Mechanisms of anemia in SHP-1 protein tyrosine phosphatase-deficient "viable motheaten" mice.
Viable motheaten mice (abbreviated gene symbol me(v)) are deficient in SHP-1, a critical negative regulator of signal transduction in hematopoietic cells. These mice exhibit severe immune dysfunction accompanied by hyperproliferation of myeloid cells, widespread inflammatory lesions, and regenerative anemia. The aim of this study was to investigate the mechanisms underlying anemia in me(v)/me(v) mice. Multiple hematologic parameters, osmotic fragility, and erythropoietin levels were measured to characterize the anemia in me(v)/me(v) mice. B-cell-deficient me(v)/me(v) Igh-6(null) mice were generated to assess the role of anti-erythrocyte antibodies. Coombs assays and flow cytometry were carried out for detection of anti-erythrocyte antibodies. Oxidant production by macrophages, glutathione levels, and lipid peroxidation products in erythrocytes were measured, as was the impact of oxidant on the ultrastructure of me(v)/me(v) erythrocytes. Erythroid maturation and erythrocyte plasma membrane integrity were assessed with flow cytometry by evaluating CD71 expression and annexin V labeling. The regenerative anemia of me(v)/me(v) mice was associated with erythrocyte changes that were independent of the presence of anti-erythrocyte antibodies. Erythrocytes from me(v)/me(v) mice had increased fragility and heightened susceptibility to oxidant damage. Macrophages from me(v)/me(v) mice demonstrated a higher basal level of oxidant production and enhanced production after stimulation. Oxidant damage in me(v)/me(v) erythrocytes was evidenced by a significant elevation of lipid peroxidation and diminished levels of glutathione. Our results support the hypothesis that as a consequence of severe inflammatory disease, me(v)/me(v) erythrocytes are subject to exceptionally high oxidative stress resulting in oxidation of phospholipids in the erythrocyte membrane with subsequent hemolysis.


INTERNAL LIMITING MEMBRANE PEELING DURING PARS PLANA VITRECTOMY FOR RHEGMATOGENOUS RETINAL DETACHMENT: Cost Analysis, Review of the Literature, and Meta-analysis.
To evaluate the visual and potential economic impact of primary internal limiting membrane (ILM) peeling in primary treatment of rhegmatogenous retinal detachment. A PubMed search was performed to extract data regarding the rate of epiretinal membrane formation and the rate of secondary pars plana vitrectomy with membrane peel after repair of rhegmatogenous retinal detachment with or without ILM peeling. Data were aggregated and analyzed in a meta-analysis. This information was used to perform a cost analysis to determine the economic ramifications of primary ILM peeling. Six included studies compared the outcomes of eyes receiving pars plana vitrectomy for rhegmatogenous retinal detachment repair with and without primary ILM peel. The cumulative rate of epiretinal membrane formation was 29% (86/295) in the eyes without ILM peel and 3% (8/289) in the eyes with ILM peel. The cumulative rate of secondary pars plana vitrectomy/membrane peel was 16% (22/141) in the eyes without ILM peel and 0% (0/158) in the eyes with ILM peel. The weighted summary point estimate odds ratio was 0.083 (95% confidence interval 0.042-0.164), indicating a statistically significant protective effect across the 6 studies of ILM peeling and the development of epiretinal membrane. Based on published data, the average dollars saved by conducting a primary ILM peel was $615 in a facility setting and $364 in an ambulatory surgical center. Published, mainly retrospective, data suggest that primary ILM peel in rhegmatogenous retinal detachment repair may have a significant reduction in the rate of postoperative epiretinal membrane and may lessen the need for secondary pars plana vitrectomy/membrane peel. Furthermore, from an economic perspective, the reduction in the need for secondary surgery may justify the higher cost with primary ILM peel.


The importance of extracellular matrix for cell function and in vivo likeness.
Fibrotic diseases may be described as a disease of the extracellular matrix, where the balance between matrix formation and degradation has been shifted leading to an accumulation of matrix. Currently a fit for purpose model and readily available approach are adapted when doing cell cultures, which may not reflect physiology and pathophysiology optimally. The aim of this review is to draw special attention to the similarities and differences of current state of the art in vitro and ex vivo models, with special focus on the proteins, cell-cell interactions, and correct matrix composition, which may be a better representative of in vivo conditions in a disease where the extracellular matrix is the central player. We reviewed current literature with emphasis on the role of the extracellular matrix in health and disease, different fibrotic disease models, and highlighting the importance of this when looking at translational science. To further our fibrotic research one paramount problem is to fundamentally understand the core of the disease, the production and degradation of the extracellular matrix. For a surprisingly long time the ECM has been underestimated until recently, with the discovery that the ECM may control cell phenotype through cell-matrix interactions. This highlights the need of a native ECM when investigating pathways and response to potential therapy. Clearly, both in vitro and in vivo models provide fit to purpose benefits, but in particular for the fibrosis field we may ask, do single cell cultures in monolayers recapitulate the complicated ECM environment controlling cell fate?


Reelin controls the positioning of brainstem serotonergic raphe neurons.
Serotonin (5-HT) acts as both a morphogenetic factor during early embryonic development and a neuromodulator of circuit plasticity in the mature brain. Dysregulation of serotonin signaling during critical periods is involved in developmental neurological disorders, such as schizophrenia and autism. In this study we focused on the consequences of defect reelin signaling for the development of the brainstem serotonergic raphe system. We observed that reelin signaling components are expressed by serotonergic neurons during the critical period of their lateral migration. Further, we found that reelin signaling is important for the normal migration of rostral, but not caudal hindbrain raphe nuclei and that reelin deficiency results in the malformation of the paramedian raphe nucleus and the lateral wings of the dorsal raphe nuclei. Additionally, we showed that serotonergic neurons projections to laminated brain structures were severely altered. With this study, we propose that the perturbation of canonical reelin signaling interferes with the orientation of tangentially, but not radially, migrating brainstem 5-HT neurons. Our results open the window for further studies on the interaction of reelin and serotonin and the pathogenesis of neurodevelopmental disorders.


The Clinical Breast Care Project: an important resource in investigating environmental and genetic contributions to breast cancer in African American women.
Age at diagnosis, pathological characteristics, and tumor behavior differ between African American (AAW) and Caucasian women (CW) with breast cancer, with AAW having more aggressive tumors and higher mortality rates. Although both societal and molecular contributions to these disparities have been suggested, the African American population has traditionally been under-represented in research and clinical protocols, limiting the power of epidemiologic and molecular studies to provide better understanding of disease pathogenesis in this minority population. The Clinical Breast Care Project (CBCP) has developed a large tissue and blood repository from patients undergoing treatment for breast cancer, with previous history of breast cancer, counseled in the Risk Reduction Clinic, screened by routine mammography, or undergoing elective reductive mammoplasty. Recruitment of AAW into the CBCP was successful; 25% of the 2,454 female patients were African American, including 35% disease-free, 3% high-risk, 40% benign, 8% preinvasive and 14% with invasive breast disease. More than 500 data fields regarding lifestyle choices, socioeconomic status, health history and geography were collected from all participants, and all consenting individuals provided blood specimens for genomic and proteomic studies. Tissues were collected from all patients undergoing surgical procedures using protocols that preserve the macromolecules for downstream research applications. In addition, patients were followed after diagnosis, with >85% of patients providing ongoing and updated demographic and clinical information. Thus, recruitment efforts in the CBCP have resulted in collection of well-annotated information and research-quality specimens from a large number of AAW. This unique resource will allow for the identification of biological and environmental factors associated with the identification of genetic and non-genetic factors associated with the occurrence, detection, prognosis, or survival of breast cancer in AAW.


Plasmodium falciparum Eukaryotic Translation Initiation Factor 3 is Stabilized by Quinazoline-Quinoline Bisubstrate Inhibitors.
Malaria drug resistance is hampering the fight against the deadliest parasitic disease affecting over 200 million people worldwide. We recently developed quinoline-quinazoline-based inhibitors (as compound 70) as promising new antimalarials. Here, we aimed to investigate their mode of action by using thermal proteome profiling (TPP). The eukaryotic translation initiation factor 3 (EIF3i) subunit I was identified as the main target protein stabilized by compound 70 in Plasmodium falciparum. This protein has never been characterized in malaria parasites. P. falciparum parasite lines were generated expressing either a HA tag or an inducible knockdown of the PfEIF3i gene to further characterize the target protein. PfEIF3i was stabilized in the presence of compound 70 in a cellular thermal shift Western blot assay, pointing that PfEIF3i indeed interacts with quinoline-quinazoline-based inhibitors. In addition, PfEIF3i-inducible knockdown blocks intra-erythrocytic development in the trophozoite stage, indicating that it has a vital function. We show that PfEIF3i is mostly expressed in late intra-erythrocytic stages and localizes in the cytoplasm. Previous mass spectrometry reports show that PfEIF3i is expressed in all parasite life cycle stages. Further studies will explore the potential of PfEIF3i as a target for the design of new antimalarial drugs active all along the life cycle of the parasite.


Reduction of HLA donor specific antibodies in heart transplant patients treated with proteasome inhibitors for antibody mediated rejection.
In this project, we describe proteasome inhibitor (PI) treatment of antibody-mediated rejection (AMR) in heart transplantation (HTX). From January 2018 to September 2021, 10 patients were treated with PI for AMR: carfilzomib (CFZ) n = 8; bortezomib (BTZ) n = 2. Patients received 1-3 cycles of PI. All patients had ≥1 strong donor-specific antibody (DSA) (mean fluorescence intensity [MFI] > 8000) in undiluted serum. Most DSAs (20/21) had HLA class II specificity. The MFI of strong DSAs had a median reduction of 56% (IQR = 13%-89%) in undiluted serum and 92% (IQR = 53%-95%) at 1:16 dilution. Seventeen DSAs in seven patients were reduced > 50% at 1:16 dilution after treatment. Four DSAs from three patients did not respond. DSA with MFI > 8000 at 1:16 dilution was less responsive to treatment. 60% (6/10) patients presented with graft dysfunction; 4/6 recovered ejection fraction > 40% after treatment. Pathologic AMR was resolved in 5/7 (71.4%) of patients within 1 year after treatment. 9/10 (90%) patients survived to 1 year after AMR diagnosis. Using PI in AMR resulted in significant DSA reduction with some resolution of graft dysfunction. Larger studies are needed to evaluate PI for AMR.


