tbuckley/cabot-search huggingface dataset:
Cutaneous Drug Reactions
Authors: C K Svensson, E W Cowen, A A Gaspari
Journal: Pharmacological Reviews (2001)

Cutaneous drug reactions are the most frequently occurring adverse reactions to drugs. Among hospitalized patients, the incidence of these reactions ranges from 1 to 3%. The frequency of cutaneous reactions to specific drugs may exceed 10%. These reactions may range from mildly discomforting to those that are life-threatening. Anti-infective and anticonvulsant agents are among the drugs most commonly associated with adverse reactions in the skin. We describe and illustrate the clinical morphology of the most common cutaneous drug reactions, as well as drugs that most commonly precipitate specific reactions. The varied nature of the reactions that do occur, even with specific agents, indicates a multiplicity of mechanisms available whereby cutaneous drug reactions may be initiated. Although a variety of terms have been proposed for categorizing cutaneous drug reactions, we propose that reactions are best defined based upon mechanisms, where known. In this review, we assess the current knowledge of four categories of cutaneous drug reactions: immediate-type immune-mediated reactions, delayed-type immune-mediated reactions, photosensitivity reactions, and autoimmune syndromes. Moreover, we describe evidence that viral infection is an important predisposing factor for the development of cutaneous drug reactions upon drug administration. Finally, we review the current knowledge of the type and mechanisms of cutaneous drug reactions to several categories of drugs.
AGXT Gene Mutations and Their Influence on Clinical Heterogeneity of Type 1 Primary Hyperoxaluria
Authors: ANTONIO AMOROSO, DOROTI PIRULLI, FIORELLA FLORIAN, DANIELA PUZZER, MICHELE BONIOTTO, SERGIO CROVELLA, SILVIA ZEZLINA, ANDREA SPANÒ, GINA MAZZOLA, SILVANA SAVOLDI, CRISTINA FERRETTINI, SILVIA BERUTTI, MICHELE PETRARULO, MARTINO MARANGELLA
Journal: Journal of the American Society of Nephrology (2001)

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder that is caused by a deficiency of alanine: glyoxylate aminotransferase (AGT), which is encoded by a single copy gene (AGXT). Molecular diagnosis was used in conjunction with clinical, biochemical, and enzymological data to evaluate genotype-phenotype correlation. Twenty-three unrelated, Italian PH1 patients were studied, 20 of which were grouped according to severe form of PH1 (group A), adult form (group B), and mild to moderate decrease in renal function (group C). All 23 patients were analyzed by using the single-strand conformation polymorphism technique followed by the sequencing of the 11 AGXT exons. Relevant chemistries, including plasma, urine and dialyzate oxalate and glycolate assays, liver AGT activity, and pyridoxine responsiveness, were performed. Both mutant alleles were found in 21 out of 23 patients, and 13 different mutations were recognized in exons 1, 2, 4, and 10. Normalized AGT activity was lower in the severe form than in the adult form (P < 0.05). Double heterozygous patients presented a lower age at the onset of the disease (P = 0.025), and they were more frequent in group A (75%) than in the group B (14%; P = 0.0406). The T444C mutation was more frequent in the severe form (P < 0.05), and the opposite was observed for G630A (P < 0.05). G630A mutation homozygotes had a higher AGT residual activity (P = 0.00001). This study confirms the allelic heterogeneity of the AGXT, which could to some extent be responsible for the phenotypic heterogeneity in PH1.
Mapping of Familial Thoracic Aortic Aneurysm/Dissection With Patent Ductus Arteriosus to 16p12.2–p13.13
Authors: Philippe Khau Van Kien, Flavie Mathieu, Limin Zhu, Alain Lalande, Christine Betard, Mark Lathrop, François Brunotte, Jean-Eric Wolf, Xavier Jeunemaitre
Journal: Circulation (2005)

