Generalized Network Psychometrics: Combining Network and Latent Variable Models.
We introduce the network model as a formal psychometric model, conceptualizing the covariance between psychometric indicators as resulting from pairwise interactions between observable variables in a network structure. This contrasts with standard psychometric models, in which the covariance between test items arises from the influence of one or more common latent variables. Here, we present two generalizations of the network model that encompass latent variable structures, establishing network modeling as parts of the more general framework of structural equation modeling (SEM). In the first generalization, we model the covariance structure of latent variables as a network. We term this framework latent network modeling (LNM) and show that, with LNM, a unique structure of conditional independence relationships between latent variables can be obtained in an explorative manner. In the second generalization, the residual variance-covariance structure of indicators is modeled as a network. We term this generalization residual network modeling (RNM) and show that, within this framework, identifiable models can be obtained in which local independence is structurally violated. These generalizations allow for a general modeling framework that can be used to fit, and compare, SEM models, network models, and the RNM and LNM generalizations. This methodology has been implemented in the free-to-use software package lvnet, which contains confirmatory model testing as well as two exploratory search algorithms: stepwise search algorithms for low-dimensional datasets and penalized maximum likelihood estimation for larger datasets. We show in simulation studies that these search algorithms perform adequately in identifying the structure of the relevant residual or latent networks. We further demonstrate the utility of these generalizations in an empirical example on a personality inventory dataset.


Global prevalence and economic and humanistic burden of astigmatism in cataract patients: a systematic literature review.
To systematically review the published evidence on the prevalence and economic and humanistic burden of astigmatism in cataract patients. For this systematic literature review, the Medline, PubMed, Embase, and Cochrane databases were searched from 1996 to September 2015 for available scientific literature that met the inclusion criteria. Studies published in the English language reporting prevalence and humanistic and economic burden in patients diagnosed with cataract and astigmatism were included. Of 3,649 papers reviewed, 31 studies from 32 publications met the inclusion criteria of this review. Preexisting astigmatism ≥1 D was present in up to 47% of cataract eyes. The cost burden of residual uncorrected astigmatism after cataract surgery was driven by the cost of spectacles, which was estimated to range from $2,151 to $3,440 in the US and $1,786 to $4,629 in Europe over a lifetime. In cataract patients, both preexisting and postoperative residual astigmatism were associated with poor vision-related patient satisfaction and quality of life, as well as higher spectacle burden. Astigmatism correction during cataract surgery appears to improve visual outcomes and results in overall lifetime cost savings compared to astigmatism correction with postoperative vision correction. There is a high prevalence of preexisting astigmatism in cataract patients. Although published data are limited, both preoperative astigmatism and postoperative residual astigmatism affect visual function and vision-related quality of life, resulting in increased humanistic burden. Suboptimal correction of astigmatism during cataract surgery drives the continuous need for vision correction with spectacles in the postoperative period. Patients must bear the out-of-pocket expenses, since payers often do not reimburse the cost of spectacles. Greater access to astigmatism correction during cataract surgery could improve visual outcomes and quality of life in patients. More research is required to gain a better understanding of the disease burden of astigmatism in cataract patients.


Novel molecular changes induced by Nrg1 hypomorphism and Nrg1-cannabinoid interaction in adolescence: a hippocampal proteomic study in mice.
Neuregulin 1 (NRG1) is linked to an increased risk of developing schizophrenia and cannabis dependence. Mice that are hypomorphic for Nrg1 (Nrg1 HET mice) display schizophrenia-relevant behavioral phenotypes and aberrant expression of serotonin and glutamate receptors. Nrg1 HET mice also display idiosyncratic responses to the main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol (THC). To gain traction on the molecular pathways disrupted by Nrg1 hypomorphism and Nrg1-cannabinoid interactions we conducted a proteomic study. Adolescent wildtype (WT) and Nrg1 HET mice were exposed to repeated injections of vehicle or THC and their hippocampi were submitted to 2D gel proteomics. Comparison of WT and Nrg1 HET mice identified proteins linked to molecular changes in schizophrenia that have not been previously associated with Nrg1. These proteins are involved in vesicular release of neurotransmitters such as SNARE proteins; enzymes impacting serotonergic neurotransmission, and proteins affecting growth factor expression. Nrg1 HET mice treated with THC expressed a distinct protein expression signature compared to WT mice. Replicating prior findings, THC caused proteomic changes in WT mice suggestive of greater oxidative stress and neurodegeneration. We have previously observed that THC selectively increased hippocampal NMDA receptor binding of adolescent Nrg1 HET mice. Here we observed outcomes consistent with heightened NMDA-mediated glutamatergic neurotransmission. This included differential expression of proteins involved in NMDA receptor trafficking to the synaptic membrane; lipid raft stabilization of synaptic NMDA receptors; and homeostatic responses to dampen excitotoxicity. These findings uncover novel proteins altered in response to Nrg1 hypomorphism and Nrg1-cannabinoid interactions that improves our molecular understanding of Nrg1 signaling and Nrg1-mediated genetic vulnerability to the neurobehavioral effects of cannabinoids.


[Distal phalanx metastasis in operated bronchial carcinoma].
A 54 years old man who admitted with thoracolomber pain and pain at left knee had history of left pneumonectomy four months ago for squamous cell lung carcinoma. At physical examination swelling and hotness at the left knee, swelling and redness of the distal phalanx of the right third finger were found. Distal phalanx was not observed at the X-ray which was taken for suspect of metastasis. Incision biopsy was performed from this lesion and microscopic findings of the material were evaluated as metastatic squamous cell carcinoma. Bone metastasis are seen frequently at bronchial carcinoma, but hand metastasis are seen in 0.2% of all cases. This case is represented because of the rare metastatic localisation of bronchial carcinoma.


Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development.
The generation of natural regulatory T cells (nTregs) is crucial for the establishment of immunologic self-tolerance and the prevention of autoimmunity. Still, the origin of nTregs and the mechanisms governing their differentiation within the thymus are poorly understood, particularly in humans. It was recently shown that conventional dendritic cells (cDCs) in human thymus were capable of inducing nTreg differentiation. However, the function of plasmacytoid DCs (pDCs), the other major subset of thymic DCs, remains unknown. Here we report that pDCs resident in the human thymus, when activated with CD40 ligand (CD40L) plus interleukin-3, efficiently promoted the generation of CD4(+)CD25(+)Foxp3(+) nTregs from autologous thymocytes. The progenitors of these nTregs were selectively found within CD4(+)CD8(+) thymocytes that had accomplished positive selection, as judged by their CD69(hi)TCR(hi) phenotype. Supporting the involvement of the CD40-CD40L pathway in pDC-induced nTreg generation, we show that positively selected CD4(+)CD8(+) progenitors specifically transcribed CD40L in vivo and up-regulated CD40L expression on T-cell receptor engagement, thereby promoting the activation of pDCs. Finally, evidence is provided that nTregs primed by pDCs displayed reciprocal interleukin-10/transforming growth factor-beta cytokine expression profiles compared with nTregs primed by cDCs. This functional diversity further supports a nonredundant tolerogenic role for thymic pDCs in the human thymus.


Polysaccharide intercellular adhesin or protein factors in biofilm accumulation of Staphylococcus epidermidis and Staphylococcus aureus isolated from prosthetic hip and knee joint infections.
Nosocomial staphylococcal foreign-body infections related to biofilm formation are a serious threat, demanding new therapeutic and preventive strategies. As the use of biofilm-associated factors as vaccines is critically restricted by their prevalence in natural staphylococcal populations we studied the distribution of genes involved in biofilm formation, the biofilm phenotype and production of polysaccharide intercellular adhesin (PIA) in clonally independent Staphylococcus aureus and Staphylococcus epidermidis strains isolated from prosthetic joint infections after total hip or total knee arthroplasty. Biofilm formation was detected in all S. aureus and 69.2% of S. epidermidis strains. Importantly, 27% of biofilm-positive S. epidermidis produced PIA-independent biofilms, in part mediated by the accumulation associated protein (Aap). Protein-dependent biofilms were exclusively found in S. epidermidis strains from total hip arthroplasty (THA). In S. aureus PIA and proteins act cooperatively in biofilm formation regardless of the infection site. PIA and protein factors like Aap are of differential importance for the pathogenesis of S. epidermidis in prosthetic joint infections (PJI) after THA and total knee arthroplasty (TKA), implicating that icaADBC cannot serve as a general virulence marker in this species. In S. aureus biofilm formation proteins are of overall importance and future work should focus on the identification of functionally active molecules.


Problems of ascertainment of congenital anomalies.
Problems of ascertainment bedevil the investigation of the etiology of congenital anomalies in singletons and in multiple births by epidemiological methods. It is shown that the definition of the population of affected births is ambiguous and that the problem of tracing etiology is complicated by the systematic way in which anomalies may be missed at birth. The available methods of dealing with problems of ascertainment are reviewed. Methods of adjusting for possible bias of ascertainment of affected births, by fitting statistical models to data from several sources, have been employed in some previous studies. In these methods, it is assumed that there are no errors of diagnosis or of recording. However, it is shown that there may be discrepancies in recorded diagnoses between sources, rendering this assumption untenable. In these methods, it is also assumed that the model which is the best fit to the data on the ascertained cases in also the best model for the cases which were not ascertained. This assumption is tested indirectly in a retrospective analysis of data from Aberdeen and Belfast collected concurrently through routine recording systems. It is demonstrated that there was a social process in ascertainment which renders the methods of adjusting for bias of ascertainment at best very complicated and at worst inapplicable.


Optical elastography: tracking surface waves with digital image correlation.
Elastography consists in evaluating the propagation speed of waves into a tissue to estimate its stiffness. Usually this method is based on Ultrasounds, magnetic resonance imaging or optical coherent tomography. This paper proposes a simple optic method using ultrafast cameras. Based on digital image correlation (DIC), the tracking of elastic surface wave from white light intensity pattern, allows estimating the propagation speed as an indicator of the tissue local stiffness. Two configurations are presented: (1) 2D imaging of a flat phantom surface with a single camera and (2) 3D imaging of a curved phantom surface with two cameras. As a feasibility study of the first configuration, surface wave speed was measured on isotropic and anisotropic phantoms. Comparisons with ultrasound methods fully validate this approach. Although more sophisticated, the second configuration account for propagation distortions caused by locally curved topology. Triangulation techniques used to retrieve local topology are named stereo-correlation in the field of biomechanics. Stereo-elastography is thus proposed to determine tissue local elasticity from any soft tissue surface wave.


