Congenital epulis: a rare diagnosis in paediatric surgery.
Congenital epulis of the newborn is a rare tumour which is usually benign. The first description of a case is attributed to Neumann in 1871. The word "epulis" is derived from Greek and means "on the gum" or "gum boil". Epulis is also known as a congenital gingival granular cell tumour because of its histological features. Since 1871, 216 cases have been reported. Female babies are affected 8-10 times more often than males. Epulis is located on the maxillary ridge twice as often as on the mandible, mostly as single tumours but rarely as multiple tumours. Macroscopically, epulis is a pedunculated tumour with a smooth or lobulated surface. The basis of the tumour is the alveolar mucosa. The size varies from a few millimetres to 9 cm in diameter. After birth, the tumour normally does not increase in size. Microscopic examination shows a central mass of granular cells. This mass is surrounded by a stratified squamous mucosa. The histogenesis of the tumour is unknown. Spontaneous regression of congenital epulis has been reported in four cases. However, surgical excision is generally indicated due to interference with feeding or respiration. Recurrence of the tumour after surgery has not been reported yet.


Refraction of space-time wave packets in a dispersive medium.
Space-time (ST) wave packets are a class of pulsed optical beams whose spatiotemporal spectral structure results in propagation invariance, tunable group velocity, and anomalous refractive phenomena. Here, we investigate the refraction of ST wave packets normally incident onto a planar interface between two dispersive, homogeneous, isotropic media. We formulate a new, to the best of our knowledge, refractive invariant for ST wave packets in this configuration, from which we obtain a law of refraction that determines the change in their group velocity across the interface. We verify this new refraction law in ZnSe and CdSe, both of which manifest large chromatic dispersion at near-infrared frequencies in the vicinity of their band edges. ST wave packets can thus be utilized in nonlinear optics for bridging large group-velocity mismatches in highly dispersive scenarios.


DNA-Repair Gene Mutations Are Highly Prevalent in Circulating Tumour DNA from Multiple Myeloma Patients.
Mutational characterisation utilising plasma (PL)-derived circulating tumour DNA (ctDNA) in multiple myeloma (MM) has been recently described. Mutational analyses of paired bone marrow (BM) MM cell DNA and ctDNA from 76 patients (n = 24, new diagnosis (ND), n = 52, relapsed/refractory (RR)) for (ras/raf signaling pathway) and tumour protein p53 (TP53) mutations using the OnTarget™ Mutation Detection (OMD) platform was performed. The total number and proportions of mutations in each of the compartments (BM-specific, PL-specific or shared) was significantly higher in RR patients compared to ND patients (p = 0.0002 and p < 0.0001, respectively). Patients with > 2 mutations or > 1% fractional abundance (FA) in the PL had significantly shorter overall survival (OS) (p = 0.04 and p = 0.0006, respectively). Patients with PL-specific TP53 mutations had significantly shorter OS compared to patients with no PL-TP53 mutations (p = 0.003), while no differences were observed in patients with (K-ras) KRAS mutations. Targeted deep amplicon sequencing (TAS) of matched PL and BM samples from 36 MM patients for DNA-repair and RAS-RAF pathway genes found that DNA-repair genes were present at significantly higher levels in the PL when compared to RAS-RAF mutations (p = 0.0095). We conclude that ctDNA analysis identifies a higher prevalence of potentially actionable DNA-repair gene mutated subclones than BM analysis.


Comparative Molecular and Immunoregulatory Analysis of Extracellular Vesicles from Candida albicans and Candida auris.
Candida auris is a recently described multidrug-resistant pathogenic fungus that is increasingly responsible for health care-associated outbreaks across the world. Bloodstream infections of this fungus cause death in up to 70% of cases. Aggravating this scenario, the disease-promoting mechanisms of C. auris are poorly understood. Fungi release extracellular vesicles (EVs) that carry a broad range of molecules, including proteins, lipids, carbohydrates, pigments, and RNA, many of which are virulence factors. Here, we carried out a comparative molecular characterization of C. auris and Candida albicans EVs and evaluated their capacity to modulate effector mechanisms of host immune defense. Using proteomics, lipidomics, and transcriptomics, we found that C. auris released EVs with payloads that were significantly different from those of EVs released by C. albicans. EVs released by C. auris potentiated the adhesion of this yeast to an epithelial cell monolayer, while EVs from C. albicans had no effect. C. albicans EVs primed macrophages for enhanced intracellular yeast killing, whereas C. auris EVs promoted survival of the fungal cells. Moreover, EVs from both C. auris and C. albicans induced the activation of bone marrow-derived dendritic cells. Together, our findings show distinct profiles and properties of EVs released by C. auris and by C. albicans and highlight the potential contribution of C. auris EVs to the pathogenesis of this emerging pathogen. IMPORTANCE Candida auris is a recently described multidrug-resistant pathogenic fungus that is responsible for outbreaks across the globe, particularly in the context of nosocomial infections. Its virulence factors and pathogenesis are poorly understood. Here, we tested the hypothesis that extracellular vesicles (EVs) released by C. auris are a disease-promoting factor. We describe the production of EVs by C. auris and compare their biological activities against those of the better-characterized EVs from C. albicans. C. auris EVs have immunoregulatory properties, of which some are opposite those of C. albicans EVs. We also explored the cargo and structural components of those vesicles and found that they are remarkably distinct compared to EVs from C. auris's phylogenetic relative Candida albicans.


Evaluation of the erythroid regenerative response in two different models of experimentally induced iron deficiency anemia.
Anemia was induced in weanling Sprague Dawley rats either by feeding an iron-deficient diet or by chronic phlebotomy. The erythroid regenerative response was then evaluated before and after a hemolytic event, and results were compared with those of a third group of control nonphlebotomized rats fed an iron-replete diet. Diet and phlebotomy groups developed a similar degree of anemia (mean hemoglobin concentration 7.9 g/dL and 7.8 g/dL, respectively; controls, 13.9 g/dL) and hypoferremia (mean serum iron concentration 25.4 microgram/dL and 34.9 microgram/dL, respectively; controls, 222.0 microgram/dL). However, the anemia in diet rats was nonregenerative (reticulocyte count, 83.1 X 10(3) cells/microliter) and associated with bone marrow erythroid hypoplasia; whereas the anemia in phlebotomy rats was regenerative (reticulocyte count, 169.6 X 10(3) cells/microliter) and associated with bone marrow erythroid hyperplasia. Thrombocytosis was seen in diet rats (1,580 X 10(3) cells/microliter) but not phlebotomy rats (901 X 10(3) cells/microliter) when compared with controls (809 X 10(3) cells/microliter). To further evaluate the regenerative capability, phenylhydrazine (PHZ) was administered to induce hemolysis. Erythrocyte mass declined approximately 25% in all groups, including controls. The reticulocytosis (265.3 X 10(3) cells/microliter) seen in phlebotomy rats was earlier and significantly greater than that seen in either diet or control rats. Hemoglobin concentration returned to pre-PHZ concentrations (7.9 g/dL) in phlebotomy rats within 4 days posthemolysis. In diet rats, the maximal regenerative response (176.3 X 10(3) cells/microliter) was not seen until 8 days posthemolysis, and hemoglobin (7.5 g/dL) did not return to pre-PHZ concentrations during the 8-day study. In many aspects, the anemia seen following diet- or phlebotomy-induced iron deficiency was similar. However, the erythroid regenerative capability varied depending on the mechanism by which anemia was induced and furthermore altered the efficiency of hemoglobin production following a hemolytic event. These results suggest that the availability of iron in the diet may modulate the pathogenesis of iron deficiency anemia.


Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies.
Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance (1H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR "magnetic resonance spectroscopy"). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were 1H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = -0.38; 95% CI, -0.69 to -0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = -0.50; 95% CI, -0.80 to -0.20), but not in unmedicated patients (SMD = -0.27; 95% CI, -0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.


Effects of Different Exercise Strategies and Intensities on Memory Performance and Neurogenesis.
It is well established that physical exercise affects both hippocampal neurogenesis and memory functions. Until now, distinctive effects of controlled and voluntary training (VT) on behavior and neurogenesis as well as interactions between exercise intensity, neurogenesis and memory performance are still elusive. The present study tested the impact of moderate controlled and VT on memory formation and hippocampal neurogenesis and evaluated interactions between exercise performance, learning efficiency and proliferation of progenitor cells in the hippocampus. Our data show that both controlled and VT augmented spatial learning and promoted hippocampal neurogenesis. Regression analysis revealed a significant linear increase of the amount of new hippocampal neurons with increased exercise intensity. Regression analysis of exercise performance on retention memory performance revealed a quadratic, inverted u-shaped relationship between exercise performance and retention of spatial memory. No association was found between the amount of newborn neurons and memory performance. Our results demonstrate that controlled training (CT), if performed with an appropriate combination of speed and duration, improves memory performance and neurogenesis. Voluntary exercise elevates neurogenesis dose dependently to high levels. Best cognitive improvement was achieved with moderate exercise performance.


[Docosahexaenoic acid inhibits hypoxia-induced pulmonary arterial smooth muscle cells phenotype switching by inhibiting NFATc1 signaling].
Objective: To explore the molecular mechanism of docosahexaenoic acid (DHA) on regulating the phenotype switching of hypoxia-induced pulmonary arterial smooth muscle cells (PASMCs). Methods: The PASMCs were isolated from Sprague Dawley rats. PASMCs were divided into five groups: normal control group, hypoxia group (1%O(2, )94%N(2, )5% CO(2) stimulation for 12 hours), hypoxia+ DHA group (10 μmol/L DHA pretreatment followed by 12 hours hypoxia), hypoxia+ DHA+ NFATc1 overexpression group (transfection of the NFATc1 lentivirus for 24 hours, followed by hypoxia stimulation for 12 hours after 10 μmol/L DHA treatment), and hypoxia+ DHA+ siNFATc1 group (transfection the siNFATc1 for 24 hours, followed by hypoxia stimulation for 12 hours after 10 μmol/L DHA treatment). The hypoxia stimulation was achieved by use of a special hypoxia incubator (1%O(2, )94%N(2, )5%CO(2)). The expressions of NFATc1 of various groups were determined by qRT-PCR and Western blot. The expression of α-SMA was determined by immunofluorescence staining, qRT-PCR and Western blot. The expression of SM22 was determined by qRT-PCR. The proliferation of PASMC was determined by EDU staining. Results: The mRNA and protein expression levels of NFATc1 were significantly upregulated in hypoxia group compared with the normal control group (P<0.05), while hypoxia-induced upregulation of NFTAc1 could be significantly downregulated by DHA treatment (P<0.05). The α-SMA positive cell number, protein and mRNA levels of α-SMA and the mRNA level of SM22 were significantly lower in the hypoxia group than in normal control group, which could be significantly reversed by DHA, the protective effects could then be abolished by NFATc1 overexpression. Above indices were significantly lower in the hypoxia+ DHA+ siNFATc1 group than in hypoxia+ DHA+ NFATc1 overexpression group (P<0.05). The proliferation of PASMCs was significantly higher in the hypoxia group than in the control group (P<0.05), and which could be significantly reduced by DHA (P<0.05), and the protective effect of DHA could be significantly abolished by overexpression of NFATc1 (P<0.05). The proliferation of PASMCs was significantly lower in the hypoxia+ DHA+ siNFATc1 group than in the hypoxia+ DHA+ overexpression NFATc1 group (P<0.05). Conclusion: DHA could prevent hypoxia-induced PASMCs phenotype switching and proliferation by inhibiting NFATc1 signaling.


