tbuckley/cabot-search huggingface dataset:
Modulation of Suppressor-Cell Activity by Cimetidine in Patients with Common Variable Hypogammaglobulinemia
Authors: William B. White, Mark Ballow
Journal: New England Journal of Medicine (1985)

Because of evidence of a possible immunoregulatory role for cimetidine, an antagonist to histamine H2 receptors, we studied the effects of this drug in five adult patients with common variable hypogammaglobulinemia. Three patients had excessive suppressor-cell function associated with panhypogammaglobulinemia, whereas the other two had no apparent T-cell defects. The patients were given a one-month course of oral cimetidine (1200 mg daily in four divided doses). Subsequently, the three patients with excessive suppressor-cell function had a marked reduction in suppressor activity along with a decrease in the number of suppressor cells (T8+). One of these three had a marked rise in both in vitro immunoglobulin secretion and serum immunoglobulin concentrations, which was reversible after the drug was stopped for three months and reproducible when therapy with cimetidine was repeated. There was no difference in immunoglobulin secretion or suppressor-cell activity while taking cimetidine between the two patients with common variable hypogammaglobulinemia without excessive suppressor-cell activity and control patients with duodenal ulcers. The data suggest that H2-receptor antagonists may decrease excessive suppressor-cell activity and allow endogenous immunoglobulin production in some patients with common variable hypogammaglobulinemia.
The Tarsal-Tunnel Syndrome
Authors: Joseph Goodgold, Harvey P. Kopell, Neil I. Spielholz
Journal: New England Journal of Medicine (1965)

THE occurrence of peripheral neuropathies caused by compression incident to anatomic alteration has received considerable attention in recent years. Perhaps the best known of these compressive or entrapment neuropathies involves the median nerve as it passes under the transverse carpal ligament at the wrist. The carpal-tunnel syndrome that results is clinically identified by characteristic motor-sensory deficits in the median-nerve distribution in the hand.The tarsal-tunnel syndrome, resulting from compression of the posterior tibial nerve, is not as often recognized as its counterpart in the wrist. It is always useful in the recognition of a disease to have its clinical features . . .
T3 Mitochondrial transfer is an important mechanism by which Mesenchymal Stromal Cells (MSC) facilitate macrophage phagocytosis in the<i>in vitro</i>and<i>in vivo</i>models of Acute Respiratory Distress Syndrome (ARDS)
Authors: MV Jackson, TJ Morrison, CM O’Kane, DF McAuley, AD Krasnodembskaya
Journal: Thorax (2015)

<h3>Background</h3> ARDS remains a major cause of respiratory failure in critically ill patients with no specific therapy. MSC based cell therapy is a promising candidate and is being used in clinical trials for ARDS. However the mechanisms of MSC effect in lung injury are not very well understood. Islam <i>et al</i>., 2012 showed mitochondrial transfer from MSC to alveolar epithelial cells was protective in the mouse model of LPS induced pneumonia. Pathophysiology of ARDS is underpinned by dysregulated inflammation and pulmonary macrophages are key cellular mediators of the lung immune response. This study was undertaken to test if MSC could transfer their mitochondria to macrophages and to investigate the effects of MSC mitochondria transfer on macrophage function in the <i>in vivo</i> and <i>in vitro</i> models of ARDS. <h3>Methods</h3> <i>In vivo</i> studies were performed using a mouse model of <i>E.coli</i> pneumonia induced ARDS. C56BL/6 mice were infected with <i>E.coli</i>, human bone marrow-derived MSC or PBS instilled intra-nasally 4 h after infection. For <i>in vitro</i> studies primary human monocyte-derived macrophages (MDM) were infected with <i>E.coli</i> and co-cultured with MSC in contact. MSC mitochondria were pre-stained with MitoTracker Red and MDM stained for CD45 expression. Double positive cells were visualised with confocal microscopy and quantified using flow cytometry. Phagocytosis was assessed using fluorescent <i>E.coli</i> bioparticles by flow cytometry. <h3>Results</h3> When co-cultured with MSC &gt;90% of MDMs acquired MitoRed fluorescence, indicating mitochondrial transfer from BM-MSC. Confocal imaging revealed presence of Mito-Red positive tunnelling nanotubules (TNTs) formed by MSC<i>. In vivo</i> &gt;78% of CD11c<sup>hi</sup>/F4–80+ alveolar macrophages retained MSC mitochondria at 24 hr post infection. Alveolar macrophages that had acquired MSC mitochondria had a significantly higher phagocytic index compared to those without suggesting enhancement of phagocytic capacity. Inhibition of TNT formation in MSC resulted in decreased transfer to macrophages by 60%, coupled with significant abrogation of MSC effect on macrophage phagocytosis <i>in vitro</i> and anti-microbial effect seen with MSC <i>in vivo</i>. <h3>Conclusions</h3> Our findings suggest that anti-microbial activity of macrophages is enhanced at least partially by transfer of BM-MSC mitochondria through TNTs, representing an important mechanism of MSC effect in ARDS. Supported by: MRC MR/L017229/1. <h3>Reference</h3> 1 Islam MN, Das SR, Emin MT, <i>et al.</i> Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. <i>Nat Med</i>. 2012;<b>18</b>:759–65
117PD Clinical relevance of DNA damage modulator checkpoint kinase 1 (CHK1) and cancerous inhibitor of protein phosphatase 2A (CIP2A) in human gliomas
Authors: A. Khanna, B. Stringer, K. Ensbey, Z. Jahaan, A. Boyd, K. McDonald, B. Day, J. Pimanda
Journal: Annals of Oncology (2015)
Prolonged Gluten Administration in Normal Subjects
Authors: Robert A. Levine, Gordon W. Briggs, Richard S. Harding, Leroy B. Nolte
Journal: New England Journal of Medicine (1966)

