tbuckley/cabot-search huggingface dataset:
Agonist and antagonist effects of interferon alpha and beta on activation of human macrophages. Two classes of interferon gamma receptors and blockade of the high-affinity sites by interferon alpha or beta.
Authors: R Yoshida, H W Murray, C F Nathan
Journal: The Journal of Experimental Medicine (1988)

H2O2-releasing capacity and limited antitoxoplasma activity could be induced in human macrophages (derived from monocytes cultured greater than or equal to 5 d) but not in monocytes themselves (cells cultured less than or equal to 4 d) by a further 3-d incubation with pure natural or rIFN-alpha or -beta. More than 3 pM (10 U/ml) of these IFNs was required, with greatest effects at approximately 300 pM (10(3) U/ml). At 300 pM, H2O2-releasing capacity was enhanced 4.4 +/- 1.6-fold over medium control (mean +/- SD for natural INF-alpha, rIFN-alpha A, rIFN-alpha D, and rIFN-beta) compared to an 8.4 +/- 4.8-fold increase with rIFN-gamma (100 pM, 100 U/ml) in the same experiments. Unexpectedly, low concentrations of IFN-alpha or -beta (3 fM-300 pM) blocked induction of H2O2-releasing capacity by rIFN-gamma (10 pM), with a 50% inhibitory dose of approximately 80 fM. However, IFN-alpha or -beta (3 fM-300 pM) could not inhibit the effect of higher concentrations of rIFN-gamma (1 nM). In contrast to results with monocytes or young macrophages, Scatchard plots of binding of 125I-rIFN-gamma to mature macrophages (day 8 of culture) indicated two classes of binding sites: approximately 2,000 high-affinity sites (Kd approximately 0.43 nM) and approximately 23,000 low-affinity sites (Kd approximately 6.4 nM) per cell. Binding of 125I-rIFN-gamma to the high- but not the low-affinity sites was blocked by simultaneously added IFN-alpha or -beta, with a 50% inhibitory dose of approximately 2 U/0.25 ml (approximately 2 pM), or reversed by subsequently added IFN-alpha or -beta. Thus, differentiation of human mononuclear phagocytes in vitro is accompanied by the emergence of (a) an agonist response to submicromolar concentrations of IFN-alpha or -beta, (b) antagonism of the effect of picomolar IFN-gamma by femtomolar IFN-alpha or -beta, (c) two classes of IFN-gamma-Rs, and (d) nonstimulatory binding of IFN-alpha or -beta to the high- but not the low-affinity IFN-gamma-Rs, with higher affinity than rIFN-gamma itself. We speculate that traces of IFN-alpha or -beta derived from stromal cells, parenchymal cells, or resident macrophages may dampen the activation of mature tissue macrophages by the small amounts of IFN-gamma that diffuse from inflammatory sites into normal tissues. Such a mechanism could constrain the potentially destructive phenomenon of macrophage activation to areas where monocytes have recently immigrated and/or the concentration of IFNs is high.
Abstract PD01-03: Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment
Authors: KJ Beelen, M Opdam, TM Severson, RHT Koornstra, A Vincent, J Wesseling, JJ Muris, EMJJ Berns, JB Vermorken, PJ van Diest, SC Linn
Journal: Cancer Research (2012)

Abstract BACKGROUND: Activation of the PI3K/MAPK pathways results in anti-estrogen resistance in vitro, however a biomarker that can predict clinical resistance has not yet been identified. Common drivers of these pathways are PIK3CA mutations, loss of PTEN and over-expression of HER2 and IGF-1R. We aimed to test the prognostic and predictive value of PI3K/MAPK pathway drivers as well as downstream activated proteins in postmenopausal breast cancer patients. METHODS: We collected primary tumor tissue from 563 ERα positive breast cancer patients who were randomized between tamoxifen (1–3 years) versus no adjuvant systemic therapy. PIK3CA hotspot mutations were assessed by Sequenom Mass Spectrometry. Immunohistochemistry was performed for expression of PTEN, IGF-1R and the downstream markers p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interaction between these markers and treatment. RESULTS: No significant interaction between any of the tested PI3K/MAPK pathways drivers and tamoxifen was found. [/bold]However, interactions were identified between tamoxifen and the downstream activated proteins (p-AKT(Thr308), p- mTOR, p-p70S6K and p-ERK1/2). After correcting for multiple testing, p-p70S6K remained significantly associated with tamoxifen resistance. Patients whose tumor did not express p-p70S6K did derive significant benefit from tamoxifen (HR 0.24, 95 % CI= 0.12–0.47, p &amp;lt; 0.0001), while patients whose tumor did express p-p70S6K did not (multivariate HR=1.02, 95% CI=0.48–2.21, p = 0.95), p for interaction 0.003. CONCLUSION: We conclude that the downstream marker of PI3K/MAPK activation p-p70S6K predicts tamoxifen resistance in ERα positive postmenopausal breast cancer patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD01-03.
Acute trust takes over treatment centre after 53m pay off to private company
Authors: C. Mahony
Journal: BMJ (2013)

An “undesirable” payment of £53m (€61m; $81m) to a private company to withdraw from an underperforming independent sector treatment centre (ISTC) highlights the risk of commercial organisations winning NHS contracts, the BMA has said.

