tbuckley/cabot-search huggingface dataset:
The Pros and Cons of Diagnosing Diabetes With A1C
Authors: Enzo Bonora, Jaakko Tuomilehto
Journal: Diabetes Care (2011)

An International Expert Committee was convened in 2008 by the American Diabetes Association (ADA), the European Association for the Study of Diabetes, and the International Diabetes Federation to consider the means for diagnosing diabetes in nonpregnant individuals, with particular focus on the possibility to indicate A1C as an alternative if not a better tool (1). After reviewing the available literature and a thorough discussion on the advantages and the limits of previous diagnostic strategies (essentially based on fasting glucose assessment) and the considered alternative approach (based on A1C measurement), a consensus was reached that the latter (i.e., A1C) should be included among diagnostic tools for diabetes and, with the exception of a number of clinical conditions, should even be preferred in diabetes diagnosis in nonpregnant adults.

The main conclusion of the International Expert Committee was implemented in the most recent clinical recommendations issued by the ADA. However, in these guidelines, A1C is indicated as a diagnostic tool alternative but not superior to blood glucose, leaving to the health care professional the decision about what test to use in an individual.

The World Health Organization is currently examining the proposal made by the International Expert Committee and is carefully addressing the controversial issues still remaining, most of which have been the subject of letters to the editor and articles recently published in the literature. Nevertheless, the use of A1C for diagnosing diabetes is rapidly becoming a reality in many Western countries.

In the text that follows, one of us (E.B.) will present the main points supporting A1C (pros) and the other (J.T.) will illustrate the main counterpoints challenging A1C (cons) as the primary tool for diabetes diagnosis. The text has been prepared in full coordination and the final conclusions represent the opinion of both authors. Tables 1 and 2 summarize the …
Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis
Authors: Elizabeth P. Sampaio, Amy P. Hsu, Joseph Pechacek, Hannelore I. Bax, Dalton L. Dias, Michelle L. Paulson, Prabha Chandrasekaran, Lindsey B. Rosen, Daniel S. Carvalho, Li Ding, Donald C. Vinh, Sarah K. Browne, Shrimati Datta, Joshua D. Milner, Douglas B. Kuhns, Debra A. Long Priel, Mohammed A. Sadat, Michael Shiloh, Brendan De Marco, Michael Alvares, Jason W. Gillman, Vivek Ramarathnam, Maite de la Morena, Liliana Bezrodnik, Ileana Moreira, Gulbu Uzel, Daniel Johnson, Christine Spalding, Christa S. Zerbe, Henry Wiley, David E. Greenberg, Susan E. Hoover, Sergio D. Rosenzweig, John N. Galgiani, Steven M. Holland
Journal: Journal of Allergy and Clinical Immunology (2013)
Re-treatment of Patients With Chronic Hepatitis C Who Do Not Respond to Peginterferon-α2b
Authors: Donald M. Jensen
Journal: Annals of Internal Medicine (2009)

Background: Many patients with chronic hepatitis C have not responded to therapy with pegylated interferon plus ribavirin. Objective: To evaluate use of peginterferon-α2a plus ribavirin to re-treat nonresponders to peginterferon-α2b plus ribavirin. Design: Randomized, parallel-group trial conducted between September 2003 and February 2007. Patients and researchers were not blinded to intervention assignment. Random assignment was centralized, computer-generated, and stratified by geographic region, hepatitis C virus (HCV) genotype, and histologic diagnosis. Setting: 106 international centers. Patients: 950 nonresponders to 12 or more weeks of therapy with peginterferon-α2b plus ribavirin. Intervention: Peginterferon-α2a, 360 µg/wk, for 12 weeks, then 180 µg/wk to complete 72 weeks (group A) or 48 weeks (group B), or peginterferon-α2a, 180 µg/wk for 72 weeks (group C) or 48 weeks (group D). All patients received ribavirin, 1000 or 1200 mg/d. Measurements: Sustained virologic response (SVR), defined as undetectable (<50 IU/mL) HCV RNA levels 24 weeks after the end of treatment. Results: The SVR rates in groups A (n = 317), B (n = 156), C (n = 156), and D (n = 313) were 16%, 7%, 14%, and 9%, respectively (relative risk [RR] for group A vs. group D [the primary comparison], 1.80 [95% CI, 1.17 to 2.77]; P = 0.006). Extended treatment duration increased SVR rates (16% for 72 weeks [groups A and C] vs. 8% for 48 weeks [groups B and D]; RR, 2.00 [CI, 1.32 to 3.02]; P < 0.001). Complete viral suppression (HCV RNA level <50 IU/mL)at week 12 was achieved in 21% of patients in groups A and B and 13% of those in groups C and D. Rates of SVR were 49% (77 of 157 patients) and 4% (32 of 719 patients) among those with and without complete viral suppression at week 12, respectively. Limitation: Nonresponders to peginterferon-α2a plus ribavirin were not evaluated. Conclusion: Re-treating nonresponders to therapy with peginterferon-α2b plus ribavirin for 72 weeks significantly increases SVR rates compared with re-treating them for 48 weeks. The overall SVR rate was low, but patients who are most likely to respond to re-treatment can be identified at week 12. Primary Funding Source: Roche.
Plitidepsin alone or with dacarbazine (DTIC) as first-line treatment for advanced unresectable melanoma (AUM)
Authors: R. Plummer, L. Hayward, P. Lorigan, V. Soriano, V. Moiseyenko, S. Szyldergemajn, R. Prados, J. Smyth, H. Calvert
Journal: Journal of Clinical Oncology (2009)