AN etiologic role of wheat gluten in the pathogenesis of nontropical sprue has been established.1 2 3 4 5 There is conflicting evidence over whether gluten produces steatorrhea in the rat.6 , 7 Although the statement has been made that gluten does not result in toxicity when fed to normal subjects,8 few data regarding possible deleterious effects of prolonged gluten administration in man exist. Previous investigations were performed almost exclusively in patients with nontropical sprue.1 , 3 , 4 Studies in normal persons or patients with malabsorption, excluding nontropical sprue, have been limited in scope and duration and have not shown any harmful effects of gluten supplementation on gastrointestinal absorption. . . .
SP0169 Imaging Diagnosis of Polymyalgia Rheumatica
Authors: M.A. Cimmino
Journal: Annals of the Rheumatic Diseases (2015)

Polymyalgia rheumatica (PMR) is an inflammatory disease of the elderly characterized by the nonspecific findings of girdle pain and stiffness and constitutional symptoms: as a result its differential diagnosis ranges from rheumatic, to infective and neoplastic diseases. PMR patients also often show peripheral arthritis, which fact further complicates the diagnosis. The main differential diagnosis in patients with suspected PMR is EORA, which also may present with girdle pain and raised inflammation. Both conditions also share a common genetic background and patients with cured PMR can relapse as EORA. Many studies have addressed clinical and laboratory discriminating clues, with only peripheral arthritis being effective. However, peripheral arthritis, being present in up to 40% of PMR patients, has a poor predictive value. In a recent study, US clues for the diagnosis of PMR were the presence of subacromial-subdeltoid bursitis, low frequency of knee menisci chondrocalcinosis and low power Doppler scores at the wrist. Conversely, effusion and synovitis of wrist, metacarpophalangeal joints, metatarsophalangeal joints, and tendinous calcaneal calcifications or Achilles enthesitis were more frequent in patients with diagnoses other than PMR. In a study with 18F-FDG positron emission/computed tomography (PET/CT), PMR patients showed higher uptake of the ischiatic, trochanteric and interspinous bursae compared to EORA patients. Shoulders were not evaluated because of their anatomical complexity and the difficulty of precisely localizing inflammation. In the clinic, follow-up over time is often the only way to help differential diagnosis: if glucocorticoid treatment is effective despite its tapering and peripheral arthritis does not become chronic, the diagnosis of PMR is likely to be correct. <h3>Disclosure of Interest</h3> None declared
Interference with an Implantable Defibrillator by an Electronic Antitheft-Surveillance Device
Authors: Peter A. Santucci, Janet Haw, Richard G. Trohman, Sergio L. Pinski
Journal: New England Journal of Medicine (1998)

