tbuckley/cabot-search huggingface dataset:
Clinical presentation and molecular pathophysiology of autosomal dominant hemochromatosis caused by a novel ferroportin mutation
Authors: William J. H. Griffiths, Roman Mayr, Ian McFarlane, Martin Hermann, David J. Halsall, Heinz Zoller, Timothy M. Cox
Journal: Hepatology (2009)

Mutations in the SLC40A1 gene, which encodes ferroportin, are associated with autosomal dominant hemochromatosis. Ferroportin is inhibited directly by hepcidin, a key iron-regulatory peptide, and functional consequences of SLC40A1 mutations account for observed phenotypic differences in patients with ferroportin disease. We describe a large pedigree with a novel SLC40A1 mutation and, through in vitro analysis, elucidate the associated molecular mechanism of iron overload. The entire coding sequence of the SLC40A1 gene was sequenced in a pedigree, presenting with autosomal dominant hyperferritinemia. The functional effects of a novel SLC40A1 mutation were studied by overexpression of wild-type and mutant ferroportin fusion proteins in human embryonic kidney cells. Iron export was studied in these cells using 59Fe transport assays; subcellular localization of ferroportin was examined by way of confocal microscopy. A novel SLC40A1 mutation p.R489K segregated with iron overload in a family with clinical and histopathological signs of macrophage-type ferroportin disease. Human embryonic kidney cells overexpressing p.R489K ferroportin showed decreased iron export capacity when compared with wild-type ferroportin overexpressing cells. Subcellular localization studies demonstrated that p.R489K ferroportin was retained abnormally within an intracellular compartment. Conclusion: We report a novel pathological SLC40A1 variant associated with abnormal cell surface expression of ferroportin due to intracellular retention of the mutant protein. These findings predict macrophage-type ferroportin disease, the phenotype observed in this kindred. Study of the molecular cell biology of ferroportin and its mutants is key to understanding the pathogenesis of this increasingly recognized form of hemochromatosis, which responds poorly to conventional therapy. (Hepatology 2009.)
HYPONATREMIA AND HEMODYNAMIC CHANGES FOLLOWING PERCUTANEOUS LEFT ATRIAL APPENDAGE LIGATION WITH THE LARIAT DEVICE
Authors: Ryan Maybrook, Jayasree Pillarisetti, Vivek Yarlagadda, Arun Raghav Mahankali Sridhar, Madhu Reddy, Buddhadeb Dawn, Matthew Earnest, Ryan Ferrell, Jayant Nath, Arun Kanmanthareddy, Donita Atkins, Sudharani Bommana, Rajasingh Johnson, Dhanunjaya Lakkireddy
Journal: Journal of the American College of Cardiology (2014)
Can immunisation trigger rheumatoid arthritis?
Authors: D P Symmons, K Chakravarty
Journal: Annals of the Rheumatic Diseases (1993)

Can immunisation trigger rheumatoid arthritis?Open any rheumatology textbook and it will tell you that rheumatoid arthritis (RA) results from the interaction between a susceptible host and an unidentified environmental trigger.It seems highly unlikely, however, that all cases of RA will be attributable to a single environmental factor.It is more credible that a number of
Importance of the coronary sinus lead position on the clinical benefit of biventricular pacing
Authors: Eduardo B. Saad, Ali-Reza Golshayan, Mandeep Bhargava, Yaariv Khaykin, J. David Burkhardt, Ahmad Abdul-Karim, David O. Martin, Nassir F. Marrouche, Walid I. Saliba, Robert A. Schweikert, Patrick J. Tchou, Andrea Natale
Journal: Journal of the American College of Cardiology (2003)
ACTION OF FORMALDEHYDE ON ENZYMES AND ON CERTAIN PBOTEIDS
Authors: C. L. Bliss, F. G. Novy
Journal: The Journal of Experimental Medicine (1899)