9059 Background: AUM remains incurable in most patients (pts). DTIC alone had a 8–15% response rate (RR), while plitidepsin (Aplidin [APL]) showed a 6% RR and a 14% stable disease (SD) in a Phase (Ph) II study in 35 relapsed/refractory pts after DTIC failure. Furthermore, APL + DTIC has additive activity in preclinical models. Methods: This multicenter Ph Ib study aim to determine the safe recommended dose (RD) of APL on days 1, 8 &amp; 15 + DTIC only day 1 q4wk. RD was defined as the highest dose with &gt;5 days G4 neutropenia or G4 thrombocytopenia (TC) and/or febrile neutropenia (FN); any drug-related ≥ G3 toxicity (except nausea/vomiting or hypersensitivity reaction) in cycle 1. Results: Of 28pts with AUM, 23 were evaluable for DLT; 57% were males, median (med) age was 48 y (20–77), med ECOG 0 (0–2) and med LDH was 226 IU/l (126–983). Most pts (96%) had metastasis with a median of 2 sites involved (1–5). Dose levels of APL + DICT (mg/m 2 ), were: DL1 (1.8 + 800), 7 pts; DL2 (2.4 + 800), 8 pts; DL 2b (2.4 + 1000), 5 pts; DL3 (3.0 + 800), 8 pts. Pts received 4 (2–6), 2 (2–5), 2 (1–2), 2 (1–8) median cycles respectively. The number of DLTs were 1/6, 1/7, 2/4, 2/6, respectively. DLTs were G3 ALT in 4 pts and FN + TC in 1 pt. The MTD was at DL 2B and the RD was at DL 2. There were 3 partial responses (PR, 14%) and 4 SD &gt; 3 months (19%); all PR at DL2/3. Five pts were not evaluable, 2 pts had G3 hypersensitivity reactions related to Cremophor oil (APL formulation) and 1 pt had a idiosyncratic reaction to DTIC with prolonged pancytopenia. One pt had a wrong diagnosis and 1 pt had early progressive disease (PD). Conclusions: APL + DTIC can be safely combined at ≥ 70% of their respective single- agent RD in AUM. Main DLTs were asymptomatic, transient and reversible ALT elevations. Ph Ib showed 14 % PR and 19% clinically meaningful SD. A randomised Ph II study of DTIC + APL vs APL alone is ongoing. [Table: see text]
Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system
Authors: Adrian Erlebacher, Dorothy Zhang, Albert F. Parlow, Laurie H. Glimcher
Journal: Journal of Clinical Investigation (2004)