Clinicenta, which is owned by property support services company Carillion, will be paid £53m to hand over the Lister surgicentre in Stevenage to East and North Hertfordshire NHS Trust, the local acute trust where it is sited.

The bulk of the money, £46m, represents the cost of purchasing the building and equipment but the deal includes £3m compensation to the company for ending the contract early. An additional £4m …
Therapeutic Oxygen as a Possible Cause of Pulmonary Hemorrhage in Premature Infants
Authors: D. R. Shanklin, S. L. Wolfson
Journal: New England Journal of Medicine (1967)

McADAMS1 recently re-emphasized the importance of pulmonary hemorrhage in autopsies on newborn infants and discussed this lesion in relation to other pathological findings, particularly hyaline-membrane disease and pontine necrosis. Infants with hyaline-membrane disease showed modest differences in weight and survival trends from those with pulmonary hemorrhage. Pontine necrosis, apparently a newly described lesion, was negatively correlated. A cursory review of the pathological findings in our recent clinicopathological study of premature newborn infants suggested a relation between the therapeutic use of oxygen and the presence of pulmonary hemorrhage. Accordingly, we undertook a systematic but retrospective study to make a more definite . . .
THE GUILLOTINE AND ETHYL CHLORIDE: TEAM WORK FOR THE REMOVAL OF TONSILS AND ADENOIDS
Authors: C. R. Sandiford, J. C. Clayton
Journal: BMJ (1928)

THE GUILLOTINE AND ETHYL CHLORIDE.[ Bjr 1492. These points include the presence of ani aioxacrmnc state, and a resultant increase in sarcolactic acid either locally or generally.3. We produce evidence from experiments, both in vitro and i71 vivo, that sarcolactic acid is haemolytic-in the former case to wlhole human blood, and in the latter to whole animal blood.4. Intravenous injections of sarcolactic acid into rabbits 'lhave produced haemoglobinnaemia and haemoglobinuria, followed by recovery of the animals.5. On the evidence brought forward by us, we conclude that sarcolactic acid is the causal agent in the productioni of the haemolysis in blackwater fever and these haemo- globinur ias.6.The etiology of various types, symptoms, and comn- plioations of blackwater fever is discussed in the light of this mlieclianism.
Brief Communication: Tolerability of Meropenem in Patients with IgE-Mediated Hypersensitivity to Penicillins
Authors: Antonino Romano, Marinella Viola, Rosa-Maria Guéant-Rodriguez, Francesco Gaeta, Rocco Valluzzi, Jean-Louis Guéant
Journal: Annals of Internal Medicine (2007)

Background: Although clinicians avoid giving meropenem to patients with penicillin allergy because of potential cross-reactivity, the rate of cross-reactivity between penicillins and meropenem has not been prospectively determined. Objective: To assess the tolerability of meropenem in patients with documented penicillin allergy. Design: Prospective skin testing and antibiotic challenge. Setting: Allergy units of 2 Italian medical centers. Patients: 104 consecutive participants with immediate hypersensitivity reactions to penicillins and positive skin test results to at least 1 penicillin reagent. Measurements: Skin tests to meropenem and, if results were negative, challenges with escalating doses of meropenem. Results: One participant (0.9% [95% CI, 0.02% to 5.2%]) had a positive intradermal test result to meropenem. The remaining 103 participants with negative skin test results to meropenem tolerated escalating dose challenges. Limitation: Challenges were not followed by therapeutic courses. Conclusions: These data indicate a low rate of cross-reactivity between penicillins and meropenem. Therefore, the practice of avoiding meropenem therapy in penicillin-allergic patients should be reconsidered. In patients who especially require meropenem treatment, the authors recommend pretreatment skin tests because negative results indicate tolerability.
Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis.
Authors: N Goebels, D Michaelis, M Engelhardt, S Huber, A Bender, D Pongratz, M A Johnson, H Wekerle, J Tschopp, D Jenne, R Hohlfeld
Journal: Journal of Clinical Investigation (1996)

