Chemoselective cysteine or disulfide modification via single atom substitution in chloromethyl acryl reagents.
The development of bioconjugation chemistry has enabled the combination of various synthetic functionalities to proteins, giving rise to new classes of protein conjugates with functions well beyond what Nature can provide. Despite the progress in bioconjugation chemistry, there are no reagents developed to date where the reactivity can be tuned in a user-defined fashion to address different amino acid residues in proteins. Here, we report that 2-chloromethyl acryl reagents can serve as a simple yet versatile platform for selective protein modification at cysteine or disulfide sites by tuning their inherent electronic properties through the amide or ester linkage. Specifically, the 2-chloromethyl derivatives (acrylamide or acrylate) can be obtained via a simple and easily implemented one-pot reaction based on the coupling reaction between commercially available starting materials with different end-group functionalities (amino group or hydroxyl group). 2-Chloromethyl acrylamide reagents with an amide linkage favor selective modification at the cysteine site with fast reaction kinetics and near quantitative conversations. In contrast, 2-chloromethyl acrylate reagents bearing an ester linkage can undergo two successive Michael reactions, allowing the selective modification of disulfides bonds with high labeling efficiency and good conjugate stability.


Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation.
In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. Cancer Res; 77(18); 4745-54. ©2017 AACR.


Evidence for cross-protection but not type-replacement over the 11 years after human papillomavirus vaccine introduction.
Examination of cross-protection and type replacement after human papillomavirus (HPV) vaccine introduction is essential to guide vaccination recommendations and policies. The aims of this study were to examine trends in non-vaccine-type HPV: 1) genetically related to vaccine types (to assess for cross-protection) and 2) genetically unrelated to vaccine types (to assess for type replacement), among young women 13-26 years of age during the 11 years after HPV vaccine introduction. Participants were recruited from a hospital-based teen health center and a community health department for four cross-sectional surveillance studies between 2006 and 2017. Participants completed a survey that assessed sociodemographic characteristics and behaviors, and cervicovaginal swabs were collected and tested for 36 HPV genotypes. We determined changes in proportions of non-vaccine-type HPV prevalence and conducted logistic regression to determine the odds of infection across the surveillance studies, propensity-score adjusted to control for selection bias. Analyses were stratified by vaccination status. Among vaccinated women who received only the 4-valent vaccine (n = 1,540), the adjusted prevalence of HPV types genetically related to HPV16 decreased significantly by 45.8% (adjusted odds ratio [AOR] = 0.48, 95% confidence interval [CI] = 0.31-0.74) from 2006-2017, demonstrating evidence of cross-protection. The adjusted prevalence of HPV types genetically related to HPV18 did not change significantly (14.2% decrease, AOR = 0.83, 95% CI = 0.56-1.21). The adjusted prevalence of HPV types genetically unrelated to vaccine types did not change significantly (4.2% increase, AOR = 1.09, CI = 0.80-1.48), demonstrating no evidence of type replacement. Further studies are needed to monitor for cross-protection and possible type replacement after introduction of the 9-valent HPV vaccine.


Modified polyoxometalate: a novel monocapped bi-supporting and reduced α-Keggin structure {PMo12O40[Cu(2,2'-bpy)]}[Cu(2,2'-bpy)(en)(H2O)]2.
A novel modified polyoxometalate, {PMo12O40[Cu(2,2'-bpy)]}[Cu(2,2'-bpy)(en)(H2O)]2 [2,2'-bpy is 2,2'-bipyridyl (C10H8N2) and en is ethylenediamine (C2H8N2)], has been synthesized hydrothermally and structurally characterized by elemental analysis, TG, IR, XPS and single-crystal X-ray diffraction. The structural analysis reveals that the compound contains the reduced Keggin polyanion [PMo12O40]6- as the parent unit, which is monocapped by [Cu(2,2'-bpy)]2+ fragments via four bridging O atoms on an {Mo4O4} pit and bi-supported by two [Cu(2,2'-bpy)(en)(H2O)]2+ coordination cations simultaneously. There exist strong intramolecular π-π stacking between the capping and supporting units, which play a stabilizing role during the crystallization of the compound. Adjacent POM clusters are further aggregated to form a three-dimensional supramolecular network through noncovalent forces, hydrogen bonding and π-π stacking interactions. In addition, the photocatalytic properties were investigated in detail, and the results indicated that the compound can be used as a photocatalyst towards the decomposition of the organic pollutant methylene blue (MB).


Demyelinating optic neuritis: clinical features and differential diagnosis.
Optic neuritis is a common cause of sudden visual impairment in young adults. Early recognition by the clinician would alleviate much of the anxiety experienced by sufferers, but other conditions that may cause permanent blindness must be excluded. These can usually be discerned from the history and confirmed by a brief neuro-ophthalmological examination.


Cannabis and the Cornea.
Purpose: While cannabis has the potential to reduce corneal pain, cannabinoids might induce side effects. This review article examines the effects of cannabinoids on the cornea. As more states and countries consider the legalization of adult cannabis use, health-care providers will need to identify ocular effects of cannabis consumption.Methods: Studies included in this review examined the connection between cannabis and the cornea, more specifically anti-nociceptive and anti-inflammatory actions of cannabinoids. NCBI Databases from 1781 up to December 2019 were consulted.Results: Five studies examined corneal dysfunctions caused by cannabis consumption (opacification, decreased endothelial cell density). Twelve studies observed a reduction in corneal pain and inflammation (less lymphocytes, decreased corneal neovascularization, increased cell proliferation and migration).Conclusion: More than half of the studies examined the therapeutic effects of cannabinoids on the cornea. As the field is still young, more studies should be conducted to develop safe cannabinoid treatments for corneal diseases.


Novel families of vacuolar amino acid transporters.
Amino acids are compartmentalized in the vacuoles of microorganisms and plants. In Saccharomyces cerevisiae, basic amino acids accumulate preferentially into vacuoles but acidic amino acids are almost excluded from them. This indicates that selective machineries operate at the vacuolar membrane. The members of the amino acid/auxin permease family and the major facilitator superfamily involved in the vacuolar compartmentalization of amino acids have been recently identified in studies using S. cerevisiae. Homologous genes for these transporters are also found in plant and mammalian genomes. The physiological significance in response to nitrogen starvation can now be discussed.


The quantitative determination of glycosaminoglycans in urine with Alcian Blue 8GX.
1. The effect of MgCl(2) concentration on the interaction of Alcian Blue 8GX and glycosaminoglycans in the urine of patients with mucopolysaccharidosis was studied by using a new quantitative micro method for the measurement of Alcian Blue-glycosaminoglycan complexes. This provided a means of measuring the critical electrolyte concentrations of urinary glycosaminoglycans. 2. Theoretical considerations based on the preceding paper (Whiteman, 1973) and experimental evidence provided here show that Alcian Blue 8GX may be used for the direct quantitative determination of total urinary glycosaminoglycans. The method is simple, requires sample volumes of 50mul or less, and gives results comparable with those obtained by other more complicated methods.


[Acute focal bacterial nephritis].
Acute focal bacterial nephritis is a very rare type of infective nephritis. It is characterised by groups of abscesses of 1 to 5 mm. situated in the renal cortex with pus tracking to the papillae. Urography is normal or suggests a non-specific enlargement. On sonography, non-homogeneous foci with reduced echogenicity are observed. Unenhanced CT shows indefinite lesions of reduced density, which do not enhance as much as the surrounding parenchyma after contrast injection. On angiography these areas appear as hypovascular lesions. The disease must be differentiated from a malignant renal tumour and from an acute renal abscess. The clinical findings and the results of sonographic and radiological observations on five patients with acute focal bacterial nephritis are described.


Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34.
We performed genetic mapping studies of an 11-generation pedigree with an autosomal dominant, juvenile-onset motor-systems disease. The disorder is characterized by slow progression, distal limb amyotrophy, and pyramidal tract signs associated with severe loss of motor neurons in the brain stem and spinal cord. The gene for this disorder, classified as a form of juvenile amyotrophic lateral sclerosis (ALS), is designated "ALS4." We performed a genomewide search and detected strong evidence for linkage of the ALS4 locus to markers from chromosome 9q34. The highest LOD score (Z) was obtained with D9S1847 (Z=18.8, recombination fraction of .00). An analysis of recombinant events identified D9S1831 and D9S164 as flanking markers, on chromosome 9q34, that define an approximately 5-cM interval that harbors the ALS4 gene. These results extend the degree of heterogeneity within familial ALS syndromes, and they implicate a gene on chromosome 9q34 as critical for motor-neuron function.


[Dietary fatty acids and delta 5 desaturation by rat liver microsomes].
This paper reports a comparative study of the influence of dietary fats on the delta 5 desaturation of dihomo-gamma-linolenic acid (20:3 n-6) to arachidonic acid (20:4 n-6) using rat liver microsomes. The kinetic conditions needed to measure the specific activity of desaturation have been described. The rate of delta 5 desaturation was studied at two substrate levels. In a first series of experiments, the liver microsomes of animals maintained on a chow diet showed less desaturation activity than those of animals fed a fat-free diet. For longer periods of control (fat-free) diet time, the amount of 20:4 n-6 produced in vitro was depressed and the 20:3 n-9/20:4 n-6 ratio in total lipids was enhanced. In a second series of experiments, groups of rats were fed semi-synthetic diets which contained 5 or 10% of dietary fats with different percentages of linoleic acid (18:2 n-6), alpha-linolenic acid (18:3 n-3), oleic acid (18:1 n-9) or saturated fatty acids. Liver microsomal delta 5 desaturase activities that were generally depressed, when compared with control rats, were moderately affected by dietary fats, except with a diet containing saturated fatty acids or alpha-linolenic acid for which delta 5 desaturation was decreased. These observations are discussed in relation with the recent literature.


