tbuckley/cabot-search huggingface dataset:
Novel <i>TET2</i> Mutations Associated With UPD4q24 in Myelodysplastic Syndrome
Authors: Azim M. Mohamedali, Alexander E. Smith, Joop Gaken, Nicholas C. Lea, Syed A. Mian, Nigel B. Westwood, Corinna Strupp, Norbert Gattermann, Ulrich Germing, Ghulam J. Mufti
Journal: Journal of Clinical Oncology (2009)

Purpose Cryptic chromosomal aberrations, such as regions of uniparental disomy (UPD), have been shown to harbor homozygous mutations and are a common feature in myelodysplastic syndrome (MDS). We investigated the sequence integrity of 4q24 candidate tumor suppressor gene TET2 in MDS patients with UPD on chromosome 4. Patients and Methods The coding exons of TET2 were analyzed by 454 deep sequencing and Sanger sequencing in nine patients with UPD on 4q. Four patients had refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) and UPD4q24, and five patients (refractory anemia with excess blasts-II, n = 1; 5q– syndrome, n = 1; RCMD-RS, n = 1; refractory anemia, n = 1; refractory cytopenia with multilineage dysplasia, n = 1) had no UPD4q24. Results Mutations on TET2 were identified in all four patients with UPD4q24. These were localized to exons 3, 6, and 9 and resulted in two premature stop codons, one frameshift mutation, and one cysteine to glycine amino acid change. Mutant clone size varied between 30% and 85%. One patient with UPD outside of q24 (UPD4q28.3) displayed additional TET2 mutations, but these were at low clonal levels (13%, 4%, and 4% for a silent mutation, a 180-base pair deletion in exon 3, and a lysine to phenylalanine substitution in exon 11, respectively). The other patients who did not have UPD4q24 did not have verifiable TET2 mutations. Conclusion Our data identify novel TET2 mutations in a dominant clone in patients with UPD4q24. The presence of UPD4q24 and mutations in RCMD-RS patients may suggest specificity to this subtype. Our preliminary results need to be confirmed in a large cohort of all MDS subtypes.
Mind-Forg'd Manacles: A History of Madness in England From the Restoration to the Regency
Authors: Louis L. Lunsky
Journal: JAMA (1988)

The title of this book,<i>Mind-Forg'd Manacles</i>, according to the author is a quotation from Blake, "to convey the sense in which society first created instruments of cultural torture, such as a theology of eternal damnation, which drove some out of their minds, and then additionally stigmatized the mad frequently as evil and dangerous." It is still axiomatic that the way the mentally ill are treated reflects the concerns and sensitivities of our culture. In England prior to the 19th century, no institutions had been developed to assume control of the mad. According to the author, "Around 1800 no more than a few thousand lunatics" were confined in all of England. By contrast, by 1900 the total number of mentally ill confined had skyrocketed to more than 100 000. The author concludes that psychiatry, with the help of Parliament and the courts, had become a social instrument for the control
Successful treatment of amyopathic dermatomyositis with topical tacrolimus
Authors: M. Ueda, R. Makinodan, M. Matsumura, M. Ichihashi
Journal: British Journal of Dermatology (2003)

Sir, The response of cutaneous lesions of dermatomyositis (DM) to therapy is sometimes poor despite the improvement in treating myositis with oral corticosteroids.1 The term amyopathic DM (ADM) refers to patients who, after 2 years of biopsy‐confirmed cutaneous manifestations of DM, have no clinical evidence of proximal muscle weakness and no serum muscle enzyme abnormalities.2 Treatment with oral corticosteroids is usually avoided for ADM and it has a favourable long‐term prognosis.3 However, cutaneous lesions of ADM are also refractory to several therapeutic modalities.1, 2, 4 Topical tacrolimus is a new immunosuppressive agent that has been used successfully to treat patients with atopic dermatitis. We describe a patient with ADM whose cutaneous lesions were responsive to topical tacrolimus after unsuccessful treatment with topical corticosteroids. A 26‐year‐old woman presented with a 6‐month history of periorbital heliotrope, violaceous papules over her proximal interphalangeal and metacarpophalangeal joints, poikilodermatous erythema on her upper back and nape of the neck, and periungal erythema. She had no history of muscle weakness. Her levels of creatinine phosphokinase, aldolase and lactate dehydrogenase were within the normal ranges. Antinuclear antibody, anti‐dsDNA antibody, anti‐SS‐A antibody and anti‐Jo‐1 antibody were negative. Levels of KL‐6 and serum tumour markers (carcinoembryonic antigen, cancer antigen 125, carbohydrate antigen 19‐9, α‐fetoprotein and squamous cell carcinoma antigen) were within the normal ranges. Electromyography (proximal muscle group) and a muscle biopsy (deltoid area) did not reveal myositis. Serial screening for neoplasia was negative. Skin biopsy of a lesion on her finger revealed pathological findings compatible with DM. She had been treated only with topical corticosteroids for the skin lesions and had been examined periodically for muscle status. Because she did not develop muscle weakness and had no serum muscle enzyme abnormalities for 2 years since appearance of the skin lesions, the diagnosis of confirmed ADM was made. As her skin lesions did not respond to topical corticosteroids, treatment with topical tacrolimus ointment 0·1% twice daily was initiated. Two weeks after starting this treatment, almost all of the erythema on her face had significantly improved. After 4 weeks, the poikilodermatous erythema on her back and nape of the neck had also improved and the Gottron's papules on her fingers gradually improved. No adverse effects were noted.
Post-Mortem Procedures: An Illustrated Textbook
Authors: David M. Spain
Journal: JAMA (1980)

