Immune-mediated Coombs negative intravascular haemolysis in systemic lupus erythematosus (SLE).
A 27-year-old woman presented with a history of excessive hair loss, loss of appetite, loss of weight, amenorrhoea and loss of axillary and pubic hair for 6 months followed by fever and vomiting for 5 months and abdominal pain for 1 month. During the course of her illness, the patient developed intravascular haemolysis as evidenced by a drop in haemoglobin, indirect hyperbilirubinaemia, raised lactate dehydrogenase (LDH) and haemoglobinuria. Examination revealed severe pallor, mild icterus, elevated jugular venous pressure, generalised lymphadenopathy and hyperpigmentation. Investigations revealed severe anaemia, indirect hyperbilirubinaemia, raised LDH and negative Coombs test. Antinuclear antibody and anti-dsDNA, anti-Sm and anti-SS-A/Ro antibodies were positive and complement C3 was low. The patient was diagnosed to have systemic lupus erythematosus and immune-mediated intravascular haemolysis and was treated with prednisolone and hydroxychloroquine. Haemolysis resolved following steroid therapy, and during follow-up, there were no further episodes of haemolysis.


A Clinical Drug-Drug Interaction Study Assessing a Novel Drug Transporter Phenotyping Cocktail With Adefovir, Sitagliptin, Metformin, Pitavastatin, and Digoxin.
A new probe drug cocktail containing substrates of important drug transporters was tested for mutual interactions in a clinical trial. The cocktail consisted of (predominant transporter; primary phenotyping metric): 10 mg adefovir-dipivoxil (OAT1; renal clearance (CLR )), 100 mg sitagliptin (OAT3; CLR ), 500 mg metformin (several renal transporters; CLR ), 2 mg pitavastatin (OATP1B1; clearance/F), and 0.5 mg digoxin (intestinal P-gp, renal P-gp, and OATP4C1; peak plasma concentration (Cmax ) and CLR ). Using a randomized six-period, open change-over design, single oral doses were administrated either concomitantly or separately to 24 healthy male and female volunteers. Phenotyping metrics were evaluated by noncompartmental analysis and compared between periods by the standard average bioequivalence approach (boundaries for ratios 0.80-1.25). Primary metrics supported the absence of relevant interactions, whereas secondary metrics suggested that mainly adefovir was a victim of minor drug-drug interactions (DDIs). All drugs were well tolerated. This cocktail may be another useful tool to assess transporter-based DDIs in vivo.


Clinical antiangiogenic effect of recombinant adenovirus-p53 combined with hyperthermia for advanced cancer.
To assess the safety and clinical antiangiogenic effect of recombinant adenovirus-p53 (rAd-p53) combined with hyperthermia plus or not plus radiotherapy in advanced cancer. Expression of Vascular epithelial growth factor (VEGF) after intratumoral injection of rAd-p53 was assayed by immunohistochemistry (IHC) imaging. Forty-four patients with advanced cancer were enrolled into this clinical study. The patients were intratumorally injected with rAd-p53 (Gendicine) at a dose of 1×10(12) vp once a week, with a total of 4-54 (mean 7.7) times. Total of 4-29 (mean 8.5) times of hyperthermia was given to the patients. Among the 44 patients, 30 patients were concurrently added with radiotherapy of a total dose 30-76 Gy/15-38 f/3-8 w (mean 58 Gy). Before and after intratumoral injection of rAd-p53, the VEGF IHC positive cell scores were 2.80 and 1.50, respectively (P=0.031). The treatment of rAd-p53 combined with hyperthermia plus or not plus radiotherapy in advanced cancer achieved CR rate of 13.60% (6/44), and PR rate of 29.6% (13/44), and thus the effective rate was 43.2%. In addition to 6 patients with CR, 19 patients (19/38, 50.0%) had low density area (LDA) of more than 50% area on CT image within tumor indicating tumor tissue necrosis. Our data indicate that rAd-p53 inhibits VEGF expression and angiogenesis, and promotes tumor necrosis and shrinkage induced by hyperthermia plus or not plus radiotherapy in advanced cancer.


[Childhood obesity: recent advances and an experimental contribution].
This work, in addition to the peculiar medical aspects of the children obesity, synthesize the experimental findings about the main plasmatic antioxidants (uric acid, ascorbic acid, retinol, coenzyme Q10, lycopene) and the platelet fatty acids profile in groups of children according to the following BMI criteria: 43 with a BMI ranging between 25 and 29; 43 with a BMI ranging between 21.7 e 22.9 and 20 with a BMI ranging between 18.5 e 20; average age 10.49 +/- 2.66. The antioxidants show a particular behaviour: in fact they decrease according to the BMI recorded within the groups. About this issue the international literature is not consistent. Probably different results can be found in more severe condition of obesity. Another important result is for the platelet fatty acid, independently from the BMI, weight etc. compared to the other subjects. The difference found is for the stearic acid, from 15 to 21 point of percentage, compared to all the other groups investigated. In agreement with the international literature, stearic acid seems to have an important role in the control of the platelet activation. This finding, could offer a better possibility to understand the progression of the atherosclerosis towards the ischemic condition, according to the age. The utilisation of particular mathematic models, the Artificial Neural Network, beyond the normal advanced statistic methods, has open to the understanding of phenomena, otherwise, inexplicable. With the Artificial Neural Network (ANN) it has been possible to classify the children using the ANN map built for the depressive condition (platelet fatty acids markers: palmitic acid, linoleic acid, arachidonic acid) and the ANN map built for the ischemic condition (platelet fatty acids markers: oleic acid, linoleic acid, arachidonic acid). Examining the maps, a certain percentage of children seems to be at high risk for several psychiatric conditions with respect to the major depression, while for the ischemic pathology the children are in the same position of the ischemic subjects. Because we know that the children are not ischemic, probably they have the same biochemical characteristics but are protected by the high level of stearic acid and by the high degree of saturation of the platelets. For this reason, children cannot belong to the map area of the major depression, which, in turn, is characterized by a very high degree of unsaturation of the fatty acids. Further studies are needed to better understand the complex situation of the children from the biochemical and psychiatric point of view.


Neural Cognition and Affective Computing on Cyber Language.
Characterized by its customary symbol system and simple and vivid expression patterns, cyber language acts as not only a tool for convenient communication but also a carrier of abundant emotions and causes high attention in public opinion analysis, internet marketing, service feedback monitoring, and social emergency management. Based on our multidisciplinary research, this paper presents a classification of the emotional symbols in cyber language, analyzes the cognitive characteristics of different symbols, and puts forward a mechanism model to show the dominant neural activities in that process. Through the comparative study of Chinese, English, and Spanish, which are used by the largest population in the world, this paper discusses the expressive patterns of emotions in international cyber languages and proposes an intelligent method for affective computing on cyber language in a unified PAD (Pleasure-Arousal-Dominance) emotional space.


Host species exploitation and discrimination by animal parasites.
Parasite species often show differential fitness on different host species. We developed an equation-based model to explore conditions favouring host species exploitation and discrimination. In our model, diploid infective stages randomly encountered hosts of two species; the parasite's relative fitness in exploiting each host species, and its ability to discriminate between them, was determined by the parasite's genotype at two independent diallelic loci. Relative host species frequency determined allele frequencies at the exploitation locus, whereas differential fitness and combined host density determined frequency of discrimination alleles. The model predicts instances where populations contain mixes of discriminatory and non-discriminatory infective stages. Also, non-discriminatory parasites should evolve when differential fitness is low to moderate and when combined host densities are low, but not so low as to cause parasite extinction. A corollary is that parasite discrimination (and host-specificity) increases with higher combined host densities. Instances in nature where parasites fail to discriminate when differential fitness is extreme could be explained by one host species evolving resistance, following from earlier selection for parasite non-discrimination. Similar results overall were obtained for haploid extensions of the model. Our model emulates multi-host associations and has implications for understanding broadening of host species ranges by parasites.This article is part of the themed issue 'Opening the black box: re-examining the ecology and evolution of parasite transmission'.


Acute Effects of Progressive Sled Loading on Resisted Sprint Performance and Kinematics.
Pareja-Blanco, F, Pereira, LA, Freitas, TT, Alcaraz, PE, Reis, VP, Guerriero, A, Arruda, AFS, Zabaloy, S, De Villarreal, ES, and Loturco, I. Acute effects of progressive sled loading on resisted sprint performance and kinematics. J Strength Cond Res 36(6): 1524-1531, 2022-We examined the effects of 5 loading conditions (0, 20, 40, 60, and 80% of body-mass [BM]) on resisted sprint performance and kinematics in male rugby players over different distances. Ten players from the Brazilian National Team (20.1 ± 3.3 years; 88.7 ± 18.8 kg; 178.3 ± 6.2 cm) performed 20-m sprints under the 5 loading conditions. Sprint times in 5, 10, and 20 m were recorded. Stride length (SL), and hip, knee, and ankle angles were measured using an eight-sensor motion analysis system. The kinematic parameters were calculated over the different distances. Heavier loads led to significantly greater velocity loss (p < 0.001-0.05). Significant reductions in SL were also observed when comparing 0% BM and all resisted sprints in all assessed distances (p < 0.001-0.05, effect size [ES]: 1.35-4.99). Very heavy (80% BM) sled load provoked significantly greater decreases in SL than the rest of loading conditions (p < 0.01-0.05). Important kinematic alterations were observed for all loading conditions and sprint distances when compared with 0% BM (ES: 0.76-1.79, for hip-angle; 0.20-1.40, for knee-angle; and 0.73-1.88, for ankle-angle). Moreover, 80% BM induced significantly higher hip flexion, lower knee flexion, and higher ankle dorsiflexion than 20% BM condition at 5-10 and 10-20 m distances (p < 0.05). Lighter sled loads (<40% BM) seem to be more adequate to improve speed ability without provoking drastic changes in the unloaded sprinting technique, whereas heavier loads may be more suitable for optimizing horizontal force production and thus, acceleration performance.


