tbuckley/cabot-search huggingface dataset:
Profile of the Immune and Inflammatory Response in Individuals With Prediabetes and Type 2 Diabetes
Authors: Vera Grossmann, Volker H. Schmitt, Tanja Zeller, Marina Panova-Noeva, Andreas Schulz, Dagmar Laubert-Reh, Claus Juenger, Renate B. Schnabel, Tobias G.J. Abt, Rafael Laskowski, Jörg Wiltink, Eberhard Schulz, Stefan Blankenberg, Karl J. Lackner, Thomas Münzel, Philipp S. Wild
Journal: Diabetes Care (2015)

The inflammatory and immune systems are altered in type 2 diabetes. Here, the aim was to profile the immune and inflammatory response in subjects with prediabetes and diabetes in a large population-representative sample.In total, 15,010 individuals were analyzed from the population-based Gutenberg Health Study. Glucose status was classified according to HbA1c concentration and history of diagnosis. All samples were analyzed for white blood cells (WBCs), granulocytes, lymphocytes, monocytes, platelets, C-reactive protein (CRP), albumin, fibrinogen, and hematocrit. Interleukin-18 (IL-18), IL-1 receptor antagonist (IL-1RA), and neopterin concentrations were determined in a subcohort.In total, 7,584 men and 7,426 women were analyzed (range 35-74 years), with 1,425 and 1,299 having prediabetes and diabetes, respectively. Biomarkers showed varying dynamics from normoglycemic via subjects with prediabetes to subjects with diabetes: 1) gradual increase (WBCs, granulocytes, monocytes, IL-1RA, IL-18, and fibrinogen), 2) increase with subclinical disease only (lymphocytes and CRP), 3) increase from prediabetes to diabetes only (neopterin), and 4) no variation with glucose status (hematocrit). The strongest relative differences were found for CRP, IL-1RA, and fibrinogen concentrations. Several inflammatory and immune markers were associated with the glucose status independent from cardiovascular risk factors and comorbidities, varied with disease severity and the presence of disease-specific complications in the diabetes subcohort.The inflammatory and immune biomarker profile varies with the development and progression of type 2 diabetes. Markers of inflammation and immunity enable differentiation between the early preclinical and clinical phases of the disease, disease complications, and progression.
The Spread of Obesity in a Large Social Network over 32 Years
Authors: Nicholas A. Christakis, James H. Fowler
Journal: New England Journal of Medicine (2007)

The prevalence of obesity has increased substantially over the past 30 years. We performed a quantitative analysis of the nature and extent of the person-to-person spread of obesity as a possible factor contributing to the obesity epidemic.We evaluated a densely interconnected social network of 12,067 people assessed repeatedly from 1971 to 2003 as part of the Framingham Heart Study. The body-mass index was available for all subjects. We used longitudinal statistical models to examine whether weight gain in one person was associated with weight gain in his or her friends, siblings, spouse, and neighbors.Discernible clusters of obese persons (body-mass index [the weight in kilograms divided by the square of the height in meters], > or =30) were present in the network at all time points, and the clusters extended to three degrees of separation. These clusters did not appear to be solely attributable to the selective formation of social ties among obese persons. A person's chances of becoming obese increased by 57% (95% confidence interval [CI], 6 to 123) if he or she had a friend who became obese in a given interval. Among pairs of adult siblings, if one sibling became obese, the chance that the other would become obese increased by 40% (95% CI, 21 to 60). If one spouse became obese, the likelihood that the other spouse would become obese increased by 37% (95% CI, 7 to 73). These effects were not seen among neighbors in the immediate geographic location. Persons of the same sex had relatively greater influence on each other than those of the opposite sex. The spread of smoking cessation did not account for the spread of obesity in the network.Network phenomena appear to be relevant to the biologic and behavioral trait of obesity, and obesity appears to spread through social ties. These findings have implications for clinical and public health interventions.
Evolution of<i>CONSTANS</i>Regulation and Function after Gene Duplication Produced a Photoperiodic Flowering Switch in the Brassicaceae
Authors: Samson Simon, Mark Rühl, Amaury de Montaigu, Stefan Wötzel, George Coupland
Journal: Molecular Biology and Evolution (2015)