Thromboembolic risk in hematological malignancies.
There are a growing number of studies documenting that, similarly to patients with solid cancers, also patients with hematological malignancies (i.e., acute leukemia, lymphoproliferative and myeloproliferative neoplasms and plasma cell disorders) are at increased risk of thrombosis. The pathogenesis of the hypercoagulable state associated with hematological cancers is often multifactorial. Contributor factors include tumor cell-derived procoagulants, antineoplastic therapies, central venous catheters, concomitant infections and advanced age. In this narrative review, the epidemiology, pathogenesis and management of thrombosis in patients with hematological malignancies are reviewed.


The relationship between 24 hour total heart beats or ventricular arrhythmias and cardiopulmonary function in patients with Duchenne's muscular dystrophy.
To evaluate the relationship of 24 hour total heart beats (THB) or ventricular arrhythmias and cardiopulmonary function, 29 patients with Duchenne's muscular dystrophy (DMD) were studied using Holter electrocardiographic and echocardiographic recordings. The THB were 144,428 +/- 12,237 beats per 24 hours in the child group (8 to 15 years, n = 12) and 136,355 +/- 19,991 beats per 24 hours in the adult group (16 to 25 years, n = 17). The THB in the adult group significantly correlated well with % VC (r = -0.74), PaCO2 (r = 0.67), PaO2 (r = -0.59) and the respiration rate (r = 0.71), but not in the child group. In both groups, the echocardiographic parameters of the left ventricular size and function (left ventricular dimension, ejection fraction and D/S ratio) did not significantly correlate with the THB. Premature ventricular contractions (PVCs) were observed in 14 of the 29 patients (48.3%), and high risk PVCs (Lown's grade 3-4b) were observed in 11 of these 14 patients (78.6%). Echocardiographic parameters of the left ventricular function in the high risk PVC group were significantly deteriorated as compared with the low risk PVC group (Lown's grade 0-2) (p less than 0.02-p less than 0.001). We conclude that the THB in the adult group was mainly related to depressed pulmonary function, and the severity of the PVCs in both the adult and child groups was mainly related to the degree of left ventricular dysfunction.


Structural and ultrastructural alterations, exfoliative cytology and enzyme cytochemistry and histochemistry, proliferation kinetics, immunological derangements and other causes, and clinical associations and sequallae.
Our main purpose in this review article is to present some of the vast amount of information on the subject of atrophic gastritis available at the present time. Various areas of research pertaining to this entity, including that from the author's laboratory, are reviewed in this article, encompassing histological and ultrastructural abnormalities, enzyme histochemistry, and exfoliative cytology and cytochemistry of chronic gastritis, with emphasis on the diagnostic significance of these laboratory methods. The altered cell proliferation kinetics in atrophic gastric lesions is also discussed, as well as its significance in the proliferation and reduction of glandular cells of the gastric mucosa. Furthermore, some of the more recent evidence of immunological mechanisms and other causes of chronic gastritis, such as chronic alcoholism and bile reflux, is reviewed, as well as the effects of partial gastrectomy on the gastric mucosa. The important associations and sequellae of atrophic gastritis, such as gastric ulcer, gastric polyps, and gastric cancer, are discussed in detail.


Hypogonadism in patients with sickle cell disease: central or peripheral?
There is conflicting evidence in the literature on the etiology of hypogonadism in patients with sickle cell disease (SCD). A cross-sectional study was done to determine whether hypogonadism in male patients with SCD is due to primary testicular failure or secondary pituitary/hypothalamic dysfunction and assess the association between hypogonadism and serum ferritin levels. Hormonal assessment for serum concentrations of testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) was done for 34 men with SCD and their charts were reviewed for relevant clinical variables. Eight men (24%) were classified hypogonadal based on their serum testosterone levels. These men have significantly lower LH (p = 0.001) and FSH (p = 0.01) levels than normogonadal men, indicating a central etiology. There was no significant difference between hypogonadal and normogonadal men with respect to ferritin levels (p = 0.71). Our study indicates a central etiology of hypogonadism in patients with SCD. In this small study ferritin level was not significantly related to hypogonadism.


Partial questionnaire designs, questionnaire non-response, and attributable fraction: applications to adult onset asthma.
The attributable fraction (AF) is often used to explore the policy implications of an association between a disease and an exposure. To date, there have been no proposed estimators of AF in the context of partial questionnaire designs (PQD). The PQD, first proposed in a public health context by Wacholder is often used to enhance response rates in questionnaires. It involves eliciting responses from each subject on preassigned subsets of questions, thereby reducing the burden of response. We propose a computationally efficient method of estimating logistic (or more generally, binary) regression parameters from a PQD model where there is non-response to the questionnaire and the rates of non-response differ between sub-populations. Assuming a log-linear model for the distribution of missing covariates, we employ the methods of Wacholder to motivate consistent estimating equations, and weight each subject's contribution to the estimating function by the inverse probability of responding to the questionnaire. We also propose techniques for goodness-of-fit to assist in model selection. We then use the PQD regression estimates to derive an estimate of AF similar to that proposed by Bruzzi. Finally, we demonstrate our methods using data obtained from a study on adult occupational asthma, conducted within a Massachusetts HMO. Although we concentrate on a particular type of missing data mechanism, other missing data techniques can be incorporated into AF estimation in a similar manner.


Localization by immunofluorescence and histochemical labeling of aminopeptidase N in relation to its biosynthesis in rabbit and pig enterocytes.
Antibodies raised against highly purified rabbit intestinal brush border aminopeptidase N were found in certain rabbits or pigs to crossreact with human blood-grouplike substances present in goblet cells and at the surface of the basolateral membrane of enterocytes. To obtain antibodies strictly specific for aminopeptidase, depletion of antibodies with a water-insoluble, mucus-rich fraction or human A erythrocytes was necessary. By using ultrathin frozen sections of rabbit and pig jejunum mucosa, both the brush border and a structure at the upper pole of the nucleus were labeled by the specific antiaminopeptidase antibodies. This structure, tentatively identified as the Golgi apparatus in which aminopeptidase is glycosylated, escaped detection by histochemistry, thus suggesting that the enzyme is not yet active at this stage of its intracellular processing. By contrast, histochemistry revealed active aminopeptidase molecules in another structure located under the terminal web and in the upper part of the lateral membrane.


Regulated expression and neural functions of human natural killer-1 (HNK-1) carbohydrate.
Human natural killer-1 (HNK-1) carbohydrate, comprising a unique trisaccharide HSO(3)-3GlcAβ1-3Galβ1-4GlcNAc, shows well-regulated expression and unique functions in the nervous system. Recent studies have revealed sophisticated and complicated expression mechanisms for HNK-1 glycan. Activities of biosynthetic enzymes are controlled through the formation of enzyme-complexes and regulation of subcellular localization. Functional aspects of HNK-1 carbohydrate were examined by overexpression, knockdown, and knockout studies of these enzymes. HNK-1 is involved in several neural functions such as synaptic plasticity, learning and memory, and the underlying molecular mechanisms have been illustrated upon identification of the target carrier glycoproteins of HNK-1 such as the glutamate receptor subunit GluA2 or tenascin-R. In this review, we describe recent findings about HNK-1 carbohydrate that provide further insights into the mechanism of its expression and function in the nervous system.


Histopathologic features of the spontaneous pustular lesions of Behçet's syndrome.
Papulopustular lesions are common in Behçet's syndrome (BS). A debate exists as to whether they are different from ordinary acne. This has important clinical and pathophysiologic implications. The aim of this study was to evaluate the histopathologic features of papulopustular lesions seen both in BS and acne vulgaris (AV). Representative samples were obtained from 17 patients with BS and six patients with AV. The detailed histopathologic features were evaluated by a dermatopathologist blinded to the diagnoses. Considering the epidermis, follicle epithelium, and dermis separately, no differences could be found between the two groups. The papulopustular lesions seen in these two disorders cannot be distinguished on the basis of clinical and histopathologic findings.


Surface combustion microengines based on photocatalytic oxidations of hydrocarbons at room temperature.
The concept of a surface combustion microengine that is fuelled by volatile hydrocarbons at room temperature is demonstrated on a microcantilever covered with a thin layer of titanium oxide (TiO(2)). Exposing this microengine to ultraviolet (UV) radiation and hydrocarbon vapor produces controlled bending of the microcantilever as a result of differential stress produced by photocatalytic oxidation of organic molecules on the TiO(2) coating. Compared to the motion generated solely by UV radiation or hydrocarbon adsorption, the unique photocatalytic-mechanical effects in the presence of UV and hydrocarbon produce more work and exhibit fast response. The surface combustion based microengines would require less maintenance in minimally controlled field environment and could be potentially used in construction of miniature movable machines, conversion of solar and chemical energy to mechanical work, when extended to a large array of microcantilevers. We believe such microengines can be fuelled by a variety of molecules or mixtures due to the generally favorable photocatalytic reactivity of TiO(2), thus potentially offering a broad approach for mechanical work generation from multiple energy sources.


Nonlinear saturation of the large scale flow in a laboratory model of the quasibiennial oscillation.
The quasibiennial oscillation (QBO) is the nearly periodic reversal of the large scale flow generated by internal waves in the equatorial stratosphere. Using a laboratory model experiment, we study the instability that generates the QBO and investigate its nonlinear regime. We report the first quantitative measurements of the nonlinearly saturated velocity of the flow. We show that the QBO is generated by a bifurcation that is either supercritical or subcritical depending on the dominant dissipative process. This is confirmed by a nonlinear analysis in the vicinity of the instability threshold.