Chlorpromazine affects glioblastoma bioenergetics by interfering with pyruvate kinase M2.
Glioblastoma (GBM) is the most frequent and lethal brain tumor, whose therapeutic outcome - only partially effective with current schemes - places this disease among the unmet medical needs, and effective therapeutic approaches are urgently required. In our attempts to identify repositionable drugs in glioblastoma therapy, we identified the neuroleptic drug chlorpromazine (CPZ) as a very promising compound. Here we aimed to further unveil the mode of action of this drug. We performed a supervised recognition of the signal transduction pathways potentially influenced by CPZ via Reverse-Phase Protein microArrays (RPPA) and carried out an Activity-Based Protein Profiling (ABPP) followed by Mass Spectrometry (MS) analysis to possibly identify cellular factors targeted by the drug. Indeed, the glycolytic enzyme PKM2 was identified as one of the major targets of CPZ. Furthermore, using the Seahorse platform, we analyzed the bioenergetics changes induced by the drug. Consistent with the ability of CPZ to target PKM2, we detected relevant changes in GBM energy metabolism, possibly attributable to the drug's ability to inhibit the oncogenic properties of PKM2. RPE-1 non-cancer neuroepithelial cells appeared less responsive to the drug. PKM2 silencing reduced the effects of CPZ. 3D modeling showed that CPZ interacts with PKM2 tetramer in the same region involved in binding other known activators. The effect of CPZ can be epitomized as an inhibition of the Warburg effect and thus malignancy in GBM cells, while sparing RPE-1 cells. These preclinical data enforce the rationale that allowed us to investigate the role of CPZ in GBM treatment in a recent multicenter Phase II clinical trial.


Identification of proteins from the secretory/excretory products (SEPs) of the branchiuran ectoparasite Argulus foliaceus (Linnaeus, 1758) reveals unique secreted proteins amongst haematophagous ecdysozoa.
It is hypothesised that being a blood-feeding ectoparasite, Argulus foliaceus (Linnaeus, 1758), uses similar mechanisms for digestion and host immune evasion to those used by other haematophagous ecdysozoa, including caligid copepods (e.g. sea louse). We recently described and characterised glands associated with the feeding appendages of A. foliaceus using histological techniques. The work described in the present study is the first undertaken with the objective of identifying and partially characterising the components secreted from these glands using a proteomic approach. Argulus foliaceus parasites were sampled from the skin of rainbow trout (Oncorhynchus mykiss), from Loch Fad on the Isle of Bute, Scotland, UK. The proteins from A. foliaceus secretory/excretory products (SEPs) were collected from the supernatant of artificial freshwater conditioned with active adult parasites (n = 5-9 per ml; n = 560 total). Proteins within the SEPs were identified and characterised using LC-ESI-MS/MS analysis. Data are available via ProteomeXchange with identifier PXD016226. Data mining of a protein database translated from an A. foliaceus dataset using ProteinScape allowed identification of 27 predicted protein sequences from the A. foliaceus SEPs, each protein matching the criteria of 2 peptides with at least 4 contiguous amino acids. Nine proteins had no matching sequence through OmicsBox (Blast2GO) analysis searches suggesting that Argulus spp. may additionally have unique proteins present in their SEPs. SignalP 5.0 software, identified 13 proteins with a signal sequence suggestive of signal peptides and supportive of secreted proteins being identified. Notably, the functional characteristics of identified A. foliaceus proteins/domains have also been described from the salivary glands and saliva of other blood-feeding arthropods such as ticks. Identified proteins included: transporters, peroxidases, metalloproteases, proteases and serine protease inhibitors which are known to play roles in parasite immune evasion/induction (e.g. astacin), immunomodulation (e.g. serpin) and digestion (e.g. trypsin). To our knowledge, the present study represents the first proteomic analysis undertaken for SEPs from any branchiuran fish louse. Here we reveal possible functional roles of A. foliaceus SEPs in digestion and immunomodulation, with a number of protein families shared with other haematophagous ectoparasites. A number of apparently unique secreted proteins were identified compared to other haematophagous ecdysozoa.


Chronic insomnia in kidney transplant recipients.
Recent studies confirmed that sleep disorders have a significant impact on various aspects of health in patients at different stages of chronic kidney disease. At the same time, there is an almost complete lack of information on the prevalence and correlates of insomnia in kidney transplant recipients. In a cross-sectional study, the Athens Insomnia Scale was used to assess the prevalence of insomnia in a large sample of kidney transplant recipients compared with wait-listed dialysis patients and also a matched group obtained from a nationally representative sample of the Hungarian population. The prevalence of insomnia was 15% in wait-listed patients, whereas it was only 8% in transplant recipients (P < 0.001), which, in turn, was not different from the prevalence of this sleep problem in the sample of the general population (8%). Prevalences of insomnia in the transplant group were 5%, 7%, and 14% for the groups with glomerular filtration rates (GFRs) greater than 60 mL/min (> 1.00 mL/s), 30 to 60 mL/min (0.50 to 1.00 mL/s), and less than 30 mL/min (< 0.5 mL/s), respectively (P < 0.01). However, estimated GFR was no longer associated significantly with insomnia in the transplant population after statistical adjustment for several covariates. In a multivariate model, insomnia was significantly and independently associated with treatment modality (transplantation versus wait listing), as well as the presence of depression, restless legs syndrome, and high risk for obstructive sleep apnea syndrome, and with self-reported comorbidity. The prevalence of insomnia was substantially less in the transplant group than in wait-listed dialysis patients and similar to that observed in the general population. Because this condition potentially is treatable, attention should be directed to the appropriate diagnosis and management of insomnia in the kidney transplant recipient population.


Regular Practice of Physical Activity Improves Cholesterol Transfers to High-Density Lipoprotein (HDL) and Other HDL Metabolic Parameters in Older Adults.
The effects of regular physical activity on two important anti-atherosclerosis functions of high-density lipoprotein (HDL), namely its capacity to receive both forms of cholesterol and its anti-oxidant function, were investigated in this study comparing older adults with young individuals. One-hundred and eight healthy adult individuals were enrolled and separated into the following groups: active older (60-80 yrs, n = 24); inactive older (60-79 yrs, n = 21); active young (20-34 yrs, n = 39); and inactive young (20-35 yrs, n = 24). All performed cardiopulmonary tests. Blood samples were collected in order to assess the following measures: lipid profile, HDL anti-oxidant capacity, paraoxonase-1 activity, HDL subfractions, and lipid transfer to HDL. Comparing active older and active young groups with inactive older and inactive young groups, respectively, the active groups presented higher HDL-C levels (p < 0.01 for both comparisons), unesterified cholesterol transfer (p < 0.01, p < 0.05), and intermediate and larger HDL subfractions (p < 0.001, p < 0.01) than the respective inactive groups. In addition, the active young group showed higher esterified cholesterol transfer than the inactive young group (p < 0.05). As expected, the two active groups had higher VO2peak than the inactive groups; VO2peak was higher in the two younger than in the two older groups (p < 0.05). No differences in unesterified and esterified cholesterol transfers and HDL subfractions were found between active young and active older groups. HDL anti-oxidant capacity and paraoxonase-1 activity were equal in all four study groups. Our data highlight and strengthen the benefits of regular practice of physical activity on an important HDL function, the capacity of HDL to receive cholesterol, despite the age-dependent decrease in VO2peak.


Cross species genomic analysis identifies a mouse model as undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma.
Undifferentiated pleomorphic sarcoma/Malignant Fibrous Histiocytoma (MFH) is one of the most common subtypes of human soft tissue sarcoma. Using cross species genomic analysis, we define a geneset from the LSL-Kras(G12D); Trp53(Flox/Flox) mouse model of soft tissue sarcoma that is highly enriched in human MFH. With this mouse geneset as a filter, we identify expression of the RAS target FOXM1 in human MFH. Expression of Foxm1 is elevated in mouse sarcomas that metastasize to the lung and tissue microarray analysis of human MFH correlates overexpression of FOXM1 with metastasis. These results suggest that genomic alterations present in human MFH are conserved in the LSL-Kras(G12D); p53(Flox/Flox) mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model.


[Changes in blood microelements in lymphedema].
Reviews data on 548 patients with various stages and forms of lymphedema; formed elements of the blood and plasma were analyzed in 84 of these, aged 16 to 64. Zinc, iron, cobalt, antimony, cesium, cerium, selenium, scandium, rubidium, chromium levels were measured by neutral activation technique. Changes in concentrations of plasma trace elements and formed elements of the blood were detected, related to the disease stage. Analysis of blood trace elements in patients with lymphedema appears to be a useful criterion for the assessment of disorders in lymph outflow in various stages of the disease.


Male predominance in ketosis-prone diabetes mellitus.
The incidence of ketosis-prone diabetes mellitus (KPDM) shows a higher prevalence in men. The clear male predominance of this syndrome and its underlying pathogenesis mechanisms are unclear. KPDM, once described as atypical diabetes mellitus, idiopathetic type 1 diabetes (type 1B diabetes) and flatbush diabetes, is an uncommon form of diabetes characterized by severe reversible insulin deficiency. KPDM was first described and mostly observed in males of African-American descent and recently in Asian populations, including Japanese and Chinese. Patients with KPDM often present acutely with diabetic ketoacidosis without any immunological autoantibody to islet antigens of classic type 1 diabetes but demonstrate clinical and metabolic features of type 2 diabetes. Accumulating data indicated that gender-related body fat distribution, hormonal and genetic factors are associated with the diabetic process and the human glucose homeostasis and metabolism. A controversial question is whether and to what degree those factors contribute to the phenomenon of male predominance in KPDM. The present review focuses on the role of gender hormones and other potential precipitating factors in explaining the male predominance in KPDM patients.


[Clinical highfield MR].
MRI-imaging using a field strength above 2 Tesla -- recently termed "highfield MRI" -- has come into clinical use in the last three years. For technical reasons, the initial application of highfield MRI concentrated on examinations of the brain. By improving the technology and solving specific problems, it has now become possible to perform total body scans. Only a few studies have been carried out to determine whether the use of highfield MRI is advantageous compared to scanning at the usual field strengths, and what these advantages might be. MR-angiography of cerebral vessels as well as certain aspects of structural imaging of the brain seem to benefit. BOLD contrast fMRI, perfusion analysis and spectroscopy all seem to improve. For total body scanning, it is already possible to examine certain areas in "1.5 Tesla quality", in some cases shortening scanning time considerably. This survey summarises the present state of knowledge, realising that the presentation might not be all-comprising since progress in this field is very dynamic.


Calcified hematoma of the greater omentum in an F-15 fighter pilot.
A high performance aircraft test pilot who presented with acalculous cholecystitis was found to have a calcified omental hematoma adjacent to the gallbladder. Omental hematomas have not previously been linked to flight in high performance aircraft. Current prevailing hypotheses regarding etiologies of omental hematomas include rapid blood flow shifts and venous fragility. Forces encountered in high performance aircraft may increase the chance of omental hemorrhage.