Implantable cardioverter–defibrillators have an important role in the treatment of patients with ventricular arrhythmias. Electromagnetic interference with permanent pacemakers and implantable defibrillators may have deleterious effects.1–11 Electronic antitheft-surveillance devices, which are widely used in stores, libraries, and other places to prevent theft, are a potential source of electromagnetic interference. Approximately 400,000 of these devices are in use worldwide. Electromagnetic interference with implantable defibrillators can generally be divided into four types. The most common type involves an overcounting of the ventricular rate. Misinterpretation of rapid rates may lead to inappropriate antitachycardia pacing or the delivery of shocks. Since the current . . .
Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome
Authors: Simon Völkl, Anne Rensing-Ehl, Andrea Allgäuer, Elisabeth Schreiner, Myriam Ricarda Lorenz, Jan Rohr, Christian Klemann, Ilka Fuchs, Volker Schuster, André O. von Bueren, Nora Naumann-Bartsch, Eleonora Gambineri, Kathrin Siepermann, Robin Kobbe, Michaela Nathrath, Peter D. Arkwright, Maurizio Miano, Klaus-Daniel Stachel, Markus Metzler, Klaus Schwarz, Anita N. Kremer, Carsten Speckmann, Stephan Ehl, Andreas Mackensen
Journal: Blood (2016)
Surgical Closure of Defects of the Interauricular Septum by Use of an Atrial Well
Authors: Robert E. Gross, Alfred A. Pomeranz, Elton Watkins, Edward I. Goldsmith
Journal: New England Journal of Medicine (1952)

DEFECTS of the interauricular septum in the human being carry a variable prognosis. Small openings are known to be tolerated rather well through a long span of life. Large defects give left-to-right shunts that enormously increase the flow of blood through the right side of the heart and the pulmonary circuit, thereby leading to right-sided heart failure in early or middle ages. The gravity of the problem makes it quite worth while to develop methods whereby defects of moderate or large size can be closed surgically. This communication summarizes certain of our investigations, which were made in the effort to . . .
Case 19-1975
Authors: Willard M. Daggett, Karl H. Proppe
Journal: New England Journal of Medicine (1975)

Presentation of CaseA 31-year-old woman was admitted to the hospital because of a calcified abdominal mass.She was well until 10 years earlier, when pain developed in the right lower quadrant of the abdomen, and she entered another hospital. Examination disclosed that she was febrile. A Grade 2 systolic ejection murmur was heard over the precordium, without radiation. There was tenderness with spasm in the right lower abdominal quadrant. Laparotomy revealed no abnormality, and a normal appendix was excised. Postoperatively, blood cultures yielded a growth of alpha-hemolytic streptococci, and a diagnosis of subacute bacterial endocarditis was made. She was . . .
Better survival with epidermal growth factor receptor exon 19 deletion than with exon 21 mutation in gefitinib-treated non-small cell lung cancer patients is due to differential inhibition of downstream signals
Authors: J. Zhu, Y. Wu, W. Zhong, G. Zhang, R. Li, X. Zhang, A. Guo, Y. Zhang, S. An, T. S. Mok
Journal: Journal of Clinical Oncology (2008)

14501 Background: Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Clinical data show different sensitivity to TKI treatment in patients with an EGFR exon 19 deletion versus L858R mutation. We investigated whether these two mutations produced differences in the phosphorylation of EGFR and downstream signal proteins, and in vitro sensitivity. Methods: This retrospective study analyzed NSCLC patients with an exon 19 deletion or exon 21 mutation of EGFR, comparing the response rate and overall survival with gefitinib treatment in these NSCLC patients. Two stable cell lines expressing these mutations were obtained by transfection of del746–750 and L858R mutation to an EGFR negative 293 cell line with a retrovirus system. Autophosphorylation of EGFR, Akt, and Erk was detected using Western blotting, and cell proliferation and inhibition tests were conducted to evaluate the bio-behavior of these cells. Results: Fifty-seven patients were included; 26 had a somatic mutation in exon 19 or 21. Patients with an exon 19 deletion had a median overall survival of 483 days, whereas median overall survival in those with the exon 21 point mutation was 168 days (p = 0.047) and the responsive rate were different among exon 19 deletion, exon 21 point mutation, wild type and double mutation. Based on Western blot analysis, gefitinib inhibited the autophosphorylation of EGFR, Akt, and Erk to a greater degree in exon 19 deletion cells than in L858R mutation cells. Gefitinib produced G1 arrest in more of the cells with an exon 19 deletion than with the L858R mutation and this arrestment was time relating. Conclusions: NSCLC patients with an EGFR exon 19 deletion survive longer following treatment with gefitinib than those with the exon 21 point mutation. This might be attributable to differences in inhibition of the autophosphorylation of EGFR and downstream signal proteins such as Akt and Erk. No significant financial relationships to disclose.
T4 Optically detectable antimicrobial peptides enable the immediate detection of bacteria and fungi in the lung
Authors: AR Akram, N Avlonitis, M Vendrell, S Chankeshwara, N McDonald, T Aslam, E Scholefield, T Walsh, C Haslett, M Bradley, K Dhaliwal
Journal: Thorax (2015)