Fatty acid and essential oil composition of three Tunisian caraway (Carum carvi L.) seed ecotypes.
The essential oil and fatty acid composition of Tunisian annual caraway (Carum carvi L.) seeds from three ecotypes was investigated by gas chromatography and gas chromatography-mass spectrometry analyses. Total fatty acid (TFA) proportion of caraway seeds varied from 2.95% to 5.68% (w/w). The fatty acid composition revealed that Tunisian caraway seed oil is rich in an unusual fatty acid-petroselinic acid-the proportion of which varied from 31.53% and 38.36% of TFA. Essential oil yields were relatively low and ranged from 0.86% to 1.20% (w/w). Forty-one volatile compounds were identified, the main ones being carvone (76.78-80.53%) and limonene (13.05-20.29%). Tunisian caraway seed oil is rich in an unusual fatty acid-petroselinic acid-which is of potential industrial significance. In addition, Tunisian caraway essential oil is carvone chemotype. This fact is of great economic interest due to the several applications of carvone in the alimentary and medicinal industries.


Facial and physical features of Aicardi syndrome: infants to teenagers.
Aicardi syndrome is a sporadic disorder that affects primarily females and is hypothesized to be caused by heterozygous mutations in an X-linked gene. Its main features include of a triad of infantile spasms, agenesis of the corpus callosum, and distinctive chorioretinal lacunae. Additional common findings include moderate to profound mental retardation, gray matter heterotopia, gyral anomalies, and vertebral and rib defects. To date, no consistent facial dysmorphisms have been described. We examined 40 girls with Aicardi syndrome and determined that consistent facial features appeared in over half the study participants and included a prominent premaxilla, upturned nasal tip, decreased angle of the nasal bridge, and sparse lateral eyebrows. Externally apparent microphthalmia was seen in 10/40 (25%). Various skin lesions (including multiple nevi, skin tags, hemangiomas, one giant melanotic nevus, and a history of a previously removed angiosarcoma) were present in 8/40 (20%). Hand abnormalities were seen in 3/40 (7.5%) and included camptodactyly, proximal placement of the thumb and hypoplasia of the fifth finger. This study clearly delineates the existence of a distinctive facial phenotype of Aicardi syndrome not previously described. We recommend that features of a prominent premaxilla with upturned nasal tip and vascular malformations/vascular tumors be added to the modified diagnostic criteria in order to improve the ability of geneticists to diagnose Aicardi syndrome.


Immunochemical definition of the new dr specificity 8WDRw13.
Using two alloantisera produced by planned immunization of blood donor volunteers, a new specificity was defined residing on human Ia molecules. The specificity is possessed by the following human lymphoid cell lines: Reh, NALM-1, B89, KM-3 and BJAB, and appears to be the same as the DRw13 specificity discovered in the 8th International Histocompatibility Workshop. A radioimmunoassay for typing w13 on peripheral blood lymphocytes was established. A population and family study supports the genetic control by the HLA-DR locus. The phenotypic frequency in an Italian population was 3.7 percent. The relationship between w13 and the MT2 supertypic specificity was confirmed at the molecular level and the papain sensitivity of w13-carrying molecules was determined.


Rapid on-site detection of explosives on surfaces by ambient pressure laser desorption and direct inlet single photon ionization or chemical ionization mass spectrometry.
Considering current security issues, powerful tools for detection of security-relevant substances such as traces of explosives and drugs/drug precursors related to clandestine laboratories are required. Especially in the field of detection of explosives and improvised explosive devices, several relevant compounds exhibit a very low vapor pressure. Ambient pressure laser desorption is proposed to make these substances available in the gas phase for the detection by adapted mass spectrometers or in the future with ion-mobility spectrometry as well. In contrast to the state-of-the-art thermal desorption approach, by which the sample surface is probed for explosive traces by a wipe pad being transferred to a thermal desorber unit, by the ambient pressure laser desorption approach presented here, the sample is directly shockwave ablated from the surface. The laser-dispersed molecules are sampled by a heated sniffing capillary located in the vicinity of the ablation spot into the mass analyzer. This approach has the advantage that the target molecules are dispersed more gently than in a thermal desorber unit where the analyte molecules may be decomposed by the thermal intake. In the technical realization, the sampling capillary as well as the laser desorption optics are integrated in the tip of an endoscopic probe or a handheld sampling module. Laboratory as well as field test scenarios were performed, partially in cooperation with the Federal Criminal Police Office (Bundeskriminalamt, BKA, Wiesbaden, Germany), in order to demonstrate the applicability for various explosives, drugs, and drug precursors. In this work, we concentrate on the detection of explosives. A wide range of samples and matrices have been investigated successfully.


Intention to leave among staff nurses in small- and medium-sized hospitals.
To explore the factors associated with the intention to leave among nurses in small- and medium-sized hospitals and to determine the predictors about work environment and rewards. Compared with large hospitals, insight into the working conditions, rewards and turnover of nurses working for these hospitals is lacking internationally. Cross-sectional study design. Data were obtained from the Korean Nurses Association's 2016 Welfare Policy and System Improvement Survey. Of the participants, data from 951 staff nurses working three shifts were analysed using hierarchical multiple regression to explore the predictors of nurses' turnover intention. This study complied with the Strengthening the Reporting of Observational studies in Epidemiology. The perceived pay level satisfaction was the most obvious and persistent predictor of the intention to leave. Living benefits were shown to be scarcely satisfied, rendering considerable influence on turnover intention. Concerning aspects related to the working environment, the implementation of contract-abiding working hours and nurse-friendly night shift schedules reduced the turnover intention of nurses. Nurses in small- and medium-sized hospitals are likely to have particular challenges in terms of professional growth. When fundamental rewards and basic working conditions are acceptable to nurses, their turnover can be reduced, and the professional growth can also be expected. Hospitals with a high nurse turnover rate need to preferentially verify these factors perceived by their nurses and to improve to increase nurses' retention. Understanding the determinants of intention to leave can lead to the development of strategies that persuade nurses to remain employed. These findings inform policymakers, nurse managers and hospital managers of the causes of nurses' intentions to leave in small- and medium-sized hospitals. Our findings also provide empirical data on the working conditions and rewards of these nurses and suggest strategies for their retention.


Terms and conditions apply: Critical issues for readability and jargon in mental health depression apps.
Mental health services are turning to technology to ease the resource burden, but privacy policies are hard to understand potentially compromising consent for people with mental health problems. The FDA recommends a reading grade of 8. To investigate and improve the accessibility and acceptability of mental health depression app privacy policies. A mixed methods study using quantitative and qualitative data to improve the accessibility of app privacy policies. Service users completed assessments and focus groups to provide information on ways to improve privacy policy accessibility, including identifying and rewording jargon. This was supplemented by comparisons of mental health depression apps with social media, music and finance apps using readability analyses and examining whether GDPR affected accessibility. Service users provided a detailed framework for increasing accessibility that emphasised having critical information for consent. Quantitatively, most app privacy policies were too long and complicated for ensuring informed consent (mental health apps mean reading grade = 13.1 (SD = 2.44)). Their reading grades were no different to those for other services. Only 3 mental health apps had a grade 8 or less and 99% contained service user identified jargon. Mental health app privacy policies produced for GDPR weren't more readable and were longer. Apps specifically aimed at people with mental health difficulties are not accessible and even those that fulfilled the FDA's recommendation for reading grade contained jargon words. Developers and designers can increase accessibility by following a few rules and should, before launching, check whether the privacy policy can be understood.


[Effect of BMP-7 on the transdifferentiation of cultured human tubular epithelial cell induced by TGF-beta1].
To observe the effect of bone morphogenetic protein-7 (BMP-7) on the transdifferentiation of cultured human tubular epithelial cell (HKC) induced by TGF-beta1 and to elucidate its possible mechanism. The cultured HKC cells were divided into 5 groups: serum-free group (negative control); single TGF-beta1 treated group (positive control); single BMP-7 treated group; combined TGF-beta1 and BMP-7 treated group; and BMP-7 pre-treated group. Expression of keratin of HKC cells was assessed by indirect enzyme immunohistochemistry (IEI), expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin by immunohistological method, percentage of alpha-SMA positive HKC cells by flow cytometry, and mRNA expression of alpha-SMA, TGF-beta1, and TGF-beta type II receptor by reverse transcription PCR. The expression of alpha-SMA and the percentage of alpha-SMA positive HKC cells markedly increased after having been treated by TGF-beta1 while the expression of E-cadherin and keratin decreased. In the group pre-treated with BMP-7 (50 ng/ml) and then added with TGF-beta1 (8 ng/ml), expression of alpha-SMA was significantly lower than in the positive control group, while expression of E-cadherin and keratin significantly higher than in the positive control group. Measurement of the percentage of alpha-SMA positive HKC found significant deference between the combined TGF-beta1 and BMP-7 treated group and the positive control group (9.7% vs 19.8%; 5.8% vs 19.8%; P < 0.05). Significant difference existed between the BMP-7 (50 ng/ml) pre-treated group and the positive control group (8.7% vs 19.8%, P < 0.05). mRNA expression of alpha-SMA was measured by RT-PCR and the results showed that it significantly decreased in the group treated or pre-treated with BMP-7 (50 ng/ml) (15% and 12% of the results in the positive control group, respectively). The mRNA expression levels of both TGF-beta1 and its type II receptor significantly decreased (28% and 19%; 47% and 36%, compared with the positive control group, respectively). Transdifferentiation of cultured renal epithelial cell induced by TGF-beta1 can be inhibittd by certain levels of BMP-7, cultured together with TGF-beta1 or pretreated. BMP-7 can prevent and inhibit the mRNA expression of TGF-beta1 and its type II receptor, which may be an important mechanism by which BMP-7 inhibit the transdifferentiation of renal tubular epithelial cell.