Environmental control of flowering allows plant reproduction to occur under optimal conditions and facilitates adaptation to different locations. At high latitude, flowering of many plants is controlled by seasonal changes in day length. The photoperiodic flowering pathway confers this response in the Brassicaceae, which colonized temperate latitudes after divergence from the Cleomaceae, their subtropical sister family. The CONSTANS (CO) transcription factor of Arabidopsis thaliana, a member of the Brassicaceae, is central to the photoperiodic flowering response and shows characteristic patterns of transcription required for day-length sensing. CO is believed to be widely conserved among flowering plants; however, we show that it arose after gene duplication at the root of the Brassicaceae followed by divergence of transcriptional regulation and protein function. CO has two close homologs, CONSTANS-LIKE1 (COL1) and COL2, which are related to CO by tandem duplication and whole-genome duplication, respectively. The single CO homolog present in the Cleomaceae shows transcriptional and functional features similar to those of COL1 and COL2, suggesting that these were ancestral. We detect cis-regulatory and codon changes characteristic of CO and use transgenic assays to demonstrate their significance in the day-length-dependent activation of the CO target gene FLOWERING LOCUS T. Thus, the function of CO as a potent photoperiodic flowering switch evolved in the Brassicaceae after gene duplication. The origin of CO may have contributed to the range expansion of the Brassicaceae and suggests that in other families CO genes involved in photoperiodic flowering arose by convergent evolution.
Stiff man syndrome presenting with low back pain
Authors: A Bastin
Journal: Annals of the Rheumatic Diseases (2002)

Stiff man syndrome (SMS) is a rare, disabling neurological disorder characterised by progressive muscle rigidity and painful episodic spasms of the axial and proximal limb muscles. Diagnosis is based on the recognition of typical clinical features and characteristic EMG findings.1 However, although it is well described, SMS is probably underdiagnosed because of a lack of awareness of its clinical manifestations. It may present to a range of specialties and should be considered in all patients with unexplained back pain, stiffness, and muscle spasms. We present a typical case of stiff man syndrome in a patient who was referred to our unit, having previously been seen by a number of doctors and a neurosurgeon, without a diagnosis.

A 42 year old man with a 28 year history of insulin dependent diabetes mellitus (IDDM) and a two year history …
HIV-1 Nef Induces Proliferation and Anchorage-Independent Growth in Podocytes
Authors: Mohammad Husain, G. Luca Gusella, Mary E. Klotman, Irwin H. Gelman, Michael D. Ross, Elissa J. Schwartz, Andrea Cara, Paul E. Klotman
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. HIV-associated nephropathy (HIVAN) is now the third leading cause of end-stage renal disease in the African American population. HIV-1 infects renal tubular and glomerular epithelial cells or podocytes, cells that are a critical part of the filtration barrier. HIV-1 infection induces the loss of podocyte differentiation markers and increases podocyte proliferation. It has been previously shown that HIV-infection induces loss of contact inhibition. Here, the HIV-1 gene responsible for proliferative changes is identified by using cultured podocytes in vitro. The HIV-1 proviral construct, pNL4-3 was rendered noninfectious by replacing the HIV-1 gag/pol sequences with an EGFP reporter gene (pNL4-3: ΔG/P-EGFP). This construct was then pseudotyped with VSV.G envelope to infect podocytes that were conditionally immortalized with SV-40 T antigen. In addition, mutated constructs were engineered with premature stop codons in the HIV-1 env, vif, vpr, vpu, nef, or rev genes. The parental construct and all the other mutated constructs, with the exception of nef, induced proliferation under nonpermissive conditions and anchorage-independent growth (colony formation in soft agar) under permissive conditions. In contrast, deletion of nef markedly reduced proliferation and colony formation. Although tat alone, or tat plus rev induced marginal levels of anchorage-independent growth, coexpression with nef significantly increased colony formation. Finally, stable expression of Nef in a retroviral vector, pBabe-puro, was sufficient to induce increased proliferation and colony formation. Moreover, nef induced saturation density and loss of contact inhibition. These data indicate that Nef induces multiple proliferative effects in podocytes in culture and that nef may therefore be an important gene in the pathogenesis of HIVAN in vivo.
LSC 2014 abstract - Deciphering of the mechanism of the anti-asthmatic action of the CXCL12 neutraligand, chalcone 4
Authors: Francois Daubeuf, Dominique Bonnet, Virgile Beckaert, Ali Ouadi, Patrice Marchand, David Brasse, Patrick Gizzi, Marcel Hibert, Jean-Luc Galzi, Nelly Frossard
Journal: European Respiratory Journal (2014)