Radiculomyelopathy associated with herpes simplex genitalis treated with adenosine arabinoside.
A case of herpes simplex genitalis producing radiculomyelopathy with urinary retention is reported. The patient was treated with adenosine arabinoside intravenously and made a complete recovery over 4 weeks. Although herpes simplex genitalis is common, neurological sequelae, particularly cord involvement, are distinctly rare. It should, nevertheless, be considered in the differential diagnosis of urinary retention, with or without long-tract signs, in young patients.


Platelet-derived growth factor and heparin-like glycosaminoglycans regulate thrombospondin synthesis and deposition in the matrix by smooth muscle cells.
Platelet-derived growth factor (PDGF), a smooth muscle cell (SMC) mitogen, and heparin-like glycosaminoglycans, known inhibitors of SMC growth and migration, were found to regulate thrombospondin synthesis and matrix deposition by cultured rat aortic SMC. The synthesis and distribution of thrombospondin was examined in growth-arrested SMCs, in PDGF-stimulated SMCs, and in heparin-treated SMCs using metabolic labeling and immunofluorescence techniques. Thrombospondin synthesis in response to purified PDGF occurred within 1 h after addition of growth factor to growth-arrested SMCs, peaked at 2 h, and returned to baseline levels by 5 h. The induction of synthesis of thrombospondin by PDGF was dose dependent, with a maximal effect observed at 2.5 ng/ml. Actinomycin D (2 micrograms/ml) inhibited thrombospondin induction by PDGF, suggesting a requirement for new RNA synthesis. In the presence of heparin and related polyanions, the incorporation of thrombospondin into the SMC extracellular matrix was markedly reduced. This effect was dose dependent with a maximal effect observed at a heparin concentration of 1 microgram/ml. Heparin did not affect the ability of SMCs to synthesize thrombospondin in response to PDGF. We interpret these data to suggest a role for thrombospondin in the SMC proliferative response to PDGF and in the regulation of SMC growth and migration by glycosaminoglycans.


BCG protects toddlers during a tuberculosis outbreak.
In 2007, an outbreak of tuberculosis occurred in a toddler population attending two child care centres in Cork, Ireland. Of 268 children exposed, 18 were eventually diagnosed with active tuberculosis. We present the initial clinical and radiographic characteristics of the active disease group. Mantoux testing was positive in only 66% of cases. All cases were either pulmonary or involved hilar adenopathy on chest radiograph; there were no cases of disseminated disease or meningitis. 24% of the exposed children had been previously vaccinated with BCG, and no case of active disease was found in this group (p = 0.016), suggesting a profound protective effect of BCG in this population. Our experience provides evidence supporting a protective effect of BCG against pulmonary disease in young children.


Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies.
Inactivation of the cyclin-dependent kinase inhibitors p16INK4A and p15INK4B are frequent alterations in neoplasia, often resulting from homozygous deletion or promoter region hypermethylation. We have analyzed both modes of inactivation of p15INK4B and p16INK4A in the major types of adult and pediatric hematological malignancies. Hypermethylation of p15INK4B, without alteration of p16INK4A, was an almost universal finding in adult acute myelogenous leukemia, and occurred very frequently in adult acute lymphocytic leukemia and pediatric acute myelogenous leukemia and acute lymphocytic leukemia. In contrast, neither p15INK4B nor p16INK4A were inactivated in any stage of chronic myelogenous leukemia. Hypermethylation of p16INK4A, often without alterations of p15INK4B, was found in non-Hodgkin's lymphoma and was much more frequent in cases with high-grade than low-grade histology. Enriched normal bone marrow stem cells had no detectable promoter region methylation of these genes, as analyzed by a newly developed PCR method. Remarkably distinct patterns of inactivation of p15INK4B and p16INK4A characterize different types of hematological malignancy, and alterations in these tumor suppressor genes are one of the most common alterations in hematological malignancies.


Biological active ingredients of traditional Chinese herb Astragalus membranaceus on treatment of diabetes: a systematic review.
Diabetes mellitus (DM) is a serious chronic metabolic disease which disease afflicting at present now afflicts approximately 4% of world population worldwide. Nowadays, the need for more potent and safe drugs to supply the present anti-diabetic and treated drugs has become an imperative. Astragalus membranaceus, the most common Chinese herb and key-component of many Chinese herbal anti-diabetic formulas, is rich in anti-diabetic compounds: polysaccharides (APS), saponins (ASS), and flavonoids (ASF) etc. Because of its various biological activities, especially its antidiabetic properties, that continuously arouse different studies. Recent studies focused on type 1 and type 2 treatment, respectively caused by autoimmune destruction of pancreatic beta cells and insulin resistance and deficient glucose metabolism. Its total polysaccharides, saponins and flavonoids fractions and several isolated compounds have been the most studied. This paper discusses diabetic treatment and pharmacological action of the biological ingredients in relation to diabetes mellitus and diabetic complications.


Alabama Regional Medical Program.
The story that follows attempts to chronicle the history of one state's involvement with the Heart Disease, Cancer and Stroke Amendments of 1965, subsequently known as Regional Medical Programs. It is a history of an enterprise fraught with problems, but energized by the will, skill and imagination of scores of public officials and citizens who, over the decade of the program's formal existence, bent every effort to insure the realization of its fundamental purpose: putting the best, most advanced medical knowledge within the reach of the greatest number of citizens. The following is a chronicle of the Alabama Regional Medical Program.


This is the Table I Want! Interactive Data Transformation on Desktop and in Virtual Reality.
Data transformation is an essential step in data science. While experts primarily use programming to transform their data, there is an increasing need to support non-programmers with user interface-based tools. With the rapid development in interaction techniques and computing environments, we report our empirical findings about the effects of interaction techniques and environments on performing data transformation tasks. Specifically, we studied the potential benefits of direct interaction and virtual reality (VR) for data transformation. We compared gesture interaction versus a standard WIMP user interface, each on the desktop and in VR. With the tested data and tasks, we found time performance was similar between desktop and VR. Meanwhile, VR demonstrates preliminary evidence to better support provenance and sense-making throughout the data transformation process. Our exploration of performing data transformation in VR also provides initial affirmation for enabling an iterative and fully immersive data science workflow.


Determination of enzyme activities for prenatal diagnosis of respiratory chain deficiency.
Genetic counselling and prenatal diagnosis are major issues of mitochondrial respiratory chain deficiency, especially as these conditions are largely untreatable. In the absence of known mitochondrial or nuclear gene mutations, measurement of respiratory chain enzyme activities represents the only possibility to prevent recurrence of the disease in affected families. We carried out enzymatic prenatal diagnosis in 21 pregnancies from 10 unrelated couples using uncultured choriocytes and/or amniocytes. Twelve babies were born and are healthy, seven pregnancies were discontinued early on because of an enzyme deficiency detected prenatally. In two cases, a fetus which appeared normal after early and/or late prenatal diagnosis, turned out to be affected. We conclude that a deficient enzyme activity is indicative of recurrence, but a normal result at 10 weeks of gestation does not give conclusive evidence as to the outcome of the pregnancy. We therefore suggest the following procedure: (1) a choriocentesis or an amniocentesis in early pregnancy when the proband expresses the disease in cultured skin fibroblasts; (2) a second amniocentesis at 28 weeks' gestation should be offered to avoid false negative results due to a possible late expression of the disease, in combination with: (3) a careful and repeated ultrasound survey for detection of growth failure in the third trimester; (4) prenatal diagnosis should not be performed in case of late onset clinical symptoms in the proband; and (5) parents should be aware of the possibility of false negative results. Prenatal diagnosis should not be proposed for a complex I deficiency as this enzyme activity cannot be accurately measured in fetal cells.


[Towards a strategy for quality assurance: satisfaction in the utilization of medical care]
This study aims to develop methodological tools to assess and guarantee quality of medical care by investigating satisfaction of expectations by objects of care (patients), medical institutions (directors), and direct providers of care (health personnel). The perspectives of this analysis included the structure, process, and outcomes of medical care. Perhaps the novelty of the research is its democratic approach, i.e., the three main protagonists' freedom of expression regarding medical care and the questioning of such aspects as individual, social, and professional satisfaction and the work environment, ultimately leading to the humanization of the work and thus to quality of care.


[A proposal to improve sick leaves granted by physicians].
From time to time, sick leaves granted by physicians, cause concern among professionals, patients and institutions that administer the funds required to finance the days of work. This document analyzes different aspects of the form that must be filled by the physician to grant the sick leave, reflects on some important difficulties that are faced by health care professionals to complete the document and proposes changes to the form to correct such difficulties. Also, a proposal for a fairest solution for professionals and patients is presented.


Colorectal Cancer Screening in US Seniors Ages 76-84 Years.
The US Preventive Services Task Force recommends patient-physician discussions about the appropriateness of colorectal cancer (CRC) screening among adults ages 76-84 years who have never been screened. In this study, we used data from the 2010 National Health Interview Survey to examine patterns of CRC screening and provider recommendation among seniors ages 76-84 years, and made some comparisons to younger adults. Nationally-representative samples of 1379 adults ages 76-84 years and 8797 adults ages 50-75 years responded to questions about CRC screening status, receipt of provider recommendation, and discussion of test options; 22.7% (95% CI 20.1-25.3) of seniors ages 76-84 had never been tested for CRC and therefore were not up-to-date with guidelines; 3.9% (95% CI 2.0-7.6) of these individuals reported a recent provider recommendation for screening. In multivariate analyses, the likelihood of never having been tested was significantly greater for seniors of other/multiple race or Hispanic ethnicity; with high school or less education; without private health insurance coverage; who had ≤ 1 doctor visit in the past year; without recent screening for breast, cervical, or prostate cancer; with no or unknown CRC family history; or with ≤ 1 chronic disease. Among the minority of respondents ages 50-75 and 76-84 reporting a provider recommendation, 73.2% indicated that the provider recommended particular tests, which was overwhelmingly colonoscopy (≥ 89 %). Nearly one-quarter of adults 76-84 have never been screened for CRC, and rates of provider recommendation in this group are very low. Greater attention to informed CRC screening discussions with screening-eligible seniors is needed.


