tbuckley/cabot-search huggingface dataset:
Letter to the editor: authors’ response
Authors: Alexandra L Quittner, Dave Barker, Lutz Goldbeck, Alistair Duff, Janice Abbott
Journal: Thorax (2015)

Dear editors

We thank Drs Webb and Bryon for their comments1 on our TIDES paper.2 We are responding to their critiques of our study. Beyond clarifying the ‘devilish details’ they highlighted, we want to emphasise the clinical significance of our results2—a substantial proportion of our patients reported elevated symptoms of depression (17%) and anxiety (29%) across nine countries. Higher rates were reported by parents: depression (37.3% of mothers, 31.3% of fathers) and anxiety (47.8% of mothers, 35.2% of fathers). Although the ‘absolute’ number of individuals who have depression or anxiety is difficult to ascertain with any screening tool, it is clear that psychological distress is common and has been associated with worse: self-management, pulmonary function, quality of life, and increased hospitalisations and healthcare costs.3 ,4 We can no longer minimise the extent of the problem and its impact on the health of individuals with CF.

Our response to the ‘details’: First, 6088 participants completed the depression and anxiety screening, with a small …
Development of specific T-cell responses to Candida and tetanus antigens in partial DiGeorge syndrome
Authors: Carla M. Davis, Vikas S. Kancherla, Ashwini Reddy, Wenyaw Chan, Hung-Wen Yeh, Lenora M. Noroski, Howard Rosenblatt, William T. Shearer, Javier Chinen
Journal: Journal of Allergy and Clinical Immunology (2008)
Acute myocardial infarction associated with high dose intravenous immunoglobulin infusion for autoimmune disorders. A study of four cases
Authors: O Elkayam, D Paran, R Milo, Y Davidovitz, D Almoznino-Sarafian, D Zeltser, M Yaron, D Caspi
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVE</h3> To report on four patients with autoimmune disorders who developed acute myocardial infarction (MI) during or soon after treatment with high dose intravenous immunoglobulins (IVIG) and to determine the clinical profile of patients prone to this complication. <h3>METHODS</h3> The clinical history of the four patients is reported with details concerning age, sex, indication for IVIG treatment, risk factors, timing of the MI and outcome. The relevant medical literature has been reviewed. <h3>RESULTS</h3> The patients, three men and one woman, aged 42–67, received IVIG treatment for different autoimmune disorders. All had a history of atherosclerosis or previous risk factors such as hypertension, stroke, hyperlipidaemia and obesity. Two of the patients suffered a MI after the first infusion of IVIG while the others—after the 5th and 15th pulses. MI occurred during the infusion in two patients and after a few days in the others. All the patients recovered from the acute event. These observations are in concert with sporadic cases of IVIG related thrombosis reported in the medical literature. <h3>CONCLUSION</h3> In patients with vascular risk factors such as old age, hypertension, history of stroke or coronary artery disease, the possibility of IVIG related vascular complications should be considered and IVIG prescribed with a cautious reweighted risk/benefit consideration.
US signs contract with ZMapp maker to accelerate development of the Ebola drug
Authors: M. McCarthy
Journal: BMJ (2014)

The US government has signed a multimillion dollar contract with the maker of the experimental Ebola drug ZMapp to accelerate the drug’s development.

Under the contract the US Biomedical Advanced Research and Development Authority (BARDA) will provide funding, expertise, and technical support to the drug company, Mapp Biopharmaceutical, of San Diego, California. BARDA is the US agency tasked with developing medical countermeasures—including vaccines, medicines, diagnostics, and medical equipment—to respond to chemical, biological, radiological, or nuclear incidents or attacks, as well as pandemics …
A Novel Role for Tachykinin Neurokinin-3 Receptors in Regulation of Human Bronchial Ganglia Neurons
Authors: Allen C. Myers, Roy G. Goldie, Douglas W. P. Hay
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

