Miracle-dz/UniFAR-FTUs huggingface dataset:
Charcot‐Marie‐Tooth disease and related neuropathies: Mutation distribution and genotype‐phenotype correlation

Charcot‐Marie‐Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N‐myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N‐myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT‐causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22. The peripheral myelin protein 22 mutation W28R was associated with CMT1 and profound deafness. One patient with a CMT2 clinical phenotype had three myelin protein zero mutations (I89N+V92M+I162M). Because one‐third of the mutations we report arose de novo and thereby caused chronic sporadic neuropathy, we conclude that molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy.
Pregnancy Loss and Endometriosis: Pathogenic Role of Anti‐Laminin‐1 Autoantibodies

Abstract: Laminin‐1 is a major multifunctional glycoprotein that forms an integral part of the scaffolding network of basement membranes, and is the earliest synthesized component during embryogenesis. This protein (α1β1γ1) plays an important role in basement membrane assembly and epiblast differentiation during embryonic development. Anti‐laminin‐1 autoantibodies are known to cause infertility and recurrent spontaneous abortion in animals. Recently, we reported that the presence of IgG anti‐laminin‐1 antibodies (Abs) in the blood is significantly associated with recurrent first‐trimester miscarriages and subsequent negative pregnancy outcomes. Interestingly, these antibodies are also strongly associated with infertility, especially infertility caused by endometriosis. Laminin‐α1, laminin‐β1, and laminin‐γ1 mRNAs were also detected in 90% of endometriotic lesions, and all laminin‐α1, laminin‐β1, and laminin‐γ1 chains were localized to the basement membranes of glandular epithelium in endometriotic peritoneal lesions. ELISA showed specific reactivity of the autoantibodies to a particular region of the laminin‐1 molecule, that is, the α1 chain G domain. IgM monoclonal anti‐laminin‐1 Abs, which we recently established, also recognized the G domain and cross‐reacted with human α1 chain located in the basement membrane of the glandular epithelium of human endometrium. We also established an animal model that produced high titers of anti‐laminin‐1 Abs after immunization with mouse laminin‐1. Anti‐laminin‐1 Abs from the immunized mice caused a higher fetal resorption rate with lower embryonic and placental weights. Thus, anti‐laminin‐1 Abs may be important in the development of autoimmune‐mediated reproductive failures, and the assessment of the such antibodies may provide a novel means for noninvasive diagnosis of endometriosis.
Improved outcome after severe head injury with a new therapy based on principles for brain volume regulation and preserved microcirculation.

OBJECTIVE To assess the new "Lund therapy" of posttraumatic brain edema, based on principles for brain-volume regulation and improved microcirculation. DESIGN A prospective, nonrandomized outcome study over a 5-yr period on severely head-injured patients with increased intracranial pressure, comparing the results with a historical control group with the same selection criteria for patients who were treated according to conventional principles. SETTING General intensive care unit of a university hospital. PATIENTS Fifty-three consecutive head-injured patients with a Glasgow Coma Score of <8, and with increased intracranial pressure (>25 mm Hg), despite conventional treatment. INTERVENTIONS Interstitial fluid resorption was obtained by lowering intracapillary hydrostatic pressure, by preserving normal colloid osmotic pressure, and by maintaining a normovolemic (normal albumin/serum and hemoglobin/serum), not overtransfused patient. Intracapillary pressure was reduced by the combination of precapillary vasoconstriction (low-dose thiopental, dihydroergotamine) and reduction of mean arterial pressure, the latter attained with a beta1-antagonist (metoprolol 0.2 to 0.3 mg/kg/24 hrs iv) and an alpha2-agonist (clonidine 0.4 to 0.8 microg/kg x 4 to 6 iv). Clonidine, in combination with normovolemia, also improves microcirculation by reducing catecholamines in plasma. Intracranial blood volume was reduced by arterial (low-dose thiopental sodium and dihydroergotamine) and large-vein (dihydroergotamine) vasoconstriction. The start dose of dihydroergotamine (maximum 0.9 microg/kg/hr) was successively reduced toward discontinuation within 4 to 5 days. MEASUREMENTS AND MAIN RESULTS There were 8% of patients who died and the neurologic conditions of 13% remained severely damaged, compared with 47% and 11%, respectively, for the control group. CONCLUSIONS The low mortality compared with previous outcome studies strongly indicates that this therapy improves outcome for severe head injuries. However, a randomized, controlled study is needed to reach general acceptance of this new therapy.
In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome

Mesenchymal stromal cells (MSCs) have been investigated as a treatment for various inflammatory diseases because of their immunomodulatory and reparative properties. However, many basic questions concerning their mechanisms of action after systemic infusion remain unanswered. We performed a detailed analysis of the immunomodulatory properties and proteomic profile of MSCs systemically administered to two patients with severe refractory acute respiratory distress syndrome (ARDS) on a compassionate use basis and attempted to correlate these with in vivo anti‐inflammatory actions. Both patients received 2 × 106 cells per kilogram, and each subsequently improved with resolution of respiratory, hemodynamic, and multiorgan failure. In parallel, a decrease was seen in multiple pulmonary and systemic markers of inflammation, including epithelial apoptosis, alveolar‐capillary fluid leakage, and proinflammatory cytokines, microRNAs, and chemokines. In vitro studies of the MSCs demonstrated a broad anti‐inflammatory capacity, including suppression of T‐cell responses and induction of regulatory phenotypes in T cells, monocytes, and neutrophils. Some of these in vitro potency assessments correlated with, and were relevant to, the observed in vivo actions. These experiences highlight both the mechanistic information that can be gained from clinical experience and the value of correlating in vitro potency assessments with clinical effects. The findings also suggest, but do not prove, a beneficial effect of lung protective strategies using adoptively transferred MSCs in ARDS. Appropriate randomized clinical trials are required to further assess any potential clinical efficacy and investigate the effects on in vivo inflammation.
Reconstruction of maxillary defect with musculo‐adipose rectus free flap

The rectus myocutaneous free flap (RMFF) is used for medium to large maxillectomy defects. However, in patients with central obesity the inset could be difficult due to the bulk from excessive layer of adipose tissue. We describe a modification of the RMFF for patients with excessive central obesity with a flap consisting of adipose tissue with minimal rectus muscle; the musculo‐adipose rectus free flap (MARF).
Human immunodeficiency virus type 1 Vif- mutant particles from restrictive cells: role of Vif in correct particle assembly and infectivity

Disruption of the vif gene of human immunodeficiency virus (HIV) type 1 affects virus infectivity to various degrees, depending on the T-cell line used. We have concentrated our studies on true phenotypic Vif- mutant particles produced from CEMx174 or H9 cells. In a single round of infection, Vif- virus is approximately 25 (from CEMx174 cells) to 100 (from H9 cells) times less infectious than wild-type virus produced from these cells or than the Vif- mutant produced from HeLa cells. Vif- virions recovered from restrictive cells, but not from permissive cells, are abnormal both in terms of morphology and viral protein content. Notably, they contain much reduced quantities of envelope proteins and altered quantities of Gag and Pol proteins. Although wild-type and Vif- virions from restrictive cells contain similar quantities of viral RNA, no viral DNA synthesis was detectable after acute infection of target cells with phenotypically Vif- virions. To examine the possible role of Vif in viral entry, attempts were made to rescue the Vif- defect in H9 cells by pseudotyping Vif+ and Vif- HIV particles with amphotropic murine leukemia virus envelope. Vif- particles produced in the presence of HIV envelope could not be propagated when pseudotyped. In contrast, when only the murine leukemia virus envelope was present, significant propagation of Vif- HIV particles could be detected. These results demonstrate that Vif is required for proper assembly of the viral particle and for efficient HIV Env-mediated infection of target cells.
Evaluating Strategies for Resource Finding in a Peer-to-Peer Grid