Identification of Abundant and Evolutionarily Conserved Opioid Receptor Circular RNAs in the Nervous System Modulated by Morphine.
Circular RNAs (circRNAs) are a distinct category of single-stranded, covalently closed RNAs formed by backsplicing. The functions of circRNAs are incompletely known and are under active investigation. Here, we report that in addition to traditional linear mRNAs (linRNA), mouse, rat, and human opioid receptor genes generate exonic circRNA isoforms. Using standard molecular biologic methods, Oprm1 circRNAs (circOprm1) were detected in RNAs of rodent and human brains and spinal cords, as well as human neuroblastoma cells, suggesting evolutionary conservation. Sequencing confirmed backsplicing using canonical splice sites. Oprm1 circRNAs were sense-stranded circRNAs resistant to RNase R digestion. The relative abundance of Oprm1 circRNA to linRNA determined by quantitative reverse transcription polymerase chain reaction varied among mouse brain regions, with circRNA isoforms predominating in rostral structures and less abundant in brain stem. Chronic morphine exposure in mice increased brain circOprm1e2.3 and circOprm1.e2.e3.e4(302) levels by 1.5- to 1.6-fold relative to linRNA. Sequence analysis predicted numerous microRNA binding sites within Oprm1 circRNA sequences, suggesting a potential role in microRNA sequestration through sponging. In addition, we observed that other opioid receptor genes including δ, κ, and nociceptin receptor genes produced similar circRNAs. In conclusion, all members of the opioid receptor gene family express circRNAs, with Oprm1 circRNA levels exceeding those of linear forms in some regions. SIGNIFICANCE STATEMENT: The modulation of Oprm1 circular RNA (circRNA) expression by morphine, coupled with the high abundance and existence of potential miRNA binding sites with circRNA sequences suggests the potential role of Oprm1 circRNAs in chronic opioid effects such as tolerance.


Patterns of peroxidative ethane emission from submerged rice seedlings indicate that damage from reactive oxygen species takes place during submergence and is not necessarily a post-anoxic phenomenon.
Using ethane as a marker for peroxidative damage to membranes by reactive oxygen species (ROS) we examined the injury of rice seedlings during submergence in the dark. It is often expressed that membrane injury from ROS is a post-submergence phenomenon occurring when oxygen is re-introduced after submergence-induced anoxia. We found that ethane production, from rice seedlings submerged for 24-72 h, was stimulated to 4-37 nl gFW(-1), indicating underwater membrane peroxidation. When examined a week later the seedlings were damaged or had died. On de-submergence in air, ethane production rates rose sharply, but fell back to less than 0.1 nl gFW(-1) h(-1) after 2 h. We compared submergence-susceptible and submergence-tolerant cultivars, submergence starting in the morning (more damage) and in the afternoon (less damage) and investigated different submergence durations. The seedlings showed extensive fatality whenever total ethane emission exceeded about 15 nl gFW(-1). Smaller amounts of ethane emission were linked to less extensive injury to leaves. Partial oxygen shortage (O(2) levels <1%) imposed for 2 h in gas phase mixtures also stimulated ethane production. In contrast, seedlings under anaerobic gas phase conditions produced no ethane until re-aerated: then a small peak was observed followed by a low, steady ethane production. We conclude that damage during submergence is not associated with extensive anoxia. Instead, injury is linked to membrane peroxidation in seedlings that are partially oxygen deficient while submerged. On return to air, further peroxidation is suppressed within about 2 h indicating effective control of ROS production not evident during submergence itself.


Somatotype of Italian rugby players.
Our aim was to collect lacking first-hand data on Italian rugby players. The Heath/Carter anthropometric somatotype method was applied to 28 "A" League performers (RP) aged 25 +/- 3.9 years of age. Their somatotypes and dimensions were compared with those found in previous studies on athletes involved in the same sporting activity, with data collected on 25 "sedentary" young Italians, and with Bailey et al.'s study on Canadians (1982). On average, the RP group resulted as being endomorphic mesomorphs (3.1 +/- 1.1 - 5.6 +/- 1.3 - 1.4 +/- 1.1), a result that is congruent with international data. They differed significantly from the balanced mesomorph CG (2.3 +/- 1.0 - 4.5 +/- 1.2 - 2.5 +/- 1.4) for all the measurements taken, apart from bi-epycondylar width. The peculiar somatotype scores found are congruent with the needs of rugby, an aerobic-anaerobic discipline which requires performers with great muscular power associated with a capacity to furnish energy, mainly through the anaerobic metabolism.


[Effects of Par-4 gene silencing induced by siRNA on the expression of Smac gene, activity of caspase-3, and apoptosis of human bone marrow mesenchymal stem cells].
To investigate the effects of Par-4 gene silencing induced by siRNA on the expression of Smac gene, activity of caspase-3, and apoptosis of human bone marrow mesenchymal stem cells (hBMSCs). Bone marrow was obtained from a healthy young man and hBMSCs were isolated and cultured. Two siRNAs (Par-4-siRNA-1 and -2) targeting Par-4 gene were chemically synthesized. Eukaryocytic expression vectors containing these Par-4 siRNA sequences were established and transfected into the hBMSCs. The hBMSCs were divided into 4 groups: non-transfected hBMSCs (normal control group), blank Pae-4 plasmid transfected hBMSCs (Par4 control group), Par4-siRNA-1 transfected hBMSCs, and Par-4-siRNA-2 transfected hBMSCs. The expression of Par-4 mRNA was detected by real-time PCR. Another hBMSCs were inoculated in DMEM and divided into 4 groups: non-transfected normal hBMSCs, glutamate (an apoptosis inducer) + non-transfected hBMSC group, glutamine + Par-4-siRNA-1 hBMSC group, and glutamate + Par4-SiRNS-2 hBMSC group. Flow cytometry was used to detect the apoptotic rate. The relative activity of caspase-3 was determined by colorimetric assay. Western blotting was used to detect the Smac protein expression. The relative mRNA expression levels of Par-4 gene of the Par-4-siRNA-1 hBMSCs, Par-4 SiENA-2 hBMSCs, and Par-4 control hBMSCs were 0.12 +/- 0.03, 0.33 +/- 0.09, and 0.97 +/- 0.02 respectively, decreased by 88%, 67%, and 3% respectively compared with that of the normal control. The percentages of apoptotic cells of the glutamate + Par-4-siRNA-1 hBMSCs was (37.2 +/- 6.3)%, significantly lower than that of the glutamate + non-transfected hBMSC group [(58.9 +/- 8. 9)%, F = 58.26, P < 0.01). The Smac protein expression level of the glutamate + non-transfected hBMSC group was significantly higher than that of the normal control group (P < 0.01); however, the Smac protein expression level of the Par-4-siRNA-1 hBMSC group was significantly lower than that of the glutamate + non-transfected hBMSC group (P < 0.01). The caspase-3 activity of the glutamate + Par-4-siRNA-1 hBMSC group was significantly lower than that of the glutamate + non-transfected BMSC group (P < 0.01). Par-4-siRNA-1 inhibits markedly the apoptosis of the hBMSCs induced by glutamate. Par-4 gene silencing induced by siRNA inhibits the apoptosis of hBMSCs. The mechanism of the inhibition may be closely related to suppression of the up-regulation of Smac gene expression and caspase-3 activity.


Intracranial malignant meningioma with multiple spinal metastases--a case report and literature review: case report.
Case report. To report a case and review the literature on intracranial malignant meningioma with metastasis to the spine. Because so few cases have been recognized and reported, the radiologic and pathologic assessment, pathway of metastasis, and the concepts of surgical resection and other palliative management of this disease are still controversial. A big lobulated mass in the left frontal lobe containing calcifications and tumor bleeding was resected. Pathologic findings indicated malignant meningioma due to bone destruction and dura invasion grossly, and tumor cellular atypism with mitotic activity and massive tumor necrosis microscopically. Radiotherapy followed, and brain computed tomography revealed no definite evidence of recurrence. Three months later, spinal magnetic resonance imaging revealed multiple bone metastasis in lower T-L-S1, and pathologic fracture of L1 with compression of the dural sac and spinal cord. Surgical resection was done for decompression, fixation, and pathologic proof. Both pathologic and immunohistochemical survey found evidence consistent with malignant meningioma with spinal metastasis. Advanced treatment was refused, and the patient died. Spinal magnetic resonance imaging should be performed because of the high spinal metastatic rate, especially when spinal symptoms and signs are present. Immunohistochemical study has an important role in the differential diagnosis of primary or metastatic intracranial neoplasms.


Transcriptomic and molecular genetic analysis of the cell wall salvage response of Aspergillus niger to the absence of galactofuranose synthesis.
The biosynthesis of cell surface-located galactofuranose (Galf)-containing glycostructures such as galactomannan, N-glycans and O-glycans in filamentous fungi is important to secure the integrity of the cell wall. UgmA encodes an UDP-galactopyranose mutase, which is essential for the formation of Galf. Consequently, the ΔugmA mutant lacks Galf-containing molecules. Our previous work in Aspergillus niger work suggested that loss of function of ugmA results in activation of the cell wall integrity (CWI) pathway which is characterized by increased expression of the agsA gene, encoding an α-glucan synthase. In this study, the transcriptional response of the ΔugmA mutant was further linked to the CWI pathway by showing the induced and constitutive phosphorylation of the CWI-MAP kinase in the ΔugmA mutant. To identify genes involved in cell wall remodelling in response to the absence of galactofuranose biosynthesis, a genome-wide expression analysis was performed using RNAseq. Over 400 genes were higher expressed in the ΔugmA mutant compared to the wild-type. These include genes that encode enzymes involved in chitin (gfaB, gnsA, chsA) and α-glucan synthesis (agsA), and in β-glucan remodelling (bgxA, gelF and dfgC), and also include several glycosylphosphatidylinositol (GPI)-anchored cell wall protein-encoding genes. In silico analysis of the 1-kb promoter regions of the up-regulated genes in the ΔugmA mutant indicated overrepresentation of genes with RlmA, MsnA, PacC and SteA-binding sites. The importance of these transcription factors for survival of the ΔugmA mutant was analysed by constructing the respective double mutants. The ΔugmA/ΔrlmA and ΔugmA/ΔmsnA double mutants showed strong synthetic growth defects, indicating the importance of these transcription factors to maintain cell wall integrity in the absence of Galf biosynthesis.


Surgical case of aortic root and thoracic aortic aneurysm after the Wheat procedure.
A 52 year-old man underwent aortic valve replacement and ascending aortic replacement (Wheat procedure) for acute dissection (Stanford type A) and aortic regurgitation (grade 3/4). At that time, the aortic root was slightly dilated at about 45 mm and the descending aorta was within a normal range at about 35 mm. Forty months after the initial operation, a follow-up chest enhanced computed tomography showed an aortic root aneurysm about 60 mm in diameter, a thoracic aortic aneurysm about 70 mm in diameter and chronic aortic dissection. First we performed the Bentall procedure, innominate artery and left common carotid artery replacement by 12 mm, and 10 mm Hemashield grafts during selective cerebral perfusion. After 10 weeks, we carried out aortic arch, descending aorta and left subclavian artery replacement. The postoperative course was uneventful and postoperative examination demonstrated a good surgical result. Histological findings of the aortic aneurysm wall showed cystic medial necrosis, but Marfan's syndrome was excluded clinically. We could diagnose aortic root aneurysm by regular follow-up chest enhanced computed tomography (CT) and echocardiography. Therefore, cases with slight dilation of the aortic root in the Wheat procedure should undergo regular follow-up evaluation by chest enhanced CT and echocardiography.