The following general conclusions may be drawn from the preceding work: Fibrin is altered by formaldehyde and is then less easily digested by pepsin and by trypsin. Papaïn is apparently unable to digest fibrin even when this is exposed to very weak formaldehyde (1:1000) for a very short time. The casein of milk, on contact with formaldehyde, undergoes rapid alteration and is as a result not coagulated by rennet, or but very slowly. Such altered casein, like similar fibrin, is not readily digested by the proteolytic ferments. The longer the formaldehyde acts on casein and on fibrin the more marked is the result. Pepsin is not affected by a one per cent solution of formaldehyde, even when the mixture has stood for four weeks. Even a five per cent solution of formaldehyde acting for three weeks has no effect on pepsin. Contrary results obtained by others are due to an alteration of the fibrin by the formaldehyde. A putrid solution of pepsin in distilled water one month old digests fibrin as readily as a fresh solution. Rennet is not affected even by a four per cent solution of formaldehyde acting for several weeks. The absence of coagulation at times is due to the action of formaldehyde on the casein of the milk and not on the rennet ferment. Papaïn is very quickly altered by formaldehyde, even in very dilute solution. Moreover, it is unable to digest fibrin that has been exposed to the action of a very dilute solution of formaldehyde for a short time. Trypsin is altered by formaldehyde to such an extent that digestion of fibrin will not take place, or but very slowly. The extent to which trypsin is affected by formaldehyde depends largely upon the amount of organic matter present, as well as on the amount of ferment in the solution. Amylopsin is not destroyed by very dilute solutions of formaldehyde, but stronger solutions decrease the activity of the ferment, and if used in sufficient concentration will destroy it completely. Ptyalin, like the diastatic ferment of the pancreas, is not destroyed by dilute solutions of formaldehyde. If the latter is used in rather strong concentration and allowed to act for some time it will destroy the ferment. The action of formaldehyde is more rapid and more marked at a slightly elevated temperature than at ordinary room temperature. Malt diastase, unlike the diastatic ferments of the saliva and pancreatic solution, is not destroyed by formaldehyde when this is used in moderate amount and at ordinary temperature. Unlike pepsin, a solution of malt diastase readily undergoes decomposition on standing even for one or more days. This destruction is undoubtedly due to bacteria since it does not take place when formaldehyde is present. Consequently the favoring action which formaldehyde apparently exerts on diastase really consists in the inhibition of the growth of micro-organisms, and hence the diastase is protected against decomposition.
Constipation and its management
Authors: M. A Kamm
Journal: BMJ (2003)

Options go beyond laxatives and include behavioural treatment as well as new drugs 

Although slow to emerge, major advances have occurred in understanding the causes and management of constipation. It now receives the attention deserved of a symptom that affects a quarter of the population at some time. Most important is the recognition that different pathophysiological processes can result in the final common symptoms of decreased bowel frequency or impaired rectal evacuation. Different clinical syndromes require different therapeutic approaches.

Bowel frequency is influenced by several factors including intake of dietary fibre, emotional make up, and psychological morbidity. Introspective individuals have a lower bowel frequency and produce less stool than extroverts. Infrequent bowel actions in the absence of symptoms can be regarded as part of the normal spectrum of bowel frequency. Low bowel frequency is more common in women.

Controlled cross sectional studies have shown that psychological morbidity is commonly associated with severe constipation.1 In some patients it is the key causative factor. Other factors include childhood problems such as sexual or physical abuse, loss of a parent through death or separation, or disturbed toileting behaviour. Underlying depression is another cause. For some the gut is their “outlet valve” for the normal stresses of living. The pathways between brain and gut that link emotions to bowel function have been largely characterised and shown to involve cerebral corticotrophin releasing factor and efferent autonomic pathways. Although psychological factors should be sought at …
Hormonal Content of Thyroid Replacement Preparations
Authors: Robert W. Rees-Jones
Journal: JAMA (1980)

ACCORDING to present pharmaceutical industry estimates, there were 15 million prescriptions written in the last year for thyroid replacement in the United States. Of these, approximately 50% were for synthetic hormones, and the remainder were for preparations derived from animal sources. At present, both generic thyroid and levothyroxine preparations are available, and their use has been encouraged by recent changes in prescription regulations. Since the Food and Drug Administration still accepts the<i>United States Pharmacopeia</i>standard based on organic iodine content for this medication, there is no specification of the precise hormonal content of these tablets. This study reports the triiodothyronine (T<sub>3</sub>) and thyroxine (T<sub>4</sub>) content of a number of generic thyroid and T<sub>4</sub>preparations, using a radioimmunoassay.<sup>1</sup>This survey was occasioned by the experience of a patient who received a biologically ineffective thyroid tablet. <h3>Report of a Case</h3> A 54-year-old woman with primary hypothyroidism since
Levodopa Therapy and Malignant Melanoma
Authors: Arthur J. Sober
Journal: JAMA (1978)