In this country, in recent years, there has been a steady decline in the number of postmortem examinations. Part of this failure to obtain autopsy consents is based on a lack of public education concerning their value. But equally contributory are the unfortunate attitudes of too many clinicians, derived from their lack of appreciation of the many purposes served by the postmortem examination. A properly performed autopsy is invaluable, if not essential, to forensic medicine and in the primary education of medical students and the continuing education of physicians. The autopsy permits the determination of the definitive cause of death in difficult and puzzling cases and the development of ongoing data bases for medical research and epidemiologic studies. We evaluate the quantitative and qualitative accuracy of laboratory tests and other techniques by the type and character of the pathological alterations in the various tissues of the body, as revealed at
Eosinophils altered phenotypically and primed by culture with granulocyte/macrophage colony-stimulating factor and 3T3 fibroblasts generate leukotriene C4 in response to FMLP.
Authors: W F Owen, J Petersen, K F Austen
Journal: Journal of Clinical Investigation (1991)

Normodense eosinophils failed to generate leukotriene C4 (LTC4) in response to incremental concentrations of FMLP but did produce LTC4 when stimulated with calcium ionophore A23187. Normodense eosinophils, maintained in culture with 10(-11) M granulocyte/macrophage colony-stimulating factor (GM-CSF) in the presence of 3T3 fibroblasts, became responsive to transmembrane stimulation with FMLP by day 4 with a maximal effect by day 7. After 7 d of culture, hypodense eosinophils stimulated with 2 x 10(-7) M FMLP generated 26 ng LTC4/10(6) cells, and LTC4 biosynthesis was blocked by N-tertbutoxy-carbonyl-L-methionyl-L-leucyl-L-phenylalanine (N-t-BOC-MLP). Neither calcium ionophore stimulation of LTC4 from endogenous arachidonic acid nor substrate-initiated production of LTC4 from incorporated LTA4 changed when eosinophils were cocultured with GM-CSF and 3T3 fibroblasts. Furthermore, when incubated with 10(-6) M FMLP, normodense eosinophils generated no net superoxide measured by the reduction of cytochrome c, whereas replicate eosinophils cultured for 7 d with 10(-11) M GM-CSF and 3T3 fibroblasts reduced a net of 17 nmol of cytochrome c/10(6) cells. These studies suggest that primed and phenotypically altered eosinophils present at an extravascular site may exert pathobiologic effects by responding to soluble ligands in the tissues.
Breast Cancer Subtypes in Northern Chinese Women.
Authors: J. Gao, X. Zhang, B. Zhang, J. Wang, X. Liang
Journal: Cancer Research (2009)