Mitral valvar anomalies and discrete subaortic stenosis.
On the basis of our clinical experience, we hypothesized that the role of mitral valvar anomalies in the development and recurrence of discrete subaortic stenosis might be underestimated. From January 1994 to October 2000, the anatomy of the mitral valve and its relationship to the other components of the left ventricular outflow tract were studied by echocardiography in a series of 73 consecutive patients referred to our institution for surgical correction of discrete subaortic stenosis. In all patients for whom it was considered advisable, surgical correction of the mitral anomaly was performed, together with resection of the fibro-muscular subaortic stenosis. One or more mitral valvar anomalies were found in 35 patients (48%). They could be grouped into five categories: insertion of a papillary muscle into the aortic leaflet, insertion of a papillary muscle into the ventricular wall, "muscularization" of the subaortic portion of the aortic leaflet, anomalous insertion of the valvar tissue into the ventricular wall, and accessory valvar tissue. In all cases with anomalous mitral valvar anatomy, surgical correction was feasible. It consisted of transection of the anomalous papillary muscle or its attachment, resection of accessory valvar tissue, and/or patch enlargement of the aortic leaflet. The incidence of mitral valvar anomalies associated with subaortic stenosis is probably underestimated. Our data suggest that they should be systematically searched for during the evaluation of all cases of subaortic stenosis. Their surgical correction is generally feasible, and might improve the mid and long term results.


Cerebral Toxoplasmosis Masquerading Cns Lymphoma on FDG PET-CT in Post Renal Transplant Patient.
20 year old post renal transplant patient developed recurrent episodes of seizure. MRI revealed focal lesion in right parieto-occipital lobe with perilesional edema. FDG PET-CT revealed multiple hypermetabolic lesions in bilateral cerebral hemisphere. Subsequent biopsy from the lesion demonstrated bradyzoites of Toxoplasma gondii with inflammatory cells and thereby, a confirmatory diagnosis of cerebral toxoplasmosis was made. This case demonstrates the fact that increased FDG uptake in cerebral lesions in post transplant patient should be interpreted with caution and confirmed with histopathological correlation.


Male and female physicians show different patterns of gender bias: a paper-case study of management of irritable bowel syndrome.
Research has raised concerns about gender bias in medicine, i.e. that men and women might be treated differently due to gender-stereotyped attitudes among physicians. The authors investigated gender differences in medical management of a common health problem, irritable bowel syndrome (IBS). In a national examination for Swedish house officers, the examinees were allocated to suggest management of IBS in either a male or female paper-patient. The case description was identical in both genders with the exception of prior prostate and gynaecological symptoms. The open answers were coded for analysis. A total of 289 physicians (45% women) participated. Chi-squared tests were used to measure differences in proportions. In variables focusing on medication, weight, gynaecological problems, tobacco, alcohol, thyroid function, proposed diagnoses, X-ray of the colon, and advice about lifestyle, significant or close to significant gender differences were seen. Both male and female physicians made gender differences but they did not show the same pattern of differences. The results suggest that gender bias is involved in medical management of IBS but men and women physicians may show disparate patterns of gender bias. There is a need for larger studies on gender differences in medical management with designs making it possible to consider the gender of both the patient and the physician. Furthermore, the results call attention to 'knowledge-mediated gender bias', a phenomenon implying that once knowledge about gender differences in a condition has been established, this might in fact cause gender-biased assessments of individual patients in clinical practice.


Diversity of meso-scale architecture in human and non-human connectomes.
Brain function is reflected in connectome community structure. The dominant view is that communities are assortative and segregated from one another, supporting specialized information processing. However, this view precludes the possibility of non-assortative communities whose complex inter-community interactions could engender a richer functional repertoire. We use weighted stochastic blockmodels to uncover the meso-scale architecture of Drosophila, mouse, rat, macaque, and human connectomes. We find that most communities are assortative, though others form core-periphery and disassortative structures, which better recapitulate observed patterns of functional connectivity and gene co-expression in human and mouse connectomes compared to standard community detection techniques. We define measures for quantifying the diversity of communities in which brain regions participate, showing that this measure is peaked in control and subcortical systems in humans, and that inter-individual differences are correlated with cognitive performance. Our report paints a more diverse portrait of connectome communities and demonstrates their cognitive relevance.


Survival in Limited Disease Small Cell Lung Cancer According to N3 Lymph Node Involvement.
There are several definitions of limited disease (LD) in small cell lung cancer (SCLC), differing with respect to N3 disease accepted. We analyzed patients from a randomized trial comparing two schedules of thoracic radiotherapy (TRT) in LD SCLC to investigate whether there were survival differences between N3 subcategories (n=144). Patients with a baseline CT scan available were analysed. Patients received four courses of cisplatin/etoposide and TRT of 45 Gy/30 fractions (twice daily) or 42 Gy/15 fractions (once daily). Median overall survival (OS) was 23.3 months in the whole cohort. N3-patients (n=37) had shorter survival than those with N0-2 (16.7 vs. 33.0 months; p<0.001). There were no significant OS-differences between the N3 subcategories, but patients with metastases to two or more N3 regions had shorter survival than other N3 patients (13.4 vs. 19.9 months; p=0.011). There were no survival differences between the N3 subcategories, suggesting that all N3 disease should be considered as LD.


Lipoatrophic diabetes in an elderly woman: clinical course and serum adipocytokine concentrations.
Generalized lipodystrophy is a rare disorder of adipose tissue, whose etiology remains unknown. Pathophysiology of this disorder is characterized by generalized loss of body fat associated with an infrequent form of diabetes mellitus (lipoatrophic diabetes). Main features of this form of diabetes mellitus are the severe insulin resistance and the absence of ketoacidosis. Lipodystrophy can be congenital or acquired. In the acquired form, metabolic disturbances usually begin in the first years of life and the response to conventional treatment is very poor. Some alterations in serum adipocytokines have been described in this disease. We report the case of a 74-year-old woman with acquired generalized lipodystrophy who presented with low-normal serum concentrations of leptin, low adiponectin and resistin levels, and high serum levels of TNF alpha. Patient was initially treated with fenofibrate, metformin and high doses of subcutaneous insulin achieving an adequate metabolic control. During this period, serum adipocytokines were periodically measured. We comment on the different etiopathogenic mechanisms and the therapeutic modalities of this rare syndrome.


Plant chemistry and local adaptation of a specialized folivore.
Local adaptation is central for creating and maintaining spatial variation in plant-herbivore interactions. Short-lived insect herbivores feeding on long-lived plants are likely to adapt to their local host plants, because of their short generation time, poor dispersal, and geographically varying selection due to variation in plant defences. In a reciprocal feeding trial, we investigated the impact of geographic variation in plant secondary chemistry of a long-lived plant, Vincetoxicum hirundinaria, on among-population variation in local adaptation of a specialist leaf-feeding herbivore, Abrostola asclepiadis. The occurrence and degree of local adaptation varied among populations. This variation correlated with qualitative and quantitative differences in plant chemistry among the plant populations. These findings provide insights into the mechanisms driving variation in local adaptation in this specialized plant-herbivore interaction.


Three-dimensional kinematics of leaf-cutter ant mandibles: not all dicondylic joints are simple hinges.
Insects use their mandibles for a variety of tasks, including food processing, material transport, nest building, brood care, and fighting. Despite this functional diversity, mandible motion is typically thought to be constrained to rotation about a single fixed axis. Here, we conduct a direct quantitative test of this 'hinge joint hypothesis' in a species that uses its mandibles for a wide range of tasks: Atta vollenweideri leaf-cutter ants. Mandible movements from live restrained ants were reconstructed in three dimensions using a multi-camera rig. Rigid body kinematic analyses revealed strong evidence that mandible movement occupies a kinematic space that requires more than one rotational degree of freedom: at large opening angles, mandible motion is dominated by yaw. But at small opening angles, mandibles both yaw and pitch. The combination of yaw and pitch allows mandibles to 'criss-cross': either mandible can be on top when mandibles are closed. We observed criss-crossing in freely cutting ants, suggesting that it is functionally important. Combined with recent reports on the diversity of joint articulations in other insects, our results show that insect mandible kinematics are more diverse than traditionally assumed, and thus worthy of further detailed investigation. This article is part of the theme issue 'Food processing and nutritional assimilation in animals'.


Label-Free Homogeneous Electroanalytical Platform for Pesticide Detection Based on Acetylcholinesterase-Mediated DNA Conformational Switch Integrated with Rolling Circle Amplification.
This study addresses the need for sensitive pesticide assay by reporting a new label-free and immobilization-free homogeneous electroanalytical strategy, which combines acetylcholinesterase (AChE)-catalyzed hydrolysis product-mediated DNA conformational switch and rolling circle amplification (RCA) to detect organophosphorous and carbamate pesticides in a "signal-on" mode. When target pesticides were present, AChE activity was inhibited and could not trigger the following DNA conformational change and the RCA reaction, which results in numerous methylene blue (MB) molecules in a free state, generating a strong electrochemical response. This proposed strategy was highly sensitive for omethoate detection with a detection limit as low as 2.1 μg/L and a linear range from 10 to 10 000 μg/L. Furthermore, this strategy was demonstrated to be applicable for pesticide detection in real samples. Thus, this novel label-free homogeneous electroanalytical strategy holds great promise for pesticide detection and can be further exploited for sensing applications in the environment and the food safety field.


Social anxiety disorder and the psychobiology of self-consciousness.
Individuals with social anxiety disorder (SAD) are characterized by fear or anxiety about social situations, but also by important alterations in self-referential processing. Given advances in our understanding of the neurocircuitry and neurochemistry of SAD, the question arises of the relationship between this research and an emergent literature on the psychobiology of self and self-consciousness. A number of investigations of SAD have highlighted altered activity in the medial prefrontal cortex (mPFC; involved in self-representation), insula (involved in interoceptive processing), and other structures that play a role in bodily self-consciousness, as well as the potential value of interventions such as selective serotonin reuptake inhibitors (SSRI) and self-focused reappraisal in normalizing such changes. Future studies to more closely investigate associations between psychobiological alterations and changes in self-related processing in SAD, may be useful in shedding additional light on both SAD and self-consciousness.


Association of 22 cytokine gene polymorphisms with tuberculosis in Macedonians.
To examine the possible role of 22 cytokine gene polymorphisms in host susceptibility to or protection against tuberculosis (TB) in Macedonians. 301 healthy unrelated individuals and 75 patients with pulmonary TB were studied. Cytokine genotyping was performed by PCR with sequence-specific priming (PCR-SSP) (Heidelberg kit). TNF-alpha-238/G, IL-1R psti1970/C, IL-1beta + 3962/T:T, IL-4-1098/T:T, IFNgamma utr5644/A:A, IL-10-1082/G:G, IL-4-590/C:C, IL-10/ATC, IL-4/TCT, IL-4/TCC, IL-10/ATC:GCC, IL-4/TCT:TTT, IL-4/TCC:TTC, IL-10/GCC:GCC and IL-4/TCC:TCC were positively associated with TB, while protective association was identified for IL-4-098/G, IL-1beta + 3962/C, IFNgamma utr5644/T, IL-1beta + 3962/C:T, IL-4-1098/G:T, IL-4-590/C:T, IFNgamma utr5644/A:T, IL-4/GCC, IL-4/TTC and IL-4/GCC:TTC. These results suggest that some cytokine polymorphisms are significantly associated and affect host susceptibility/resistance to TB in Macedonians.


