[Role of viral infections in the pathogenesis of type 1 diabetes].
The precise role of viral infections in the pathogenesis of type 1 diabetes is still the subject of an important discussion. Coxsackievirus B4 (CVB4) is the virus the most implicated by a series of epidemiological studies. Pathogenic mechanisms underlying such a relationship implicate a molecular mimicry between CVB4 sequences and beta-cell autoantigens, but mainly a persistent CVB4 infection of pancreatic beta cells followed by a release of sequestered beta antigens and a "bystander" activation of autoreactive T cells. The demonstration of intrathymic expression of antigens specific of peripheral tissues has opened a novel research perspective. We have shown that CVB4 is able to infect in a persistent and producive manner human thymic epithelial cell cultures and human fetal thymic lobes in organotypic cultures. This infection induces an important thymic dysfunction characterized by a severe depletion of thymocytes (thymic T cells) and an up-regulated expression by thymic epithelial and T cells of class I proteins encoded by the major histocompatibility complex (MHC-I). Such thymic dysfunction might be responsible for a decrease of beta-cell central self-tolerance and anti-CVB4 cytotoxic CD8 T-cell activity. CVB4-induced thymic dysfunction would contribute in close association with the peripheral "bystander" effect to the destruction of insulin-secreting islet beta cells and to the development of type 1 diabetes.


The assessment of efficacy, toxicity and quality of care in long-term drug treatment.
Drug studies in man are usually divided into four phases. The first phase is to establish that the drug has a pharmacological action in man and in which dose range it occurs. The second phase is a study of the therapeutic effect of the drug in small numbers of closely observed patients. The third phase consists of large-scale studies which may involve hundreds or thousands of patients; such studies are designed to accumulate less detailed information about efficacy and to provide information about low frequency toxic events. At the end of this stage the drug is submitted to a regulatory body for a license to market it. Information derived from these studies usually has several important deficiencies. There is unlikely to be much evidence about the efficacy of the drug in relation to that of other substances used to treat the same condition. The carefully regulated conditions of the clinical trial may bear little relationship to the way the drug will be used in practice. Most important, the evidence obtained on efficacy may relate chiefly to the pharmacological action of the drug, e.g. in lowering blood pressure or blood sugar, or reducing inflammation, and may not bear directly upon therapeutic outcome. For these reasons much attention is being focused on monitoring of the way drugs are used after marketing. To provide evidence of therapeutic efficacy may require studies of such large scale and high cost that they are beyond the research of individual pharmaceutical companies and will require national or international action. Monitoring of the way drugs are used inevitably means studying not just the performance of the drug but also of the doctors who prescribe it. Studies that have been made of the quality of care of patients treated with anti-hypertensive drugs and those requiring anticoagulants are not reassuring concerning the general level of such quality.


An interprofessional palliative care oncology rehabilitation program: effects on function and predictors of program completion.
After treatment, patients with active cancer face a considerable burden from the effects of both the disease and its treatment. The Palliative Rehabilitation Program (prp) is designed to ameliorate disease effects and to improve the patient's functioning. The present study evaluated predictors of program completion and changes in functioning, symptoms, and well-being after the program. The program received referrals for 173 patients who had finished anticancer therapy. Of those 173 patients, 116 with advanced cancer were eligible and enrolled in the 8-week interprofessional prp; 67 completed it. Measures of physical, nutritional, social, and psychological functioning were evaluated at entry to the program and at completion. Participants experienced significant improvements in physical performance (p < 0.000), nutrition (p = 0.001), symptom severity (p = 0.005 to 0.001), symptom interference with functioning (p = 0.003 to 0.001), fatigue (p = 0.001), and physical endurance, mobility, and balance or function (p = 0.001 to 0.001). Reasons that participants did not complete the prp were disease progression, geographic inaccessibility, being too well (program not challenging enough), death, and personal or unknown reasons. A normal level of C-reactive protein (<10 mg/L, p = 0.029) was a predictor of program completion. Patients living with advanced cancers who underwent the interprofessional prp experienced significant improvement in functioning across several domains. Program completion can be predicted by a normal level of C-reactive protein.


Quantitative aspects of fecal Rhodococcus (Corynebacterium) equi in foals.
Quantitative aspects of fecal Rhodococcus (Corynebacterium) equi in newborn foals for 12 weeks after birth were investigated on two horse breeding farms. R. equi was found in the feces of foals during week 1 of life. The greatest numbers of R. equi were present in the feces of foals during the first 8 weeks of their lives, which coincides with the age when foals are most liable to be exposed to R. equi.


Extended depth from focus reconstruction using NIH ImageJ plugins: quality and resolution of elevation maps.
In this work, NIH ImageJ plugins for extended depth-from-focus reconstructions (EDFR) based on spatial domain operations were compared and tested for usage optimization. Also, some preprocessing solutions for light microscopy image stacks were evaluated, suggesting a general routine for the ImageJ user to get reliable elevation maps from grayscale image stacks. Two reflected light microscope image stacks were used to test the EDFR plugins: one bright-field image stack for the fracture of carbon-epoxy composite and its darkfield corresponding stack at same (x,y,z) spatial coordinates. Image quality analysis consisted of the comparison of signal-to-noise ratio and resolution parameters with the consistence of elevation maps, based on roughness and fractal measurements. Darkfield illumination contributed to enhance the homogeneity of images in stack and resulting height maps, reducing the influence of digital image processing choices on the dispersion of topographic measurements. The subtract background filter, as a preprocessing tool, contributed to produce sharper focused images. In general, the increasing of kernel size for EDFR spatial domain-based solutions will produce smooth height maps. Finally, this work has the main objective to establish suitable guidelines to generate elevation maps by light microscopy.


The bisphosphonomethyl analogue of 2,3-bisphosphoglycerate inhibits yeast but not wheat-germ phosphoglycerate mutase.
The bisphosphonomethyl analogue of 2,3-bisphosphoglycerate [4-phosphono-2-(phosphonomethyl) butanoate] was a potent competitive inhibitor of cofactor-dependent phosphoglycerate mutase from yeast, with a Ki of 0.8 mM. In contrast, the analogue did not affect the activity of cofactor-independent phosphoglycerate mutase from wheat germ. It is considered that this compound should be particularly useful for n.m.r. spectroscopic studies on the mechanism of action of cofactor-dependent phosphoglycerate mutases.


Coverage with evidence development: the Ontario experience.
For non-drug technologies, there is often residual uncertainty following systematic review, mainly due to inadequate evidence of efficacy. The unwillingness to make decisions in the presence of uncertainty may lead to passive diffusion and intuitive decision making with or without public pressure. This may affect health system sustainability. There is increasing interest in post-market evaluation through processes that include coverage with evidence development (CED) to address residual uncertainty regarding effectiveness and cost-effectiveness. Global experience of CED has been slow to develop despite their potential contribution to decision making. Ontario's field evaluation program to better inform decision making represents a collaboration between physicians, policy decision makers and academic centers. We report results of the first ten CEDs from this program to assess whether they achieved their objective of influencing policy by addressing residual uncertainty following systematic review. Since 2003, nineteen field evaluation studies to resolve residual uncertainty following systematic review have been completed, ten of which met the criteria of CED and are the focus of this report. There was more than one patient subgroup or intervention in three of the CEDs. This provided the basis for evaluating thirteen outcomes. In each case, the CED addressed the uncertainty and led to a decision based on the systematic review and CED result. The CEDs led to adoption of the technology in six instances, modified adoption in three instances and withdrawal in four instances. CED makes an important contribution to translating evidence to decision making. Methodologies are needed to increase the scope and reduce timelines for CEDs, such as the use of linked comprehensive and robust data sets and collaborative studies with other jurisdictions. CED before making long-term funding decisions, especially where there is uncertainty of effectiveness, safety or cost-effectiveness, should be increasingly funded by health systems.


Image segmentation using association rule features.
A new type of texture feature based on association rules is described. Association rules have been used in applications such as market basket analysis to capture relationships present among items in large data sets. It is shown that association rules can be adapted to capture frequently occurring local structures in images. The frequency of occurrence of these structures can be used to characterize texture. Methods for segmentation of textured images based on association rule features are described. Simulation results using images consisting of man made and natural textures show that association rule features perform well compared to other widely used texture features. Association rule features are used to detect cumulus cloud fields in GOES satellite images and are found to achieve higher accuracy than other statistical texture features for this problem.


Metastatic testicular tumor requiring inferior vena cava resection.
A patient undergoing radical retroperitoneal lymphadenectomy for metastatic embryonal cell testicular carcinoma is presented. Tumor resection required removal of the inferior vena cava due to transmural invasion. The inferior vena cava was replaced using externally stented polytetrafluoroethylene (PTFE) graft. Patency was documented by postoperative Doppler studies, duplex scanning, and computed tomographic scanning. Stented PTFE is currently the graft of choice for inferior vena caval replacement.


Cerebellar Transcranial Direct Current Stimulation Improves Maximum Isometric Force Production during Isometric Barbell Squats.
Maximum contraction force (MVC) is an important predictor of athletic performance as well as physical fitness throughout life. Many everyday life activities involve multi-joint or whole-body movements that are determined in part through optimized muscle strength. Transcranial direct current stimulation (tDCS) has been reported to enhance muscle strength parameters in single-joint movements after its application to motor cortical areas, although tDCS effects on MIVC in compound movements remain to be investigated. Here, we tested whether anodal tDCS and/or sham stimulation over primary motor cortex (M1) and cerebellum (CB) improves maximum isometric contraction force (MIVC) during isometric barbell squats (iBS). Our results provide novel evidence that CB stimulation enhances MIVC during iBS. Although this indicates that parameters relating to muscle strength can be modulated through anodal tDCS of the cerebellum, our results serve as an initial reference point and need to be extended. Therefore, further studies are necessary to expand knowledge in this area of research through the inclusion of different tDCS paradigms, for example investigating dynamic barbell squats, as well as testing other whole-body movements.