Concern has been voiced over a role for levodopa in the induction or stimulation of growth of cutaneous malignant melanoma. Prospective query of 1,099 patients of the Melanoma Clinical Cooperative Group at the time of presentation of their primary melanoma showed only one patient who had been taking levodopa. It was concluded that levodopa, if a factor in the induction of melanoma, must be playing an inconsequential role in the rapid rise in incidence observed for this tumor over the past decade.
Slowly dividing neural progenitors are an embryonic origin of adult neural stem cells
Authors: Shohei Furutachi, Hiroaki Miya, Tomoyuki Watanabe, Hiroki Kawai, Norihiko Yamasaki, Yujin Harada, Itaru Imayoshi, Mark Nelson, Keiichi I Nakayama, Yusuke Hirabayashi, Yukiko Gotoh
Journal: Nature Neuroscience (2015)
Intrabody applications in neurological disorders: progress and future prospects
Authors: Todd W. Miller, Anne Messer
Journal: Molecular Therapy (2005)

Single-chain Fv and single-domain antibodies retain the binding specificity of full-length antibodies, but they can be expressed as single genes in phage or yeast surface-display libraries, thus allowing efficient in vitro selection from a naive human repertoire. Selected genes can then be expressed intracellularly in mammalian cells as intrabodies, with the potential for alteration of the folding, interactions, modifications, or subcellular localization of their targets. These reagents have been developed as therapeutics against cancer and HIV. Since misfolded and accumulated intracellular proteins characterize a wide range of neurodegenerative disorders, they are also potentially useful intrabody targets. Here, we review the extension of intrabody technology to the nervous system, in which studies of Huntington's disease have been used to develop the approach, and anti-synuclein and -β-amyloid strategies are in the early stages of development. Research on several other neurodegenerations, including Parkinson's, Alzheimer's, and prion diseases, provides support for the development of intrabodies directed against specific targets, or possibly against more common downstream targets, as novel therapeutics and as drug discovery tools.
Effects of exertion on hormone secretion.
Authors: A G Dessypris, F Fyhrquist, B A Lamberg
Journal: BMJ (1977)

Effects of exertion on hormone secretion SIR,-We have already reported changes in plasma cortisol, testosterone, growth hormone, renin activity, and serum osmolality in a group of Finnish sportsmen who ran a non- competitive marathon over the classical course in Athens in October 1973.1-Asthese data suggested a correlation between physical fitness and changes in hormone profiles we investigated a similar group of nine amateur
The death of Claudius
Authors: V J Marmion, T E J Wiedemann
Journal: Journal of the Royal Society of Medicine (2002)

Although the lifestyle of the Roman Emperor Claudius was characterized by overwork, gluttony and poor health, he survived to the remarkable age of 64. Even then, the circumstances of his death aroused suspicion. Was he poisoned?

The Claudians were amongst the oldest patrician families in Roman society, and they entered the imperial line through the marriage of Livia to the Emperor Augustus (Box 1). The early life of her grandson Claudius was not propitious. His physical disabilities were such that, when he assumed the toga virilis on reaching his majority, he was taken for the ceremony at night; and similarly, in 6 AD, on the occasion of a gladiatorial spectacle in memory of his father Drusus, Augustus required him to attend covered in a cloak. Through his early studies Claudius became a considerable historian and acquired a detailed knowledge of the law, but there seemed no likelihood that this ungainly figure would ever be nominated Emperor. The death of Augustus in 14 AD put him fourth in line of succession, after Tiberius, Germanicus and Gaius Caligula. However, Germanicus died, and 4 years of despotic horror led to the assassination of the Emperor Caligula in 41 AD.



Box 1

Claudius and his relations



Claudius' first public office had been as consul at the beginning of Caligula's rule; and his performance in that post must have impressed the praetorians greatly to account for his rapid selection as Emperor. The 13 years of his reign were marked by progress through consolidation, the conquest of Britain (which he visited for sixteen days) and the development of the imperial civil service. He was married four times—to Plautia, Paetina, Messalina and Agrippina. In the matter of his death, suspicion has fallen particularly upon Agrippina.
Low Plasma Levels of Vitamin B <sub>6</sub> Are Independently Associated With a Heightened Risk of Deep-Vein Thrombosis
Authors: M. Cattaneo, R. Lombardi, A. Lecchi, P. Bucciarelli, P.M. Mannucci
Journal: Circulation (2001)