Ultrastructural and immunohistochemical characterization of the tunica albuginea in Peyronie's disease and veno-occlusive dysfunction.
The tunica albuginea and corpus cavernosum from patients with Peyronie's disease (PD), patients with veno-occlusive dysfunction (VOD), and those from normal control subjects were studied by transmission electron microscopy and immunohistochemical staining for type I, III, and V collagens, platelet-derived growth factor (PDGF) AA and BB homodimers, and PDGF alpha and beta receptors. Ultrastructural modifications resembling a fibrotic reaction were detected in the two pathological tunica albuginea, but not in those from control subjects. Ultrastructural data demonstrated a general increase in fibrous and amorphous extracellular matrix material in the pathological tunica albuginea. The amorphous material probably represents glycoproteins and proteoglycans. The fibrous material, representing collagen, appears disorganized in the tissue and does not display the typical and homogeneous diameter, size, and spatial arrangement. Large areas of extracellular and intracytoplasmic, partially degraded, fibers are visible. An increased type I/III collagen ratio was detected by immunohistochemistry in the two pathological tunica albuginea. Moreover, a strong expression of type V collagen, correlated to fibroblasts, was revealed. Fibroblasts from control tissues, on the other hand, were totally negative. Finally, PDGF AA and BB were positive in fibroblasts from pathological tunica albuginea but were negative in control tissues. PDGF beta receptor was positive in pathological and normal tissue fibroblasts. Tunica albuginea from PD and VOD show similar ultrastructural and immunohistochemical alterations, whereas the corpus cavemosum shows no visible modifications.


Seeding Propensity and Characteristics of Pathogenic αSyn Assemblies in Formalin-Fixed Human Tissue from the Enteric Nervous System, Olfactory Bulb, and Brainstem in Cases Staged for Parkinson's Disease.
We investigated α-synuclein's (αSyn) seeding activity in tissue from the brain and enteric nervous system. Specifically, we assessed the seeding propensity of pathogenic αSyn in formalin-fixed tissue from the gastric cardia and five brain regions of 29 individuals (12 Parkinson's disease, 8 incidental Lewy body disease, 9 controls) using a protein misfolding cyclic amplification assay. The structural characteristics of the resultant αSyn assemblies were determined by limited proteolysis and transmission electron microscopy. We show that fixed tissue from Parkinson's disease (PD) and incidental Lewy body disease (ILBD) seeds the aggregation of monomeric αSyn into fibrillar assemblies. Significant variations in the characteristics of fibrillar assemblies derived from different regions even within the same individual were observed. This finding suggests that fixation stabilizes seeds with an otherwise limited seeding propensity, that yield assemblies with different intrinsic structures (i.e., strains). The lag phase preceding fibril assembly for patients ≥80 was significantly shorter than in other age groups, suggesting the existence of increased numbers of seeds or a higher seeding potential of pathogenic αSyn with time. Seeding activity did not diminish in late-stage disease. No statistically significant difference in the seeding efficiency of specific regions was found, nor was there a relationship between seeding efficiency and the load of pathogenic αSyn in a particular region at a given neuropathological stage.


Effects of hippocampal lesions on adaptive intake of diets with disproportionate amounts of amino acids.
Bilateral double electrolytic overlapping lesions were placed in dorsal-lateral hippocampus of male 230 g rats, and their food intake responses to the ingestion of diets containing disproportionate amounts of amino acids were examined. Rats with such lesions and intact control rats maintained their normal intakes of the 6% casein basal diet or a threonine basal amino acid diet postoperatively. However, they exhibited marked initial food intake depression, similar to that of intact rats, when fed the threonine imbalanced amino acid diet. Also, animals with lesions in certain areas of the dorsal-lateral hippocampus showed facilitated adaptation to the amino acid imbalanced diet. Similar severe reduction in food intake with relative lack of adaptation were observed in both the intact controls and rats with hippocampal lesions when fed amino acid diets completely devoid of threonine. Initial food intake of rats with hippocampal lesions was inhibited drastically as was the case with the intact controls when fed a 75% casein high protein diet. All rats, either intact or lesioned, showed similar slow adaptation patterns with the prolonged ingestion of the high protein diet. The initial food intake responses and facilitated adaptation of the animals bearing lesions in certain areas of the hippocampus suggest that such areas are not crucially involved in the inhibition of food intake of rats fed disproportionate amounts of dietary amino acids. Rather, such areas of lesions in the hippocampus may play a role in a system governing the behavioral adaptation of the intake of amino acid imbalanced diets but not of diets containing amino acids in general excess. This would also indicate that different mechanisms control the intake of amino acid imbalanced diets and diets containing amino acids in excess.


Clonal Lineage Diversity, Antibiotic Resistance, and Virulence Determinants Among Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Isolated from Nurses at a Teaching Hospital in Ilam, Iran: Successful Nares Decolonization by Mupirocin.
Staphylococcus aureus is known to be responsible for nosocomial infections, and the typing method was useful in managing the reservoir of bacteria. The main aim of this study was to determine the prevalence of S. aureus in the nares and hands of nurses working in Imam Khomeini hospital, Ilam, Iran, as well as to determine the clonal relatedness, antimicrobial susceptibility profiles, different virulence, and resistance determinants among these isolates. The evolution of mupirocin activity in the eradication of methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) colonization in the nares of the healthcare workers in Ilam, Iran, was also determined in this study. In this cross-sectional study, 80 nurses, auxiliary nurses, and service workers from Imam Khomeini Hospital were enrolled. MRSA, antibiotic susceptibility, and virulence determinants were evaluated. Then, the isolates were subjected to pulsed field gel electrophoresis (PFGE) and Staphylococcal cassette chromosome mec typing. Our results demonstrated that 23% of isolates were MRSA. PFGE results demonstrated that pulsotypes A (3 out of 30; 10%) and J (3 out of 30; 10%), pulsotypes E (2 out of 30; 6.7%), M (2 out of 30; 6.7%), P(2 out of 30; 6.7%), and V (2 out of 30; 6.7%) were the most predominant pulsotypes, respectively. We cannot give conclusive suggestions about the correlation between nasal carriage and infections, but we suggest the monitoring of all healthcare workers annually, decontamination of their noses by using mupirocin and other antistaphylococcal agents, and also the washing of their hands at least every 2 h.


Prevention of antimicrobial prescribing among infants following maternal vaccination against respiratory syncytial virus.
SignificanceStrategies to reduce consumption of antimicrobial drugs are needed to contain the growing burden of antimicrobial resistance. Respiratory syncytial virus (RSV) is a prominent cause of upper and lower respiratory tract infections, as a single agent and in conjunction with bacterial pathogens, and may thus contribute to the burden of both inappropriately treated viral infections and appropriately treated polymicrobial infections involving bacteria. In a double-blind, randomized, placebo-controlled trial, administering an RSV vaccine to pregnant mothers reduced antimicrobial prescribing among their infants by 12.9% over the first 3 mo of life. Our findings implicate RSV as an important contributor to antimicrobial exposure among infants and demonstrate that this exposure is preventable by use of effective maternal vaccines against RSV.


A surgical approach to a vascular malformation in the plantar medial foot.
Vascular malformations are infrequent findings in the foot, especially the plantar medial foot. Deeper vascular malformations may be more difficult to diagnose due to the depth and oblique course of the medial neurovascular structures into plantar aspect of the foot. The authors present an interesting case report of a vascular anomaly mimicking a heel spur syndrome and describe a surgical approach for the resection of this type of lesion with a 10-month follow-up.


Mathematical model of cylindrical form tolerance.
Tolerance is essential for integration of CAD and CAM. Unfortunately, the meaning of tolerances in the national standard is expressed in graphical and language forms and is not adaptable for expression, processing and data transferring with computers. How to interpret its semantics is becoming a focus of relevant studies. This work based on the mathematical definition of form tolerance in ANSI Y14.5.1M-1994, established the mathematical model of form tolerance for cylindrical feature. First, each tolerance in the national standard was established by vector equation. Then on the foundation of tolerance's mathematical definition theory, each tolerance zone's mathematical model was established by inequality based on degrees of feature. At last the variance area of each tolerance zone is derived. This model can interpret the semantics of form tolerance exactly and completely.


Subcellular localization of neuronal nuclei (NeuN) antigen in size and calcitonin gene-related peptide (CGRP) populations of dorsal root ganglion (DRG) neurons during acute peripheral inflammation.
Pseudo-unipolar cell bodies of somatosensory primary neurons are located in the dorsal root ganglia (DRG). The somatic and peripheral domains of DRG neurons are often studied in sensory pain research to understand molecular mechanisms involved in the activation of pain and maintenance of inflammation. Adjuvant-induced arthritis (AIA) is an inflammatory model that elicits a robust and rapid onset immune response with a maximal swelling period of 24-48 h and persisting for several weeks. The AIA model in the hind paw of the rat elicits a potent inflammatory response of the dermis and epidermis, leading to protein expression changes for sensitization of many DRG neurons; however, it is unknown if the AIA model in the hind paw of the rat induces DRG neuronal injury, necrosis, or apoptosis at the somatic level. Neuronal nuclei (NeuN) antigen is a biomarker for post-mitotic neurons, neuronal identification, protein alterations, injury, and loss. Calcitonin gene-related peptide (CGRP) is expressed in C and Aδ DRG neurons, a subset of DRG neurons known to play a role in peripheral sensitization. The focus of this research was to evaluate the expression pattern of NeuN immunoreactivity, in size (soma) and CGRP subpopulations of DRG neurons in naïve and inflamed groups. Confirmed by both immunofluorescence and immunoprecipitation, DRG neuronal expression of NeuN was localized to nuclear and cytoplasmic subcellular compartments. NeuN increased within the nucleus of small CGRP positive DRG neurons during inflammation, indicating a potential role for NeuN in a subset of nociceptive neurons.