TDP-43 proteinopathy and mitochondrial abnormalities in neurodegeneration.
Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Importantly, TDP-43 proteinopathy, characterized by aberrant phosphorylation, ubiquitination, cleavage or nuclear depletion of TDP-43 in neurons and glial cells, is a common prominent pathological feature of various major neurodegenerative diseases including ALS, FTD, and Alzheimer's disease (AD). Although the pathomechanisms underlying TDP-43 proteinopathy remain elusive, pathologically relevant TDP-43 has been repeatedly shown to be present in either the inside or outside of mitochondria, and functionally involved in the regulation of mitochondrial morphology, trafficking, and function, suggesting mitochondria as likely targets of TDP-43 proteinopathy. In this review, we first describe the current knowledge of the association of TDP-43 with mitochondria. We then review in detail multiple mitochondrial pathways perturbed by pathological TDP-43, including mitochondrial fission and fusion dynamics, mitochondrial trafficking, bioenergetics, and mitochondrial quality control. Lastly, we briefly discuss how the study of TDP-43 proteinopathy and mitochondrial abnormalities may provide new avenues for neurodegeneration therapeutics.


Treating Speech Movement Hypokinesia in Parkinson's Disease: Does Movement Size Matter?
This study evaluates the effects of a novel speech therapy program that uses a verbal cue and gamified augmented visual feedback regarding tongue movements to address articulatory hypokinesia during speech in individuals with Parkinson's disease (PD). Five participants with PD participated in an ABA single-subject design study. The treatment aimed to increase tongue movement size using a combination of a verbal cue and augmented visual feedback and was conducted in 10 45-min sessions over 5 weeks. The presence of visual feedback was manipulated during treatment. Articulatory working space of the tongue was the primary outcome measure and was examined during treatment and in cued and uncued sentences pre- and posttreatment. Changes in speech intelligibility in response to a verbal cue pre- and posttreatment were also examined. During treatment, 4/5 participants showed a beneficial effect of visual feedback on tongue articulatory working space. At the end of the treatment, they used larger tongue movements when cued, relative to their pretreatment performance. None of the participants, however, generalized the effect to the uncued sentences. Speech intelligibility of cued sentences was judged as superior posttreatment only in a single participant. This study demonstrated that using an augmented visual feedback approach is beneficial, beyond a verbal cue alone, in addressing articulatory hypokinesia in individuals with PD. An optimal degree of articulatory expansion might, however, be required to elicit a speech intelligibility benefit.


Congenital cytomegalovirus infection in infants infected with human immunodeficiency virus type 1.
To determine the rate of in utero transmission of cytomegalovirus (CMV) in perinatally HIV-exposed infants and to determine whether coinfection with CMV in early life affects outcome. Infants born to HIV-infected women between March, 1988, and March, 1995, were evaluated (n = 206). Congenital or in utero CMV infection was defined as a positive CMV culture or shell vial assay on urine obtained in the first 3 weeks of life. HIV-infected infants either had positive serology beyond 18 months of age or, for an infant younger than 18 months, had a positive HIV PCR or HIV culture on at least two separate occasions. There were 30 HIV-infected and 171 uninfected infants (144 who seroreverted and 27 infants with at least 2 negative HIV PCR or culture results and normal immunologic studies during the first 6 months of age). Urine culture for CMV was obtained during the first 3 weeks of life on 154 infants: 24 of 30 (80%) HIV-infected infants; and 130 of 171 (76%) HIV-uninfected infants. Overall 10 of 154 (6.5%) infants were infected with CMV: 5 of 24 (21%) HIV-infected and 5 of 130 (3.8%) HIV-uninfected infants. The rate of in utero CMV infection was significantly higher in HIV-infected infants (P = 0.008). Dually infected infants were more immunosuppressed than their CMV-negative counterparts. At 3 months of age the percentage of CD4+ T lymphocytes (P = 0.0021) and CD4:CD8 ratios (P = 0.0018) were significantly lower in the CMV-infected infants than in the CMV-uninfected infants. At 6 months of age the absolute CD4+ T lymphocyte counts (P = 0.0038), percentage of CD4+ T lymphocytes (P = 0.044) and CD4:CD8 ratios (P = 0.037) were significantly lower in the CMV-infected infants. The mean survival of HIV-infected infants who were coinfected with CMV in early life (5 in utero and 1 perinatally infected infant identified at 7 weeks) was 24.77 months. Kaplan-Meier survival analysis indicated a trend toward decreased survival in the infants who were coinfected with CMV in early life (P = 0.088). Congenital CMV infection is more common in HIV-infected infants than in HIV-uninfected infants. Infection with CMV in early life is associated with greater immunosuppression and may be associated with a more rapid progression of HIV infection in infants.


A cross-sectional survey on parasites of chickens in selected villages in the subhumid zones of South-eastern Nigeria.
A study was carried out to identify and estimate the prevalence of ecto- and endoparasites of village chicken between April and July 2008 in three local councils of Enugu state, Nigeria. A total of 1038 chickens comprising of 468 chicks, 207 growers and 363 adults were examined during the house to house survey for ectoparasites, gastrointestinal helminths and coccidia infections. Our finding showed that 41% were infected with ectoparasites with lice, fleas, and mites having prevalence rates of 62.2%, 35.7% and 2.1%, respectively. Helminths and coccidia had prevalence of 35.5% each. Among the helminths Ascaridia, galli was the most dominant species (17.2%). Generally, there was a significantly higher helminth infestation relative to the ectoparasites (P < .05), high prevalence of mixed infections and absence of tick infestation. Parasitism could be big constraint to production in the study area and we recommend a sustainable control strategy.


Myocutaneous flaps: the Saskatoon experience.
The purpose of this study was to determine the results of myocutaneous flap procedures performed in three Saskatoon hospitals between 1977 and 1979. Twenty-two flap procedures were performed on 17 patients. Eleven patients were suffering from decubitus ulcers and 6 had other wounds. Myocutaneous flaps have a place in the early surgical management of decubitus ulcers. Fluorescein given intravenously in some patients during operation was used to assess flap viability; 4 out of 10 flaps required trimming as a result. The myocutaneous flap technique provides rapid and durable closure for a wide variety of tissue defects which are otherwise difficult to cover.


Reactivation of hepatitis B virus after withdrawal of erlotinib.
Reactivation of hepatitis B virus (hbv) is a reported complication for patients undergoing chemotherapy, particularly immunochemotherapy with anti-CD20 agents such as rituximab. However, as the use of molecularly targeted agents increases, the risk of viral reactivation is less clearly defined. Here, we present the case of a 62-year-old woman with newly diagnosed EGFR mutation-positive metastatic non-small-cell lung cancer (nsclc). Per interview, our patient had a remote history of hbv infection. She was started on erlotinib and developed profound diarrhea leading to renal failure that required hospital admission and temporary discontinuation of erlotinib. At 8 days after erlotinib cessation, she had a marked spike in her liver function tests, with viral serologies that were consistent with hbv reactivation. Although erlotinib and other tyrosine kinase inhibitors (tkis) are not classically associated with hbv reactivation, hbv reactivation can occur even in the setting of tki withdrawal. Before tki initiation, careful patient screening in those at risk for hbv should be performed to attenuate preventable hepatotoxicity and to differentiate between other causes of hepatotoxicity (for example, drug-induced toxicity).


Muscle involvement and motor function in amyoplasia.
The most common form of arthrogryposis multiplex congenita (AMC) is amyoplasia. Diagnostic criteria are highly specific, with decreased muscle mass, typical contractures and limb positioning at birth. Intellectual development is normal. The aims of this study were to investigate how muscle strength and contractures affect motor function in amyoplasia, and to relate current functional status to joint positions at birth. Medical records were reviewed and a clinical examination was performed, with investigation of muscle strength, range of motion, and motor function. Thirty-five patients with amyoplasia participated and were divided into three functional groups: 11 community ambulators, 11 household ambulators, and 7 non-ambulators. Six children less than 2 years old were not categorized. Community ambulators had the best muscle strength and none had knee flexion contractures extending 20 degrees. Household ambulators had severe contractures in the lower limbs, but good muscle strength in the upper limbs. Non-ambulators had most severe contractures and most severely reduced muscle strength. Most of the non-ambulators were born with hips in severe abduction, flexion and external rotation. Good and very good correlations were found between muscle strength and motor function, and only moderate correlations between range of motion and motor function. We conclude that more attention should be paid to developing muscle strength, with early stimulation of active movement, and that periods of immobilization should be minimized. Further, ultrasound or MRI of muscle tissue in the newborn period would be useful to evaluate prerequisites for future development of muscle strength and thereby anticipate response to therapy.


State of the art in selection of variables and functional forms in multivariable analysis-outstanding issues.
How to select variables and identify functional forms for continuous variables is a key concern when creating a multivariable model. Ad hoc 'traditional' approaches to variable selection have been in use for at least 50 years. Similarly, methods for determining functional forms for continuous variables were first suggested many years ago. More recently, many alternative approaches to address these two challenges have been proposed, but knowledge of their properties and meaningful comparisons between them are scarce. To define a state of the art and to provide evidence-supported guidance to researchers who have only a basic level of statistical knowledge, many outstanding issues in multivariable modelling remain. Our main aims are to identify and illustrate such gaps in the literature and present them at a moderate technical level to the wide community of practitioners, researchers and students of statistics. We briefly discuss general issues in building descriptive regression models, strategies for variable selection, different ways of choosing functional forms for continuous variables and methods for combining the selection of variables and functions. We discuss two examples, taken from the medical literature, to illustrate problems in the practice of modelling. Our overview revealed that there is not yet enough evidence on which to base recommendations for the selection of variables and functional forms in multivariable analysis. Such evidence may come from comparisons between alternative methods. In particular, we highlight seven important topics that require further investigation and make suggestions for the direction of further research. Selection of variables and of functional forms are important topics in multivariable analysis. To define a state of the art and to provide evidence-supported guidance to researchers who have only a basic level of statistical knowledge, further comparative research is required.