Population dynamics of anthropophilic mosquitoes during the northeast monsoon season in the malaria epidemic zone of Sri Lanka.
Mosquito-borne diseases are a major health problem in Sri Lanka. Human biting mosquitoes were collected during the night (18.00-06.00 hours) at Nikawehera village, in the malaria endemic intermediate rainfall zone of the country. Collections were made at monthly intervals in the period October 1991 to April 1992, which included the main rainy season due to the northeast monsoon (October-January). Thirteen Anopheles, eleven Culex, three Aedes, three Mansonia and one Armigeres species were identified, including known vectors of malaria, Bancroftian filariasis, Japanese encephalitis and dengue fever. Mosquito human-biting rates were highest in December. The main malaria vector Anopheles culicifacies showed peak biting between 18.00 and 23.00 hours whereas the predominant culicines Culex fuscocephala and Cx quinquefasciatus preferred to bite after midnight. In 1991-92 the prevalence of some species of anophelines at Nikawehera differed markedly from that observed in 1990-91 and the possible reasons are discussed.


Targeting AXL in NSCLC.
State-of-the-art cancer precision medicine approaches involve targeted inactivation of chemically and immunologically addressable vulnerabilities that often yield impressive initial anti-tumor responses in patients. Nonetheless, these responses are overshadowed by therapy resistance that follows. AXL, a receptor tyrosine kinase with bona fide oncogenic capacity, has been associated with the emergence of resistance in an array of cancers with varying pathophysiology and cellular origins, including in non-small-cell lung cancers (NSCLCs). Here in this review, we summarize AXL biology during normal homeostasis, oncogenic development and therapy resistance with a focus on NSCLC. In the context of NSCLC therapy resistance, we delineate AXL's role in mediating resistance to tyrosine kinase inhibitors (TKIs) deployed against epidermal growth factor receptor (EGFR) as well as other notable oncogenes and to chemotherapeutics. We also discuss the current understanding of AXL's role in mediating cell-biological variables that function as important modifiers of therapy resistance such as epithelial to mesenchymal transition (EMT), the tumor microenvironment and tumor heterogeneity. We also catalog and discuss a set of effective pharmacologic tools that are emerging to strategically perturb AXL mediated resistance programs in NSCLC. Finally, we enumerate ongoing and future exciting precision medicine approaches targeting AXL as well as challenges in this regard. We highlight that a holistic understanding of AXL biology in NSCLC may allow us to predict and improve targeted therapeutic strategies, such as through polytherapy approaches, potentially against a broad spectrum of NSCLC sub-types to forestall tumor evolution and drug resistance.


Abnormal thymocyte maturation in spontaneously diabetic BB rats involves the deletion of CD4-8+ cells.
The object of this study was to further characterize the pathophysiology of the peripheral T lymphopenia in the BB rat. Towards this end, surface markers on unseparated thymocytes and purified thymocyte subsets from age- and sex-matched diabetes-resistant (BBn) and diabetes-prone (BBd) rats were analyzed by two-color flow cytometry. The proportions of thymocytes falling into each of the four main phenotypic subsets were comparable in BBn (n = 9) and BBd (n = 8) rats: respectively, 4.6 +/- 0.6% and 4.4 +/- 0.8%, CD4-8-; 68.1 +/- 1.9% and 71.1 +/- 3.2%, CD4+8+; 18.3 +/- 1.5% and 15.4 +/- 2.3%, CD4+8-; 9.1 +/- 0.9% and 9.1 +/- 1.0%, CD4-8+. In addition, absolute numbers of thymocytes were not significantly different. The levels of expression of CD4, TCR-alpha beta within each thymocyte subset were comparable in BBn and BBd animals as were the anti-TCR-induced proliferative responses of their CD4+8- and CD4-8+ thymocytes. However, phenotypic abnormalities within the CD4-8+ thymocyte subset of the BBd rat were found. A very significant (p less than 0.005) deletion of mature CD4-8+, TCR-alpha beta + thymocytes and a proportional increase (p less than 0.005) of immature CD4-8+, TCR-alpha beta low thymocytes. Moreover, a twofold decrease of CD8 expression by mature CD4-8+ thymocytes was observed in BBd animals. These results suggest that an impaired thymic maturation contributes to the peripheral T lymphopenia of the BBd rat.


Backyard pigs are a reservoir of zoonotic hepatitis E virus in southern Brazil.
Hepatitis E virus (HEV) is the causative agent of acute hepatitis worldwide. There is no seroprevalence study in backyard farms, which are characterized by suboptimal hygienic conditions in Brazil. We aimed to determine the seroprevalence and genetic diversity of HEV in backyard pigs in Brazil. Swine serum samples collected in 2012 (n=731) and 2014 (n=713) were analysed. The presence of anti-HEV immunoglobulin G in pig serum was evaluated by indirect enzyme-linked immunosorbent assay. Reverse transcription polymerase chain reaction was performed and phylogenetic analyses were carried out based on the partial ORF1 and ORF2 coding regions. Anti-HEV antibodies were detected in 77.6% (567/731; 95% confidence interval [CI] 74.5 to 90.6%) of serum samples in 2012 and 65.5% (467/713; 95% CI 62.0 to 69.0%) in 2014. The herd seroprevalence was 91.7% (187/204; 95% CI 91% to 99%) in 2012 and 83.7% (164/196; 95% CI 78% to 89%) in 2014. Further, HEV RNA was detected in 0.8% (6/713) of samples from 2014. Phylogenetic analysis showed three different genotype 3 subtypes with high similarity to human HEV strains. This study showed that backyard pigs are a reservoir of HEV and alerts us to the need to control infection and spillover from backyard farms. MF438128-MF438135.


Intravoxel incoherent motion: application in differentiation of hepatocellular carcinoma and focal nodular hyperplasia.
We aimed to explore whether intravoxel incoherent motion (IVIM)-related parameters of hepatocellular carcinoma (HCC) and focal nodular hyperplasia (FNH) demonstrate differences that could be used to differentiate and improve diagnostic efficiency. A total of 27 patients, including 22 with HCC and 5 with FNH, underwent liver 3.0 T magnetic resonance imaging for routine sequences. They were concurrently examined by IVIM diffusion-weighted imaging (DWI) scanning with 11 different b values (0-800 s/mm2). IVIM-derived parameters, such as pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f), and apparent diffusion coefficient (ADCtotal), were quantified automatically by post-processing software and compared between HCC and FNH groups. A receiver operating characteristic (ROC) curve was then created to predict their diagnostic value. D* was weak in terms of reproducibility among the other parameters. ADCtotal, D, and D* were significantly lower in the HCC group than in the FNH group, while f did not show a significant difference. ADCtotal and D had the largest area under the curve values (AUC; 0.915 and 0.897, respectively) and similarly high efficacy to differentiate the two conditions. IVIM provides a new modality to differentiate the HCC and FNH. ADCtotal and D demonstrated outstanding and comparable diagnosing utility.


Role of Spm-Cer-S1P signalling pathway in MMP-2 mediated U46619-induced proliferation of pulmonary artery smooth muscle cells: protective role of epigallocatechin-3-gallate.
During remodelling of pulmonary artery, marked proliferation of pulmonary artery smooth muscle cells (PASMCs) occurs, which contributes to pulmonary hypertension. Thromboxane A2 (TxA2) has been shown to produce pulmonary hypertension. The present study investigates the inhibitory effect of epigallocatechin-3-gallate (EGCG) on the TxA2 mimetic, U46619-induced proliferation of PASMCs. U46619 at a concentration of 10 nM induces maximum proliferation of bovine PASMCs. Both pharmacological and genetic inhibitors of p(38)MAPK, NF-κB and MMP-2 significantly inhibit U46619-induced cell proliferation. EGCG markedly abrogate U46619-induced p(38)MAPK phosphorylation, NF-κB activation, proMMP-2 expression and activation, and also the cell proliferation. U46619 causes an increase in the activation of sphingomyelinase (SMase) and sphingosine kinase (SPHK) and also increase sphingosine 1 phosphate (S1P) level. U46619 also induces phosphorylation of ERK1/2, which phosphorylates SPHK leading to an increase in S1P level. Both pharmacological and genetic inhibitors of SMase and SPHK markedly inhibit U46619-induced cell proliferation. Additionally, pharmacological and genetic inhibitors of MMP-2 markedly abrogate U46619-induced SMase activity and S1P level. EGCG markedly inhibit U46619-induced SMase activity, ERK1/2 and SPHK phosphorylation and S1P level in the cells. Overall, Sphingomyeline-Ceramide-Sphingosine-1-phosphate (Spm-Cer-S1P) signalling axis plays an important role in MMP-2 mediated U46619-induced proliferation of PASMCs. Importantly, EGCG inhibits U46619 induced increase in MMP-2 activation by modulating p(38)MAPK-NFκB pathway and subsequently prevents the cell proliferation.


Social provocation modulates decision making and feedback processing: Examining the trajectory of development in adolescent participants.
Increasingly, research is turning to the ways in which social context impacts decision making and feedback processing in adolescents. The current study recorded electroencephalography to examine the trajectory of development across adolescence, with a focus on how social context impacts cognition and behaviour. To that end, younger (10-12 years) and older (14-16 years) adolescents played a modified Taylor Aggression Paradigm against two virtual opponents: a low-provoker and a high-provoker. During the task's decision phase (where participants select punishment for their opponent), we examined two event-related potentials: the N2 and the late positive potential (LPP). During the outcome phase (where participants experience win or loss feedback), we measured the feedback related negativity (FRN). Although N2 amplitudes did not vary with provocation, LPP amplitudes were enhanced under high provocation for the younger group, suggesting that emotional reactivity during the decision phase was heightened for early adolescents. During the outcome phase, the FRN was reduced following win outcomes under high provocation for both groups, suggesting that a highly provocative social opponent may influence the reward response. Collectively, the data argue that social context is an important factor modulating neural responses in adolescent behavioural and brain development.


