tbuckley/cabot-search huggingface dataset:
Autoantibodies in autoimmune liver disease: biomarkers versus epiphenomena
Authors: C. Selmi, M. E. Gershwin
Journal: Gut (2010)

Serum autoantibodies have steadily established themselves as critical biomarkers for the diagnosis of autoimmune diseases. This is well illustrated in the case of primary biliary cirrhosis (PBC) in which antimitochondrial antibodies (AMAs) are a major diagnostic criterion, being both sensitive and specific, despite lacking prognostic significance. The mitochondrial autoantigen was identified >20 years ago1 and rigorous dissection of the immune response subsequently led to the development of molecular methods to increase the test specificity and sensitivity, and the identification of autoreactive CD4 and CD8 cells. This example of AMAs reminds us that the recognition of an autoantigen can become a milestone in understanding the disease. This paradigm may well be illustrated in data described in this issue of Gut by Terjung and colleagues ( see page 808 ). In this report, the authors demonstrate that β tubulin isotype 5 (TBB-5), the atypical pANCA autoantigen, further suggesting that the TBB-5 bacterial precursor FtsZ leads to tolerance breakdown and chronic inflammation.2

The history of autoantibodies reactive with the cytoplasm of neutrophils (ANCAs) has been a difficult and conflicting field. Similar to antinuclear antibodies, ANCAs are a non-uniform family of antibodies recognising diverse cytoplasmic constituents of human neutrophilic …
Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans
Authors: Katherine Esposito, Francesco Nappo, Raffaele Marfella, Giovanni Giugliano, Francesco Giugliano, Myriam Ciotola, Lisa Quagliaro, Antonio Ceriello, Dario Giugliano
Journal: Circulation (2002)

Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-alpha, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione.Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-alpha, and IL-18 levels rose (P<0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher (P<0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-alpha levels higher (P<0.05) than those of control subjects. The increase in plasma cytokine levels during the clamping lasted longer (4 hours versus 2 hours, P<0.01) in the IGT subjects than in the control subjects, and the cytokine peaks of IGT subjects after the first glucose pulse were higher (P<0.05) than those of control subjects. On another occasion, 10 control and 8 IGT subjects received the same glucose pulses as above during an infusion of glutathione; plasma cytokine levels did not show any significant change from baseline after the 3 glucose pulses.Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT. This suggests a causal role for hyperglycemia in the immune activation of diabetes.
Bile Acid Signaling in Metabolic Disease and Drug Therapy
Authors: Tiangang Li, John Y. L. Chiang
Journal: Pharmacological Reviews (2014)

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid-activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein-coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver.
Inappropriate Drug Use in Advanced Dementia—Reply
Authors: Jennifer Tjia, Becky A. Briesacher
Journal: JAMA Internal Medicine (2015)

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Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma.
Authors: I M Adcock, S J Lane, C R Brown, T H Lee, P J Barnes
Journal: The Journal of Experimental Medicine (1995)

Glucocorticosteroids are a very effective treatment for asthma and other chronic inflammatory diseases. However, a small proportion of patients is resistant to the therapeutic effects of glucocorticoids. Pharmacokinetic and ligand binding studies suggest that the molecular abnormality in steroid resistance lies distal to nuclear translocation. We have previously reported that there is a decreased ability of glucocorticoid receptors (GR) to bind to the DNA-binding site in peripheral blood mononuclear cells (PBMC) after dexamethasone treatment. This reduced DNA binding was due to a decrease in the number of receptors available rather than an alteration in affinity for DNA. To study this reduced DNA binding, we examined the ability of the nuclear translocated transcription factors activator protein 1 (AP-1), nuclear factor kappa B (NF-kappa B) and cyclic AMP response element-binding protein (CREB) to bind to their DNA-binding sites and to interact with GR in PBMC from patients with steroid-sensitive and steroid-resistant asthma. There was a significant reduction in the interaction between GR and AP-1 in these steroid-resistant patients, although interaction with other transcription factors activated in inflammation (NF-kappa B and CREB) was unaffected. An increase in the basal levels of AP-1 DNA binding was also detected in the nuclei from steroid-resistant asthmatic patients. There were no differences in the amount of messenger RNA detected for the components of AP-1, c-Fos and c-Jun, nor in the sequences of these messenger RNAs. These results suggest either that the ability of the GR to bind to glucocorticoid response elements and AP-1 is altered in steroid-resistant patients or that increased levels of AP-1 prevent GR DNA binding, and that this may be the molecular basis of resistance to the antiinflammatory effect of steroids in these cells.
Heart Rate Recovery After Exercise Is a Predictor of Silent Myocardial Ischemia in Patients With Type 2 Diabetes
Authors: Tomohide Yamada, Takashi Yoshitama, Kunihiko Makino, Tetsuo Lee, Fumihiko Saeki
Journal: Diabetes Care (2011)