Discovery of a Prefusion Respiratory Syncytial Virus F-Specific Monoclonal Antibody That Provides Greater In Vivo Protection than the Murine Precursor of Palivizumab.
Palivizumab, a humanized murine monoclonal antibody that recognizes antigenic site II on both the prefusion (pre-F) and postfusion (post-F) conformations of the respiratory syncytial virus (RSV) F glycoprotein, is the only prophylactic agent approved for use for the treatment of RSV infection. However, its relatively low neutralizing potency and high cost have limited its use to a restricted population of infants at high risk of severe disease. Previously, we isolated a high-potency neutralizing antibody, 5C4, that specifically recognizes antigenic site Ø at the apex of the pre-F protein trimer. We compared in vitro and in vivo the potency and protective efficacy of 5C4 and the murine precursor of palivizumab, antibody 1129. Both antibodies were synthesized on identical murine backbones as either an IgG1 or IgG2a subclass and evaluated for binding to multiple F protein conformations, in vitro inhibition of RSV infection and propagation, and protective efficacy in mice. Although 1129 and 5C4 had similar pre-F protein binding affinities, the 5C4 neutralizing activity was nearly 50-fold greater than that of 1129 in vitro In BALB/c mice, 5C4 reduced the peak titers of RSV 1,000-fold more than 1129 did in both the upper and lower respiratory tracts. These data indicate that antibodies specific for antigenic site Ø are more efficacious at preventing RSV infection than antibodies specific for antigenic site II. Our data also suggest that site Ø-specific antibodies may be useful for the prevention or treatment of RSV infection and support the use of the pre-F protein as a vaccine antigen.IMPORTANCE There is no vaccine yet available to prevent RSV infection. The use of the licensed antibody palivizumab, which recognizes site II on both the pre-F and post-F proteins, is restricted to prophylaxis in neonates at high risk of severe RSV disease. Recommendations for using passive immunization in the general population or for therapy in immunocompromised persons with persistent infection is limited because of cost, determined from the high doses needed to compensate for its relatively low neutralizing potency. Prior efforts to improve the in vitro potency of site II-specific antibodies did not translate to significant in vivo dose sparing. We isolated a pre-F protein-specific, high-potency neutralizing antibody (5C4) that recognizes antigenic site Ø and compared its efficacy to that of the murine precursor of palivizumab (antibody 1129) matched for isotype and pre-F protein binding affinities. Our findings demonstrate that epitope specificity is an important determinant of antibody neutralizing potency, and defining the mechanisms of neutralization has the potential to identify improved products for the prevention and treatment of RSV infection.


Phylogenetic analysis of 3C protease (3C(pro)) coding region of Foot-and-mouth disease virus type A.
Nucleotide sequence analysis of the 3C protease (3C(pro)) region of Foot-and-mouth disease virus type A (FMDV-A) isolates from India has revealed incongruous phylogenetic grouping between 3C(pro) and VP1 region possibly due to the genetic recombination or independent evolution of non-structural and structural protein coding regions. Similar to the VP1 region, the emerging VP3(59)-deletion group maintained its genetic distinctiveness at 3C(pro) region and was found to be diverging with time. Two lineage specific signature aa residues were detected for the deletion group in proof of lineage specific drift or selection events. 3C(pro) region exhibited high degree of conservation as evident from low dN/dS ratio (0.036) and percentage of variable aa positions (20%). A transmembrane domain from aa 27 to 44 could be predicted that possibly anchors 3C to intracellular membranes for better interaction with RNA replication complex. On the basis of sequence conservation, the likelihood that the region aa 121-150 was carrying a vaccine exploitable T-cell epitope was very high.


A Case Report: Mucinous Tubular and Spindle Cell Carcinoma of Kidney with Spindle Cell Predominance Mimicking Mesenchymal Tumour.
Mucinous tubular and spindle cell carcinoma (MTSCC) of kidney is a rare variant of renal cell carcinoma which was first described in the 2004 World Health Organization classification of tumours of the kidney. Morphologically, MTSCC is composed of tubules merging with bland-appearing spindle cells in a myxoid/mucinous stroma. Diverse morphological patterns have been reported in MTSCC; however, a spindle cell predominant morphology mimicking a mesenchymal tumour is rare and only two cases have been reported so far. We report a case of MTSCC with spindle cell predominance in kidney which was a diagnostic challenge. Though MTSCC usually shows an indolent course, there have been cases showing aggressive behaviour even with bland morphology. Hence, a thorough histopathological evaluation with ancillary studies are required to differentiate spindle cell predominant MTSCC from its mimics. Our case was a 40-year-old female who was incidentally found to have a well-defined hypodense lesion measuring around 2 cm in the upper pole of the right kidney. Right partial nephrectomy was performed which showed a 2.7 × 2.5 × 2 cm well-defined grey tan tumour without necrosis or haemorrhage, limited to kidney. Histopathological examination showed sheets of bland-appearing spindle cells mimicking a mesenchymal tumour. The tumour was extensively sampled, revealing small foci of tubule formation and mucinous stroma. Tumour cells were positive for CK7, AMACR, and PAX8. A final diagnosis of MTSCC was made. Hereby, we discuss ways of differentiating MTSCC from other spindle cell tumours of the kidney.


Gene expression analysis in response to lung toxicants: I. Sequencing and microarray development.
A key challenge in measuring gene expression changes in the lung in response to site-selective toxicants is differentiating between target and nontarget areas. The toxicity for the cytotoxicant 1-nitronaphthalene is highly localized in the airway epithelium. Target cells comprise but a fraction of the total lung cell mass; measurements from whole lung homogenates are not likely to reflect what occurs at the target site. Additionally, the use of generic microarrays to measure expression in airway epithelium may not provide a good representation of transcripts present at the site of toxic action. cDNA libraries from airway and alveolar subcompartments of rat lung were sequenced for the development of a custom microarray representative of these lung regions. We identified 7,460 nonredundant rat lung sequences. Nearly 30% of the sequences on this array are not present on the Affymetrix Rat GeneChip 230. A 20,000-element microarray was developed that delineates differences in gene expression between subcompartments. This is the first in a series of articles employing this microarray for detecting gene expression changes during acute injury produced by 1-nitronaphthalene and subsequent repair.


Cloning of cDNAs encoding a rabbit renal brush border membrane protein immunologically related to band 3. Sequence similarity with microsomal dipeptidase.
Distinct anion transport processes have been identified in the mammalian renal proximal tubule, but none of the responsible proteins or genes have been isolated. A 43 kDa rabbit microvillus membrane protein that is immunologically related to the erythroid anion exchanger (band 3) was a candidate for a renal anion transporter. To examine the structural relationship with band 3, we cloned cDNAs encoding the 43 kDa protein. The 43 kDa band-3-like protein was purified, and a novel sequence of 24 amino acids was obtained from the N-terminus. Degenerate oligonucleotides were synthesized based on this sequence, and the polymerase chain reaction with single-sided specificity was used to amplify and clone a 1330 bp cDNA from rabbit renal cortex. Additional overlapping 272 bp and 1123 bp cDNAs were obtained by synthesizing and screening a rabbit renal cortical cDNA library. The composite sequence was 1483 bp, terminated with (A)16, and was similar in size to the principal transcript expressed in rabbit renal cortex. The single long open reading frame was predicted to encode a protein composed of 410 amino acids with a molecular mass of 45,193 Da; 15 amino acids predicted to reside at the N-terminus were absent in the mature protein and may constitute a signal peptide. There was only limited sequence similarity with human erythroid band 3. Rather, the sequence was highly similar to microsomal dipeptidase, including the presence of a signal peptide and a consensus sequence for covalent linkage to glycosylphosphatidylinositol. In summary, the 43 kDa protein from rabbit renal cortex that is recognized by a monospecific antibody to erythroid band 3 is most likely a microvillus membrane dipeptidase.


An improved mechanical air puff stimulator that allows activation of a variety of endoepithelial receptors and is suitable for the study of reflexes in animals and humans.
Studies of endoepithelial-triggered reflexes, such as nasal respiratory reflexes, are difficult to carry out in humans without a non-traumatic and reliable stimulation device. The air puff stimulator described allows us to deliver air puffs of brief duration at various intensities, frequencies, and temperatures. The stimulation is non-traumatizing and non-nociceptive. We have successfully used it in animals as a source of specific stimuli to enable us to study central and peripheral neuronal responses evoked by activation of endonasal dynamically sensitive receptors. Immunohistochemical studies of the c-fos expression evoked during sneezing elicited by air puffs provided additional evidence for the specificity of this particular stimulation technique. We suggest that the use of such a non-traumatizing air puff stimulator could be extended to human studies. It might be particularly useful in developmental studies of endoepithelial-triggered reflexes such as those respiratory reflexes whose immaturity at birth can be life-threatening.


Detergents in drainage systems for buildings.
Current soil waste vent (SWV) system design guides aim to produce ventilated drainage networks for buildings which protect attached water trap seals from unwanted air pressure effects. Such effects may cause trap seal failure that are caused by airflow induction during discharge. The ventilation design guides are based on steady-state experiments utilising cold clean water as a test media. However, most 'grey' and 'black' water sources are dosed with detergent, and are often warm, which significantly alters the behaviour when compared to clean water. Thus, current design standards provide only approximations of SWV system response. Results indicate that induced airflows in warm detergent-dosed water can be significantly higher than those measured in clean water systems, by a factor of more than 2. This paper quantifies the effect of detergents in SWV systems in terms of observed air entrainment rates and previously published research on the factors that contribute to air entrainment. Results of previous work are cast into dimensionless groupings suitable for inclusion into a mathematical simulation model based on a finite difference scheme. It utilises the method of characteristics as a solution technique to simulate drainage system operation via the equations that define unsteady partially filled or full bore pipe flows and the boundary conditions represented by water traps and other common system components.


[Functional results of gastric resection in peptic ulcer].
The results of surgical treatment of 406 patients with gastric and duodenal ulcers are analysed. The postoperative lethality was 0.49%. The author has used the technique of gastric resection with the artificial sphincter formation from the seromuscular flap of a gastric stump. At the late period after the operation, the mild degree dumping-syndrome developed in 2.6%, reflux-gastritis--in 5% of the patients.