A tumor-associated mutation of FYVE-CENT prevents its interaction with Beclin 1 and interferes with cytokinesis.
The tumor suppressor activity of Beclin 1 (BECN1), a subunit of class III phosphatidylinositol 3-kinase complex, has been attributed to its regulation of apoptosis and autophagy. Here, we identify FYVE-CENT (ZFYVE26), a phosphatidylinositol 3-phosphate binding protein important for cytokinesis, as a novel interacting protein of Beclin 1. A mutation in FYVE-CENT (R1945Q) associated with breast cancer abolished the interaction between FYVE-CENT and Beclin 1, and reduced the localization of these proteins at the intercellular bridge during cytokinesis. Breast cancer cells containing the FYVE-CENT R1945Q mutation displayed a significant increase in cytokinetic profiles and bi-multinuclear phenotype. Both Beclin 1 and FYVE-CENT were found to be downregulated in advanced breast cancers. These findings suggest a positive feedback loop for recruitment of FYVE-CENT and Beclin 1 to the intercellular bridge during cytokinesis, and reveal a novel potential tumor suppressor mechanism for Beclin 1.


Deciphering structural bases of intestinal and hepatic selectivity in targeting pregnane X receptor with indole-based microbial mimics.
Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure-activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure-activity relationships (SAR) between indole mimics and receptors, PXR and AhR.


Characterization of the interactions between the active site of a protein tyrosine kinase and a divalent metal activator.
Protein tyrosine kinases are important enzymes for cell signalling and key targets for anticancer drug discovery. The catalytic mechanisms of protein tyrosine kinase-catalysed phosphorylation are not fully understood. Protein tyrosine kinase Csk requires two Mg2+ cations for activity: one (M1) binds to ATP, and the other (M2) acts as an essential activator. Experiments in this communication characterize the interaction between M2 and Csk. Csk activity is sensitive to pH in the range of 6 to 7. Kinetic characterization indicates that the sensitivity is not due to altered substrate binding, but caused by the sensitivity of M2 binding to pH. Several residues in the active site with potential of binding M2 are mutated and the effect on metal activation studied. An active mutant of Asn319 is generated, and this mutation does not alter the metal binding characteristics. Mutations of Glu236 or Asp332 abolish the kinase activity, precluding a positive or negative conclusion on their role in M2 coordination. Finally, the ability of divalent metal cations to activate Csk correlates to a combination of ionic radius and the coordination number. These studies demonstrate that M2 binding to Csk is sensitive to pH, which is mainly responsible for Csk activity change in the acidic arm of the pH response curve. They also demonstrate critical differences in the metal activator coordination sphere in protein tyrosine kinase Csk and a protein Ser/Thr kinase, the cAMP-dependent protein kinase. They shed light on the physical interactions between a protein tyrosine kinase and a divalent metal activator.


Role of the IFN I system against the VHSV infection in juvenile Senegalese sole (Solea senegalensis).
Senegalese sole is susceptible to marine VHSV isolates but is not affected by freshwater isolates, which may indicate differences regarding virus-host immune system interaction. IFN I induces an antiviral state in fish, stimulating the expression of genes encoding antiviral proteins (ISG). In this study, the stimulation of the Senegalese sole IFN I by VHSV infections has been evaluated by the relative quantification of the transcription of several ISG (Mx, Isg15 and Pkr) after inoculation with marine (pathogenic) and freshwater (non-pathogenic) VHSV isolates. Compared to marine VHSV, lower levels of RNA of the freshwater VHSV induced transcription of ISG to similar levels, with the Isg15 showing the highest fold induction. The protective role of the IFN I system was evaluated in poly I:C-inoculated animals subsequently challenged with VHSV isolates. The cumulative mortality caused by the marine isolate in the control group was 68%, whereas in the poly I:C-stimulated group was 5%. The freshwater VHSV isolate did not cause any mortality. Furthermore, viral RNA fold change and viral titers were lower in animals from the poly I:C + VHSV groups than in the controls. The implication of the IFN I system in the protection observed was confirmed by the transcription of the ISG in animals from the poly I:C + VHSV groups. However, the marine VHSV isolate exerts a negative effect on the ISG transcription at 3 and 6 h post-inoculation (hpi), which is not observed for the freshwater isolate. This difference might be partly responsible for the virulence shown by the marine isolate.


Transcatheter Aortic Valve Implantation in Patients With Severe Aortic Stenosis Hospitalized With Acute Heart Failure.
Optimal timing and outcomes of transcatheter aortic valve implantation (TAVI) in patients presenting with acute heart failure (AHF) remain unclear. In this consecutive cohort of 1,547 patients with severe aortic stenosis undergoing TAVI, the AHF status at admission was collected, and patients were classified into AHF and elective TAVI groups. In the AHF group, early TAVI was defined as TAVI performed ≤60 hours after emergency room arrival. The primary outcome was all-cause mortality at 30-day and 2-year after TAVI. There were 139 (9%) patients who underwent TAVI while hospitalized with AHF. At baseline, this group had higher rates of chronic kidney disease, higher Society of Thoracic Surgeons score, and lower left ventricular ejection fraction. After adjusting for baseline differences, the AHF group had significantly higher all-cause mortality at 30-day and 2-year than the elective TAVI group (8% vs 2%; p = 0.002, and 33% vs 18%; p = 0.002, respectively). In the AHF group, 43 (31%) patients underwent early treatment with TAVI. No significant difference in all-cause mortality at 30-day was observed between early and non-early TAVI groups (5% vs 10%; p = 0.617). All-cause mortality at 2-year was lower in the early TAVI groups (16% vs 40%, log-rank p = 0.022); however, after multivariable adjustment, the difference was barely statistically significant (p = 0.053). In conclusion, TAVI in patients with AHF was associated with worse short and long-term outcomes. In AHF setting, early TAVI did not significantly reduce all-cause mortality at 30-day; however, it showed a strong trend for lower all-cause mortality at 2-year.


Imaginative reality observed during early language development.
The authors argue that our thinking about psychic reality is challenged by research observations of the child during the period of early language development. The toddler, at the beginnings of propositional speech, expresses the capacity for 'two kinds of psychic reality'. A world of imaginative pretence occurs quite early, and supplements the child's everyday experience. The toddler is not confused by these two experiential worlds and, correspondingly, the use of imaginative activity is strongly supported by caregivers. While in some ways there is a rich history of developmental observation and psychoanalytic thinking about such early imaginative activity, its significance is only now being appreciated. Imaginative reality refers to a process in which the child makes use of what is familiar in the remembered past in order to try out a world of new possibilities in the present that, to some extent, are oriented towards the future. Conditional modes of thinking that are affectively meaningful are thereby engaged and practised in play. The authors present vivid observations that illustrate the early imaginative pretence mode of psychic reality. The observations are followed by a developmental discussion integrating recent research with psychoanalytic theory. As would be expected, thinking about early imaginative reality leads to a variety of new questions for research and clinical work.


How to prevent viremia rebound? Evidence from a PRRSv data-supported model of immune response.
Understanding what determines the between-host variability in infection dynamics is a key issue to better control the infection spread. In particular, pathogen clearance is desirable over rebounds for the health of the infected individual and its contact group. In this context, the Porcine Respiratory and Reproductive Syndrome virus (PRRSv) is of particular interest. Numerous studies have shown that pigs similarly infected with this highly ubiquitous virus elicit diverse response profiles. Whilst some manage to clear the virus within a few weeks, others experience prolonged infection with a rebound. Despite much speculation, the underlying mechanisms responsible for this undesirable rebound phenomenon remain unclear. We aimed at identifying immune mechanisms that can reproduce and explain the rebound patterns observed in PRRSv infection using a mathematical modelling approach of the within-host dynamics. As diverse mechanisms were found to influence PRRSv infection, we established a model that details the major mechanisms and their regulations at the between-cell scale. We developed an ABC-like optimisation method to fit our model to an extensive set of experimental data, consisting of non-rebounder and rebounder viremia profiles. We compared, between both profiles, the estimated parameter values, the resulting immune dynamics and the efficacies of the underlying immune mechanisms. Exploring the influence of these mechanisms, we showed that rebound was promoted by high apoptosis, high cell infection and low cytolysis by Cytotoxic T Lymphocytes, while increasing neutralisation was very efficient to prevent rebounds. Our paper provides an original model of the immune response and an appropriate systematic fitting method, whose interest extends beyond PRRS infection. It gives the first mechanistic explanation for emergence of rebounds during PRRSv infection. Moreover, results suggest that vaccines or genetic selection promoting strong neutralising and cytolytic responses, ideally associated with low apoptotic activity and cell permissiveness, would prevent rebound.


Magnetoencephalography in twins reveals a strong genetic determination of the peak frequency of visually induced γ-band synchronization.
Many aspects of brain processing are intimately linked to brain rhythms. Essentially all classical brain rhythms, i.e., delta, theta, alpha, beta, and sleep waves, are highly heritable. This renders brain rhythms an interesting intermediate phenotype for cognitive and behavioral traits. One brain rhythm that has been particularly strongly linked to cognition is the gamma rhythm: it is involved in attention, short- and long-term memory, and conscious awareness. It has been described in sensory and motor cortices, association and control structures, and the hippocampus. In contrast to most other brain rhythms, the gamma frequency highly depends on stimulus and task conditions, suggesting a low heritability. However, the heritability of gamma has not been assessed. Here, we show that visually induced gamma-band synchronization in humans is strongly genetically determined. Eighty twin subjects (20 monozygotic and 20 dizygotic twin pairs) viewed a moving sinusoidal grating while their brain activity was recorded using magnetoencephalography. The stimulus induced spectrally confined gamma-band activity in sensors over visual cortex in all subjects, with individual peak frequencies ranging from 45 to 85 Hz. Gamma-band peak frequencies were highly correlated across monozygotic twins (r = 0.88), but not across dizygotic twins (r = 0.32) or unrelated subjects (r = 0.02). This implies a heritability of the gamma-band frequency of 91%. This strong genetic determination suggests that gamma-related cognitive functions are under close genetic control.


Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme.
To investigate the structural features of wild and mutant forms of the pPAF-AH enzyme that are responsible for coronary artery disease. Mutant variants of human pPAF-AH having either V279F, Q281R, or both were modelled and evaluated for stereo chemical and structural correctness. The 3D coordinates of substrate PAF were retrieved from the PubChem database was solvated and minimized on Discovery Studio, and docked to the wild and mutant enzyme models. The top docked pose complex was refined by MD simulation. pPAF-AH model comprises of 420 amino acids in a α/β-hydrolase fold that contains a substrate-binding hydrophobic channel with an active site pocket having a catalytic triad of Ser273, Asp296 and His351. Mutations at positions 279 and 281 are opposite one another on the middle of 12 residues long H5 helix that forms the hydrophobic core of the enzyme. V279F causes a tilt on the axis of the mutation bearing helix to avoid steric clashes with the hydrophobic residues on the β-sheets adjacent to it, inducing subtle conformational changes on the H5-β8 loop, β8 sheet, and the loop bearing Asp296. A cascade of conformational changes induces a change in the orientation of His351 resulting in loss of hydrogen bonded interaction with catalytic Ser273. Q281R causes a shortening of H5 and β8, which induces conformational changes of the loops bearing Ser273 and Asp296, respectively. Simultaneous conformational changes of secondary structural elements result in the flipping of His351 causing a break in the catalytic triad. Also, there is a compromise in the substrate-binding area and volume in the mutants resulting in loss of binding to its substrate. Mutant enzymes show changes at the site of the mutation, secondary motif conformations and global structural conformations that adversely affect the active site, decrease substrate channel volume and decrease stability, thereby affecting enzymatic function.


Cardiovascular pharmacology. II: The use of catecholamines, pressor agents, digitalis, and corticosteroids in CPR and emergency cardiac care.
The Cardiovascular Pharmacology II panel met during the AHA National Conference on Standards and Guidelines for CPR and emergency cardiac care to consider the use of catecholamines, pressor agents, digitalis, and corticosteroids during advanced cardiac life support. During cardiac arrest, catecholamines and pressor agents have been shown to improve the rate of success of resuscitation. The useful properties of these drugs are mediated by strong alpha-adrenergic stimulation resulting in improved coronary perfusion. beta-Adrenergic stimulation during cardiac arrest is unimportant for resuscitation and potentially harmful. Studies have not demonstrated a difference between mixed agonists and alpha-agonists with respect to overall outcome. Consequently, the panel recommended that epinephrine continue to be the primary vasopressor for use during cardiac arrest. For cardiovascular support in the hemodynamically unstable patient, the panel recommended that drugs be chosen for specific pharmacologic actions that will allow the needed physiologic manipulation guided by objective hemodynamic measurements. The panel found that digitalis preparations and corticosteroids have very limited use in emergency cardiac care.


Distal movement of maxillary molars in nongrowing patients with the skeletal anchorage system.
It is now possible to predictably move maxillary molars distally in nongrowing patients with the skeletal anchorage system (SAS) and to improve malocclusions without having to extract the premolars and regardless of the patient's compliance. The purposes of this study were to investigate the amount of distal movement of the maxillary first molars, the type of movement, the difference between actual and predicted amounts of distalization, and the relationship between the amount of distalization and age. Twenty-five nongrowing patients (22 female, 3 male) successfully treated with the SAS were the subjects in this study. The amount and the type of distalization, the difference between predicted and resulting amounts of distalization, and the relationship between the patient's age and the amount of distalization were analyzed with wide-opening cephalometric radiographs. The average amount of distalization of the maxillary first molars was 3.78 mm at the crown level and 3.20 mm at the root level. The amount of distalization at the crown level was significantly correlated with the average value of treatment goals (3.60 mm). The maxillary molars were predictably distalized in accordance with the individualized treatment goals without regard to patient age and extraction of the third or second molars. The SAS is a viable noncompliance modality to move maxillary molars for distally correcting maxillary protrusions and malocclusions characterized by maxillary incisor crowding.


Mulan: multiple-sequence alignment to predict functional elements in genomic sequences.
Multiple sequence alignment analysis is a powerful approach for translating the evolutionary selective power into phylogenetic relationships to localize functional coding and noncoding genomic elements. The tool Mulan (http://mulan.dcode.org/) has been designed to effectively perform multiple comparisons of genomic sequences necessary to facilitate bioinformatic-driven biological discoveries. The Mulan network server is capable of comparing both closely and distantly related genomes to identify conserved elements over a broad range of evolutionary time. Several novel algorithms are brought together in this tool: the tba multisequence aligner program used to rapidly identify local sequence conservation and the multiTF program to detect evolutionarily conserved transcription factor binding sites in alignments. Mulan is integrated with the ERC Browser, the UCSC Genome Browser for quick uploads of available sequences and supports two-way communication with the GALA database to overlay GALA functional genome annotation with sequence conservation profiles. Local multiple alignments computed by Mulan ensure reliable representation of short- and large-scale genomic rearrangements in distant organisms. Recently, we have also introduced the ability to handle duplications to permit the reliable reconstruction of evolutionary events that underlie the genome sequence data. Here, we describe the main features of the Mulan tool that include the interactive modification of critical conservation parameters, visualization options, and dynamic access to sequence data from visual graphs for flexible and easy-to-perform analysis of differentially evolving genomic regions.


Pseudoscopic imaging in a double diffraction process with a slit: critical point properties.
Pseudoscopic (inverted depth) images that keep a continuous parallax were shown to be possible by use of a double diffraction process intermediated by a slit. One diffraction grating directing light to the slit acts as a wavelength encoder of views, while a second diffraction grating decodes the projected image. The process results in the enlargement of the image under common white light illumination up to infinite magnification at a critical point. We show that this point corresponds to another simple-symmetry object-observer system. Our treatment allows us to explain the experience by just dealing with main ray directions.


Blood flow controls bone vascular function and osteogenesis.
While blood vessels play important roles in bone homeostasis and repair, fundamental aspects of vascular function in the skeletal system remain poorly understood. Here we show that the long bone vasculature generates a peculiar flow pattern, which is important for proper angiogenesis. Intravital imaging reveals that vessel growth in murine long bone involves the extension and anastomotic fusion of endothelial buds. Impaired blood flow leads to defective angiogenesis and osteogenesis, and downregulation of Notch signalling in endothelial cells. In aged mice, skeletal blood flow and endothelial Notch activity are also reduced leading to decreased angiogenesis and osteogenesis, which is reverted by genetic reactivation of Notch. Blood flow and angiogenesis in aged mice are also enhanced on administration of bisphosphonate, a class of drugs frequently used for the treatment of osteoporosis. We propose that blood flow and endothelial Notch signalling are key factors controlling ageing processes in the skeletal system.


Defining the ability of cyclophosphamide preconditioning to enhance the antigen-specific CD8+ T-cell response to peptide vaccination: creation of a beneficial host microenvironment involving type I IFNs and myeloid cells.
Although cyclophosphamide (CTX) has been clearly shown to enhance active specific and adoptive immunotherapies, the mechanism(s) underlying these beneficial effects have not been clearly defined. To define the impact of CTX preconditioning on the antigen-specific CD8 T-cell response to peptide vaccination, we used an adoptive transfer model based on the OT-1 T-cell receptor transgenic mouse. CTX preconditioning dramatically enhanced the antigen-specific CD8 T-cell response to peptide vaccination. Specifically, CTX significantly enhanced the expansion and function of responding CD8 T cells as demonstrated by flow cytometry and cytokine production. In parallel experiments, we attempted to define the mechanism(s) underlying these beneficial effects of CTX therapy. CTX therapy increased the relative number and activation status of myeloid dendritic cells, and was associated with the induction of significant levels of the inflammatory cytokines interferon-alpha, monocyte chemoattractant protein-1, and IL-6. Adoptive transfer experiments into type I IFNR-/- and CR3-/- mice confirmed that the beneficial effects of CTX were at least partially dependent on type I interferons and myeloid cells. Adoptive transfer of up to 150x10(6) naive spleen cells at the time of antigen-specific CD8 T-cell transfer did not abrogate the effects of CTX therapy, suggesting that the creation of a niche in the immune system may not be required. CTX decreased the absolute, but not relative number of CD4+CD25+ Treg cells, consistent with the possibility that regulatory T cells may be targeted by CTX therapy. Of note, combination therapy with CTX and a synthetic TLR3 agonist further enhanced the antigen-specific CD8+ T-cell response. Taken together, our data suggest that CTX modulates specific components of the innate immune system resulting in a beneficial host microenvironment. Specific targeting of these components may enhance the effectiveness of CTX preconditioning for adoptive immunotherapy.


Caffeinated alcohol beverages: a public health concern.
Consumption of alcohol mixed with caffeinated energy drinks is becoming popular, and the number of pre-mixed caffeinated alcohol products on the worldwide market is increasing. There is public health concern and even occasional legal restriction relating to these drinks, due to associations with increased intoxication and harms. The precise nature and degree of the pharmacological relationship between caffeine and alcohol is not yet elucidated, but it is proposed that caffeine attenuates the sedative effects of alcohol intoxication while leaving motor and cognitive impairment unaffected. This creates a potentially precarious scenario for users who may underestimate their level of intoxication and impairment. While legislation in some countries has restricted production or marketing of pre-mixed products, many individuals mix their own energy drink-alcohol 'cocktails'. Wider dissemination of the risks might help balance marketing strategies that over-emphasize putative positive effects.


Clinical behavior of a cohort of adult women with facial acne treated with combined oral contraceptive: ethinylestradiol 20 µg/dienogest 2 mg.
Acne vulgaris is the most common skin disease. It affects the young adult female population and generates great impact on physical and mental health. One of the treatments with good results for affected women is combined oral contraceptive pills (COCPs). The aim of this study was to determine the clinical effect of facial acne management with ethinylestradiol 20 µg/dienogest 2 mg in a cohort of Colombian adult women. A cohort of 120 female university students was followed for 12 months. These participants were enrolled in the Sexual and Reproductive Health Program of the Santiago de Cali University. This cohort admitted women between 18 and 30 years old who had chosen to start birth control with ethinylestradiol 20 µg/dienogest 2 mg COCPs, did not have contraindi cations to the use of COCPs, and had been diagnosed with acne. Monthly monitoring of facial acne lesion count was performed. Relative changes in facial lesion count were identified. At the end of follow-up, the percentage of reduction of lesions was 94% and 23% of women had a 100% reduction in acne lesions. In conclusion, the continued use of the ethinylestradiol 20 µg/dienogest 2 mg COCPs reduced inflammatory and non-inflammatory acne lesions in reproductive-age women between 18 and 30 years of age with no severe acne.