Slow heart rate recovery (HRR) predicts all-cause mortality. This study investigated the relationship between silent myocardial ischemia (SMI) and HRR in type 2 diabetes.The study enrolled 87 consecutive patients with type 2 diabetes and no chest symptoms. They underwent treadmill exercise testing and single-photon emission computed tomography imaging with thallium scintigraphy. Patients with abnormal myocardial perfusion images also underwent coronary angiography.SMI was diagnosed in 41 patients (47%). The SMI group showed slower HRR than the non-SMI group (18 ± 6 vs. 30 ± 12 bpm; P < 0.0001). HRR was significantly associated with SMI (odds ratio 0.83 [95% CI 0.75-0.92]; P = 0.0006), even after adjustment for maximal exercise workload, resting heart rate, maximum heart rate, rate pressure product, HbA(1c), use of sulfonamides, and a history of cardiovascular disease.HRR can predict SMI in patients with type 2 diabetes.
<i>RAS</i>and<i>RAF</i>mutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis
Authors: O.E. Dadzie, S. Yang, A. Emley, M. Keady, J. Bhawan, M. Mahalingam
Journal: British Journal of Dermatology (2009)

Distinguishing banal melanocytic aggregates contiguous with malignant melanoma can be a histological challenge but is essential because of the potential for a spurious Breslow measurement.Our aim was to ascertain whether the histological distinction between the two relates to differences in the prevalence of mutations in genes significant in melanomagenesis.Mutations in BRAF codon 600, NRAS1 codons 12/13, NRAS2 codons 60/61 and KRAS codons 12/13 were ascertained in 18 cases of primary cutaneous malignant melanoma contiguous with banal melanocytic aggregates using laser capture microdissection.Overall, 12 of 18 cases (67%) exhibited a mutation in at least one gene. BRAF V600E appeared to be the most commonly mutated gene in both the melanocytic aggregate (seven of 18, 39%) and the melanoma (four of 18, 22%). Both populations demonstrated a similar BRAF genomic profile in 11 of 18 cases (61%) (two BRAF V600E, nine BRAF-WT), a similar KRAS genomic profile in 14 of 18 cases (78%) (one KRAS G12V, 13 KRAS-WT) and a similar NRAS2 genomic profile in 14 of 18 cases (all WT). Of interest, we noted a relatively high prevalence of KRAS mutations (five of 18, 28%). The frequency of KRAS mutations in the melanocytic aggregate (five of 18, 28%) was second to BRAF V600E, while in melanoma, the frequency was also second to BRAF V600E but equalled that of NRAS2 (1 of 18, 6%). No NRAS1 mutations were observed. BRAF and RAS mutations appeared to be mutually exclusive with only three of 18 cases (17%) demonstrating a mutation in both genes (melanocytic aggregate only).Our findings hint towards the interpretation of banal melanocytic aggregates serving as precursor lesions.
THE BACTERIOLOGY OF BOVINE ABORTION, WITH SPECIAL REFERENCE TO ACQUIRED IMMUNITY
Authors: Theobald Smith
Journal: The Journal of Experimental Medicine (1919)

In a large herd of dairy cattle and young stock the bacteriological examination of 109 cases of abortion which included a relatively thorough study of the fetus and a study of the membranes, or swabs from the uterus whenever obtainable, gave the following results. 62, or 57 per cent, were associated with Bacillus abortus. 26, or 23.8 per cent, were associated with spirilla. 2, or 1.8 per cent, were associated with Bacillus pyogenes. 19, or 17.4 per cent, were either sterile or else the digestive and respiratory tracts had been invaded during or after birth with miscellaneous bacteria. Bacillus abortus was absent according to cultures and animal tests. Such a relatively large proportion of cases of abortion without Bacillus abortus as the inciting agent is noteworthy. In general Bacillus abortus was associated with first pregnancies. Its presence diminished rapidly in frequency in later pregnancies. Assuming in a general way that purchased cows coming from small herds were free from any immunity and that their first pregnancy in the new herd is equivalent to that of a native heifer and may be counted as the first, we have Bacillus abortus associated with the first pregnancy in 42, with the second in 14, with the third in 5, and with the fourth in 1. Spirilla were distributed as follows: (a) in purchased cows, first pregnancy, 6; second pregnancy, 9; third pregnancy, 5; and fourth pregnancy, 3; (b) in native cows, first pregnancy, 0; third pregnancy, 1; sixth pregnancy, 1; and eighth pregnancy) 1. The relation of infection with spirilla to acquired immunity is not clear and more data from large herds are needed to define both etiological and immunological bearings of the spirilla. Thus far spirilla have not been encountered in native heifers of the herd giving birth the first time. A tentative explanation to be offered is that the young stock is kept segregated from the older and purchased cows until shortly before calving. The occasional discharge of a fetus among the young stock in pasture tends to keep up the disease due to Bacillus abortus. Later on association with older cows brings about infection with spirilla (Vibrio fetus) and more rarely with other possible agencies of fetal disease. On the other hand, abortions may occur among the pastured stock from time to time and remain unrecognized. Not until both groups of animals are subjected to the same daily scrutiny will it be possible to affirm that abortion associated with spirilla does or does not occur among young stock.
Hypothermia Therapy after Traumatic Brain Injury in Children
Authors: James S. Hutchison, Roxanne E. Ward, Jacques Lacroix, Paul C. Hébert, Marcia A. Barnes, Desmond J. Bohn, Peter B. Dirks, Steve Doucette, Dean Fergusson, Ronald Gottesman, Ari R. Joffe, Haresh M. Kirpalani, Philippe G. Meyer, Kevin P. Morris, David Moher, Ram N. Singh, Peter W. Skippen
Journal: New England Journal of Medicine (2008)