Physicochemical and biological characterization of polyethylenimine-graft-poly(ethylene glycol) block copolymers as a delivery system for oligonucleotides and ribozymes.
Two different series of polyethylenimine (PEI) block copolymers grafted with linear poly(ethylene glycol) (PEG) were investigated as delivery systems for oligodeoxynucleotides (ODN) and ribozymes. The resulting interpolyelectrolyte complexes were characterized with respect to their physicochemical properties, protection efficiency against enzymatic degradation, complement activation, and biological activity under in vitro conditions. The effect of PEG molecular weight and the graft density of PEG blocks on complex characteristics was studied with two different series of block copolymers. The resulting ODN complexes were characterized by photon correlation spectroscopy (PCS) and laser Doppler anemometry (LDA) to determine complex size and zeta potential. Electrophoresis was performed to study the protective effects of the different block copolymers against enzymatic degradation of ODN. Intact ODN was quantified via densitometric analysis. Ribozymes, a particularly unstable type of oligonucleotides, were used to examine the influence of block copolymer structure on biological activity. The stabilization of ribozymes was also characterized in a cell culture model. Within the first series of block copolymers, the grafted PEG chains (5 kDa) had marginal influence on the complex size. Two grafted PEG chains were sufficient to achieve a neutral zeta potential. Within the second series, size and zeta potential increased with an increasing number of PEG chains. A high number of short PEG chains resulted in a decrease in complex size to values comparable to that of the homopolymer PEI 25 kDa and a neutral zeta potential, indicating a complete shielding of the charges. Complement activation decreased with an increasing number of short PEG 550 Da chains. Ribozyme complexes with PEG-PEI block copolymers achieved a 50% down-regulation of the target mRNA. This effect demonstrated an efficient stabilization and biological activity of the ribozyme, which was comparable to that of PEI 25 kDa. PEGylated PEI block copolymers represent a promising new class of drug delivery systems for ODN and ribozymes with increased biocompatibility and physical stability.


Diffusion-limited PBPK model for predicting pulmonary pharmacokinetics of florfenicol in pig.
For most bacterial lung infections, the concentration of unbound antimicrobial agent in lung interstitial fluid has been thought to be responsible for antimicrobial efficacy. In this study, a diffusion-limited physiologically based pharmacokinetic (PBPK) model was developed to predict the pulmonary pharmacokinetics of florfenicol (FF) in pigs. The model included separate compartments corresponding to blood, diffusion-limited lung, flow-limited muscle, liver, and kidney and an extra compartment representing the remaining carcass. The absorption rate constant and renal and hepatic clearance of FF were determined in vivo. Other parameters were taken from the literature or optimized based on existing pharmacokinetic data. All mathematical operations during the development of the model were performed using acslXtreme version 184.108.40.206 (Aegis Technologies Group, Inc., Huntsville, AL, USA). The model accurately predicted the concentration-time courses of FF in lung interstitial fluid, serum, and plasma following different dosing schedules, except at the dose of 15 mg/kg. When compared with the tissue residue data, the model generally underestimated the FF concentration at the injection site, whereas it gave good predictions of FF concentrations in lung, liver, and kidney at early time points. The model predictions provide a scientific basis for the dosage regimen design of FF.


Adenosine induced ventricular fibrillation in Wolff-Parkinson-White syndrome.
VF was observed in four patients (group A) with preexcited AF presenting to the emergency department who had been given 12 mg of adenosine. These patients were resuscitated and underwent electrophysiological study and catheter ablation of the accessory pathway (AP). In a control (group B) of five patients with manifest AP, sustained AF was induced by rapid atrial pacing during electrophysiological study and 12 mg of adenosine was administered. The ECG and electrophysiologic features in the two groups were compared. All patients had a single manifest AP. In group A, three patients had a left free-wall AP and one patient had a posteroseptal AP, while in the control group all had left free-wall APs. The antegrade AP effective refractory period (ERP) in groups A and B was 227 +/- 29 and 289 +/- 37 ms, respectively (P < 0.05). The atrial ERP was 210 +/- 17 versus 219 +/- 21 ms, respectively, in groups A and B (P > 0.05). The shortest R-R interval during AF in group A was 246 +/- 51 ms and 301 +/- 60 ms in group B (P value < 0.05). After adenosine, no patient in group B developed VF. Adenosine may cause VF when administered during preexcited AF. This phenomenon is seen in patients having APs with short refractory periods.


Dissecting plasmodesmata molecular composition by mass spectrometry-based proteomics.
In plants, the intercellular communication through the membranous channels called plasmodesmata (PD; singular plasmodesma) plays pivotal roles in the orchestration of development, defence responses, and viral propagation. PD are dynamic structures embedded in the plant cell wall that are defined by specialized domains of the endoplasmic reticulum (ER) and the plasma membrane (PM). PD structure and unique functions are guaranteed by their particular molecular composition. Yet, up to recent years and despite numerous approaches such as mutant screens, immunolocalization, or screening of random cDNAs, only few PD proteins had been conclusively identified and characterized. A clear breakthrough in the search of PD constituents came from mass-spectrometry-based proteomic approaches coupled with subcellular fractionation strategies. Due to their position, firmly anchored in the extracellular matrix, PD are notoriously difficult to isolate for biochemical analysis. Proteomic-based approaches have therefore first relied on the use of cell wall fractions containing embedded PD then on "free" PD fractions whereby PD membranes were released from the walls by enzymatic degradation. To discriminate between likely contaminants and PD protein candidates, bioinformatics tools have often been used in combination with proteomic approaches. GFP fusion proteins of selected candidates have confirmed the PD association of several protein families. Here we review the accomplishments and limitations of the proteomic-based strategies to unravel the functional and structural complexity of PD. We also discuss the role of the identified PD-associated proteins.


Association of arylamine N-acetyltransferases NAT1 and NAT2 genotypes to laryngeal cancer risk.
Genetically polymorphic xenobiotic metabolizing enzymes are supposed to be host factors for an individual's cancer susceptibility. A total of 255 laryngeal cancer patients was genotyped for NAT1 and NAT2 and compared with 510 reference individuals, matched by age and gender. NAT1 genotypes (NAT1*3, *4, *10, and *11 ) were found equally distributed between cases and control individuals. However, there was a significant overrepresentation of 20 (7.8%) homozygous NAT2 genotypes coding for rapid acetylation (NAT2*4/*4 and NAT2*4/*12A) amongst laryngeal cancer patients versus 19 (3.7%) such individuals in the control group (odds ratio 2.18, 95% confidence limits 1.13, 4.22; P = 0.018). Furthermore, an increasing NAT2*4/*4 frequency in cases with strong cigarette consumption was observed, but also in non-smokers. Heterozygous genotypes of NAT2*4/slow were not overrepresented. These results correspond with earlier findings in lung cancer. Analysis of NAT1 and NAT2 combinations revealed a linkage disequilibrium between NAT1*10 and NAT2*4; NAT1*10 frequency was twofold higher in NAT2*4/*4 carriers than in slow NAT2 coding genotypes. In conclusion, the distinct genotype NAT2*4/*4 proved to be a rare, but powerful host risk factor for larynx carcinoma. These data support the notion that an individual's specific NAT2 genotype may be decisive for the organ of his smoking-initiated cancer.


Neuropsychiatric correlates of olfactory identification and traumatic brain injury in a sample of impulsive violent offenders.
Olfactory deficits have a diverse etiology and can be detected with simple olfactory tests. Key olfactory pathways are located within the frontal and temporal lobes where they are vulnerable to damage due to head trauma. Orbitofrontal cortex (OFC) integrity is important for olfaction and aspects of behavioral regulation. We measured olfactory identification ability in a sample of impulsive violent offenders to determine its associations with history of traumatic brain injury (TBI) and a range of neuropsychiatric indices, including proxies for cognitive ability, impulsivity and social connectedness. Male participants were drawn from the ReINVEST study, a randomized controlled trial of sertraline to reduce recidivism in violent impulsive offenders. Criteria for participation in the study included a minimum age of 18 years, a documented history of two or more violent offenses, and a score of 70 or above on the Barratt Impulsiveness Scale (BIS-11). The 16-item "Sniffin sticks" (SS) odor identification test (OI) was administered as were standardized questionnaires regarding previous TBI, additional measures to screen cognition [word reading test of the Wechsler Individuals Achievement Test (WIAT), social connectedness (the Duke Social Support Scale), and a range of other neuropsychiatric conditions or symptoms]. The sample SS scores were compared against published age-specific norms. Univariate and multivariate analyses were performed with SS score (linear regression, within those without hyposmia) or hyposmia (logistic regression) as the outcome. The mean OI scores were lower than population norms and 16% of participants were classified as hyposmic. Univariate analyses showed associations of SS score with age, WIAT score, impulsivity, TBI and TBI severity, social connectedness, childhood sexual abuse, suicidality and current use of heroin. In multivariate analyses, age, TBI severity and WIAT remained as significant independent predictors of SS score (within the normosmic range) or hyposmia (logistic regression). Olfactory performance was associated with multiple behavioral phenomena in a pattern that would be consistent with this serving as a proxy for orbitofrontal functioning. As such, OI testing may have utility in further studies of offenders. In future, we will examine whether olfactory score predicts recidivism or response to the administration of sertraline, in terms of reducing recidivism.


The transdermal contraceptive patch: a new approach to hormonal contraception.
The transdermal contraceptive patch delivers ethinyl estradiol and norelgestromin (17-deacetylnorgestimate) at a rate over seven days that results in efficacy paralleling that achieved with oral contraceptives. Due to the pharmacokinetics of the system, adequate steroid levels are maintained for two days beyond the recommended duration of use of an individual patch, with resulting maintenance of efficacy. With perfect use, the failure rate is 0.70 pregnancies per 100 woman-years and for typical use, the rate is 0.88 pregnancies per 100 woman-years. Body weight above 90 kilograms (198 pounds) is associated with lower efficacy. Cycle control is similar to that achieved by oral contraceptives. With the exception of a transient increase in breast tenderness, the side effect profile is similar to that noted by oral contraceptive users. A major advantage of this method compared to oral contraceptives is a nearly 90% perfect adherence to the dosing schedule across all age groups. Partial or total detachment of the patch occurs at an overall rate of 3.8%. This rate is not affected by warm humid climates, vigorous exercise, or exposure to saunas or water baths.