[Prolonged allergen challenge in a guinea pig model of allergic rhinitis leads to nasal mucosa remodeling].
The aim of this study was to use a guinea pig model of prolonged allergic-induced rhinitis to characterize the feature of nasal mucosa remodeling. Forty-eight male Hartley guinea pigs were randomly divided into six groups: allergen challenged groups (Group OVA(2w) , Group OVA(6w) and Group OVA(12w)) and control groups respectively (Group Sal(2w), Group Sal(6w) and Group Sal(12w)). Each group had 8 guinea pigs. To develop a guinea pig model of nasal mucosa remodeling, ovalbumin-sensitized guinea pigs were repeatedly challenged with allergen twice a week from two weeks to 12 weeks. Matched control groups were challenged with physiological saline. Nasal lavage was performed 24 hours after the last intranasal challenge. Then nasal mucosa were obtained. HE, AB-PAS, MT, and immunohistochemical staining against transforming growth factor-beta1 (TGF-beta1) were performed. Eosinophil cationic protein (ECP) and OVA-special IgE (OVA-sIgE) were detected by ELISA in nasal lavage fluid. (1) The levels of OVA-sIgE in nasal lavage fluid in Group OVA(6w) and Group OVA(12w) were significantly different from Group OVA(2w), while the levels of ECP had no significant difference among the experiment groups. The levels of OVA-sIgE and ECP in experiment groups were significantly different from control groups respectively (P < 0.01). (2) Grade 0 and Grade 1 of epithelial damage were significantly different in Group OVA(6w) and Group OVA(12w) when compared with from Group OVA(2w) (P < 0.01). At the same time, Grade 0 and Grade 1 of epithelial damage were statistically different in the experiment groups when compared with the respectively control groups (P < 0.05). (3) Goblet gland hyperplasia and collagen deposit within the extracellular matrix (ECM) were easily found in Group OVA(6w) and Group OVA(12w) compared with Group OVA(2w) (P < 0.01). The number of goblet gland and the ratio of collagen deposit were statistically more in Group OVA(6w) and Group OVA(12w) than in Group Sal(6w) and Group Sal(12w) (P < 0.05). That feature of the ratio of collagen deposit did not show in Group OVA(2w) versus Group Sal(2w). (4) Increased TGF-beta1 expressions were observed in Group OVA(6w) and Group OVA(12w) compared with Group OVA(2w) (P < 0.01). Those increasing expressions were also observed in experiment groups rather than in the respectively control groups (P < 0.01). Epithelial damage, goblet cells hyperplasia and collagen deposition in ECM were observed as the features of remodeling in this guinea pig model of allergic rhinitis under prolonged allergen challenge. Epithelial damage, excessive expression of related cytokines and enhancement activity of enzymes were observed in early time after challenge of allergen. The features of goblet cells hyperplasia and collagen deposition in ECM were observed at a later stage.


Recognition of fresh human tumor by human peripheral blood lymphocytes transduced with a bicistronic retroviral vector encoding a murine anti-p53 TCR.
The p53 protein is markedly up-regulated in a high proportion of human malignancies. Using an HLA-A2 transgenic mouse model, it was possible to isolate high-avidity murine CTLs that recognize class I-restricted human p53 epitopes. We isolated the alpha- and beta-chain of a TCR from a highly avid murine CTL clone that recognized the human p53(264-272) epitope. These genes were cloned into a retroviral vector that mediated high efficiency gene transfer into primary human lymphocytes. Efficiencies of >90% for gene transfer into lymphocytes were obtained without selection for transduced cells. The p53 TCR-transduced lymphocytes were able to specifically recognize with high-avidity, peptide-pulsed APCs as well as HLA-A2.1+ cells transfected with either wild-type or mutant p53 protein. p53 TCR-transduced cells demonstrated recognition and killing of a broad spectrum of human tumor cell lines as well as recognition of fresh human tumor cells. Interestingly, both CD8+ and CD4+ subsets were capable of recognizing and killing target cells, stressing the potential application of such a CD8-independent TCR molecule that can mediate both helper and cytotoxic responses. These results suggest that lymphocytes genetically engineered to express anti-p53 TCR may be of value for the adoptive immunotherapy of patients with a variety of common malignancies.


Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation.
Vascular endothelial growth factor-C (VEGF-C)-induced lymphangiogenesis and increased tissue drainage have been reported to inhibit acute and chronic inflammation, and an activated lymphatic endothelium might mediate peripheral tolerance. Using transgenic mice overexpressing VEGF-C in the skin, we found that under inflammatory conditions, VEGF-C-mediated expansion of the cutaneous lymphatic network establishes an immune-inhibitory microenvironment characterised by increased regulatory T (Treg) cells, immature CD11c+CD11b+ dendritic cells (DCs) and CD8+ cells exhibiting decreased effector function. Strikingly, lymphatic endothelial cell (LEC)-conditioned media (CM) potently suppress DC maturation with reduced expression of MHCII, CD40, and IL-6, and increased IL-10 and CCL2 expression. We identify an imbalance in prostaglandin synthase expression after LEC activation, favoring anti-inflammatory prostacyclin synthesis. Importantly, blockade of LEC prostaglandin synthesis partially restores DC maturity. LECs also produce TGF-ß1, contributing to the immune-inhibitory microenvironment. This study identifies novel mechanisms by which the lymphatic endothelium modulates cellular immune responses to limit inflammation.


[Symposium "infections, recently worth noticing". Introductory address].
There was once an idea that the extensive development of antibiotics and vaccines would cause most bacterial and viral infections to fade away someday. However, the occurrence of antibiotic resistant bacteria and variant viruses proved this to be illusion. The spread of HIV infection, since there is no way to cure it so far, is of great concern. The occurrence of methicillin resistant Staphylococcus aureus (MRSA) presents another difficulty in preventing nosocomial infections due to the existence of healthy carriers. The out-break of MRSA in wards is one of the most serious problems in hospital management. HCV is capable of inducing chronic hepatitis, hepatic cirrhosis and hepatoma. HCV is thus a more serious concern today than HBV, since preventive measures against HBV by vaccination and anti-HBV immunoglobulin are fully established. We, doctors, nurses and clinical technologists are apt to be exposed to these hazardous microorganisms and thus should take appropriate precautions during routine work. The present symposium was planned to present recent research on these microorganisms, HIV, MRSA and HCV, so that we can improve our measures to prevent them.


Strategies to reduce mycotoxin levels in maize during storage: a review.
Maize (Zea mays L.) is one of the main cereals as a source of food, forage and processed products for industry. World production is around 790 million tonnes of maize because as a staple food it provides more than one-third of the calories and proteins in some countries. Stored maize is a man-made ecosystem in which quality and nutritive changes occur because of interactions between physical, chemical and biological factors. Fungal spoilage and mycotoxin contamination are of major concern. Aspergillus and Fusarium species can infect maize pre-harvest, and mycotoxin contamination can increase if storage conditions are poorly managed. Prevention strategies to reduce the impact of mycotoxin in maize food and feed chains are based on using a hazard analysis critical control point systems (HACCP) approach. To reduce or prevent production of mycotoxins, drying should take place soon after harvest and as rapidly as feasible. The critical water content for safe storage corresponds to a water activity (a(w)) of about 0.7. Problems in maintaining an adequately low a(w) often occur in the tropics where high ambient humidity make the control of commodity moisture difficult. Damage grain is more prone to fungal invasion and, therefore, mycotoxin contamination. It is important to avoid damage before and during drying, and during storage. Drying maize on the cob before shelling is a very good practice. In storage, many insect species attack grain and the moisture that can accumulate from their activities provides ideal conditions for fungal activity. To avoid moisture and fungal contamination, it is essential that the numbers of insects in stored maize should be kept to a minimum. It is possible to control fungal growth in stored commodities by controlled atmospheres, preservatives or natural inhibitors. Studies using antioxidants, essential oils under different conditions of a(w), and temperature and controlled atmospheres have been evaluated as possible strategies for the reduction of fungal growth and mycotoxin (aflatoxins and fumonisins) in stored maize, but the cost of these treatments is likely to remain prohibitive for large-scale use.


[Coexistence of chronic lymphoid leukemia and Hodgkin's disease. Immunohistochemical study].
We report a new case of coincidence of chronic lymphocytic leukemia (CLL) and mixed cellularity Hodgkin's disease (HD) in the same lymph node. These findings were corroborated by immunohistochemical study showing Reed-Sternberg (RS) cells, with typical immunophenotype in an inflammatory background, closely related to a small neoplastic lymphoid cell population. This is an uncommon feature, and, to our knowledge, this is the first case published in the Spanish literature.


SCM-198 Alleviates Endometriosis by Suppressing Estrogen-ERα mediated Differentiation and Function of CD4+CD25+ Regulatory T Cells.
Background: Endometriosis (EMS), a typical endocrine immune disorder, associates with dramatically increased estrogen production and disorganized immune response in ectopic focus. Peritoneal regulatory T cells (Tregs) expansion in women with EMS and their pathogenic role attributable to endometriotic immunotolerance has been reported. Whether local high estrogen promotes EMS by discipling Tregs needs to be further explored. Up to date, there is no effective medicine for the treatment of EMS. SCM-198 is a synthetic leonurine with multiple physiological activities. Whether SCM-198 could regulate Tregs via estrogen and facilitate the radical cure of EMS has not yet been reported. Methods: Proportion of Tregs in peritoneal fluid of patients with EMS was firstly analyzed via flow cytometry. Peritoneal estrogen concentration and the mRNA levels of estrogen receptor α (ERα) and estrogen receptor β (ERβ) of Tregs were detected by ELISA and RT-PCR, respectively. Grouped in vitro induction assays were performed to explore the effects of SCM-198 and estrogen signaling on Tregs. Cell invasion and viability assays were utilized to detect the crosstalk between Tregs and ectopic endometrial stromal cells (eESCs), with or without SCM-198 treatment. Furthermore, EMS mice models were established to verify the therapeutic effects of SCM-198. Results: Increased Tregs were found in peritoneal fluid of EMS patients, accompanied with estrogen-ERα overactivation. Estrogen-ERα triggered the expansion of Tregs and their cytokine production (IL-10 and TGF-β1), which could be reversed by SCM-198 treatment. Moreover, SCM-198 abated the invasion and viability of eESCs enhanced by Tregs. In vivo experiments confirmed that SCM-198 obviously retarded the growth of ectopic lesions and downregulated the functions of Tregs via estrogen-ERα inactivation. Conclusions: These data suggest that SCM-198 attenuates Tregs expansion via the inhibition of estrogen-ERα signaling in EMS and offer a promising therapy for such a refractory disease.