A note on the control function approach with an instrumental variable and a binary outcome.
Unobserved confounding is a well known threat to causal inference in non-experimental studies. The instrumental variable design can under certain conditions be used to recover an unbiased estimator of a treatment effect even if unobserved confounding cannot be ruled out with certainty. For continuous outcomes, two stage least squares is the most common instrumental variable estimator used in epidemiologic applications. For a rare binary outcome, an analogous linear-logistic two-stage procedure can be used. Alternatively, a control function approach is sometimes used which entails entering the residual from the first stage linear model as a covariate in a second stage logistic regression of the outcome on the treatment. Both strategies for binary response have previously formally been justified only for continuous exposure, which has impeded widespread use of the approach outside of this setting. In this note, we consider the important setting of binary exposure in the context of a binary outcome. We provide an alternative motivation for the control function approach which is appropriate for binary exposure, thus establishing simple conditions under which the approach may be used for instrumental variable estimation when the outcome is rare. In the proposed approach, the first stage regression involves a logistic model of the exposure conditional on the instrumental variable, and the second stage regression is a logistic regression of the outcome on the exposure adjusting for the first stage residual. In the event of a non-rare outcome, we recommend replacing the second stage logistic model with a risk ratio regression.


Melatonin and carcinogenesis in mice: the 50th anniversary of relationships.
The history of studies of melatonin effects on cancer in mice is outlined, the main lesson being that the systemic in vivo effects of melatonin on animals may overwhelm the in vitro effects found using tissue explants or cell cultures. In particular, the timing of melatonin administration is of crucial importance for using the drug, which is freely available over counter and thus needs no licensing for its applications in oncology.


Novel Therapeutics for Multiple Sclerosis Designed by Parasitic Worms.
The evolutionary response to endemic infections with parasitic worms (helminth) was the development of a distinct regulatory immune profile arising from the need to encapsulate the helminths while simultaneously repairing tissue damage. According to the old friend's hypothesis, the diminished exposure to these parasites in the developed world has resulted in a dysregulated immune response that contributes to the increased incidence of immune mediated diseases such as Multiple Sclerosis (MS). Indeed, the global distribution of MS shows an inverse correlation to the prevalence of helminth infection. On this basis, the possibility of treating MS with helminth infection has been explored in animal models and phase 1 and 2 human clinical trials. However, the possibility also exists that the individual immune modulatory molecules secreted by helminth parasites may offer a more defined therapeutic strategy.


Patient positioning using implanted gold markers with the Novalis Body system in the thoracic spine.
To evaluate the effectiveness of implanted gold marker registration compared with bony fusion alignment for patient positioning using the Novalis Body system. Eighteen treatment fractions of stereotactic spinal radiotherapy were analyzed for three patients who each had three implanted gold seeds placed near their spinal lesions before radiotherapy. At each treatment session, the registration was first performed using bony fusion and then verified by another bony fusion, followed by registration with implanted markers. The software reported the calculated shifts for both methods. In addition, the actual three-dimensional coordinate positions of the markers were read using PTDReader software. Implanted marker positions were analyzed for variations in individual maker coordinate displacement, interseed distances, and area transcribed by them. Measured positional differences between the two fusion methods were applied to actual treatment plans to assess the resulting dosimetric differences in the treatment plans. Both fusion algorithms were shown to localize the patient well, within 1.5 mm, but the implanted marker fusion consistently related less deviation from the planned isocenter, by approximately 0.5 mm, than did the bony fusion. Exceptions to this localization occurred when the average interseed distances were less than 3.0 cm and resulted in the two registration methods being equivalent. Implanted spine markers were also shown to have less than 0.7 mm deviation from the planned marker coordinates, indicating no migration of the seeds. Dose distributions were found to be highly dependant on differences in fusion method, with spinal cord doses up to 350% greater with bony fusion than with implanted markers. Implanted markers used with the Novalis Body system have been shown to be more effective in patient positioning than the bony fusion method in the thoracic spine.


Ultrasonographic description of succenturiate placenta.
Postpartum hemorrhage may occur in cases of a retained succenturiate lobe. More catastrophic is rupture of the fetal vessels connecting the lobe to the placenta. A case is presented demonstrating the sonographic description of a large succenturiate lobe.


A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci.
The hereditary disorder ataxia telangiectasia (A-T) is associated with striking cellular radiosensitivity that cannot be attributed to the characterized cell cycle checkpoint defects. By epistasis analysis, we show that ataxia telangiectasia mutated protein (ATM) and Artemis, the protein defective in patients with RS-SCID, function in a common double-strand break (DSB) repair pathway that also requires H2AX, 53BP1, Nbs1, Mre11, and DNA-PK. We show that radiation-induced Artemis hyperphosphorylation is ATM dependent. The DSB repair process requires Artemis nuclease activity and rejoins approximately 10% of radiation-induced DSBs. Our findings are consistent with a model in which ATM is required for Artemis-dependent processing of double-stranded ends with damaged termini. We demonstrate that Artemis is a downstream component of the ATM signaling pathway required uniquely for the DSB repair function but dispensable for ATM-dependent cell cycle checkpoint arrest. The significant radiosensitivity of Artemis-deficient cells demonstrates the importance of this component of DSB repair to survival.


Thematic analysis of youth mental health providers' perceptions of neuropsychological assessment services.
A growing number of quantitative studies have investigated the utility of neuropsychological assessment in mental health settings. However, to the best of our knowledge, no previous study has qualitatively explored youth mental health providers' perceptions of neuropsychological assessment services. A more in-depth understanding of the perceived advantages and barriers associated with neuropsychological assessment in youth mental health settings is critical to better inform policy, practice and service uptake. Thus, the aim of this study was to qualitatively explore clinicians' views about neuropsychological assessments for youth with mental health concerns. A single open-ended qualitative question, included as part of an anonymous cross-sectional online survey, was completed by clinicians (N = 206) treating or assessing adolescents and young adults within Australian primary care mental health centres (headspace). Responses were analysed using an inductive approach to thematic analysis. Five main themes were identified. Clinicians (a) identified barriers to accessing neuropsychological assessments (53%), (b) indicated a range of mixed outcomes following neuropsychological assessment (39%), (c) highlighted a need for neuropsychological assessments (22%), (d) reported a lack of awareness about this resource (10%) and (e) described practice issues associated with neuropsychological services (4%). This study uncovered perceived factors contributing to reduced access to neuropsychological assessment in Australian youth mental health settings. Given potential adverse outcomes resulting from this clinical service gap, efforts should be made to address factors contributing to poorer access, thereby mitigating the impact of poor access on the management of mental illness in youth. Several strategies, including funding neuropsychological assessments, are discussed.


Validation of the American Thoracic Society-Infectious Diseases Society of America guidelines for hospital-acquired pneumonia in the intensive care unit.
The 2005 guidelines of the American Thoracic Society-Infectious Diseases Society of America Guidelines for Hospital for managing hospital-acquired pneumonia classified patients according to time of onset and risk factors for potentially drug-resistant microorganisms to select the empirical antimicrobial treatment. We assessed the microbial prediction and validated the adequacy of these guidelines for antibiotic strategy. We prospectively observed 276 patients with intensive care unit-acquired pneumonia. We classified patients into group 1 (early onset without risk factors for potentially drug-resistant microorganisms; 38 patients) and group 2 (late onset or risk factors for potentially drug-resistant microorganisms; 238 patients). We determined the accuracy of guidelines to predict causative microorganisms and the influence of guidelines adherence in patients' outcome. Microbial prediction was lower in group 1 than in group 2 (12 [50%] of 24 vs 119 [92%] of 129; P < .001) mainly because of potentially drug-resistant microorganisms in 10 patients (26%) from group 1. Guideline adherence was higher in group 2 (153 [64%] vs 7 [18%]; P < .001). Guideline adherence resulted in more treatment adequacy than did nonadherence (69 [83%] vs 45 [64%]; P = .013) and a trend toward better response to empirical treatment in group 2 only but did not influence mortality. Reclassifying patients according to the risk factors for potentially drug-resistant microorganisms of the former 1996 American Thoracic Society guidelines increased microbial prediction in group 1 to 21 (88%; P = .014); all except 1 patient with potentially drug-resistant microorganisms were correctly identified by these guidelines. The 2005 guidelines predict potentially drug-resistant microorganisms worse than the 1996 guidelines. Adherence to guidelines resulted in more adequate treatment and a trend to a better clinical response in group 2, but it did not influence mortality.


[Treatment of tinnitus with iontophoresis and local anesthesia].
50 previously unsuccessfully treated patients suffering from tinnitus were given local-anaesthesia-iontophoresis. By iontophoresis it is possible to build up an electric field, in which a local anaesthetic (lidocaine hydrochloride) is able to penetrate through the tympanic membrane. Experimentally it has been proven that this local anaesthetic has a direct effect on the inner ear. In contrast to intravenous and intratympanal application there are no toxic side effects when applying local-anaesthesia-iontophoresis. Tinnitus was reduced completely or partly in 31 patients after repeated application to one or both ears. No connection was seen between the success of therapy and the origin of the tinnitus. Treatment was unsuccessful in 19 cases. No serious side effects were seen. Local-anaesthesia-iontophoresis can be recommended as an attempt to treat tinnitus, especially in those cases who have not yet responded to drugs.


High frequency optical coherence tomography assessment of homogenous neck coverage by intrasaccular devices predicts successful aneurysm occlusion.
High frequency optical coherence tomography (HF-OCT) is a novel intravascular imaging technology developed for use in the cerebral vasculature. We hypothesize that HF-OCT characterization of intrasaccular device neck coverage can prognosticate exclusion of the aneurysm from the circulation. Bifurcation and sidewall aneurysms were made in six dogs. Seven aneurysms were treated with next generation intrasaccular devices (NGID) and four with traditional platinum coils. HF-OCT was performed to interrogate gaps in the neck coverage, coil herniation, or acute thrombus formation. Animals were re-imaged at 7, 30, 90, and 180 days following aneurysm embolization. An automated image processing method segmented the devices at the neck of the aneurysm and quantified neck coverage. The largest coverage gap was used to predict aneurysm occlusion at 180 days. No difference was found in occlusion rates between the coil and NGID groups (P=0.45). Successful segmentation of the NGID construct was achieved in all cases. A coverage gap >1 mm2 was found to predict failed aneurysm occlusion (P=0.047). This threshold was able to predict all cases of failed occlusion. The average number of devices needed to treat the aneurysm was lower in the NGID group (1.9 vs 6.75, P=0.009). HF-OCT showed strong agreement with scanning electron microscopy (bias 0.0024 mm2 (95% CI -0.0279, 0.0327)). HF-OCT enables precise and accurate measurement of coverage gaps at the neck of aneurysms treated with intrasaccular devices in vivo. We provide in vivo evidence that uniform aneurysm neck coverage by intrasaccular devices is critical for aneurysm occlusion.


