tbuckley/cabot-search huggingface dataset:
Central Hypotensive Action of Clonidine Requires Nitric Oxide
Authors: Lawrence W. Dobrucki, Camilo L. Cabrera, David F. Bohr, Tadeusz Malinski
Journal: Circulation (2001)

Background- Clonidine has an antihypertensive effect by its action in the brain and, because we observed that the tonic production of nitric oxide (NO) in the brain is required to maintain blood pressure at its low, normotensive level, the current study was designed to determine whether the hypotensive action of clonidine resulted from its stimulation of excess NO in the brain. Methods and Results- Porphyritic microsensors were used to quantify NO concentration in the nucleus tractus solitarius (NTS) in vitro in brain slices and in vivo in the anesthetized rat. In both preparations, the basal production of NO in the NTS was 15+/-3 nmol/L. In vitro stimulation of the NTS with clonidine (50 nmol/L) resulted in an increase in the NO concentration to 84+/-7 nmol/L. In vivo, the intracerebroventricular (ICV) infusion of clonidine (0.03 microgram) caused an increase in NO concentration in the NTS to 128+/-17 nmol/L. This ICV injection of clonidine caused a fall in mean arterial pressure of -22+/-1 mm Hg and a decrease of heart rate of -18+/-2%. The blockade of NO production with N(G)-nitro-L-arginine-methyl ester (2 micromol; delivered ICV, 30 minutes before the clonidine) reduced responses to clonidine for both mean arterial pressure and heart rate (-3+/-1 mm Hg and -2+/-1% change, respectively). Conclusion- The stimulation of the release of NO in the brain by clonidine contributes to its central antihypertensive action.
The role of pH, PCO2, and bicarbonate in regulating rat diaphragm citrate content
Authors: Sheldon Adler
Journal: Journal of Clinical Investigation (1970)

Intact rat diaphragms were exposed in vitro to varying CO(2) tensions and bicarbonate concentrations, and the steady-state citrate content of diaphragm muscle was measured to investigate the relationship between metabolism and extracellular pH, P(CO2), and (HCO(3) (-)). In addition, rat hemidiaphragms were incubated with 1,5-citrate-(14)C under different acid-base conditions, and (14)CO(2) production was determined as a measure of citrate oxidation. Acidification of the bathing medium achieved by raising CO(2) tension or lowering (HCO(3) (-)) was associated with a decrease in muscle citrate content. On the other hand, alkalinization of the medium induced by lowering CO(2) tension or raising (HCO(3) (-)) caused tissue citrate content to rise. At a physiologic extracellular pH value of approximately 7.40, citrate content was decreased or normal depending on the CO(2)/HCO(3) (-) combination employed to attain the pH. Under low bicarbonate and low P(CO2) conditions, citrate content was reduced. A similar result was found at external pH values of 7.15, implying that at these two extracellular pH levels (HCO(3) (-)) primarily determines citrate content. When changes in citrate content were compared with intracellular pH data reported earlier using the same intact diaphragm preparation, no simple relation between citrate content and intracellular pH was found. The effect of acidity on citrate content seems related to a change in citrate oxidation since the latter increased progressively with increasing degrees of medium acidity. These results show that cellular metabolism is not a simple function of extracellular pH but is dependent on the particular combination of P(CO2) and bicarbonate employed to achieve the pH value. These studies also suggest that accumulation or disposal of organic acids, such as citric acid, helps to regulate cellular acidity thereby contributing to the cells' defense against external acid-base disorders.
Erratum: Corrigendum: The landscape of somatic mutations in Down syndrome–related myeloid disorders
Authors: Kenichi Yoshida, Tsutomu Toki, Yusuke Okuno, Rika Kanezaki, Yuichi Shiraishi, Aiko Sato-Otsubo, Masashi Sanada, Myoung-ja Park, Kiminori Terui, Hiromichi Suzuki, Ayana Kon, Yasunobu Nagata, Yusuke Sato, RuNan Wang, Norio Shiba, Kenichi Chiba, Hiroko Tanaka, Asahito Hama, Hideki Muramatsu, Daisuke Hasegawa, Kazuhiro Nakamura, Hirokazu Kanegane, Keiko Tsukamoto, Souichi Adachi, Kiyoshi Kawakami, Koji Kato, Ryosei Nishimura, Shai Izraeli, Yasuhide Hayashi, Satoru Miyano, Seiji Kojima, Etsuro Ito, Seishi Ogawa
Journal: Nature Genetics (2013)
Development of gastric dysplasia in pernicious anaemia: a clinical and endoscopic follow up study of 80 patients.
Authors: U Armbrecht, R W Stockbrugger, J Rode, G G Menon, P B Cotton
Journal: Gut (1990)