Strategies for extraction of quantitative data from volumetric dynamic cardiac positron emission tomography data.
The ability of positron emission tomography (PET) to serve as a useful myocardial perfusion indicator is well established. We describe a methodology for obtaining reliable quantitative kinetic parameters from dynamic cardiac PET data. Reconstructed images of the myocardium are subdivided into three-dimensional volumes of interest which are used to obtain quantitative measures of myocardial perfusion over physiologically meaningful anatomical regions. The quantitation technique rigorously models the uncertainty of estimated parameters while compensating for effects such as patient motion and partial volumes to arrive at model parameters with well-established confidence intervals.


Efficient access to cyclic ureas via Pd-catalyzed cyclization.
[Structure: see text] An efficient regioselective method for the preparation of structurally diverse imidazopyridinones and benzoimidazolones starting from readily available and economical starting materials is described. High-yielding reductive alkylation of electron-deficient o-haloarylamines followed by treatment with inexpensive N-chlorosulfonyl isocyanate afforded primary ureas in good overall yields. A Pd-catalyzed urea cyclization reaction furnished imidazopyridinones and benzoimidazolones in excellent yields. Overall, the developed chemistry provides rapid access to pharmaceutically important heterocyclic compounds with high efficiency.


Influence of the insertion time and number of polyps on miss rate in colonoscopy.
Colorectal polyps can be missed even during a meticulous colonoscopy by an experienced colonoscopist. The aim of this study was to investigate patient-, procedure-, and polyp-related factors affecting the miss rate of polyps on colonoscopy. From March 2001 to February 2006, a total of 285 patients undergoing screening colonoscopy followed within 2 months by colonoscopy for polypectomy were enrolled. The main outcome measurements were factors associated with miss rates of polyp and the conditions for reducing missed polyps on colonoscopy. From the 285 colonoscopy pairs, a total of 1326 polyps were found. Overall, 350 of the 1326 polyps were missed (26.4%). Among those, 59 polyps (4.4%) were only seen on the first colonoscopy and 291 polyps (21.9%) were found only at the second colonoscopy. Patient-related factors were male sex (Odds Ratio (OR) 2.11, 95% Confidence Interval (CI) 1.21-3.70) and older age (OR 2.51, 95% CI 1.48-4.30). Procedure-related factors were colonoscopy by clinical fellows (OR 2.20, 95% CI 1.02-4.84) and delayed insertion time (OR 4.10, 95% CI 2.14-7.86). Polyp-related factors were more than four numbers of polyps (OR 4.48, 95% CI 1.91-10.5). However, a large polyp was less frequently missed on colonoscopy (OR 0.10, 95% CI 0.05-0.19). In usual clinical practice, colon polyps were frequently missed on colonoscopy. Comprehensive analysis of patient should be required to reduce the miss rates.


A generic knowledge-guided image segmentation and labeling system using fuzzy clustering algorithms.
Segmentation of an image into regions and the labeling of the regions is a challenging problem. In this paper, an approach that is applicable to any set of multifeature images of the same location is derived. Our approach applies to, for example, medical images of a region of the body; repeated camera images of the same area; and satellite images of a region. The segmentation and labeling approach described here uses a set of training images and domain knowledge to produce an image segmentation system that can be used without change on images of the same region collected over time. How to obtain training images, integrate domain knowledge, and utilize learning to segment and label images of the same region taken under any condition for which a training image exists is detailed. It is shown that clustering in conjunction with image processing techniques utilizing an iterative approach can effectively identify objects of interest in images. The segmentation and labeling approach described here is applied to color camera images and two other image domains are used to illustrate the applicability of the approach.


Restriction fragment length polymorphism of ovine casein genes: close linkage between the alpha s1-, alpha s2-, beta- and kappa-casein loci.
Restriction fragment length polymorphism (RFLP) of ovine casein genes was investigated. Genomic DNA from 56 rams was digested with 10 restriction endonucleases and Southern blots probed with the four ovine casein cDNAs (alpha s1-, beta-, alpha s2- and kappa-Cn). Five enzymes, namely, BglI, PvuII, RsaI, TaqI and HindIII revealed nine different RFLPs. The inheritance of six of these polymorphisms was studied by segregation analysis of gametes in nine rams' families, and each of them could be related to the existence of alleles at the relevant casein locus. A close linkage between the four ovine casein genes was demonstrated since no recombination within the four pairs of loci examined, alpha s1-beta-Cn, alpha s1-kappa-Cn, beta-kappa-Cn and alpha s2-kappa-Cn, was observed in the progeny of double heterozygous rams. The casein genes are thus clustered in the ovine species as in the case of other mammals.


[Role of intracellular Ca-depots in the mechanism of action of caffeine on excitation-contraction coupling in the frog myocardium].
Caffeine inotropic effects on frog atrial and ventricular muscle were studied under different patterns of stimulation. It was found that in the course of repetitive stimulation (0.5/s) caffeine produced transient potentiation and following inhibition of contractions which were accompanied by an increase in the rate of tension development, a decrease of the time to peak tension, an increase in relaxation duration and a decrease in the relaxation rate. Caffeine reduced the increment of contraction amplitude in Bowdich staircase under stimulation of the heart muscle with a series of impulses. It was concluded that caffeine caused the depletion of calcium in the intracellular stores. On the basis of literature and our data a scheme was proposed to account for two-phase caffeine action on the frog myocardium. According to this scheme caffeine acts simultaneously on both stages of excitation-contraction coupling: it alters calcium current and prevents Ca accumulation in the intracellular stores.


Marked gastric foveolar hyperplasia associated with active cytomegalovirus infection.
Transient protein-losing gastropathy with marked gastric rugal hypertrophy, a Menetrier's disease-like process, is an uncommon condition of unknown etiology. Most of these cases have been reported in pediatric patients; the clinical course is usually favorable. Cytomegalovirus infection has been implicated as a possible etiology in many of the reported cases. This type of Ménétrier's-like disease has not been well documented in adult patients. We describe here an elderly man who presented with severe protein-losing gastropathy and large polypoid nodules in the stomach. Gastric mucosal biopsies revealed marked gastric foveolar hyperplasia with morphological evidence of cytomegalovirus (CMV) infection. Immunohistochemical analysis demonstrated an aberrant topographic distribution of staining for transforming growth factor-alpha and transforming growth factor-beta receptor II, as described in other cases of Ménétrier's disease in the literature. This transient Ménétrier's-like disease associated with CMV infection should be considered in the differential of both pediatric and adult patients with GI protein loss.


Birefringence of a medium of tenuous parallel cylinders.
A general expression for the form birefringence of a medium of parallel cylinders of arbitrary sizes and separations has been developed. It is necessary to assume only that the refractive index fluctuations through the medium are sufficiently small. This expression has been evaluated for a model of retinal nerve fiber layers. The birefringence of these layers has considerable potential as a diagnostic tool since it is expected to be sensitive to structural changes associated with retinal pathologies. Although accurate measurements of this birefringence have not yet been carried out they appear to be feasible or may soon be so.


Heterogeneous mutations in the glucose-6-phosphatase gene in Japanese patients with glycogen storage disease type Ia.
Glycogen storage disease type Ia (GSD-Ia) is an autosomal recessive disorder of glycogen metabolism caused by glucose-6-phosphatase (G6Pase) deficiency. It is characterized by short stature, hepatomegaly, hypoglycemia, hyperuricemia, and lactic acidemia. Various mutations have been reported in the G6Pase gene (G6PC). However, in Japanese patients, a g727t substitution was found to be the major cause of GSD-Ia, accounting for 20 of 22 mutant alleles [Kajihara et al., 1995], and no other mutations have been found in this population. We analyzed four Japanese GSD-Ia patients and identified three other mutations in addition to the g727t. They included two missense mutations (R83H and P257L) and one nonsense mutation (R170X). Each of the three mutations exhibited markedly decreased G6Pase activity when expressed in COS7 cells. A patient homozygous for R170X showed multiple episodes of profound hypoglycemia associated with convulsions, while P257L was associated with a mild clinical phenotype. The presence of R170X in three unrelated families may implicate that it is another important mutation in the etiology of GSD-Ia in Japanese patients. Thus, the detection of non-g727t mutations is also important in establishing the DNA-based diagnosis of GSD-Ia in this population.


A Review on Finite Element Modeling and Simulation of the Anterior Cruciate Ligament Reconstruction.
The anterior cruciate ligament (ACL) constitutes one of the most important stabilizing tissues of the knee joint whose rapture is very prevalent. ACL reconstruction (ACLR) from a graft is a surgery which yields the best outcome. Taking into account the complicated nature of this operation and the high cost of experiments, finite element (FE) simulations can become a valuable tool for evaluating the surgery in a pre-clinical setting. The present study summarizes, for the first time, the current advancement in ACLR in both clinical and computational level. It also emphasizes on the material modeling and properties of the most popular grafts as well as modeling of different surgery techniques. It can be concluded that more effort is needed to be put toward more realistic simulation of the surgery, including also the use of two bundles for graft representation, graft pretension and artificial grafts. Furthermore, muscles and synovial fluid need to be included, while patellofemoral joint is an important bone that is rarely used. More realistic models are also required for soft tissues, as most articles used isotropic linear elastic models and springs. In summary, accurate and realistic FE analysis in conjunction with multidisciplinary collaboration could contribute to ACLR improvement provided that several important aspects are carefully considered.


In vitro initiation of DNA replication in simian virus 40 chromosomes.
A soluble system has been developed that can initiate DNA replication de novo in simian virus 40 (SV40) chromatin isolated from virus-infected monkey cells as well as in circular plasmid DNA containing a functional SV40 origin of replication (ori). Initiation of DNA replication in SV40 chromatin required the soluble fraction from a high-salt nuclear extract of SV40-infected cells, a low-salt cytosol fraction, polyethylene glycol, and a buffered salts solution containing all four standard deoxyribonucleoside triphosphates. Purified SV40 large tumor antigen (T-ag) partially substituted for the high-salt nucleosol, and monoclonal antibodies directed against SV40 T-ag inhibited DNA replication. Replication began at ori and proceeded bidirectionally to generate replicating DNA intermediates in which the parental strands remained covalently closed, as observed in vivo. Partial inhibition of DNA synthesis by aphidicolin resulted in accumulation of newly initiated replicating intermediates in this system, a phenomenon not observed under conditions that supported completion of replication only. However, conditions that were optimal for initiation of replication repressed conversion of late-replicating intermediates into circular DNA monomers. Most surprising was the observation that p-n-butylphenyl-dGTP, a potent and specific inhibitor of DNA polymerase-alpha, failed to inhibit replication of SV40 chromatin under conditions that completely inhibited replication of plasmid DNA containing the SV40 ori and either purified or endogenous DNA polymerase-alpha activity. In contrast, all of these DNA synthesis activities were inhibited equally by aphidicolin. Therefore, DNA replication in mammalian cells is carried out either by DNA polymerase-alpha that bears a unique association with chromatin or by a different enzyme such as DNA polymerase-delta.


