Showing 1 – 20 of 72
Relevance | Newest | Oldest |
  • JAMA October 12, 2011

    Figure 3: Pathophysiology of Celiac Disease and Potential Nondietary Therapies Being Tested in Phase 1 or 2 Clinical Trials

    Gluten peptides are poorly digested by mammalian digestive enzymes and reach the small intestinal mucosa as large polypeptides. Gluten peptides are able to cross the mucosa into the subepithelium by transcellular and/or paracellular pathways. In the subepithelium, gluten peptides are deamidated by tissue transglutaminase (Figure 2) and trigger cytotoxicity leading to mucosal damage and humoral immunity leading to antibody production. Detailed understanding of the pathophysiology of celiac disease has allowed for creation of highly targeted potential nondietary therapies (blue boxes). These include (A) alteration of gluten-containing foods through the use of alternative or genetically modified wheat varieties or through specialized food processing techniques; (B) degradation of gluten proteins in the stomach and small intestinal lumen by selected proteases; (C) preventing gluten passage into the subepithelium of the small intestine through the use of tight junction agonists; and (D) reinduction of tolerance to gluten though immune desensitization.
  • JAMA August 8, 2007

    Figure 1: Model of Pathogenesis of Granulomatous Inflammation in Wegener Granulomatosis and Therapeutic Immune Response Targets

    Immune response therapies and targets are indicated in blue boldface text. aCsernok E, Ai M, Gross WL, et al. Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway. Blood. 2006;107(11):4440-4448. bVoswinkel J, Mueller A, Kraemer JA, et al. B lymphocyte maturation in Wegener's granulomatosis: a comparative analysis of VH genes from endonasal lesions. Ann Rheum Dis. 2006;65(7):859-864.
  • JAMA September 14, 2005

    Figure 3: Mechanisms of FGF-23 Excess in Renal Phosphate-Wasting Syndromes

    In tumor-induced osteomalacia, fibroblast growth factor 23 (FGF-23) and other phosphatonins ectopically produced by a mesenchymal tumor lead to excess circulating FGF-23 levels. In autosomal dominant hypophosphatemic rickets, FGF-23 excess results from mutations in the FGF-23 gene that render the protein resistant to cleavage and inactivation. In X-linked hypophosphatemia, the mechanism of FGF-23 excess is more speculative; mutations in the PHEX endopeptidase (presumably located on osteoblasts or osteocytes), are thought to either directly or indirectly result in FGF-23 excess by interfering with processing and inactivation of FGF-23.
  • JAMA February 16, 2005

    Figure 1: Blips and Drug Levels

    Plasma human immunodeficiency virus 1 (HIV-1) RNA levels, plasma concentrations of protease and nonnucleoside reverse transcriptase inhibitors, and suggested minimum target trough concentration (as provided by drug manufacturers), for each of the 10 patients. Data markers below the black dotted line indicate undetectable levels of plasma HIV-1 RNA (<50 copies/mL). Patients were sampled 36 times. For each sample, viral RNA was measured in 2 independent laboratories. For each time point, the higher value was plotted. A total of 720 viral load measurements were expected (36 time points × 2 independent measurements × 10 patients). Of these, 713 were collected (99.03%). Of planned assays for plasma drug concentration, 98.33% were completed. M8 is the measurable active metabolite of nelfinavir. EFV indicates efavirenz; LPV, lopinavir; NFV, nelfinavir; NVP, nevirapine; RTV, ritonavir; SQV, saquinavir.
  • JAMA February 16, 2005

    Figure 3: Phylogenetic Tree of Reverse Transcriptase Sequences for Patient 136 and Associated Genotypes

    All reverse transcriptase (RT) sequences from patient 136 clustered together, away from the reference sequence HXB2 and representative baseline sequences from other study patients (top). Plasma sequences are coded by visit number, with groups of 5 consecutive visits represented by a single symbol. The resting cell reservoir was sampled only at baseline. The RT region could not be amplified from the plasma of patient 140 (thus, there was no need to assess cellular reservoir virus for comparison purposes). Genetic distance from the most recent common ancestor (horizontal scale) is not greater for blip sequences. The table on the right provides the genotype for each branch of the tree (which represents all 9 study patients). Amino acid positions in RT are shown at the top of the table (protease trees are less informative because the gene is smaller and more conserved [thus, these trees are not provided herein]; however, the protease trees showed no evidence for evolution during blips and no new drug resistance mutations). The sequence of the reference isolate HXB2 is indicated under the amino acid numbers. Positions associated with resistance to the drugs the patient was taking (zidovudine, lamivudine, and efavirenz) are shown in color. Representative polymorphisms (amino acid substitutions not associated with drug resistance that distinguish this patient’s virus population from other isolates) are also shown. No resistance mutations were detected in this patient. The L→M and L→V substitutions at position 210 are not associated with significant resistance to zidovudine. There were no missing data for this analysis except as indicated above. AA indicates amino acid; AZT, zidovudine; EFV, efavirenz; HIV, human immunodeficiency virus; 3TC, lamivudine.
  • Old Drugs for a New Bug