Background— Three loci have been shown to be responsible for nonsyndromic familial thoracic aortic aneurysms (TAAs) and aortic dissections (ADs). We recently described a large family in which TAA/AD associates with patent ductus arteriosus (PDA) and provided genetic arguments for a unique pathophysiological entity. Methods and Results— Genome-wide scan was performed in 40 subjects belonging to 3 generations in this large pedigree. Using the 7 TAA/AD cases as affected, we observed positive 2-point LOD scores on adjacent markers at chromosome 16p, with a maximum LOD score value of 2.73 at θ=0, a value that increased to 3.56 when 5 PDA cases were included. Multipoint linkage analysis yielded a maximum LOD score of 4.14 in the vicinity of marker D16S3103 . Fine mapping allowed the observation of recombinant haplotypes that delimited a critical 20-cM interval at 16p12.2-p13.13. Automatic determination of aortic compliance with cine MRI showed that all subjects bearing the disease haplotype, even asymptomatic, displayed a very low level of aortic compliance and distensibility. Aortic stiffness was strongly associated with disease haplotype with a marked effect of age, indicating subclinical and early manifestation of the disease. Conclusions— Genetic analysis of this family identified a unique locus responsible for both TAA/AD and PDA at chromosome 16p12.2-p13.13 with aortic stiffness as an early hallmark of the disease. TAA/AD with PDA is a new monogenic entity among the genetically heterogeneous group of TAA/AD disease.
Inhibition of the CXCR3-mediated pathway suppresses ultraviolet B-induced pigmentation and erythema in skin
Authors: R. Kurata, F. Fujita, K. Oonishi, K-I. Kuriyama, S. Kawamata
Journal: British Journal of Dermatology (2010)

Skin pigmentation by ultraviolet (UV) B radiation is caused in part by inflammation mediated by chemokines and cytokines secreted by keratinocytes in the irradiated area. However, such inflammatory processes have not been well documented.To elucidate the inflammation processes caused by UVB irradiation using skin-lightening agents that suppress melanin synthesis after UVB irradiation.Utilizing a three-dimensional (3D) skin model, agents that suppressed formation of sunburn cells (SBC) after UVB irradiation were screened. Molecules whose expression was upregulated by UVB irradiation and attenuated by pretreatment with the agent were then screened by gene microarray to explore the mechanism of UVB irradiation. Messenger RNA expression of the molecules identified to be responsible for melanin biosynthesis was knocked down with a Tet-off shRNA lentivirus construct to confirm the involvement of the molecule in the pigmentation pathway following UVB irradiation.Paeonia suffruticosa Andrews (PSA) pretreatment suppressed SBC formation in the 3D skin model, and erythema formation and pigmentation in volunteers exposed to UVB irradiation. Comprehensive gene analysis after UVB irradiation showed upregulation of CXCR3 and its ligands, CXCL9/monokine induced by interferon (IFN)-γ (MIG), CXCL10/10-kDa IFN-γ-induced protein (IP-10) and CXCL11/inducible T-cell α-chemoattractant (I-TAC). Upregulation of these genes was partially suppressed by PSA pretreatment. Melanin biosynthesis increased upon stimulation of CXCR3 ligands (MIG, IP-10 or I-TAC) and decreased following CXCR3 downregulation by shRNA knockdown.UVB irradiation activates CXCR3-mediated signalling that leads to melanin synthesis. PSA pretreatment shows a lightening effect partly by attenuating CXCR3-mediated signalling at the transcriptional level.
CELLULAR RECEPTORS
Authors: Hansruedy Ramseier, Jean Lindenmann
Journal: The Journal of Experimental Medicine (1971)

The possibility that a rat alloantiserum DA anti-Lewis possesses similar recognition structures for Lewis transplantation antigens, as do DA immunocompetent cells, was investigated by raising an antiserum against this alloantiserum in (Lewis x DA)F(1) hosts. This antiserum, as well as one provoked by injecting DA lymphoid cells, was active against recognition structures for Lewis antigens of DA immunocompetent cells. The anti-(DA anti-Lewis) antiserum displayed the same degree of specificity as was found previously for anti-recognition structure sera prepared by injecting parental strain lymphoid cells into F(1) hosts. Since the activities of antisera raised against cell-bound receptors or against the antigen-binding region of an immunoglobulin were indistinguishable, it was concluded that the functional part of cell-associated receptors might be structurally similar to the variable portion of an immunoglobulin.
B-cell activation by lipopolysaccharide. Distinct pathways for induction of mitosis and antibody production.
Authors: M K Hoffmann, C Galanos, S Koenig, H F Oettgen
Journal: The Journal of Experimental Medicine (1977)