This paper presents some experimental results on the evaluation of a resource finding algorithm for a peer-to- peer grid. The algorithm, which is based on "spatial computing" concepts, models a grid as a P2P overlay network, on which resources are obtained by a suitable navigation strategy that forwards a request from node to node, until one is found offering the desired amount of resources. The algorithm is experimentally evaluated by means of a software simulator, and fully characterised by assessing the performances afforded by different navigation strategies and the influence of several parameters, such as the number of nodes, their workload, the origin (node) of the resource request, etc.
Anti‐biofilm efficacy of a lactoferrin/xylitol wound hydrogel used in combination with silver wound dressings

With an epidemic increase in obesity combined with an ageing population, chronic wounds such as diabetic foot ulcers, pressure ulcers and venous leg ulcers are an increasing clinical concern. Recent studies have shown that bacterial biofilms are a major contributor to wound bioburden and interfere with the normal wound healing process; therefore, rational design of wound therapies should include analysis of anti‐biofilm characteristics. Studies using the combined treatment of bacterial biofilms with the innate immune molecule lactoferrin and the rare sugar‐alcohol xylitol have demonstrated an antimicrobial capacity against a clinical wound isolate. Studies presented here used a colony‐drip‐flow reactor biofilm model to assess the anti‐biofilm efficacy of a lactoferrin/xylitol hydrogel used in combination with commercially available silver‐based wound dressings. Log reductions in biofilm viability are compared with a commercially available wound hydrogel used in combination with the silver‐based wound dressings. For both a single species biofilm and a dual species biofilm, the lactoferrin/xylitol hydrogel in combination with the silver wound dressing Acticoat™ had a statistically significant reduction in biofilm viability relative to the commercially available wound hydrogel. This study also demonstrated a statistical interaction between the lactoferrin/xylitol hydrogel and the silver wound dressing.
Pseudomonas Aeruginosa Bacteraemia in Two UK District Hospitals

Pseudomonas aeruginosa bacteraemia is associated with significant morbidity and mortality. We retrospectively studied the epidemiology of bacteraemia due to P. aeruginosa in two UK district hospitals so as to determine prevention strategies and assess the efficacy and compliance with local hospital antibiotic guidelines. Eighty six episodes occurred in 85 patients over the 3 year period. There was a year on year increase in bacteraemias, due predominantly to an increased proportion of community-onset episodes. Urinary catheterisation was a significant risk factor, along with anaemia, renal disease, malignancy and diabetes. The antibiotic guidelines were adequate for 92.8% of episodes but only 73.8% of patients received adequate therapy. Failure to follow the guidelines was principally due to unwillingness to use gentamicin due to concerns about nephrotoxicity. The antibiotic guidelines may need reviewing to accommodate this problem and further work is required to address urinary catheter care in both the hospital and community. Pseudomonas aeruginosa should be considered a significant pathogen when patients are admitted with features of sepsis.
Coactivator PC4 Mediates AP-2 Transcriptional Activity and Suppresses ras-Induced Transformation Dependent on AP-2 Transcriptional Interference

ABSTRACT ras oncogene-transformed PA-1 human teratocarcinoma cells have abundant AP-2 mRNA but, paradoxically, little AP-2 transcriptional activity. We have previously shown that overexpression of AP-2 in nontumorigenic variants of PA-1 cells results in inhibition of AP-2 activity and induction of tumorigenicity similar to that caused by ras transformation of PA-1 cells. Evidence indicated the existence of a novel mechanism of inhibition of AP-2 activity involving sequestering of transcriptional coactivators. In this study, we found that PC4 is a positive coactivator of AP-2 and can restore AP-2 activity in ras-transformed PA-1 cells. Relative to vector-transfected ras cell lines,ras cell lines stably transfected with and expressing the PC4 cDNA have a diminished growth rate and exhibit a loss of anchorage-independent growth, and they are unable to induce the formation of tumors in nude mice. These data suggest that a transcriptional coactivator, like a tumor suppressor, can have a growth-suppressive effect on cells. Our experiments are the first to show that ras oncogenes and oncogenic transcription factors can induce transformation through effects on the transcription machinery rather than through specific programs of gene expression.
The effect of ouabain on tension in isolated respiratory tract smooth muscle of humans and other species