Intersession reliability of fMRI activation for heat pain and motor tasks.
As the practice of conducting longitudinal fMRI studies to assess mechanisms of pain-reducing interventions becomes more common, there is a great need to assess the test-retest reliability of the pain-related BOLD fMRI signal across repeated sessions. This study quantitatively evaluated the reliability of heat pain-related BOLD fMRI brain responses in healthy volunteers across 3 sessions conducted on separate days using two measures: (1) intraclass correlation coefficients (ICC) calculated based on signal amplitude and (2) spatial overlap. The ICC analysis of pain-related BOLD fMRI responses showed fair-to-moderate intersession reliability in brain areas regarded as part of the cortical pain network. Areas with the highest intersession reliability based on the ICC analysis included the anterior midcingulate cortex, anterior insula, and second somatosensory cortex. Areas with the lowest intersession reliability based on the ICC analysis also showed low spatial reliability; these regions included pregenual anterior cingulate cortex, primary somatosensory cortex, and posterior insula. Thus, this study found regional differences in pain-related BOLD fMRI response reliability, which may provide useful information to guide longitudinal pain studies. A simple motor task (finger-thumb opposition) was performed by the same subjects in the same sessions as the painful heat stimuli were delivered. Intersession reliability of fMRI activation in cortical motor areas was comparable to previously published findings for both spatial overlap and ICC measures, providing support for the validity of the analytical approach used to assess intersession reliability of pain-related fMRI activation. A secondary finding of this study is that the use of standard ICC alone as a measure of reliability may not be sufficient, as the underlying variance structure of an fMRI dataset can result in inappropriately high ICC values; a method to eliminate these false positive results was used in this study and is recommended for future studies of test-retest reliability.


Tandem action of glycosyltransferases in the maturation of vancomycin and teicoplanin aglycones: novel glycopeptides.
The glycopeptides vancomycin and teicoplanin are clinically important antibiotics. The carbohydrate portions of these molecules affect biological activity, and there is great interest in developing efficient strategies to make carbohydrate derivatives. To this end, genes encoding four glycosyltransferases, GtfB, C, D, E, were subcloned from Amycolatopsis orientalis strains that produce chloroeremomycin (GtfB, C) or vancomycin (GtfD, E) into Escherichia coli. After expression and purification, each glycosyltransferase (Gtf) was characterized for activity either with the aglycones (GtfB, E) or the glucosylated derivatives (GtfC, D) of vancomycin and teicoplanin. GtfB efficiently glucosylates vancomycin aglycone using UDP-glucose as the glycosyl donor to form desvancosaminyl-vancomycin (vancomycin pseudoaglycone), with k(cat) of 17 min(-1), but has very low glucosylation activity, < or = 0.3 min(-1), for an alternate substrate, teicoplanin aglycone. In contrast, GtfE is much more efficient at glucosylating both its natural substrate, vancomycin aglycone (k(cat) = 60 min(-1)), and an unnatural substrate, teicoplanin aglycone (k(cat) = 20 min(-1)). To test the addition of the 4-epi-vancosamine moiety by GtfC and GtfD, synthesis of UDP-beta-L-4-epi-vancosamine was undertaken. This NDP-sugar served as a substrate for both GtfC and GtfD in the presence of vancomycin pseudoaglycone (GtfC and GtfD) or the glucosylated teicoplanin scaffold, 7 (GtfD). The GtfC product was the 4-epi-vancosaminyl form of vancomycin. Remarkably, GtfD was able to utilize both an unnatural acceptor, 7, and an unnatural nucleotide sugar donor, UDP-4-epi-vancosamine, to synthesize a novel hybrid teicoplanin/vancomycin glycopeptide. These results establish the enzymatic activity of these four Gtfs, begin to probe substrate specificity, and illustrate how they can be utilized to make variant sugar forms of both the vancomycin and the teicoplanin class of glycopeptide antibiotics.


[Health behavior of smokers--results of the TACOS (Transitions in Alcohol Consumption and Smoking) Study].
The German TACOS Project (Transitions in Alcohol Consumption and Smoking) provided an opportunity to examine the patterns of health behaviours (nutrition, physical activity, alcohol consumption) of current smokers, ex-smokers and non-smokers with special regard to different degrees of severity of nicotine dependence. Data were collected in the adult general population of Lübeck and 46 surrounding communities, resulting in a representative sample of 4075 individuals. In this sample, 37.3% were current smokers, 22.5% were ex-smokers, 25.0% of smokers were severely nicotine-dependent. As in other empirical investigations, current smokers had an unhealthy lifestyle in general. Smokers compared to ex-smokers and non-smokers consumed unhealthy foods more frequently, reported less physical activity and were more likely to consume hazardous levels of alcohol. Special attention was paid to comparing different degrees of severity of nicotine dependence. A high degree of nicotine dependence was associated with poor health behaviours. Data show that smoking, unhealthy nutrition, lack of physical activity, and hazardous levels of alcohol consumption occur in combination and that unhealthy behaviour patterns vary according to the severity of nicotine dependence. The presence of multiple unhealthy behaviours requires special secondary preventive interventions for smokers. The association of these combined health hazards must be controlled in determining the independent health risk due to one of these factors.


Personalized evolutionary hypothesis in genomics and auxiliary lymph node through diverse subtelomeric signal profile.
Few available data on the genomic-somatic evolution in breast cancer create limitation to provide the appropriate clinical managements. As an example, human subtelomeres (ST) are diverse-prone and variable targets. STs, as hot spots, have positive and negative impacts on the status of health and malady. We showed higher subtelomere signal copy number (SCN) of specific chromosomes in genomics than in auxiliary lymph node (ALN). Dissimilarity of signal intensity (SI) is found for all chromosomes. Significantly higher SI in genomics than in ALN cells were specified as chromosomes 5, 6, 9-12, 16-19 for weak; 1, 5-9, 19, X for medium; and 2, 5, 9, 10, 16, 18 for strong SI. For lacking, and presence of one and two SCNs; p/q ratio reflected differences for all chromosomes; but, 2, 3, 5, 7, 8, 10, 16, 18, 20, and X chromosomes were involved for three SCN. Chromosomes 1, 4, 9, 12, 17-19 lacked three SCN in ALN and lymphocytes. Weak SI ratio was higher in p- than in q-arm in majority of chromosomes. Manner of evolution and diversity in p- and q-arms is expressive of a novel definition as two diverse domains with a personalized insight. These data have been accompanied by periodic charts as ST array profiles which provide specific and individualized pattern in breast neoplasm. Such profiling at genomics level could be considered as a prediction through the patients' life. Moreover, subtelomere territory by interacting with protein expression of Ki67, cyclin D1, and cyclin E; and molecular targets including telomere length at genomics and somatic level provides package of information to bridge cancer cell biology to the cancer clinic as "puzzling paradigm."


Coordination dynamics of large-scale neural circuitry underlying rhythmic sensorimotor behavior.
In coordination dynamics, rate is a nonspecific control parameter that alters the stability of behavioral patterns and leads to spontaneous pattern switching. We used fMRI in conjunction with measures of effective connectivity to investigate the neural basis of behavioral dynamics by examining two coordination patterns known to be differentially stable (synchronization and syncopation) across a range of rates (0.75 to 1.75 Hz). Activity in primary auditory and motor cortices increased linearly with rate, independent of coordination pattern. On the contrary, activity in a premotor-cerebellar circuit varied directly with the stability of the collective variable (relative phase) that specifies coordinated behavioral patterns. Connectivity between premotor and motor cortices was also modulated by the stability of the behavioral pattern indicative of greater reliance on sensorimotor integration as action becomes more variable. By establishing a critical connection between behavioral and large scale brain dynamics, these findings reveal a basic principle for the neural organization underlying coordinated action.


The Added Value of Patch Testing Beyond the Baseline Tray.
The patch test is the standard for diagnosing allergic contact dermatitis. Standardized trays allow the examination of the most prevalent allergens, whereas customized trays are more appropriate for addressing specific allergens and require expertise. They are therefore usually performed in specialized clinics. We assessed the results of 4355 patch tests performed between 2012 and 2020 in a contact dermatitis clinic located in a large tertiary medical center. All patients were tested using the European baseline series and additional trays as clinically indicated. We assessed the frequency of relevant positive reactions outside the European baseline series. We then examined the added value and number of tests (NNTs) that need to be performed to elicit one relevant positive reaction per tray and common allergens. Nine hundred fifty-four patients (21.9%) had 1 or more positive relevant reactions; 43.3% tested positive for an allergen outside the European baseline series (OEBS). The acrylate and fragrance trays were highly represented among the positive and relevant reactions OEBS with NNTs of 4.4 and 6.8, respectively. 2-Hydroxyethyl methacrylate is the most prevalent allergen OEBS and is considered a marker for acrylate sensitivity with a high rate of cross-reactions and concordance rate of 85%, justifying its addition to the EBS in 2018. Other highly represented allergens include chloramphenicol, 2-hydroxyethyl acrylate, and Amerchol L-101, a lanolin derivative. The cosmetics and textile trays, although often tested, have relatively low added values of 3.7% and 2.3%, respectively. Surprisingly, the cutaneous adverse drug reaction series tray (CAD-1000) yielded no positive reactions, whereas testing the patients' medication yielded positive results in 10.9% of the cases. Expanded patch testing is crucial to accurately diagnose allergic contact dermatitis and almost doubles the number of patients with relevant positive reactions. Acrylate sensitivity is an emerging epidemic with a high positive reaction rate and low NNT, as is sensitivity to the allergens in the fragrance tray. 2-Hydroxyethyl methacrylate is a reliable marker for acrylate sensitivity with a concordance rate of 85%. Chloramphenicol is a common culprit and should be added to the standard tray in countries with a high usage rate. A low NNT was also observed when testing the patients' own cosmetics and medications; this should, therefore, be encouraged. The textile tray yielded a relatively high NNT; however, it should be performed when clinically indicated in the absence of a reliable marker in the EBS.