The role played by macrophages in two effects of lipopolysaccharide (LPS) on the immune system of the mouse-substitution for helper T cells and induction of B-cell mitosis-has been investigated. C3H/HeJ mice are unresponsive and do not produce (as other strains do) antibody to 2,4,6-trinitrophenol (TNP) conjugated with autologous mouse erythrocytes (MRBC-TNP) in the presence of LPS. We found that C3H/HeJ spleen cells produce antibody to MRBC-TNP when (a) LPS and macrophages from LPS-responsive C3HeB/FeJ mice or (b) tumor necrosis serum ([TNS] induced by LPS in responsive mice) are added. The mitotic response was not restored. The findings suggest that adjuvanticity and mitogenicity represent distinct pathways of B-cell activation by LPS, subject to different regulatory mechanisms.
Mechanochemical Stimulation of MCF7 Cells with Rod‐Shaped Fe–Au Janus Particles Induces Cell Death Through Paradoxical Hyperactivation of ERK
Authors: Devrim Kilinc, Anna Lesniak, Suad A. Rashdan, Dhruv Gandhi, Agata Blasiak, Paul C. Fannin, Alex von Kriegsheim, Walter Kolch, Gil U. Lee
Journal: Advanced Healthcare Materials (2014)

Multifunctional nanoparticles that actively target‐specific tissues are studied for cancer diagnosis and treatment. Magnetically and optically active particles are of particular interest because they enable multiple imaging modalities and physically modulated therapies, such as magnetic hyperthermia. Fe–Au nanorods are synthesized that have a long iron segment, coated with polyethylene glycol, and a short gold tip functionalized with heregulin (HRG), a known ligand of ErbB family of receptors. HRG–nanorods preferentially target MCF7 cells relative to MDA‐MB‐231 cells, as demonstrated in a novel microfluidics device. Targeting rates of these classical breast cancer cells correlate with their differential expression of ErbB2/3 receptors. HRG–nanorod binding stimulates the extracellular signal‐regulated kinase 1/2 (ERK) phosphorylation in MCF7 cells. The increase in ERK phosphorylation is linked to “active zones,” dynamic regions in the cell periphery, which exhibit higher rates of particle binding than the rest of the cell. Periodically stretching cells using magnetic tweezers further activates ERK, which leads to cell death in cells co‐treated with B‐Raf inhibitors, through ERK hyperactivation. Although to a lesser extent, cell death is also achieved through magnetic hyperthermia. These results demonstrate nanoscale targeting and localized mechanochemical treatment of specific cancer cell lines based on their receptor expression using multifunctional nanoparticles.
Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Cancer
Authors: Shalini Jain, Xiao Wang, Chia-Chi Chang, Catherine Ibarra-Drendall, Hai Wang, Qingling Zhang, Samuel W. Brady, Ping Li, Hong Zhao, Jessica Dobbs, Matt Kyrish, Tomasz S. Tkaczyk, Adrian Ambrose, Christopher Sistrunk, Banu K. Arun, Rebecca Richards-Kortum, Wei Jia, Victoria L. Seewaldt, Dihua Yu
Journal: Cancer Research (2015)