Overexpression of Pygopus2 protects HeLa cells from vinblastine-induced apoptosis.
Pygopus, a very important component of the Wnt signaling transcriptional complex, has multiple functions in both Wnt-dependent and -independent pathways. Human Pygopus2 (Pygo2) is expressed in many cancers and plays an important role in tumor growth. In the present study, we generated human carcinoma (HeLa) cell lines stably expressing Pygo2, which counteracts vinblastine- induced apoptosis. The anti-apoptotic function was determined by DNA fragmentation, sub-G1 appearance, loss of mitochondrial membrane potential (Deltapsim) and the activation of caspase-9 and caspase-3. In addition, we found that Pygo2 effectively blocks vinblastineinduced c-Jun and AP-1 activation, maintains the anti-apoptotic protein Bcl-2 in an unphosphorylated state, and thus can render cells resistant to apoptosis. However, Pygo2 does not alter the vinblastine-induced cell cycle changes. Here, we describe an anti-apoptotic activity exerted by Pygo2 through blocking activation of the JNK/AP-1 signaling pathway induced by vinblastine.


Human mesenchymal stem cells: insights from a surrogate in vivo assay system.
Mesenchymal stem cells (MSC) are multipotent cells that have been isolated from the bone marrow of multiple species that can be induced to differentiate into at least bone, cartilage, and adipose tissue in vitro. Using a model of in utero cellular transplantation in which human MSC are transplanted into fetal lambs, we have shown that MSC can engraft in multiple tissues and persist for over one year. Furthermore, these cells can differentiate into cardiac and skeletal myocytes, bone marrow stromal cells, adipocytes, thymic epithelial cells, and chondrocytes. These observations lend support to the potential utility of MSC for cellular and/or gene therapy in the treatment of a variety of congenital or acquired diseases such as osteogenesis imperfecta, muscular dystrophy, lysosomal storage diseases, and for enhancement of bone marrow transplantation.


Asialoglycoprotein (ASGP) receptors induced by apoptosis. Their immunohistochemical localization in neonatal rat hepatocytes.
Immunohistochemical detection of asialoglycoprotein (ASGP) receptors has been performed on neonatal rat hepatocytes in primary cultures, incubated with TGF beta, TNF alpha and retinoic acid. These substances account for the increase in the rate of apoptosis of the cell cultures and for the increase of the expression of ASGP receptors. Both modifications are higher at 24 hours of incubation.


Haloperidol impairs auditory filial imprinting and modulates monoaminergic neurotransmission in an imprinting-relevant forebrain area of the domestic chick.
In vivo microdialysis and behavioural studies in the domestic chick have shown that glutamatergic as well as monoaminergic neurotransmission in the medio-rostral neostriatum/hyperstriatum ventrale (MNH) is altered after auditory filial imprinting. In the present study, using pharmaco-behavioural and in vivo microdialysis approaches, the role of dopaminergic neurotransmission in this juvenile learning event was further evaluated. The results revealed that: (i) the systemic application of the potent dopamine receptor antagonist haloperidol (7.5 mg/kg) strongly impairs auditory filial imprinting; (ii) systemic haloperidol induces a tetrodotoxin-sensitive increase of extracellular levels of the dopamine metabolite, homovanillic acid, in the MNH, whereas the levels of glutamate, taurine and the serotonin metabolite, 5-hydroxyindole-3-acetic acid, remain unchanged; (iii) haloperidol (0.01, 0.1, 1 mm) infused locally into the MNH increases glutamate, taurine and 5- hydroxyindole-3-acetic acid levels in a dose-dependent manner, whereas homovanillic acid levels remain unchanged; (iv) systemic haloperidol infusion reinforces the N-methyl-d-aspartate receptor-mediated inhibitory modulation of the dopaminergic neurotransmission within the MNH. These results indicate that the modulation of dopaminergic function and its interaction with other neurotransmitter systems in a higher associative forebrain region of the juvenile avian brain displays similar neurochemical characteristics as the adult mammalian prefrontal cortex. Furthermore, we were able to show that the pharmacological manipulation of monoaminergic regulatory mechanisms interferes with learning and memory formation, events which in a similar fashion might occur in young or adult mammals.


Choice reaction times in depressive states.
An experiment was performed in which two components of response latency, decision time (DT) and movement time (MT), were measured in two relatively homogeneous samples of neurotic and psychotic depressive patients, together with a normal control group. It was found that whereas both DT and MT were significantly longer in the depressive samples than in the control sample, only DT was significantly longer in the psychotic than in the neurotic depressive sample. Thus while both DT and MT were elevated among the depressive samples relative to the control sample, only DT was further sensitive to clinical variations within the depressive state. DT was found to increase directly with depressive severity among an undifferentiated sample of acute depressives, which on further analysis proved to hold for the neurotic depressive sample only. MT was found to increase directly with age among the psychotic depressive sample. No other age influences were found on response latencies of depressive patients. These results are discussed in terms of a postulated impairment of the central information-processing mechanisms, as an explanation of psychomotor slowing among depressive patients.


Brasilonema lichenoides sp. nov. and Chroococcidiopsis lichenoides sp. nov. (Cyanobacteria): two novel cyanobacterial constituents isolated from a tripartite lichen of headstones.
Cyanolichens are an assemblage of fungi and cyanobacteria from diverse, cosmopolitan habitats. Typically composed of a single species of cyanobacterium, with or without another eukaryotic alga, here we present two novel cyanobionts isolated from an undescribed tripartite lichen. This endolithic lichen was isolated from a granite cemetery tombstone from Jacksonville, FL, and contains two potentially nitrogen-fixing cyanobionts. Employing a total evidence approach, we characterized the cyanobionts using molecular (the 16S rDNA and ITS gene region), morphological, and ecological data. Phylogenetic analyses revealed two novel taxa: Brasilonema lichenoides and Chroococcidiopsis lichenoides, both of which fell within well-supported clades. To our knowledge, this represents the first instance of a tripartite lichen with two cyanobacterial and no eukaryotic members. These types of lichens may well represent an unexplored reservoir of cyanobacterial diversity. The specific epithets are proposed under the provisions of the International Code of Nomenclature for algae, fungi, and plants.


Histological Analyses of Acute Alcoholic Liver Injury in Zebrafish.
Alcoholic Liver Disease (ALD) refers to damage to the liver due to acute or chronic alcohol abuse. It is among the leading causes of alcohol-related morbidity and mortality and affects more than 2 million people in the United States. A better understanding of the cellular and molecular mechanisms underlying alcohol-induced liver injury is crucial for developing effective treatment for ALD. Zebrafish larvae exhibit hepatic steatosis and fibrogenesis after just 24 h of exposure to 2% ethanol, making them useful for the study of acute alcoholic liver injury. This work describes the procedure for acute ethanol treatment in zebrafish larvae and shows that it causes steatosis and swelling of the hepatic blood vessels. A detailed protocol for Hematoxylin and Eosin (H&E) staining that is optimized for the histological analysis of the zebrafish larval liver, is also described. H&E staining has several unique advantages over immunofluorescence, as it marks all liver cells and extracellular components simultaneously and can readily detect hepatic injury, such as steatosis and fibrosis. Given the increasing usage of zebrafish in modeling toxin and virus-induced liver injury, as well as inherited liver diseases, this protocol serves as a reference for the histological analyses performed in all these studies.


[Genetic structure and genetic diversity of Artemisia annua varieties (strains) populations based on SCoT markers].
To reveal the genetic diversity and genetic structure in Artemisia annua varieties (strains) populations, we detected the genetic polymorphism within and among eight varieties (strains) populations (192 individuals) by the approach of Start Codon Targeted Polymorphism (SCoT). The associated genetic parameters were calculated by POPGENE1.31 and the relationship was constructed based on UPGMA method. The results showed that, using 20 screened primers, a total of 145 bands were produced, of which 122 were polymorphic loci. At species level, there was a high level of genetic diversity among eight varieties (strains) populations (PPB = 84.1% ,H = 0.217 3 and H(sp) = 0.341 9). However, at the variety (strains) population level, genetic diversity was lower, the average of genetic parameters was PPB = 41.9%, H = 0.121 5, H(pop) = 0.186 8. The Nei's genetic differentiation coefficient was 0.441 0, indicate that most of the genetic variation in this species existed within the variety populations. The gene flow (N(m) = 0.633 9) was less among populations, indicating that the degree of genetic differentiation was higher. Genetic similarity coefficient were changed from 0.755 1 to 0.985 7. By clustering analysis, eight varieties (strains) were clustered into two major categories and it was also showed the same or similar genetic background varieties (strains) have a tendency to gather in the same group. Results suggest that, in variety breeding, breeders should strengthen the exchange of bred germplasm and increase mutual penetration of excellent genes, which would broaden the genetic base of A. annua.


The new, race-free, Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) equation to estimate glomerular filtration rate: is it applicable in Europe? A position statement by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM).
The EFLM recommends not to implement the race-free Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) equation in European laboratories and to keep the 2009 version of the CKD-EPI equation, without applying a race correction factor. This recommendation is completely in line with a recent Editorial published by the European Renal Association who has also proposed to change to a novel equation only when it has considerably better performance, trying to reach global consensus before implementing such a new glomerular filtration rate (GFR) estimation equation. In Europe, this equation could be for instance the new European Kidney Function Consortium (EKFC) equation, which is population-specific, developed from European cohorts and accurate from infants to the older old. Beyond serum creatinine, the estimating equations based on cystatin C will probably gain in popularity, especially because cystatin C seems independent of race. Finally, we must keep in mind that all GFR equations remain an estimation of GFR, especially rough at the individual level. Measuring GFR with a reference method, such as iohexol clearance, remains indicated in specific patients and/or specific situations, and here also, the role of the clinical laboratories is central and should still evolve positively in the future.