<h3>Introduction</h3> The immediate detection of pathogens in the lungs of patients with unexplained pulmonary opacities in the intensive care unit would represent a significant advance in their management. An optical imaging strategy, including the endobronchial administration of bacterial specific Smartprobes, would confer a number of advantages over conventional techniques such as bronchoalveolar lavage, principally real-time detection to immediately inform antimicrobial therapy. The aims of this study were to fluorescently label and iteratively develop anti-microbial peptides to image bacteria <i>in situ</i> in the lung using fibered confocal fluorescence microscopy (FCFM). <h3>Methods</h3> Antimicrobial peptides (AMP) have been synthesised on a dendrimeric scaffold (AMP-1) and conjugated to an environmentally sensitive fluorophore called NBD, following the continuous development a linear counterpart. A further construct consists of an AMP with gram-selectivity conjugated to the NBD fluorophore (AMP-2). These are combined with FCFM to allow distal alveolar imaging at micron resolution in an <i>ex vivo</i> ovine model of bacterial infection. <h3>Results</h3> AMP-1 demonstrates bacterial binding affinity in a concentration dependent manner and labels a diverse panel of bacteria, including a panel consisting of &gt;70% of ventilator-associated pneumonia causing organisms and the pathogenic fungi <i>Aspergillus fumigatus.</i> AMP-1 demonstrates significantly higher fluorescence over isomolar linear equivalents for <i>E. coli, K. pneumoniae, P. aeruginosa</i>, MSSA, <i>A. baumannii</i> and <i>S. pneumoniae</i> (all p &lt; 0.01), is selective for bacteria over mammalian cells and has improved chemical stability over the linear equivalent when incubated with bronchoaoveolar lavage from patients with acute respiratory distress syndrome. Furthermore, AMP-1 can label <i>E. coli, K. pneumoniae, P. aeruginosa</i> and MSSA <i>in situ</i> in an <i>ex vivo </i>ovine model when instilled endobronchially and imaged with FCFM (pin vitro and remains selective for gram-negative bacteria over mammalian cells. In the <i>ex-vivo</i> model AMP-2 selectively labels the gram-negative bacterial segments (<i>P. aeruginosa, K. pneumonia</i> and <i>E. coli</i>) over the gram-positive (MSSA, MRSA and <i>S. pneumoniae</i>) or control pulmonary segments (all p &lt; 0.05). <h3>Conclusions</h3> A Smartprobe/FCFM strategy to immediately detect bacteria with gram selectivity in size relevant pre-clinical models is described, and are undergoing first-in-man translation.
Identification of Virilizing Adrenal Tumors in Hirsute Women
Authors: Jan Derksen, Suresh K. Nagesser, A. Edo Meinders, Harm R. Haak, Cornelis van de Velde
Journal: New England Journal of Medicine (1994)

Hirsutism in women is usually caused by benign adrenal or ovarian disorders, but it can also be caused by adrenal carcinoma. The most effective way to identify such carcinomas is not known.We measured serum and urinary steroids before and after the administration of 3 mg of dexamethasone per day for five days in 14 hirsute women with histologically proved adrenal tumors (12 adrenal carcinomas and 2 adrenal adenomas) and in 73 women with hirsutism of non-neoplastic origin.All the women with adrenal tumors had elevated basal serum concentrations of testosterone or dehydroepiandrosterone sulfate, as compared with 36 of the 73 women with non-neoplastic hirsutism (sensitivity, 100 percent; 95 percent confidence interval, 77 to 100; specificity, 50 percent; 95 percent confidence interval, 38 to 62). After the administration of dexamethasone, serum dehydroepiandrosterone sulfate concentrations and urinary 17-ketosteroid excretion decreased to values similar to those in normal women in all the women with non-neoplastic hirsutism, but in none of the 12 with adrenal tumors who were tested. All the women who did not have adrenal tumors had serum cortisol concentrations below 3.3 micrograms per deciliter (90 nmol per liter) after dexamethasone administration, whereas in all 12 patients tested who had tumors the values were higher. The suppression of serum dehydroepiandrosterone sulfate and cortisol and urinary 17-ketosteroid excretion excluded the likelihood of adrenal tumors with a sensitivity of 100 percent (95 percent confidence interval, 74 to 100) and a specificity of 100 percent (95 percent confidence interval, 89 to 100).Among women with hirsutism, an adrenal tumor is unlikely if the patient has normal basal serum concentrations of testosterone and dehydroepiandrosterone sulfate. In women in whom these concentrations are elevated, a tumor is unlikely if the serum concentration of dehydroepiandrosterone sulfate and urinary 17-ketosteroid excretion are in the normal basal range and the serum cortisol concentration is less than 3.3 micrograms per deciliter after the administration of dexamethasone.
Inequalities in Health
Authors: Michael Marmot
Journal: New England Journal of Medicine (2001)

