in three coexisting species of predatory semiaquatic insects: Gyrinus substriatus Steph. (Coleoptera), Gerris lacustris (L.) and Gerris argentatus Schumm. (Hemiptera). Prey capture success was observed in trials with individuals of two different species. Two prey sizes were used: fruit flies Drosophila melanogaster and Mediterranean flour moths Ephetia kuehniella (Zeller). When the two species were starved for the same period of time, G. substriatus was generally more successful at catching prey than either Gerris species, independent of prey size. However, when individuals from the formerly dominant species of the pair were less hungry (i.e. fed shortly before trials), their prey capture success decreased. Prey sharing and prey stealing were observed in trials with large prey and occurred both intra- and interspecifically. The shift in dominance with differing hunger levels and the existence of prey sharing and prey stealing may make the interspecific competition more symmetric allowing these species to coexist.


Endemic Tyrolean infantile cirrhosis is not an allelic variant of Wilson's disease.
Recently, 138 cases of infantile cirrhosis originating in several families in the Austrian province of the Tyrol were reported. This endemic Tyrolean infantile cirrhosis (ETIC) is indistinguishable from Indian childhood cirrhosis (ICC), idiopathic copper toxicosis (ICT), and resembles the early forms of Wilson's disease (WND). It has been argued that ETIC might represent an allelic variant of the WND gene, which is a copper transporting P-type ATPase (ATP7B). Assuming that ETIC results from a founder effect, a possible role for ATP7B in ETIC was investigated by association studies and haplotype sharing. Because of its lethality, the mapping of ETIC was focused on obligate gene carriers, i.e. the patients' parents. Our data indicate that ETIC is a separate genetic entity, distinct from WND.


Laryngeal mask airway versus endotracheal tube in pediatric adenotonsillectomy.
Evaluation of safety and postoperative outcomes of the laryngeal mask airway (LMA) during pediatric tonsil surgery compared to use of the endotracheal tube (ETT). Randomized controlled trial. A population-based sample of 117 patients ages 2 to 18 years requiring adenotonsillectomy, adenoidectomy, or tonsillectomy was studied. Evaluation forms covering 36 safety, surgery duration, and patient comfort variables were given to the surgeon, anesthesiologist, and phase I and phase II recovery nurses to collect data on the intra- and postoperative course. A phone survey was conducted 24 hours after surgery. At the α level following Bonferroni correction, LMA showed less coughing or gagging during the anesthesia phase for all surgeries combined (48% for ETT vs. 20% for LMA; χ(2) = 10.153, P = .002), and for ETT nontonsillectomy vs. LMA nontonsillectomy (48% for ETT vs. 3% for LMA; χ(2) = 15.196, P = .000), spontaneous ventilation was used more often in the LMA group when comparing all surgeries (χ(2) = 19.493, P = .000), and when comparing ETT tonsillectomy and LMA tonsillectomy (χ(2) = 11.131, P = .000). Use of the LMA during pediatric tonsil surgery does not appear to have any major disadvantages compared to use of the ETT. In fact, analysis of safety, comfort, complications, and postoperative problems suggests that LMA may be superior for some outcome variables such as coughing and gagging. Use of spontaneous ventilation is more common among LMA patients, although the significance of this finding is uncertain.


Dermatography: a method for permanent repigmentation of achromic burn scars.
Dermatography, a refined elaborate tattooing technique, has been used successfully in 52 patients suffering from postburn depigmentation. Materials and methods are simple and safe. Over a 5-year follow-up no adverse reactions or complications were noticed. The cosmetic results were very satisfactory both to the surgeons and to the patients. Dermatography is suggested as an alternative for treating localized achromasia, particularly when other medical therapeutic attempts have failed in repigmenting this often disfiguring condition.