Two Decades of Progress in the Asymmetric Intramolecular aza-Michael Reaction.
The asymmetric intramolecular aza-Michael reaction (IMAMR) is a very convenient strategy for the generation of heterocycles bearing nitrogen-substituted stereocenters. Due to the ubiquitous presence of these skeletons in natural products, the IMAMR has found widespread applications in the total synthesis of alkaloids and biologically relevant compounds. The development of asymmetric versions of the IMAMR are quite recent, most of them reported in this century. The fundamental advances in this field involve the use of organocatalysts. Chiral imidazolidinones, diaryl prolinol derivatives, Cinchone-derived primary amines and quaternary ammonium salts, and BINOL-derived phosphoric acids account for the success of those methodologies. Moreover, the use of N-sulfinyl imines with a dual role, as nitrogen nucleophiles and as chiral auxiliaries, appeared as a versatile mode of performing the asymmetric IMAMR.


Study of phylogenetic relationship of Turkish species of Klasea (Asteraceae) based on ISSR amplification.
Klasea is a taxonomically complex genus in which there are many problems, mostly with Klasea kotschyi and Klasea hakkiarica. It is challenging to differentiate the genera based on morphological characters alone. Revision studies performed on the basis of molecular data obtained from studies conducted in recent years have made the phylogenetic relationships and systematic positions of the taxa more apparent and reliable. In this study, Klasea, Serratula, Jurinea and Centaurea species native to Turkey, were collected from different localities of Anatolia and DNA was isolated from the collected samples. The data were analyzed ordination analyses including UPGMA and PCA using NTSYSpc 2.1. The infrageneric and intergeneric phylogenetic relationships between Klasea and other related genera were also characterized. The Klasea species were grouped into three clusters. It was determined that taxa Klasea kotschyi and Klasea hakkiarica are separate but closely related. Moreover, it was observed that the Klasea lasiocephala a separate group within the genera. Clearly the genera Klasea, Serratula, Jurinea and Centaurea are phylogenetically differentiated on the dendogram.


Kingella kingae PilC1 and PilC2 are adhesive multifunctional proteins that promote bacterial adherence, twitching motility, DNA transformation, and pilus biogenesis.
The gram-negative bacterium Kingella kingae is a leading cause of osteoarticular infections in young children and initiates infection by colonizing the oropharynx. Adherence to respiratory epithelial cells represents an initial step in the process of K. kingae colonization and is mediated in part by type IV pili. In previous work, we observed that elimination of the K. kingae PilC1 and PilC2 pilus-associated proteins resulted in non-piliated organisms that were non-adherent, suggesting that PilC1 and PilC2 have a role in pilus biogenesis. To further define the functions of PilC1 and PilC2, in this study we eliminated the PilT retraction ATPase in the ΔpilC1ΔpilC2 mutant, thereby blocking pilus retraction and restoring piliation. The resulting strain was non-adherent in assays with cultured epithelial cells, supporting the possibility that PilC1 and PilC2 have adhesive activity. Consistent with this conclusion, purified PilC1 and PilC2 were capable of saturable binding to epithelial cells. Additional analysis revealed that PilC1 but not PilC2 also mediated adherence to selected extracellular matrix proteins, underscoring the differential binding specificity of these adhesins. Examination of deletion constructs and purified PilC1 and PilC2 fragments localized adhesive activity to the N-terminal region of both PilC1 and PilC2. The deletion constructs also localized the twitching motility property to the N-terminal region of these proteins. In contrast, the deletion constructs established that the pilus biogenesis function of PilC1 and PilC2 resides in the C-terminal region of these proteins. Taken together, these results provide definitive evidence that PilC1 and PilC2 are adhesins and localize adhesive activity and twitching motility to the N-terminal domain and biogenesis to the C-terminal domain.


Current concepts of enzyme histochemistry in modern pathology.
Enzyme histochemistry serves as a link between biochemistry and morphology. It is based on metabolization of a substrate provided to a tissue enzyme in its orthotopic localization. Visualization is accomplished with an insoluble dye product. It is a sensitive dynamic technique that mirrors even early metabolic imbalance of a pathological tissue lesion, combined with the advantage of histotopographic enzyme localization. With the advent of immunohistochemistry and DNA-oriented molecular pathology techniques, the potential of enzyme histochemistry currently tends to be underrecognized. This review aims to draw attention to the broad range of applications of this simple, rapid and inexpensive method. Alkaline phosphatase represents tissue barrier functions in brain capillaries, duodenal enterocyte and proximal kidney tubule brush borders. Decrease in enzyme histochemical alkaline phosphatase activity indicates serious functional impairment. Enzyme histochemical increase in lysosomal acid phosphatase activity is an early marker of ischemic tissue lesions. Over the last four decades, acetylcholinesterase enzyme histochemistry has proven to be the gold standard for the diagnosis of Hirschsprung disease and is one of the most commonly applied enzyme histochemical methods today. Chloroacetate esterase and tartrate-resistant phosphatase are both resistant to formalin fixation, EDTA decalcification and paraffin embedding. Early enzyme histochemical insight into development of a pathologic tissue lesion and evaluation of function and vitality of tissue enhance our understanding of the pathophysiology of diseases. In this process, enzyme histochemistry constitutes a valuable complement to conventional histology, immunohistochemistry and molecular pathology for both diagnostic and experimental pathology.


[Clinico-pathological investigation on frequency and prognosis in patients with incidental prostatic carcinoma: preliminary report].
To investigate the relationship between some clinico-pathological features of incidental prostatic carcinoma and its prognosis, totally 96 consecutive cases with simple prostatectomy from 1968 to 1973 under the diagnosis of prostatic hypertrophy were examined by the 3 mm step-section technique. Twenty-one cases (21.9%) of incidental carcinoma were detected histologically. The age of the patients with or without prostatic carcinoma ranged from 59 to 81 years old, 72.0 years old on the average, and from 54 to 87 years old, 69.9 years old on the average, respectively. The weight of the specimen varied from 7 to 84 grams, 32.4 g on the average, for the patients with carcinoma, and 10 to 64 grams, 29.7 g on the average, for the patients without carcinoma. Fifteen of 21 cases showed well differentiated carcinoma. None of the Japanese histological differentiation, Gleason's classification and volume of carcinoma presumably affected the survival of the patients.


Mechanisms of egfr gene transcription modulation: relationship to cancer risk and therapy response.
The epidermal growth factor receptor (EGFR) plays a crucial role in growth, differentiation, and motility of normal as well as cancer cells. For predictive cancer diagnostics and therapeutic targeting of EGFR, it is important to know how the expression level of EGFR is controlled and related to receptor signaling. A novel transcriptional regulation mechanism has been described that depends on the length of a CA repeat in intron 1 [CA simple sequence repeat 1 (CA SSR I)] of the EGFR gene. Thereby, the number of CA repeats is inversely correlated to pre-mRNA synthesis. Indirect evidence for the importance of this mechanism includes the preferential occurrence of amplifications in cancer tissue harboring short CA repeats in this sequence and the discovery of distinct alleles in young breast cancer patients with a family history of the disease and in Japanese breast cancer patients. It can be postulated that the length of the CA repeat influences DNA bendability and, in consequence, the binding of repressor proteins. In summary, it seems that the CA SSR I represents an inherited variable for response to anti-EGFR therapies that could be determined before therapy. Moreover, the potential for synergistic effects with other polymorphism [e.g., EGFR R497K (HER-1 497K) and CCND1 A870G] leading to a simultaneous increase of EGFR signaling activity and expression should be investigated. From a practical perspective, assessment of the CA SSR I number of CA dinucleotide repeats as a predictor for clinical outcome is very attractive because it is a constant feature that does not change over time and can be easily measured in normal and cancer tissues (blood cells, skin, and tumor biopsies) in an assay that is technically simple, objective, and even quantitative.


Complex 5' genomic structure of the human prolactin receptor: multiple alternative exons 1 and promoter utilization.
Transcription of the prolactin receptor (PRLR) is under the control of multiple promoters. Following the recent demonstration of the human non-coding exon 1, hE1(N) (hE1(N1)) and the generic exon 1 hE1(3), we have identified their promoters and characterized four other novel human exons 1 (hE1(N2-5)) that are alternatively spliced to a common non-coding exon 2 in human tissues and breast cancer cells. Genomic regions containing these exons, and 5'-flanking and intronic sequences, were determined and their order was established in chromosome 5p14-13. Promoters utilized in the transcription of previously characterized PRLR exons 1 species hE1(3) (hPII) and hE1(N1) (hP(N1)) were found to employ distinct mechanisms for controlling hPRLR transcription. hPIII requires C/EBP beta and Sp1/Sp3 for basal transcriptional activity, while hP(N1) activity is conferred by domains containing an Ets element and an NR half-site. The complex promoter control system that governs transcription of the hPRLR in multiple tissues is of relevance for studies on the regulation of PRLR expression in physiological and pathological states.


Risk factors for metachronous gastric carcinoma development after endoscopic resection of gastric dysplasia: Retrospective, single-center study.
To determine the gastric adenocarcinoma (GAC) occurrence rate and related factors, we evaluated the follow-up results of patients confirmed to have gastric dysplasia after endoscopic resection (ER). We retrospectively analyzed the medical records, endoscopic examination records, endoscopic procedure records, and histological records of 667 cases from 641 patients who were followed-up for at least 12 mo, from among 1273 patients who were conformed to have gastric dysplasia after Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) of gastric mucosal lesions between January 2007 and August 2013 at the Chungnam National University Hospital. The mean follow-up period was 33.8 mo, and the median follow-up period was 29 mo (range: 12-87). During the follow-up period, the occurrence of metachronous GAC was 4.0% (27/667). The mean and median interval periods between the occurrence of metachronous GAC and endoscopic treatment of gastric dysplasia were 36.3 and 34 mo, respectively (range: 16-71). The factors related to metachronous GAC occurrence after ER for gastric dysplasia were male sex (5.3% vs 1.0%), open-type atrophic gastritis (9.5% vs 3.4%), intestinal metaplasia (6.8% vs 2.4%), and high-grade dysplasia (HGD; 8.4% vs 3.2%). Among them, male sex [OR: 5.05 (1.18-21.68), P = 0.029], intestinal metaplasia [OR: 2.78 (1.24-6.23), P = 0.013], and HGD [OR: 2.70 (1.16-6.26), P = 0.021] were independent related factors in multivariate analysis. Furthermore, 24 of 27 GAC cases (88.9%) occurred at sites other than the previous resection sites, and 3 (11.1%) occurred at the same site as the previous resection site. Male sex, intestinal metaplasia, and HGD were significantly related to the occurrence of metachronous GAC after ER of gastric dysplasia, and most GACs occurred at sites other than the previous resection sites.