Treating metastatic triple negative breast cancer with CD44/neuropilin dual molecular targets of multifunctional nanoparticles.
Metastasis of cancer makes up the vast majority of cancer-related deaths, and it usually initiates from tumor cells invasiveness and develops through tumor neovasculature. In this work, we have fabricated a CD44/neuropilin dual receptor-targeting nanoparticulate system (tLyP-1-HT NPs) with endogenous or FDA approved components for treating metastatic triple negative breast cancer (TNBC). The enhanced specific targeting of tLyP-1-HT NPs to both metastatic tumor cells and metastasis-supporting tumor neovasculature was contributed by means of CD44/neuropilin dual receptor-mediated interaction. The NPs not only effectively suppress the invasive capability of tumor cells themselves, but also significantly restrain the metastasis incidence via extravasation as well as the eventual colonization in lungs. In all the three types of TNBC-bearing mice models, orthotopic, post-metastasis and metastasis prevention models, the docetaxel-loaded tLyP-1-HT NPs exhibited markedly enhanced anti-tumor and anti-metastasis efficacy. The inhibitory rates of tLyP-1-HT NPs against orthotopic tumor growth and lung metastasis achieved 79.6% and 100%, respectively. The metastasis inhibition rate and life extension rate of the tLyP-1-HT NPs against post-pulmonary metastasis mice reached 85.1% and up to 62.5%, respectively. All the results demonstrated the designed dual receptor-targeting multifunctional NPs hold great potential in treating metastatic TNBC and lung metastasis.


Coronary Plaque Boundary Enhancement in IVUS Image by Using a Modified Perona-Malik Diffusion Filter.
We propose a modified Perona-Malik diffusion (PMD) filter to enhance a coronary plaque boundary by considering the conditions peculiar to an intravascular ultrasound (IVUS) image. The IVUS image is commonly used for a diagnosis of acute coronary syndrome (ACS). The IVUS image is however very grainy due to heavy speckle noise. When the normal PMD filter is applied for speckle noise reduction in the IVUS image, the coronary plaque boundary becomes vague. For this problem, we propose a modified PMD filter which is designed in special reference to the coronary plaque boundary detection. It can then not only reduce the speckle noise but also enhance clearly the coronary plaque boundary. After applying the modified PMD filter to the IVUS image, the coronary plaque boundaries are successfully detected further by applying the Takagi-Sugeno fuzzy model. The accuracy of the proposed method has been confirmed numerically by the experiments.


Human cord blood applications in cell therapy: looking back and look ahead.
Human umbilical cord blood (UCB) has been used as a reliable source of stem cells for blood-borne diseases and disorders. Recent advances in cell reprogramming technology to produce induced pluripotent stem (iPS) cells, which can be differentiated to multiple adult cell types, has further expanded the potential of cord blood cell therapy for treatment of non-blood-borne diseases. However, in order to harness this breakthrough technology and to provide clinical-grade cells for the patient, standardization of iPS production and differentiation, and good manufacturing practice (GMP) need to be employed. UCB is an ethical source of stem cells and has been used to treat diseases including leukemia, cancer and blood disorders. The development of iPS cell technology could potentially greatly increase the application of cord blood cells as a treatment for a broader range of diseases, UCB-iPS banks could, therefore, be a valuable complementary source of clinical-grade cells for cell therapy. The current applicability of GMP to UCB and UCB-iPS cell-based cell therapy will be discussed. Although cord blood stem cell therapies have been practiced for decades, UCB-iPS cell therapies are a new innovation currently in development. Successful clinical applications of such novel cell therapies will depend on the production of GMP-compliant cells and the establishment of cell banks.


A Dutch report on the ethics of neonatal care: a commentary.
The moral arguments and the decision-making processes arising from them in the context of the dilemmas that arise in considering the appropriateness and implementation of withholding or withdrawing treatment in certain neonates form the basis of this commentary. It is concluded that the differing opinions on management of these babies by individual paediatricians results from their differing moral outlooks rather than from any incoherence in the moral arguments set out in the Dutch report.


A rheostat model for a rapid and reversible form of imprinting-dependent evolution.
The evolutionary advantages of genomic imprinting are puzzling. We propose that genomic imprinting evolved as a mechanism that maximizes the interindividual variability in the rates of gene expression for dosage-sensitive loci that, with minimal unrelated deleterious effects, can alter the phenotype over a wide continuum. We hypothesize (1) that genomic imprinting provides a previously suggested haploid selective advantage (HSA); (2) that many imprinted genes have evolved mechanisms that facilitate quantitative hypervariability (QH) of gene expression; (3) that the combination of HSA and QH makes possible a rapid and reversible form of imprinting-dependent evolution (IDE) that can mediate changes in phenotype; and (4) that this enhanced adaptability to a changing environment provides selective advantage to the population, as an assisted form of evolution. These mechanisms may have provided at least one of the driving forces for the evolution of genomic imprinting in mammals. The rheostat model suggests that both genetic and epigenetic variants can contribute to an integrated mechanism of mixed Mendelian and non-Mendelian inheritance and suggests the possibility that the majority of variants are not intrinsically deleterious but, depending on the environment, are each potentially advantageous. Moreover, this would be a reversible form of evolution, with the ability not only to protect a silent allele from selection for many generations but to reactivate and expand it in the population quickly.


Deep Fusion of Multi-Template using Spatio-Temporal Weighted Multi-Hypergraph Convolutional Networks for Brain Disease Analysis.
Conventional functional connectivity network (FCN) based on resting-state fMRI (rs-fMRI) can only reflect the relationship between pairwise brain regions. Thus, the hyper-connectivity network (HCN) has been widely used to reveal high-order interactions among multiple brain regions. However, existing HCN models are essentially spatial HCN, which reflect the spatial relevance of multiple brain regions, but ignore the temporal correlation among multiple time points. Furthermore, the majority of HCN construction and learning frameworks are limited to using a single template, while the multi-template carries richer information. To address these issues, we first employ multiple templates to parcellate the rs-fMRI into different brain regions. Then, based on the multi-template data, we propose a spatio-temporal weighted HCN (STW-HCN) to capture more comprehensive high-order temporal and spatial properties of brain activity. Next, a novel deep fusion model of multi-template called spatio-temporal weighted multi-hypergraph convolutional network (STW-MHGCN) is proposed to fuse the STW-HCN of multiple templates, which extracts the deep interrelation information between different templates. Finally, we evaluate our method on the ADNI-2 and ABIDE-I datasets for mild cognitive impairment (MCI) and autism spectrum disorder (ASD) analysis. Experimental results demonstrate that the proposed method is superior to the state-of-the-art approaches in MCI and ASD classification, and the abnormal spatio-temporal hyper-edges discovered by our method have significant significance for the brain abnormalities analysis of MCI and ASD.


A comparison of the acquired resistance to Dipetalonema viteae stimulated in hamsters by trickle versus tertiary infections.
Two groups of hamsters were hyperinfected with Dipetalonema viteae. Each of the 15 hamsters in the first group received a total of 900 larvae given in three equal doses on days 0, 150 and 250 from the start of the experiment (tertiary-infection group). Each of the 20 hamsters in the second group received a total of 900 larvae given in 18 equal doses (50 larvae per dose) at 14 day intervals. Thus the final dose was given on day 238 from the start of the experiment (trickle-infection group). About half of the hamsters in each group were killed 100 days after the last sensitizing infection and their adult worm burdens and subcutaneous nodules were counted. The tertiary-infection group had a higher average number of adult worms per hamster, but fewer subcutaneous nodules than the trickle infection group. However, when the number of adult worms and subcutaneous nodules were added together, the sums from both groups were similar. The remaining hamsters of the above two groups, along with a group of nine previously uninfected hamsters, were given a challenge infection of 500 larvae per animal. Necropsy data taken 70-80 days after the challenge infection indicated inhibition and/or destruction of developing larval stages in the trickle + challenge-infection group, but no such acquired resistance phenomenon in the tertiary + challenge-infection or challenge-infection groups. While the mechanism remains unknown, it is clear that prior exposure to repeated small infections over an extended period stimulated a protective response to D. viteae in hamsters. This response was not seen in animals given three large infections over a similar time period.


LncRNA ZFAS1 promotes growth and metastasis by regulating BMI1 and ZEB2 in osteosarcoma.
Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. LncRNAs have recently gained widespread attention and have been shown to have crucial roles in various biological regulatory processes. ZFAS1, a newly identified lncRNA, was shown to be dysregulated in several cancers. However, little is known about the alteration and functional significance of ZFAS1 in OS. In the present study, for the first time, we revealed a functional role of ZFAS1 on OS growth and metastasis. The expression of ZFAS1 was significantly overexpressed in OS samples and cell lines, and upregulation of ZFAS1 is significantly associated with unfavorable prognosis of OS patients. Functional assays also demonstrated that ZFAS1 enhanced the growth and metastatic ability of OS cells in vitro and in vivo. Mechanistically, we found that ZFAS1 positively regulated malignant phenotypes by competitively binding the miR-200b and miR-200c and upregulating BMI1. ZFAS1 also interacted with ZEB2 and regulated ZEB2 protein stability. Furthermore, we demonstrated that SP1 functions as an upstream activated factor of ZFAS1. ZFAS1 may be a potential therapeutic target for OS tumorigenesis and progression.


[Evolution of the vaccination timetable in Morocco].
Morocco has always been aware of the importance of vaccination and has been implementing an ambitious vaccination policy for several decades. The first vaccination campaigns started in the sixties. The Extended Vaccination Program (EVP) was launched in 1981 and restructured six years later, being renamed the National Immunization Program (NIP). Regular follow-up of vaccine efficacy has led to several changes in the national vaccination timetable, including new antigens and boosters. Protection against tuberculosis, diphtheria, tetanus, whooping cough, poliomyelitis, etc. has considerably improved in Morocco. Neonatal tetanus and diphtheria have been eliminated, along with poliomyelitis (certified by WHO in 2001). Future efforts will focus on reducing urban-rural disparities, and on implementing the WHO program for eliminating measles and congenital rubella.


Interaction between glutamatergic-NMDA and cholinergic-muscarinic systems in classical fear conditioning.
A number of studies have suggested that the glutamatergic and cholinergic systems are both involved in learning and memory processes and that they interact in order to facilitate these processes. However, the role of M1-muscarinic receptors in mediating this interaction has not been elucidated. The aim of this study was to determine whether the concomitant administration of MK-801 (non-competitive NMDA antagonist) and dicyclomine (M1-muscarinic antagonist--DIC) in sub-effective doses impairs contextual fear conditioning (hippocampal-dependent task) and tone fear conditioning tasks (hippocampal-independent task). The results showed that concomitant pre-training administration of DIC (8.0 mg/kg) and MK-801 (0.07 mg/kg)--two sub-effectives doses for the contextual fear conditioning task--does impair the performance of animals on this task (as measured by freezing behavior time). Tone fear conditioning tasks were not affected by the drugs either administered separately or concurrently. The pre-training administration of sub-effective doses of MK-801 and DIC in combination impairs performance on contextual fear conditioning task (hippocampal-dependent), but not on tone fear conditioning task (hippocampal-independent). These data support the hypothesis that the interaction between glutamatergic and cholinergic systems in hippocampus-dependent learning and memory processes probably occurs through M1 receptor.