Effect of ultrasound-assisted cold plasma pretreatment to obtain sea asparagus extract and its application in Italian salami.
The effect of the glow discharge cold plasma pretreatment (CPT) was investigated on the ultrasound-assisted extraction (UAE) of phenolic compounds from sea asparagus Salicornia neei. The extract was applied in dry fermented sausage (Italian salami). Thermal extraction methods demand a long processing time, are highly energy-consuming and cause irreversible nutrient losses. It was found that CPT (discharge power of 14 W for 5 min) prior to UAE increased the antioxidant activity by 22% and 19% measured by the DPPH and ABTS assays, respectively. The S. neei extract showed high antioxidant activity, low antimicrobial activity, and was added to salami formulations with reduced-sodium nitrite content and no addition of sodium erythorbate. Despite a slight color change, lipid oxidation and texture parameters were similar to the control at the end of ripening. Furthermore, higher antioxidant activity was observed in S. neei extract supplemented salami with no impact on its sensory overall acceptability, indicating its potential as a natural alternative to synthetic additives.


Strain and gender modulate hepatic hepcidin 1 and 2 mRNA expression in mice.
Hepcidin (HEPC) plays a key role in iron homeostasis and an abnormally low level of hepcidin mRNA has been reported in HFE-1 genetic hemochromatosis. Considering the well-known phenotypic variability of this disease, especially between men and women, it is important to define factors susceptible to modulate hepatic hepcidin expression and, consequently, to influence the development of iron overload in HFE-1 hemochromatosis. Therefore, our aim was to analyze the effects of strain and gender on hepatic hepcidin expression in the mouse. C57BL/6 and DBA/2 wild-type mice were included in this study. Liver and splenic iron contents were measured. Specific hepatic Hepc1 and Hepc2 mRNA levels were quantified using real-time reverse transcription polymerase chain reaction (RT-PCR). C57BL/6 mice expressed predominantly Hepc1 mRNA, whereas Hepc2 mRNA was the main form in DBA/2 mice. In both strains, females had higher levels of iron stores and Hepc mRNAs compared to males. Our results demonstrate that the expression of both hepcidin mRNAs varies according to strain and gender. They suggest that sex and genetic background, which are regulators of hepcidin expression, could play a role in the phenotypic expression of genetic hemochromatosis.


Gallstone ileus as a complication of cholecystolithiasis.
Biliary fistula and gallston ileus are rarely found. The diagnosis is difficult. Gallstone ileus requires urgent and appropriate surgical therapy. Enterolitotomy remains the gold standard of operative treatment for gallstone ileus, but additional procedures of one-stage cholecystectomy and repair of fistula are necessary. Some researchers advise first to resolve the gallstone ileus and then to perform the elective operation for gallstone disease in more ideal circumstances. Our case had clinical evidence of ileus, which was confirmed by radiological exam. Ultrasonographic examination performed before operation did not confirm the presence of gallbladder; it did not detect a large stone located in the intestine. The patient, a 75-year-old woman, was operated on. During the procedure it was shown that the second part of the duodenum was involved in a scar and displaced to the hepatic hilus. There was no gallbladder; it was probably destroyed by a long-lasting vesicoduodenal fistula. Cholangiography also did not detect the gallbladder. Biliary passage through the common bile duct was sufficient. The hole in the duodenum wall was sutured, and Kehr drain was inserted into the common bile duct. The gallstone was removed by incision of the intestine down to the obstruction. The postoperative period was complicated by a small suppuration of the laparotomy wound. Vesicoduodenal fistula present for a long time can lead to atrophy of the gallbladder. The one-stage procedure seems to be appropriate if biliary fistula and gallstone ileus are found.


The AT-rich tract of the SV40 ori core: negative synergism and specific recognition by single stranded and duplex DNA binding proteins.
The SV40 origin of replication comprises a run of thymine and adenine residues. Integrity of this AT-rich sequence is known to be essential for replication. We set out to study whether or not these elements can work synergistically to sustain replication. Quite surprisingly, additional copies of the AT stretch linked to a functional SV40 ori core dramatically reduce its replication in Cosl cells, probably by creating some physical block. Interestingly, the same inhibiting effect can be observed with the addition in cis of the yeast ARS consensus, which is homologous to the SV40 AT stretch. This modulation is possibly due to the action of cellular factors that recognize either of the two sequences. In fact, we demonstrate the existence of factor(s) in Cosl crude nuclear extracts that in vitro can specifically bind to either of them. Moreover, we show that these sequence-specific factor(s) (MW about 50 kDa), named SOAP, recognize both single (T-rich strand) and double stranded forms of the AT tracts. Binding to single stranded AT stretches can be specifically inhibited by the corresponding duplex form, but not vice versa.