We describe a murine model of early pregnancy failure induced by systemic activation of the CD40 immune costimulatory pathway. Although fetal loss involved an NK cell intermediate, it was not due to lymphocyte-mediated destruction of the fetus and placenta. Rather, pregnancy failure resulted from impaired progesterone synthesis by the corpus luteum of the ovary, an endocrine defect in turn associated with ovarian resistance to the gonadotropic effects of prolactin. Pregnancy failure also required the proinflammatory cytokine TNF-α and correlated with the luteal induction of the prolactin receptor signaling inhibitors suppressor of cytokine signaling 1 (Socs1) and Socs3. Such links between immune activation and reproductive endocrine dysfunction may be relevant to pregnancy loss and other clinical disorders of reproduction.
Blockade of endogenous interleukin 12 results in suppression of murine streptococcal cell wall arthritis by enhancement of interleukin 10 and interleukin 1Ra
Authors: L. A B Joosten
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVE</h3> The goal of this study was to investigate the role of endogenous interleukin 12 (IL12) in acute murine streptococcal cell wall (SCW) arthritis. <h3>METHODS</h3> C57black/6 mice were injected intraperitoneally with rat anti-murine IL12 (C17.8), shortly before induction of arthritis by intra-articular injection of 25 μg SCW fragments into the right knee joint. Joint swelling and chondrocyte synthetic function was analysed several days after induction of SCW arthritis. Local cytokine profile was determined, protein by using ELISA and mRNA by RT-PCR technology. To confirm the findings at later time points, tissue chamber model of inflammation was used. Histology was performed to examine cell influx and cartilage damage. <h3>RESULTS</h3> Suppression of joint swelling was noted at days 2 and 4, whereas no suppressive effect of anti-IL12 was found at day 1. Severe inhibition of chondrocyte proteoglycan synthesis was seen at day 1 in both arthritic control and anti-IL12 treated mice. However, chondrocyte function was restored at day 4 of arthritis in the anti-IL12 injected animals, but not in the arthritic controls. Moreover, cell influx in synovial tissue and joint cavity was reduced by anti-IL12 treatment. Neutralisation of IL12 reduced the local levels of IL1β, IL12 and interferon γ, when examined shortly after induction of SCW arthritis, whereas tumour necrosis factor α levels were not affected. In contrast, IL10 and IL1Ra protein and mRNA levels were strongly up regulated in synovial tissues after IL12 blockade. Enhancement of IL10 and IL1Ra by anti-IL12 was confirmed in a tissue chamber model with SCW induced inflammation. <h3>CONCLUSIONS</h3> This study indicates that IL12 is a pro-inflammatory cytokine during onset of acute SCW arthritis. Balances of proinflammatory and anti-inflammatory cytokines were strongly improved by anti-IL12 treatment.
Colony-Stimulating Factor-1 Antibody Reverses Chemoresistance in Human MCF-7 Breast Cancer Xenografts
Authors: Patrick Paulus, E. Richard Stanley, Romana Schäfer, Dietmar Abraham, Seyedhossein Aharinejad
Journal: Cancer Research (2006)

Overexpression of colony-stimulating factor-1 (CSF-1) and its receptor in breast cancer is correlated with poor prognosis. Based on the hypothesis that blockade of CSF-1 would be beneficial in breast cancer treatment, we developed a murinized, polyethylene glycol-linked antigen-binding fragment (Fab) against mouse (host) CSF-1 (anti-CSF-1 Fab). Mice bearing human, chemoresistant MCF-7 breast cancer xenografts were treated with combination chemotherapy (CMF: cyclophosphamide, methotrexate, 5-fluorouracil; cycled twice i.p.), anti-CSF-1 Fab (i.p., cycled every 3 days for 14 days), combined CMF and anti-CSF-1 Fab, or with Ringer's solution as a control. Anti-CSF-1 Fab alone suppressed tissue CSF-1 and retarded tumor growth by 40%. Importantly, in combination with CMF, anti-CSF-1 Fab reversed chemoresistance of MCF-7 xenografts, suppressing tumor development by 56%, down-regulating expression of the chemoresistance genes breast cancer-related protein, multidrug resistance gene 1, and glucosylceramide synthase, and prolonging survival significantly. Combined treatment also reduced angiogenesis and macrophage recruitment and down-regulated tumor matrix metalloproteinase-2 (MMP-2) and MMP-12 expression. These studies support the paradigm of CSF-1 blockade in the treatment of solid tumors and show that anti-CSF-1 antibodies are potential therapeutic agents for the treatment of mammary cancer.
Associations of CTX-II with biochemical markers of bone turnover raise questions about its tissue origin: new insights from CHECK
Authors: B de Klerk, F P J G Lafeber, W E van Spil
Journal: Annals of the Rheumatic Diseases (2014)