Diagnosis and Treatment of Snapping Scapula Syndrome: A Scoping Review.
Snapping scapula syndrome (SSS) is commonly misdiagnosed and underreported due to lack of awareness. This scoping review aims to summarize the current evidence related to SSS diagnosis and treatment to aid clinicians in managing the condition more effectively. PubMed, Medline, and Embase databases were searched for studies related to the etiology, diagnosis, or treatment of SSS (database inception to March 2020). Databases were searched for available studies related to the etiology, diagnosis, or treatment of SSS. A scoping review study design was selected to explore the breadth of knowledge in the literature regarding SSS diagnosis and treatment. Level 4. Primary outcomes abstraction included accuracy of diagnostic tests, functional outcomes, and pain relief associated with various nonoperative and operative treatment options for SSS. A total of 1442 references were screened and 40 met the inclusion criteria. Studies commonly reported SSS as a clinical diagnosis and relied heavily on a focused history and physical examination. The most common signs reported were medial scapular border tenderness, crepitus, and audible snapping. Three-dimensional computed tomography had high interrater reliability of 0.972, with a 100% success rate in identifying symptomatic incongruity of the scapular articular surface. Initial nonoperative treatment was reported as successful in most symptomatic patients, with improved visual analogue scale (VAS) scores (7.7 ± 0.5 pretreatment, to 2.4 ± 0.6). Persistently symptomatic patients underwent surgical intervention most commonly involving bursectomy, superomedial angle resection, or partial scapulectomy. High satisfaction rates of surgery were reported in VAS (6.9 ± 0.7 to 1.9 ± 0.9), American Shoulder and Elbow Surgeons scores (50.3 ± 12.2 to 80.6 ± 14.9), and mean simple shoulder test scores (5.6 ± 1.0 to 10.2 ± 1.1). Focused history and physical examination is the most crucial initial step in the diagnostic process, with supplemental imaging used to assess for structural etiologies when nonoperative management fails. Nonoperative management is as effective as surgical management in pain relief and is advised for 3 to 6 months before operative treatment.


High genetic carrier frequency of Wilson's disease in France: discrepancies with clinical prevalence.
Wilson's disease (WD) is a rare autosomal recessive metabolic disease caused by ATP7B gene mutations tat cause excessively high copper levels, particularly in the liver and brain. The WD phenotype varies in terms of its clinical presentation and intensity. Diagnosing this metabolic disorder is important as a lifelong treatment, based on the use of copper chelating agents or zinc salts, is more effective if it's started early. Worldwide prevalence of WD is variable, with an average of 1/30,000. In France, a recent study based on French health insurance data estimated the clinical prevalence of the disease to be around 3/200,000. To estimate the genetic prevalence of WD in France, we analysed the ATP7B gene by Next Generation Sequencing from a large French cohort of indiscriminate subjects. We observed a high heterozygous carrier frequency of ATP7B in France. Among the 697 subjects studied, 18 variants classified as pathogenic or probably pathogenic were found at heterozygous level in 22 subjects (22 alleles/1394 alleles), yielding a prevalence of 0.032 or 1/31 subjects. This considerable and unexplained discrepancy between the heterozygous carrier frequency and the clinical prevalence of WD may be explained by the clinical variability, the incomplete penetrance and the existence of modifiers genes. It suggests that the molecular analysis of ATP7B should be interpreted with caution, always alongside copper assays (ceruloplasmin, relative exchangeable copper, 24 h-urinary copper excretion) with particular respect to exome sequencing.


The endocrine pancreas of Podarcis s. sicula Raf.: an immunocytochemical study at light and electron microscopic levels.
The endocrine pancreas of Podarcis s. sicula Raf. was investigated at light and electron microscopic levels using immunocytochemical methods. It was constituted by endocrine islets, which were concentrated more in the splenic than in the duodenal region, and never formed large clusters. At the light and electron microscope, with the peroxidase-antiperoxidase reaction (PAP) and the colloidal gold technique, four cell types were identified: glucagon-positive A-cells, insulin-positive B-cells, somatostatin-positive D-cells and pancreatic polypeptide-positive F- or PP-cells. F- or PP-cells showed a different regional distribution, being absent or very rare in the splenic lobe of the pancreas and numerous in the duodenal lobe, where they were seldom found in the islets, but were scattered in the exocrine parenchyma. The functional meaning of F-cells is discussed. The E.M. observations were carried out at the CIRUB (Centro Interdipartimentale di Ricerca sulle Ultrastrutture Biologiche) of the University of Naples.


Cold-water corals off Angola as refuge for a new Aeginella species (Crustacea: Amphipoda: Caprellidae).
A new species of caprellid amphipod, Aeginella corallina sp. nov., is described from cold-water corals off Angola. This is the first observation of this genus in the South-Atlantic. The taxon is fully described and figured and is compared with the only known species of the genus, A. spinosa, occurring in deep waters of the northern hemisphere. Both species can be clearly differentiated on the basis of the following characters: (1) pereonite 1 is provided with a large dorsal acute projection in A. spinosa, while this projection is lacking in A. corallina; (2) gnathopod 2 propodus has an acute projection distally which is lacking in A. corallina; (3) the palm of the gnathopod 2 propodus in males is densely setose and it is provided with two distal projections in A. corallina while it is scarcely setose and with less developed projections in A. spinosa; (4) distal article of the mandibular palp is provided by a setal formula of 1-x-1, being x=10-12, in A. spinosa, while in A. corallina x=2-3, and the formula 1-x-1 is not so evident and it could be considered as 1-x-0. (Zoobank: urn:lsid:zoobank.org:act:3D7EB67D-88F2-40D8-99C1-7D62F44F7163).


[The efficiency of carbamazepine in a case of post-streptococcal hemichorea].
Chorea is an infrequent disorder at the paediatric age which has a number of both hereditary and acquired causes. Post-streptococcal or Sydenham's chorea (SC) is still the main cause of chorea in children, in spite of the drop in prevalence of rheumatic fever in the last few years. SC is a benign, self-limiting disorder, but may last for several months and can be highly disabling. Several different types of symptomatic treatment have been proposed, for example corticoids, haloperidol, valproic acid, and carbamazepine. In each case, both the speed with which the clinical improvement is brought about, and the degree to which they are tolerated and the absence of side effects must be evaluated. We present a new case of SC that had been developing for three months. Carbamazepine was effective from the tenth day onwards and total remission of the symptoms was achieved in six weeks. Total follow-up time was nine months, and in this time no relapses or side effects were observed. This contribution offers new evidence supporting carbamazepine as another first choice medication in the treatment of this type of chorea.


PIKKing a way to regulate inflammation.
The phosphoinositide-3-kinase like kinases are a family of very large protein kinases. These PI3-kinase like kinase (PIKK) proteins have well-established roles in detection and repair of damage to the genome, regulation of the transcriptome and cellular metabolism. Recently there has emerged, evidence for links between these proteins and inflammation. While some of these links come from an increased understanding of the impacts of damage to the cell on inflammatory responses, others suggest that PIKK proteins also have direct roles in regulation of immune responses. Particularly evident is the link between DNA damage and innate immune response pathways. Here, we review recent findings on the PIKK family of proteins and how they impact on inflammation, particularly activation of the innate immune system.


Influence of head-out water immersion on plasma renin activity, aldosterone, vasopressin and blood pressure in late pregnancy toxaemia.
In 39 healthy pregnant women and 45 women with mild or moderate late pregnancy toxaemia (LPT) the influence of head-out water immersion on blood pressure, the renin-aldosterone system, vasopressin and plasma osmolality was examined. Water immersion induced a prompt and marked fall in systolic and diastolic blood pressure, which was significantly higher in LPT women. Simultaneously a significant decrease of plasma renin activity, aldosterone and vasopressin was noted both in healthy and toxaemic pregnant women. In contrast to healthy pregnant women in LPT haemodilution was not observed in the early phase of water immersion.


Oral 24% sucrose associated with nonnutritive sucking for pain control in healthy term newborns receiving venipuncture beyond the first week of life.
To test the hypothesis that oral administration of 24% sucrose associated with nonnutritive sucking in healthy newborns receiving venipuncture beyond the first week of life controls pain and pain-related variation in heart rate (HR) and noninvasive oxygen saturation (SpO2). A total of 66 term newborns were enrolled between February and September 2017 in the Neonatology Department of AORN Santobono-Pausilipon, Naples. They were randomly assigned to receive oral 1 mL 24% sucrose (treated group [TG], n=33; gestational age 38.53±1.49 weeks; body weight 3,035±55 g; age 22.40±6.82 weeks) or oral 1 mL 10% glucose (control group [CG], n=33; gestational age 38.91±1.45 weeks; body weight 3,203±65 g; age 23.36±7.02 weeks) 1 minute before and during venipuncture. Evaluations were carried out between 8 and 9 am in all newborns. The Neonatal Infant Pain Scale (NIPS) was used to assess pain in newborns. Outcome measurements (HR, SpO2) were obtained before (T0), during (T1), and 1 minute after (T2) venipuncture using a Nellcor bedside SpO2 patient-monitoring system. NIPS scores were recorded throughout the procedure. Statistical analysis was performed using SPSS version 20.0. Changes in HR and SpO2 were assessed by mixed ANOVA for repeated measures. NIPS scores were evaluated by Mann-Whitney U test. There were no statistically significant differences in HR or SpO2 between TG and CG at T0. HR was significantly lower in TG than CG at both T1 and T2 (P<0.05), whereas SpO2 was significantly higher in TG than CG at both T1 and T2 (P<0.05). NIPS scores were significantly lower in TG (median 0) than CG (median 6) during the entire procedure (P<0.05). Oral administration of 24% sucrose associated with nonnutritive sucking prior to and during a painful procedure has a strong impact on pain response in term newborns, reducing NIPS scores and influencing pain-associated variations in HR and SpO2. Complete analgesia during painful procedures in term newborns might prevent pain reactivity and its behavioral and neurodevelopmental consequences. Replication of this study is needed before widespread application of findings.