Sleep-disordered breathing in heart failure: characteristics and implications.
Sleep-disordered breathing, namely obstructive sleep apnea (OSA) and central sleep apnea (CSA), are both often encountered in the setting of heart failure (HF), and have distinct differences in terms of prevalence, pathophysiology and consequences. OSA is independently associated with an increased risk for cardiovascular disease and for congestive HF in the general population. It is conceivable that this breathing disorder may have particularly deleterious effects in patients with coexisting heart disease, especially in those with a failing heart. There are considerable data addressing the interaction between OSA and the cardiovascular system, which underscore the importance of an early detection of this breathing disorder, especially in patients with HF. CSA is generally considered a consequence rather than a cause of HF, and is correlated with the severity of hemodynamic impairment. However, when present, it is associated with increased arrhythmic risk and higher cardiac mortality. Potential mechanisms implicated in the genesis of this breathing pattern and the possible therapeutic options, which have been proven to be effective in the clinical setting, are discussed.


Establishment and characterization of a new human glioblastoma cell line, NYGM.
A cell line designated NYGM was established from a human cerebral glioblastoma multiforme (GBM) obtained from a 75-year-old Japanese woman. The cell line has grown slowly without interruption and has been propagated continuously by serial passages (more than 80 passage) during the past 3 years. The cultured cells were fusiform or polyhedral in shape. The population doubling time was 24 hours. The chromosomal number varied between 77 and 88, with modal chromosomal number of 84. NYGM cells concomitantly expressed MET receptor tyrosine kinase (a product of c-met protooncogene) and its ligand HGF/SF (hepatocyte growth factor/scatter factor), as well as HGF activator and HGF activator inhibitors. The cells might be useful for the study of pericellular regulation of HGF/SF-MET signaling and HGF activation of GBM cells.


Factors predicting peripheral blood progenitor cell collection from pediatric donors for allogeneic transplantation.
Although several studies have reported on the use of children as donors for peripheral blood progenitor cells (PBPC), no specific characteristics have been identified as predictors of PBPC collection in this population. In this study we analyzed predictive factors for PBPC collection in pediatric donors. We retrospectively analyzed factors predicting the yield for a target CD34+ cell dose of > or =4x10(6)/Kg donor or recipient body weight, in 105 aphereses from 76 healthy pediatric donors (36 boys and 40 girls) included in the Spanish National Donor Registry. Mobilization consisted of granulocyte colony-stimulating factor (G-CSF) in single doses of 10 microg/kg per day subcutaneously for 4 or 5 days. Apheresis started after the fourth dose of G-CSF. Median age and body weight were 10 years (range 1-18) and 42 kg (range 9-89), respectively. The median number of CD34+ cells/kg recipient body weight was 4.22 (range 0.1-32). On multivariate analysis variables that had a significant negative impact on the CD34+ cell yield, considering the recipient's body weight were the total blood volume processed (regression coefficient (RC): 0.41, 95% CI: 0.21-0.81; p=0.01) and day of apheresis other than first (RC: 0.16, 95% CI: 0.07-0.34; p<0.0001). When considering donor's body weight the variables that positively influenced collection were younger age (RC: 6.79, 95% CI: 1.57-29.25; p<0.01) and large volume leukapheresis (RC: 3.33, 95% CI: 1.13-9.77; p<0.02). Our data suggest that pediatric donors mobilized by G-CSF may donate sufficient numbers of CD34+ cells for allogeneic transplantation. The variables that influenced the yield were the donor's age, blood volume processed and the first day of the apheresis.


A role for histamine in human-malignant glioma-cells.
Histaminergic neuron cells send fiber terminals to almost all parts of the brain, and the histamine receptors on astrocytes are the main targets of central histaminergic neurons. But no proof of the significance of histamine and its specific receptors on human malignant astrocytoma cells has been presented to date. Our results show that six malignant glioma cell lines used in this experiment secreted histamine into the culture medium and that the histamine stimulated their DNA synthesis in a dose-dependent manner. Moreover, histamine induced accumulation of inositol triphosphate (IP3) in all cell lines in either a time- or a dose-dependent manner, whereas cAMP accumulation was not induced by it in any of these cell lines, indicating that these cell lines express the H-1-receptors but not the H-2-receptors. In vivo, thus, malignant glioma may possibly produce histamine, which then would stimulate their neoplastic behavior mediated by the H-1-receptor.


Evaluation of the validity of a convolution method for incorporating tumour movement and set-up variations into the radiotherapy treatment planning system.
Modern radiotherapy techniques have developed to a point where the ability to conform to a particular tumour shape is limited by organ motion and set-up variations. The result is that dose distributions displayed by treatment planning systems based on static beam modelling are not representative of the dose received by the patient during a fractionated course of radiotherapy. The convolution-based method to account for these variations in radiation treatment planning systems has been suggested in previous work. The validity of the convolution method is tested by comparing the dose distribution obtained from this convolution method with the dose distribution obtained by summing the contribution to the total dose from each fraction of a fractionated treatment (for increasing numbers of fractions) and simulating random target position variations between fractions. For larger numbers of fractions (approximately or > 15) which are the norm for radical treatment schemes, it is clear that incorporation of movement by a convolution method could potentially produce a more accurate dose distribution. There are some limitations that have been identified, however, especially in relation to the heterogeneous nature of patient tissues, which require further investigation before the technique could be applied clinically.


A randomized, double-blind, parallel-group, duration-finding study of oral terbinafine and open-label, high-dose griseofulvin in children with tinea capitis due to Microsporum species.
Tinea capitis, a common clinical pattern of dermatophyte infection in children is becoming a public health hazard in some countries. Several studies have reported terbinafine to be a safe and well-tolerated fungicidal drug for the treatment of this infection. However, the optimal treatment duration for its use in the treatment of tinea capitis caused by Microsporum species has not yet been determined. (i) To establish the optimal duration for terbinafine treatment to bring about complete cure of tinea capitis due to Microsporum infection in a large paediatric population, and (ii) to obtain information on the maximum therapeutic effect of the existing therapy. This parallel-group, double-blind, multicentre study was conducted in Europe and South America. Patients were randomized to one of four oral terbinafine treatment arms (6, 8, 10 or 12 weeks treatment) or to an open label, 12-week, high-dose griseofulvin (20 mg x kg(-1) x day(-1)) arm at a 1 : 1 : 1 : 1 : 1 ratio. All patients were followed up for 4 weeks after the end of the treatment phase. In this group of 134 intention-to-treat patients, effective treatment was observed at the end of study in 62% of patients treated with terbinafine for 6 weeks and in 63% treated for 8 weeks. Mycological cure was obtained in 59% and 57%, respectively, and clinical cure in 76% and 80%. In the griseofulvin group, effective treatment was 88%, mycological cure was 76% and clinical cure 96%. However, these high rates were believed to be due to the high dosage of this drug and the prolonged course of treatment. Complete cure was observed at the end of study in 62% patients treated with terbinafine for 6 weeks, in 60% treated for 8 weeks and in 84% patients treated with griseofulvin for 12 weeks. Although there was no statistical trend between the duration of terbinafine treatment within the groups for complete cure at the end of study, there was a positive correlation between the daily dose of terbinafine (mg x kg(-1)) and complete cure. Terbinafine therapy for 6 weeks could represent an alternative to griseofulvin for the treatment of Microsporum tinea capitis. However, further clinical trials are required in order to optimize the dose regimen to allow higher cure rates to be reached.


Nonlinear analysis of irregular animal vocalizations.
Animal vocalizations range from almost periodic vocal-fold vibration to completely atonal turbulent noise. Between these two extremes, a variety of nonlinear dynamics such as limit cycles, subharmonics, biphonation, and chaotic episodes have been recently observed. These observations imply possible functional roles of nonlinear dynamics in animal acoustic communication. Nonlinear dynamics may also provide insight into the degree to which detailed features of vocalizations are under close neural control, as opposed to more directly reflecting biomechanical properties of the vibrating vocal folds themselves. So far, nonlinear dynamical structures of animal voices have been mainly studied with spectrograms. In this study, the deterministic versus stochastic (DVS) prediction technique was used to quantify the amount of nonlinearity in three animal vocalizations: macaque screams, piglet screams, and dog barks. Results showed that in vocalizations with pronounced harmonic components (adult macaque screams, certain piglet screams, and dog barks), deterministic nonlinear prediction was clearly more powerful than stochastic linear prediction. The difference, termed low-dimensional nonlinearity measure (LNM), indicates the presence of a low-dimensional attractor. In highly irregular signals such as juvenile macaque screams, piglet screams, and some dog barks, the detectable amount of nonlinearity was comparatively small. Analyzing 120 samples of dog barks, it was further shown that the harmonic-to-noise ratio (HNR) was positively correlated with LNM. It is concluded that nonlinear analysis is primarily useful in animal vocalizations with strong harmonic components (including subharmonics and biphonation) or low-dimensional chaos.