Dairy farm worker milking equipment training with an E-learning system.
In many farms, the logistics of on-farm training are a limiting factor due to communication challenges in the workplace (i.e., cultural differences, language barriers, impaired listening skills) and limited access to industry professionals. The use of E-learning systems may help to improve communication and can be sensitive to cultural challenges. The objectives of this study were to (1) identify how many of the high-priority problems in the milking parlor relate to milker training in the areas of milking equipment and milking routine, (2) design and test an E-learning training system for dairy farm milkers related to milking equipment, and (3) gain feedback targeted to improve subsequent E-learning training modules. An interactive online training course on basic checks of the milking equipment was developed with a cloud-based authoring software. A total of 95 dairy farm workers on 15 commercial dairy farms in northern New York State (USA) were trained and participated in the study. Milk quality professionals performed an initial evaluation of 3 main areas: equipment analysis, milker assessment, and cow assessment. The 3 most important risk factors for mastitis were summarized for each farm. A training event was scheduled with milkers guided by a bilingual (English and Spanish) professional in milk quality. Over 50% of the farms (8/15) had one or more of the top 3 priorities involving problems with milking equipment, which milkers could have detected and reported to management. All participants completed the module, 95% stated that they felt capable of checking the equipment before milking, and 86% felt more confident in reporting equipment problems to the manager after having taken the course. There were also differences between managers' and milkers' statements on how and whether milking equipment training was offered or not on the farm. This can be explained due to the lack of or secondary to poor communication between managers and employees on training objectives and goals on the farm. Our results also show that milking equipment issues which milkers could detect and report are common on dairy farms and reinforces the need for additional milker training in this area.


Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling.
The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given time in each cell. However, cellular stress responses trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Using single-molecule RNA FISH, we measured the kinetics of the HTLV-1 transcriptional reactivation in peripheral blood mononuclear cells (PBMCs) isolated from HTLV-1+ individuals. The abundance of the HTLV-1 sense and antisense transcripts was quantified hourly during incubation of the HTLV-1-infected PBMCs ex vivo. We found that, in each cell, the sense-strand transcription occurs in two distinct phases: the initial low-rate transcription is followed by a phase of rapid transcription. The onset of transcription peaked between 1 and 3 hours after the start of in vitro incubation. The variance in the transcription intensity was similar in polyclonal HTLV-1+ PBMCs (with tens of thousands of distinct provirus insertion sites), and in samples with a single dominant HTLV-1+ clone. A stochastic simulation model was developed to estimate the parameters of HTLV-1 proviral transcription kinetics. In PBMCs from a leukemic subject with one dominant T-cell clone, the model indicated that the average duration of HTLV-1 sense-strand activation by Tax (i.e. the rapid transcription) was less than one hour. HTLV-1 antisense transcription was stable during reactivation of the sense-strand. The antisense transcript HBZ was produced at an average rate of ~0.1 molecules per hour per HTLV-1+ cell; however, between 20% and 70% of HTLV-1-infected cells were HBZ-negative at a given time, the percentage depending on the individual subject. HTLV-1-infected cells are exposed to a range of stresses when they are drawn from the host, which initiate the viral reactivation. We conclude that whereas antisense-strand transcription is stable throughout the stress response, the HTLV-1 sense-strand reactivation is highly heterogeneous and occurs in short, self-terminating bursts.


Asymptomatic bacteriuria in pregnancy.
Asymptomatic bacteriuria (ASB) is associated with adverse maternal and neonatal outcomes and is routinely screened for and treated in the first trimester. Prevalence of ASB in the second and third trimesters of pregnancy is unknown. The aim is to determine the prevalence of ASB in the second and third trimesters of pregnancy. Prospective cohort study of 150 pregnant women. Mid-stream urine samples were tested for ASB in the second (24-28+6 ) and third (32-36+6 ) trimesters. Women were assigned to one of two groups: (i) ASB in any trimester of pregnancy and (ii) no evidence of ASB in pregnancy. Maternal and neonatal outcomes were compared between groups. Among 143 women included in the study, the rate of ASB was 4.9% (2.1, 2.1 and 3.2% in the first, second and third trimesters, respectively). Of those with ASB, 14% had it in every trimester, whereas 43% had it on two or more samples. Of those with ASB in pregnancy, 43% were detected for the first time in the third trimester. Rates of maternal and neonatal outcomes were not statistically significantly different between the two groups. No women with ASB were induced for chorioamnionitis or growth restriction. The rate of ASB was highest in the third trimester of pregnancy, with rates of 2.1, 2.1 and 3.2% in the first, second and third trimesters, respectively. This study was underpowered to assess maternal and fetal outcomes. Although numbers were small, the absence of ASB in the first trimester was a poor predictor of ASB in the third trimester.