Missed Distal Tracheal Foreign Body in Consecutive Bronchoscopies in a 6-year-old Boy.
It is unusual but not uncommon for foreign bodies to be missed at bronchoscopy. This case report highlights the importance of the clinical history in the diagnosis of aspirated foreign bodies and the usefulness of chest imaging modalities. A 6-year-old boy presented with recurrent breathlessness and cough of 2 months. He was said to have aspirated the base cap of a pen at about the time symptoms started. He had two sessions of rigid bronchoscopy and a session of flexible bronchoscopy at three different hospitals. He had an initial rigid bronchoscopy which failed to show the foreign body (FB). A chest computerized tomographic scan demonstrated the FB, which was retrieved at combined flexible/rigid bronchoscopy. Although rigid bronchoscopy is the gold standard for managing airway foreign bodies, there remains a false negative rate for this procedure and where necessary, appropriate imaging may compliment rigid bronchoscopy, especially where there is some confusion.


Brief history and biology of skin grafting.
Skin grafting is a modern addition to surgery but with ancient roots. Its biology has come to light only within the last 50 years, and research continues into its basic mechanisms. A brief history of skin grafting from Susruta to Reverdin and Ollier and the mechanisms of skin grafting featuring recent research effects are reviewed.


Determination of critical levels of residual oxygen to minimize discoloration of sliced packaged Norwegian salami under light display.
Discoloration of sliced packaged salami is contributing to rejection of the product, food waste and economical loss. A combination of residual O2 in the headspace of packages and light is causing photooxidation and deterioration of colour. The aim of this study was to establish maximum tolerable concentrations of residual O2 in packages of salami slices with 100% N2 under light display at 4 and 20°C. Salami sausages had variable inherent O2 consumption rate. Storage of salami in 1% O2 in darkness did not induce discoloration. The upper limits for O2 for avoiding discoloration under light were variable in the range 0.1-1.0%, depending on temperature and type of salami. Display at 20°C increased the rate of O2 depletion compared to 4°C. To minimize discoloration, sliced and packaged salami should be stored in darkness at approximately 20°C until the level of residual O2 is reduced below a critical limit.


Conservation of recognition of antibody and T-cell-defined alloantigens between species of equids.
Serological and cellular assays and molecular techniques were used to define features of the major histocompatibility complex (MHC) of the donkey With this information in hand, immune recognition of MHC determinants within and between donkeys and horses was compared. An antibody-mediated, complement-dependent, microcytotoxicity assay using a variety of antisera to donkey histocompatibility antigens, including those induced as a result of intraspecies or interspecies pregnancy in horse mares and jenny donkeys, delineated five donkey leukocyte antigen (DoLA) specificities. Antisera raised across species barriers (horse anti-donkey and donkey anti-horse) recognized polymorphic antigenic determinants in the target species. These determinants were often indistinguishable from polymorphic antigens recognized by alloantisera raised within horses or donkeys. The data indicate that a strong correlation exists between the serological antigenic types identified and the specificity of cytotoxic T lymphocytes raised by lymphocyte co-cultures, either within or between species. Moreover, in an analysis of a small number of donkey MHC class I cDNA gene sequences, no features distinguishing horse or donkey MHC class I molecules were identified. These molecular findings explain in large measure why antibody- and T-cell-defined alloantigen recognition is conserved among these closely related equids.


Similar survival in patients following heart transplantation receiving induction therapy using daclizumab vs. basiliximab.
Induction therapy with interleukin-2 receptor antagonists has been established as an effective immunosuppressive strategy in the management of heart transplant (HTx) recipients. We compared outcomes following HTx in patients receiving basiliximab, daclizumab, or no induction therapy. We investigated post-transplant prognosis of patients receiving basiliximab (n=67), daclizumab (n=98) or no induction therapy (n=70). Patients treated with daclizumab (50.3 ± 14.7 years) were younger than those receiving basiliximab (55.8 ± 11.2 years) or no induction therapy (54.9 ± 14.1 years; both P<0.05). Patients receiving either induction therapy showed better survival 1 year after HTx (95%) than those without induction therapy (82%; P<0.001). Survival was similar between patients receiving basiliximab and daclizumab. The incidence of acute cellular or antibody-mediated rejections did not differ among the groups. The main reason that patients did not receive induction therapy was ongoing infection (65.7%), which was more common in patients on ventricular assist device (VAD) support than those without VAD (76.1% vs. 45.8%; P=0.004). The VAD-related infection rate in the entire study cohort was 29.7% (35/118 VAD recipients). Survival following HTx was worse in patients not receiving induction therapy. No differences were noted in survival or the incidence of rejection between the daclizumab- and basiliximab-treated groups. Induction therapy was less used in patients with infection, which was related to prior VAD support.


In vitro effects of a mixture of Escherichia coli heat-stable enterotoxins on chloride flux in everted jejunal sacs of male pigs.
In vitro effects of a mixture of Escherichia coli heat-stable enterotoxins (STa and STb) on isolated jejunum of 3-week-old male pigs were studied, using everted intestinal sac techniques. Heat-stable enterotoxins increased chloride secretion and chloride absorption in everted intestinal sacs. The increase of secretory flux was greater than that for absorptive flux. Vasoactive intestinal peptide (6 x 10(-9) M) increased chloride secretion, but had no effect on chloride absorption. Neither vasoactive intestinal peptide nor pilocarpine (10(-5) M) had additive effect to ST. Secretory effects of ST were not blocked by atropine (2 x 10(-5) M), clonidine (10(-6) M), or morphine (4.2 x 10(-6) M).


Hematologic and biochemical changes associated with human T lymphotropic virus type 1 infection in Jamaica: a report from the population-based blood donors study.
We investigated changes in hematologic and biochemical parameters associated with human T lymphotropic virus type 1 (HTLV-1) infection, antibody titer, and provirus load. Additionally, on a subset of participants, we assessed the epidemiologic relationship of HTLV-1 with Strongyloides stercoralis. Among volunteer blood donors in Jamaica, HTLV-1 carriers (n=482) were frequency matched with HTLV-1 negative subjects (n=355) by age (+/-5 years), sex, and date of blood donation (+/-3 months). HTLV-1 antibody titer, provirus load, S. stercoralis IgG antibodies, complete blood cell count, blood chemistry, and urinalysis parameters were measured. HTLV-1 carriers, compared with HTLV-1-negative individuals, had elevated levels of cleaved lymphocytes (24.5% vs. 16.4%), any lymphocyte abnormalities (atypical, cleaved, and reactive lymphocytes combined, 45.7% vs. 35.4%), and gamma-glutamyl transferase levels (21.2 vs. 19.6 IU/L), as well as lower eosinophil count (2.6% vs. 3.1%). Among carriers, HTLV-1 antibody titer (n=482) was inversely correlated with mean corpuscular volume (r=-0.10) and positively correlated with levels of total protein (r=0.16), phosphorus (r=0.12), and lactate dehydrogenase (r=0.24). HTLV-1-provirus load (n=326) was higher among carriers with cleaved lymphocytes and any lymphocyte abnormalities. Provirus load was inversely correlated with hemoglobin (r=-0.11), mean corpuscular volume (r=-0.15), neutrophil (r=-0.12), and eosinophil (r=-0.19) levels and was positively correlated with lactate dehydrogenase levels (r=0.12). Provirus load was significantly higher among male than female subjects. S. stercoralis antibodies were detected in 35 (12.1%) of 288 participants but were not associated with HTLV-1 status, antibody titer, or provirus load. Markers of HTLV-1 infection (infection status, antibody titer, and provirus load) are associated with hematologic and biochemical alterations, such as lymphocyte abnormalities, anemia, decreased eosinophils, and elevated lactate dehydrogenase levels.


Control of the Fluid Viscosity in a Mock Circulation.
A mock circulation allows the in vitro investigation, development, and testing of ventricular assist devices. An aqueous-glycerol solution is commonly used to mimic the viscosity of blood. Due to evaporation and temperature changes, the viscosity of the solution drifts from its initial value and therefore, deviates substantially from the targeted viscosity of blood. Additionally, the solution needs to be exchanged to account for changing viscosities when mimicking different hematocrits. This article presents a method to control the viscosity in a mock circulation. This method makes use of the relationship between temperature and viscosity of aqueous-glycerol solutions and employs the automatic control of the viscosity of the fluid. To that end, an existing mock circulation was extended with an industrial viscometer, temperature probes, and a heating nozzle band. The results obtained with different fluid viscosities show that a viscosity controller is vital for repeatable experimental conditions on mock circulations. With a mixture ratio of 49 mass percent of aqueous-glycerol solution, the controller can mimic a viscosity range corresponding to a hematocrit between 29 and 42% in a temperature range of 30-42°C. The control response has no overshoot and the settling time is 8.4 min for a viscosity step of 0.3 cP, equivalent to a hematocrit step of 3.6%. Two rotary blood pumps that are in clinical use are tested at different viscosities. At a flow rate of 5 L/min, both show a deviation of roughly 15 and 10% in motor current for high rotor speeds. The influence of different viscosities on the measured head pressure is negligible. Viscosity control for a mock circulation thus plays an important role for assessing the required motor current of ventricular assist devices. For the investigation of the power consumption of rotary blood pumps and the development of flow estimators where the motor current is a model input, an integrated viscosity controller is a valuable contribution to an accurate testing environment.


Brain networks involved in viewing angry hands or faces.
Most neuropsychological research on the perception of emotion concerns the perception of faces. Yet in everyday life, hand actions are also modulated by our affective state, revealing it, in turn, to the observer. We used functional magnetic resonance imaging (fMRI) to identify brain regions engaged during the observation of hand actions performed either in a neutral or an angry way. We also asked whether these are the same regions as those involved in perceiving expressive faces. During the passive observation of emotionally neutral hand movements, the fMRI signal increased significantly in dorsal and ventral premotor cortices, with the exact location of the 'peaks' distinct from those induced by face observation. Various areas in the extrastriate visual cortex were also engaged, overlapping with the face-related activity. When the observed hand action was performed with emotion, additional regions were recruited including the right dorsal premotor, the right medial prefrontal cortex, the left anterior insula and a region in the rostral part of the supramarginal gyrus bilaterally. These regions, except for the supramarginal gyrus, were also activated during the perception of angry faces. These results complement the wealth of studies on the perception of affect from faces and provide further insights into the processes involved in the perception of others underlying, perhaps, social constructs such as empathy.