Acoustically responsive polydopamine nanodroplets: A novel theranostic agent.
Ultrasound-induced cavitation has been used as a tool of enhancing extravasation and tissue penetration of anticancer agents in tumours. Initiating cavitation in tissue however, requires high acoustic intensities that are neither safe nor easy to achieve with current clinical systems. The use of cavitation nuclei can however lower the acoustic intensities required to initiate cavitation and the resulting bio-effects in situ. Microbubbles, solid gas-trapping nanoparticles, and phase shift nanodroplets are some examples in a growing list of proposed cavitation nuclei. Besides the ability to lower the cavitation threshold, stability, long circulation times, biocompatibility and biodegradability, are some of the desirable characteristics that a clinically applicable cavitation agent should possess. In this study, we present a novel formulation of ultrasound-triggered phase transition sub-micrometer sized nanodroplets (~400 nm) stabilised with a biocompatible polymer, polydopamine (PDA). PDA offers some important benefits: (1) facile fabrication, as dopamine monomers are directly polymerised on the nanodroplets, (2) high polymer biocompatibility, and (3) ease of functionalisation with other molecules such as drugs or targeting species. We demonstrate that the acoustic intensities required to initiate inertial cavitation can all be achieved with existing clinical ultrasound systems. Cell viability and haemolysis studies show that nanodroplets are biocompatible. Our results demonstrate the great potential of PDA nanodroplets as an acoustically active nanodevice, which is highly valuable for biomedical applications including drug delivery and treatment monitoring.


HF readmissions drop after initiatives.
By analyzing heart failure readmissions and collaborating with post-acute providers and community organizations, Essentia Health-St. Joseph's Medical Center in Brainerd, MN, cut its readmission rate from 18% to a low of 6%. An interdisciplinary team analyzed readmissions, interviewed patients who were readmitted, and developed the program. Initiatives include setting primary care appointments while patients are in the hospital, following up after discharge, and creating order sets that include best practices. The hospital staff meet regularly with post-acute providers and social service agencies to brainstorm ways to create smoother transitions and ensure that patients get what they need after discharge.


A pH-responsive nanocontainer based on hydrazone-bearing hollow silica nanoparticles for targeted tumor therapy.
A pH-responsive drug delivery system based on hollow mesoporous silica nanoparticles (HMSNs) was fabricated for targeted tumor therapy by using hydrazone bonds as pH-sensitive linkers and hyaluronic acid (HA) molecules as both blocking and targeting agents. HMSNs were synthesized with good dispersion and dimensions of around 88 nm. Detailed material characterisation suggested that the drug delivery system was successfully constructed. It displayed a fast pH stimulus response for controlled drug release in vitro. Besides, systematic biological investigations revealed that the drug delivery system had good biocompatibility, which could effectively target tumor cells and deliver therapeutic cargo to induce tumor cell apoptosis in vitro and suppression of tumor growth in vivo. This study reports a promising drug delivery system for potential clinical application against tumor therapy.


A novel CD11c.DTR transgenic mouse for depletion of dendritic cells reveals their requirement for homeostatic proliferation of natural killer cells.
Dendritic cells (DC) are known to support the activation of natural killer (NK) cells. However, little is known about the role for DC in NK-cell homeostasis. In order to investigate this question, a novel bacterial artificial chromosome transgenic mouse model was generated in which the diphtheria toxin receptor is expressed under the CD11c promoter. In these mice efficient DC depletion can be achieved over prolonged periods of time by multiple injections of diphtheria toxin. We show here that NK cells require DC for full acquisition of effector function in vivo in response to the bacterial-derived TLR ligand CpG. Importantly, DC were found to play an instrumental role for maintaining normal homeostasis of NK cells. This is achieved by IL-15 production by DC, which supports the homeostatic proliferation of NK cells.


Bench-Top Fabrication of an All-PDMS Microfluidic Electrochemical Cell Sensor Integrating Micro/Nanostructured Electrodes.
In recent years, efforts in the development of lab-on-a-chip (LoC) devices for point-of-care (PoC) applications have increased to bring affordable, portable, and sensitive diagnostics to the patients' bedside. To reach this goal, research has shifted from using traditional microfabrication methods to more versatile, rapid, and low-cost options. This work focuses on the benchtop fabrication of a highly sensitive, fully transparent, and flexible poly (dimethylsiloxane) (PDMS) microfluidic (μF) electrochemical cell sensor. The μF device encapsulates 3D structured gold and platinum electrodes, fabricated using a shape-memory polymer shrinking method, which are used to set up an on-chip electrochemical cell. The PDMS to PDMS-structured electrode bonding protocol to fabricate the μF chip was optimized and found to have sufficient bond strength to withstand up to 100 mL/min flow rates. The sensing capabilities of the on-chip electrochemical cell were demonstrated by using cyclic voltammetry to monitor the adhesion of murine 3T3 fibroblasts in the presence of a redox reporter. The charge transfer across the working electrode was reduced upon cell adhesion, which was used as the detection mechanism, and allowed the detection of as few as 24 cells. The effective utilization of simple and low cost bench-top fabrication methods could accelerate the prototyping and development of LoC technologies and bring PoC diagnostics and personalized medicine to the patients' bedside.


SNAP-tagged Chikungunya Virus Replicons Improve Visualisation of Non-Structural Protein 3 by Fluorescence Microscopy.
Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes febrile disease, muscle and joint pain, which can become chronic in some individuals. The non-structural protein 3 (nsP3) plays essential roles during infection, but a complete understanding of its function is lacking. Here we used a microscopy-based approach to image CHIKV nsP3 inside human cells. The SNAP system consists of a self-labelling enzyme tag, which catalyses the covalent linking of exogenously supplemented synthetic ligands. Genetic insertion of this tag resulted in viable replicons and specific labelling while preserving the effect of nsP3 on stress granule responses and co-localisation with GTPase Activating Protein (SH3 domain) Binding Proteins (G3BPs). With sub-diffraction, three-dimensional, optical imaging, we visualised nsP3-positive structures with variable density and morphology, including high-density rod-like structures, large spherical granules, and small, low-density structures. Next, we confirmed the utility of the SNAP-tag for studying protein turnover by pulse-chase labelling. We also revealed an association of nsP3 with cellular lipid droplets and examined the spatial relationships between nsP3 and the non-structural protein 1 (nsP1). Together, our study provides a sensitive, specific, and versatile system for fundamental research into the individual functions of a viral non-structural protein during infection with a medically important arthropod-borne virus (arbovirus).


UK circulating strains of human parainfluenza 3: an amplicon based next generation sequencing method and phylogenetic analysis.
Background: Human parainfluenza viruses type 3 (HPIV3) are a prominent cause of respiratory infection with a significant impact in both pediatric and transplant patient cohorts. Currently there is a paucity of whole genome sequence data that would allow for detailed epidemiological and phylogenetic analysis of circulating strains in the UK. Although it is known that HPIV3 peaks annually in the UK, to date there are no whole genome sequences of HPIV3 UK strains available. Methods: Clinical strains were obtained from HPIV3 positive respiratory patient samples collected between 2011 and 2015. These were then amplified using an amplicon based method, sequenced on the Illumina platform and assembled using a new robust bioinformatics pipeline. Phylogenetic analysis was carried out in the context of other epidemiological studies and whole genome sequence data currently available with stringent exclusion of significantly culture-adapted strains of HPIV3. Results: In the current paper we have presented twenty full genome sequences of UK circulating strains of HPIV3 and a detailed phylogenetic analysis thereof. We have analysed the variability along the HPIV3 genome and identified a short hypervariable region in the non-coding segment between the M (matrix) and F (fusion) genes. The epidemiological classifications obtained by using this region and whole genome data were then compared and found to be identical. Conclusions: The majority of HPIV3 strains were observed at different geographical locations and with a wide temporal spread, reflecting the global distribution of HPIV3. Consistent with previous data, a particular subcluster or strain was not identified as specific to the UK, suggesting that a number of genetically diverse strains circulate at any one time. A small hypervariable region in the HPIV3 genome was identified and it was shown that, in the absence of full genome data, this region could be used for epidemiological surveillance of HPIV3.


The social organization of representations of history: the textual accomplishment of coming to terms with the past.
This paper is concerned with the social organization of collective memory and representations of history in the context of how post-communist democracies reckon with former regimes. It specifically centres on the textual accomplishment of coming to terms with the past in the 'Tismăneanu Report' condemning Communism in Romania. The focus is on how the Report displays and shapes the ideological contours of coming to terms with the past around a particular 'social representation' of history. Several constitutive features of the Report that facilitate bringing off a particular 'representation of history' are identified: (a) the construction of a practical framework for the inquiry as a matter of public concern and attention; (b) the production of 'Communism' as an empirical category with uniquely bound features; and (c) the structuring of time by bringing together a political agenda and national identity. The present argument tries to place representations of history (and coming to terms with the past) as something in need of constitution rather than simply relied on. It is suggested that a conception of coming to terms with the past as a textual accomplishment may lead to a fuller appreciation of the structure, function and salience of representations of history as integral part of moral/political/legal courses of action.


Dynamics of a rigid rod in a disordered medium with long-range spatial correlation.
We investigate the diffusion of a rigid rodlike object in a two-dimensional disordered host medium, which consists of static pointlike sources of force. The points are distributed with long-range spatial correlation and interact with the rod via a repulsive potential. The time dependence of the rod's center-of-mass mean-squared displacement and its rotational mean-squared displacement are obtained for various degrees of long-range spatial correlation and rod's lengths. These transport characteristics are compared to those obtained in previous studies for the case of homogeneous distribution of force points. It is shown that existence of long-range correlation among force points makes the center of mass diffusion anomalous.


Contingent color aftereffects: reassessing old conclusions.
Although there is considerable evidence supporting an associative interpretation of contingent color aftereffects, there are data that appear inconsistent with this interpretation. New findings from seven experiments are presented indicating that, contrary to earlier claims, contingent color aftereffects are observed after induction with (1) single orthogonal black bars on colored backgrounds, (2) geometric forms, and (3) two orthogonal grids of the same color. The results of these experiments are relevant to an associative interpretation of contingent color aftereffects, as well as to assessing alternative interpretations of the phenomenon.