Preventing breast cancer will require the development of targeted strategies that can effectively block disease progression. Tamoxifen and aromatase inhibitors are effective in addressing estrogen receptor-positive (ER(+)) breast cancer development, but estrogen receptor-negative (ER(-)) breast cancer remains an unmet challenge due to gaps in pathobiologic understanding. In this study, we used reverse-phase protein array to identify activation of Src kinase as an early signaling alteration in premalignant breast lesions of women who did not respond to tamoxifen, a widely used ER antagonist for hormonal therapy of breast cancer. Src kinase blockade with the small-molecule inhibitor saracatinib prevented the disorganized three-dimensional growth of ER(-) mammary epithelial cells in vitro and delayed the development of premalignant lesions and tumors in vivo in mouse models developing HER2(+) and ER(-) mammary tumors, extending tumor-free and overall survival. Mechanistic investigations revealed that Src blockade reduced glucose metabolism as a result of an inhibition in ERK1/2-MNK1-eIF4E-mediated cap-dependent translation of c-Myc and transcription of the glucose transporter GLUT1, thereby limiting energy available for cell growth. Taken together, our results provide a sound rationale to target Src pathways in premalignant breast lesions to limit the development of breast cancers.
Specific Cardiomyopathy Caused by Multisystemic Lipid Storage in Jordan’s Anomaly
Authors: Yuichi Oshima, Hisao Hirota, Hiroyuki Nagai, Masahiro Izumi, Yoshikazu Nakaoka, Tomoaki Osugi, Yasushi Fujio, Hitone Tateyama, Masanori Kikui, Keiko Yamauchi-Takihara, Ichiro Kawase
Journal: Circulation (2002)
Central Obesity Is an Independent Risk Factor for Albuminuria in Nondiabetic South Asian Subjects
Authors: Prataap K. Chandie Shaw, Stefan P. Berger, Marko Mallat, Marijke Frölich, Friedo W. Dekker, Ton J. Rabelink
Journal: Diabetes Care (2007)

OBJECTIVE— South Asians have a high prevalence of central obesity. When the diagnosis of diabetes is made, they have a very high risk of developing renal failure. In the current study, we explored the hypothesis that central obesity is associated with the development of renal injury, before the manifestation of diabetes. RESEARCH DESIGN AND METHODS— We invited first-degree nondiabetic relatives of South Asian type 2 diabetic patients for investigation of microalbuminuria and diabetes. Subjects who used antihypertensive or antidiabetic medication were excluded. We performed a glucose tolerance test according to the classic World Health Organization criteria. A total of 205 subjects were normoglycemic; we excluded 25 subjects because of impaired glucose tolerance, and 30 subjects were excluded because of de novo diabetes. Central obesity was measured by waist-to-hip ratio (WHR). Albuminuria was measured as albumin-to-creatinine ratio (ACR) in the early-morning urine. RESULTS— Central obesity was independently related with albuminuria in the 205 normoglycemic subjects. We found no relation of fasting blood glucose or systolic blood pressure with albuminuria. Multivariate analysis for the presence of increased albuminuria (median ACR &amp;gt;0.31 mg/mmol) showed a relative risk of 4.1 for the highest versus the lowest tertile of WHR (P = 0.002). CONCLUSIONS— Central obesity is an early and independent risk factor for increased albuminuria in normoglycemic South Asian subjects. This could explain the high incidence of diabetic renal disease in South Asians, probably by the mechanism of insulin resistance and endothelial dysfunction in the pre-diabetic state.
(24) Lymphomatoid papulosis and poikiloderma
Authors: S.B. Bittiner, R.E. Church
Journal: British Journal of Dermatology (1986)

Journal Article (24) Lymphomatoid papulosis and poikiloderma Get access S.B. Bittiner, Drs, S.B. Bittiner, Drs Search for other works by this author on: Oxford Academic Google Scholar R.E. Church R.E. Church Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 115, Issue s30, 1 July 1986, Pages 68–69, https://doi.org/10.1111/j.1365-2133.1986.tb07719.x Published: 01 July 1986
Erythrocyte stages of Plasmodium falciparum exhibit a high nitric oxide synthase (NOS) activity and release an NOS-inducing soluble factor.
Authors: D Ghigo, R Todde, H Ginsburg, C Costamagna, P Gautret, F Bussolino, D Ulliers, G Giribaldi, E Deharo, G Gabrielli, G Pescarmona, A Bosia
Journal: The Journal of Experimental Medicine (1995)

