tbuckley/cabot-search huggingface dataset:
Dissection of the Ascending Thoracic Aorta
Authors: C A Nienaber
Journal: New England Journal of Medicine (1994)

Figure 1. Dissection of the Ascending Thoracic Aorta. A dissecting aneurysm of the ascending segment of the thoracic aorta was diagnosed by two-dimensional transesophageal echocardiography. The horizontal imaging plane is approximately 3 cm above the aortic valve and shows a separation of the true lumen (TL) and the false lumen (FL) of the dissecting aneurysm. A color-coded flow signal in blue identifies flow away from the aortic valve in the true lumen. An echogenic crescent-shaped thrombus (Thr) almost completely fills the false lumen and leaves only a narrow unobstructed mural rim. Two images, taken at slightly different gray-scale gain settings, . . .
A Novel Testis-Stimulating Factor in Familial Male Precocious Puberty
Authors: Penelope K. Manasco, Mary E. Girton, Richard L. Diggs, John L. Doppman, Penelope P. Feuillan, Kevin M. Barnes, Gordon B. Cutler, D. Lynn Loriaux, Barry D. Albertson
Journal: New England Journal of Medicine (1991)

Familial male precocious puberty is a gonadotropin-independent form of precocious puberty that occurs only in males. The cause of the disorder is unknown. To examine the hypothesis that the plasma of boys with familial male precocious puberty contains a novel stimulator of testicular testosterone production, we developed a bioassay using adult male cynomolgus monkeys.We collected plasma from 12 boys with familial male precocious puberty, 7 normal prepubertal boys of similar ages and with similar plasma gonadotropin levels, and 1 boy with hypogonadotropic hypogonadism and infused it into the testicular artery of adult male cynomolgus monkeys that had been pretreated with gonadotropin-releasing-hormone antagonist to inhibit the endogenous secretion of gonadotropins. Testicular venous effluent was collected at 15-minute intervals for 3 or 5 hours for the measurement of testosterone.The mean (+/- SE) peak testosterone response, as compared with base line, was significantly greater in the monkeys infused with plasma from the 12 boys with familial male precocious puberty than in the monkeys infused with plasma from the 7 normal prepubertal boys and the boy with hypogonadotropic hypogonadism (385 +/- 51 vs. 184 +/- 25 percent, P less than 0.005) in the three-hour studies. Plasma from 92 percent of the boys with familial male precocious puberty and 12.5 percent of the normal prepubertal boys stimulated a response greater than 195 percent of base-line values. In the animals studied for five hours after receiving a second dose of antagonist, the mean peak testosterone response, as compared with base line, was significantly greater in the monkeys infused with plasma from three boys with familial male precocious puberty than in the monkeys infused with plasma from three normal prepubertal boys (363 +/- 81 vs. 115 +/- 6 percent, P less than 0.01). The mean area under the testosterone-response curve was significantly larger in the monkeys infused with plasma from the boys with familial male precocious puberty in the five-hour studies (154 +/- 34 vs. -58 +/- 10 percent, P less than 0.005), but not in the three-hour studies.These findings support the presence of a circulating testis-stimulating factor in the plasma of boys with familial male precocious puberty. The production of such a factor would explain the biologic nature of the disorder.
Notch Signaling and the Skeleton
Authors: Stefano Zanotti, Ernesto Canalis
Journal: Endocrine Reviews (2016)

Notch 1 to 4 receptors are important determinants of cell fate and function, and Notch signaling plays an important role in skeletal development and bone remodeling. After direct interactions with ligands of the Jagged and Delta-like families, a series of cleavages release the Notch intracellular domain (NICD), which translocates to the nucleus where it induces transcription of Notch target genes. Classic gene targets of Notch are hairy and enhancer of split (Hes) and Hes-related with YRPW motif (Hey). In cells of the osteoblastic lineage, Notch activation inhibits cell differentiation and causes cancellous bone osteopenia because of impaired bone formation. In osteocytes, Notch1 has distinct effects that result in an inhibition of bone resorption secondary to an induction of osteoprotegerin and suppression of sclerostin with a consequent enhancement of Wnt signaling. Notch1 inhibits, whereas Notch2 enhances, osteoclastogenesis and bone resorption. Congenital disorders of loss- and gain-of-Notch function present with severe clinical manifestations, often affecting the skeleton. Enhanced Notch signaling is associated with osteosarcoma, and Notch can influence the invasive potential of carcinoma of the breast and prostate. Notch signaling can be controlled by the use of inhibitors of Notch activation, small peptides that interfere with the formation of a transcriptional complex, or antibodies to the extracellular domain of specific Notch receptors or to Notch ligands. In conclusion, Notch plays a critical role in skeletal development and homeostasis, and serious skeletal disorders can be attributed to alterations in Notch signaling.
Familial Chromosome-2, 3 Translocation Ascertained through an Infant with Multiple Malformations
Authors: Catherine S. N. Lee, Peter B. owen, Herman Rosenblum, Lydia Linsao
Journal: New England Journal of Medicine (1964)