Polymyositis (PM) and dermatomyositis (DM) are the prototypical inflammatory diseases of skeletal muscle. In PM, CD8+ T cells invade and destroy muscle fibers, whereas humoral effector mechanisms prevail in DM. We studied the expression of the cytotoxic mediator perforin in inflammatory cells in PM and DM muscle by semiquantitative PCR, immunohistochemistry and confocal laser microscopy. Similar levels of perforin mRNA were expressed in PM and DM, and abundant perforin-expressing CD3+CD8+ and CD3+ CD4+ T cells were observed in both diseases. However, there was a striking difference in the intracellular localization of perforin. In DM, perforin was distributed randomly in the cytoplasm of the inflammatory T cells. In contrast, 43% of the CD8+ T cells that contacted a muscle fiber in PM showed perforin located vectorially towards the target muscle fiber. The results suggest (a) that the random distribution of perforin in the cytoplasm of muscle-infiltrating T cells observed in DM reflects nonspecific activation, and (b) that the vectorial orientation observed only in PM reflects the specific recognition via the T cell receptor of an antigen on the muscle fiber surface, pointing to a perforin- and secretion-dependent mechanism of muscle fiber injury.
Cyclophosphamide
Authors: Alfred D. Steinberg
Journal: New England Journal of Medicine (1984)

Cyclophosphamide is a cytotoxic immunosuppressive and anticancer drug that has been used to treat a large variety of human disorders. It alkylates and phosphorylates important cellular macromolecules and preferentially kills cells that are rapidly dividing, but it is also effective against nonproliferating cells.1 The drug is critical to the effectiveness of many cancer-treatment regimens, in which it is often combined with other antitumor agents. Cyclophosphamide is also associated with serious adverse effects, including secondary cancer, severe leukopenia with infection, and hemorrhagic cystitis.Since cyclophosphamide can suppress immune responses mediated by both B cells and T cells, many physicians have turned . . .
Evidence for a parathyroid hormone-dependent influence of calcium on the glomerular ultrafiltration coefficient.
Authors: H D Humes, I Ichikawa, J L Troy, B M Brenner
Journal: Journal of Clinical Investigation (1978)

Experiments were performed on 36 plasma-expanded Munich-Wistar rats to examine the effects of acute hypercalcemia on the determinants of glomerular ultrafiltration. Elevation of total plasma calcium concentration to an average value of 13.2 +/- 0.5 mg/dl, by acute infusion of calcium chloride into nonthyroparathyroidectomized (non-TPTX) rats, resulted in significant declines in single nephron and whole kidney glomerular filtration rate. These declines were due primarily to a fall in the glomerular capillary ultrafiltration coefficient (Kf), to a mean value approximately 60% below that determined in the pre-infusion period. These changes were not seen in a separate group of sham-treated non-TPTX rats. It is of interest that these effects of acute hypercalcemia were largely abolished in rats that underwent acute TPTX before hypercalcemia. Infusion of a submaximally phosphaturic dose of parathyroid hormone, together with calcium chloride, into a second group of acute TPTX rats, however, had the effect of reproducing the striking declines in filtration rate and Kf noted in non-TPTX rats given calcium chloride alone. These findings suggest that the decline in filtration rate associated with hypercalcemia is due largely to the reduction in Kf, the latter dependent upon the presence of parathyroid hormone.
A case of angiosarcoma arising on a closed shunt in a patient with chronic renal failure
Authors: Fuminao Kamijo, Yukiko Kiniwa, Yasufumi Goto, Shiho Shirota, Aya Kobayashi, Asuka Tanaka, Masao Fukuzawa, Toshiaki Saida
Journal: Journal of the American Academy of Dermatology (2011)
Optic Neuritis in Cystic Fibrosis of the Pancreas
Authors: Paul S. Lietman, Paul A. di Sant' Agnese, Vernon Wong
Journal: JAMA (1964)

Optic neuritis with diminution of visual acuity was observed in six children with cystic fibrosis. Postmortem examination of the eyes was made in two of them. Strong circumstantial evidence suggested that chloramphenicol administered for prolonged courses of treatment was responsible. Special attention should be paid to diminution of visual acuity in the course of chloramphenicol therapy and this drug should be administered whenever possible in courses not exceeding four weeks. In cystic fibrosis, two separate types of ocular lesions are encountered: retinal vascular changes which do not affect vision and optic neuritis following prolonged chloramphenicol therapy. Both conditions are apt to coexist in fibrocystics with severe pulmonary involvement.
Hepatic Chemotherapy by Arterial and Venous Infusion
Authors: William S. Fletcher, James J. Chandler, Sarah S. Donaldson
Journal: JAMA (1964)