Nitric oxide (NO), a highly diffusible cellular mediator involved in a wide range of biological effects, has been indicated as one of the cytotoxic agents released by leukocytes to counteract malaria infection. On the other hand, NO has been implicated as a mediator of the neuropathological symptoms of cerebral malaria. In such circumstances NO production has been thought to be induced in host tissues by host-derived cytokines. Here we provide evidence for the first time that human red blood cells infected by Plasmodium falciparum (IRBC) synthesize NO. The synthesis of NO (measured as citrulline and nitrate production) appeared to be very high in comparison with human endothelial cells; no citrulline and nitrate production was detectable in noninfected red blood cells. The NO synthase (NOS) activity was very high in the lysate of IRBC (while not measurable in that of normal red blood cells) and was inhibited in a dose-dependent way by three different NOS inhibitors (L-canavanine, NG-amino-L-arginine, and NG-nitro-L-arginine). NOS activity in P. falciparum IRBC is Ca++ independent, and the enzyme shows an apparent molecular mass &amp;lt; 100 kD, suggesting that the parasite expresses an isoform different from those found in mammalian cells. IRBC release a soluble factor able to induce NOS in human endothelial cells. Such NOS-inducing activity is not tissue specific, is time and dose dependent, requires de novo protein synthesis, and is probably associated with a thermolabile protein having a molecular mass &amp;gt; 100 kD. Our data suggest that an increased NO synthesis in P. falciparum malaria can be directly elicited by soluble factor(s) by the blood stages of the parasite, without necessarily requiring the intervention of host cytokines.
Altered Gq/G11 guanine nucleotide regulatory protein expression in a rat model of hepatocellular carcinoma: Role in mitogenesis
Authors: Iain H. McKillop, Max C. Schmidt, Paul A. Cahill, James V. Sitzmann
Journal: Hepatology (1999)

Guanine nucleotide regulatory proteins (G–proteins) represent an important transmembrane pathway whereby extra–cellular signals are transduced to intracellular signaling pathways. The mitogen–activated protein kinase (MAPK) cascade has been identified as a key factor in transducing numerous mitogenic stimuli. MAPK activity is regulated via numerous receptor types, including those linked to Gq/G11–proteins, which regulate phospholipase–C activity. We hypothesized that alterations in a Gq/G11–PLC pathway may contribute to the enhanced cellular mitogenesis characteristic of hepatocellular carcinoma (HCC), possibly via a MAPK–dependent pathway. By using an in vivo model of HCC we investigated changes in Gq/G11–protein expression in tumorigenic tissue versus adjacent, non–neoplastic liver. In addition we addressed the role of Gq/G11–proteins in the regulation of MAPK–linked mitogenesis by using rat hepatic tumorigenic cells (H4IIE) and isolated hepatocytes in culture. Western blot analysis showed significant increases in Gqα and G11α expression in tumorigenic liver versus normal liver specimens, an effect that was augmented in cultured H4IIE cells versus isolated cultured hepatocytes. Furthermore, phosphoinositol specific phospholipase–C (PLC) activity was significantly increased in HCC versus normal liver. A specific PLC inhibitor (Et–18–OCH 3 ) caused a dose–dependent decrease in serum stimulated DNA synthesis in both cultured H4IIE cells and isolated rat hepatocytes, the H4IIE cell line showing greater sensitivity to Et–18–OCH 3 . In addition, serum–stimulated MAPK activity was significantly enhanced in H4IIE versus cultured hepatocytes. Moreover, treatment with Et–18–OCH 3 significantly attenuated serum stimulated MAPK activity in both cultured hepatocytes and H4IIE cells. Furthermore, U73122 (Gqα–PLC specific uncoupler) and GP2A (Gqα specific inhibitor) mirrored the effects of those observed for Et–18–OCH 3 whereas PD98059 (specific MEK inhibitor) completely abolished serum–stimulated DNA synthesis in tumorigenic H4IIE cells. We conclude that HCC is associated with enhanced Gq/G11–PLC expression/activity as compared with normal liver. Furthermore, a PLC–linked MAPK cascade plays a significant role in the progression of the enhanced mitogenesis characteristic of HCC.
Apoptosis is a major mode of cell death caused by ischaemia and ischaemia/reperfusion injury to the rat intestinal epithelium
Authors: H Ikeda, Y Suzuki, M Suzuki, M Koike, J Tamura, J Tong, M Nomura, G Itoh
Journal: Gut (1998)