STRUCTURAL heterozygosis is the existence in heterozygous state of an interchromosomal or intrachromosomal rearrangement. Fragmentation of two chromosomes and the mutual exchange through reunion of the fragments1 is known as reciprocal translocation. In the human being translocations are usually ascertained through cases with abnormal phenotypes,2 3 4 5 6 7 8 9 couples with repeated abortions10 , 11 or coincidental findings.In this paper we report a family with a reciprocal translocation between chromosomes 2 and 3. Transmission by balanced carriers in two generations was observed. The duplication deficiency of the genetic complement in 1 infant was manifested in multiple malformations that prompted the karyotype analysis in this kindred. . . .
Familial Clustering of Hepatitis B Infection
Authors: Wolf Szmuness, Alfred M. Prince, Robert L. Hirsch, Betsy Brotman
Journal: New England Journal of Medicine (1973)

In a survey among 449 family contacts of blood donors from 197 households containing carriers of hepatitis B antigen, 6.7 per cent were antigen positive, as compared with 0.8 per cent in control households. The greatest prevalence of B antigen was among siblings (19.7 per cent) and other genetic family contacts (8 per cent). In spouses B antigen was less frequently detected (3.4 per cent). Hepatitis B antibody was detected three times more frequently in the study households than in control households. No differences in prevalence of hepatitis B antibody between specific relatives of antigen carriers were seen. Familial clustering does not appear to be correlated with the presence or absence of liver damage in the asymptomatic donor carrier. Neither venereal nor Maternal-Fetal transmission seems to be of primary importance in the spread of hepatitis B infections in these surveyed families. The evidence supports the hypothesis that hepatitis B virus can be transmitted nonparenterally. (N Engl J Med 289:1162–1166, 1973)
The β-Agonist Dilemma
Authors: Benjamin Burrows, Michael D. Lebowitz
Journal: New England Journal of Medicine (1992)

THE paper by Spitzer et al. in this issue of the Journal 1 suggests that inhaled β-agonists may be responsible for an increase in the severity of asthma and a higher death rate from the disease. This is the latest in a series of papers that have questioned the safety of this class of drugs for the treatment of asthma.An increase in the death rate from asthma in the United Kingdom during the 1960s was temporally associated with the widespread use of inhalers delivering high-potency isoproterenol, a relatively nonselective β-agonist. In the 1970s, an increase in the mortality rate from . . .
Photochemotherapy of Psoriasis with Oral Methoxsalen and Longwave Ultraviolet Light
Authors: John A. Parrish, Thomas B. Fitzpatrick, Lewis Tanenbaum, Madhukar A. Pathak
Journal: New England Journal of Medicine (1974)

Oral administration of a photoactive drug, 8-methoxypsoralen (methoxsalen), followed by exposure to a high-intensity, longwave ultraviolet-light system resulted in complete clearing of generalized psoriasis in 21 patients. In 16 of these cases, a paired comparison showed methoxsalen followed by longwave ultraviolet light to be more effective than conventional ultraviolet light. 8-Methoxypsoralen followed by exposure to longwave ultraviolet light has previously been shown to inhibit epidermal DNA synthesis; this may be its mechanism of action in psoriasis, a disorder characterized by an accelerated cell cycle and rate of DNA synthesis. The term photochemotherapy is used to emphasize the point that the effect on epidermal proliferation and the therapeutic response require the interaction of light and drug. (N Engl J Med 291:1207–1211, 1974)
Treatment of Postmenopausal Osteoporosis with Calcitriol or Calcium
Authors: Murray W. Tilyard, George F.S. Spears, Janet Thomson, Susan Dovey
Journal: New England Journal of Medicine (1992)

Osteoporosis is a common problem whose management is controversial. To evaluate the efficacy and safety of calcitriol (1,25-dihydroxyvitamin D3) in the treatment of postmenopausal osteoporosis, we conducted a three-year prospective, multicenter, single-blind study in 622 women who had one or more vertebral compression fractures. The women were randomly assigned to receive treatment with calcitriol (0.25 μg twice a day) or supplemental calcium (1 g of elemental calcium daily) for three years. New vertebral fractures were detected by means of lateral roentgenography of the spine each year, and calcium absorption was measured in 392 of the women.
Fatal Seronegative Ehrlichiosis in a Patient with HIV Infection
Authors: Christopher D. Paddock, David P. Suchard, Kevin L. Grumbach, W. Keith Hadley, Russell L. Kerschmann, Nancy W. Abbey, Jaqueline E. Dawson, Burt E. Anderson, Kimetha G. Sims, J. Stephen Dumler, Brian G. Herndier
Journal: New England Journal of Medicine (1993)