The neuropeptide tachykinins and their receptors have been implicated in the pathogenesis of lung disease, although the role of the tachykinin neurokinin-3 receptor has not been elucidated. Using confocal microscopy, we identified tachykinin neurokinin-3 receptors on human bronchial parasympathetic ganglion neurons. Electrophysiologic recordings demonstrated that activation of sensory nerve fibers, either by antidromic stimulation or capsaicin, depolarized these neurons. This response was mimicked by exogenously applied tachykinin neurokinin-3 receptor–selective agonist, senktide analogue, but not significantly by tachykinin neurokinin-1 or neurokinin-2 receptor–selective agonists. Responses to endogenous tachykinins or exogenous selective tachykinin neurokinin-3 receptor activation with senktide analogue were inhibited by the selective tachykinin neurokinin-3 receptor antagonists, SB 223412 or SB 235375. We provide the first evidence that tachykinin neurokinin-3 receptors regulate human bronchial parasympathetic ganglion neurotransmission by activation of a peripheral reflex. This pathway may play a significant role in controlling bronchomotor tone and air flow to the lung.
Identification of ROBO1 as a Novel Hepatocellular Carcinoma Antigen and a Potential Therapeutic and Diagnostic Target
Authors: Hirotaka Ito, Shin-ichi Funahashi, Naoko Yamauchi, Junji Shibahara, Yutaka Midorikawa, Shigeto Kawai, Yasuko Kinoshita, Akira Watanabe, Yoshitaka Hippo, Toshihiko Ohtomo, Hiroko Iwanari, Atsushi Nakajima, Masatoshi Makuuchi, Masashi Fukayama, Yuichi Hirata, Takao Hamakubo, Tatsuhiko Kodama, Masayuki Tsuchiya, Hiroyuki Aburatani
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Hepatocellular carcinoma is the most common primary malignancy of the liver and accounts for as many as one million deaths annually worldwide. The present study was done to identify new transmembrane molecules for antibody therapy in hepatocellular carcinoma. Experimental Design: Gene expression profiles of pooled total RNA from three tissues each of moderately differentiated and poorly differentiated hepatocellular carcinoma were compared with those of normal liver, noncancerous liver tissue in hepatocellular carcinoma patients, 30 normal tissue samples, and five fetal tissue samples. Target genes up-regulated specifically in hepatocellular carcinoma were validated by immunohistochemical analysis and complement-dependent cytotoxicity assay using monoclonal antibodies generated against target molecules. Results: The human homologue of the Drosophila Roundabout gene, axon guidance receptor homologue 1, ROBO1/DUTT1, a member of the immunoglobulin superfamily, was highly expressed in hepatocellular carcinoma, whereas it showed only a limited distribution in normal tissues. On immunohistochemical analysis using a newly generated anti-ROBO1 monoclonal antibody, positive signals were observed in 83 of 98 cases of hepatocellular carcinoma (84.7%). The mAb B2318C induced complement-dependent cytotoxicity in ROBO1-expressing cell lines and in the liver cancer cell line PLC/PRF/5. Strikingly, the ectodomain of ROBO1 was detected not only in the culture medium of liver cancer cell lines (PLC/PRF/5, HepG2, etc.) but also in sera from hepatocellular carcinoma patients (6 of 11). Conclusions: This is the first report that ROBO1 is overexpressed in hepatocellular carcinoma and shed into serum in humans. These observations suggest that ROBO1 is a potential new serologic marker for hepatocellular carcinoma and may represent a new therapeutic target.
Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature
Authors: Jan Kazenwadel, Genevieve A. Secker, Yajuan J. Liu, Jill A. Rosenfeld, Robert S. Wildin, Jennifer Cuellar-Rodriguez, Amy P. Hsu, Sarah Dyack, Conrad V. Fernandez, Chan-Eng Chong, Milena Babic, Peter G. Bardy, Akiko Shimamura, Michael Y. Zhang, Tom Walsh, Steven M. Holland, Dennis D. Hickstein, Marshall S. Horwitz, Christopher N. Hahn, Hamish S. Scott, Natasha L. Harvey
Journal: Blood (2011)
An unusual case of haemoptysis
Authors: R. Newton, S. Kemp, Z. Zoumot, G.-Z. Yang, A. Darzi, P. L Shah
Journal: Thorax (2010)

An unusual case of haemoptysisA 65-year-old Filipino man presented with a cough productive of heavily bloodstained sputum for 1 month with slight weight loss.He had chronic obstructive pulmonary disease from a 60 pack-year smoking history, having quit 20 years previously, and his chronic mild dyspnoea was stable.He had been treated for pulmonary tuberculosis 9 years previously but had not travelled abroad for 3 years.He had no other medical or family history and was taking no medications.Investigations included a high-resolution CT scan (figure 1a) and fibreoptic bronchoscopy (figure 1b).Coliforms and a co-amoxiclav-resistant Proteus were cultured from purulent bronchoalveolar lavage (BAL) fluid from the left lower lobe.Both organisms were sensitive to ciprofloxacin.The BAL fluid was negative for mycobacteria, and cytology showed no malignancy.Endobronchial biopsy samples (EBBx) showed mucosa with active chronic inflammation including eosinophils and some dystrophic calcification.Bronchoscopic probe-based confocal laser endomicroscopy (pCLE) of a tracheal lesion is shown in figure 1d.pCLE is a new bronchoscopic technique which detects autofluorescence to obtain near histological quality real-time in situ images of the alveolus 1 and bronchial basement membrane.
Charles Henry de Boer
Authors: F. d. B. R. d. Boer
Journal: BMJ (2013)

Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles possess potent antiproliferative activity against certain cancer cells, similar to the unfluorinated 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495). In “sensitive” cancer cells, DF 203 is metabolized by, can induce expression of, and binds covalently to CYP1A1. Metabolism appears to be essential for its antiproliferative activity through DNA adduct formation. However, a biphasic dose-response relationship compromises its straightforward development as a chemotherapeutic agent. We investigated whether fluorinated benzothiazoles inhibit cancer cell growth without the biphasic dose-response, and whether the fluorinated benzothiazoles are also metabolized into reactive species, with binding to macromolecules in sensitive cancer cells. One fluorinated benzothiazole, 2-(4-amino-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) did exhibit potent, antiproliferative activity without a biphasic dose-response. The fluorinated benzothiazoles were also metabolized only in cells, which subsequently showed evidence of cell death. We used microsomes from genetically engineered human B-lymphoblastoid cells expressing cytochromes P450 (CYP1A1, CYP1A2, or CYP1B1) to clarify the basis for fluorinated benzothiazole metabolism. 5F 203 induced CYP1A1 and CYP1B1 mRNA expression in sensitive breast and renal cancer cells, whereas 5F 203 induced CYP1A1 mRNA but not CYP1B1 mRNA expression in sensitive ovarian cancer cells. 5F 203 did not induce CYP1A1 or CYP1B1 mRNA expression in any “resistant” cancer cells. The fluorinated benzothiazoles induced CYP1A1 protein expression exclusively in sensitive cells. [<sup>14</sup>C]5F 203 bound substantially to subcellular fractions in sensitive cells but only minimally in resistant cells. These data are concordant with the antiproliferative activity of fluorinated benzothiazoles deriving from their ability to become metabolized and bind to macromolecules within sensitive cells.
The gut microbiota, dietary extremes and exercise
Authors: Georgina L Hold
Journal: Gut (2014)

Better understanding of the proportion of children who ever receive special educational needs (SEN) provision or social care services during school years is highly relevant for healthcare as reductions in one or more of these services could impact on healthcare. Using the National Pupil Database linked to the all-of-England children looked after return and children in need census, we estimated the cumulative incidence of SEN status among (1) children ever in care during school, (2) children in need but not care, and (3) neither. We observed a very high proportion of children who were in care or need during school years had SEN provision at some point (83% and 65%, respectively), and that a high proportion of children in neither of these groups did so, too (37%). Healthcare, SEN provision and social care services focus on a similar population of children. Better integration of these services could lead to synergies and cost-efficiencies and better support for these children and their families.
Long-Term Outcomes of Diabetic Patients With Critical Limb Ischemia Followed in a Tertiary Referral Diabetic Foot Clinic
Authors: Luigi Uccioli, Roberto Gandini, Laura Giurato, Sebastiano Fabiano, Enrico Pampana, Vincenza Spallone, Erika Vainieri, Giovanni Simonetti
Journal: Diabetes Care (2010)

OBJECTIVE We describe the long-term outcomes of 510 diabetic patients with critical limb ischemia (CLI) and an active foot ulcer or gangrene, seen at the University Hospital of Rome Tor Vergata, a tertiary care clinic. RESEARCH DESIGN AND METHODS These patients were seen between November 2002 and November 2007 (mean follow-up 20 ± 13 months [range 1–66 months]). The Texas Wound Classification was used to grade these wounds that were either class C (ischemia) and D (ischemia+infection) and grade 2–3 (deep–very deep). This comprehensive treatment protocol includes rapid and extensive initial debridement, aggressive use of peripheral percutaneous angioplasty, empirical intravenous antibiotic therapy, and strict follow-up. RESULTS The protocol was totally applied (with percutaneous angioplasty [PA+]) in 456 (89.4%) patients and partially (without percutaneous angioplasty [PA−]) in 54 (10.6%) patients. Outcomes for the whole group and PA+ and PA− patients are, respectively: healing, n = 310 (60.8%), n = 284 (62.3%), and n = 26 (48.1%); major amputation, n = 80 (15.7%), n = 67 (14.7%), and n = 13 (24.1%); death, n = 83 (16.25%), n = 68 (14.9%), and n = 15 (27.8%); and nonhealing, n = 37 (7.25%), n = 37 (8.1%), and n = 0 (0%) (χ2 &amp;lt;0.0009). Predicting variables at multivariate analysis were the following: for healing, ulcer dimension, infection, and ischemic heart disease; and for major amputation, ulcer dimension, number of minor amputations, and age. Additional predicting variables for PA+ patients were the following: for healing, transcutaneous oxygen tension [ΔTcPo2]; and for major amputation, basal TcPo2, basal A1C, ΔTcPo2, and percutaneous angioplasty technical failure. CONCLUSIONS Early diagnosis of CLI, aggressive treatment of infection, and extensive use of percutaneous angioplasty in ischemic affected ulcers offers improved outcome for many previously at-risk limbs. Ulcer size &amp;gt;5 cm2 indicates a reduced chance of healing and increased risk of major amputation. It was thought that all ulcers warrant aggressive treatment including percutaneous angioplasty and that treatment should be considered even for small ischemic ulcers.
p12CDK2-AP1 Gene Therapy Strategy Inhibits Tumor Growth in an <i>In vivo</i> Mouse Model of Head and Neck Cancer
Authors: Marxa L. Figueiredo, Yong Kim, Maie A.R. St. John, David T.W. Wong
Journal: Clinical Cancer Research (2005)