Reduced attentional inhibition for peripheral distractors of angry faces under central perceptual load in deaf individuals: evidence from an event-related potentials study.
Studies have shown that deaf individuals distribute more attention to the peripheral visual field and exhibit enhanced visual processing for peripheral stimuli relative to hearing individuals. This leads to better detection of peripheral target motion and simple static stimuli in hearing individuals. However, when threatening faces that represent dangerous signals appear as non-targets in the periphery, it remains unclear whether deaf individuals would retain an advantage over hearing individuals in detecting them. In this study, 23 deaf and 28 hearing college students were included. A modified perceptual load paradigm and event-related potentials (ERPs) were adopted. In the task, participants were instructed to search for a target letter in a central letter array, while task-irrelevant face distractors (happy, neutral, and angry faces) were simultaneously presented in the periphery while the central perceptual load was manipulated. Behavioral data showed that angry faces slowed deaf participants' responses to the target while facilitating the responses of hearing participants. At the electrophysiological level, we found modulation of P1 amplitude by central load only in hearing individuals. Interestingly, larger interference from angry face distractors was associated with higher P1 differential amplitude only in deaf individuals. Additionally, the amplitude of N170 for happy face distractors was smaller than that for angry and neutral face distractors in deaf participants. The present data demonstrates that, despite being under central perceptual load, deaf individuals exhibit less attentional inhibition to peripheral, goal-irrelevant angry faces than hearing individuals. The result may reflect a compensatory mechanism in which, in the absence of auditory alertness to danger, the detection of visually threatening information outside of the current attentional focus has a high priority.


A case of alpha-thalassemia-2 associated with pulmonary infarction.
Pulmonary infarction is an entity of medical significance that develops concurrently in beta-thalassemia but not in alpha-thalassemia. The reason for this difference is yet to be elucidated. We have evaluated a 21-year-old male alpha-thalassemia-2 patient who had profound microcytic anemia and pulmonary infarction. Analysis of the alpha-globin gene revealed -alpha3.7/alpha alpha genotype. His mother also had the same heterozygous gene deletion, though she had neither anemia nor pulmonary infarction. Since the patient had no other predisposition to pulmonary infarction, it is suggested that there is a close etiologic relationship between morphologic abnormality of the erythrocytes caused by alpha-thalassemia-2 and development of pulmonary infarction.


Understanding the use of telemedicine across different opioid use disorder treatment models: A scoping review.
The COVID-19 pandemic has instigated the development of telemedicine-mediated provision of medications for opioid use disorder such as buprenorphine and methadone, referred to as TMOUD in this study. As services start to return to pre-pandemic norms, there is a debate around the role of TMOUD as addition to or replacement of the conventional cascade of care for people with opioid use disorder (PWOUD). This scoping review is designed to characterize existing TMOUD services and provide insights to enable a more nuanced discussion on the role of telemedicine in the care of PWOUD. The literature search was conducted in OVID Medline, CINAHL, and PsycINFO, from inception up to and including April 2023, using the Joanna Briggs Institute methodology for scoping reviews. The review considered any study design that detailed sufficient descriptive information on a given TMOUD service. A data extraction form was developed to collect and categorize a range of descriptive characteristics of each discrete TMOUD model identified from the obtained articles. A total of 45 articles met the inclusion criteria, and from this, 40 discrete TMOUD services were identified. In total, 33 services were US-based, three from Canada, and one each from India, Ireland, the UK, and Norway. Through a detailed analysis of TMOUD service characteristics, four models of care were identified. These were TMOUD to facilitate inclusion health, to facilitate transitions in care, to meet complex healthcare needs, and to maintain opioid use disorder (OUD) service resilience. Characterizing TMOUD according to its functional benefits to PWOUD and OUD services will help support evidence-based policy and practice. Additionally, particular attention is given to how digital exclusion of PWOUD can be mitigated against.


Desmoid-type fibromatosis of the head and neck in children: a case report and review of the literature.
Desmoid-type fibromatosis is defined as an intermediate tumor that rarely occurs in the head and neck of children. There is no doubt as to the value of complete surgical excision for desmoid-type fibromatosis. However, in pediatric patients, surgeons may often be concerned about making a wide excision because of the potential for functional morbidity. Some studies have reported a lack of correlation between margin status and recurrence. Therefore, we discussed our findings with a focus on the state of surgical margins. We report an unusual case of a 9-month-old Japanese girl who prior to presenting at our hospital underwent debulking surgery twice with chemotherapy for desmoid-type fibromatosis of the tongue at another hospital. We performed a partial glossectomy and simultaneous reconstruction with local flap and achieved microscopic complete resection. We also reviewed available literature of pediatric desmoid-type fibromatosis in the head and neck. We described successful treatment for the refractory case of pediatric desmoid-type fibromatosis. The review results showed that some microscopic incomplete resections of tumors in pediatric patients with desmoid-type fibromatosis tended to be acceptable with surgical treatment.


Personal resilience and coping Part II: Identifying resilience and coping among U.S. military service members and veterans with implications for work.
U.S. military personnel face challenging situations including frequent deployments, family separations, and exposure to war. Identifying coping strategies used by the most resilient service members and veterans could positively influence military resiliency training programs. The purposes of this paper are to investigate the relationship between coping and resilience among U.S. military active service members and veterans, to identify the coping strategies used by those considered most resilient, and to discuss coping and resilience as they relate to the workplace. U.S. military active service members and veterans (N = 191) completed a demographic survey and two self-report questionnaires: The 14-Item Resilience Scale [1] and the Brief COPE [2]. Active duty service members had higher resilience scores than veterans (p < 0.05), but both fell into the moderate range. Coping strategies were not significantly different between the two groups (p > 0.05). Active service members' resilience was predicted by their use of positive reframing and less use of self-blame as coping strategies, accounting for 52.3% of the variance (R2 = 0.523, F(2, 60) = 32.92, p = 0.000). Veterans' resilience was predicted by longer time-in-service, greater use of humor, and less use of self-blame as coping strategies, explaining 44.8% of the variance (R2 = 0.448, F(3, 116) = 31.408, p = 0.000). This research identifies the positive coping strategies, and least-used negative coping strategies, of the U.S. service members and veterans in our study population with higher resilience scores. Incorporating this information into military- or veteran-based resilience training is likely to increase training effectiveness.


Barcoding of arrow worms (Phylum Chaetognatha) from three oceans: genetic diversity and evolution within an enigmatic phylum.
Arrow worms (Phylum Chaetognatha) are abundant planktonic organisms and important predators in many food webs; yet, the classification and evolutionary relationships among chaetognath species remain poorly understood. A seemingly simple body plan is underlain by subtle variation in morphological details, obscuring the affinities of species within the phylum. Many species achieve near global distributions, spanning the same latitudinal bands in all ocean basins, while others present disjunct ranges, in some cases with the same species apparently found at both poles. To better understand how these complex evolutionary and geographic variables are reflected in the species makeup of chaetognaths, we analyze DNA barcodes of the mitochondrial cytochrome oxidase c subunit I (COI) gene, from 52 specimens of 14 species of chaetognaths collected mainly from the Atlantic Ocean. Barcoding analysis was highly successful at discriminating described species of chaetognaths across the phylum, and revealed little geographical structure. This barcode analysis reveals hitherto unseen genetic variation among species of arrow worms, and provides insight into some species relationships of this enigmatic group.


CXCR6 promotes atherosclerosis by supporting T-cell homing, interferon-gamma production, and macrophage accumulation in the aortic wall.
T lymphocytes are thought to be important in atherosclerosis, but very little is known about the mechanisms of lymphocyte recruitment into atherosclerosis-prone aortas. In this study we tested the hypothesis that CXCR6, a chemokine receptor that is expressed on a subset of CD4+ T helper 1 cells and natural killer T cells, is involved in lymphocyte homing into the aortic wall and modulates the development and progression of atherosclerosis. To investigate the role of CXCR6 in the development and progression of atherosclerosis, we bred CXCR6-deficient (CXCR6(GFP/GFP)) mice with apolipoprotein E-deficient (ApoE(-/-)) mice. We found that CXCR6(GFP/GFP)/ApoE(-/-) mice fed a Western diet for 17 weeks or a chow diet for 56 weeks had decreased atherosclerosis compared with ApoE(-/-) controls. Flow cytometry analysis of the aortas from CXCR6(GFP/GFP)/ApoE(-/-) mice showed that the reduction of atherosclerosis was accompanied by a decreased percentage of CXCR6+ T cells within the aortas. Short-term homing experiments demonstrated that CXCR6 is involved in the recruitment of CXCR6+ leukocytes into the atherosclerosis-prone aortic wall. The reduced percentage of CXCR6+ T cells within the aortas resulted in significantly diminished production of interferon-gamma and reduction of CD11b+/CD68+ macrophages in the aorta. These data provide evidence for a proatherosclerotic role of CXCR6. Absence of CXCR6 alters the recruitment of CXCR6+ leukocytes and modulates the local immune response within the aortic wall.


Two distinct modes of microsatellite mutation processes: evidence from the complete genomic sequences of nine species.
We surveyed microsatellite distribution in 10 completely sequenced genomes. Using a permutation-based statistic, we assessed for all 10 genomes whether the microsatellite distribution significantly differed from expectations. Consistent with previous reports, we observed a highly significant excess of long microsatellites. Focusing on short microsatellites containing only a few repeat units, we demonstrate that this repeat class is significantly underrepresented in most genomes. This pattern was observed across different repeat types. Computer simulations indicated that neither base substitutions nor a combination of length-dependent slippage and base substitutions could explain the observed pattern of microsatellite distribution. When we introduced one additional mutation process, a length-independent slippage (indel slippage) operating at repeats with few repetitions, our computer simulations captured the observed pattern of microsatellite distribution.