1 The Na+, K+‐pump has been implicated in animal models of airway hyperreactivity. We examined the effects of inhibiting the Na+, K+‐pump and Na+, Ca2+‐exchange on isometric tone of isolated trachealis from humans and other species. 2 In preparations from 5 out of 9 humans, strong spontaneous contractions (36–48 h−1; up to 1.8 g) developed within 25 min. 3 Ouabain (10−7‐10−5 m) caused an immediate and sustained contraction. This response was not blocked by atropine, diphenhydramine, or cimetidine. 4 Contractions were also elicited when the normal physiological solution was changed to a K+‐free solution, a procedure which inhibits the Na+, K+‐pump, and in reduced (15 mm) Na+ solution, which inhibits Na+, Ca2+ exchange. 5 In preparations of dog and guinea‐pig isolated trachea, ouabain (10−5 m) caused a multiphasic response; in the rabbit, ouabain was without effect. K+‐free solution was without effect in the dog preparations and produced relaxation of the guinea‐pig trachea. Guinea‐pig tracheae responded to a low Na+ solution with a strong contraction. 6 Our findings indicate that: (a) human airway smooth muscle may be a spontaneously contracting muscle, at least in vitro, (b) a prolonged contraction to ouabain is unique for the human airway smooth muscle among the animals tested, as is the contraction in a K+‐free medium, and (c) the contractile response does not involve acetylcholine or histamine release, but may involve a Na+, Ca2+‐exchange mechanism. These results suggest that the level of Na+, K+‐pump activity could play a role in determining the degree of bronchomotor tone in humans.
Increase of methicillin resistance in Staphylococcus aureus caused by deletion of a gene whose product is homologous to lytic enzymes

A spontaneous high-level methicillin-resistant mutant, SRM1648, for which the MIC of methicillin is 1,600 microg/ml, was isolated on a plate containing 400 microg of the antibiotic/ml on which had been cultured the low-level methicillin-resistant Staphylococcus aureus SR17238, for which the MIC is 6.3 microg/ml. Analysis of the chromosomal DNAs of the mutant and the parental strains by the restriction landmark genomic scanning method with two-dimensional electrophoresis of restriction fragments revealed a 1.6-kb deletion in the chromosome of the mutant. The HindIII fragment of 2.5 kb containing this deleted region was cloned into a plasmid vector and introduced into the parental strain. A deletion mutant reconstructed in the presence of a low concentration of methicillin by integration and excision of the recombinant plasmid exhibited a high level of resistance (methicillin MIC, 1,600 microg/ml), confirming that the deletion had caused the elevation of the resistance level. Sequence analysis indicated that the deletion occurred in three consecutive open reading frames (ORFs). The predicted amino acid sequence of the first ORF showed high homology with both RelA and SpoT of Escherichia coli, which are involved in the synthesis and hydrolysis of guanosine 5',3'-polyphosphate, and that of the third ORF showed a relatively high homology to the lytic enzyme encoded by the lytC gene of Bacillus subtilis. We also isolated another high-level resistant mutant with a deletion within the third ORF, which suggested that inactivation of some lytic enzyme resulted in the increased resistance.
After we #VoteLeave we can #TakeControl

This study explores the use of personal pronouns in the context of political agitation on Twitter in the run-up to the EU referendum 2016. Using a combination of corpus linguistic and discourse analytical techniques, it shows notable differences in the way in which personal pronouns were employed by Leavers and Remainers. In particular, we emerged as a significant factor distinguishing the online rhetoric of the two camps with Leavers using we more often and in a much more versatile manner. This study contributes to the growing body of research on ambient affiliations in political communication offering insights into the ways in which personal pronouns are strategically deployed to create imagined collectives for the purpose of political bonding and agitation online.
Diagnosing childhood tumors: A review of 147 cutting needle biopsies in 110 children.