STUDIES IN THIS and other laboratories indicate that both primary and secondary hepatic tumors receive essentially all of their blood supply from the hepatic artery.<sup>1,2</sup>Accordingly, the dual circulation of the liver presents a unique opportunity to study the effect of intra-arterial infusion of a chemotherapeutic agent while counter-acting the local and systemic effects of the drug by the simultaneous infusion of an antagonist into the portal venous circulation. Since the 5-year survival rate of patients with hepatic metastases or carcinoma of the gallbladder is 0% to 2%, it seems worthwhile to evaluate the safety and efficacy of this method of therapy with currently available drugs. <h3>Methods and Materials</h3> Healthy, adult, mixed-breed dogs, weighing 20 to 30 kg (44 to 66 1b), were used for this experiment. The animals were anesthetized with sodium pentobarbital and opened through an upper abdominal midline incision. Following liver biopsy, a No. 90 polyethylene
Sudoriparous angioma—regression following intravascular aethoxysclerol, a sclerosing agent
Authors: C.R. SRINIVAS, P.L.N.G. RAO
Journal: British Journal of Dermatology (1988)

We report a case of sudoriparous angioma on the dorsum and plantar aspect of the left foot which increased in size on standing, and which was accompanied by sweating in the overlying epidermis and throbbing pain. The lesion regressed considerably following intravascular injection of i% aethoxysclerol.
Monitoring thiopurine methyltransferase (TPMT) activity in inflammatory bowel disease: is it worth it?
Authors: T. Gledhill, A. Hurst, L. Brown, P. Bliss
Journal: Gut (2011)

<h3>Introduction</h3> Azathioprine and 6-mercaptopurine are immunosuppressants used to treat inflammatory bowel disease (IBD). Marrow toxicity occurs in 3% of patients receiving these drugs. Some practitioners propose that checking Thiopurine methyltransferase (TPMT) activity can predict this myelosuppression and improve patient safety. Currently such practice is not widespread. <h3>Methods</h3> The aim was to review our current practice and determine if knowledge of TPMT activity prior to starting thiopurines leads to fewer myelosuppressive events and therapy adjustments. Data from IBD patients taking thiopurines between 2007 and 2010 were reviewed for measurement of TPMT activity, incidence of leucopenia (white cell count &lt;4.0) and dosage changes as a result of leucopenia. <h3>Results</h3> 229 patients received a thiopurine between 2007 and 2010. Of these, 82 (35.8%) had a TPMT result available. No patients were deficient in TPMT (&lt;10 μ/l). There were 68 patients (82.9%) identified with low levels of TPMT (10–67 μ/l) and 14 patients (17.1%) had normal TPMT levels (68–150 μ/l). No patients in our cohort had high levels of activity (&gt;150 μ/l). Overall, leucopenia was identified in 45 patients (19.7%). The majority, 35 patients (78%), had a mild transient leucopenia needing no dose adjustment. 7 patients developed leucopenia which did not resolve and required dose reduction and 3 patients had therapy stopped. Of those patients with low TPMT activity, 18/68 developed leucopenia (26.5%), 1 had therapy stopped and 2 reduced. Two patients (14.3%) with normal TPMT activity developed leucopenia, of which only one had therapy stopped. In patients with no TPMT result, 25 (16.9%) developed leucopenia of which 1 patient had therapy stopped and 5 had therapy reduced. There were no serious adverse events relating to immunosuppression during the study period. <h3>Conclusion</h3> Although there were no patients deficient in TPMT, there was a higher than expected number with low levels.1 Such low TPMT activity levels were associated with a higher incidence of mild transient leucopenia. However, the incidence of clinically significant leucopenia requiring dosage change was the same in all study groups although absolute numbers are small. Although measurement of TPMT activity may have a role in identifying the 1 in 300 patients who are deficient and at risk of developing severe myelosuppression,1 initiating thiopurine use in IBD without measuring TPMT activity appears to be safe with standard blood monitoring.
Ginseng and High Blood Pressure
Authors: Ronald K. Siegel
Journal: JAMA (1980)