Human infection with Ehrlichia chaffeensis, a recently identified bacterium included in the family Rickettsiaceae,1,2 results in an acute, generally self-limited, febrile illness associated with cytopenia and hepatic-enzyme abnormalities. Several hundred cases of E. chaffeensis infection have been recognized since 1986, although ehrlichiosis has not been described in patients infected with the human immunodeficiency virus (HIV). We report the course of a fatal seronegative ehrlichial infection in a woman with advanced HIV infection. The infection was diagnosed by light and electron microscopy, immunohistochemical techniques, and the polymerase chain reaction. The potential for successful antimicrobial treatment, combined with the possible absence . . .
Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings
Authors: Mark C Genovese, Fang Yang, Mikkel Østergaard, Nils Kinnman
Journal: Annals of the Rheumatic Diseases (2016)

Objective To assess early effects on joint structures of VX-509 in combination with stable disease-modifying antirheumatic drug (DMARD) therapy using MRI in adults with rheumatoid arthritis (RA). Methods This phase II, placebo-controlled, double-blind, dose-ranging study randomised patients with RA and inadequate DMARD response to VX-509 100 mg (n=11), 200 mg (n=10) or 300 mg (n=10) or placebo (n=12) once daily for 12 weeks. Outcome measures included American College of Rheumatology score (ACR20; improvement of ≥20%) and disease activity score (DAS28) using C reactive protein (CRP), and the RA MRI scoring (RAMRIS) system. Results ACR20 response at week 12 was 63.6%, 60.0% and 60.0% in the VX-509 100-mg, 200-mg and 300-mg groups, respectively, compared with 25.0% in the placebo group. DAS28-CRP scores decreased in a dose-dependent manner with increasing VX-509 doses. Decreases in RAMRIS synovitis scores were significantly different from placebo for all VX-509 doses (p&lt;0.01) and for RAMRIS osteitis scores (p&lt;0.01) for VX-509 300 mg. Treatment was generally well tolerated. Conclusions VX-509 plus a DMARD reduced the signs and symptoms of RA in patients with an inadequate response to a DMARD alone. MRI responses were detected at week 12. Treatment was generally well tolerated. Trial registration number NCT01754935; results.
HistoScanning, a new device to enhance ultrasound’s contribution to clinical assessment of pelvic masses
Authors: H. Bleiberg, J. Akakpo, S. Granberg, M. Sideri, R. Mashiach, P. Autier, D. Nir
Journal: Journal of Clinical Oncology (2006)

5056 Background: HistoScanning (HS) is a medical device developed to improve interpretation of echography. Ovarian (OV) HistoScanning (OVHS) performs computerized analysis of voxel files generated during transvaginal ultrasonography (TVS). OVHS was integrated into a protocol for investigation of ovarian pathologies, primarily cancer (OVCa). Methods: A study was initiated; a/ to standardize the echography procedure, b/ to evaluate OVHS ability to differentiate cancerous to non-cancerous pelvic masses under appropriate conditions. Women (W) ≥18 years old planned to have complete removal of ≥1 OV were eligible. Exclusion criteria include previous diagnosis of OV cancer, pelvic surgery, radiotherapy or chemotherapy for breast or OVCa. Real 3D-TVS were performed before surgery and the voxel data sent to AMD. After OVHS results were locked in the study’s data base, pathological reports were sent to the clinical research organization and the OVHS results were compared to histology. Results: From 09.2004 to 07.2005, 486 data files were obtained from 9 institutions. 120 were used for calibration, 97 had no surgery, and 269 met the protocol requirements. Pelvic histology includes normal OV (87), benign tumors (T) (78), past endometriosis (9), borderline cancers (21), adenocarcinomas (53), carcinomatosis (12), metastases (4) and other cancers (3), others (2). 91 cancers were correctly diagnosed (sensitivity 98%). Reason for false negatives was: lack of voxel data for the lesion (1) and pathology volume bellow US resolution (‘Cystadenofibroma with foci of low malignant potential; Borderline‘) (1). When gain used during TVS was appropriate, the false positive (FP) rate was 3% for normal tissues and 17% for benign tumors. When gain used was inappropriate, FP rate was 10% and 41%, respectively. Conclusion: OVHS seems highly sensitive for the diagnosis of pelvic masses while having an acceptable specificity. A study using 3D-TVS performed with controlled gain level is ongoing. [Table: see text]
Malignant Hyperthermia: A Pharmacogenetic Disease of Skeletal and Cardiac Muscle
Authors: Beverley A. Britt
Journal: New England Journal of Medicine (1974)