[Assessment of ADHD with EEG].
Many children with ADHD develop epilepsy, and approximately 20% of children with epilepsy also have ADHD. In this article we discuss the use of EEG in connection with ADHD in children, with emphasis on the diagnosis of comorbid epilepsy. The article is based on a literature search in PubMed, personal literature archives and the authors' own experience with the use of EEG, treatment of epilepsy and the diagnosis and treatment of ADHD in children and adolescents. A moderately elevated prevalence of epileptiform EEG activity is described in children with ADHD without epilepsy compared with healthy children, during both wakefulness and sleep. Selected material and a lack of controlled blinded studies probably explain much of this difference. The significance of epileptiform EEG activity in children with ADHD without seizures is uncertain. Evaluating the extent to which EEG findings may explain the symptoms and whether anti-epileptic drugs should be tried is a specialist task. In many studies, spectral analysis of the frequency content of the EEG (QEEG) has shown higher slow theta activity and a higher theta/beta ratio in children with ADHD. Seizure symptoms, disturbed sleep quality, significant changes in behaviour or regression of cognitive ability in children with ADHD should lead to paediatric neurological assessment with EEG and possibly a 24-hour EEG. In our view, the QEEG variables are artifact-prone and biologically unspecific. We therefore do not recommend the use of QEEG as a stand-alone diagnostic marker.


Atrial premature complexes and heart rate have prognostic significance in 1-month atrial fibrillation recurrence after electrical cardioversion.
The aim of this study was to investigate the significance of simple 24-h Holter (24H) data after electrical cardioversion (CV) for atrial fibrillation (AF) recurrence. We prospectively studied 47 consecutive patients subjected to CV, who successfully converted to sinus rhythm. All underwent echocardiography and 24H after CV. AF recurrence was studied at 14 days and 1 month by second 24H or by interim report of AF. About 53.2% remained in sinus rhythm (group I) and the rest recurred to AF (group II). Group I had fewer atrial premature complexes per hour (APC/h) (P = 0.002) and lower maximum (max HR), average, and minimum heart rates compared with group II (all Ps < 0.05). The optimal value of APC/h and max HR with best sensitivity and specificity was 32 APC/h and 90 bpm, respectively. These findings were the predictors of AF recurrence [hazard ratio (HR) = 4.5 with 95% CI = 1.7-11.7 and HR = 4.3 with 95% CI = 1.7-10.9, respectively]. Patients with the combination of both predictors had greater HR of AF recurrence compared with those with < 32 APC/h and max HR < 90 bpm (HR = 8.8 with 95% CI = 2.5-31.4). Patients with frequent APC/h and high max HR are at high risk for 1-month AF recurrence after electrical CV.


Molecular structure of human galactokinase: implications for type II galactosemia.
Galactokinase functions in the Leloir pathway for galactose metabolism by catalyzing the MgATP-dependent phosphorylation of the C-1 hydroxyl group of alpha-D-galactose. The enzyme is known to belong to the GHMP superfamily of small molecule kinases and has attracted significant research attention for well over 40 years. Approximately 20 mutations have now been identified in human galactokinase, which result in the diseased state referred to as Type II galactosemia. Here we report the three-dimensional architecture of human galactokinase with bound alpha-D-galactose and Mg-AMPPNP. The overall fold of the molecule can be described in terms of two domains with the active site wedged between them. The N-terminal domain is dominated by a six-stranded mixed beta-sheet whereas the C-terminal motif contains six alpha-helices and two layers of anti-parallel beta-sheet. Those residues specifically involved in sugar binding include Arg37, Glu43, His44, Asp46, Gly183, Asp186, and Tyr236. The C-1 hydroxyl group of alpha-D-galactose sits within 3.3 A of the gamma-phosphorus of the nucleotide and 3.4 A of the guanidinium group of Arg37. The carboxylate side chain of Asp186 lies within approximately 3.2 A of the C-2 hydroxyl group of alpha-D-galactose and the guanidinium group of Arg37. Both Arg37 and Asp186 are strictly conserved among both prokaryotic and eukaryotic galactokinases. In addition to providing molecular insight into the active site geometry of the enzyme, the model also provides a structural framework upon which to more fully understand the consequences of the those mutations known to give rise to Type II galactosemia.


Experiments and Modeling of Boric Acid Permeation through Double-Skinned Forward Osmosis Membranes.
Boron removal is one of the great challenges in modern wastewater treatment, owing to the unique small size and fast diffusion rate of neutral boric acid molecules. As forward osmosis (FO) membranes with a single selective layer are insufficient to reject boron, double-skinned FO membranes with boron rejection up to 83.9% were specially designed for boron permeation studies. The superior boron rejection properties of double-skinned FO membranes were demonstrated by theoretical calculations, and verified by experiments. The double-skinned FO membrane was fabricated using a sulfonated polyphenylenesulfone (sPPSU) polymer as the hydrophilic substrate and polyamide as the selective layer material via interfacial polymerization on top and bottom surfaces. A strong agreement between experimental data and modeling results validates the membrane design and confirms the success of model prediction. The effects of key parameters on boron rejection, such as boron permeability of both selective layers and structure parameter, were also investigated in-depth with the mathematical modeling. This study may provide insights not only for boron removal from wastewater, but also open up the design of next generation FO membranes to eliminate low-rejection molecules in wider applications.


Transferrin-receptor-mediated iron accumulation controls proliferation and glutamate release in glioma cells.
Transferrin receptors (TfR) are overexpressed in brain tumors, but the pathological relevance has not been fully explored. Here, we show that TfR is an important downstream effector of ets transcription factors that promotes glioma proliferation and increases glioma-evoked neuronal death. TfR mediates iron accumulation and reactive oxygen formation and thereby enhanced proliferation in clonal human glioma lines, as shown by the following experiments: (1) downregulating TfR expression reduced proliferation in vitro and in vivo; (2) forced TfR expression in low-grade glioma accelerated proliferation to the level of high-grade glioma; (3) iron and oxidant chelators attenuated tumor proliferation in vitro and tumor size in vivo. TfR-induced oxidant accumulation modified cellular signaling by inactivating a protein tyrosine phosphatase (low-molecular-weight protein tyrosine phosphatase), activating mitogen-activated protein kinase and Akt and by inactivating p21/cdkn1a and pRB. Inactivation of these cell cycle regulators facilitated S-phase entry. Besides its effect on proliferation, TfR also boosted glutamate release, which caused N-methyl-D-aspartate-receptor-mediated reduction of neuron cell mass. Our results indicate that TfR promotes glioma progression by two mechanisms, an increase in proliferation rate and glutamate production, the latter mechanism providing space for the progressing tumor mass.


Transfer of Pseudomonas flectens Johnson 1956 to Phaseolibacter gen. nov., in the family Enterobacteriaceae, as Phaseolibacter flectens gen. nov., comb. nov.
Pseudomonas flectens Johnson 1956, a plant-pathogenic bacterium on the pods of the French bean, is no longer considered to be a member of the genus Pseudomonas sensu stricto. A polyphasic approach that included examination of phenotypic properties and phylogenetic analyses based on 16S rRNA, rpoB and atpD gene sequences supported the transfer of Pseudomonas flectens Johnson 1956 to a new genus in the family Enterobacteriaceae as Phaseolibacter flectens gen. nov., comb. nov. Two strains of Phaseolibacter flectens were studied (ATCC 12775(T) and LMG 2186); the strains shared 99.8 % sequence similarity in their 16S rRNA genes and the housekeeping gene sequences were identical. Strains of Phaseolibacter flectens shared 96.6 % or less 16S rRNA gene sequence similarity with members of different genera in the family Enterobacteriaceae and only 84.7 % sequence similarity with Pseudomonas aeruginosa LMG 1242(T), demonstrating that they are not related to the genus Pseudomonas. As Phaseolibacter flectens formed an independent phyletic lineage in all of the phylogenetic analyses, it could not be affiliated to any of the recognized genera within the family Enterobacteriaceae and therefore was assigned to a new genus. Cells were Gram-negative, straight rods, motile by means of one or two polar flagella, fermentative, facultative anaerobes, oxidase-negative and catalase-positive. Growth occurred in the presence of 0-60 % sucrose. The DNA G+C content of the type strain was 44.3 mol%. On the basis of phenotypic properties and phylogenetic distinctiveness, Pseudomonas flectens Johnson 1956 is transferred to the novel genus Phaseolibacter gen. nov. as Phaseolibacter flectens gen. nov., comb. nov. The type strain of Phaseolibacter flectens is ATCC 12775(T) = CFBP 3281(T) = ICMP 745(T) = LMG 2187(T) = NCPPB 539(T).


[Aspergillosis of the central nervous system (clinical observation and review of literature)].
Aspergillosis of the central nervous system presents a challenge faced with the problems arising from the establishing the diagnosis, the low efficiency of treatment, and high mortality rates (about 95% as shown by some data). This paper presents a clinical case of a patient with aspergillosis-induced central nervous system lesion verified by autopsy. Possible errors in the diagnosis and treatment of the patient are analyzed. The literature data including clinical cases, etiopathogenesis, and clinical manifestations and its possible complications are presented. Groups of patients at risk for invasive aspergillosis are considered. The paper gives the data available in the foreign literature on the methods and efficiency of treatment and mortality rates in different groups of patients. The urgency of the problem in the diagnosis and treatment of cerebral aspergillosis rises with the increased number of patients with immunological disorders due to infectious diseases (HIV), social (drug addiction, alcoholism), environmental, and other factors.