<h3>To the Editor.—</h3> The initial CLINICAL NOTE on ginseng abuse syndrome (241:1614, 1979) reported that 10% of the long-term ginseng users studied had hypertension together with nervousness, sleeplessness, skin eruptions, and morning diarrhea. Several other users also had hypertension but no other symptoms. These results have raised a number of questions concerning the magnitude of the changes in the blood pressure. The 22 subjects in whom hypertension developed following chronic abuse of ginseng all had substantial elevations in both systolic and diastolic blood pressures. These subjects included 20 men, 21 to 35 years of age, who at the start of the study had normal ranges of systolic (105 to 140 mm Hg) and diastolic (62 to 90 mm Hg) blood pressures, with a group mean of 125/78 mm Hg. Following at least 13 weeks of ginseng use, the group mean rose to 150/96 mm Hg. Eight of these subjects used
403. Long-Term, High alpha-L-iduronidase Expression in MPS I Dogs Following Neonatal, Intravenous, Retroviral Vector Gene Therapy
Authors: Anne Traas, Ping Wang, Xiucui Ma, Patricia O'Donnell, Meg Sleeper, Gus Aguirre, Mark Haskins, Katherine P. Ponder
Journal: Molecular Therapy (2006)

Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to deficient activity of alpha-L-iduronidase (IDUA). Manifestations include bone and joint disease, heart disease, and neurological dysfunction. The MPS I dog has a G to A transition in the donor splice site of intron 1 creating a premature termination codon at the exon-intron junction. The disease in the dog resembles the clinical manifestation in humans. We treated six MPS I dogs at three days of age intravenously with 2.5 to 10.1×10E9 (mean 3.6+/-2.9 SD) transducing units (TU)/kg of a retroviral vector (RV) expressing canine IDUA from the human 1-antitrypsin promoter (hAAT-cIDUA-WPRE). The group had 22-749 nmol/ml/hr of serum IDUA activity (mean=337+/-334; normal=14.6 +/-2.4, N=7) (Fig. 1). The 3 oldest dogs at more than 1 year of age have stable activity at 1.3x, 2.1x, and 41× normal. The serum activity was not proportional to the dose. Clinically in the dog, early manifestations of MPS I are much less severe than those of MPS VII previously reported. Early signs include facial dysmorphia, prolapse of the 3rd eyelid, corneal clouding, mitral valve insufficiency, and joint disease. The 3 RV-treated dogs at 1 year of age showed improvement in corneal clouding, facial dysmorphia, 3rd eyelid prolapse, and valvular heart disease. Corneal clouding scores were 0/3,1/3, and 0/3 for the RV-treated dogs (serum IDUA activity of 35, 22, and 684 nmol/ml/h, respectively) compared with scores of 2/3 for four 6 month-old untreated MPS I dogs. Scores for facial dysmorphia were 0/4 for all RV-treated dogs compared to 2-3/4 for 3 untreated dogs. No treated MPS I dog exhibited 3rd eyelid prolapse, a sign seen in all untreated dogs. At 1 year of age, none of the 3 RV-treated dogs had a cardiac murmur, whereas two of the three oldest untreated MPS I dogs had a grade 2/6 murmur of mitral insufficiency. Two untreated dogs were euthanized at 1 year of age due to signs of severe cervical spinal cord disease, no signs of which are present in any of the treated dogs, the oldest of which is 17 months. One dog was treated with 1.3X10E9 TU/kg at 7 weeks of age and at 6 weeks post-treatment has 2.9 nmol/ml/hr (17% of normal) IDUA activity in serum (I-173, Fig 1), which has been stable since 4 days post-transduction. These data show that in contrast to previous treatment modalities, neonatal, intravenous, RV gene therapy was successful in producing stable serum IDUA levels in MPS I dogs, improving early clinical disease.
Case 44-1980
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, John W. Melski, George F. Murphy
Journal: New England Journal of Medicine (1980)

Presentation of CaseAn 18-year-old woman was admitted to the hospital because of abdominal pain and a neurologic disorder.She was in excellent health until one year earlier, when she began to have progressive blurring of vision in the left eye. A physician found color desaturation with a central scotoma to red and marked papilledema; the right eye appeared normal. Prednisone, 100 mg daily, was begun by mouth, but vision in the left eye deteriorated to total blindness over the next four weeks. Ten months before admission she entered another hospital, where the general physical examination was negative. Vision in . . .
Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation
Authors: Marcela Moncada-Vélez, Rubén Martinez-Barricarte, Dusan Bogunovic, Xiao-Fei Kong, Lizbeth Blancas-Galicia, Cengiz Tirpan, Guzide Aksu, Quentin B. Vincent, Bertrand Boisson, Yuval Itan, Noé Ramírez-Alejo, Satoshi Okada, Alexandra Y. Kreins, Vanessa L. Bryant, Jose Luis Franco, Mélanie Migaud, Sara Espinosa-Padilla, Marco Yamazaki-Nakashimada, Francisco Espinosa-Rosales, Necil Kutukculer, Laurent Abel, Jacinta Bustamante, Guillaume Vogt, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis
Journal: Blood (2013)