The chemokine receptor CXCR4 and its chemokine CXCL12 are involved in the recruitment of immune and inflammatory cells as successfully demonstrated in the airways using agents that block either CXCL12 or CXCR4 ( Hachet-Haas et al JBC 2008 ). We here highlight the unique relationship between pharmacokinetics and anti-asthmatic activity of chalcone 4, a CXCL12 neutraligand. Balb/c mice were sensitized (OVA+alum) and challenged (OVA or solvent, i.n., D17-20). Chalc4 or vehicle were administered i.n. 2h before each challenge. Chalc4 reduces airway hyperresponsiveness measured by whole body plethysmography (45±7%) and Flexivent® (37±5%), as well as eosinophilia (54±2%), IL5 (75±6% ) and mucus (84±2%) in BAL and lung collagen (78±8%). IgE in plasma and IL4 in BALF are not changed, indicating a downstream effect on sensitization. In addition, chalc4 reduces recruitment of M1 macrophages (62±4%), and their production of TNFα in response to CXCL12 (98±4%). In parallel, chalc4 significantly reduces the levels of CXCL12 in the lung (20%). SPECT imaging performed with  123 I-chalc4 and the pharmacokinetics (UHPLC-MS/MS) show that chalc4 rapidly leaves the lung (
Lipid droplets in atherosclerotic fatty streaks of human aorta
Authors: P. Dieter Lang, William Insull
Journal: Journal of Clinical Investigation (1970)

Preparations of lipid droplets and droplet-free tissue residue (cytoplasm + membranes + nuclei) were obtained by homogenization and centrifugal separation from intimal fatty streak lesions of aortic atherosclerosis of 21 adults who had died suddenly. Neutral lipids and phospholipids were analyzed by quantitative thin-layer chromatography and cholesteryl ester fatty acids by gas-liquid chromatography. Optical properties of droplets were evaluated by differential counting and sizing procedures with the polarizing microscope. The droplets occurred in mixtures of two forms distinguished by their optical properties, anisotropic (i.e. liquid crystals) and isotropic (true liquids). Both forms had average diameters of about 1.8 mu, with a range of 0.5-5mu. The proportions of the two forms varied with temperature as individual droplets changed their form; anisotropic forms averaged 83.7% at degrees C and 37.8% at 37 degrees C, with isotropic forms being 16.3 and 62.2% respectively. The proportions of anisotropic forms at 22 degrees C decreased with age. These forms were not separated for chemical analysis. The droplets contained about half the lipid in the lesions. The composition of the lipids of the droplet mixture was remarkably uniform and strikingly different from that of the droplet-free residue, respectively: cholesteryl esters 94.9% vs. 38.7%, free cholesterol 1.7% vs. 18.6%, total phospholipids 1.0% vs. 38.6%, and triglycerides 2.4% vs. 4.0%. The proportions of individual phospholipids, with the exception of lysolecithin, were also different between the preparations. In the droplets only the proportions of lecithin correlated positively with the proportion of anisotropic forms (at 22 degrees C). Droplet cholesteryl esters were particularly rich in oleic acid and when compared to residue esters had more palmitoleic (+0.7%), oleic (+12.3%), and eicosatrienoic (+2.4%) and less palmitic (-2.2%), linoleic (-12.4%), and arachidonic (-1.6%) acids. The proportions of most individual fatty acids of droplets and residue correlated positively. The lipids of the residue closely resemble those reported for the normal intima.The observations that these droplets are prominent in the morphology of the fatty streak lesions, and that their high content of oleate-rich cholesteryl esters is similar to that reported for analysis of the whole lesions, suggest that the droplets may be involved in the pathogenesis of the fatty streak lesions of artherosclerosis in man.
Hsp90 prevents interaction between CHIP and HERG proteins to facilitate maturation of wild-type and mutant HERG proteins
Authors: Chisato Iwai, Peili Li, Yasutaka Kurata, Yoshiko Hoshikawa, Kumi Morikawa, Nani Maharani, Katsumi Higaki, Tetsuro Sasano, Tomomi Notsu, Yuko Ishido, Junichiro Miake, Yasutaka Yamamoto, Yasuaki Shirayoshi, Haruaki Ninomiya, Akira Nakai, Shigeo Murata, Akio Yoshida, Kazuhiro Yamamoto, Masayasu Hiraoka, Ichiro Hisatome
Journal: Cardiovascular Research (2013)