[Autotransplantation of tooth germs].
The authors explained, after an attentive review of literature, the clinic and therapeutic procedures about dental germs' transplant. They show the indications for this surgical operation, the procedure for selection of grafting germs and the current surgical technique to do it.


Growth defect and mutator phenotypes of RecQ-deficient Neurospora crassa mutants separately result from homologous recombination and nonhomologous end joining during repair of DNA double-strand breaks.
RecQ helicases function in the maintenance of genome stability in many organisms. The filamentous fungus Neurospora crassa has two RecQ homologs, QDE3 and RECQ2. We found that the qde-3 recQ2 double mutant showed a severe growth defect. The growth defect was alleviated by mutation in mei-3, the homolog of yeast RAD51, which is required for homologous recombination (HR), suggesting that HR is responsible for this phenotype. We also found that the qde-3 recQ2 double mutant showed a mutator phenotype, yielding mostly deletions. This phenotype was completely suppressed by mutation of mus-52, a homolog of the human KU80 gene that is required for nonhomologous end joining (NHEJ), but was unaffected by mutation of mei-3. The high spontaneous mutation frequency in the double mutant is thus likely to be due to NHEJ acting on an elevated frequency of double-strand breaks (DSBs) and we therefore suggest that QDE3 and RECQ2 maintain chromosome stability by suppressing the formation of spontaneous DSBs.


Evaporation of sessile drops containing colloidal rods: coffee-ring and order-disorder transition.
Liquid drops containing insoluble solutes when dried on solid substrates leave distinct ring-like deposits at the periphery or along the three-phase contact line-a phenomena popularly known as the coffee-ring or the coffee stain effect. The formation of such rings as well as their suppression is shown to have applications in particle separation and disease diagnostics. We present an experimental study of the evaporation of sessile drops containing silica rods to elucidate the structural arrangement of particles in the ring, an effect of the addition of surfactant and salt. To this end, the evaporation of aqueous sessile drops containing model rod-like silica particles of aspect ratio ranging from ∼4 to 15 on a glass slide is studied. We first show that when the conditions such as (1) solvent evaporation, (2) nonzero contact angle, (3) contact line pinning, (4) no surface tension gradient driven flow, and (5) repulsive particle-particle/particle-substrate interactions, that are necessary for the formation of the coffee-ring are met, the suspension drops containing silica rods upon evaporation leave a ring-like deposit. A closer examination of the ring deposits reveals that several layers of silica rods close to the edge of the drop are ordered such that the major axis of the rods are oriented parallel to the contact line. After the first few layers of ordered arrangement of particles, a random arrangement of particles in the drop interior is observed indicating an order-disorder transition in the ring. We monitor the evolution of the ring width and particle velocity during evaporation to elucidate the mechanism of the order-disorder transition. Moreover, when the evaporation rate is lowered, the ordering of silica rods is observed to extend over large areas. We demonstrate that the nature of the deposit can be tuned by the addition of a small quantity of surfactant or salt.


Radiotherapy and chemotherapy of limb tumours.
The place of radiotherapy and chemotherapy-separately, together, and in combination with surgery-in the treatment of limb tumours affecting skin, soft tissue, and bone is discussed.


The use of neonatal bubble Continuous Positive Airway Pressure in a rural hospital setting.
This retrospective review examined the introduction of bubble Continuous Positive Airway Pressure (bCPAP) in resuscitating neonates in a rural hospital environment. A retrospective audit of all emergent neonatal presentations to a rural emergency department (ED) over a 5-year period prior to (pre) and a 3.5-year period following the introduction of bCPAP (post). Sixty-seven neonatal resuscitations (31 pre- and 36 post-introduction of bCPAP) were reviewed, having an average gestation of 37.4 weeks and birth weight of 3,110g, with no significant difference in characteristics between groups. Time in the ED was significantly longer post-bCPAP (202±93 vs 156±70 mins), but time applying T-piece assisted ventilation was significantly reduced (55±40 vs 94 ± 84 mins). There was an 11% reduction in the use of aeromedical retrieval and an 18% reduction in admissions to the regional level III neonatal intensive care unit (NICU) with a corresponding increase in admissions to local level II NICU. The introduction of bCPAP into a rural hospital setting is technically feasible and results in less time spent on technically demanding hand ventilation, fewer admissions to level III neonatal intensive care units and a reduction in the use of aeromedical retrieval assets.


Repetitive Immunization at Multiple Sites (RIMMS) of Mice, Rats, and Hamsters.
The repetitive immunization at multiple sites (RIMMS) protocol capitalizes on the animal's innate immune system, which is genetically preprogrammed to recognize many antigens. By repetitively immunizing the animal, B cells that recognize the antigen are kept continuously expanding until the lymph nodes are harvested for hybridoma generation. This is a good method for making a more diverse repertoire of antibodies or antibodies directed against conformational epitopes.


An Electrostatic Net Model for the Role of Extracellular DNA in Biofilm Formation by Staphylococcus aureus.
Staphylococcus aureus is an important human pathogen that can form biofilms on various surfaces. These cell communities are protected from the environment by a self-produced extracellular matrix composed of proteins, DNA, and polysaccharide. The exact compositions and roles of the different components are not fully understood. In this study, we investigated the role of extracellular DNA (eDNA) and its interaction with the recently identified cytoplasmic proteins that have a moonlighting role in the biofilm matrix. These matrix proteins associate with the cell surface upon the drop in pH that naturally occurs during biofilm formation, and we found here that this association is independent of eDNA. Conversely, the association of eDNA with the matrix was dependent on matrix proteins. Both proteinase and DNase treatments severely reduced clumping of resuspended biofilms; highlighting the importance of both proteins and eDNA in connecting cells together. By adding an excess of exogenous DNA to DNase-treated biofilm, clumping was partially restored, confirming the crucial role of eDNA in the interconnection of cells. On the basis of our results, we propose that eDNA acts as an electrostatic net, interconnecting cells surrounded by positively charged matrix proteins at a low pH. Extracellular DNA (eDNA) is an important component of the biofilm matrix of diverse bacteria, but its role in biofilm formation is not well understood. Here we report that in Staphylococcus aureus, eDNA associates with cells in a manner that depends on matrix proteins and that eDNA is required to link cells together in the biofilm. These results confirm previous studies that showed that eDNA is an important component of the S. aureus biofilm matrix and also suggest that eDNA acts as an electrostatic net that tethers cells together via the proteinaceous layer of the biofilm matrix.


Team-based learning student assessment instrument (TBL-SAI) for assessing students acceptance of TBL in a Saudi medical school. Psychometric analysis and differences by academic year.
To assess psychometric properties of team-based learning student assessment instrument (TBL-SAI) and TBL acceptance by student academic year. A cross-sectional study was conducted at College of Medicine, University of Bisha, Bisha, Saudi Arabia, between February and May 2018. Students (n=109) from second- to fourth-year were scored on TBL-SAI scale (33-items). Principal axis factoring with varimax rotation was conducted on the scale to identify the emerged factors. Cronbach's alpha, item-total correlation were used to check the reliability and validity of the instrument. Cronbach's alpha for the total scale was 0.798. The means scores of TBL-SAI scale and each subscale was favorable. On factoring analysis, 27-items of revised TBL-SAI scale were retained and 7 factors emerged. Factor 1 stands for TBL satisfaction; factors 2, 4, 5, 6 stand for TBL versus lecture preference, factors 3 and 7 stand for TBL accountability. The scale was positively correlated with each TBL favor subscale, ranged between 0.328 and 0.756. Year-4 students scored higher (p less than 0.001) on TBL-SAI compared to year-2 or year-3 students. The revised TBL-SAI is valid and reliable tool to measure the favor of TBL. Longitudinal studies across all academic levels are recommended to provide a clearer picture of the students' acceptance rate of TBL.


Montmorillonite-catalysed formation of RNA oligomers: the possible role of catalysis in the origins of life.
Large deposits of montmorillonite are present on the Earth today and it is believed to have been present at the time of the origin of life and has recently been detected on Mars. It is formed by aqueous weathering of volcanic ash. It catalyses the formation of oligomers of RNA that contain monomer units from 2 to 30-50. Oligomers of this length are formed because this catalyst controls the structure of the oligomers formed and does not generate all possible isomers. Evidence of sequence-, regio- and homochiral selectivity in these oligomers has been obtained. Postulates on the role of selective versus specific catalysts on the origins of life are discussed. An introduction to the origin of life is given with an emphasis on reaction conditions based on the recent data obtained from zircons 4.0-4.5Ga.


A short-term screening test for teratogens using differentiating neuroblastoma cells in vitro.
Thirty-nine teratogenic and 18 nonteratogenic compounds were tested using an assay based on the ability of agents to interfere with normal growth and differentiation of murine neuroblastoma cells (clone N1E-115) in culture. Induction of differentiation in cells under growth-promoting conditions and inhibition of differentiating cells over a period of 7 days was dose-dependent, with the lowest effective dose not being highly toxic. Eighty-six percent of the compounds were correctly identified by the assay. The proportions of both false negatives (10%) and false positives (22%) were of the same order or better than in current, comparable tests. The possibilities offered by the system in rapid screening for teratogenic potential of environmental agents are discussed.


P.S. for post-Soviet: A glimpse to a life of persons with intellectual disabilities.
This article focuses on the situation of persons with intellectual disabilities in the developing post-Soviet countries and aims to review the extent to which services offered to them promote values of the Convention on the Rights of Persons with Disabilities and empower these persons to lead fulfilling lives. Interviews with experts revealed that post-Soviet countries form a peculiar cluster among other developing countries, which has specific attributes. First of all, there prevails a strong stigmatization, which consequently leads to the predominant silent mandate to isolate those with intellectual disabilities in big residential care institutions. Second, the governments' lack political will to start the reforms and initiatives of nongovernmental organizations which they do not sustain (or, assumingly, are even suppressed). As a result, persons with intellectual disabilities find themselves stuck between the Soviet tradition of exclusion and simulated superficial reforms.