Background Elevated plasma levels of total homocysteine (tHcy) before and after an oral methionine load (PML) are associated with an elevated risk of deep-vein thrombosis (DVT). We investigated whether plasma levels of B vitamins that are involved in Hcy metabolism are associated with an elevated risk of DVT. Methods and Results We compared 397 cases with previous DVT with 585 matched healthy controls. The plasma levels of folate, vitamin B 12 , vitamin B 6, , and fasting and PML tHcy were measured. The ORs for DVT associated with high (&gt;95th percentile) fasting levels and PML increases of tHcy were 2.1 (95% CI, 1.2 to 3.4) and 2.4 (95% CI, 1.5 to 3.9) after adjustment for established risk factors for DVT. Fasting plasma levels and PML increases in tHcy correlated negatively with vitamin levels. The crude OR for folate levels in the lowest quartile compared with the highest was 1.5 (95% CI, 1.1 to 2.1), and that for B 6 levels in the lowest and second quartiles compared with the highest was 1.5 (95% CI, 1.0 to 2.1). However, after adjustment for established risk factors and fasting and PML tHcy, the ORs for B 6 levels in the lowest and second quartiles only remained statistically significant (lowest quartile: OR, 1.8; 95% CI, 1.2 to 2.8; second quartile, OR, 1.9; 95% CI, 1.3 to 2.9). Conclusions High fasting and PML tHcy and low vitamin B 6 plasma levels are associated with an elevated risk for DVT independently of established risk factors for DVT. The association of low vitamin B 6 levels with the risk for DVT is independent of fasting and PML tHcy levels.
Epidemic of Chronic Nephritis of Unknown Aetiology
Authors: B. Milojcic
Journal: BMJ (1960)

ANGINA PECTORIS BRITISHof the disease phases of increased and decreased pain occur.For this reason caution must be exercised in pressing the claims of a new preparation before extended trials have been made.We believe, however, in view of our results, that such trials of cavodil are fully justified and should be undertaken. SummaryA controlled " double-blind" trial of cavodil has been made in 28 patients with angina pectoris.Improvement occurred in almost twice as many patients with cavodil as with the control tablet, and in some patients this improvement was remarkable.It is suggested that an extended trial of this drug is fully justified and should be undertaken.Side-effects were minimal and unimportant.
Clearer Picture Emerging of Methotrexate Role as Part of Rheumatoid Arthritis Treatment
Authors: Timothy F. Kirn
Journal: JAMA (1988)

SOME RHEUMATOLOGISTS say that gold injections, penicillamine, and antimalarials relieve symptoms for only about 50% of patients with rheumatoid arthritis, in part because efficacy often wanes over time. Thus, for more than a decade, many rheumatologists have been treating patients whose symptoms are intransigent with the cancer drug methotrexate—often with good results, but not without a measure of trepidation because cirrhosis has been attributed to methotrexate in some patients receiving long-term therapy for psoriasis. Three recent studies, presented at the annual meeting of the American Rheumatism Association in Houston, may help allay some fears. While investigators found some evidence of changes in the liver, they found no cirrhosis that they felt should be attributed to methotrexate. "For right now, we're cautiously optimistic," says James E. Brick, MD, assistant professor of medicine at West Virginia School of Medicine, Morgantown. Methotrexate was first used to treat rheumatoid arthritis in the early 1950s,
Nasal potentials at high altitude
Authors: H. Mairbäurl, N. Mason, P. Bärtsch
Journal: European Respiratory Journal (2005)

To the Editors: 

In their recent publication in the European Respiratory Journal , Sartori et al . 1 explain the difference between their results and previous studies by arguing that in other studies “no particular care was taken to locate the electrode in the inferior turbinate”, without contacting the investigators who performed the measurements that they criticise. This argument is not acceptable for us. We can assure them that we paid very careful attention to the placement of the nasal electrode as we are well aware that potentials vary considerably in magnitude in different …
Intravenous Delivery of siRNA Targeting CD47 Effectively Inhibits Melanoma Tumor Growth and Lung Metastasis
Authors: Yuhua Wang, Zhenghong Xu, Shutao Guo, Lu Zhang, Arati Sharma, Gavin P Robertson, Leaf Huang
Journal: Molecular Therapy (2013)