The development of gastric dysplasia and neoplasia in patients with pernicious anaemia has been evaluated in a prospective clinical and endoscopic follow up study. After initial screening of 80 patients between 1978 and 1980, one patient underwent total gastrectomy for a gastric malignancy and 12 were kept under surveillance and underwent endoscopy at a mean interval of 14 months. In the remaining 67 patients further investigation was attempted six to seven years after the initial investigation. The continuous follow up study identified carcinoids in one patient and an adenoma with severe dysplasia in a further patient. The grade and site of mucosal dysplasia differed from one investigation to the next, but no overall progression was observed. Of the 79 patients, eight had died by the time of the reinvestigation, two of unknown cause and six of causes unrelated to pernicious anaemia. In 38 of the remaining 71 patients, clinical data only were available, with no evidence of new gastric malignancy. In 27 patients it was possible to perform an upper gastrointestinal endoscopy, when no change in the degree of dysplasia was detected. In six patients no follow up information was obtainable. In conclusion, patients with pernicious anaemia should be investigated by upper gastrointestinal endoscopy soon after diagnosis. Polyps should be removed wherever possible. In the presence of severe mucosal dysplasia or polyps that are not removed, frequent reinvestigation should be performed, provided the patient is eligible for gastric surgery. In the remaining patients, follow up endoscopies at about five year intervals would seem sufficient.
Rationale for use and clinical responsiveness of hexafluoro-1,25-dihydroxyvitamin D<sub>3</sub>for the treatment of plaque psoriasis: a pilot study
Authors: C. Durakovic, A. Malabanan, M.F. Holick
Journal: British Journal of Dermatology (2001)

Background Vitamin D analogues are useful in topical therapy of psoriasis. Objectives To evaluate the effect of hexafluoro-1,25-dihydroxyvitamin D3 (F6-1,25(OH)2D3) in treatment of psoriasis. Methods Fifteen patients with plaque-type psoriasis were enrolled in a single centre double-blind, right/left comparison, placebo-controlled study, and received 0·1 g of petrolatum containing 5 µg of F6-1,25(OH)2D3 or 0·1 g of petrolatum (placebo) for 3 months. After completion of this double-blind study, a subset of these patients (n = 12) applied F6-1,25(OH)2D3 ointment (50 µg g−1 of petrolatum) to all their lesions (total area, 100–5000 cm2, mean area: 3300 m2) for 2 months as a single application at night. Results The mean severity score in the right/left-sided controlled topical F6-1,25(OH)2D3 (50 µg g−1) therapy group showed a decrease of 85%. In contrast, the mean severity score for the placebo-treated areas showed a decrease of 45% (P < 0·001). In the 12 patients who subsequently applied F6-1,25(OH)2D3 (50 µg g−1) ointment to all of their lesions, 91·6% showed moderate to excellent improvement. The mean Psoriasis Area and Severity Index score decreased by 44·9% (from 33·6 ± 15 to 18·5 ± 13). No effect on calcium homeostasis was noted. Adverse events included mild irritation in two patients that resolved during therapy. Conclusions Topical F6-1,25(OH)2D3 is a safe and effective once a day treatment for psoriasis.
Clinical Significance of Magnetic Resonance Cholangiopancreatography (MRCP) Compared to Endoscopic Retrograde Cholangiopancreatography (ERCP)
Authors: R. E. Hintze, A. Adler, W. Veltzke, H. Abou-Rebyeh, R. Hammerstingl, T. Vogl, R. Felix
Journal: Endoscopy (1997)

Background and Study Aims: The clinical importance of magnetic resonance cholangiopancreatography (MRCP) as a noninvasive diagnostic modality for investigation of the biliary tree and pancreatic duct system is under debate. Using endoscopic retrograde cholangiopancreatography (ERCP) as the gold standard, this study determined in a prospective, blinded fashion the sensitivity and further statistic values of MRCP findings for evaluation of the biliary and pancreatic tract.
Human T cell hybridomas secreting factors for IgA-specific help, polyclonal B cell activation, and B cell proliferation.
Authors: L Mayer, S M Fu, H G Kunkel
Journal: The Journal of Experimental Medicine (1982)