Impact of postoperative complications on long-term survival in bladder cancer patients.
To determine the impact of postoperative complications on long-term survival outcomes in patients with bladder cancer undergoing radical cystectomy. This retrospective multi-institutional study included 766 bladder cancer patients who underwent radical cystectomy between 2011 and 2017. Patient characteristics, perioperative outcomes, all complications within 90 days after surgery and survival outcomes were collected. Each complication was graded based on the Clavien-Dindo system, and grouped using a standardized grouping method. The Comprehensive Complication Index, which incorporates all complications into a single formula weighted by their severity, was utilized. Overall survival and recurrence-free survival (local, distant or urothelial recurrences) were stratified by Comprehensive Complication Index (high: ≥26.2; low: <26.2). A multivariate model was utilized to identify independent prognostic factors. The incidence of any and major complications (≥Clavien-Dindo grade III) was 70 and 24%, respectively. In terms of Comprehensive Complication Index, 34% (261/766) of the patients had ≥26.2. Patients with Comprehensive Complication Index ≥ 26.2 had shorter overall survival (4-year, 59.5 vs. 69.8%, respectively, log-rank test, P = 0.0037) and recurrence free survival (51.9 vs. 60.1%, respectively, P = 0.0234), than those with Comprehensive Complication Index < 26.2. The Cox multivariate model identified the age, performance status, pT-stage, pN-stage and higher CCI (overall survival: HR = 1.35, P = 0.0174, recurrence-free survival: HR = 1.26, P = 0.0443) as independent predictors of both overall survivial and recurrence-free survival. Postoperative complications assessed by Comprehensive Complication Index had adverse effects on long-term survival outcomes. Physicians should be aware that major postoperative complications can adversely affect long-term disease control.


Ultraviolet exposure is a reinforcing stimulus in frequent indoor tanners.
Investigations into tanners' reasons for tanning have focused primarily on the perception of improved appearance. Reported relaxing effects of tanning suggest the possibility of a physiologic effect of UV that drives tanning behavior. We sought to determine if there is a physiologic reinforcing effect of UV exposure, separate from appearance motivation, that may contribute to tanning behavior. We determined the reinforcing effect of UV light in a series of controlled, blinded, repeated-choice trials of UV carefully designed to separate as cleanly as possible reinforcing effects of UV exposure from other factors including perceived benefits of having a tan. A total of 14 young adults who used tanning beds regularly were exposed to otherwise identical UV and non-UV tanning bed stimuli on Mondays and Wednesdays for 6 weeks. On Fridays, participants had concurrent access to the two beds. The primary dependent variable was the percentage of choice sessions during which more UV than non-UV tanning was chosen. In all, 12 participants chose additional tanning exposure on Fridays and, of these, 11 consistently used the UV bed for that exposure. Of the total 41 occasions when participants chose to tan on Friday, 39 sessions (95%) were for the UV bed and only two for the non-UV bed. A more relaxed and less tense mood was reported after UV exposure compared with after non-UV exposure (P=.008 and P=.002, respectively). When exposed to UV and non-UV under blinded conditions, frequent tanners can distinguish the two conditions and undertake further UV exposure, indicating that UV is a reinforcing stimulus. The relaxing and reinforcing effects of UV exposure contribute to tanning behavior in frequent tanners and should be explored in greater detail.


Ocular immune privilege and CD1d-reactive natural killer T cells.
Immune privilege in the eye is, in part, associated with the development of an antigen-specific systemic tolerance termed anterior chamber-associated immune deviation (ACAID). Natural killer T (NKT) cells express T-cell receptor and natural killer (NK) markers and are classified as innate immune cells partly because they produce cytokines within minutes of signals. The aim of this study was to elucidate the role of murine NKT cells in the induction of T regulatory cells in anterior chamber-associated immune deviation. Anterior chamber-associated immune deviation T regulatory cell generation ability was examined in the following NKT cell-deficient mice: SJL mice, CDld or Jalpha281 knockout (KO) mice on C57BL/6 (B6) background, and NKT cell-depleted mice. To detect T regulatory cells, splenic T cells were harvested 7 days after anterior chamber inoculation of ovalbumin (50 microg/2 microL in Hanks balanced salt solution [HBSS]), mixed with ovalbumin-primed T cells (effector) and ovalbumin-pulsed antigen-presenting cells (stimulator), and then cotransferred into the ear pinnae of a syngeneic naive mouse (local adoptive transfer assay). Ear swelling was measured 24 hours later. Anterior chamber-inoculated B6 mice developed T regulatory cells, but all natural killer T cell-deficient mice did not generate T regulatory cells unless they were reconstituted with natural killer T cells. We also found that the number of splenic natural killer T cells were increased in anterior chamber-inoculated B6 mice and those natural killer T cells produced IL-10. CD1d-reactive natural killer T cells are essential for the induction of T regulatory cells in anterior chamber-associated immune deviation through their IL-10 production and are involved in the maintenance of immune privilege of the eye.


The reliability of a maximal isometric hip strength and simultaneous surface EMG screening protocol in elite, junior rugby league athletes.
Firstly to describe the reliability of assessing maximal isometric strength of the hip abductor and adductor musculature using a hand held dynamometry (HHD) protocol with simultaneous wireless surface electromyographic (sEMG) evaluation of the gluteus medius (GM) and adductor longus (AL). Secondly, to describe the correlation between isometric strength recorded with the HHD protocol and a laboratory standard isokinetic device. Reliability and correlational study. A sample of 24 elite, male, junior, rugby league athletes, age 16-20 years participated in repeated HHD and isometric Kin-Com (KC) strength testing with simultaneous sEMG assessment, on average (range) 6 (5-7) days apart by a single assessor. Strength tests included; unilateral hip abduction (ABD) and adduction (ADD) and bilateral ADD assessed with squeeze (SQ) tests in 0 and 45° of hip flexion. HHD demonstrated good to excellent inter-session reliability for all outcome measures (ICC(2,1)=0.76-0.91) and good to excellent association with the laboratory reference KC (ICC(2,1)=0.80-0.88). Whilst intra-session, inter-trial reliability of EMG activation and co-activation outcome measures ranged from moderate to excellent (ICC(2,1)=0.70-0.94), inter-session reliability was poor (all ICC(2,1)<0.50). Isometric strength testing of the hip ABD and ADD musculature using HHD may be measured reliably in elite, junior rugby league athletes. Due to the poor inter-session reliability of sEMG measures, it is not recommended for athlete screening purposes if using the techniques implemented in this study.


In leprosy the presence of mycobacteria in the nerve is an essential factor in the cycle and spectrum of Mycobacterium leprae infection.
A total of 220 untreated leprosy patients who underwent parallel skin and nerve biopsies are included in this study, which is intended to evaluate the extent of previously reported differences in bacillary load between skin and nerve lesions in leprosy and to describe the response of peripheral blood lymphocytes to Mycobacterium leprae antigens in such patients. In 161 patients out of the 220, the skin and nerve biopsies were diagnostic for leprosy. When patients were grouped according their skin and nerve lesions, the 3 groups observed were (1) paucibacillary skin and nerve lesions; (2) multibacillary skin and nerve lesions, and (3) paucibacillary skin and multibacillary nerve lesions. There was no observation of a group of patients with multibacillary skin and paucibacillary nerve lesions. In all patients with multibacillary nerve lesions, regardless of the type of skin lesions, a low response of peripheral blood lymphocytes to M. leprae was consistently noted. These results suggest that the bacillary load in the nerve is certainly one of the factors determining the immunological spectrum observed in leprosy.


Modelling extracellular electrical stimulation: part 3. Derivation and interpretation of neural tissue equations.
A common approach in modelling extracellular electrical stimulation is to represent neural tissue by a volume conductor when calculating the activating function as the driving term in a cable equation for the membrane potential. This approach ignores the cellular composition of tissue, including the neurites and their combined effect on the extracellular potential. This has a number of undesirable consequences. First, the two natural and equally valid choices of boundary conditions for the cable equation (i.e. using either voltage or current) lead to two mutually inconsistent predictions of the membrane potential. Second, the spatio-temporal distribution of the extracellular potential can be strongly affected by the combined cellular composition of the tissue. In this paper, we develop a mean field volume conductor theory to overcome these shortcomings of available models. This method connects the microscopic properties of the constituent fibres to the macroscopic electrical properties of the tissue by introducing an admittivity kernel for the neural tissue that is non-local, non-instantaneous and anisotropic. This generalizes the usual tissue conductivity. A class of bidomain models that is mathematically equivalent to this class of self-consistent volume conductor models is also presented. The bidomain models are computationally convenient for simulating the activation map of neural tissue using numerical methods such as finite element analysis. The theory is first developed for tissue composed of identical, parallel fibres and then extended to general neural tissues composed of mixtures of neurites with different and arbitrary orientations, arrangements and properties. Equations describing the extracellular and membrane potential for the longitudinal and transverse modes of stimulation are derived. The theory complements our earlier work, which developed extensions to cable theory for the micro-scale equations of neural stimulation that apply to individual fibres. The modelling framework provides a number of advantages over other approaches currently adopted in the literature and, therefore, can be used to accurately estimate the membrane potential generated by extracellular electrical stimulation.


Biomechanical deformable image registration of longitudinal lung CT images using vessel information.
Spatial correlation of lung tissue across longitudinal images, as the patient responds to treatment, is a critical step in adaptive radiotherapy. The goal of this work is to expand a biomechanical model-based deformable registration algorithm (Morfeus) to achieve accurate registration in the presence of significant anatomical changes. Six lung cancer patients previously treated with conventionally fractionated radiotherapy were retrospectively evaluated. Exhale CT scans were obtained at treatment planning and following three weeks of treatment. For each patient, the planning CT was registered to the follow-up CT using Morfeus, a biomechanical model-based deformable registration algorithm. To model the complex response of the lung, an extension to Morfeus has been developed: an initial deformation was estimated with Morfeus consisting of boundary conditions on the chest wall and incorporating a sliding interface with the lungs. It was hypothesized that the addition of boundary conditions based on vessel tree matching would provide a robust reduction of the residual registration error. To achieve this, the vessel trees were segmented on the two images by thresholding a vesselness image based on the Hessian matrix's eigenvalues. For each point on the reference vessel tree centerline, the displacement vector was estimated by applying a variant of the Demons registration algorithm between the planning CT and the deformed follow-up CT. An expert independently identified corresponding landmarks well distributed in the lung to compute target registration errors (TRE). The TRE was: [Formula: see text], [Formula: see text] and [Formula: see text] mm after rigid registration, Morfeus and Morfeus with boundary conditions on the vessel tree, respectively. In conclusion, the addition of boundary conditions on the vessels significantly improved the accuracy in modeling the response of the lung and tumor over the course of radiotherapy. Minimizing and modeling these geometrical uncertainties will enable future plan adaptation strategies.