Abstract Introduction: Breast cancer is currently regarded as a heterogeneous disease. Gene expression analysis has identified several subtypes that differ in prognosis and therapy response. Little is known about the distribution of these subtypes among native Chinese women.Patientsand Method: From December 2006 to November 2008, 1,133 women were diagnosed with invasive breast cancer in Shanxi province cancer hospital and 818 had assessable information for ER, PR, and Her-2/neu status. Based on immunohistochemical surrogates for ER, PR, and Her-2/neu status obtained from the department of pathology, the molecular subtypes were defined as: luminal A (ER+ and/or PR+, HER2−), luminal B (ER+ and/or PR+, HER2+), basal-like (ER−, PR−, HER2−), and Her-2/neu (ER−, PR−, and HER2+).Results: Luminal A was the most prevalent breast cancer subtype (70.6%), compared with the luminal B breast cancer subtype (15%), basal-like breast cancer subtype (9.6%), and Her-2/neu breast cancer subtype (4.8%). The frequency of Her2 positive breast cancer was 19.88% in the cohort studied. The luminal B breast cancer subtype was largely presented in patients aged less than 50 years old (58.8%) compared with the luminal A subtype (48.5%), basal-like subtype (52.6%) and Her-2/neu breast cancer subtypes (47.4%). The largest tumor size was basal-like breast cancer (28.1mm), followed by luminal B (25.8mm), Her-2/neu (25.7mm) and luminal A (23mm) (P = 0.003). The lymph node status did not vary among the four groups, however, the mean number of lymph nodes metastasis was significantly different with 3.2, 2.9, 5.7 and 4.9 for luminal A, luminal B, Her-2/neu and basal-like subtypes respectively (P = 0.005).Conclusions: The distribution of breast cancer subtypes in Northern Chinese women was similar to other ethnicities. The basal-like and Her-2/neu breast cancer subtypes were associated with unfavorable clinical features. Further studies will identify the difference in treatment response and prognosis among the four subtypes in this cohort. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3168.
In Vivo RNAi-Mediated α-Synuclein Silencing Induces Nigrostriatal Degeneration
Authors: Oleg S Gorbatyuk, Shoudong Li, Kevin Nash, Marina Gorbatyuk, Alfred S Lewin, Layla F Sullivan, Ronald J Mandel, Weijun Chen, Craig Meyers, Fredric P Manfredsson, Nicholas Muzyczka
Journal: Molecular Therapy (2010)

Two small-interfering RNAs (siRNAs) targeting alpha-synuclein (alpha-syn) and three control siRNAs were cloned in an adeno-associated virus (AAV) vector and unilaterally injected into rat substantia nigra pars compacta (SNc). Reduction of alpha-syn resulted in a rapid (4 week) reduction in the number of tyrosine hydroxylase (TH) positive cells and striatal dopamine (DA) on the injected side. The level of neurodegeneration induced by the different siRNAs correlated with their ability to downregulate alpha-syn protein and mRNA in tissue culture and in vivo. Examination of various SNc neuronal markers indicated that neurodegeneration was due to cell loss and not just downregulation of DA synthesis. Reduction of alpha-syn also resulted in a pronounced amphetamine induced behavioral asymmetry consistent with the level of neurodegeneration. In contrast, none of the three control siRNAs, which targeted genes not normally expressed in SNc, showed evidence of neurodegeneration or behavioral asymmetry, even at longer survival times. Moreover, co-expression of both rat alpha-syn and alpha-syn siRNA partially reversed the neurodegenerative and behavioral effects of alpha-syn siRNA alone. Our data show that alpha-syn plays an important role in the rat SNc and suggest that both up- and downregulation of wild-type alpha-syn expression increase the risk of nigrostriatal pathology.
Diminished Lymphoblast 5′-Nucleotidase Activity in Acute Lymphoblastic Leukemia with T-Cell Characteristics
Authors: Gregory H. Reaman, Neil Levin, Andrew Muchmore, Betty J. Holiman, David G. Poplack
Journal: New England Journal of Medicine (1979)

SINCE leukemic cells express certain cell-surface markers common to normal human lymphocytes, acute lymphoblastic leukemia can be differentiated immunologically into T-cell, B-cell and null (non-T, non-B-cell) types.1 2 3 Classification of acute lymphoblastic leukemia in this manner has led to an increased awareness of the unusual biologic heterogeneity that exists in this lymphoid malignancy, and such classification has probable prognostic and therapeutic value.4 5 6 Studies of the activity of various enzymatic systems in leukemic cells have produced information about the biologic differences both between leukemic cells and their normal lymphoid counterparts and within immunologic subclasses of acute lymphoblastic leukemia.Consistent and well defined . . .
Thoughts on the Management of Incurable Chronic Heart-Disease
Authors: C. M. Durrant
Journal: BMJ (1875)

to which the sufferers were exposed either fungoid spores or marsh malaria.Once more I would add, that I have had the privilege of conversing familiarly with medical and other residents of Sierra Leone, Cape Coast Castle, Rangoon, Birmah, Fernando Po, the Gold Coast, the aguish districts of South America and the United States, the worst part of the West Indies, the fen districts of Cambridgeshire, and the worst parts of Italy.Some of my informants have had aguc repeatedly; others have seen every onie around them, including negroes, down with fever (I do not refer, of course, to ycllow or other contagious fever), whilst they have escaped wholly during a residence of five years on the same spot.The experience thus olNtained is not to be despised, even although I have no personal knowledgc of other malarious districts than those of Camnbridgeshire and Italy.
Women at risk of HIV can continue to use hormonal contraception but with condoms
Authors: A. Gulland
Journal: BMJ (2012)

Women at high risk of acquiring HIV can continue to use injectable hormonal contraceptives, despite research indicating that their use increases women’s susceptibility to infection with HIV, concludes a World Health Organization review of evidence.