We examined the role of Hsp90 in expression and maturation of wild-type (WT) and mutant ether-a-go-go related gene (HERG) proteins by using Hsp90 inhibitors, geldanamycin (GA) and radicicol, and Hsp90 overexpression. The proteins were expressed in HEK293 cells or collected from HL-1 mouse cardiomyocytes, and analysed by western blotting, immunoprecipitation, immunofluorescence, and whole-cell patch-clamp techniques. GA and radicicol suppressed maturation of HERG-FLAG proteins and increased their immature forms. Co-expression of Hsp90 counteracted the effects of Hsp90 inhibitors and suppressed ubiquitination of HERG proteins. Overexpressed Hsp90 also inhibited the binding of endogenous C-terminus of Hsp70-interacting protein (CHIP) to HERG-FLAG proteins. Hsp90-induced increase of functional HERG proteins was verified by their increased expression on the cell surface and enhanced HERG channel currents. CHIP overexpression decreased both mature and immature forms of HERG-FLAG proteins in cells treated with GA. Hsp90 facilitated maturation of endogenous ERG proteins, whereas CHIP decreased both forms of ERG proteins in HL-1 cells. Mutant HERG proteins harbouring disease-causing missense mutations were mainly in the immature form and had a higher binding capacity to CHIP than the WT; Hsp90 overexpression suppressed this association. Overexpressed Hsp90 increased the mature form of HERG(1122fs/147) proteins, reduced its ubiquitinated form, increased its immunoreactivity in the endoplasmic reticulum and on the plasma membrane, and increased the mutant-mediated membrane current. CHIP overexpression decreased the immature form of HERG(1122fs/147) proteins. Enhancement of HERG protein expression through Hsp90 inhibition of CHIP binding might be a novel therapeutic strategy for long QT syndrome 2 caused by trafficking abnormalities of HERG proteins.
Ipilimumab administration for advanced melanoma in patients with pre-existing Hepatitis B or C infection: a multicenter, retrospective case series
Authors: Sowmya Ravi, Kristen Spencer, Mary Ruisi, Nageatte Ibrahim, Jason J Luke, John A Thompson, Keisuke Shirai, David Lawson, Heddy Bartell, Ragini Kudchadkar, Ngoc Thi Gunter, Janice M Mehnert, Evan J Lipson
Journal: Journal for ImmunoTherapy of Cancer (2014)

Ipilimumab is a fully human, monoclonal antibody directed against Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) that has demonstrated a survival benefit and durable disease control in patients with advanced melanoma. Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis. Because clinical trials of ipilimumab excluded patients with pre-existing hepatitis B or C infection, there is a paucity of data on the safety of ipilimumab administration to that patient population. Here, we report the largest case series to date of patients with hepatitis B or C who received ipilimumab for advanced melanoma. Two of the nine patients described in this case series experienced fluctuations in their liver function tests (LFTs) and were subsequently treated with corticosteroids. Although this is a small series, the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab, and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection. The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options.
Internet Marketing of Herbal Products
Authors: Charles A. Morris
Journal: JAMA (2003)