Titration of extra-PEEP against intrinsic-PEEP in severe asthma by electrical impedance tomography: A case report and literature review.
The use of extra-positive end-expiratory pressure (PEEP) at a level of 80% intrinsic-PEEP (iPEEP) to improve ventilation in severe asthma patients with control ventilation remains controversial. Electrical impedance tomography (EIT) may provide regional information for determining the optimal extra-PEEP to overcome gas trapping and distribution. Moreover, the experience of using EIT to determine extra-PEEP in severe asthma patients with controlled ventilation is limited. A severe asthma patient had 12-cmH2O iPEEP using the end-expiratory airway occlusion method at Zero positive end-expiratory pressures (ZEEP). How to titrate the extra-PEEP to against iPEEP at bedside? An incremental PEEP titration was performed in the severe asthma patient with mechanical ventilation. An occult pendelluft phenomenon of the ventral and dorsal regions was found during the early and late expiration periods when the extra-PEEP was set to <6 cmH2O. If the extra-PEEP was elevated from 4 to 6 cmH2O, a decrease in the end-expiratory lung impedance (EELI) and a disappearance of the pendelluft phenomenon were observed during the PEEP titration. Moreover, there was broad disagreement as to the "best" extra-PEEP settings according to the various EIT parameters. The regional ventilation delay had the lowest extra-PEEP value (10 cmH2O), whereas the value was 12 cmH2O for the lung collapse/overdistension index and 14 cmH2O for global inhomogeneity. The extra-PEEP was set at 6 cmH2O, and the severe whistling sound was improved. The patient's condition further became better under the integrated therapy. A broad literature review shows that this was the 3rd case of using EIT to titrate an extra-PEEP to against PEEPi. Importantly, the visualization of occult pendelluft and possible air release during incremental PEEP titration was documented for the first time during incremental PEEP titration in patients with severe asthma. Examining the presence of the occult pendelluft phenomenon and changes in the EELI by EIT might be an alternative means for determining an individual's extra-PEEP.


Fragment-based Drug Discovery Successful Contributions to Current Pharmacotherapeutic Agents Arsenal against Aggressive Cancers: A Mini-Review.
After a decade of approval of the drug vemurafenib in 2011, the hopeless scenario imposed by some severe cancer types has been mitigated by the magic bullets developed through fragment-based drug discovery. Moreover, this recent approach to medicinal chemistry has been successfully practiced by academic laboratories and pharmaceutical industry workflows focused on drug design with an enhanced profile for chemotherapy of aggressive tumors. This mini-review highlights the successes achieved by these research campaigns in the fruitful field of the molecular fragment paradigm that resulted in the approval of six new anticancer drugs in the last decade (2011-2021), as well as several promising clinical candidates. It is a particularly encouraging opportunity for other researchers who want to become aware of the applicability and potency of this new paradigm applied to the design and development of powerful molecular weapons in the constant war against these merciless scourges of humanity.


Occurrence of cryptosporidial oocysts and giardia cysts in bottled mineral water commercialized in the city of Campinas, State of São Paulo, Brazil.
The consumption of bottled mineral water has significantly increased in Brazil so that it is in the interest of public health to determine the parasitological and microbiological status of some brands of Brazilian mineral water available in the town of Campinas, São Paulo, Brazil. For this purpose, detection of protozoa by direct immunofluorescence technique and microbiological parameters were determined for each specimen after membrane filtration. Giardia cysts were not present while cryptosporidial oocysts were detected in two samples. The counts of protozoa varied from 0.2 to 0.5 oocysts/l. The detected level of Pseudomonas aeruginosa and heterotrophic bacteria reflected the level of organic enrichment of the water.


Using SMS as a tool to reduce exclusions experienced by caregivers of people with disabilities in a resource-limited Colombian community.
The community of El Codito, located in the mountainside on the perimeter of Bogota, Colombia, is considered one of the most vulnerable and resource-limited communities in the region. This community-based research (CBR) project used short message service (SMS) messaging as a tool for information access and social interaction with caregivers of people with disabilities (PWD). Using a focused ethnographic method, this research evaluated the experience of caregivers participating in the project. In addition to primarily qualitative methods, supplementary quantitative message data was also collected. This project utilized free and open source software for SMS message distribution. Caregivers experienced the project as a window to possibility; the possibility of a social support network, the possibility of community participation and the possibility of change. During the three-month implementation, a total of 56 information messages were sent to caregivers, 20 question messages were received from caregivers and 30 social interaction messages were sent by caregivers to the group. The proliferation of mobile phones in this resource-limited setting provided a feasible method for reducing the exclusion of PWD and caregivers. SMS was a useful tool for sharing information and reducing the isolation experienced by this socially excluded population. Implications for Rehabilitation Mobile phones are a prevalent technology in many resource-limited settings; short message service (SMS) is a feasible tool for sharing information and reducing isolation experienced by people with disabilities (PWD) and their families. When developing technology-based projects in resource-limited settings, the field of rehabilitation could apply principles from the field of Information and Communication Technology for Development (ICT4D). Projects in resource-limited settings could consider using a community-based research (CBR) approach. This collaborative approach can enhance the contextual relevance of the project. Caregivers of PWD found the project to be both useful and meaningful, and as a result of the project became more involved in their community.


Activator protein-2gamma (AP-2gamma) expression is specifically induced by oestrogens through binding of the oestrogen receptor to a canonical element within the 5'-untranslated region.
The activator protein 2 (AP-2) transcription factors are essential proteins for oestrogenic repression of the ERBB2 proto-oncogene in breast cancer cells. In the present study, we have examined the possible oestrogenic regulation of AP-2 genes themselves in breast-tumour-derived lines. As early as 1 h after oestrogen treatment, AP-2gamma mRNA was markedly increased, whereas AP-2alpha was down-regulated, but with slower kinetics, and AP-2beta was not affected at all. Addition of anti-oestrogens ablated these effects. Modulation of the protein levels corresponded to changes in the transcript levels, thus suggesting that in oestrogen-treated cells, an inversion of the balance between AP-2alpha and AP-2gamma isoforms occurs. The 5'-untranslated region (5'-UTR) of the human AP-2gamma gene contains one consensus and one degenerate oestrogen-responsive element (ERE). Reporter constructs carrying the AP-2gamma promoter and the 5'-UTR were up-regulated by oestrogens in transient transfection assays. Deletion of the most conserved (but not of the degenerate) ERE from reporter constructs abrogated the oestrogenic response, although both ERE-containing segments were footprinted in DNaseI protection assays. In vitro binding assays demonstrated the ability of oestrogen receptor alpha (ERalpha) to bind to this site, and chromatin immunoprecipitation analysis of the endogenous gene showed that ERalpha occupies this region in response to oestrogens. We conclude that AP-2gamma is a primary oestrogen-responsive gene and suggest that AP-2 proteins may mediate some oestrogenic responses.


The value of C-reactive protein in the management of shunt infections.
Shunt infections and their management remain a clinically important problem in patients with hydrocephalus. The authors evaluated, in comparison with traditional parameters, C-reactive protein (CRP) in blood/serum (S-CRP) and in cerebrospinal fluid (CSF; C-CRP) for its power to identify and treat patients with infected shunts. On 84 different occasions, CSF and blood samples from 59 children suspected of having shunt/CSF infections were obtained and evaluated. An infection was proven by a CSF culture in 35 of 84 evaluations. Values for S-CRP in infected individuals were higher than in noninfected ones (91.8 +/- 70.2 mg/L compared with 16.1 +/- 28.3 mg/L, p < 0.0001). The sensitivity of S-CRP testing was 97.1%, the specificity 73.5%, the negative predictive value 97.3%, and the receiver operating characteristic area 91.6%. The probability of shunt/CSF infection--provided that the S-CRP level was greater than 7 mg/L--rose from 41.7% (prevalence) to a posttest level of 72.3%. Specificity and posttest probability were 87.8 and 87.2%, respectively, if cases with other concurrent infections were excluded. The probability of missing a CSF/shunt infection at an S-CRP lower than 7 mg/L was 2.7%. All other diagnostic parameters did not yield useful test results. The rate of reinfection was elevated in patients in whom S-CRP levels were greater than 7 mg/L at the time of shunt reimplantation. Analysis of these data suggests that the S-CRP level should be included in the first-line workup of patients with suspected shunt/CSF infection. It seems justified to avoid performing a shunt tap if S-CRP levels are less than 7 mg/L. A larger multicenter trial is necessary to confirm these promising diagnostic results and to deliver hard data concerning whether or not a normalized S-CRP level is a reliable indicator of successful antibiotic therapy and whether a shunt can be safely reimplanted.


Measurement of [Formula: see text] production with additional jet activity, including [Formula: see text] quark jets, in the dilepton decay channel using pp collisions at [Formula: see text].
Jet multiplicity distributions in top quark pair ([Formula: see text]) events are measured in pp collisions at a centre-of-mass energy of 8 TeV with the CMS detector at the LHC using a data set corresponding to an integrated luminosity of 19.7[Formula: see text]. The measurement is performed in the dilepton decay channels ([Formula: see text], [Formula: see text], and [Formula: see text]). The absolute and normalized differential cross sections for [Formula: see text] production are measured as a function of the jet multiplicity in the event for different jet transverse momentum thresholds and the kinematic properties of the leading additional jets. The differential [Formula: see text] and [Formula: see text] cross sections are presented for the first time as a function of the kinematic properties of the leading additional [Formula: see text] jets. Furthermore, the fraction of events without additional jets above a threshold is measured as a function of the transverse momenta of the leading additional jets and the scalar sum of the transverse momenta of all additional jets. The data are compared and found to be consistent with predictions from several perturbative quantum chromodynamics event generators and a next-to-leading order calculation.


The Relevance of Iron in the Pathogenesis of Multiple System Atrophy: A Viewpoint.
Iron is essential for cellular development and maintenance of multiple physiological processes in the central nervous system. The disturbance of its homeostasis leads to abnormal iron deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Iron toxicity has been established in the pathogenesis of Parkinson's disease; however, its contribution to multiple system atrophy (MSA) remains elusive. MSA is characterized by cytoplasmic inclusions of misfolded α-synuclein (α-SYN) in oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs). Remarkably, the oligodendrocytes possess high amounts of iron, which together with GCI pathology make a contribution toward MSA pathogenesis likely. Consistent with this observation, the GCI density is associated with neurodegeneration in central autonomic networks as well as olivopontocerebellar and striatonigral pathways. Iron converts native α-SYN into a β-sheet conformation and promotes its aggregation either directly or via increasing levels of oxidative stress. Interestingly, α-SYN possesses ferrireductase activity and α-SYN expression underlies iron mediated translational control via RNA stem loop structures. Despite a correlation between progressive putaminal atrophy and iron accumulation as well as clinical decline, it remains unclear whether pathologic iron accumulation in MSA is a secondary event in the cascade of neuronal degeneration rather than a primary cause. This review summarizes the current knowledge of iron in MSA and gives evidence for perturbed iron homeostasis as a potential pathogenic factor in MSA-associated neurodegeneration.