The review determined that overall the evidence that the risk of transmission of HIV to women was raised by the use of hormonal contraceptives was inconclusive and that women at high risk of HIV could continue to use injectable hormonal contraceptives but along with condoms.

WHO published its advice in guidance on Thursday 16 February in response to a study published online in Lancet Infectious Diseases in October 2011 that …
Case of Cancer of Pancreas, Accompanied by Phlegmasia Dolens
Authors: L. Cane
Journal: BMJ (1883)

RExiRR8. 1 Sussex County M. 27 years.Setting com-Syncope."Heart in ad-Hospital.pound -fracvanced fatty de- tured leg.generation." 2 Children's Hos-M.9 .. Opening abs-Syncope.No p.m. "Died a pital, Man-ces,.few minutes chester.after the operation was finished.
Effects of short-term, diet-induced hypercholesterolemia on systemic hemodynamics, myocardial blood flow, and infarct size in awake dogs with acute myocardial infarction.
Authors: S Sakamoto, M Kashiki, N Imai, C S Liang, W B Hood
Journal: Circulation (1991)

BACKGROUND Short-term cholesterol feeding has been shown to affect vasomotor tone and increase infarct size in anesthetized rabbits. The purpose of the study was to determine whether acute hypercholesterolemia reduced collateral flow to ischemic myocardium and increased infarct size in the awake dog. METHODS AND RESULTS Acute myocardial infarction was produced in awake dogs by a 4-hour left anterior descending coronary artery occlusion followed by 6-hour reperfusion after either a cholesterol-supplemented diet (n = 14) or a control diet of dog chow (n = 15) for 10 days. Infarct size was determined using nitroblue tetrazolium staining. In two subgroups, a 15-minute transient occlusion of the left anterior descending coronary artery was produced before the diet treatments and was compared with occlusion after diet treatments, so that the effects of hypercholesterolemia of collateral flow could be determined by paired comparisons. Cholesterol feeding increased plasma cholesterol to 288 +/- 52 mg/dl, which was twofold to threefold that in the control group (127 +/- 35 mg/dl), but had no effects on baseline systemic hemodynamics and myocardial blood flow. Coronary artery occlusion produced similar increases in heart rate, mean aortic pressure, left atrial pressure, and plasma norepinephrine in both groups of animals. However, cholesterol feeding reduced collateral flow to ischemic myocardium and increased infarct size, compared with the control group. The infarct size correlated with ischemic myocardial blood flow in both groups, but the slopes of regression lines relating the two variables did not differ between the two groups. CONCLUSIONS Short-term, diet-induced hypercholesterolemia increased infarct size in awake dogs. This change results, at least in part, from a decrease in collateral blood flow to ischemic myocardium during coronary artery occlusion.
Ethical and Legal Issues Related to the Use of Computer Programs in Clinical Medicine
Authors: RANDOLPH A. MILLER
Journal: Annals of Internal Medicine (1985)

As computer programs are used with increasing frequency in the clinical setting, ethicists, lawyers, computer scientists, clinicians, and patients must confront a group of problems: In what situations is it appropriate to use a medical computer program? Who should use these programs and how should they be used? What is the legal status of a computer program that provides medical advice? Can a proper balance be achieved between confidentiality of patient information and shared access to records by health care personnel? How can regulatory agencies, physicians, and patients determine if a program is safe for human use? Will programs be able to communicate with users well enough to prevent clinically harmful misunderstandings? Because few if any definitive answers are yet available, these questions remain the subject of much discussion.
Paternity by a seemingly infertile vasectomised man
Authors: I S Edwards
Journal: BMJ (1993)

education for general practitioners was also provided.People concerned about possible lesions were encouraged to consult their general practitioner, who could refer those with suspect lesions direct to a pigmented lesion clinic, avoiding the waiting list for appointments to dermatology clinics.The effect of these campaigns on incidence by stage and on mortality are still being evaluated; preliminary results from western Scotland indicate some possible benefit to women but not yet to men.2
Nonsustained Ventricular Tachycardia in Severe Heart Failure
Authors: Hernan C. Doval, Daniel R. Nul, Hugo O. Grancelli, Sergio D. Varini, Saul Soifer, Gianni Corrado, Sergio Dubner, Omar Scapin, Sergio V. Perrone
Journal: Circulation (1996)