Malignant hyperthermia was first reported by Denborough in 19621 as a potentially lethal, autosomal dominant syndrome of unknown aetiology. The condition he described consisted of fulminant crises triggered by potent inhalational anesthetic agents, the outstanding features of which were fever, tachycardia, tachypnea and cyanosis. In the few intervening years much has been learned about this remarkable pharmacogenetic disturbance of the skeletal and cardiac muscles.Before anesthesia some members of many, but not all, malignant-hyperthermia-susceptible families have a greater than normal muscle bulk and power. Associated with this generalized muscularity may be localized areas of muscle weakness such as ptosis, kyphoscoliosis, . . .
Pharmacokinetic analysis and pharmacodynamic evidence of autophagy inhibition in patients with newly diagnosed glioblastoma treated on a phase I trial of hydroxychloroquine in combination with adjuvant temozolomide and radiation (ABTC 0603).
Authors: M. R. Rosenfeld, S. A. Grossman, S. Brem, T. Mikkelsen, D. Wang, S. Piao, L. E. Davis, P. J. O'Dwyer, R. K. Amaravadi
Journal: Journal of Clinical Oncology (2010)

3086 Background: Preclinical studies indicate autophagy inhibition by hydroxychloroquine (HCQ) can augment the efficacy of DNA damaging cancer therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) of HCQ in combination with adjuvant chemoradiation and temozolomide (TMZ) for glioblastoma (GBM). Methods: A 3+3 phase I trial design was conducted in surgically resected GBM patients (Pts). Pts received HCQ (200 -800 mg po qd) with radiation therapy (RT) and concurrent TMZ (75 mg/m2 po qd) followed by adjuvant TMZ (150-200 mg/m2 po qd ) 5/28 days for up to 6 cycles. Limited pharmacokinetic (PK) sampling and a novel high performance liquid chromatography/tandem mass spectroscopy assay for HCQ and metabolites were used to build a population PK model and blood concentration relationships. Quantitative electron microscopy (EM) and immunoblotting against the autophagy marker LC3 were used to assess therapy-associated changes in autophagic vesicles (AV) in peripheral blood mononuclear cells (PBMC). Results: 17 patients were enrolled at 6 centers with 15 pts evaluable for dose limiting toxicities (DLT). No DLT was observed in cohorts 1 or 2 (200, 400 mg HCQ). In cohort 3 (800 mg HCQ) 3/3 pts experienced Grade 3-4 neutropenia and thrombocytopenia, one with fever and sepsis. Deescalation of HCQ to 400 mg and 600 mg qd resulted in no DLTs and HCQ 600 mg qd was found to be the MTD. PK analysis indicated dose-proportional exposure for HCQ. Concentrations of HCQ which preclinical studies indicate are required for autophagy inhibition were achieved. Significant therapy-associated increases in AV with confirmatory elevations in LC3II were observed in PBMC in 1/5 pts at 400 mg, 2/3 patients at 600 mg and 2/2 patients at 800 mg HCQ. Conclusions: HCQ 600 mg is the MTD in this regimen and population. Dose-dependent myelosuppresion suggests a mechanistic interaction between HCQ and TMZ/RT. A novel PD assay for autophagy inhibition detected HCQ dose-dependent changes in AV in PBMC. Analyses of PK-PD interactions and a phase II study are underway. No significant financial relationships to disclose.
M16 Are we shouting loud enough? – A comparison of primary versus secondary care spirometry
Authors: EJA Harris, S Grant, S Yarde, G O’Connell-Ramsay, S Sturney, J Suntharalingam
Journal: Thorax (2015)