[Induction of microsomal cytochromes in the rat liver after intravenous administration of emulsions of perfluoro-organic compounds].
Intravenous injections of perfluoroorganic emulsions to rats in a dose of 3 ml/kg led to changes in the composition and activity of enzymes of the liver microsomal membrane monooxygenase system. At the peak of induction, i. e., on the 3rd post-injection day, the levels of microsomal cytochromes P-450 and b5 increased 2.8- and 1.9-fold, respectively, as compared to the control. Simultaneously, the rate of NADPH oxidation in the microsomes and the rate of hydroxylation of substrates I and II showed an increase. Conversely, the rate of NADPH-dependent peroxidation of microsomal lipids on the 2nd-4th post-injection days reached its minimal values. These injections stimulated the detoxicating function of rat liver as evidenced from the duration of the hexenal sleep of the animals. All the changes in the monooxygenase system parameters were temporary and reached the control level on the 10th-14th days after injection. It was demonstrated that the main component of the perfluoroorganic emulsions, perfluorodecalin, was responsible for the induction of the monooxygenase system enzymes.


Mapping functional domains of colicin M.
Colicin M (Cma) lyses Escherichia coli cells by inhibiting murein biosynthesis through hydrolysis of the phosphate ester between C(55)-polyisoprenol and N-acetylmuramyl (MurNAc)-pentapeptide-GlcNAc in the periplasm. To identify Cma functional domains, we isolated 54 point mutants and small deletion mutants and examined their cytotoxicity levels. Activity and uptake mutants were distinguished by osmotic shock, which transfers Cma into the periplasm independent of the specific FhuA receptor and the Ton system. Deletion of the hydrophobic helix α1, which extends from the compact Cma structure, abolished interference with the antibiotic albomycin, which is transported across the outer membrane by the same system as Cma, thereby identifying α1 as the Cma site that binds to FhuA. Deletion of the C-terminal Lys-Arg strongly reduced Cma translocation across the outer membrane after binding to FhuA. Conversion of Asp226 to Glu, Asn, or Ala inactivated Cma. Asp226 is exposed at the Cma surface and is surrounded by Asp225, Asp229, His235, Tyr228, and Arg236; replacement of each with alanine inactivated Cma. We propose that Asp226 directly participates in phosphate ester hydrolysis and that the surrounding residues contribute to the active site. These residues are strongly conserved in Cma-like proteins of other species. Replacement of other conserved residues with alanine inactivated Cma; these mutations probably altered the Cma structure, as particularly apparent for mutants in the unique open β-barrel of Cma, which were isolated in lower yields. Our results identify regions in Cma responsible for uptake and activity and support the concept of a three-domain arrangement of Cma.


Molecular materials as interfacial layers and additives in perovskite solar cells.
Solar cells based on organo-metal halide perovskites have gained unprecedented research interest over the last few years due to their low-cost solution processability, high power conversion efficiency, which has recently reached a certified value of 25.2%, and abundance of raw materials. Nevertheless, the best efficiencies remain below the Shockley-Queisser theoretical limit of 32.5% due to several losses arising from either defect traps present in the bulk of the perovskite absorber or at the device heterointerfaces. While bulk defects are detrimental for the device performance by mainly limiting the open circuit voltage, interfacial layers are also crucial. They dictate the charge transfer/transport from the perovskite layer to the collecting electrodes, hence influencing the device photocurrent, but also act as protective barriers against oxygen and moisture penetration. Molecular materials and additives are widely used to improve the bulk properties of perovskite absorbers through the formation of high-quality perovskite films with superior optoelectronic properties, and improved crystallinity, and also of electronically clean interfaces with minimum losses during charge transfer/transport. In this review, we analyze the predominant pathways that contribute to voltage and current losses due to poor interfaces and also due to non-radiative recombination losses arising from inferior perovskite morphology and its inherent polycrystalline and highly defective nature. We then discuss strategies for achieving interfacial organic and inorganic molecular materials for application as electron and hole transport layers in perovskite solar cells with ideal energy levels, high charge mobilities and improved thermal, photo, and structural stability. Moreover, the prerequisites for molecular additives to achieve dimensionality engineering, defect passivation, molecular cross-linking, interfacial energy alignment and electronic doping are thoroughly discussed. Finally, we examine prospects for future research directions and commercialization.


Comparison of compound and cross-modal training on postoperative visual relearning of visual decorticate rats.
The effects of postoperative bimodal compound conditioning and cross-modal transfer of learning on behavior were compared by training rats prior to visual decortication to avoid shock with visual intensity cues. On Postop Day 6, rats were given avoidance training in one of three cue conditions: auditory intensity cues (cross-modal), paired auditory and visual cues (compound conditioning), or no cues (no-training control). On Postop Day 7 rats in the no-training control and the cross-modal transfer conditions were retrained with the visual discrimination while rats in the compound conditioning group were either retrained with the visual intensity cue or trained with the auditory intensity cue. Postoperative cross-modal transfer training enhanced visual relearning whereas bimodal compound conditioning interfered with relearning. However, compound conditioning facilitated subsequent auditory discrimination learning. These results support the notion of an injury-induced neurological bias that is increased after bimodal compound conditioning and reduced after cross-modal training. Potential implications for neurological rehabilitation are also discussed.


Altered activity in the hippocampus is more detrimental to classical conditioning than removing the structure.
Hippocampal ablation has no effect on the acquisition of the rabbit's classically conditioned nictitating membrane response. Systemic administration of scopolamine, which alters hippocampal neuronal activity, severely retards acquisition of the conditioned response in normal animals and those with cortical ablations. In animals with hippocampal ablations, however, scopolamine has no effect on conditioning. These findings suggest that altered neuronal activity in the hippocampus is more detrimental to conditioning than removing the structure.


[Thoracic diagnostic requirements of an intensive care unit from the anesthesiology viewpoint].
Diagnostic procedures of the thorax in intensive-care units are conventional x-ray chest images, chest images by digital luminescence radiography, sonography and transoesophageal Doppler echocardiography. In addition to these bedside methods the stationary usable techniques, such as computed tomography, digital subtraction angiography and the seldom in intensive care patients used computed nuclear spin resonance tomography (NMR) are applicable. The selection of the above mentioned techniques depends on the availability and the quality of the methods as well as the qualifications of the involved staff. The diagnostic procedures of the chest must be arranged depending on the decision if patients have to be transported or not. In conclusion it can be stated that in spite of growing technical preconditions the availability of the methods in immobile patients and the diagnostic potency of the techniques have to be examined.


Kestel: an early bronze age source of tin ore in the taurus mountains, Turkey.
An ancient mine located at Kestel on the outskirts of Nigde, in the Taurus Mountains of south central Turkey, has been dated by radiocarbon and pottery type to the third millennium B.C. Archeological soundings in the mine located cassiterite (tin oxide) in the detritus of ancient mining activity. Cassiterite is also present in veins and, as placer deposits, in streams nearby. Since tin is used with copper in order to form bronze but is thinly distributed in the earth's crust, the presence of tin ore at Kestel offers a source for the much sought after tin of the Bronze Age. The discovery of an ancient mine containing cassiterite sheds light on this question, but also greatly complicates the accepted picture of regional economic patterns in the highland resource areas of Anatolia and of interregional metal exchange in the formative periods of urbanization and metal use in the eastern Mediterranean.


The importance of nutritional factors and dietary management of Hashimoto's thyroiditis.
Hashimoto (HT) is an autoimmune disease in which destruction of the thyroid occurs as a result of lymphocyte infiltration. It is caused by an increased level of titers of antibody against thyroid peroxidase (TPO) and thyroglobulin (TG). Because of that,in HT patients, changes are observed in the level and metabolism of thyroid hormones, which leads to unspecified physical and psychological symptoms. A high level of antibodies attacking thyroid antigens has been positively correlated with the symptoms. From the etiological point of view, the most important are genetic factors; however, environmental factors are necessary to provoke the immune system to attack until the process is over. Scientists indicate specified stress, toxification, microbiota dysbiosis and under- or over-nutrition, to name only a few. Dietotherapy of Hashimoto's is based on the proper nourishment of the body and regulation of the immune system by an anti-inflammatory diet. Observational and controlled trials have shown frequent nutrition deficiencies in HT patients. In literature, there is evidence for selenium, potassium, iodine, copper, magnesium, zinc, iron, vitamin A, C, D and B. The role of the proper level of protein intake, dietary fibre and unsaturated fatty acids, especially the n-3 family, has been indicated. HT patients should often eliminate lactose because of intolerance and interactions with levothyroxine and gluten because of possible interactions of gliadin with thyroid antigens. The article describes the nutrition factors of HT patients, and share nutrition recommendations for diet therapy.


Adenoid cystic carcinoma of Bartholin's Gland. Case report with review of the literature.
Adenoid cystic carcinoma of Bartholin's gland is characterized by slow growth, local invasion, and sometimes distant metastasis. There is no consensus regarding the optimal treatment. We report herein a rare case of stage II adenoid cystic carcinoma of Bartholin's gland that was successfully treated by wide local excision of the tumor and ipsilateral inguinal and pelvic lymphadenectomy. A 54-year-old Japanese woman was admitted complaining of painless, gradually increasing vulvar mass existing from ten years before. Local examination revealed a 3 x 2-cm hard mass in the left labium major. Pathological examination of subsequent excisional biopsy revealed adenoid cystic carcinoma originating in the Bartholin's gland. A wide local resection of the tumor with inguinal and pelvic lymphadenectomy was performed. The tumor was completely excised with free margins. There was no metastasis in the resected lymph nodes. The patient was diagnosed as having stage II vulvar cancer according to the International Federation of Gynecologists and Obstetricians classification (1988). The patient is now healthy without evidence of recurrence at 5 years after surgery. Adenoid cystic carcinoma of Bartholin's cyst at early stage can be treated by wide local excision as a primary surgery.