<i>Background and aims</i>—Injuries caused by ischaemia and ischaemia/reperfusion in the small intestine have been widely accepted as resulting in necrosis. The aim of this study was to ascertain whether apoptosis also occurs. <i>Methods</i>—Intestinal epithelium from rats subjected to ischaemia (15–90 minutes) and ischaemia/reperfusion (15 minutes ischaemia followed by 15–75 minutes of reperfusion) was studied using histological, immunohistochemical, and molecular biological methods as well as FACS. <i>Results</i>—Mucosal injury was induced by both ischaemia and ischaemia/reperfusion. Detachment of epithelial cells from the villous stroma was an early morphological change indicating mucosal injury. More than 80% of the detached cells exhibited characteristic morphological features of apoptosis (condensation of chromatin and nuclear fragmentation). The remainder demonstrated necrotic features. The apoptotic cells eventually underwent spontaneous degeneration with membrane rupture, a process morphologically identical to necrosis. DNA fragmentation was also confirmed by immunohistochemical methods and agarose gel electrophoresis. <i>Conclusion</i>—Apoptosis is a major mode of cell death in the destruction of rat small intestinal epithelial cells induced by ischaemia and ischaemia/reperfusion injury. Disruption of epithelial cell-matrix interactions (“anoikis”) may play an important part in induction of apoptosis in detached enterocytes.
Hepatic cytoprotection by prostaglandins: Theories unlimited
Authors: Robert A. Levine
Journal: Hepatology (1988)

16,16 Dimethyl prostaglandin E 2 (dmPGE 2 ), a known cytoprotective agent, was examined for its ability to alter the course of fulminant hepatitis in an experimental model of fulminant viral hepatitis, murine hepatitis virus type 3 (MHV-3). Fully susceptible BALB/cJ mice, infected with 100 50% lethal doses (LD 50 ) of MHV-3 developed histologic and biochemical evidence of fulminant hepatitis, as evidenced by massive hepatic necrosis with hypoglycemia, metabolic acidosis, and a markedly elevated serum alanine aminotransferase (ALT) (mean, 1,402 ± 619 IU/liter). In contrast, animals treated with dmPGE 2 either before or after infection (up to 48 h) demonstrated a marked reduction in both histologic and biochemical evidence of liver damage as characterized by normal blood glucose, total CO 2 , and ALT determinations (mean ALT, 63 ± 40 IU/liter). Treatment of infected mice with PGF 2 demonstrated no cytoprotective effects. High titers of infectious virus were recovered from the livers of both dmPGE 2 -treated and -untreated animals throughout the course of infection. In a parallel in vitro study, dmPGE 2 (10 −4 -10 −8 M) demonstrated a similar cytoprotective effect on monolayers of isolated cultured hepatocytes from fully susceptible BALB/cJ mice infected at a multiplicity of infection of 0.1, 1.0, and 10.0. In addition, splenic macrophages recovered from infected and untreated BALB/cJ mice demonstrated a marked augmentation in procoagulant activity (PCA) from a basal 10 ± 5 mU/10 6 splenic macrophages to a maximum of 615 ± 102 mU/10 6 splenic macrophages, whereas no increase in macrophage PCA was detected in infected animals treated with dmPGE 2 . These results suggest that dmPGE 2 , without detectably altering viral replication or infectivity in vivo , confers a marked cytoprotective effect on hepatocytes both in vivo and in vitro , and prevents the induction of macrophage PCA in vivo in fully susceptible BALB/cJ mice after murine hepatitis virus type 3 infection.