A new information system for medical practice.
A data bank containing our clinical experience with more than 3,000 patients with suspected and documented ischemic heart disease is being used to expand our ability to care for patients. This report describes how the experience is documented, stored, and retrieved so that it can be used in patient management. Data acquisition is integrated with patient care by means of forms that are part of the patient record. Follow-up information is obtained at six months, one year, and yearly thereafter. All data are stored in a computer information system that allows the doctor to recall the experience of patients like his new patient. Prognostic information is available on each new patient both on-line and in the form of a printed laboratory report. The data bank represents an initial chapter of a computer textbook of medicine.


Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design.
In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug-drug interactions. We recently developed methods for high-speed functional screening and quantitative structure-activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.


Novel carbohydrate structures of cathepsin B from porcine spleen.
Two 13-residue glycopeptides were isolated from the digestion of purified porcine spleen cathepsin B by Staphylococcus aureus protease using high performance liquid chromatography. The major peptide, which is about 73% of the total, had the amino acid sequence His-His-Val-Asn(CH2O)-Gly-Ser-Arg-Pro-Pro-Cys-Thr-Gly-Glu. This peptide contains only a single N-acetylglucosamine residue linked to asparagine at the fourth residue by a beta-linkage. The minor peptide had a single amino acid replacement in a sequence otherwise identical to that of the major peptide. A serine was found at residue 10 instead of a half-cystine. The minor peptide also contains different carbohydrates, which were determined using proton NMR to be Man alpha 1----6 Man beta 1----4 GlcNAc beta 1----4(Fuc alpha 1----6)GlcNAc beta 1----n Asn. These results suggest that the cathepsin B carbohydrates are processed in vivo by enzymic systems specific to each isozyme.


Birth prevalence rates of skeletal dysplasias.
This study establishes the prevalence rates at birth of the skeletal dysplasias which can be diagnosed in the perinatal period or during pregnancy. Using a population-based register of congenital anomalies, a prevalence rate of 3.22 0/000 was observed. The most frequent types of skeletal dysplasia were achondroplasia and osteogenesis imperfecta (0.64 0/000, 1/15,000 births), thanatophoric dysplasia and achondrogenesis (0.28 0/000). The mutation rate for achondroplasia was higher in our material than in the other studies: 3.3 x 10(-5) per gamete per generation. Our study demonstrates that prenatal diagnosis by ultrasound is possible in some skeletal dysplasias.


Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats.
Recent studies have shown that the inflammatory process is involved in the pathogenesis of diabetic nephropathy. Fourteen-membered ring macrolides, including erythromycin, have anti-inflammatory, as well as antibacterial effects. The aim of this study was to investigate the renoprotective effects of erythromycin in streptozotocin (STZ)-induced diabetic rats. STZ-induced diabetic rats were treated orally with erythromycin (5 mg/kg body weight) or vehicle every day for 8 weeks. To evaluate the effect of erythromycin treatment, we measured urinary albumin excretion, and examined the following in the kidney: histological changes, the expression of intercellular adhesion molecule-1 (ICAM-1), macrophage infiltration, and nuclear factor-kappa B (NF-kappaB) activity. Erythromycin significantly reduced urinary albumin excretion without affecting blood glucose levels and blood pressure. Erythromycin also attenuated glomerular hypertrophy, mesangial expansion, macrophage infiltration and ICAM-1 expression in renal tissues. The expression of the gene encoding TGFB1 (also known as TGF-beta1), type IV collagen protein production and NF-kappaB activity in renal tissues were increased in diabetic rats and reduced by erythromycin treatment. Erythromycin prevented renal injuries without changes of blood glucose levels and blood pressure in experimental diabetic rats. These results suggest that the renoprotective effects of erythromycin are based on its anti-inflammatory effect via suppression of NF-kappaB activation. Modulation of microinflammation with erythromycin may provide a new approach for diabetic nephropathy.


Alaproclate effects on voltage-dependent K+ channels and NMDA receptors: studies in cultured rat hippocampal neurons and fibroblast cells transformed with Kv1.2 K+ channel cDNA.
The effects of alaproclate on voltage-dependent K+ currents and N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acidA (GABAA) receptor currents were investigated in cultured rat hippocampal neurons using whole-cell voltage clamp recording techniques. Alaproclate produced a concentration-dependent block of the sustained voltage-dependent K+ current activated by depolarization from -60 to +40 mV (IC50, 6.9 microM). At similar concentrations alaproclate also blocked the sustained voltage-dependent K+ current in fibroblast cells transformed to stably express Kv1.2 K+ channels. Analysis of tail currents and the voltage-dependence of the alaproclate block suggested an open-channel blocking mechanism. Alaproclate also produced a potent block of NMDA receptor currents in hippocampal neurons (IC50, 1.1 microM), but did not affect GABAA receptor currents (concentrations up to 100 microM). The alaproclate block of NMDA receptors occurred predominantly by an open-channel mechanism, although the drug was also able to block closed NMDA channels at a much slower rate. The interaction of alaproclate with NMDA receptors (activated by 10 microM NMDA) appeared to be governed by a first order binding reaction with forward and reverse rate constants of 6.7 x 10(3) M-1 s-1, and 0.025 sec-1, respectively (at -60 mV). At depolarized potentials the alaproclate-induced block of the NMDA receptor current was strongly reduced, a result opposite to that seen with the voltage-activated K+ currents, suggesting that the K+ channel block may occur at a superficial internal site, whereas the NMDA receptor block occurs at a deep external site. (+)-Alaproclate was a more potent blocker of K+ currents than (-)-alaproclate, whereas a reversed stereoselectivity was observed for NMDA receptor current, supporting the view that alaproclate block of the two channel types occurs at structurally distinct binding sites.


Reduction of Growth Rate as the Major Process in the Miniaturization of the Sand Dollar Sinaechinocyamus mai.
Sinaechinocyamus mai is an extremely small sand dollar, the maximum size being 10.9 mm. It has been suggested that Sinaechinocyamus is a miniaturized progenetic sand dollar that closely resembles the juveniles of Scaphechinus. In this study, we investigated the mechanisms responsible for the miniaturization. Our analysis of population dynamics, maturity, and annual reproductive cycles suggests that the growth rates of S. mai are about 19% the growth rates of Scaphechinus mirabilis, which reaches a maximum size of 88 mm. The developmental stages of oral and aboral surfaces were defined on the basis of the number of discontinuous interambulacral plates and the number of tube-foot porepairs, pairs, respectively. The patterns of the oral and aboral surfaces of the two species were compared, both at original size and after the Scaphechinus mirabilis pattern had been reduced to a size proportional to that of S. mai (i.e., to 19% original). On the oral surface, the patterns were different at the original sizes, but similar when the proportional sizes were compared; this indicates that the development of the oral plates is age-dependent in S. mai. On the aboral surface, the patterns were similar at the original sizes, but different in the proportional comparison, indicating that the development of the aboral plates is size-dependent in S. mai. S. mai becomes sexually mature at the age of 2 years, and Scaphechinus mirabilis matures probably at about the same age. Our data suggest that the reduction of growth rate (neoteny) is a more important mechanism of miniaturization in S. mai than is precocious cessation (progenesis).


Understanding the causes and consequences of measles virus persistence.
Measles is an acute systemic viral disease with initial amplification of infection in lymphoid tissue and subsequent spread over 10-14 days to multiple organs. Failure of the innate response to control initial measles virus (MeV) replication is associated with the ability of MeV to inhibit the induction of type I interferon and interferon-stimulated antiviral genes. Rather, the innate response is characterized by the expression of proteins regulated by nuclear factor kappa B and the inflammasome. With eventual development of the adaptive response, the rash appears with immune cell infiltration into sites of virus replication to initiate the clearance of infectious virus. However, MeV RNA is cleared much more slowly than recoverable infectious virus and remains present in lymphoid tissue for at least 6 months after infection. Persistence of viral RNA and protein suggests persistent low-level replication in lymphoid tissue that may facilitate maturation of the immune response, resulting in lifelong protection from reinfection, while persistence in other tissues (for example, the nervous system) may predispose to development of late disease such as subacute sclerosing panencephalitis. Further studies are needed to identify mechanisms of viral clearance and to understand the relationship between persistence and development of lifelong immunity.


[CNS processing of pain in functional somatic syndromes].
Functional pain syndromes usually are characterized by a local or generalized increase in pain sensitivity, spontaneous ongoing pain, and a variety of other common symptoms. Classification or definition of a syndrome is usually somewhat arbitrarily based on the predominantly affected body region or a main symptom, resulting in significant overlap between conditions. Support for the involvement of the central nervous system (CNS) comes from the frequent comorbidity of affective disorders and symptomatology, disturbances in cognitive function, changes in neuroendocrine function, and dysregulation of the autonomic nervous system, although only subgroups of patients are affected. Findings of neuroimaging studies in functional pain syndromes typically reveal plausible correlates for the patients' subjective complaints and indicate a central augmentation in pain processing but also in other sensory systems including a postulated interoceptive system. The pathophysiology of this augmentation is not clear, and the importance of peripheral input remains unresolved, as well as the contribution of spinal and supraspinal mechanisms. Affective and cognitive factors clearly influence pain processing in these syndromes, but do not fully explain the observed augmentation. For FMS, chronic low back pain, and irritable bowel syndrome a dysfunction of the descending inhibitory systems is supported by these findings. However, longitudinal studies are needed to confirm the causality of the reported associations and to establish a primary role of the CNS in these syndromes. Current techniques like VBM and H-MRS have revealed potential yet highly variable structural abnormalities of the CNS in several of the syndromes, but clinical relevance and conclusions from these studies remain far from clear. New theoretical concepts should drive prospective and interdisciplinary research based on well-defined hypotheses to use the full potential of the current neuroimaging techniques.