Results of a Community-based, Randomized Study Comparing a Clear Liquid Diet With a Low-residue Diet Using a Magnesium Citrate Preparation for Screening and Surveillance Colonoscopies.
Current bowel preparations for colonoscopy include a clear liquid diet (CLD) along with consumption of a laxative. This dietary restriction along with large volume bowel preparations are barriers to compliance and willingness among patients in scheduling screening examinations. The aim of our study was to compare the efficacy and tolerability of a low-volume split dose magnesium citrate bowel preparation in patients on a low-residue diet (LRD) with those on a CLD. In this single center, single blinded, randomized controlled trial, patients scheduled for outpatient colonoscopies were assigned to either a CLD or a LRD 1 day before the examination. Both groups received a split dose magnesium citrate preparation. The quality of the preparation was rated using the Boston Bowel Preparation Scale (BBPS). Patient satisfaction and side effects were evaluated using a questionnaire. We were unable to detect a significant difference in the BBPS scores between the LRD and CLD groups (P=0.581). A significantly higher percentage of patients in the LRD group rated the diet as easy compared with the CLD group (P<0.001). Satisfaction scores were significantly higher in the LRD group, compared with the CLD group (P<0.001). The side effect profiles of both arms were similar. There was no significant difference between LRD and CLD in patients using a magnesium citrate bowel preparation for screening and surveillance colonoscopies. Patient satisfaction scores were higher with a LRD compared with a CLD. We believe the LRD should be the recommended diet in patients using a standard bowel preparation for screening and surveillance colonoscopy.


Communication of health risk in substance-dependent populations: A systematic review of randomised controlled trials.
Individuals with substance use problems are at greater risk of chronic diseases due to their unhealthy lifestyle behaviours (e.g. alcohol use, smoking, physical inactivity, poor nutrition). There is increasing evidence that health risk communication is crucial in improving risk perception and knowledge of chronic diseases, and both factors are associated with health behaviour change. The aim of this systematic review is to provide a comprehensive overview of the current state of evidence on health risk communication on people with substance use problems. A systematic search identified peer reviewed studies from the databases MEDLINE, PsycINFO, CINAHL and Scopus. Data were extracted from the included studies and a narrative synthesis of the results was conducted. Eight articles, representing five unique studies, were included in the review. The overall risk of bias of the included studies was considered to be low. The studies evaluated the use of message framing and personalised/customised recommendations across smoking cessation and patient engagement with methadone maintenance treatment. Results revealed that message framing, specifically gain-framed messages, had a positive impact on smoking cessation. Risk perception, sex and level of nicotine dependence were also found to be associated with smoking cessation. The limited number of studies provides preliminary evidence that health risk communication promotes smoking cessation. However, studies included in the review were characterised by heterogeneous methods and measures. Further investigation of health risk communication using adequately powered randomised controlled trial is warranted.


High throughput heme assay by detection of chemiluminescence of reconstituted horseradish peroxidase.
In living organisms, heme is an essential molecule for various biological functions. Recent studies also suggest that heme functions as organelle-derived signal that regulates fundamental cell processes. Furthermore, estimation of heme is widely used for studying various blood disorders. In this regard, development of a rapid, sensitive, and high throughput heme assay has been sought. The most frequently used method of measuring heme by pyridine hemochrome is time, labor, and material intensive, and therefore limiting in its utility for large scale, high throughput analysis. Recently, we reported alternative method that is sensitive and specific to heme, which is based on the ability of horseradish peroxidase (HRP) apo-enzyme to reconstitute with heme to form an active holo-enzyme. Here, we developed high throughput heme assay by performing reactions on multi-well plate with highly sensitive chemiluminescence detection reagents. Detection of chemiluminescence in charged coupled device (CCD)-based gel doc apparatus enables simultaneous measurement of multiple samples. Furthermore, the high sensitivity of this assay allowed a direct measurement of heme in solvent extracts after dilution. This assay is sensitive, quick, provides a large dynamic range, and is well suited for large-scale analysis of heme extracted from minute amount of samples.


Clinical Value of Hybrid TOF-PET/MR Imaging-Based Multiparametric Imaging in Localizing Seizure Focus in Patients with MRI-Negative Temporal Lobe Epilepsy.
Temporal lobe epilepsy is the most common type of epilepsy. Early surgical treatment is superior to prolonged medical therapy in refractory temporal lobe epilepsy. Successful surgical operations depend on the correct localization of the epileptogenic zone. This study aimed to evaluate the clinical value of hybrid TOF-PET/MR imaging-based multiparametric imaging in localizing the epileptogenic zone in patients with MR imaging-negative for temporal lobe epilepsy. Twenty patients with MR imaging-negative temporal lobe epilepsy who underwent preoperative evaluation and 10 healthy controls were scanned using PET/MR imaging with simultaneous acquisition of PET and arterial spin-labeling. On the basis of the standardized uptake value and cerebral blood flow, receiver operating characteristic analysis and a logistic regression model were used to evaluate the predictive value for the localization. Statistical analyses were performed using statistical parametric mapping. The values of the standardized uptake value and cerebral blood flow, as well as the asymmetries of metabolism and perfusion, were compared between the 2 groups. Histopathologic findings were used as the criterion standard. Complete concordance was noted in lateralization and localization among the PET, arterial spin-labeling, and histopathologic findings in 12/20 patients based on visual assessment. Concordance with histopathologic findings was also obtained for the remaining 8 patients based on the complementary PET and arterial spin-labeling information. Receiver operating characteristic analysis showed that the sensitivity and specificity of PET, arterial spin-labeling, and combined PET and arterial spin-labeling were 100% and 81.8%, 83.3% and 54.5%, and 100% and 90.9%, respectively. When we compared the metabolic abnormalities in patients with those in healthy controls, hypometabolism was detected in the middle temporal gyrus (P < .001). Metabolism and perfusion asymmetries were also located in the temporal lobe (P < .001). PET/MR imaging-based multiparametric imaging involving arterial spin-labeling may increase the clinical value of localizing the epileptogenic zone by providing concordant and complementary information in patients with MR imaging-negative temporal lobe epilepsy.


Protein arginine deiminase 4 inhibition is sufficient for the amelioration of collagen-induced arthritis.
Citrullination of joint proteins by the protein arginine deiminase (PAD) family of enzymes is recognized increasingly as a key process in the pathogenesis of rheumatoid arthritis. This present study was undertaken to explore the efficacy of a novel PAD4-selective inhibitor, GSK199, in the murine collagen-induced arthritis model of rheumatoid arthritis. Mice were dosed daily from the time of collagen immunization with GSK199. Efficacy was assessed against a wide range of end-points, including clinical disease scores, joint histology and immunohistochemistry, serum and joint citrulline levels and quantification of synovial autoantibodies using a proteomic array containing joint peptides. Administration of GSK199 at 30 mg/kg led to significant effects on arthritis, assessed both by global clinical disease activity and by histological analyses of synovial inflammation, pannus formation and damage to cartilage and bone. In addition, significant decreases in complement C3 deposition in both synovium and cartilage were observed robustly with GSK199 at 10 mg/kg. Neither the total levels of citrulline measurable in joint and serum, nor levels of circulating collagen antibodies, were affected significantly by treatment with GSK199 at any dose level. In contrast, a subset of serum antibodies reactive against citrullinated and non-citrullinated joint peptides were reduced with GSK199 treatment. These data extend our previous demonstration of efficacy with the pan-PAD inhibitor Cl-amidine and demonstrate robustly that PAD4 inhibition alone is sufficient to block murine arthritis clinical and histopathological end-points.


Gene expression and fast construction of distributed evolutionary representation.
The gene expression process in nature produces different proteins in different cells from different portions of the DNA. Since proteins control almost every important activity in a living organism, at an abstract level, gene expression can be viewed as a process that evaluates the merit or "fitness" of the DNA. This distributed evaluation of the DNA would not be possible without a decomposed representation of the fitness function defined over the DNAs. This paper argues that, unless the living body was provided with such a representation, we have every reason to believe that it must have an efficient mechanism to construct this distributed representation. This paper demonstrates polynomial-time computability of such a representation by proposing a class of efficient algorithms. The main contribution of this paper is two-fold. On the algorithmic side, it offers a way to scale up evolutionary search by detecting the underlying structure of the search space. On the biological side, it proves that the distributed representation of the evolutionary fitness function in gene expression can be computed in polynomial-time. It advances our understanding about the representation construction in gene expression from the perspective of computing. It also presents experimental results supporting the theoretical performance of the proposed algorithms.


Pioneer growth cone morphologies reveal proximal increases in substrate affinity within leg segments of grasshopper embryos.
We have compared the morphologies of approximately 5000 antibody-labeled afferent pioneer growth cones fixed at various stages of growth along their characteristic path over the epithelium in the legs of grasshopper embryos, and have used growth cone morphology as an indicator of differences in the affinity of the epithelial substrate for pioneer growth cones in vivo. Growth cone morphologies differ markedly between different locations in limb buds, and also in the same location in limbs at different stages of differentiation. Growth cones characteristically extend branches and lamellae circumferentially along segment boundaries, and filopodia and lamellae are retained (or extended) longer there. Where they contact a relatively well-differentiated segment boundary, the growth cones also abruptly reorient circumferentially. In the proximal regions of limb segments, growth cones consistently have a high degree of branching and lamellae; previously formed axons also extend secondary branches and spread there as development progresses. Low incidence of these morphologies is observed at all stages in the distal regions of limb segments. Thus, neuronal morphologies correlate both spatially and temporally with the differentiation of limb segmentation. These results suggest the following: Detailed growth cone morphology is a reliable indicator of differences in extrinsic guidance cues. The affinity of the epithelial substrate for afferent pioneer growth cones increases proximally within segments, with a peak at the segment boundary. (This affinity could be based on surface density of adhesion molecules or on nonadhesive molecules that actively regulate growth cone extension.) Increasing epithelial affinity within segments appears to act as a proximal guidance cue for afferent pioneer growth cones. Pioneer growth cones are observed to navigate proximally in circumstances where proximally located guidepost cells differentiate too late to guide them.