Minimally invasive resection for mediastinal ectopic parathyroid glands.
We reviewed our experience with ectopic mediastinal parathyroidectomy. Between March 1980 and September 2010, mediastinal parathyroidectomy was performed in 33 patients with hypercalcemia secondary to hyperparathyroidism. Primary hyperparathyroidism was the main diagnosis in 32 patients (97%). Technetium-sestamibi scan was used in 23 (70%) for preoperative localization. Minimally invasive resections were performed in 18 patients (55%), and 15 (45%) underwent open surgery. The most common minimally invasive surgery approach was video-assisted thoracoscopy in 9 patients (27%); the most common open approach was median sternotomy in 11 (33%). Intraoperative parathyroid hormone monitoring was used in 22 patients (67%). The ectopic glands were intrathymic in 15 patients (45%), in the aortopulmonary window in 7 (21%), and in other intrathoracic locations in the remaining 11 (33%). Parathyroid adenomas were identified in 21 patients (64%); parathyroid hyperplasia and carcinoma were identified in 9 (27%) and 3 (9%), respectively. No early mortality occurred in either group. Reoperation was required in 1 patient in the minimally invasive surgery group because of hemothorax. Morbidity occurred in 8 patients (24%), the most common of which was hypocalcemia in 4 (12%). The mean length of stay was significantly shorter in the minimally invasive surgery group (2 versus 6 days; p < 0.001) but mortality and morbidity were not statistically different between the two groups (p = 0.05). Mean follow-up was 3 ± 3.7 years. Minimally invasive mediastinal parathyroidectomy has similar outcomes to open surgery, with significantly shorter length of hospital stay.


Medical need, scientific opportunity and the drive for antimalarial drugs.
Continued and sustainable improvements in antimalarial medicines through focused research and development are essential for the world's future ability to treat and control malaria. Unfortunately, malaria is a disease of poverty, and despite a wealth of scientific knowledge there is insufficient market incentive to generate the competitive, business-driven industrial antimalarial drug research and development that is normally needed to deliver new products. Mechanisms of partnering with industry have been established to overcome this obstacle and to open up and build on scientific opportunities for improved chemotherapy in the future.


Genome-wide identification and characterization of a panel of house-keeping genes in Schistosoma japonicum.
Quantitative real-time polymerase chain reaction (qPCR), as one of the most sensitive and precise gene expression analysis methods, is frequently used to validate data obtained in high-through-put assays. qPCR requires reference genes with stable transcription for accurate normalization. However, no systematic studies on such genes have been performed in the genus Schistosoma japonicum. In this study, eight novel candidate genes selected from a microarray analysis and four commonly used reference genes were systematically validated in a series of qPCR experiments. Based on the results of geNorm, Normfinder, BestKeeper, and the comparative delta-cycle threshold (ΔCT) integrated analysis, the genes PSMD4, NDUFV2, and TPC2L were found to be most stably expressed in all S. japonicum developmental stages; meanwhile, ACTB and TUBA were found as the least stably expressed genes. This study provided, at the first time, data for genes that can be explored as reliable references in transcriptomic analysis of S. japonicum.