Cellular congenital mesoblastic nephroma: what are the options.
Cellular congenital mesoblastic nephroma is a potentially aggressive variant of the usually benign congenital mesoblastic nephroma. Our recent experience with 3 patients with cellular congenital mesoblastic nephroma prompted a critical review of the literature to evaluate risk factors for recurrence and present treatment programs. A total of 38 patients, including our 3 patients, with cellular congenital mesoblastic nephroma were divided into 2 groups: those with recurrent (7) and those with nonrecurrent (31) tumors. A statistical comparison of clinical and pathological data was performed. Of the 7 patients with local recurrence and/or pulmonary metastasis, 3 died. The average time to first recurrence was 5.4 months. Histological differences were not predictive of recurrent disease. Pathologically positive surgical margins (p less than or equal to 0.02) were the only statistically significant variable suggesting recurrent disease. While the presenting age was not predictive of recurrence (p equals 0.27), the relative risk of recurrence doubles in the first 3 months of life and quadruples after 6 months of life. Treatment programs also were evaluated. An infant with cellular congenital mesoblastic nephroma, regardless of age, is cured with surgery alone given clear pathological margins. In 4 of 5 children with recurrent tumors Wilms tumor treatment agents (vincristine and actinomycin D) failed to control local or distant disease. Of these cases 2 subsequently were treated with sarcomatous chemotherapy (vincristine, cyclophosphamide and doxorubicin) and both are in remission. These agents may prove to be more efficacious in the treatment of local or metastatic disease.


Relationships between host phylogeny, host type and bacterial community diversity in cold-water coral reef sponges.
Cold-water coral reefs are known to locally enhance the diversity of deep-sea fauna as well as of microbes. Sponges are among the most diverse faunal groups in these ecosystems, and many of them host large abundances of microbes in their tissues. In this study, twelve sponge species from three cold-water coral reefs off Norway were investigated for the relationship between sponge phylogenetic classification (species and family level), as well as sponge type (high versus low microbial abundance), and the diversity of sponge-associated bacterial communities, taking also geographic location and water depth into account. Community analysis by Automated Ribosomal Intergenic Spacer Analysis (ARISA) showed that as many as 345 (79%) of the 437 different bacterial operational taxonomic units (OTUs) detected in the dataset were shared between sponges and sediments, while only 70 (16%) appeared purely sponge-associated. Furthermore, changes in bacterial community structure were significantly related to sponge species (63% of explained community variation), sponge family (52%) or sponge type (30%), whereas mesoscale geographic distances and water depth showed comparatively small effects (<5% each). In addition, a highly significant, positive relationship between bacterial community dissimilarity and sponge phylogenetic distance was observed within the ancient family of the Geodiidae. Overall, the high diversity of sponges in cold-water coral reefs, combined with the observed sponge-related variation in bacterial community structure, support the idea that sponges represent heterogeneous, yet structured microbial habitats that contribute significantly to enhancing bacterial diversity in deep-sea ecosystems.


The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination.
During embryonic development of the inner ear, the sensory primordium that gives rise to the organ of Corti from within the cochlear epithelium is patterned into a stereotyped array of inner and outer sensory hair cells separated from each other by non-sensory supporting cells. Math1, a close homolog of the Drosophila proneural gene atonal, has been found to be both necessary and sufficient for the production of hair cells in the mouse inner ear. Our results indicate that Math1 is not required to establish the postmitotic sensory primordium from which the cells of the organ of Corti arise, but instead is limited to a role in the selection and/or differentiation of sensory hair cells from within the established primordium. This is based on the observation that Math1 is only expressed after the appearance of a zone of non-proliferating cells that delineates the sensory primordium within the cochlear anlage. The expression of Math1 is limited to a subpopulation of cells within the sensory primordium that appear to differentiate exclusively into hair cells as the sensory epithelium matures and elongates through a process that probably involves radial intercalation of cells. Furthermore, mutation of Math1 does not affect the establishment of this postmitotic sensory primordium, even though the subsequent generation of hair cells is blocked in these mutants. Finally, in Math1 mutant embryos, a subpopulation of the cells within the sensory epithelium undergo apoptosis in a temporal gradient similar to the basal-to-apical gradient of hair cell differentiation that occurs in the cochlea of wild-type animals.


Branched-chain amino acids as adjunctive-alternative treatment in patients with autism: a pilot study.
The branched-chain amino acid (BCAA) is a group of essential amino acids that are involved in maintaining the energy balance of a human being as well as the homoeostasis of GABAergic, glutamatergic, serotonergic and dopaminergic systems. Disruption of these systems has been associated with the pathophysiology of autism while low levels of these amino acids have been discovered in patients with autism. A pilot open-label, prospective, follow-up study of the use of BCAA in children with autistic behaviour was carried out. Fifty-five children between the ages of 6 and 18 participated in the study from May 2015 to May 2018. We used a carbohydrate-free BCAA-powdered mixture containing 45·5 g of leucine, 30 g of isoleucine and 24·5 g of valine in a daily dose of 0·4 g/kg of body weight which was administered every morning. Following the initiation of BCAA administration, children were submitted to a monthly psychological examination. Beyond the 4-week mark, BCAA were given to thirty-two people (58·18 %). Six of them (10·9 %) discontinued after 4-10 weeks owing to lack of improvement. The remaining twenty-six children (47·27 %) who took BCAA for longer than 10 weeks displayed improved social behaviour and interactions, as well as improvements in their speech, cooperation, stereotypy and, principally, their hyperactivity. There were no adverse reactions reported during the course of the treatment. Although these data are preliminary, there is some evidence that BCAA could be used as adjunctive treatment to conventional therapeutic methods for the management of autism.


How should we test infant handedness?
As soon as infants grasp objects, they exhibit some degree of hand preference. Although all studies agree that the number of non-lateralized infants remains high during the first months of life, there is no consensus on the percentage of right- and left-handed infants. Reasons might be the different formulae used to calculate an handedness index, the basis on which handedness categories are distinguished, and the number of trials per session. In this study we aimed to provide a valid method of testing handedness, reliable without being lengthy so as to combine it with other evaluations. We tested 46 infants at 9 and 11 months by giving them 34 trials. We compared the results using 2 of the most used formulae, including the bimanual grasps or not, and considering the first 5, 10, 15, 20, 26, 31, or all 34 trials. The results show that different formulae do not give significantly different results as long as bimanual grasps are included. The number of trials is important: 15 trials are necessary for the reliability of the classification into handedness categories. Giving more trials does not provide substantial additional information.


Augmented forearm vasoconstriction during dynamic exercise in healthy older men.
We tested the hypothesis that the nonactive limb vasoconstriction evoked during large-muscle dynamic exercise becomes augmented with aging in humans. Sixteen young control subjects (age, 26 +/- 1 year) and twelve older (65 +/- 1 year) healthy men with similar chronic physical activity levels were studied during supine leg cycling exercise. Both peak work load (1,100 +/- 60 versus 1,400 +/- 40 kpm/min) and peak O2 uptake (1.85 +/- 0.10 versus 2.38 +/- 0.07 l/min) were lower in the older men (p < 0.05). There were no differences in the two groups under conditions of quiet supine (basal) rest. During cycling for 5 minutes each at mild, moderate, and heavy submaximal intensities (approximately 45%, 65%, and 85% of peak O2 uptake), the increases in arterial blood pressure generally were similar in the young and older subjects; however, heart rate rose less in the older men (p < 0.05). Whole forearm blood flow (venous occlusion plethysmography) was lower and vascular resistance was higher (approximately 55-90%) in the older men at all loads (p < 0.05), but the steady-state forearm skin blood flow responses (laser Doppler velocimetry) were not different in the two groups. The increases in antecubital venous norepinephrine concentrations were greater in the older men at each work load (p < 0.05), although the plasma epinephrine responses were similar in the two groups. In other studies, 1) peak whole forearm reactive hyperemia and vascular conductance after sustained circulatory arrest (ischemia) were slightly (approximately 20%) but not significantly lower in the older men and 2) the forearm vasoconstrictor and plasma norepinephrine responses to a nonexercise sympathoexcitatory stimulus (limb immersion in ice water) tended to be blunted in the older men. During brief, submaximal, large-muscle dynamic exercise, healthy older men demonstrate augmented forearm vasoconstriction that is probably caused by greater constriction of skeletal muscle resistance vessels; this appears to be mediated, at least in part, by increased sympathetic outflow. These altered sympathetic vasoconstrictor adjustments do not represent a nonspecific hyperresponsiveness to acute stress with human aging. Finally, the regulation of arterial blood pressure appears to be normal in these healthy older men.


Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46,XY sex reversal, and severe adrenal failure.
Disruption of the P450 side-chain cleavage cytochrome (P450scc) enzyme due to deleterious mutations of the CYP11A1 gene is thought to be incompatible with fetal survival because of impaired progesterone production by the fetoplacental unit. We present a 46,XY patient with a homozygous disruption of CYP11A1. The child was born prematurely with complete sex reversal and severe adrenal insufficiency. Laboratory data showed diminished or absent steroidogenesis in all pathways. Molecular genetic analysis of the CYP11A1 gene revealed a homozygous single nucleotide deletion leading to a premature termination at codon position 288. This mutation will delete highly conserved regions of the P450scc enzyme and thus is predicted to lead to a nonfunctional protein. Both healthy parents were heterozygous for this mutation. Our report demonstrates that severe disruption of P450scc can be compatible with survival in rare instances. Furthermore, defects in this enzyme are inherited in an autosomal-recessive fashion, and heterozygote carriers can be healthy and fertile. The possibility of P450scc-independent pathways of steroid synthesis in addition to the current concept of luteoplacental shift of progesterone synthesis in humans has to be questioned.


Preparation and preliminary evaluation of technetium-99m-labeled fragment E1 for thrombus imaging.
Fragment E1 labeled with 123I has been previously shown to permit imaging of thrombi in patients within as little as 20 min after injection. Because of the relatively rapid localization and blood disappearance of this protein, 99mTc would be the most clinically acceptable radionuclide for labeling Fragment E1. In this study, human fragment E1 was derivatized with a hydrazino nicotinate function to permit radiolabeling with reduced technetium. The modification reaction was carried out while the fragment E1 was protected in a complex, so that the modification occurred in nonfunctional regions of the fragment E1 molecule. After radiolabeling with 99mTc, the modified fragment E1 retained its functional activity, as judged by its binding to fragment DD in vitro. The ability of 99mTc-fragment E1 to produce images of venous thrombi was demonstrated in animal models. Images were focally positive within 20 min to 1 hr after injection. Thrombus-to-blood ratios exceeded those from 125I-fibrinogen in the same animals. This method of labeling appears to provide an alternative radiolabel to 123I without compromising the function of fragment E1.