Hypothermia therapy improves survival and the neurologic outcome in animal models of traumatic brain injury. However, the effect of hypothermia therapy on the neurologic outcome and mortality among children who have severe traumatic brain injury is unknown.In a multicenter, international trial, we randomly assigned children with severe traumatic brain injury to either hypothermia therapy (32.5 degrees C for 24 hours) initiated within 8 hours after injury or to normothermia (37.0 degrees C). The primary outcome was the proportion of children who had an unfavorable outcome (i.e., severe disability, persistent vegetative state, or death), as assessed on the basis of the Pediatric Cerebral Performance Category score at 6 months.A total of 225 children were randomly assigned to the hypothermia group or the normothermia group; the mean temperatures achieved in the two groups were 33.1+/-1.2 degrees C and 36.9+/-0.5 degrees C, respectively. At 6 months, 31% of the patients in the hypothermia group, as compared with 22% of the patients in the normothermia group, had an unfavorable outcome (relative risk, 1.41; 95% confidence interval [CI], 0.89 to 2.22; P=0.14). There were 23 deaths (21%) in the hypothermia group and 14 deaths (12%) in the normothermia group (relative risk, 1.40; 95% CI, 0.90 to 2.27; P=0.06). There was more hypotension (P=0.047) and more vasoactive agents were administered (P<0.001) in the hypothermia group during the rewarming period than in the normothermia group. Lengths of stay in the intensive care unit and in the hospital and other adverse events were similar in the two groups.In children with severe traumatic brain injury, hypothermia therapy that is initiated within 8 hours after injury and continued for 24 hours does not improve the neurologic outcome and may increase mortality. (Current Controlled Trials number, ISRCTN77393684 [controlled-trials.com].).
Serglycin Is a Theranostic Target in Nasopharyngeal Carcinoma that Promotes Metastasis
Authors: Xin-Jian Li, Choon Kiat Ong, Yun Cao, Yan-Qun Xiang, Jian-Yong Shao, Aikseng Ooi, Li-Xia Peng, Wen-Hua Lu, Zhongfa Zhang, David Petillo, Li Qin, Ying-Na Bao, Fang-Jing Zheng, Claramae Shulyn Chia, N. Gopalakrishna Iyer, Tie-Bang Kang, Yi-Xin Zeng, Khee Chee Soo, Jeffrey M. Trent, Bin Tean Teh, Chao-Nan Qian
Journal: Cancer Research (2011)

Nasopharyngeal carcinoma (NPC) is known for its high-metastatic potential. Here we report the identification of the proteoglycan serglycin as a functionally significant regulator of metastasis in this setting. Comparative genomic expression profiling of NPC cell line clones with high- and low-metastatic potential revealed the serglycin gene (SRGN) as one of the most upregulated genes in highly metastatic cells. RNAi-mediated inhibition of serglycin expression blocked serglycin secretion and the invasive motility of highly metastatic cells, reducing metastatic capacity in vivo. Conversely, serglycin overexpression in poorly metastatic cells increased their motile behavior and metastatic capacity in vivo. Growth rate was not influenced by serglycin in either highly or poorly metastatic cells. Secreted but not bacterial recombinant serglycin promoted motile behavior, suggesting a critical role for glycosylation in serglycin activity. Serglycin inhibition was associated with reduced expression of vimentin but not other epithelial-mesenchymal transition proteins. In clinical specimens, serglycin expression was elevated significantly in liver metastases from NPC relative to primary NPC tumors. We evaluated the prognostic value of serglycin by immunohistochemical staining of tissue microarrays from 263 NPC patients followed by multivariate analyses. High serglycin expression in primary NPC was found to be an unfavorable independent indicator of distant metastasis-free and disease-free survival. Our findings establish that glycosylated serglycin regulates NPC metastasis via autocrine and paracrine routes, and that it serves as an independent prognostic indicator of metastasis-free survival and disease-free survival in NPC patients.
Renal Tubular Acidosis in Infants: the Several Kinds, Including Bicarbonate-Wasting, Classic Renal Tubular Acidosis
Authors: Elisabeth McSherry, Anthony Sebastian, R. Curtis Morris
Journal: Journal of Clinical Investigation (1972)