CD47 is a "self marker" that is usually overexpressed on the surface of cancer cells to enable them to escape immunosurveillance. Recognition of CD47 by its receptor, signal regulatory protein α (SIRPα), which is expressed in the macrophages, inhibits phagocytic destruction of cancer cells by the macrophages. In this study, we have first shown that clinical isolates of human melanoma significantly upregulate CD47, possibly as a mechanism to defend themselves against the macrophages. We then exploited RNA interference (RNAi) technology to test the hypothesis that knocking down CD47 in the tumor cells will render them targets for macrophage destruction; hence, creating a novel anti-cancer therapy. Anti-CD47 siRNA was encapsulated in a liposome-protamine-hyaluronic acid (LPH) nanoparticle (NP) formulation to address the challenge of targeted delivery of siRNA-based therapeutics in vivo. Efficient silencing of CD47 in tumor tissues with systemic administration of LPH(CD47) also significantly inhibited the growth of melanoma tumors. In a lung metastasis model, LPH(CD47) efficiently inhibited lung metastasis to about 27% of the untreated control. Moreover, no hematopoietic toxicity was observed in the animals that received multiple doses of LPH(CD47). Our findings indicate CD47 as a potential prognostic marker for melanoma development as well as a target for therapeutic intervention with RNAi-based nanomedicines.
Recurrent Hematuria
Authors: Nicholas Chiorazzi
Journal: JAMA (1974)

IN 1948, Abel and Brown<sup>1</sup>described a young black soldier who underwent nephrectomy because of severe unilateral hematuria and the suspicion of a renal neoplasm. Histopathologic examination of the excised kidney showed only sickled red blood cells (RBCs) in the medullary vessels. Since then, it has been recognized that sickle cell anemia may be associated with a variety of renal functional and morphological alterations that can be considered under the classification of "sickle cell nephropathy." It is noteworthy that all of the patients with hematuria have been described by the authors as "Negro" or of the "colored race." <h3>Report of a Case</h3> A 28-year-old white woman, mother of three, was admitted to North Shore University Hospital for the evaluation of hematuria. The patient was born in Georgia of white Anglo-Saxon parents. The family history showed no evidence of bleeding dyscrasias and interracial marriage. The patient's medical history was noncontributory.
Coronary Arteriography in the Intact Dog
Authors: FELIX PEARL, MEYER FRIEDMAN, NORMAN GRAY, BRUCE FRIEDMAN
Journal: Circulation (1950)

A method is described whereby the coronary arteries of dogs with intact chests can be regularly demonstrated roentgenologically by the use of small amounts of Diodrast injected through a specially devised catheter which is passed to the aortic sinus through a peripheral artery. The artery is preserved by suture. Electrocardiograms taken during the procedure were normal. The aortic valves of two excised hearts previously subjected to forceful trauma by the catheter, showed no abnormality. Characteristic arteriograms are reproduced, showing coronary arteries, separate cusps of the aortic valves, and the proximal aorta.
Risk factors for severity of diabetic polyneuropathy: intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study cohort.
Authors: P J Dyck, J L Davies, D M Wilson, F J Service, L J Melton, P C O'Brien
Journal: Diabetes Care (1999)

Chronic hyperglycemia relates to the occurrence of diabetic polyneuropathy (DPN), but has not yet been shown to relate to its overall severity In addition, the degree and duration of hyperglycemia, which measure of chronic hyperglycemia is most predictive of defined levels of severity of DPN, and which other putative risk factors are involved remain unknown.In a longitudinal study of 264 diabetic individuals in Rochester, MN, risk factors and other diabetic complications assessed at regular intervals during an average of approximately 7 years were tested for their association with a composite score of severity of DPN at the last examination.In multivariate analysis, diabetic retinopathy severity level (at last examination), mean ln(24-h proteinuria x duration of diabetes), and mean GHb were the main covariates for severity of DPN (R2 = 0.33). Excluding markers of microvessel and macrovessel disease, the independent risk factors were mean In(GHb x duration of diabetes), GHb, and type of diabetes (R2 = 0.23).We found that diabetic microvessel disease, chronic hyperglycemia exposure, and type of diabetes are associated with severity of DPN, and we believe these factors are implicated in its cause. Each of the five markers of microvessel disease was a strong covariate for severity of DPN. Mean GHb predicts severity of DPN better than duration of diabetes, and the latter predicts severity of DPN better than mean fasting plasma glucose. Knowing the severity of microvessel disease, the degree of chronic hyperglycemia exposure, and the type of diabetes provides useful information to evaluate whether a coexisting polyneuropathy and its severity is probably due to diabetes.