Turbulent particle transport in streams: can exponential settling be reconciled with fluid mechanics?
Most ecological studies of particle transport in streams that focus on fine particulate organic matter or benthic invertebrates use the Exponential Settling Model (ESM) to characterize the longitudinal pattern of particle settling on the bed. The ESM predicts that if particles are released into a stream, the proportion that have not yet settled will decline exponentially with transport time or distance and will be independent of the release elevation above the bed. To date, no credible basis in fluid mechanics has been established for this model, nor has it been rigorously tested against more-mechanistic alternative models. One alternative is the Local Exchange Model (LEM), which is a stochastic advection-diffusion model that includes both longitudinal and vertical spatial dimensions and is based on classical fluid mechanics. The LEM predicts that particle settling will be non-exponential in the near field but will become exponential in the far field, providing a new theoretical justification for far-field exponential settling that is based on plausible fluid mechanics. We review properties of the ESM and LEM and compare these with available empirical evidence. Most evidence supports the prediction of both models that settling will be exponential in the far field but contradicts the ESM's prediction that a single exponential distribution will hold for all transport times and distances.


[Geographic pathology of cardiovascular diseases in Belgium (author's transl)].
The association in many populations of the fat content of the diet and frequency of ischemic heart disease is mentioned. The author gives a summary of papers showing on one hand, a high correlation between the content of the diet in saturated fatty acids and ischemic heart disease morbidity and mortality rates, and, on the other hand, the protective effect of a change towards more polyunsaturated fatty acids in the diet. Several teams of Belgian researchers have recently published new facts on this matter. In the Northern Flemish speaking part of the country, saturated fatty acids have been partially replaced by polyunsaturated fatty acids from vegetable sources. This change has been followed by a general decrease of ischemic heart disease incidence, prevalence and mortality rates. In the Southern French speaking part of the country, the alimentary changes have not occurred so far; the ischemic heart disease morbidity and mortality rates stand higher.


RA regulation of keratin expression and myogenesis suggests different ways of regenerating muscle in adult amphibian limbs.
Formation of a regeneration blastema following limb amputation is believed to occur through a process of dedifferentiation. It has been suggested, however, that the cells contributed to the blastema by the stump muscle are satellite-like cells, rather than cells originated by dedifferentiation. We have previously shown that simple epithelial keratins 8 and 18 are expressed in the mesenchymal progenitor cells of the regenerating amphibian limb and in cultured cells with myogenic potential, and that their expression appears to be causally related to changes in proliferation and differentiation. We show here that retinoic acid (RA) affects the expression of these keratins differently in myogenic cells originated from normal limb and limb blastema. Furthermore, we find that the effects of RA on proliferation, myogenic differentiation and adhesion of these cells also differ. In fact, whereas RA does not affect keratin expression, proliferation or myogenic differentiation in blastemal cells, it does decrease keratin levels and thymidine incorporation and increase myogenesis in cells from normal limb. Conversely, RA increases cell adhesion only in blastemal cells. Significantly, these effects of RA on cultured cells are consistent with those observed in vivo. Overall the results presented here suggest that in the urodele limb there are two distinct cell populations with myogenic potential, one originating from dedifferentiation and one equivalent to the satellite cells of the mammalian muscle, which are likely to be primarily involved in blastema formation and muscle repair, respectively.


Optical modeling of fiber organic photovoltaic structures using a transmission line method.
An optical model has been developed and evaluated for the calculation of the external quantum efficiency of cylindrical fiber photovoltaic structures. The model is based on the transmission line theory and has been applied on single and bulk heterojunction fiber-photovoltaic cells. Using this model, optimum design characteristics have been proposed for both configurations, and comparison with experimental results has been assessed.


Early suppression of NFkappaB and IL-8 in bronchial epithelium after ozone exposure in healthy human subjects.
Exposure to elevated concentrations of ozone, a common air pollutant, has been associated with numerous adverse health effects. We have previously reported the time-course of ozone-induced airway inflammation, demonstrating an early up-regulation of vascular endothelial adhesion molecules in bronchial mucosa at 1.5 hours, followed by a neutrophilic infiltration 6 hours after exposure to 0.2 ppm ozone. We hypothesized that the neutrophilic infiltration in the bronchial mucosa would reflect an early increase in bronchial epithelial expression of redox-sensitive transcription factors and kinases regulating neutrophil chemoattractant expression. To test this hypothesis, endobronchial biopsies were obtained from healthy human subjects (n = 11) 1.5 hours after 0.2 ppm of ozone and filtered air exposures (lasting for 2 hours) and stained for mitogen-activated protein kinases (MAPKs), transcription factors, and neutrophil chemoattractants. Total epithelial staining was quantified, as well as the extent of nuclear translocation. Contrary to expectation, ozone significantly suppressed total and nuclear expression of nuclear factor kappaB (NFkappaB) in bronchial epithelial cells (p = 0.02 and p = 0.003 respectively). Similarly, the total staining for phosphorylated C-jun was suppressed (p = 0.021). Expression of interleukin 8 (IL-8) in the bronchial epithelium was likewise decreased after ozone (p = 0.018), while GRO-alpha, ENA-78, C-fos, p-p38, p-JNK, and p-ERK stainings were unchanged. These data suggest that the redox-sensitive NFkappaB and activator protein 1 (AP-1) pathways within the human bronchial epithelium do not seem to be involved in the early inflammatory cell recruitment pathways in healthy subjects exposed to ozone.


Dating couples' attachment styles and patterns of cortisol reactivity and recovery in response to a relationship conflict.
This study investigated theoretically predicted links between attachment style and a physiological indicator of stress, salivary cortisol levels, in 124 heterosexual dating couples. Cortisol was assessed at 7 points before and after an experimental conflict negotiation task, creating a trajectory of stress reactivity and recovery for each participant. Growth modeling of cortisol data tested hypotheses that (a) insecurely attached individuals show patterns of greater physiological stress reactions to interpersonal conflict than do securely attached individuals and (b) people with insecurely attached partners show patterns of greater stress in reaction to relationship conflict than those with securely attached partners. Hypothesis 1 was supported, but men and women differed in the type of insecure attachment that predicted stress trajectories. Hypothesis 2 was supported for men, but not for women. The discussion emphasizes the role of gender role norms and partner characteristics in understanding connections between adult attachment and patterns of cortisol responses to interpersonal stress.


Toponostics of invasive ductal breast carcinoma: combination of spatial protein expression imaging and quantitative proteome signature analysis.
Due to enormous advances in quantitative proteomics and in immunohistochemistry (pathology), the two research areas have now reached the state to be successfully interwoven in order to tackle challenges in toponostics and to open tumor-targeted systems pathology approaches. In this study the differential expressions of candidate proteins nucleophosmin, nucleoside diphosphate kinase A/B (NDKA/B), osteoinducive factor (mimecan), and pyru-vate kinase M2 from a quantitative proteome signature for invasive ductal breast cancer were determined by immunohistochemistry on 53 tissue slices from formalin-fixed and paraffin-embedded tumor and control tissue samples from ten patients and fourteen controls. In addition, 87 images from the Human Protein Atlas representing seven tumor and nine normal breast tissue samples were investigated by computer-assisted semi-quantitative density measurements on nucleophosmin, nucleoside diphosphate kinase A/B (NDKA/B), osteoinducive factor (mimecan), pyruvate kinase M2, glyceraldehyde-3-phosphate dehydro-genase (GAP-DH), and mimecan (osteoinductive factor). Both IHC data sets match well to each other and support the quantitative proteome analysis data. Determining spatial distribution of signature protein expressions by protein imaging on morphologically intact tissue samples at the sub-cellular level and, hence, keeping all topological information, presents an added value to quantitative proteome data. Such comprehensive data sets are needed for both, pathway analyses and for "next generation clinical diagnostics" approaches.


Eating behavior and the experience of hunger following gastric bypass surgery for morbid obesity.
Numerous different factors may contribute to the varying degrees of success observed following gastric bypass surgery. It is likely that alterations in the subjective experiences of hunger and satiety, as well as behavioral factors, are important. Our aim was to investigate the association of several factors, including qualitative aspects of hunger and satiety, eating patterns, and the emotional valence of different foods, to the weight loss that occurred following obesity surgery. A questionnaire covering aspects of hunger, eating and satiety was administered to three groups: (1) a group of people who had undergone gastric bypass surgery with an acceptable weight loss; (2) a morbidly obese group of patients prior to their surgical intervention; (3) a group of people of normal weight. There were significant differences amongst the three groups in scoring on standardized eating disorder scales, in the amount they could eat, and in the experience of hunger. The presurgery, waiting-list group was more receptive to food-related than interoceptive cues when deciding to stop eating. 'Eating styles' also differed across the groups. It is concluded that changes in specific food-related behaviors and other psychological variables interact with the physical restriction to eating. The relative weighting of other variables needs further exploration.


Spironolactone in pulmonary arterial hypertension: results of a cross-over study.
The renin-angiotensin-aldosterone system is implicated in the pathophysiology of pulmonary arterial hypertension. We undertook this study to determine the effects of spironolactone, a mineralocorticoid receptor blocker, on collagen metabolism in pulmonary arterial hypertension patients. After obtaining institutional review board approval and informed consent, 42 pulmonary arterial hypertension patients were prospectively enrolled and 35 patients completed the 16-week randomized double-blinded crossover clinical trial. Subjects received 50 mg spironolactone or placebo and at the end of week 8, treatment arm was switched. Circulating levels of collagen biomarkers, brain natriuretic peptide, and aldosterone levels were measured, and six-minute walk distance, liver function tests, and echocardiogram data were collected at weeks 0, 8, and 16. Mean age was 45 ± 15 years and 87% were females. At baseline, brain natriuretic peptide and aldosterone levels were 74 ± 95 pg/ml and 7 ± 8 pg/ml, respectively. There was no change in the levels of amino-terminal propeptide of procollagen type III (PIIINP), MMP-9, TIMP-1, and MMP-9/TIMP-1 ratio at weeks 8 and 16 compared to baseline values in placebo arm and treatment arm. The baseline six-min walk distance was 436 ± 115 meters at baseline and no change in walk distance was noted at weeks 8 and 16 (P = 0.372). None of the patients developed hyperkalemia or liver function test abnormalities at weeks 8 and 16 requiring discontinuation of study drug. Our study showed no change in collagen metabolite levels in pulmonary arterial hypertension patients treated with spironolactone. Spironolactone was safe and well tolerated by pulmonary arterial hypertension patients with no increased hyperkalemia or liver function test abnormalities.