Correlation of thermodilution-derived extravascular lung water and ventilation/perfusion-compartments in a porcine model.
This study examines the correlation between the transpulmonary thermodilution derived extravascular lung water content (EVLW) and the ventilation/perfusion-distribution ([Formula: see text]) measured by multiple inert gas elimination (MIGET) in a porcine model. [Formula: see text] measured by micropore membrane inlet mass spectrometry-MIGET (MMIMS-MIGET) and EVLW were simultaneously measured in twelve pigs in the heathy state, with impaired gas exchange from repetitive lung lavage and after 3 h of ventilation. The relationship between [Formula: see text] compartments and EVLW was analysed by linear correlation and regression. Considerable increases in EVLW and [Formula: see text] mismatching were induced through the lavage procedure. Significant correlations between the EVLW and the [Formula: see text] fractions representing pulmonary shunt and low [Formula: see text] were found. Perfusion to the normal [Formula: see text] regions was inversely correlated to the EVLW. Increased EVLW is associated with increased low [Formula: see text] and shunt, but not equal to pulmonary shunt alone. Beneath true shunt EVLW can also be associated with low [Formula: see text] regions.


Functional heterodimeric amino acid transporters lacking cysteine residues involved in disulfide bond.
The protein mediating system L amino acid transport, AmAT-L, is a disulfide-linked heterodimer of a permease-related light chain (AmAT-L-lc) and the type II glycoprotein 4F2hc/ CD98. The Schistosoma mansoni protein SPRM1 also heterodimerizes with h4F2hc, inducing amino acid transport with different specificity. In this study, we show that the disulfide bond is formed by heavy chain C109 with a Cys residue located in the second putative extracellular loop of the multi-transmembrane domain light chain (C164 and C137 for XAmAT-L-lc and SPRM1, respectively). The non-covalent interaction of Cys-mutant subunits is not sufficient to allow coimmunoprecipitation, but cell surface expression of the light chains is maintained to a large extent. The non-covalently linked transporters display the same transport characteristics as disulfide bound heterodimers, but the maximal transport rates are reduced by 30-80%.


Comparison of the Efficacy, Safety, Pharmacokinetic and Immunogenicity of UJVIRA (ZRC-3256, Trastuzumab Emtansine) With the Kadcyla (Trastuzumab Emtansine) in the Treatment of HER2-Positive Metastatic Breast Cancer: A Randomized, Open-Label, Multicenter Study in India.
UJVIRA is the first DCGI approved biosimilar of trastuzumab emtansine (Kadcyla) which may offer an alternative cost-effective treatment option for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer patients in India. This article summarizes the available clinical evidence supporting the biosimilarity of UJVIRA and Kadcyla with respect to efficacy, pharmacokinetic, safety, and immunogenicity. A phase 3, randomized, open-label, active-controlled study was conducted at 31 sites across India. A total of 168 patients were enrolled and randomized to receive either UJVIRA or Kadcyla. Of which, only first 50 patients were included in pharmacokinetic assessment. UJVIRA or Kadcyla were administered at a dose of 3.6 mg/kg by intravenous infusion every 3 weeks (21 days) for 8 cycles or until disease progression or unmanageable toxicity, whichever was earlier. The study assessed efficacy (ORR), safety, pharmacokinetics, and immunogenicity. The ORR at the end of Week 24 was 37.76% in the UJVIRA and 33.33% in the Kadcyla group. The risk difference was 4.42% [-12.01, 20.85]. It met noninferiority margin of -15%. The pharmacokinetic parameters were comparable between groups. No antidrug antibody was detected in any of the treatment groups. The overall safety profile in terms of TEAEs and laboratory abnormalities was also comparable between the treatment groups. Results demonstrated biosimilarity between UJVIRA and Kadcyla in terms of efficacy, safety, pharmacokinetics, and immunogenicity. Therefore, UJVIRA could prove to be a cost-effective treatment alternative for HER2-positive metastatic breast cancer patients in India.


[Study of different pattern of immuno-modulatory mechanism by tonifying kidney and invigorating spleen].
To observe the acting pattern on the immune system by tonifying the Kidney (TK). Three composite recipes were used on the 7- and 14-day corticosterone rat model to study the effect of recipes on the different pattern of immuno-modulatory and neuroendocrinological systems. The immune system of Invigorate the Spleen(IS) group was well protected in either 7-day or 14-day experiment, without any effect of IS recipe acting on the neuroendocrine system, it suggested that IS recipe might have direct action on immune system, while TK group with no effect on neuroendocrine-immune (NEI) system in 7-day experiment, but showed the remarkable protective effect of the whole NEI system until 14-day experiment. The results indicated that TK recipe is acting on the neuro endocime system first, and then influence the immune system. It means that the action was through down pathway of NEI network.