2,4-Dinitrophenol and carbonylcyanide p-trifluoromethoxyphenylhydrazone activate the glutathione S-conjugate transport ATPase of human erythrocyte membranes.
2,4-Dinitrophenol (DNPOH) and carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP), two classical uncouplers of mitochondrial oxidative phosphorylation, were found to stimulate human erythrocyte membrane vesicle ATPase activity. Both compounds competed with S-(2,4-dinitrophenyl)glutathione (DNPSG) for activation of the glutathione S-conjugate transport ATPase. Stimulation of the ATPase by DNPOH or FCCP occurred with Vmax values 4-6 times greater than that with DNPSG. The K0.5 for DNPOH (195 microM) was similar to that of DNPSG (196 microM), while that for FCCP (4.3 microM) was 40 times lower. Vanadate inhibits both the DNPOH- and FCCP-stimulated ATPase activities, as previously reported for the glutathione S-conjugate ATPase. The stimulation of erythrocyte vesicle ATPase activities by these classical uncoupling agents does not result from increased proton conductance across the vesicle membrane: monensin, gramicidin and nystatin, all of which increase proton conductance, but by different mechanisms, do not stimulate erythrocyte vesicle ATPase activity. Verapamil, a known P-glycoprotein ATPase activator also does not stimulate human erythrocyte membrane ATPase activity. These results show that relatively small, monoanionic lipophilic compounds such as DNPOH and FCCP can activate the glutathione S-conjugate transport ATPase. The higher Vmax values for activation by these agents than by DNPSG make possible a more sensitive assay of this transport ATPase activity. The results raise the question of whether these substances and other small anionic, lipophilic compounds are also transported by this system.


Amination of Aryl Halides and Esters Using Intensified Continuous Flow Processing.
Significant process intensification of the amination reactions of aryl halides and esters has been demonstrated using continuous flow processing. Using this technology traditionally difficult amination reactions have been performed safely at elevated temperatures. These reactions were successfully conducted on laboratory scale coil reactor modules with 1 mm internal diameter (ID) and on a preparatory scale tubular reactor with 6 mm ID containing static mixers.


A new tool to assess duration of untreated illness: Psychopathological Onset and Latency to Treatment Questionnaire (POLT-Q).
Duration of untreated illness (DUI) has been increasingly investigated as a predictor of clinical outcome and course in different psychiatric disorders. To date, however, there are no tools for measuring this variable. Our group developed the Psychopathological Onset and Latency to Treatment Questionnaire (POLT-Q), focused on the onset of psychiatric disorders. Aim of this study was to assess the reproducibility and manageability of POLT-Q. Fifty consecutive in- and out-patients aged 16-65 with different DSM-5 psychiatric disorders were recruited. Two raters were present during the interview: one of them administered the POLT-Q to the patient and both independently completed the questionnaire. Collected values were compared using Cohen's Kappa test and McNemar test. 62.5% of the replies showed a 100% consistency between the two raters. In the 6.25% the agreement was <95%. For all the replies, the K coefficient was >0.8, a high degree of agreement. The POLT-Q assesses variables related to the psychopathological onset and first pharmacological treatment and, according to present findings, it represents a convenient, reliable and standardised measure for DUI. Further studies on larges sample are needed to confirm our preliminary results.


Fabrication of biomatrix/polymer hybrid scaffold for heart valve tissue engineering in vitro.
Decellularized extracellular matrix has been suggested as a scaffold for heart valve tissue engineering or direct implantation. However, cell removal impairs the physical properties of the valve leaflet structure and the biomechanical properties of the valve leaflet. Matrix/polymer hybrid scaffold with improved biomechanical characteristics may be advantageous. Mesenchymal stem cells were obtained from rats. Porcine aortic valve leaflets were decellularized enzymatically and coated with biodegradable poly-4-hydroxybutyrate using an electrospinning technique, reseeded and cultured over a time period of 14 days. The morphologic, biochemical, and biomechanical characteristics of hybrid scaffolds were tested. Morphologic and biochemical assays indicated that mesenchymal stem cells survive and proliferate on hybrid scaffolds, and control decellularized scaffolds revealed comparable amounts of cell mass, 4-hydroxyproline and collagen after cultured in vitro for 14 days. Mechanical testing indicated hybrid scaffolds had superior tensile strength and elastic modulus. Altogether this study demonstrates the feasibility and improved biomechanical characteristics of a novel hybrid heart valve leaflet scaffold for an application in tissue engineering.


Causes of diarrheal disease in soldiers stationed in Lebanon and in northern Israel.
A study of acute gastroenteritis in soldiers was carried out during a 1-year period. Causes of diarrhea were compared between 33 soldiers stationed in southern Lebanon and 174 soldiers stationed in northern Israel. Shigella sp. caused 42.4% of diarrheal disease in Lebanon, compared with only 19.0% of cases in Israel. Sh. flexneri was a more common cause of bacillary dysentery in Lebanon than in Israel (71.4 vs. 18.2%, respectively), and caused a more severe illness.


Effect of hydrogen bonding on the compressive strength of dihydroxypoly(p-phenylenebenzobisoxazole) fibers.
By the introduction of binary hydroxyl groups into poly(p-phenylenebenzoxazole) (PBO) macromolecular chains, a series of dihydroxypoly(p-phenylenebenzobisoxazole) (DHPBO) chains were prepared, and the effect of the hydroxyl groups on the axial compression property of DHPBO fibers was investigated. The variable-temperature Fourier transform infrared spectrum proved the existence of hydrogen bonds in DHPBO chains. Furthermore, the axial compression bending test showed that the introduction of hydroxyl groups into macromolecular chains apparently improved the compression resistance property of DHPBO fibers. Finally, a proposed arrangement of the hydrogen bonding in DHPBO fibers is presented.


Regulation of experimental allergic encephalomyelitis. III. Demonstration of effector cells in tolerant rats.
Effector cells, which transfer experimental allergic encephalomyelitis (EAE), can be demonstrated in the spleens of Lewis rats which have been rendered tolerant to myelin basic protein (BP). Transfer of EAE was achieved following in vitro culture of tolerant donor spleen cells with antigen. The donor animals were, themselves, protected against EAE induced by active challenge with BP in complete Freund's adjuvant, although BP-activated effector spleen cells could partially override this protection. The finding that effector cells are present in unresponsive animals supports the hypothesis that immunologic self tolerance is actively regulated by suppressor mechanisms.


p38MAPK and MK2 pathways are important for the differentiation-dependent human papillomavirus life cycle.
Amplification of human papillomaviruses (HPV) is dependent on the ATM DNA damage pathway. In cells with impaired p53 activity, DNA damage repair requires the activation of p38MAPK along with MAPKAP kinase 2 (MK2). In HPV-positive cells, phosphorylation of p38 and MK2 proteins was induced along with relocalization to the cytoplasm. Treatment with MK2 or p38 inhibitors blocked HPV genome amplification, identifying the p38/MK2 pathway as a key regulator of the HPV life cycle.


Geographical distribution of ticks in Turkey.
Turkey's tick fauna is composed of about 32 species in two families and ten genera in mammals, reptiles, and birds. The ticks of veterinary significance in the family Ixodidae comprise seven genera with 28 different species. Ixodes spp. are mostly seen in northern Turkey. It is likely that the high rainfall and the intensive forest in this area may contribute to this observation. To date, the following species have been found to be sporadically present: Amblyomma variegatum in Hatay province (border to Syria), Boophilus kohlsi in southeastern Turkey (border of Syria), Ornithodorus in Central and East Anatolia, and Otobius megnini in East Anatolia (Malatya Province). Ticks of the genera Haemaphysalis, Hyalomma, Boophilus, Dermacentor, Rhipicephalus, and Argas are widespread throughout Anatolia. Thus, their role in the epidemiology of important human and livestock diseases such as Crimean-Congo hemorrhagic fever, Lyme disease, and diseases caused by hemoparasites needs to be examined in greater detail.


Seroprevalence of hepatitis and human immuno-deficiency virus in multitransfused patients from a pediatric hematology clinic.
Transfusion transmitted hepatitis has been a severe problem in Turkey in pediatric cancer patients and in chronic congenital anemia. The aim of the present study was to investigate the prevalence of hepatitis B, hepatitis C and human immunodeficiency virus infections in these patients in a University Hospital. Multi-transfused 66 children (59 acute leukemia, 6 thalassemia major, 1 severe hereditary spherocytosis) diagnosed and followed-up between May, 2000 and December, 2006 were evaluated. Screening of all the patients for HbsAg, anti-HBs, anti-HBc, anti-HCV and anti-HIV was performed at presentation and during the last follow-up. Serologic studies of leukemic patients were also repeated at the end of the chemotherapy. Hepatitis B vaccination was administered to unvaccinated patients with anemia. All blood products were provided by Blood Bank of the Center. No patient was found HBsAg, anti-HCV or anti-HIV positive at diagnosis and at the end of the therapy. There was history of hepatitis B vaccination in only 42% of the patients at diagnosis due to administration of this vaccine to newborns since 1998. At the beginning of the study, 45 % (n=27) of the leukemic patients were immune for hepatitis B, but after completion of the intensive chemotherapy seropositivity persisted in only 28.8 % (n=17). Transmission of these viruses is no longer a real problem even in multitransfused immunosuppressed children in Pediatric Hematology Units as a result of the improvements in screening of voluntary blood donors, administration of disposable material in clinics and vaccination by hepatitis B.


Awareness of Postdural Puncture Headache Among Specialists who Perform Lumbar Punctures and/or Monitor Patients Following the Procedure.
Lumbar puncture (LP) is performed by specialists in different branches of medicine, complications may be encountered in various settings. In our study, we evaluated the awareness and knowledge of the diagnosis and treatment of post-dural puncture headache (PDPH) among specialists who performed LP and/or encountered complications. This was a prospective questionnaire/scale study of 253 physicians: LP performers (anaesthesiologists, Group A; others, Group B) and those who worked in departments that did not perform LP but frequently encountered complications following LP (Group C). The questionnaire assessed specialization, frequency of LPs utilization, needle types used, positions employed, awareness of LP complications, diagnosis, management, and risk factors for PDPH. Group A had the highest percentage of physicians who stated they had knowledge about PDPH (Group A: 96.4%, Group B: 77.3%, Group C: 39.4%; P=0.000). Group C was found to be statistically less informed than the other two groups (P=0.000). It was determined that only one (1%) physician from Group C correctly answered the question about the diagnostic criteria for PDPH. To our knowledge this is the first study in which the awareness of PDPH has been compared according to physicians' fields of specialisation. We believe that post-specialty training programs should be organized for physicians who will either perform LP or monitor patients who have undergone LP, and the curriculum content in relevant specialties should be reviewed.