[Study on therapeutic dosimetry of HIFU ablation tissue].
It is a difficult problem in high intensity focused ultrasound (HIFU) therapeutic dosimetry that how to use a BFR to ablate a mass in tissue and to determine the energy-efficiency relation, that is, the scale of biological effects of HIFU. A mass lesion was realized in this study according to a treatment principle of damaging tissue from BFRs to fascicle lesions, slice lesions and a mass lesion. A 1.6 MHz transducer, 150 mm in diameter and with a focal length of 120 mm, was used. The focal intensities (I(SATA)) were 0-27 000 W/cm2 and the scanning speeds were 1-4 mm/s. The distance between every fascicle lesion was 5-10 mm and the distance between two slice lesions was 10-20 mm. Different irradiation depths of fascicle slice and mass lesion were observed after HIFU procedures in this study. The dosage of HIFU required for tissue coagulated necrosis was evaluated with energy of HIFU (J) per cubic millimeter (mm3), i.e., J/mm3 which was defined as energy-efficiency factor (EEF). Results showed that EEF needed for producing fascicle lesions increased with the increase of irradiation depth. EEF required for inducing various lesions in biological tissue was different. Generally, it followed the law: EEF(mase)< EEF(slice)<EEF(fascicle). EEF for slice lesion was not simply a summation of EEFs for fascicle lesions at different irradiation depths, although the slice lesion was assembled with fascicle lesions at different irradiation depths in the same treatment slice. In the same way, EEF for a mass lesion was not simple summation of EEFs for slice lesions at different layers. So HIFU therapeutic dosimetry can be carried on investigation by using EEF, Factors of affecting EEF of HIFU include acoustic power, exposure time, irradiation depth, tissue structure, and tissue functional status. Besides, another important factor is the change of the acoustic environment in tissue during the HIFU procedure.


Conception rates in farm mink (Neovison vison) in relation to first mating date, age and color variety.
The aim of the study was to analyze the effects of the first mating date, age and color variety on the conception rates in farm mink. We analyzed female mink reproductive performance in 492 Sapphire and 463 Standard Black females over 3 or 4 years. The analysis included the number of inefficient matings, the interval between the first inefficient mating and the efficient mating (copulation) and the conception rates. The results show a significant effect of female's age and color variety on the conception rates. The youngest, yearling females of either color needed a higher number of matings per conception, as compared to older, 2- and 3-year-old females. Black females demonstrated a higher number of inefficient matings (1.066), as compared with Sapphires (0.730). Yearling females were most often mated from 1 to 10 March, and older females from 11 to 20 March. Older females achieved better conception rates than the yearlings. Dates between 11 and 25 March proved to be the optimum for the first mating, since the highest conception rates were observed if the females had mated during this period.


Cone Contrast Test for Color Vision Deficiency Screening Among a Cohort of Military Aircrew Applicants.
PURPOSE: To evaluate the use of the Cone Contrast Test (CCT) as a color vision screening tool in an Asian population of aircrew applicants and compare it against the Ishihara Psuedo Isochromatic Plates (PIP) - Edridge Lantern Test (ELT) screening pathway, assessing its impact on attrition with CCT cut-off scores of 55 and 75.METHODS: This is a retrospective review of 862 Republic of Singapore Airforce aircrew applicants tested with CCT and Ishihara PIP-ELT combination as screening. CCT repeatability was analyzed by comparing the subject's interocular (right vs. left eye) scores measured as the coefficient of repeatability (COR), with COR differing by ≥15 points considered to be outside normal limits.RESULTS: Of the applicants, 17 (1.97%) failed to achieve a CCT score of ≥55 (5 protan, 12 deutan), while 26 (3.02%) applicants failed to achieve a score ≥75 (5 protan, 21 deutan). Of the 17 applicants who obtained a CCT score of <55, 16 failed the Ishihara PIP test. The only applicant who passed the Ishihara PIP test had a CCT score of 50. Of all applicants, 1.7% had a COR of ≥15, with 93.3% of them identified as color vision deficient (CVD). Our results demonstrated excellent test repeatability, with 99.9% (835 out of 836) of color vision normal (CVN) applicants achieving a COR of <15 points.CONCLUSION: Our study demonstrated a high correlation between the CCT (passing score of ≥55) and the Ishihara PIP. Employing the CCT with a passing score of ≥75, instead of the Ishihara PIP-ELT combination, led to an increase in attrition rate of 0.7-3.0%.Chay IW, Lim SWY, Tan BBC. Cone Contrast Test for color vision deficiency screening among a cohort of military aircrew applicants. Aerosp Med Hum Perform. 2019; 90(2):71-76.


Snake venom proteinase inhibitors. III. Isolation of five polypeptide inhibitors from the venoms of Hemachatus haemachatus (Ringhal's corbra) and Naja nivea (Cape cobra) and the complete amino acid sequences of two of them.
Five proteinase inhibitors which all inhibit the activity of bovine trypsin [EC 22.214.171.124] were isolated from African Elapid venoms of Hemachatus haemachatus (HHV, Ringhal's cobra) and Naja nivea (NNV, Cape cobra). All the inhibitors were essentially homogeneous by polyacrylamide gel electrophoresis in the presence or absence of sodium dodecylsulfate. Amino acid analysis and terminal analysis also supported their chemical homogeneities, except for one of the two inhibitors from Hemachatus haemachatus venom. The isolated inhibitors had a molecular weight of about 6,500, consisting of 52 to 57 amino acid residues, and they were all devoid of tryptophan. However, their amino acid compositions differed from each other. One of the three inhibitors isolated from Naja nivea venom, designated NNV inhibitor Ia, was unique, in that 4 half-cystinyl residues per mole fof the polypeptide were present, whereas all the others contained six residues. Of the isolated proteinase inhibitors, the complete amino acid sequences of two major inhibitors were established by manual and automatic Edman degradations and standard enzymatic techniques. Each of the inhibitors, designated HHV inhibitor II and NNV inhibitor II, consisted of 57 amino acid with arginine and glycine at the NH2- and COOH-termini, respectively. Both contained six half-cystines in disulfide linkages, and their overall amino acid sequences were similar, showing 91% homology. The two inhibitors differed in sequence by only five amino acid replacements, Asp-3 to Arg; Tyr-17 to Arg; Leu-25 to Arg; Gln-32 to Glu; and Arg-52 to His, in the 57 residue peptide chain. Comparing the amino acid sequences of these two cobra venom inhibitors with those of Russell's viper venom inhibitor II and bovine pancreatic trypsin inhibitor (BPTI), about 50% homology was found in their sequences. The 6 half-cystinyl residues of these inhibitors were in the same linear positions. Moreover, the regions which are structurally and functionally important in the well-known BPTI molecule were found with extremely high sequence homology in the cobra venom inhibitors. These findings strongly suggest that the cobra venom inhibitors as well as Russell's viper inhibitor II have very similar conformations to that established for BPTI.


Parasite-derived arginase influences secondary anti-Leishmania immunity by regulating programmed cell death-1-mediated CD4+ T cell exhaustion.
The breakdown of L-arginine to ornithine and urea by host arginase supports Leishmania proliferation in macrophages. Studies using arginase-null mutants show that Leishmania-derived arginase plays an important role in disease pathogenesis. We investigated the role of parasite-derived arginase in secondary (memory) anti-Leishmania immunity in the resistant C57BL/6 mice. We found that C57BL/6 mice infected with arginase-deficient (arg(-)) L. major failed to completely resolve their lesion and maintained chronic pathology after 16 wk, a time when the lesion induced by wild-type L. major is completely resolved. This chronic disease was associated with impaired Ag-specific proliferation and IFN-γ production, a concomitant increase in programmed cell death-1 (PD-1) expression on CD4(+) T cells, and failure to induce protection against secondary L. major challenge. Treatment with anti-PD-1 mAb restored T cell proliferation and IFN-γ production in vitro and led to complete resolution of chronic lesion in arg(-) L. major-infected mice. These results show that infection with arg(-) L. major results in chronic disease due in part to PD-1-mediated clonal exhaustion of T cells, suggesting that parasite-derived arginase contributes to the overall quality of the host immune response and subsequent disease outcome in L. major-infected mice. They also indicate that persistent parasites alone do not regulate the quality of secondary anti-Leishmania immunity in mice and that the quality of the primary immune response may be playing a hitherto unrecognized dominant role in this process.


What's Next for Sotorasib in NSCLC?
The CodeBreaK 200 trial showed that sotorasib led to a 34% decrease in relative risk of disease progression or death compared with docetaxel but yielded no improvement in overall survival. Despite the KRAS inhibitor's high cost, less toxicity likely tips the balance in its favor. Subgroup analyses and combination trials are underway to optimize treatment with sotorasib and other KRAS inhibitors.


Hemolytic performance of a MagLev disposable rotary blood pump (MedTech Dispo): effects of MagLev gap clearance and surface roughness.
Mechanical shaft seal bearing incorporated in the centrifugal blood pumps contributes to hemolysis and thrombus formation. In addition, the problem of durability and corrosion of mechanical shaft seal bearing has been recently reported from the safety point of view. To amend the shortcomings of the blood-immersed mechanical bearings, a magnetic levitated centrifugal rotary blood pump (MedTech Dispo Model 1; Tokyo Medical and Dental University, Tokyo, Japan) has been developed for extracorporeal disposable application. In this study, the hemolytic performance of the MedTech Dispo Model 1 centrifugal blood pump system was evaluated, with special focus on the narrow blood path clearance at the magnetic bearing between rotor and stator, and on the pump housing surface roughness. A pump flow of 5 L/min against the head pressure of 100 mm Hg for 4 h was included in the hemolytic test conditions. Anticoagulated fresh porcine blood was used as a working fluid. The clearance of blood path at the magnetic bearing was in the range of 100-250 micro m. Pump housing surface roughness was controlled to be around Ra = 0.1-1.5 micro m. The lowest hemolytic results were obtained at the clearance of 250 micro m and with the polished surface (Ra = 0.1 micro m) yielding the normalized index of hemolysis (NIH) of less than 0.001 g/100 L, which was 1/5 of the Biopump BP-80 (Medtronic Inc., Minneapolis, MN, USA, and 1/4 of the BPX-80. In spite of rough surface and narrow blood path, NIH levels were less than clinically acceptable level of 0.005 g/100 L. The noncontact, levitated impeller system is useful to improve pump performance in blood environment.