Cortical response to levodopa in Parkinson's disease patients with dyskinesias.
Levodopa-induced dyskinesias are a common and disabling side effect of dopaminergic therapy in Parkinson's disease, but their neural mechanisms in vivo are still poorly understood. Besides striatal pathology, the importance of cortical dysfunction has been increasingly recognized. The supplementary motor area in particular, may have a relevant role in dyskinesias onset given its involvement in endogenously generated actions. The aim of the present study was to investigate the levodopa-related cortical excitability changes along with the emergence of levodopa-induced peak-of-dose dyskinesias in subjects with Parkinson's disease. Thirteen patients without dyskinesias and ten with dyskinesias received 200/50 mg fast-acting oral levodopa/benserazide following overnight withdrawal (12 hr) from their dopaminergic medication. We targeted transcranial magnetic stimulation to the supplementary motor area, ipsilateral to the most dopamine-depleted striatum defined with single-photon emission computed tomography with [123 I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane, and recorded transcranial magnetic stimulation-evoked potentials with high-density electroencephalography before and at 30, 60, and 180 min after levodopa/benserazide intake. Clinical improvement from levodopa/benserazide paralleled the increase in cortical excitability in both groups. Subjects with dyskinesias showed higher fluctuation of cortical excitability in comparison to non-dyskinetic patients, possibly reflecting dyskinetic movements. Together with endogenous brain oscillation, levodopa-related dynamics of brain state could influence the therapeutic response of neuromodulatory interventions.


What makes Grande1 retrotransposon different?
Grande1 elements constitute a family of Ty3 retrotransposons present in the Zea genus in more than 1000 copies in Zea diploperennis and maize. The sequences of three Grande1 flanking regions, two from Z. diploperennis and one from maize, reveal transposable elements as insertion targets, suggesting a preferential integration of Grande1 elements into other transposable elements. These retrotransposons are remarkable for their large size of around 14 kb, which is a consequence of a very large 3' region of more than 7 kb. Atypical entities within this region are two arrays of unrelated tandem repeats with potential stable stem-loop structures. A large portion of the same region is occupied by ORFs, although only ORF23, whose function is unknown, is presumably transcribed in antisense orientation to the reverse transcriptase ORF. Only ORF23 has a codon usage similar to the one tabulated for highly-expressed maize genes. Correspondingly, the transcript of 900 b that hybridizes with ORF23 probes is found in all the maize tissues explored. This is despite the high level of methylation in the DNA of Grande1. Genomic RNA has not been detected in any tissue or situation studied, probably reflecting a non-functional retrotransposon. The origin of ORF23 and the remainder 3' region might be due to a transduction event.


LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons.
Recent studies have demonstrated that the lipopolysaccharide (LPS) receptor (TLR4) is expressed in TRPV1 containing trigeminal sensory neurons. In this study, we evaluated whether LPS activates trigeminal neurons, and sensitizes TRPV1 responses via TLR4. To test this novel hypothesis, we first demonstrated that LPS binds to receptors in trigeminal neurons using competitive binding. Second, we demonstrated that LPS evoked a concentration-dependent increase in intracellular calcium accumulation (Ca(2+))(i) and inward currents. Third, LPS significantly sensitized TRPV1 to capsaicin measured by (Ca(2+))(i), release of calcitonin gene-related peptide, and inward currents. Importantly, a selective TLR4 antagonist blocked these effects. Analysis of these data, collectively, demonstrates that LPS is capable of directly activating trigeminal neurons, and sensitizing TRPV1 via a TLR4-mediated mechanism. These findings are consistent with the hypothesis that trigeminal neurons are capable of detecting pathogenic bacterial components leading to sensitization of TRPV1, possibly contributing to the inflammatory pain often observed in bacterial infections.


Biopsychosocial profile of women with dyspareunia.
To compare biopsychologic profiles of women with dyspareunia with a matched no-pain control sample, and to determine whether dyspareunia subtypes based on physical findings have different psychosocial profiles from matched controls. One hundred and five women with dyspareunia and 105 matched no-pain control women underwent standard gynecologic examination, endovaginal ultrasound, and colposcopy. They also completed a structured interview inquiring about pain other than dyspareunia, sexual function, and history of abuse, the Brief Symptom Inventory, the Sexual Opinion Survey, and the Locke-Wallace Marital Adjustment Scale. In comparison with women who do not experience pain with intercourse, the dyspareunia sample was found to have more physical pathology on examination, and they reported more psychologic symptomatology, more negative attitudes toward sexuality, higher levels of impairment in sexual function, and lower levels of marital adjustment. They did not report more current or past physical or sexual abuse. However, when the undifferentiated dyspareunia sample was divided into subtypes based on physical findings from the gynecologic examinations, the pattern of significant differences from controls varied according to dyspareunia subtype. Elevated psychologic symptomatology and relationship maladjustment were confined to the subtype with no discernible physical findings who reported levels of sexual function not significantly different from matched controls. The vulvar vestibulitis subtype suffered the highest levels of sexual impairment, although this subtype was not characterized by higher levels of psychologic symptoms than controls. As an undifferentiated group, women with dyspareunia have more physical pathology, psychologic distress, sexual dysfunction, and relationship problems. However, this pattern of differences appears to vary depending on the presence and type of physical findings evident on examination. Dyspareunia is a heterogeneous disorder requiring comprehensive gynecologic and psychosocial assessment to determine differentiated treatment strategies.


Prostate cancer incidence and diagnosis in men with PSA levels >20 ng/ml: is it possible to decrease the number of biopsy cores?
To define if less number of cores would be sufficient to diagnose prostate cancer (PCa) in men with PSA levels >20 ng/ml and to reveal the cancer detection rates in this population. The data of the men who had 12-core prostate biopsy with a PSA value >20 ng/mg were reviewed. We recorded age, prostate volume, PSA level, and pathology report findings. Patients grouped according to PSA levels and compared for PCa detection rates, and several parameters. We created 16 prostate biopsy scenarios (S1-S16) and applied these to our database to find out the best biopsy protocol to detect PCa. A total of 336 patients with a mean age of 70.5 (47-91) years were included. Mean PSA level was 190.6 (20-5474) ng/ml. PCa detection rates were 55.3%, 81.0%, and 97.7% in patients with PSA levels 20-49.99, 50-99.99, and ≥100 ng/ml, respectively. PSA level was correlated to clinically more important digital rectal examination findings. We selected 2 cores in S1-S6, 4 cores in S7-S12, and 6 cores in S13-S16. We calculated the sensitivity of each scenario and found that all scenarios in PSA Group 3 had a sensitivity >95%. In Group 2, S8, S10, S13, and S14 and in Group 1, only S14 had sensitivity >95%. It is not necessary to take 10-12 core biopsy samples in men with PSA levels >20 ng/ml. We recommend taking 2, 4, and 6 samples for patients with PSA levels ≥100 ng/ml, 50-99.99 ng/ml, and 20-49.99 ng/ml, respectively.


Incidence and Outcomes of Central Venous Catheter-related Blood Stream Infection in Patients with Inflammatory Bowel Disease in Routine Clinical Practice Setting.
Patients with inflammatory bowel disease (IBD) occasionally require central venous catheter (CVC) placement to support a therapeutic plan. Given that CVC can predispose patients to infection, this investigation was undertaken to assess the incidence, risk factors, and outcomes of CVC-related blood stream infection (CRBSI) in patients with IBD during routine clinical practice. Data were compiled using retrospective chart reviews of 1367 patients treated at our IBD center between 2007 and 2012 during routine clinical practice. Among the 1367 patients, 314 who had received CVC placements were included. Patients with positive blood culture were considered as "definite" CRBSI, whereas "possible" CRBSI was defined as patients in whom fever alleviated within 48 hours post-CVC without any other infection. Patients' demographic variables including age, body mass index, serum albumin, duration of CVC placement, use of antibiotics, medications for IBD, and perioperative status between CRBSI and non-CRBSI subgroups were compared by applying a multivariate Poisson logistic regression model. Among the 314 patients with CVC placement, there were 83 CRBSI cases (26.4%). The average time to the onset of CRBSI was 22.5 days (range 4-105 days). The jugular vein access was found to be the most serious risk of CRBSI (risk ratio 2.041 versus subclavian vein). All patients with CRBSI fully recovered. In this investigation, regardless of the patients' demographic features including immunosuppressive therapy, up to 30% of febrile IBD patients with CVC showed CRBSI. It is believed that CVC placement per se is a risk of CRBSI in patients with IBD.


Loneliness as the cause and the effect of problematic Internet use: the relationship between Internet use and psychological well-being.
The current research started from the assumption that one of the major motives driving individuals' Internet use is to relieve psychosocial problems (e.g., loneliness, depression). This study showed that individuals who were lonely or did not have good social skills could develop strong compulsive Internet use behaviors resulting in negative life outcomes (e.g., harming other significant activities such as work, school, or significant relationships) instead of relieving their original problems. Such augmented negative outcomes were expected to isolate individuals from healthy social activities and lead them into more loneliness. Even though previous research suggests that social use of the Internet (e.g., social networking sites, instant messaging) could be more problematic than entertainment use (e.g., downloading files), the current study showed that the former did not show stronger associations than the latter in the key paths leading to compulsive Internet use.


Assessing the impact of MRI based diagnostics on pre-treatment disease classification and prognostic model performance in men diagnosed with new prostate cancer from an unscreened population.
Pre-treatment risk and prognostic groups are the cornerstone for deciding management in non-metastatic prostate cancer. All however, were developed in the pre-MRI era. Here we compared categorisation of cancers using either only clinical parameters or with MRI enhanced information in men referred for suspected prostate cancer from an unscreened population. Data from men referred from primary care to our diagnostic service and with both clinical (digital rectal examination [DRE] and systematic biopsies) and MRI enhanced attributes (MRI stage and combined systematic/targeted biopsies) were used for this study. Clinical vs MRI data were contrasted for clinico-pathological and risk group re-distribution using the European Association of Urology (EAU), American Urological Association (AUA) and UK National Institute for Health Care Excellence (NICE) Cambridge Prognostic Group (CPG) models. Differences were retrofitted to a population cohort with long-term prostate cancer mortality (PCM) outcomes to simulate impact on model performance. We further contrasted individualised overall survival (OS) predictions using the Predict Prostate algorithm. Data from 370 men were included (median age 66y). Pre-biopsy MRI stage reassignments occurred in 7.8% (versus DRE). Image-guided biopsies increased Grade Group 2 and ≥ Grade Group 3 assignments in 2.7% and 2.9% respectively. The main change in risk groups was more high-risk cancers (6.2% increase in the EAU and AUA system, 4.3% increase in CPG4 and 1.9% CPG5). When extrapolated to a historical population-based cohort (n = 10,139) the redistribution resulted in generally lower concordance indices for PCM. The 5-tier NICE-CPG system outperformed the 4-tier AUA and 3-tier EAU models (C Index 0.70 versus 0.65 and 0.64). Using an individualised prognostic model, changes in predicted OS were small (median difference 1% and 2% at 10- and 15-years' respectively). Similarly, estimated treatment survival benefit changes were minimal (1% at both 10- and 15-years' time frame). MRI guided diagnostics does change pre-treatment risk groups assignments but the overall prognostic impact appears modest in men referred from unscreened populations. Particularly, when using more granular tiers or individualised prognostic models. Existing risk and prognostic models can continue to be used to counsel men about treatment option until long term survival outcomes are available.