A randomized trial comparing winged versus conventional plastic stents for malignant bile duct strictures.
Stent insertion at endoscopic retrograde cholangiopancreatography (ERCP) is an established therapy for managing malignant biliary obstruction. Conventional plastic stents with a tubular design are most commonly used despite limited patency. Plastic stents with a winged design may theoretically increase the duration of stent patency. The aim of this study was to compare stent patency of the winged versus conventional plastic stents in patients with malignant biliary obstruction. A prospective, randomized subject-blinded trial was conducted. Patients with malignant biliary obstruction were randomized (1:1) to either a 10 French winged stent or 7 or 10 French conventional plastic stent. Strictures greater than 1 cm distal to the hilum were included. Patients were followed clinically to determine the frequency of stent failure until surgery, death or study closure. Fifty-eight patients were enrolled. Following 9 exclusions, 49 patients were randomized to a winged (n = 23) or conventional stent (n = 26). Median time to stent failure was 89 (95 % CI 26-NA) vs 143 (95 % CI 33 - 266) days ( P = 0.963) for the winged and conventional group, respectively. Stent failure for the winged group occurred in 11 (48 %) compared to 14 (54 %) in the conventional group. Median survival was 123 (95 % CI 81 - 189) vs 342 days (95 % CI 123 - 704) (p = 0.084) in the winged and conventional group respectively. There were no procedure related adverse events. Improvement in stent patency was not seen with the winged stent when compared to the conventional plastic stent.


Folate Biosynthesis, Reduction, and Polyglutamylation and the Interconversion of Folate Derivatives.
Many microorganisms and plants possess the ability to synthesize folic acid derivatives de novo, initially forming dihydrofolate. All the folic acid derivatives that serve as recipients and donors of one-carbon units are derivatives of tetrahydrofolate, which is formed from dihydrofolate by an NADPH-dependent reduction catalyzed by dihydrofolate reductase (FolA). This review discusses the biosynthesis of dihydrofolate monoglutamate, its reduction to tetrahydrofolate monoglutamate, and the addition of glutamyl residues to form folylpolyglutamates. Escherichia coli and Salmonella, like many microorganisms that can synthesize folate de novo, appear to lack the ability to transport folate into the cell and are thus highly susceptible to inhibitors of folate biosynthesis. The review includes a brief discussion of the inhibition of folate biosynthesis by sulfa drugs. The folate biosynthetic pathway can be divided into two sections. First, the aromatic precursor chorismate is converted to paminobenzoic acid (PABA) by the action of three proteins. Second, the pteridine portion of folate is made from GTP and coupled to PABA to generate dihydropteroate, and the bifunctional protein specified by folC, dihydrofolate synthetase, or folylpolyglutamate synthetase, adds the initial glutamate molecule to form dihydrofolate (H2PteGlu1, or dihydropteroylmonoglutamate). Bacteriophage T4 infection of E. coli has been shown to cause alterations in the metabolism of folate derivatives. Infection is associated with an increase in the chain lengths in folylpolyglutamates and particularly the accumulation of hexaglutamate derivatives.


Dynamics of Electrically Modulated Colloidal Droplet Transport.
Electrically actuated transport dynamics of colloidal droplets, on a hydrophobic dielectric film covering an array of electrodes, is studied here. Specifically, the effects of the size and electrical properties (zeta-potential) of the colloidal particles on such transport characteristics are investigated. For the colloidal droplets, the application of an electrical voltage leads to additional attenuation of the local dielectric-droplet interfacial tension. This is due to the electrically triggered enhanced colloidal particle adsorption at the dielectric-droplet interface, in the immediate vicinity of the droplet three-phase contact line (TPCL). The extent of such interfacial particle adsorption, and hence, the extent of the consequential reduction in the interfacial tension, is dictated by the combined effects of the three-phase contact line spreading, particle size, the interfacial electrostatic interaction between the colloidal particles (if charged) and the charged dielectric surface above the activated electrode, and the interparticle electrostatic repulsion. The electrical driving force of varying magnitude, stemming from this altered solid-liquid interfacial tension gradient in the presence of the colloidal particles, culminates in different droplet transport velocity and droplet transfer frequency for different colloidal droplets. We substantiate the inferences from our experimental results by a quasi-steady state force balance model for colloidal droplet transport. We believe that the present work will provide an accurate framework for determining the optimal design and operational parameters for digital microfluidic chips handling colloidal droplets, as encountered in a plethora of applications.


Anti-ROR1 scFv-EndoG as a Novel Anti-Cancer Therapeutic Drug
Aim: Immunotoxins are proteins that consist of an antibody fragment linked to a toxin, used as agents for targeted therapy of cancers. Although the most potent immunotoxins are made from bacterial and plant toxins, obstacles which contribute to poor responses are immunogenicity in patients and rapid development of neutralizing antibodies. In the present study we proposed a new therapeutic immunotoxin for targeted cancer therapy of ROR1 expressing cancers: an anti ROR1 single chain fragment variable antibody (scFv)-endonuclease G (anti ROR1 scFv-EndoG). Methods: The three-dimensional structure of anti ROR1 scFv-EndoG protein was modeled and structure validation tools were employed to confirm the accuracy and reliability of the developed model. In addition, stability and integrity of the model were assessed by molecular dynamic (MD) simulation. Results: All results suggested the protein model to be acceptable and of good quality. Conclusions: Anti-ROR1 scFv-EndoG would be expected to bind to the ROR1 extracellular domain by its scFv portion and selectively deliver non-immunogenic human endonuclease G enzyme as an end-stage apoptosis molecule into ROR1-expressing cancer cells and lead rapidly to apoptosis. We believe that anti ROR1 and other anti-tumor antigen scFv-EndoG forms may be helpful for cancer therapy.


Health-Related Quality of Life Is Severely Affected in Primary Orthostatic Tremor.
Primary orthostatic tremor (POT) is a movement disorder characterized by unsteadiness upon standing still due to a tremor affecting the legs. It is a gradually progressive condition with limited treatment options. Impairments in health-related quality of life (HQoL) seem to far exceed the physical disability associated with the condition. A multi-center, mixed-methodology study was undertaken to investigate 40 consecutive patients presenting with POT to four movement disorder centers in France. HQoL was investigated using eight quantitative scales and a qualitative study which employed semi-structured interviews. Qualitative data were analyzed with a combination of grounded-theory approach. Our results confirm that HQoL in POT is severely affected. Fear of falling was identified as the main predictor of HQoL. The qualitative arm of our study explored our initial results in greater depth and uncovered themes not identified by the quantitative approach. Our results illustrate the huge potential of mixed methodology in identifying issues influencing HQoL in POT. Our work paves the way for enhanced patient care and improved HQoL in POT and is paradigmatic of this modern approach for investigating HQoL issues in chronic neurological disorders.


High specific capacitance of manganese-based colloidal system with rare earth modification.
Ever-increasing global energy consumption has increased aggregate demand on electrochemical energy storage devices with high energy density. Over the past few decades, manganese oxides have attracted wide attention due to their abundant reserves, low cost, environmental friendliness, and high theoretical capacity. However, most reported manganese-based materials have exhibited capacity far below the theoretical capacity, which was only on the basis of Mn3+/Mn4+ couple. The rich chemistry of manganese enables it to exist in various valence states, such as Mn0, Mn2+, Mn3+, Mn4+, and Mn7+, providing great opportunity for discovering new manganese-based electrode systems. Herein, we formed a Mn2+/Mn4+ couple from a manganese-based colloidal system with rare earth (RE) modification, which was formed in-situ on nickel (Ni) foam in KOH electrolyte under an electric field assistance. The Mn-based colloidal electrode, with Mn:Ce mass ratio of 1:0.5, achieved a high specific capacitance of 2985 F g-1 at 3 A g-1, which was higher than the theoretical capacity of 2193 F g-1 on the basis of the Mn3+/Mn4+ couple. After the addition of Ce3+, the prepared sample exhibited improved rate capability performance. Our manganese-based colloidal electrode with RE modification delivered a high specific capacitance of 1223 F g-1 at 20 A g-1, with 54.5% retention of 2243 F g-1 at 3 A g-1 at Mn:Ce mass ratio of 1:0.05. Colloidal electrode systems involving Mn-based colloids are a novel way to engineer the electrochemical performance of inorganic materials.


Reflecting on type 2 diabetes prevention: more questions than answers!
Given the enormous public health and economic burden posed by the global epidemic of type 2 diabetes mellitus (T2DM), intervention in the prediabetes stage of disease to prevent progression to T2DM and its vascular complications seems the most sensible approach. Precisely how best to intervene remains the subject of much debate. Prudent lifestyle changes have been shown to significantly reduce the risk of progression in individuals with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Although lifestyle modifications are notoriously difficult to maintain, there is evidence that intensive intervention results in continued preventive benefit after the stopping of structured counselling. A number of drug therapies, including metformin, acarbose, orlistat and rosiglitazone, have also been proven effective in preventing progression from IFG/IGT, but unresolved issues still remain. Specifically, whether large numbers of individuals with glucose dysregulation who may never progress to T2DM should be exposed to the risk of pharmacological adverse effects is a topic of discussion and debate. Furthermore, there are limited data on the effectiveness of implementing interventions during the prediabetic state to prevent cardiovascular complications that may be hyperglycaemia related. A recent American Diabetes Association (ADA) consensus statement on IFG/IGT recommends lifestyle modification for individuals with IFG or IGT. Of note, the ADA consensus statement introduces the option of adding metformin treatment to lifestyle changes in those individuals who have combined IFG/IGT plus an additional risk factor for progression and who also have some features that increase the likelihood of benefiting from metformin treatment. The dipeptidyl peptidase-4 inhibitors are a new class of oral antidiabetic agents that, in addition to being effective in improving glycaemic control, may exert beneficial effects in preserving beta-cell function. These characteristics, combined with a low risk of hypoglycaemia, weight neutrality and what appears - so far - to be a relatively benign tolerability profile, make these agents intriguing candidates for preventive treatment.


Sonochemical growth of nanomaterials in carbon nanotube.
Recent achievements in investigations of carbon nanotubes (CNTs) filled with ternary chalcohalides (antimony sulfoiodide (SbSI) and antimony selenoiodide (SbSeI)) are presented. Parameters of sonochemical encapsulation of nanocrystalline semiconducting ferroelectric SbSI-type materials in CNTs are reported. This low temperature technology is convenient, fast, efficient and environmentally friendly route for producing novel type of hybrid materials useful for nanodevices. Structure as well as optical and electrical properties of SbSI@CNTs and SbSeI@CNTs are described. Advantages of ultrasonic joining of such filled CNTs with metal microelectrodes are emphasized. The possible applications of these nanomaterials as gas sensors are shown.