To test the potential of p12(CDK2-AP1) (p12), a cell cycle regulator and cyclin-dependent kinase-2-associating protein commonly down-regulated in head and neck squamous cell carcinoma ( approximately 70%), as a gene therapy in inhibiting head and neck squamous cell carcinoma growth in vivo.We addressed the effect of p12 expression on tumor growth by using a well-established squamous cell carcinoma VII/SF floor of mouth xenograft mouse model. The effect of therapy on tumor growth was determined for: (a) no treatment, (b) PBS, (c) vehicle (1,2-dioleoyloxy-3-trimethylammonium propane:cholesterol liposomes / 5% dextrose), (d) empty vector controls, and (e) p12-encoding vector experimental groups.p12 gene therapy significantly induced antitumor effects as compared with controls, including (a) size and weight of p12-treated tumors decreased by 51% to 72% compared with all controls (P < 0.02), (b) tumor growth rate post-therapy was inhibited by 55% to 64% compared with empty vector controls (P < 0.0001), and (c) p12 expression was higher in p12-treated than controls (P < 0.002) by two-tailed t test analyses. Mechanistically, p12 treatment affected cell turnover kinetics as assessed by apoptotic and cell proliferation indices. p12 therapy significantly increased terminal nucleotidyl transferase-mediated nick end labeling (P < 0.05) and morphology-based apoptotic indices (P < 0.05) as well as significantly decreased Ki-67 cell proliferation indices (P < 0.001) compared with controls, resulting in a net cell turnover reduction in p12-treated tumors.We show that this novel therapeutic modality can significantly induce antitumor responses in vivo. These results support a role for p12 as a novel tumor growth suppressor gene therapy and suggest that optimization and/or combination with current therapies may hold considerable promise in preparation for clinical trials.
A <sub>2b</sub> Adenosine Receptor Regulates Hyperlipidemia and Atherosclerosis
Authors: Milka Koupenova, Hillary Johnston-Cox, Alexander Vezeridis, Haralambos Gavras, Dan Yang, Vassilis Zannis, Katya Ravid
Journal: Circulation (2011)

The cAMP-elevating A(2b) adenosine receptor (A(2b)AR) controls inflammation via its expression in bone marrow cells.Atherosclerosis induced by a high-fat diet in apolipoprotein E-deficient mice was more pronounced in the absence of the A(2b)AR. Bone marrow transplantation experiments indicated that A(2b)AR bone marrow cell signals alone were not sufficient to elicit this effect. Intriguingly, liver expression of the A(2b)AR in wild-type mice was vastly augmented by a high-fat diet, raising the possibility that this upregulation is of functional significance. A(2b)AR genetic ablation led to elevated levels of liver and plasma cholesterol and triglycerides and to fatty liver pathology typical of steatosis, assessed by enzymatic assays and analysis of liver sections. Western blotting and quantitative polymerase chain reaction revealed elevated expression of the following molecules in the liver of A(2b)AR-null mice: the transcription factor sterol regulatory element binding protein-1 (SREBP-1) and its 2 downstream targets and regulators of lipogenesis, acetyl CoA carboxylase and fatty acid synthase. Pharmacological activation or inhibition of A(2b)AR in primary hepatocytes confirmed the regulation of SREBP-1 by this receptor. A(2b)AR-mediated changes in cAMP were found to regulate levels of the transcriptionally active form of SREBP-1. Finally, adenovirally mediated restoration of the A(2b)AR in the liver of A(2b)AR-null mice reduced the lipid profile and atherosclerosis. Similarly, in vivo administration of the A(2b)AR ligand BAY 60-6853 in control mice on a high-fat diet reduced the lipid profile and atherosclerosis.This study provides the first evidence that the A(2b)AR regulates liver SREBP-1, hyperlipidemia, and atherosclerosis, suggesting that this receptor may be an effective therapeutic target.
Inhibition of 5α-reductase activity in human skin by zinc and azelaic acid
Authors: D. STAMATIADIS, MARIE-CLAIRE BULTEAU-PORTOIS, IRENE MOWSZOWICZ
Journal: British Journal of Dermatology (1988)