Human T-T hybridomas were established by fusion of concanavalin A-activated OKT-4+ T cells with hypoxanthine guanine phosphoribosyl transferase-deficient as well as nondeficient T cell lines. Four hybrids were selected for further study. Supernatant from hybrid clone J1.3 specifically enhanced IgA production and secretion by isolated human B cells, with increases in IgA plaque-forming cells approaching those seen with addition of autologous T cells and pokeweed mitogen. A monoclonal lymphocytic leukemia with membrane IgA also differentiated to IgA plasma cells by this supernatant. Evidence suggests that this hybrid supernatant acts on post-switch IgA-committed B cells. The other hybrids were not isotype specific; hybrid J2S1 enhanced polyclonal Ig secretion and hybrids K1 and K8 induced B cell proliferation without induction of Ig secretion.
P24. Aviscumine enhances NK- cytotoxicity against tumor cells
Authors: G Gamerith, A Amann, B Schenk, T Auer, JM Huber, K Cima, H Lentzen, J Löffler-Ragg, H Zwierzina, W Hilbe
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts The mistletoe lectin I belongs to a new class of anticancer drugs with type II ribosomal inhibitor activity. The recombinant mistletoe lectin (aviscumine) has shown immunomodulatory and cytotoxic activity in preclinical models as well as potential antitumor effects in phase I and
Exposure and accumulation of cadmium in populations from Japan, the United States, and Sweden
Authors: Tord Kjellström
Journal: Environmental Health Perspectives (1979)

Studies were carried out in Japan, United States, and Sweden regarding comparability of analytical methods for cadmium, daily intake of cadmium via food, daily amount of cadmium in feces, concentrations of cadmium in different tissues and the body burden of cadmium, urinary excretion of cadmium and cadmium concentrations in blood. It was found that the cadmium intake via food among adults is about 35 μg/day in Japan (Tokyo) and about 17 μg/day in the U.S. (Dallas) and Sweden (Stockholm). It varies with age in a way similar to calorie intake. Body burden increases rapidly with age. The half-time of cadmium is longer in muscles than in liver or kidneys. In the cross-sectional population samples studied (smokers and nonsmokers mixed) the average cadmium body burden at age 45 was about 21 mg in Japan, 9 mg in the U.S., and 6 mg in Sweden. Among nonsmokers in the U.S. and Sweden the body burden at age 45 was about 5–6 mg. The difference in average body burden for smokers and nonsmokers is explained by differences in smoking habits. Cadmium excretion in urine was closely correlated with body burden and about 0.005–0.01% of body burden is excreted daily in urine. Cadmium concentration in the blood was a good indicator of average recent intake over a 3-month period. Neither blood cadmium nor urine cadmium changed immediately after an increase of exposure level.
Hepatic Cirrhosis Occurring in Two Children of the Same Family
Authors: F. W. Jollye
Journal: BMJ (1892)

CASE iv.-Male, aged 6. Family history of rheumatism.Thin, neurotic.Catches cold easily, subject to skin eruiptions.Complains of suprapubic pain; dysuria; no calculus present.Urine acid, offensive odour; uric acid and urates.CASE v.-A thin, neurotic boy, aged 4. Family history of rheumatism; has had tonsillitis.Suffers from constipation; pain on defaecation; at times incontinence of fTeces ; micturition slow and delayed; occasional incontinence.Urine acid; uricacid andurates.CASE VI.--A thin boy, aged 9. Family history of phthisis.Complains of diarrhcea; abdomen distended; fulness and tenderness in right iliac fossa.Urine very acid; uric acid and urates; trace of albumen.CASE viI.-A well nourished boy, aged 8. Family history of phthisis; Suffers from recurrent attacks of abdominal pain; dysuria; pain loca- lised in right iliac fossa, with fulness and tenderness on pressure tlhere.UJrine acid; oxalates.CASE viII.-Seeprevious page.
MICRO-CHANNEL STRUCTURE IDENTIFIED BY OPTICAL COHERENCE TOMOGRAPHY IS RELATED TO PLAQUE VULNERABILITY IN PATIENTS WITH CORONARY ARTERY DISEASE
Authors: Hironori Kitabata, Kohei Ishibashi, Kenichi Komukai, Takashi Tanimoto, Yasushi Ino, Shigeho Takarada, Takashi Kubo, Keizo kimura, Masato Mizukoshi, Toshio Imanishi, Takashi Akasaka
Journal: Journal of the American College of Cardiology (2010)
Acute skin failure
Authors: M.-J. Guerry, M. Lemyze
Journal: BMJ (2012)