BACKGROUND/PURPOSE The aims of this study were to evaluate the diagnostic accuracy and safety of cutting needle biopsy for diagnosis in children with tumors suspected for malignancy. METHODS Medical records and biopsy slides recorded from 1988 to 1999 were reviewed. One hundred ten patients had undergone a total of 147 cutting needle biopsies. The biopsy was performed under ultrasound guidance, using a 1.2-mm (18 gauge) Biopsy-cut biopsy needle. The diagnoses were benign tumors (n = 8), malignant tumors (n = 84), and nonneoplastic diseases (n = 18), with repeat biopsy performed in 24 patients. RESULTS The diagnostic accuracy of cutting needle biopsies was 89% (131 of 147). The accuracy for pretreatment diagnosis was 88% (102 of 116), and for confirming or excluding a recurrence or metastasis 93% (26 of 28). The sensitivity of this method was 82% (86 of 105), and the positive predictive value 99% (86 of 87). Nondiagnostic cutting needle biopsy (n = 16) was not related to the age of the patient, experience of the radiologist, number of needle insertions, or site of puncture. No patient exhibited tumor growth along the needle tract. Complications occurred in 10 cases (7%) and pain in 20 (14%). CONCLUSION Cutting needle biopsy is an accurate and safe procedure with a low learning threshold that is recommended for diagnosing malignancies in childhood.
Multiple cytokine biomarkers in heart failure

Raised levels of circulating proinflammatory cytokines are associated with disease progression and adverse outcomes in chronic heart failure patients. Inflammatory markers may be predictive of congestive heart failure and myocardial infarction, allowing enhanced risk stratification. The profile of cytokine blood levels differs in accordance with the initiating cause and type of heart failure. Therefore, subclassification of heart failure patients based on cytokine measurements could potentially identify subgroups of patients, permitting tailored or personalized therapy. During inflammatory states, cytokine production is often regulated by activation of other cytokines, resulting in a perpetuating, complex cytokine cascade. Thus, single-assay measurement of cytokines provides limited information, and to obtain a more comprehensive picture of immune activation, multiple cytokines need to be analyzed simultaneously. With the technological development in multiplex protein analyses, multiplexing cytokines has become simple, fast and reproducible. Luminex technology represents one platform for simultaneous measurements of several cytokines, and has gained increasing interest among researchers in recent years. However, the measurement of multiple cytokines as part of a multimarker prognostic or diagnostic biomarker approach remains to be implemented in current clinical practice, as current knowledge of the underlying biology of cytokine release in heart disease is still too limited and a bioinformatic tool for interpretation of cytokine profiles is needed. Nevertheless, multiplex protein analyses are likely to constitute an important part of experimental and clinical research on heart failure and cytokines, paving the way for more accurate heart failure treatment.
Osteopontin: an interfacial extracellular matrix protein in mineralized tissues.

Among the noncollagenous matrix proteins found in mineralized tissues (MTs), colloidal-gold immunocytochemistry has demonstrated that the ultrastructural distribution of osteopontin (OPN) is unique in that this protein preferentially accumulates at MT interfaces. In bone, OPN is present as a major component of cell- and matrix-matrix interfacial structures termed laminae limitantes and cement lines, respectively. Here, we review the implications of this distinct, interfacial tissue distribution as it relates to the properties and functional motifs of OPN (e.g. RGD, polyAsp, phosphorylation) in different MTs, and more specifically, how it pertains to current theory on the cellular and extracellular matrix (ECM) events associated with bone remodeling. The production of OPN as one of the earliest, and latest, secretory activities of the osteoblast lineage is discussed, together with a consideration of the role of OPN in cement lines and laminae limitantes in bone and in other normal, pathological and healing MTs such as teeth, kidney stones, bone wound healing and implant osseointegration. Further to its ability to influence cell dynamics, calcification and possibly tissue cohesion in MTs, it is proposed that OPN in cement lines may also promote adhesion between apposing substrata. With regard to this latter function, it is suggested that the molecular interactions within, and biomechanical properties of, such an OPN-rich interfacial zone may be important in minimizing strain-induced fatigue damage and microcrack propagation in bone and across other MT interfaces.