Prevotella copri-related effects of a therapeutic food for malnutrition.
Preclinical and clinical studies are providing evidence that the healthy growth of infants and children reflects, in part, healthy development of their gut microbiomes1-5. This process of microbial community assembly and functional maturation is perturbed in children with acute malnutrition. Gnotobiotic animals, colonized with microbial communities from children with severe and moderate acute malnutrition, have been used to develop microbiome-directed complementary food (MDCF) formulations for repairing the microbiomes of these children during the weaning period5. Bangladeshi children with moderate acute malnutrition (MAM) participating in a previously reported 3-month-long randomized controlled clinical study of one such formulation, MDCF-2, exhibited significantly improved weight gain compared to a commonly used nutritional intervention despite the lower caloric density of the MDCF6. Characterizing the 'metagenome assembled genomes' (MAGs) of bacterial strains present in the microbiomes of study participants revealed a significant correlation between accelerated ponderal growth and the expression by two Prevotella copri MAGs of metabolic pathways involved in processing of MDCF-2 glycans1. To provide a direct test of these relationships, we have now performed 'reverse translation' experiments using a gnotobiotic mouse model of mother-to-offspring microbiome transmission. Mice were colonized with defined consortia of age- and ponderal growth-associated gut bacterial strains cultured from Bangladeshi infants/children in the study population, with or without P. copri isolates resembling the MAGs. By combining analyses of microbial community assembly, gene expression and processing of glycan constituents of MDCF-2 with single nucleus RNA-Seq and mass spectrometric analyses of the intestine, we establish a principal role for P. copri in mediating metabolism of MDCF-2 glycans, characterize its interactions with other consortium members including Bifidobacterium longum subsp. infantis, and demonstrate the effects of P. copri-containing consortia in mediating weight gain and modulating the activities of metabolic pathways involved in lipid, amino acid, carbohydrate plus other facets of energy metabolism within epithelial cells positioned at different locations in intestinal crypts and villi. Together, the results provide insights into structure/function relationships between MDCF-2 and members of the gut communities of malnourished children; they also have implications for developing future prebiotic, probiotic and/or synbiotic therapeutics for microbiome restoration in children with already manifest malnutrition, or who are at risk for this pervasive health challenge.


Autoimmune Thyroid Diseases and Thyroid Cancer in Pemphigus: A Big Data Analysis.
There is a little consensus regarding the association of pemphigus with autoimmune thyroid diseases. While this association had been confirmed by some observational studies, others had refuted it. We aimed to study the association between pemphigus and Hashimoto's thyroiditis, Grave's disease, and thyroid cancer using a large-scale real-life computerized database. A cross-sectional study was performed to compare pemphigus patients with age-, sex-, and ethnicity-matched control subjects regarding the prevalence of overt thyroid diseases. Chi-square and t-tests were used for univariate analysis, and a logistic regression model was used for multivariate analysis. The study was performed using the computerized database of Clalit Healthcare Services ensuring 4.5 million individuals. A total of 1,985 pemphigus patients and 9,874 controls were included in the study. The prevalence of Hashimoto's thyroiditis (12.9 vs. 11.9%; P = 0.228), Graves's disease (0.7 vs. 0.7%; P = 0.986), and thyroid cancer (0.7 vs. 0.5%; P = 0.305) were comparable among patients with pemphigus and control subjects. In sex-stratified analysis, pemphigus associated significantly with Hashimoto's thyroiditis among male patients (OR, 1.36; 95% CI, 1.04-1.79). In multivariate analysis adjusting for potential confounding factors, no independent associations between the conditions were revealed. Study findings were robust to sensitivity analysis that included only patients under pemphigus-specific treatments. In conclusion, Hashimoto's thyroiditis was found to be associated with pemphigus only among male patients, but not among all patients. Physicians treating patients with pemphigus might be aware of this possible association. This study does not provide a clue for an association of pemphigus with Grave's disease or thyroid cancer.


UHV STM I(V) and XPS studies of aryl diazonium molecules assembled on Si(111).
Molecular layers formed from 4-trifluoromethylbenzenediazonium tetrafluoroborate and 4-Methylbenzenediazonium tetrafluoroborate have been assembled on H-passivated Si(111) and studied by UHV STM and XPS. STM imaging shows well-developed Si(111) step edges and terraces both on Si(111):H and Si(111) substrates covered with a molecular layer. STM I(V) data acquired at different tip-substrate separations reveals a factor of approximately 10 enhancement in current for positive bias voltage when current flows through the 4-trifluoromethyl molecule when compared to the 4-methyl variant. The observed current enhancement in I(V) can be understood by comparing the projected density of states of the two molecule-Si systems calculated using a density functional theory local density approximation after geometry optimization was performed via the conjugate gradient method. XPS data independently confirm that H-passivated Si(111) remains oxygen free for short exposures to ambient conditions and provide evidence that the molecules chemically react with the silicon surface.


Examining the Overlap Between ADHD and Autism Spectrum Disorder (ASD) Using Candidate Endophenotypes of ADHD.
Objective: Recent discussions of aetiological overlap between ADHD and Autism Spectrum Disorder (ASD) require comparative studying of these disorders. We examined performance of ASD patients with (ASD+) and without (ASD-) comorbid ADHD, ADHD patients, and controls for selected putative endophenotypes of ADHD: Intrasubject Variability (ISV) of reaction times, working memory (WM), inhibition, and temporal processing. We found that patients with ADHD or ASD+, but not ASD-, had elevated ISV across the entire task battery and temporal processing deficits, and that none of the groups were impaired in WM or inhibition. High levels of ISV and generally poor performance in ASD+ patients were only partially due to additive effects of the pure disorders. Overall, we conclude that, within our limited but heterogeneous task battery, ISV and temporal processing deficits are most sensitive to ADHD symptomatology and that controlling for ADHD comorbidity is mandatory when assessing ISV in autism.


Esophageal pH-monitoring in nonbrachycephalic dogs; a reference.
To establish parameters that describe acidic gastroesophageal reflux (GER) events in nonbrachycephalic, hospitalized dogs without gastrointestinal disease following short total intravenous anesthesia, to establish upper reference limits for parameters that describe GER. Clinical prospective study. Healthy, client-owned dogs presenting for elective orthopedic surgery. Dogs were sedated with IM methadone (0.2 mg/kg) and medetomidine (5 ug/kg), followed by alfaxalone total intravenous anesthesia. The Digitrapper esophageal dual pH monitoring probe was placed transnasally into the esophagus. Dogs were unsedated during the subsequent recording period. A GER event was defined as esophageal pH less than 4.0. Parameters that described GER were: (1) number of GER events per hour, and (2) cumulative esophageal acid exposure (percentage of recording duration) at each sensor. Upper reference limits were calculated for each parameter. Thirty-five dogs were included (median age 7 years, range 1-12). The median recording duration was 21.1 h (range 13.6-29.3). Productive regurgitation was not noted in any dog. The median number of distal and proximal GER events per hour was 0.3 (range 0-4.3) and 0 (range 0-1), respectively. The median cumulative distal and proximal esophageal acid exposure was 0.2% (range 0.3-9%) and 0% (range 0%-1%), respectively. Upper reference limits for distal and proximal GER per hour was 2.4 and 0.4, respectively, and, for cumulative distal and proximal esophageal acid exposure, 2.3% and 0%, respectively. Dogs undergoing esophageal pH monitoring in a similar hospital setting with parameters above these upper reference limits have excessive GER.


Quality of life in breast cancer survivors as identified by focus groups.
Currently, over 1,700,000 women are living with breast cancer in the United States. These long-term survivors of breast cancer are challenged to redirect their energy from issues of cancer treatment and early side effects toward quality of life issues related to long-term survivorship, such as menopause, infertility, fear of recurrence, family distress, and uncertainty. In an attempt to obtain patient perspectives on quality of life and health care issues faced by breast cancer survivors, focus group methodology was utilized in the first year of a 2 year study. The sample was stratified to represent three age groups: < 40 years, 40-60 years, and > 60, and was intended to represent different developmental levels believed to have varying experiences with quality of life and potentially divergent needs following breast cancer diagnosis. Results of these focus groups revealed unique quality of life concerns of breast cancer survivors across four domains of physical, psychological, social, and spiritual well being. Each of these domains yields important implications for future research and clinical practice.


Photophysics and halide quenching of a cationic metalloporphyrin in water.
In this work, the steady state S0-S1 and S0-S2 absorption and emission behaviour of the water-soluble tetrakis(N-methyl-4-pyridyl)porphyrin zinc(ii) tetrachloride (ZnTMPyP) in media of constant and high ionic strength, both with and without iodide ions as a fluorescence quencher, was measured. The quenching of the ZnTMPyP S1 state by iodide ions proceeds primarily through diffusion-limited interaction in an encounter pair but the formation of a loose association between the ZnTMPyP S1 state and iodide ions also provides a minor quenching pathway. The ZnTMPyP S2 state was quenched minimally by iodide, likely through an electron transfer mechanism at an average donor-acceptor distance of ~0.7 nm. The results presented here highlight the notion that significant iodide quenching of the ZnTMPyP S1 state can be a source of inefficiencies in porphyrin-based dye-sensitized solar cells. The minimal quenching of the S2 state indicates that no significant loss of efficiency will be introduced by using iodide as component of the electrolyte system in upconversion by triplet-triplet annihilation (UC-TTA) enhanced solar cells.


Glandular excision in total glandular mastectomy and modified radical mastectomy: a comparison.
Total glandular mastectomy and modified radical mastectomy were compared for the amount of breast tissue remaining after surgery. Multiple biopsies were taken from the anterior chest walls of women following total glandular mastectomy (N = 27) and modified radical mastectomy (N = 28) to try to detect any residual glandular tissue. Regardless of procedure performed, breast tissue was identified histologically in 5 percent of all biopsy specimens (159 and 161, respectively). One of every five operative fields was shown to have glandular elements in at least one of the biopsy sites; the positive biopsies did not form a discernible pattern. The residual breast tissue in each of these patients averaged less than 1 gm. On the basis of this study, modified radical mastectomy and total glandular mastectomy appear to be equally effective in removing most of the breast.