The urinary level of the carboxy-terminal telopeptide of collagen type II (uCTX-II) currently is one of the most frequently used biochemical markers for assessing collagenolysis in articular cartilage during osteoarthritis. However, we published data suggesting release of CTX-II epitope from bone in Cohort Hip and Cohort Knee (CHECK), a large cohort of subjects with very early stage knee and/or hip osteoarthritis. As was observed for markers of bone metabolism, uCTX-II showed an abrupt increase in women aged 48–53 years that appeared to be attributable to menopause.1 Moreover, earlier work had already shown that uCTX-II has specifically strong associations with marker of bone metabolism as compared …
Molecular Evolution of the Equilibrative Nucleoside Transporter Family: Identification of Novel Family Members in Prokaryotes and Eukaryotes
Authors: Yugo Acimovic, Imogen R. Coe
Journal: Molecular Biology and Evolution (2002)

Equilibrative nucleoside transporters (ENTs) are integral membrane proteins which enable the movement of hydrophilic nucleosides and nucleoside analogs down their concentration gradients across cell membranes. ENTs were only recently characterized at the molecular level, and little is known about the tertiary structure or distribution of these proteins in nonmammalian organisms. To identify conserved regions, residues, and motifs of ENTs that may indicate functionally important parts of the protein and to better understand the evolutionary history of this protein family, we conducted an exhaustive analysis to characterize and compare ENTs in taxonomically diverse organisms. We have identified novel ENT family members in humans, mice, fish, tunicates, slime molds, and bacteria. This greatly extends our knowledge on the distribution of the ENTs in eukaryotes, and we have identified, for the first time, family members in bacteria. The prokaryote ENTs are attractive models for future studies on transporter tertiary structure and mechanism of substrate translocation. Using sequence similarities, we have identified regions, residues, and motifs that are conserved across all family members. These areas are presumably correlated with function and therefore are important targets for future analysis. Finally, we propose an evolutionary history for the ENT family which clarifies the origin(s) of multiple isoforms in different taxa.
THE CHANGES OF VARIOUS CYTOKINES FROM PERIPHERAL BLOOD AND THEIR RELATIONSHIP WITH LEFT VENTRICULAR SYSTOLIC FUNCTION IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION WHO UNDERWENT SUCCESSFUL PERCUTANEOUS CORONARY INTERVENTION
Authors: Young Keun Ahn, Jin-Sook Kwon, Ae Shin Cho, Hyang Hee Cho, Jeong Sook Kim, Moon Hwa Hong, Wan Seok Kang, Myung Ho Jeong, Jong Chun Park, Jung Chaee Kang
Journal: Journal of the American College of Cardiology (2012)
Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells
Authors: María Salazar, Arkaitz Carracedo, Íñigo J. Salanueva, Sonia Hernández-Tiedra, Mar Lorente, Ainara Egia, Patricia Vázquez, Cristina Blázquez, Sofía Torres, Stephane García, Jonathan Nowak, Gian María Fimia, Mauro Piacentini, Francesco Cecconi, Pier Paolo Pandolfi, Luis González-Feria, Juan L. Iovanna, Manuel Guzmán, Patricia Boya, Guillermo Velasco
Journal: Journal of Clinical Investigation (2009)

Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that Δ9-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. Our data indicate that THC induced ceramide accumulation and eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3–dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo. These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.
Oligoclonal expansion of T lymphocytes with multiple second-site mutations leads to Omenn syndrome in a patient with RAG1-deficient severe combined immunodeficiency
Authors: Taizo Wada, Tomoko Toma, Hiroyuki Okamoto, Yoshihito Kasahara, Shoichi Koizumi, Kazunaga Agematsu, Hirokazu Kimura, Akira Shimada, Yasuhide Hayashi, Masahiko Kato, Akihiro Yachie
Journal: Blood (2005)
Enhancement of ileal adaptation by prednisolone after proximal small bowel resection in the rat.
Authors: J Scott, R M Batt, T J Peters
Journal: Gut (1979)