Background The goal of the study was to determine the prognostic value of nonsustained ventricular tachycardia (NSVT) in total mortality in severe congestive heart failure (CHF) and in death modes. NSVT is associated with an increased mortality in CHF. However, the predictive value of NSVT as a marker for sudden death or death due to progressive heart failure has not been determined. Methods and Results Five hundred sixteen patients from the GESICA trial (33.4% with NSVT) were initially studied with the results of 24-hour Holter and 2 years of follow-up. Within 2 years, 87 of 173 patients (50.3%) with NSVT and 106 of 343 patients (30.9%) without NSVT died. Relative risk (RR) was 1.69 (95% confidence interval [CI], 1.27 to 2.24; P &lt;.0002), and Cox proportional hazard analysis was 1.62 (95% CI, 1.22 to 2.16; P &lt;.001). Sudden death increased from 8.7% (30 of 343) to 23.7% (41 of 173) in patients with NSVT (RR, 2.77; 95% CI, 1.78 to 4.44; P &lt;.001). Progressive heart failure death was also increased from 17.5% (60 of 343) to 20.8% (36 of 173) ( P =.22). Quantitative analysis of 24-hour Holter (first 295 patients) demonstrated that couplets had a similar RR to that of NSVT for both total mortality (RR, 1.81; 95% CI, 1.22 to 2.66; P &lt;.002) and sudden death (RR, 3.37; 95% CI, 1.57 to 7.25; P &lt;.0005). Couplets and/or NSVT (ventricular repetitive beats) were even more predictive for sudden death (RR, 10.1; 95% CI, 1.91 to 52.7; P &lt;.01). Conclusions In patients with CHF, NSVT is an independent marker for increased overall mortality rate and sudden death. The absence of NSVT and ventricular repetitive beats in a 24-hour Holter indicates a low probability of sudden death.
Dengue fever epidemic hits northern Australia
Authors: J. McCredie
Journal: BMJ (2009)

Authorities in northern Queensland have mounted a major public health and vector control campaign after the country’s first death related to dengue fever since 2004 was confirmed on 4 March.

More than 650 cases of the mosquito borne disease have been confirmed in the area since December, whereas in previous recent episodes 500 or so cases had been spread over more than a year, and this is the first time in Australia that all four serotypes have been found circulating simultaneously.

The largest outbreak, of type 3 dengue, is centred on the tourist …
Autonomic Epilepsy: Clonidine Blockade of Paroxysmal Catecholamine Release and Flushing
Authors: Stewart A. Metz, Jeffrey B. Halter, Daniel Porte, R. Paul Robertson
Journal: Annals of Internal Medicine (1978)

We studied a 59-year-old man with transient paroxysms of hypertension, tachycardia, and flushing in whom pheochromocytoma was excluded. Although catecholamine excretion was normal, plasma catecholamine levels rose from normal basal levels (282 ±14 pg/ml) to increased levels (585 ±67 pg/ml; ∓ SEM; n= 4) at the peak of spells. Other hormones or substrates expected to rise with nonspecific "stress" did not increase after paroxysms. Therapy with Clonidine (0.2 to 0.4 mg/day) suppressed basal catecholamines to undetectable levels and markedly reduced peak levels during spells (80 pg/ml). An epileptic pathogenesis was suggested by stereotypic olfactory and epigastric prodromata before spells, and abolition of paroxysms with the anticonvulsant carbamazepine. This patient represents a rare case of autonomic epilepsy with the seizure focus in the temporal lobe.
A different view on human albumin—authors' reply
Authors: Wei-jian Zhang, Balz Frei
Journal: Cardiovascular Research (2003)

We thank Drs Nohe and Dieterich for their comments on our recent article in this journal, in which we reported that physiological concentrations of bovine serum albumin (BSA) and recombinant human serum albumin (HSA) selectively inhibit TNFα-induced expression of vascular cell adhesion molecule-1 (VCAM-1) in human aortic endothelial cells [1]. In contrast, neither E-selectin nor intercellular adhesion molecule-1 (ICAM-1) expression were inhibited by BSA [1]. We also observed that BSA inhibits TNFα-induced VCAM-1 expression in human umbilical vein endothelial cells (HUVEC) [2]. This result is consistent with the inhibitory effect of HSA on TNFα-mediated VCAM-1 expression in HUVEC reported by Nohe et al. [3]. However, these authors also found that contaminants in two different preparations of HSA can upregulate expression of ICAM-1 and E-selectin in resting and TNFα-stimulated HUVEC, respectively [3].

Nohe …