Nonspecific alpha-naphthyl acetate esterase activity of T-lymphocytes: study in healthy newborns and children, in immune deficiencies and juvenile rheumatoid arthritis.
The aim of this study was to compare the E rosette-forming cells and nonspecific alpha naphthyl esterase (ANAE)-positive lymphocyte values in normal and pathologic situations. In newborns, the ANAE-positive lymphocytes represented less than 60% of the E rosette population. During the first year of life, E rosette-forming cells (E-RFC) reached normal values as soon as one month whereas only three-fourths of the T cells exhibited an ANAE-positive staining. In adult T cell populations, nearly 90% were ANAE-positive. Our observations of immune deficiencies suggested that the relative proportions of E-RFC and ANAE-positive lymphocytes were generally comparable to normal values. However, in the majority of the patients with very low or absent E-RFC (severe combined immune deficiencies, Di George syndrome, and congenital rubella), some ANAE-positive lymphocytes could be detected. Our immunologic survey shows that the ANAE-positive lymphocytes were in a normal range 2 years after a bone marrow transplantation in severe combined immune deficiencies patients. One child who exhibited a normal amount of E-RFC and whose lymphocytes failed to respond in vitro to mitogens had practically no ANAE-positive lymphocytes. An elevated amount of ANAE-positive cells in juvenile rheumatoid arthritis may reflect an augmentation of the T helper functions which permanently stimulated in vivo immunoglobulin production.


Lactose malabsorption in recurrent abdominal pain of childhood.
In order to evaluate the role of lactose malabsorption in children with recurrent abdominal pain, we performed a prospective controlled double-blinded study in 40 children with RAP of at least three months' duration. Children were studied for lactose malabsorption by breath hydrogen determinations after ingestion of lactose (2 gm/kg of body weight; maximum 50 gm). Lactose malabsorbers were retested with 12.5 gm lactose; lactose absorbers were retested with lactose for ability to produce hydrogen. All children underwent a dietary trial which included two lactose elimination periods. Although 12 children (30%) were lactose malabsorbers, only three malabsorbed part of the smaller, more physiologic, lactose load. Improvement rates of lactose malabsorbers and absorbers during lactose elimination were not significantly different as judged by their physicians and as determined by a 50% or more decrease in pain frequency. These results suggest that lactose malabsorption is of little importance in children with RAP.


Role of Organic Solute Transporter Alpha/Beta in Hepatotoxic Bile Acid Transport and Drug Interactions.
Organic solute transporter (OST) α/β is a key bile acid transporter expressed in various organs, including the liver under cholestatic conditions. However, little is known about the involvement of OSTα/β in bile acid-mediated drug-induced liver injury (DILI), a major safety concern in drug development. This study investigated whether OSTα/β preferentially transports more hepatotoxic, conjugated, primary bile acids and to what extent xenobiotics inhibit this transport. Kinetic studies with OSTα/β-overexpressing cells revealed that OSTα/β preferentially transported bile acids in the following order: taurochenodeoxycholate > glycochenodeoxycholate > taurocholate > glycocholate. The apparent half-maximal inhibitory concentrations for OSTα/β-mediated bile acid (5 µM) transport inhibition by fidaxomicin, troglitazone sulfate, and ethinyl estradiol were: 210, 334, and 1050 µM, respectively, for taurochenodeoxycholate; 97.6, 333, and 337 µM, respectively, for glycochenodeoxycholate; 140, 265, and 527 µM, respectively, for taurocholate; 59.8, 102, and 117 µM, respectively, for glycocholate. The potential role of OSTα/β in hepatocellular glycine-conjugated bile acid accumulation and cholestatic DILI was evaluated using sandwich-cultured human hepatocytes (SCHH). Treatment of SCHH with the farnesoid X receptor agonist chenodeoxycholate (100 µM) resulted in substantial OSTα/β induction, among other proteomic alterations, reducing glycochenodeoxycholate and glycocholate accumulation in cells+bile 4.0- and 4.5-fold, respectively. Treatment of SCHH with troglitazone and fidaxomicin together under cholestatic conditions resulted in increased hepatocellular toxicity compared with either compound alone, suggesting that OSTα/β inhibition may accentuate DILI. In conclusion, this study provides insights into the role of OSTα/β in preferential disposition of bile acids associated with hepatotoxicity, the impact of xenobiotics on OSTα/β-mediated bile acid transport, and the role of this transporter in SCHH and cholestatic DILI.


Deeply conserved synteny resolves early events in vertebrate evolution.
Although it is widely believed that early vertebrate evolution was shaped by ancient whole-genome duplications, the number, timing and mechanism of these events remain elusive. Here, we infer the history of vertebrates through genomic comparisons with a new chromosome-scale sequence of the invertebrate chordate amphioxus. We show how the karyotypes of amphioxus and diverse vertebrates are derived from 17 ancestral chordate linkage groups (and 19 ancestral bilaterian groups) by fusion, rearrangement and duplication. We resolve two distinct ancient duplications based on patterns of chromosomal conserved synteny. All extant vertebrates share the first duplication, which occurred in the mid/late Cambrian by autotetraploidization (that is, direct genome doubling). In contrast, the second duplication is found only in jawed vertebrates and occurred in the mid-late Ordovician by allotetraploidization (that is, genome duplication following interspecific hybridization) from two now-extinct progenitors. This complex genomic history parallels the diversification of vertebrate lineages in the fossil record.


Effect of beer drinking on ultrasound bone mass in women.
To study the effect of beer consumption on bone mass in a group of healthy women, by using phalangeal bone ultrasound to evaluate the amplitude-dependent speed of sound. This was a cross-sectional study of 1697 healthy women (mean age 48.4 y, body mass index (BMI) 19.0-32.0 kg/m(2)), recruited in a clinical convenience sample and screened for the existence of disease and/or medication that would affect calcium metabolism. Of this total, 710 were premenopausal, 176 were perimenopausal, and 811 were postmenopausal. The women recruited completed a questionnaire that contained detailed sections on current cigarette, alcohol, caffeine, and nutrient consumption. In terms of current alcohol intake, the subjects were classified as moderate drinkers, light drinkers, and nondrinkers. Drinkers were also analyzed according to the kind of alcohol consumed: wine or beer. Quantitative bone ultrasound values were greater in the beer drinkers compared with the no beer and/or wine drinkers. Taking the amplitude-dependent speed of sound as a dependent variable, and age, BMI, gonadal status, intake of beer and wine, and number of cigarettes per day as independent variables, we found age (beta = -1.52), BMI (beta = -3.86), gonadal status (beta = -27.47), and beer intake (beta = 1.06) to be significant. The greater bone density found in women beer drinkers might be a result of the phytoestrogen content of this alcoholic drink; this requires further investigation.


A study of the dengue epidemic and meteorological factors in Guangzhou, China, by using a zero-inflated Poisson regression model.
The aim of this study is to develop a model that correctly identifies and quantifies the relationship between dengue and meteorological factors in Guangzhou, China. By cross-correlation analysis, meteorological variables and their lag effects were determined. According to the epidemic characteristics of dengue in Guangzhou, those statistically significant variables were modeled by a zero-inflated Poisson regression model. The number of dengue cases and minimum temperature at 1-month lag, along with average relative humidity at 0- to 1-month lag were all positively correlated with the prevalence of dengue fever, whereas wind velocity and temperature in the same month along with rainfall at 2 months' lag showed negative association with dengue incidence. Minimum temperature at 1-month lag and wind velocity in the same month had a greater impact on the dengue epidemic than other variables in Guangzhou.


Preparation of H1N1 microneedles by a low-temperature process without a stabilizer.
During the manufacture of H1N1 microneedles, a stabilizer is usually added to maintain the antigenicity of the vaccine. However, finding a suitable stabilizer is difficult, and the addition of a stabilizer can limit the antigen dose and the addition of an adjuvant because of the limited volume of the microneedles. In this study, the authors evaluated whether H1N1 microneedles could be fabricated without a stabilizer by keeping the production environment at a low temperature. H1N1 microneedle patches without a stabilizer were prepared in a process that involved maintaining a low temperature of 10 °C. The protective immune response to this method of drug application was investigated by comparing it with traditional intramuscular (IM) immunization and with the use of H1N1 microneedles with a stabilizer. A process-sensitive antigen, H1N1, was stabilized without the use of a stabilizer in a process that maintained a low temperature of 10 °C. The preparation process consisted of coating and drying processes. In animal experiments, mice were immunized using an array of low-temperature H1N1 microneedles without a stabilizer (LT-MN), and they showed strong antibody responses. Compared to three other application methods of traditional IM immunization, low-temperature H1N1 microneedles with a stabilizer (LT-MN-T), and room-temperature H1N1 microneedles with a stabilizer (RT-MN-T), LT-MN produced comparable results in inducing protective immunity. A plaque reduction neutralization test found that LT-MN and LT-MN-T provided greater immunity compared with IM and RT-MN-T. A process in which the temperature is maintained at 10 °C can provide successful vaccination with H1N1 microneedles without the addition of a stabilizer. This process can be applied to various temperature-sensitive biologics.


Crystal Chemistry of Silicon--Oxygen Bonds at High Pressure: Implications for the Earth's Mantle Mineralogy.
Transformations involving a change from tetrahedrally coordinated to octahedrally coordinated silicon ((IV)Si --> (VI)Si) are observed to occur at high pressure when the mean (IV)Si-O bond compresses to approximately 1.59 angstroms based on known room-pressure crystal structures, Si-O bond compressibilities, and pressures of (IV)Si --> (VI)Si transformations. The lower two-thirds of the mantle transition zone of high-density gradient (500 to 900 kilometers) corresponds to the predicted range of (IV)Si --> (VI)Si transformations. The 10 percent density increase of this zone at zero pressure is attributed primarily to the density increase associated with the change in silicon coordination. Below 900 kilometers all silicon is predicted to be in octahedral or greater coordination. The concept of cation polyhedral stability fields is defined.