The effect of prednisolone on the adapted ileum of the rat after jejunal resection was examined. Three weeks after 50% proximal small bowel resection animals were fed pharmacological doses of soluble prednisolone (0.75 mg/kg/day) over a one week period, and killed at four weeks. Animals treated with prednisolone showed significant increases in brush border alpha-glucosidase, leucyl-2-napththylamidase and gamma-glutamyl transferase (P less than 0.01) per unit length of intestine compared with resection alone and transection reanastomosis control groups. This increase was the result of a significant enhancement (P less than 0.01) of brush border digestive enzyme activity per milligram of epithelial cell DNA-that is, per enterocyte-and was associated with a similar increase in enterocyte RNA content. In contrast, the activities of lysosomal and mitochondrial marker enzymes per milligran of DNA were similar in each group. Cell proliferation was not further stimulated by prednisolone. Thus prednisolone can selectively enhance brush border digestive capacity after intestinal resection without increasing cell proliferation. The increase in enterocyte RNA suggests that enzyme induction may be the mechanism of this effect.
Injuries about the shoulder in skiing and snowboarding
Authors: D McCall, M R Safran
Journal: British Journal of Sports Medicine (2009)

There has been a decrease in the overall injury rate, particularly the rate of lower-extremity injuries, for alpine skiing, with a resultant increase in the ratio of upper-extremity to lower-extremity injuries. The upper extremity is injured nearly twice as often during snowboarding than alpine skiing, with approximately half of all snowboarding injuries involving the upper extremity. Shoulder injuries are likely under-reported, as many patients seek evaluation for minor shoulder injuries with their local physicians, and not at the ski medical clinic, where most epidemiology studies obtain their data. Shoulder injuries account for 4 to 11% of all alpine skiing injuries and 22 to 41% of upper-extremity injuries. During snowboarding, shoulder injuries account for 8 to 16% of all injuries and 20 to 34% of upper-extremity injuries. Falls are the most common mechanism of shoulder injury, in addition to pole planting during skiing and aerial manoeuvres during snowboarding. Common shoulder injuries during skiing and snowboarding are rotator cuff strains, glenohumeral dislocations, acromioclavicular separations and clavicle fractures. It is still unclear, when comparing snowboarding and skiing injury data, which sport has the higher incidence of shoulder injuries. Stratifying shoulder injuries by type allows better delineation as to which sport has an increased incidence of certain injury patterns. The differing mechanisms of injury combined with distinct equipment for each sport plays a role in the type and frequency of shoulder injuries seen in these two subgroups. With the increased ratio of upper- to lower-extremity injuries during alpine skiing and the boom in popularity of snowboarding, shoulder injuries are seen with increasing frequency by those who care for alpine sport injuries. According to recent epidemiological data, only clavicle and humerus fractures have shown increased rates of incidence among alpine skiers. Over the past 30 years, there has been a general decrease in both upper- and lower-extremity injuries which can be attributed to improved designs of protective equipment, increased awareness of injury patterns and emphasis on prevention. In the future, physicians and therapists who treat this population must be comfortable and confident in their treatment algorithms to help keep skiers and snowboarders conditioned and ready for the slopes and develop strategies for the prevention of upper-extremity injuries associated with these activities.
c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Signaling Pathways Have Divergent Roles in CD8+ T Cell–mediated Antiviral Immunity
Authors: Nathalie Arbour, Denise Naniche, Dirk Homann, Roger J. Davis, Richard A. Flavell, Michael B.A. Oldstone
Journal: The Journal of Experimental Medicine (2002)

c-Jun NH2-terminal kinases (JNK) play important roles in T helper cell (Th) proliferation, differentiation, and maintenance of Th1/Th2 polarization. To determine whether JNKs are involved in antiviral T cell immunity, and whether JNK1 and JNK2 bear biological differences, we investigated the immune responses of JNK1-deficient and JNK2-deficient mice to lymphocytic choriomeningitis virus (LCMV). After LCMV infection, wild-type (JNK+/+) mice had a 5- to 10-fold increase in splenic CD8+ T cells. In contrast, infected JNK1−/− mice showed a significantly lower virus-specific CD8+ T cell expansion. However, JNK1−/− mice cleared LCMV infection with similar kinetics as JNK+/+ mice. Splenic T cells from LCMV-infected JNK1−/− animals produced interferon γ after stimulation with viral peptides. However, fewer JNK1−/− T cells acquired an activated phenotype (CD44hi) and more JNK1−/−CD8+CD44hi cells underwent apoptosis than JNK+/+ cells at the peak of the primary response. In contrast, LCMV-infected JNK2−/− mice generated more virus-specific CD8+ T cells than JNK+/+ mice. These results indicate that JNK1 and JNK2 signal pathways have distinct roles in T cell responses during a viral infection. JNK1 is involved in survival of activated T cells during immune responses, and JNK2 plays a role in control of CD8+ T cell expansion in vivo.