A 54 year old man with a history of alcohol related polyneuropathy, depression, and carcinoma of the vocal cord who had recently finished a course of radiotherapy presented to his general practitioner because of a sore throat and mouth. He was prescribed amoxicillin 1 g twice daily (he had received this antibiotic three months before for a throat infection). He had also been taking prednisolone (20 mg daily) and fentanyl patches (25 µg/hour) for two months, lamotrigine (50 mg daily) and clonazepam (1 mg three times daily) for five months, and paroxetine (10 mg daily) for two years. These treatments had not recently been modified. Five days later, he was admitted to the general medical ward with fever and a rapidly spreading burning skin rash that affected his face, the presternal region of his trunk, and his palms and soles. He also had painful red eyes with yellow discharge and a worsening of the inflamed ulcerations inside his mouth. 

Initially the rest of the physical examination was unremarkable, apart from tachycardia (120 beats/min), with no signs of organ dysfunction. The next day, his skin symptoms had worsened: blisters appeared and the top layers of skin on his chest came off when lightly rubbed. At the same time he fell into a stupor and experienced respiratory failure; intubation and mechanical ventilation were required. He was transferred to the intensive care unit (tertiary referral hospital).



### 1 What is your diagnosis?

#### Short answer

This is a severe adverse cutaneous drug reaction (fig 1⇓), which according to the extent of epidermal detachment, can be classified as Stevens-Johnson syndrome (SJS)-toxic …
Relative Roles of Sympathetic and Parasympathetic Nervous Systems in the Carotid Sinus Reflex in Dogs
Authors: WALTER D. BERKOWITZ, BENJAMIN J. SCHERLAG, EMANUEL STEIN, ANTHONY N. DAMATO
Journal: Circulation Research (1969)

The effects of electrical stimulation of the carotid sinus on sinus rate and atrioventricular (A-V) conduction were studied before and after alternate interruption of the vagi and sympathetic nerves to the heart in dogs. In group I, carotid sinus stimulation caused a similar absolute decrease in sinus rate before and after vagotomy, although after vagotomy the response was more latent. Subsequent administration of propranolol blocked the effects of carotid sinus stimulation on sinus rate. In group II (dogs with intact vagi), the effects of carotid sinus stimulation and bilateral occlusion of the common carotid artery on sinus rate were abolished by bilateral stellatectomy and upper thoracic ganglionectomy. In group III, the effects of carotid sinus stimulation on A-V conduction during atrial pacing at a fixed rate were not significantly altered by vagotomy and were blocked by subsequent administration of propranolol. In group IV, carotid sinus stimulation had no effect on A-V conduction after sympathetic denervation. It is concluded that the effects of the carotid sinus reflex on the heart are mediated primarily by the sympathetic nervous system efferents. In addition, evidence suggesting that sympathetic tone is a major determinant of vagal tone has been presented.
Donor-derived long-lived intragraft leukocytes are likely generated by hematopoietic stem/progenitor cells in liver
Authors: Xiao Qi Wang, Cindy K.Y. Cheung, Chung Mau Lo
Journal: Hepatology (2012)