Alcohol consumption and the risk of mortality and myocardial infarction in patients with rheumatoid arthritis.
Many studies have found that moderate alcohol consumption is associated with lower risks of mortality and myocardial infarction (MI). Our aim was to examine the potential effects of alcohol on all-cause mortality and MI in rheumatoid arthritis (RA), a risk factor condition. A cohort study (1995-2017) was conducted using medical records of RA patients from The Health Improvement Network in the United Kingdom (UK). Alcohol exposure was divided into non-drinkers, mild (1-7 UK units/week), moderate (8-14 UK units/week), moderate-high (15-21 UK units/week), and high (>21 UK units/week) consumption levels. We calculated hazard ratios (HRs) for the relation of alcohol consumption to all-cause mortality and MI, adjusting for covariates. Of 30,320 RA patients, 5,994 deaths and 1,098 MI cases occurred over 236,188 person-years. Mild-to-moderate alcohol use was associated with lower all-cause mortality in RA patients, including those taking methotrexate. The multivariable HRs (95% CI) for mortality by alcohol use category were non-drinkers 1.0, mild 0.80 (0.75-0.85), moderate 0.74 (0.67-0.82), moderate-high 0.84 (0.72-0.98), and high 0.99 (0.86-1.15). Mild, moderate-high, and high levels of alcohol use were associated with lower risk of MI among RA patients. The HRs MI risk by alcohol use category were non-drinkers 1.0, mild 0.81 (0.70-0.94), moderate 0.84 (0.68-1.04), moderate-high 0.51 (0.35-0.74), and high 0.59 (0.42-0.84). These findings suggest that mild-to-moderate alcohol use is associated with a lower mortality risk and overall alcohol use is associated with a lower MI risk in RA patients, similar to the general population.


Hearing threshold comparisons between 2001-02 NHANES and 2003-05 Fort Bliss U.S. Army Service components.
This study compares population mean hearing threshold levels in decibels (dB) at 4 kHz among the 2001-02 National Health and Nutrition Examination Survey (NHANES) (n=1872) and the 2003-05 Fort Bliss Army Active Duty (AD) (n=9096), National Guard (NG) (n=3842), and Reserve Components (RC) (n=2025) and by gender. Comparisons between male populations show that mean hearing thresholds are not significantly different (p<0.05) between U.S. Army Active Duty males and NHANES males, which differ from a 1984 U.S. Army Active Duty/1971-74 NHANES study showing significantly higher hearing thresholds for the Army Active Duty population. In addition, this study shows that Active Duty males have significantly lower hearing thresholds than National Guard males at ages <40 years old. Female groups generally have significantly lower hearing thresholds than male groups at all ages, but there are not significant differences between female military and civilian populations.


Federalism for Bioethics?
In the wake of the Dobbs decision withdrawing federal constitutional protection for reproductive rights, the United States is in the throes of federalist conflicts. Some states are enacting draconian prohibitions of abortion or gender-affirming care, whereas other states are attempting to shield providers and their patients seeking care. This article explores standard arguments supporting federalism, including that it allows for cultural differences to remain along with a structure that provides for the advantages of common security and commerce, that it provides a laboratory for confined experiments, that it is government closer to the people and thus more informed about local needs and preferences, and that it creates layers of government that can constrain one another and thus doubly protect rights. We contend that these arguments do not justify significant differences among states with respect to the recognition of important aspects of well-being; significant injustices among subnational units cannot be justified by federalism. However, as nonideal theorists, we also observe that federalism presents the possibility of some states protecting rights that others do not. Assuming that movement among subnational units is protected, those who are fortunate enough to be able to travel will be able to access rights they cannot access at home. Nonetheless, movement may not be readily available to minors, people without documentation, people with disabilities, people who lack economic resources, or people who have responsibilities that preclude travel. Only rights protection at the federal level will suffice in such cases.


The two-year incidence of hip osteoarthritis after arthroscopic hip surgery for femoroacetabular impingement syndrome.
One of the reported goals of hip preservation surgery is to prevent or delay the onset of osteoarthritis. This includes arthroscopic surgery to manage Femoroacetabular Impingement (FAI) Syndrome. The purpose of this study was to describe the prevalence of clinically-diagnosed hip OA within 2 years after hip arthroscopy for FAI syndrome, and 2) determine which variables predict a clinical diagnosis of OA after arthroscopy. Observational analysis of patients undergoing hip arthroscopy between 2004 and 2013, utilizing the Military Health System Data Repository. Individuals with prior cases of osteoarthritis were excluded. Presence of osteoarthritis was based on diagnostic codes rendered by a medical provider in patient medical records. Adjusted odds ratios (95% CI) for an osteoarthritis diagnosis were reported for relevant clinical and demographic variables. Of 1870 participants in this young cohort (mean age 32.2 years), 21.9% (N = 409) had a postoperative clinical diagnosis of hip osteoarthritis within 2 years. The 3 significant predictors in the final model were older age (OR = 1.04; 95%CI = 1.02, 1.05), male sex (OR = 1.31; 95%CI = 1.04, 1.65), and having undergone an additional hip surgery (OR = 2.33; 95% CI = 1.72, 3.16). Military status and post-surgical complications were not risk factors. A clinical diagnosis of hip osteoarthritis was found in approximately 22% of young patients undergoing hip arthroscopy in as little as 2 years. These rates may differ when using alternate criteria to define OA, such as radiographs, and likely underestimate the prevalence. A more comprehensive approach, considering various criteria to detect OA will likely be necessary to accurately identify the true rates. Females were at lower risk, while increasing age and multiple surgeries increased the risk for an OA diagnosis. OA onset still occurs after "hip preservation" surgery in a substantial number of individuals within 2 years. This should be considered when estimating rates of disease prevention after surgery. Prospective trials with sound methodology are needed to determine accurate rates and robust predictors of osteoarthritis onset after hip preservation surgery.


Homoserine and asparagine are host signals that trigger in planta expression of a pathogenesis gene in Nectria haematococca.
Some pathogenesis-related genes are expressed in fungi only when the pathogen is in the host, but the host signals that trigger these gene expressions have not been identified. Virulent Nectria haematococca infects pea plants and requires either pelA, which is induced by pectin, or pelD, which is induced only in planta. However, the host signal(s) that trigger pelD expression was unknown. Here we report the isolation of the host signals and identify homoserine and asparagine, two free amino acids found in uniquely high levels in pea seedlings, as the pelD-inducing signals. N. haematococca has evolved a mechanism to sense the host tissue environment by using the high levels of two free amino acids in this plant, thereby triggering the expression of pelD to assist the pathogenic process.


Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection.
We evaluated an all-oral regimen comprising the nucleotide polymerase inhibitor sofosbuvir (SOF) with the NS5A inhibitor ledipasvir (LDV) or the NS5B non-nucleoside inhibitor GS-9669 in patients with genotype 1 hepatitis C virus (HCV) infection. A total of 113 patients were enrolled. Sofosbuvir (400 mg once daily) and LDV (90 mg once daily) plus ribavirin (RBV) were given for 12 weeks to treatment-naïve (TN) patients (n = 25) and those who did not respond to previous therapy (prior null responders, n = 9). Sofosbuvir and GS-9669 (500 mg once daily) plus RBV were given for 12 weeks to TN patients (n = 25) and prior null responders (n = 10). Additionally, prior null responders with cirrhosis were randomly assigned to groups given a fixed-dose combination of SOF and LDV, with RBV (n = 9) or without RBV (n = 10). Finally, a group of TN patients received SOF, LDV, and RBV for 6 weeks (n = 25). The primary efficacy end point was sustained virologic response 12 weeks after therapy (SVR12). SVR12 was achieved by 25 of 25 (100%) TN patients receiving SOF, LDV, and RBV and 23 of 25 (92%) of those receiving SOF, GS-9669, and RBV. Of TN patients receiving 6 weeks of SOF, LDV, and RBV, 17 of 25 (68%) achieved SVR12. All noncirrhotic prior null responders receiving 12 weeks of SOF along with another direct-acting antiviral agent plus RBV achieved SVR12-9 of 9 (100%) of those receiving SOF, LDV, and RBV and 10 of 10 (100%) of those receiving SOF, GS-9669, and RBV. Among cirrhotic prior null responders, SVR12 was achieved by 9 (100%) of those receiving SOF, LDV, and RBV and 7 (70%) of those receiving SOF and LDVD without RBV. The most common reported adverse events were headache, fatigue, and nausea. The combination of SOF and a second direct-acting antiviral agent is highly effective in TN patients with HCV genotype 1 infection and in patients that did not respond to previous treatment. ClinicalTrials.gov ID NCT01260350.


[Streptococcal infection in a primary school population. Study during the academic year].
One hundred and seventy four children from the "República de Checoslovaquia" National School of the Centro Habana-Norte municipality were investigated during the 1976-1977 academic course months. The method of mail interview of parents was used. Every month the history of oropharyngeal infection and antibiotic administration was obtained, and bacteriology of pharyngeal exudates was performed. Antistreptolysin or AELO titers were determined at three-month intervals. Cardiovascular physical examinations were made and electrocardiograms obtained during the last month. 19,22% of exudates were positive for hemolytic streptococci. 46,56% of streptococcal strains isolated corresponded to the group A. Hemolytic streptococci isolation ranged between 10,4% in October, 1976 and 36,1% in April, 1977. The monthly distribution of the different serological groups of isolated hemolytic streptococci disclosed statistically significant differences. 78,26% of the 667 AELO reactions corresponded to titers of 200 or more Todd units. Average titers in the four stages of the serological study are between 382,42 and 463,92 Todd units. Significative differences between the results of bacteriology and serology and the physical state of oropharynx or the history of clinical manifestations were not evidenced. Manifestations of carditis or rheumatic fever were not found.