Walk the slums of Dhaka, in Bangladesh, or Accra, in Ghana, and it is not difficult to see how the urban environment of poor countries could be responsible for bad health. Walk north from Manhattan's museum district to Harlem, or east from London's financial district to its old East End, and you will be struck by the contrast between rich and poor, existing cheek by jowl. It is less immediately obvious why there should be health differences between rich and poor areas of the same city. It is even less obvious, from casual inspection of the physical environment, why life . . .
Detection of minimal residual disease (MRD) in bone marrow (BM) and peripheral blood (PB) in childhood acute lymphoblastic leukemia (ALL) by flow cytometry (FC)
Authors: E. Delbuono, Y. H. Maekawa, M. L. D. M. Lee, J. A. P. Braga, M. R. D. O. Latorre, A. L. Pires, A. S. Petrilli
Journal: Journal of Clinical Oncology (2005)

8544 Background: MRD is an important prognostic factor for children with ALL and it provides crucial information on the response to treatment and risk of relapse. However, the frequency which MRD can be monitored is limited due the discomfort and practical difficulties posed by BM aspiration. Since there are few reported studies on the value of MRD in PB, we conducted a prospective study to evaluate and to compare FC MRD measurements in BM with PB and correlate with BM morphology in children with ALL. Methods: 76 BM aspirates and 64 PB samples obtained from 40 Brazilian children with ALL were analysed during days 14(D14) and 28(D28) of remission induction therapy with a three-color FC assay. Data acquisition and analysis were performed using BD-FACSCalibur flow cytometer with Cell-Quest and Paint-a-gate softwares, respectively. Detectable MRD was defined as ≥ 0,01% cells expressing an aberrant immunophenotype(detected at diagnosis) among total events in the sample. BM morphology was analysed at the same time points. Results: in 20/36 (55,6%) BM samples, MRD was detected at D14 and in 18/40 (45%) at D28. MRD was detected in PB in 12/28(42,9%) at D14 and in 11/36(30,6%) at D28. The concordance between MRD in BM and PB was 85,7%(P<.001) at D14 and a significant level of agreement was found in 71% of samples(P<.001) at D28,although MRD levels may differ. In patients in complete morphological remission,44% had detectable MRD at D14 and 38,9% at D28. MRD was not signicantly related to sex,age,WBC count or cell lineage. Conclusions: FC is a sensitive,fast and reproducible technique for detection of MRD in children with ALL. Our findings suggest that PB could be useful in monitoring MRD,particularly in T-lineage. This study reinforces the discrepancy between traditional morphology and MRD,reaffirming its prognostic importance in childhood ALL. No significant financial relationships to disclose.
Hemodynamic and Humoral Effects of Caffeine in Autonomic Failure
Authors: Jack Onrot, Michael R. Goldberg, Italo Biaggioni, Alan S. Hollister, Dawn Kincaid, David Robertson
Journal: New England Journal of Medicine (1985)

We examined the effects of caffeine and meals on blood pressure and heart rate in 12 patients with autonomic failure. The influence of caffeine on plasma norepinephrine, epinephrine, and renin activity was also studied. Caffeine 250 mg, raised blood pressure by 12/6 mm Hg, from 129±25/78±12 (mean±S.D.) to a maximum of 141±30/84±16 mm Hg at 45 minutes (P<0.01), but did not change heart rate, levels of norepinephrine, or epinephrine, or plasma renin activity. Blood pressure fell by 28/18 mm Hg after a standardized meal, from 133±32/80±15 to a minimum of 105±21/62±12 mm Hg at 60 minutes (P<0.01 ). After pretreatment with 250 mg of caffeine, the standardized meal induced a fall of only 11/10 mm Hg, from 140±33/79±7to 129±31/69±13 mm Hg at 60 minutes (P<0.05 vs. values after the control meal). After long-term administration of caffeine (250 mg per day for seven days) in five patients, postprandial blood pressures remained higher after caffeine than after placebo (P<0.05). We conclude that caffeine is a pressor agent and attenuates postprandial hypotension in autonomic failure, and that this effect is not primarily due to elevations in sympathoadrenal activity or activation of the renin—angiotensin system. Caffeine may be useful in the treatment of orthostatic hypotension due to autonomic failure, especially in the postprandial state. (N Engl J Med 1985; 313:549–54.)