Passage of the Dietary Supplement Health and Education Act in 1994 restricted the Food and Drug Administration's control over dietary supplements, leading to enormous growth in their promotion. The Internet is often used by consumers as a source of information on such therapies.To assess the information presented and indications claimed on the Internet for the 8 best-selling herbal products.We searched the Internet using the 5 most commonly used search engines. For each, we entered the names of the 8 most widely used herbal supplements (ginkgo biloba, St John's wort, echinacea, ginseng, garlic, saw palmetto, kava kava, and valerian root). We analyzed the health content of all Web sites listed on the first page of the search results.We analyzed all accessible, English-language Web sites that pertained to oral herbal supplements. A total of 522 Web sites were identified; of these, 443 sites met inclusion criteria for the analysis.The nature of the Web site (retail or nonretail), whether it was a sponsored link, and all references, indications, claims, and disclaimers were recorded. Two reviewers independently categorized medical claims as disease or nondisease according to Food and Drug Administration criteria.Among 443 Web sites, 338 (76%) were retail sites either selling product or directly linked to a vendor. A total of 273 (81%) of the 338 retail Web sites made 1 or more health claims; of these, 149 (55%) claimed to treat, prevent, diagnose, or cure specific diseases. More than half (153/292; 52%) of sites with a health claim omitted the standard federal disclaimer. Nonretail sites were more likely than retail sites to include literature references, although only 52 (12%) of the 443 Web sites provided referenced information without a link to a distributor or vendor.Consumers may be misled by vendors' claims that herbal products can treat, prevent, diagnose, or cure specific diseases, despite regulations prohibiting such statements. Physicians should be aware of this widespread and easily accessible information. More effective regulation is required to put this class of therapeutics on the same evidence-based footing as other medicinal products.
Stroke risk factors in an incident population in urban and rural Tanzania: a prospective, community-based, case-control study
Authors: Richard W Walker, Ahmed Jusabani, Eric Aris, William K Gray, Nigel Unwin, Mark Swai, George Alberti, Ferdinand Mugusi
Journal: The Lancet Global Health (2013)

The burden of stroke on health systems in low-income and middle-income countries is increasing. However, high-quality data for modifiable stroke risk factors in sub-Saharan Africa are scarce, with no community based, case-control studies previously published. We aimed to identify risk factors for stroke in an incident population from rural and urban Tanzania.Stroke cases from urban Dar-es-Salaam and the rural Hai district were recruited in a wider study of stroke incidence between June 15, 2003, and June 15, 2006. We included cases with fi rst-ever and recurrent stroke. Community-acquired controls recruited from the background census populations of the two study regions were matched with cases for age and sex and were interviewed and assessed. Data relating to medical and social history were recorded and blood samples taken.We included 200 stroke cases (69 from Dar-es-Salaam and 131 from Hai) and 398 controls (138 from Dar-es-Salaam and 260 from Hai). Risk factors were similar at both sites, with previous cardiac event (odds ratio [OR] 7.39, 95% CI 2.42-22.53; p<0.0001), HIV infection (5.61, 2.41-13.09; p<0.0001), a high ratio of total cholesterol to HDL cholesterol (4.54, 2.49-8.28; p<0.0001), smoking (2.72, 1.49-4.96; p=0.001), and hypertension (2.14, 1.09-4.17; p=0.026) identified as significant independent risk factors for stroke. In Hai, additional risk factors of diabetes (4.04, 1.29-12.64) and low HDL cholesterol (9.84, 4.06-23.84) were also significant.We have identified many of the risk factors for stroke already reported for other world regions. HIV status was an independent risk factor for stroke within an antiretroviral-naive population. Clinicians should be aware of the increased risk of stroke in people with HIV, even in the absence of antiretroviral treatment.
Down regulation of multidrug resistance protein-1 expression in patients with early rheumatoid arthritis exposed to methotrexate as a first disease-modifying antirheumatic drug
Authors: S L Hider
Journal: Annals of the Rheumatic Diseases (2006)

Methotrexate (MTX) is the current gold standard conventional disease-modifying antirheumatic drug (DMARD) and is effluxed from cells by several transmembrane proteins, including multidrug resistance protein-1 (MRP1). It is hypothesised that the overexpression of these proteins may mediate reduced efficacy of MTX. To date, it is unclear how expression of these proteins changes over time or after exposure to drugs.To compare MRP1 expression in newly diagnosed patients with DMARD-naive rheumatoid arthritis with that in healthy controls and to investigate how MRP1 expression changed after exposure to MTX.18 newly diagnosed patients with DMARD-naive rheumatoid arthritis and 14 healthy controls were recruited. Peripheral blood mononuclear cell counts were taken at baseline and after 6 months' treatment with MTX. Cells were separated by density gradient centrifugation and MRP1 expression was measured using the QCRL-1 monoclonal antibody.MRP1 expression in patients did not seem to be up regulated compared with that in healthy controls. In patients who were positive for MRP1 at baseline (61%), treatment with MTX and folic acid led to a marked down regulation of MRP1 expression at 6 months.In patients with rheumatoid arthritis expressing MRP1, treatment with MTX and folic acid led to down regulation of MRP1 expression. Further studies are required to determine the mechanism behind this observation and whether MRP1 expression mediates altered efficacy to MTX.