[Primary intraventricular hemorrhage: an analysis of eight cases].
Primary intraventricular haemorrhage (HIVP) is a rare condition, of diverse aetiology and variable course. We present a series of eight cases of HIVP diagnosed by CT and analyze the different aetiologies. A retrospective series of 8 cases diagnosed by CT, the risk factors, clinical behaviour, complications and prognosis are evaluated. Neuroimaging findings (CT, MR and/or DIVAS) are described. The most commonly associated factor is arterial hypertension (75%). Clinically, presentation was uniform as evidence of sudden intracranial hypertension with signs of meningeal irritation with little or no neurological focal signs. The commonest complication was hydrocephalus (25%) and the chances of survival in most cases were good. Three causes of bleeding were found: an arteriovenous malformation, an aneurysm and a blood coagulation disorder. Three hypertensive patients with no obvious cause of bleeding had periependimary laguna infarcts. HIVP is an unusual condition of diverse aetiology, uniform clinical presentation and has a good short term prognosis. We suggest that pathology of the small vessels, induced by hypertension, may play a part in the aetiology of a subgroup of patients with no obvious cause of bleeding.


Somatic excision of the Ac transposable element in transgenic Arabidopsis thaliana after 5-azacytidine treatment.
We have introduced the maize Ac transposable element in Arabidopsis thaliana and found that after three selfing generations, the element is immobile and extensively methylated. Moreover, the nopaline synthase (nos) gene present on the same transferred T-DNA, was active early after transformation and regeneration, but inactive in most of the S1 progeny. We used 5-azacytidine (5AzaC) to determine whether a reduction in the methylation would affect both Ac transposition and expression of the nos gene. After treatment with 5AzaC doses from 0.3 mM to 1.0 mM, approximately 25% of the plants produced detectable amounts of nopaline, indicating that the nos gene was reactivated. Using the polymerase chain reaction (PCR) to detect the empty donor site left by Ac transposition, we demonstrated that 5AzaC also activates Ac excision in the transgenic plants. Approximately 13% of the 5AzaC treated plants (doses from 0.1 mM to 1.0 mM) were shown to have empty donor sites due to Ac excision. None of the plants cultivated in the absence of 5AzaC showed evidence for Ac transposition or reactivation of the nos gene. Further analysis using Southern blot indicate that some demethylation occurred in the genome of individual plants. These results may represent demethylation in few cells during development which may be sufficient to reactivate in these cells the expression of the nos and Ac transposase transgenes, the latter promoting Ac transposition in somatic cells.


Gastric MALT-lymphoma, gastrin and cyclooxygenases.
Malt-lymphoma, gastrin and COX-2 interaction. Low grade, mucosal associated lymphoid tissue (MALT)-lymphoma is an unique among gastric malignancies where causal involvement of Helicobacter pylori (H. pylori) infection has been proposed based on complete regression of the tumor following the eradication therapy. In this report ten primary, low-grade MALT-lymphomas have been examined before and 6 months after one week of successful eradication therapy (clarithromycin + amoxicillin + omeprazole). Gastric biopsy samples from tumor and intact antrum and corpus mucosa were obtained during endoscopy before and after eradication for assessment of expression of gastrin and gastrin receptor (CCKB-R) as well as cyclooxygenase (COX)-1 and COX-2 using RT-PCR. The gastric lumen and serum gastrin and mucosal and tumor tissue PGE2 biosynthesis were determined by RIA before and after H. pylori eradication. Eradication of H. pylori resulted in complete endoscopic and histological remission of MALT-lymphoma in 9 out of 10 patients as assessed 6 months after this eradication. Before eradication, the mRNA expression for gastrin and CCKB-R as well as mRNA expression for COX-1 and COX-2 were observed in tumor tissue and infected mucosa, while corpus mucosa expressed only CCKB-R and antrum mucosa only gastrin. Six months upon the eradication when MALT-lymphoma completely regressed both endoscopically and histologically in 9 of 10 tested subjects, the expression of gastrin and COX-2 disappeared from the former area of MALT-lymphoma tumor. Gastrin mRNA remained detectable only in antrum mucosa, CCKB-R mRNA in corpus mucosa and COX-1 mRNA both in antrum and corpus mucosa. Gastric luminal and serum gastrin levels and gastric mucosa and tumor PGE2, which were greatly elevated before eradication, became normalized after this procedure. This study demonstrates that low-grade MALT-lymphoma is linked to H. pylori infection which may promote the expression and excessive release of gastrin and COX-2 expression that could be involved in the pathogenesis of MALT-lymphoma.


The physician as a factor in outpatient medical care after laparoscopically assisted vaginal hysterectomy: a multivariate analysis.
To evaluate whether physician experience affects outpatient medical care utilization after laparoscopically assisted vaginal hysterectomy (LAVH). A total of 120 patients who underwent LAVH were included in the study; 84 underwent LAVH by 2 senior physicians, who had performed an average of 3 LAVHs per month for >6 years; 36 patients underwent LAVH by 3 junior physicians, who had performed an average of 1 case per month for < 3 years. Data were analyzed by the multiple linear regression model. The dependent variable was the number of outpatient visits within 3 months after discharge. The independent variables were patient age, parity, pelvic adhesions, chronic disease and physicians performing LAVH > 6 years. The patients in the 2 groups did not differ in age, parity, chronic disease or pelvic adhesions. The level of physician experience significantly influenced the mean number of outpatient visits after LAVH within 3 months. After controlling for patient characteristics, the mean number of outpatient visits after discharge within 3 months of LAVH performed by senior physicians with 6 years of experience was reduced (-1.98). LAVH performed by experienced physicians reduces the need for patients to seek postoperative outpatient medical care, thereby controlling medical costs incurred under the hospital global budget payment system. However, adding more variables to the multiple regression model, such as the socioeconomic status of patients, habits of seeking medical help, distance between home and hospital and relationship between patient and physician, may further explain the factors affecting outpatient medical care utilization.


Molecular design of expression systems: comparison of different control configurations using molecular mechanism models.
Molecular-level mathematical models have been used to evaluate the effectiveness of eight different configurations of repressor synthesis control on the regulation of cloned gene expression initiated from a promoter-operator sequence. Both single and dual-repressor situations were considered, employing genetically structured models for the lac and lambdaP(R) promoter-operators in example calculations. Simulation results suggest that the most effective mode of cloned gene expression control is a cross-regulation configuration carried on a multicopy plasmid. This system was able to control cloned gene transcription in the uninduced state over a broad range of plasmid copy number and also provided the highest overall transcription rate in the induced state. The general strategies suggested by these simulations should be applicable for other repressor-operator-promoter systems in diverse hosts.


Silymarin as an adjunct to glibenclamide therapy improves long-term and postprandial glycemic control and body mass index in type 2 diabetes.
Oxidative stress is increased postprandially and during long-term hyperglycemia in type 2 diabetic patients who present with poor response to glibenclamide. This study was designed to evaluate the effects of the antioxidant flavonoid silymarin in improving long-term and postprandial glycemic and weight control in type 2 diabetic patients treated with glibenclamide. Using a randomized, double-blind, placebo-controlled design, 59 type 2 diabetic patients, previously maintained on 10 mg/day glibenclamide and diet control, with poor glycemic control, were randomized into three groups: the first two groups were treated with either 200 mg/day silymarin or placebo as adjuncts to glibenclamide, and the third group was maintained on glibenclamide alone for 120 days. Fasting and 4-hour postprandial plasma glucose, glycated hemoglobin (HbA(1c)), and body mass index (BMI) were evaluated at baseline and after 120 days. Compared with placebo, silymarin treatment significantly reduced both fasting and postprandial plasma glucose excursions, in addition to significantly reducing HbA(1c) levels and BMI after 120 days. No significantly different effects were observed for placebo compared to glibenclamide alone. In conclusion, adjunct use of silymarin with glibenclamide improves the glycemic control targeted by glibenclamide, during both fasting and postprandially, an effect that may be related to increased insulin sensitivity in peripheral tissues.


Murine strain differences in response to mercuric chloride: antinucleolar antibodies production does not correlate with renal immune complex deposition.
Mercuric chloride (HgCl2) induces the production of antinucleolar antibodies (ANucA) in susceptible strains of mice. Responder strains bearing the H-2(5) haplotype as well as several ANucA resistant strains have been shown to develop renal immune complex deposits after HgCl2 treatment. Sera obtained throughout 12 to 16 weeks of HgCl2 treatment from mice of four ANucA responder strains (A.SW/SnJ, A.CA/SnJ, DBA/1J, and P/J) and one ANucA-resistant strain (C57BL/10SnJ) were examined for ANucA production. Terminal sera were also tested for the presence of anti-glomerular basement membrane antibodies, and the kidneys were examined for the deposition of IgG and C3. Only one strain, A.SW, developed significant deposits of IgG in the renal glomeruli, although all four responder strains exhibited similar ANucA induction/production profiles. The differences seen by direct immunofluorescence assay (IFA) in renal immune complex deposition between the A.SW and histocompatibility congenic A.CA mice were corroborated by individually eluting and then quantitating the deposited IgG from renal tissues of Hg-treated A.SW and A.CA mice as well as control A.SW mice. The average amount of IgG eluted from A.SW renal tissue was significantly greater than that eluted from either A.CA or control A.SW renal tissues. All eluates from Hg-treated animals gave only a nucleolar fluorescence pattern when assayed by indirect IFA against a panel of rat organ tissues. In summary, no correlation was found between ANucA production and renal IgG deposition in response to treatment with HgCl2.


Methodological considerations in human studies of gene expression in HIV-associated lipodystrophy.
In the majority of cases, HIV-associated lipodystrophy, lipoatrophy in particular, becomes clinically apparent only after months or years of continuous exposure to antiretroviral medications and, once developed, is difficult to reverse. Many lipid-related side effects of antiretroviral medications result from drug-induced changes in gene expression. As our understanding of the pathogenic mechanisms underlying HIV-associated lipodystrophy improves, it is important to be able to explore changes at a molecular level in order to fully elucidate the mechanisms whereby antiretroviral drugs exert their toxicities. Monitoring changes in gene expression in vivo may enable physicians to identify, predict or prevent drug toxicities early, before irreversible changes in body composition occur. However, monitoring changes in gene expression at a population level presents many methodological challenges that need to be addressed, over and above the considerable intra- and inter-individual variability inherent in the cellular expression of any gene. Careful collection and processing of adequate biological samples, robust laboratory processes and assays, and appropriate study design can help overcome many of these difficulties.