To the Editor We read with great interest the findings described by Shi et al. They detected high levels of donor-derived CD56+, CD3+, and CD14+ T cells in the first explanted liver grafts in both the short and long term after liver transplantation (LT). They concluded that these long-lived intragraft leukocytes in LT patients could cause long-term hematopoietic chimerism, challenging our conclusion that long-term blood chimerism is derived from hematopoietic stem/progenitor cells (HSPCs) in the liver,1 although they also suggest the possibility that it may result from hematopoiesis of relocated donor HSPCs. The critical issue here is whether the mature leukocytes in the intragraft are really long-lived. Natural killer (NK) cells (CD56+) are generally considered short-lived effector cells. Although it is still controversial, recent studies have demonstrated that NK cells have the ability to become long-lived memory cells and contribute to secondary immune responses.2 The mechanisms for NK cell longevity are unclear, but these self-renewing capable NK cells are not just simple mature NK cell proliferation. In liver tissue, CD14+ cells are mostly Kupffer cells with a lifespan of 3.8 days, which are generated and maintained by a high monocyte influx rate or local progenitor proliferation.3 However, what the local progenitor cells are and where they are derived from are yet to be clarified. Based on the understanding as outlined above, we think high levels of donor-derived T cells in recipient liver are unlikely to result from a simple mature T-cell proliferation to survive for 2 years after LT. Instead, it may generate from an existent small population of donor HSPCs1 or blood HSPCs in liver grafts (Shi et al. appears to agree with the latter point), which are able to self-renew and differentiation to maintain the mature leucocyte pool. In this sense, the findings by Shi et al. prove our hypothesis.1 Regarding the origin of HSPCs, both consistent presences in liver or from blood HSPCs are possible. We prefer the former hypothesis, because the population was maintained in liver grafts after extensive perfusion, but we did not exclude the probability of blood HSPCs in liver grafts.1 Finally, in 5 of the explanted liver grafts, Shi et al. could not detect donor-derived Lin−CD34+ HSPCs, which does not mean the HSPCs do not exist in healthy liver grafts. That Lin−CD34+ or Lin−CD45+ liver cells isolated from over 30 healthy liver grafts are able to form a hematopoietic colony and engraft in immunodeficient mice are the evidence of the presence of HSPCs in liver grafts.1 Moreover, Lin−CD34+CD38−CD90+ HSPCs only account for 0.03% of total liver cells,1 whereas the Lin−CD34+ population described by Shi et al. was based on different human leukocyte antigen markers, which might further complicate the measurement. Xiao Qi Wang*, Cindy K.Y. Cheung*, Chung Mau Lo*, * Department of Surgery The University of Hong Kong Pokfulam, Hong Kong.
Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector
Authors: Mark A. Kay, Catherine S. Manno, Margaret V. Ragni, Peter J. Larson, Linda B. Couto, Alan McClelland, Bertil Glader, Amy J. Chew, Shing J Tai, Roland W. Herzog, Valder Arruda, Fred Johnson, Ciaran Scallan, Erik Skarsgard, Alan W. Flake, Katherine A. High
Journal: Nature Genetics (2000)
Recent advances in coeliac disease genetics
Authors: K. A Hunt, D. A van Heel
Journal: Gut (2009)

Around 1 in 100 individuals of European descent have coeliac disease. An immune response in the small intestine is generated to fragments of “gluten”, storage proteins found in wheat, rye and barley. The inflammatory response leads to architectural changes in the small intestine, including villous atrophy, crypt hyperplasia and an increase in the number of intra-epithelial cells. If gluten is removed from the diet, in many cases architecture returns to normal over several months. While gluten is one well known environmental factor, inherited genetic factors are also know to affect disease susceptibility as can be seen from twin and family studies.1 Identification of these genetic factors has been advanced substantially by the first genome-wide association scan (GWAS) in coeliac disease.2 This, along with a follow-up study, has identified eight new genomic regions, seven of which contains genes with immunological functions.2 3

Until recently the only well replicated genetic association for coeliac disease was with variants in the human leucocyte antigen (HLA) region. These molecules are encoded at chromosome 6p21 in the major histocompatibility complex (MHC) region which encodes over 200 genes with immunological function.4 MHC class II molecules are encoded at gene loci HLA-DQ , HLA-DP and HLA-DR , and are expressed on professional antigen presenting cells (APCs). The function of these molecules is to present exogenous antigen to T cells.4–6 These genes are highly polymorphic resulting in the presence of many different forms such as HLA-DQ2. Ninety per cent of patients with coeliac disease express HLA-DQ2 (DNA encoded by alleles DQA1*0501 and DQB1*0201), compared to 30% of the healthy population.7

Linkage studies have been highly successful in the search for susceptibility loci in monogenic disorders but this success has not carried over into complex diseases which are thought to arise due …
Fourteen Monogenic Genes Account for 15% of Nephrolithiasis/Nephrocalcinosis
Authors: Jan Halbritter, Michelle Baum, Ann Marie Hynes, Sarah J. Rice, David T. Thwaites, Zoran S. Gucev, Brittany Fisher, Leslie Spaneas, Jonathan D. Porath, Daniela A. Braun, Ari J. Wassner, Caleb P. Nelson, Velibor Tasic, John A. Sayer, Friedhelm Hildebrandt
Journal: Journal of the American Society of Nephrology (2014)

Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of monogenic causes have been identified, the fraction of single-gene disease has not been well studied. To determine the percentage of cases that can be molecularly explained by mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput mutation analysis in a cohort of consecutively recruited patients from typical kidney stone clinics. The cohort comprised 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis (n=16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations were novel (40%). The cystinuria gene SLC7A9 (n=19) was most frequently mutated. The percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric cohorts (20.8%). Recessive causes were more frequent among children, whereas dominant disease occurred more abundantly in adults. Our study provides an in-depth analysis of monogenic causes of kidney stone disease. We suggest that knowledge of the molecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and might facilitate personalized treatment.