In four infants with renal tubular acidosis (RTA), including three with apparently classic RTA and one with Fanconi syndrome (FS), the physiologic character of the renal acidification defect was investigated. In two of the infants with apparently classic RTA, the acidification defect was physiologically separable from that described in both adult patients and children with classic RTA (type 1 RTA) in the following ways. (a) The fractional excretion of filtered bicarbonate (C(HCO3)/C(ln)) was not trivial but substantial (6-9%), as well as relatively fixed, over a broad range of plasma bicarbonate concentrations (15-26 mmoles/liter). (b) This value of C(HCO3)/C(ln), combined with a normal or near normal glomerular filtration rate, translated to renal bicarbonate wasting (RBW). (c) RBW at normal plasma bicarbonate concentrations was the major cause of acidosis, and its magnitude was the major determinant of corrective alkali therapy (5-9 mEq/kg per day), just as in the patient with FS, who was found to have type 2 ("proximal") RTA. (d) Persistence of RBW at substantially reduced plasma bicarbonate concentrations, which did not occur in FS, accounted for the spontaneous occurrence of severe acidosis and its rapid recurrence after reduction in alkali therapy. (e) During severe acidosis the urinary pH was >7, a finding reported frequently in infants with apparently classic RTA and "alkali-resistant" acidosis but rarely in adult patients with classic RTA. Continued supplements of potassium were required to maintain normokalemia during sustained correction of acidosis with alkali therapy. Yet, in at least two of the three infants with apparently classic RTA, but in distinction from the patient with FS and other patients with type 2 RTA, fractional excretion of filtered potassium decreased when plasma bicarbonate was experimentally increased to normal values. In one of the two infants with apparently classic RTA and RBW, C(HCO3)/C(ln) and the therapeutic alkali requirement decreased concomitantly and progressively over 2 yr, but RBW continued. Renal tubular acidosis has persisted in all four patients for at least 3 yr, and in three for 4 years.
A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation
Authors: Elisabetta Valoti, Marta Alberti, Agustin Tortajada, Jesus Garcia-Fernandez, Sara Gastoldi, Luca Besso, Elena Bresin, Giuseppe Remuzzi, Santiago Rodriguez de Cordoba, Marina Noris
Journal: Journal of the American Society of Nephrology (2014)

Genomic aberrations affecting the genes encoding factor H (FH) and the five FH-related proteins (FHRs) have been described in patients with atypical hemolytic uremic syndrome (aHUS), a rare condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ARF. These genomic rearrangements occur through nonallelic homologous recombinations caused by the presence of repeated homologous sequences in CFH and CFHR1-R5 genes. In this study, we found heterozygous genomic rearrangements among CFH and CFHR genes in 4.5% of patients with aHUS. CFH/CFHR rearrangements were associated with poor clinical prognosis and high risk of post-transplant recurrence. Five patients carried known CFH/CFHR1 genes, but we found a duplication leading to a novel CFHR1/CFH hybrid gene in a family with two affected subjects. The resulting fusion protein contains the first four short consensus repeats of FHR1 and the terminal short consensus repeat 20 of FH. In an FH-dependent hemolysis assay, we showed that the hybrid protein causes sheep erythrocyte lysis. Functional analysis of the FHR1 fraction purified from serum of heterozygous carriers of the CFHR1/CFH hybrid gene indicated that the FHR1/FH hybrid protein acts as a competitive antagonist of FH. Furthermore, sera from carriers of the hybrid CFHR1/CFH gene induced more C5b-9 deposition on endothelial cells than control serum. These results suggest that this novel genomic hybrid mediates disease pathogenesis through dysregulation of complement at the endothelial cell surface. We recommend that genetic screening of aHUS includes analysis of CFH and CFHR rearrangements, particularly before a kidney transplant.
Low number of examined lymph nodes in node-negative breast cancer patients is an adverse prognostic factor
Authors: I. Blancas, J.L. García-Puche, B. Bermejo, E.O. Hanrahan, C. Monteagudo, A. Martínez-Agulló, R. Rouzier, B.T. Hennessy, V. Valero, A. Lluch
Journal: Annals of Oncology (2006)