The effects of zinc sulphate and azelaic acid on 5α‐reductase activity in human skin were studied using an in vitro assay with 1,2[3H]‐testosterone as substrate. When added at concentrations of 3 or 9 mmol/1, zinc was a potent inhibitor of 5α‐reductase activity. At high concentrations, zinc could completely inhibit the enzyme activity. Azelaic acid was also a potent inhibitor of 5α‐reductase; inhibition was detectable at concentrations as low as 0.2 mmol/l and was complete at 3 mmol/l. An additive effect of the two inhibitors was observed. Vitamin B6 potentiated the inhibitory effect of zinc, but not of azelaic acid, suggesting that two different mechanisms are involved. When the three substances were added together at very low concentrations which had been shown to be ineffective alone, 90% inhibition of 5α‐reductase activity was obtained. If this inhibition is confirmed in vivo, zinc sulphate combined with azelaic acid could be an effective agent in the treatment of androgen related pathology of human skin.
A further characterization of the selective K movements observed in human red blood cells following acetylphenylhydrazine exposure
Authors: Eugene P. Orringer
Journal: American Journal of Hematology (1984)

Abstract Following brief exposure to acetylphenylhydrazine, the potassium permeability of the human erythrocyte membrane is selectively augmented. While a similar increase in potassium permeability results from the intracellular accumulation of calcium (the Gardos phenomenon), we have found a number of features that allow these two pathways to be distinguished from one another. The acetylphenylhydrazine pathway does not require calcium for its activation, and can be seen even in the presence of a molar excess of the calcium chelator EGTA. The transmembrane potassium movement via this channel has a specific requirement for the anion chloride, and it can be inhibited by furosemide. The potassium that moves through the Gardos pathway, on the other hand, can be accompanied by any permeant anion, and is inhibitable by quinidine or cetiedil. Thus, acetylphenylhydrazine exposure seems to promote K + Cl cotransport, whereas the Gardos pathway represents a potassium conductive channel. While full demonstration of both these pathways requires harsh in vitro manipulation, the large electrochemical potassium gradient favoring the movement of this cation out from the erythrocyte suggests that even a partial activation of either pathway could cause intracellular dehydration and thus contribute importantly to the pathophysiology of in vivo red cell destruction.
Down's syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse
Authors: Louisa Dunlevy, Mike Bennett, Amy Slender, Eva Lana-Elola, Victor L. Tybulewicz, Elizabeth M.C. Fisher, Timothy Mohun
Journal: Cardiovascular Research (2010)

AimsCardiac malformations are prevalent in trisomies of human chromosome 21 [Down's syndrome (DS)], affecting normal chamber separation in the developing heart. Efforts to understand the aetiology of these defects have been severely hampered by the absence of an accurate mouse model. Such models have proved challenging to establish because synteny with human chromosome Hsa21 is distributed across three mouse chromosomes. None of those engineered so far accurately models the full range of DS cardiac phenotypes, in particular the profound disruptions resulting from atrioventricular septal defects (AVSDs). Here, we present analysis of the cardiac malformations exhibited by embryos of the transchromosomic mouse line Tc(Hsa21)1TybEmcf (Tc1) which contains more than 90% of chromosome Hsa21 in addition to the normal diploid mouse genome.
Adrenal Cortical Activity in Depressive Illness
Authors: WILLIAM T. CARPENTER, WILLIAM E. BUNNEY
Journal: American Journal of Psychiatry (1971)

The authors investigated four aspects of central control of adrenal cortical activity and three aspects of peripheral metabolism. Their results suggest that the central control mechanisms function normally during depression, but the peripheral measures of cortisol activity revealed interesting abnormalities. During depression, both the production rate and the metabolic clearance rate were elevated, but a normal 24-hour mean plasma cortisol concentration was maintained. On recovery, the production rate fell while the metabolic clearance rate remained high, resulting in a low plasma cortisol concentration. The authors also discuss the implications of investigating cortisol dynamics with radio-isotope dilution methods.