<h3>Background</h3> Abnormal spirometry results are a leading cause of referral to secondary care in the UK. Spirometry performed in GP practices is often supervised by nursing staff and in secondary care by dedicated respiratory physiologists. We felt that patients who performed spirometry in secondary care would be encouraged to exhale to their full capacity and achieve higher spirometric values. <h3>Methods</h3> We collected patient spirometry values from 87 GP referral letters and compared them with the values obtained at our lung function laboratory at a district general hospital. We used a paired t-test to compare the two sets of spirometry results. <h3>Results</h3> We found that there were significant differences between the lab FEV1 (p = 0.034), FVC (p &lt; 0.0001) and FEV1/FVC ratio (p = 0.0001) compared to primary care values. There was a 77 ml average increase in FEV1 and a 241 ml average increase in FVC when spirometry was performed in our lung function lab. Importantly, when we looked at the individual results, 18 patients (21%) originally deemed to have restrictive spirometry had obstructive spirometry when performed in our lab. Six patients (7%) originally had obstructive spirometry which proved to be normal or restrictive in our lab. <h3>Conclusions</h3> A significant difference was identified between GP and secondary care spirometry. The most important aspect of this is the understanding that spirometry is effort based. Most patients require significant encouragement to perform to their limit. If a less than maximal effort is made, the FVC value is most affected. This may cause truly obstructive spirometry to appear restrictive. Primary care spirometry gave a misleading picture in 28% of cases in this cohort, resulting in instances where referrals, investigations and treatments might have been avoided and possibly managed in primary care. Effective spirometry enables more accurate diagnosis, therefore reducing the chance of under or over treatment.
Treatment of Disseminated Carcinoid Tumors Including Hepatic-Artery Catheterization
Authors: Melvin L. Reed, Fred M. Kuipers, Vainutis K. Vaitkevicius, Max D. Clark, Ellet H. Drake, William R. Eyler
Journal: New England Journal of Medicine (1963)

HEPATIC-artery catheterization by way of the brachial artery for the treatment of malignant lesions in the liver has recently been revived and expanded.1 We have had the opportunity to utilize this method of therapy in a patient with carcinoid syndrome. This communication presents our experience and rationale for antitumor therapy of disseminated carcinoid tumor and also our experience and modifications in the technic of hepatic-artery catheterization of our first 17 patients.Catheterization TechnicThe left brachial artery is isolated approximately 3 to 4 cm. proximal to the antecubital fossa and distal to the profunda branch. After distal and proximal arterial . . .
Abstract 351: Downregulation of Connexin43 by MicroRNA-130a Results in Cardiac Arrhythmias
Authors: Gene Kim, Appledene Osbourne, Saoirse McSharry, Michael Broman
Journal: Circulation Research (2013)

MicroRNAs (miRs) are endogenous ~22 nucleotide RNA molecules that are now recognized as critical regulators of diverse physiological and pathological processes; however, studies of miRs and arrhythmogenesis remain sparse. Connexin43 (Cx43), a major cardiac gap junction protein, is critical for maintaining normal cardiac electrical conduction. One aspect of arrhythmia pathogenesis that has elicited great interest has been changes in Cx43 expression. Computational analysis of messenger RNAs predicted Cx43 to be a target for miR-130a. We hypothesized that overexpression of miR-130a in adult cardiomyocytes would result in cardiac arrhythmias. To study this, we used an inducible (tetracycline-off) bigenic system to study miR-130a overexpression in the adult mouse heart. 12 weeks after induction of miR-130a, 100% (16/16) of transgenic mice demonstrated a loss of sinus rhythm and irregular ventricular activity suggestive of atrial fibrillation on surface electrocardiograms (ECG). Nonsustained ventricular tachycardia was also observed during ECG recordings. Atrial contractions could not be detected by pulse wave Doppler. Intracardiac electrocardiography confirmed the presence of atrial arrhythmias. Western blot analysis demonstrated a 90% reduction in Cx43 levels and immunofluorescent staining confirmed a near complete loss of Cx43 in transgenic compared to littermate control hearts (n=12). Morphology of the intercalated disc was evaluated by electron microscopy and showed a loss of gap junctions in transgenic hearts. To validate Cx43 as a direct target of miR-130a, we performed in vitro target assays in 3T3 fibroblasts, known to express miR-130a. Using a luciferase reporter fused to the 3’UTR of Cx43 compared to a control (SV40) 3’UTR, we found a 55% ± 6% reduction in luciferase activity with the Cx43 3’UTR (p&lt;0.01, n=9). Addition of an antisense miR-130a inhibitor resulted in a dose dependent loss of inhibitory activity of the Cx43 3’UTR reporter, with no changes seen in the control vector. In conclusion, we have identified an unappreciated role of miR-130a as a direct regulator of Cx43. Overexpression of miR-130a results in the development of a variety of important cardiac arrhythmias including atrial fibrillation and ventricular tachycardia.
Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome
Authors: Sophia R. Balderman, Allison J. Li, Corey M. Hoffman, Benjamin J. Frisch, Alexandra N. Goodman, Mark W. LaMere, Mary A. Georger, Andrew G. Evans, Jane L. Liesveld, Michael W. Becker, Laura M. Calvi
Journal: Blood (2015)