    Abstract Full Text
    JAMA. 2003; 290(13):1695-1696. doi: 10.1001/jama.290.13.1695
  • JAMA April 3, 2002

    Figure: Mean Levels of IgA1 Protease Activity Detected in Symptomatic and Carriage Isolates of Nontypeable Haemophilus influenzae

    Comparison of the levels of IgA1 protease activity (relative IGAP activity) detected in symptomatic and carriage isolates of nontypeable Haemophilus influenzae assayed on either monoclonal IgA1 (left) or polyclonal secretory IgA (sIgA; right) substrates as described in the "Methods" section. The boxes represent interquartile range (25%-75%); the solid horizontal line within the boxes, median; dashed line within the boxes, mean; and error bars, 10% to 90%. The differences between the protease levels of the symptomatic vs the carriage isolates is significant at the P<.001 level. Symptomatic isolates are defined as those obtained from symptomatic patients; carriage isolates were from asymptomatic carriers. OD indicates optical density (of culture) at 550 nm.
  • JAMA April 3, 2002

    Figure: Researchers Explore New Anti-HIV Agents

    Current anti-HIV drugs inhibit reverse transcriptase (nucleoside reverse transcriptase inhibitors [NRTIs] and nonnucleoside reverse transcriptase inhibitors [NNRTIs]) or protease. Anti-HIV drugs under development (blue) include agents that interfere with other steps in the HIV life cycle (entry inhibitors and integrase inhibitors) and a second-generation NNRTI.
  • Nontypeable Haemophilus influenzae in Carriage and Disease: A Difference in IgA1 Protease Activity Levels

    Abstract Full Text
    free access
    JAMA. 2002; 287(13):1699-1705. doi: 10.1001/jama.287.13.1699
  • JAMA November 14, 2001

    Figure 3: Prominent Differentiating Features in the Domain Architectures of Representative Human Proteins

    A protein domain is a structural and functional unit that shows evolutionary conservation and, by convention, is represented as a distinct geometric shape. Thus, proteins are made up of 1 or more such building blocks or "domains" and, depending on the types and numbers of domains, proteins with different biological capabilities are created. Many of these domains have seemingly arbitrary nomenclature that, in many cases, reflects the experimental nuances of their initial description. A library of curated protein domains with their biological descriptions is available through the Pfam and SMART databases.A, The extensive domain shuffling seen in the plasma proteases of the coagulation and complement systems. The "ancient" trypsin family serine protease domain occurs in combination with a myriad of protein interaction domains. Most of these domains are evolutionarily ancient, that is, with the exception of the Gla domain (see below); they are also observed in the fly and the worm. These include: (1) AP: Apple, originally described in the coagulation factors, predicted to possess protein- and/or carbohydrate-binding functions; (2) Kr: Kringle, named after a Danish pastry, has an affinity for lysine-containing peptides; (3) E: epidermal growth factor (EGF)-like; (4) CUB: domain first described in complement proteins and a diverse group of developmental proteins; (5) CCP: complement control protein repeats, also known as "sushi" repeats, first recognized in the complement proteins; and (6) Gla: a hyaluron-binding domain, contains γ-carboxyglutamate residues, and is seen in proteins associated with the extracellular matrix. Of note is the observation that apolipoprotein (a) likely represents a primate-specific evolutionary event. There is a tremendous expansion of the Kringle domain (dashed segment represents a total of 29 copies of the Kringle domain) in a trypsin family serine protease.B, Examples of domain accretion in nuclear regulators in the human compared with the fly. Domain accretion refers to greater numbers of a specific domain in a multidomain protein or addition of new domains to a multidomain protein. These domains include: (1) BTB: broad-complex, tramtrack, and bric-a-brac (a name that reflects its early descriptions in Drosophila), a protein interaction domain; (2) Zf: C2H2 class of DNA-binding zinc finger; (3) KRAB: Kruppel-associated box, a vertebrate-specific nuclear protein interaction domain; (4) HD: histone deacetylase, an important class of chromatin-modifying enzymes; (5) U: ubiquitin finger, a domain that targets proteins for proteolytic degradation. There is a major expansion of the numbers of C2H2 zinc fingers in the BTB or KRAB transcription factor (dashed segment represents a total of 3 copies of the Zf domain) families in the human, a feature that may reflect increased ability to mediate regulatory interactions with DNA.
  • JAMA July 11, 2001

    Figure 3: HIV-1 Protease Sequences Amplified From Plasma

    For expansion of terms, see Figure 2 legend.
  • JAMA July 11, 2001

    Figure 5. Phylogenetic Clustering of pol Sequences From Low-Level Plasma Virus in a Patient Receiving HAART.

    Detailed analysis of sequences from patient A9. Sequences from the latent reservoir of patient A9 obtained at 6 separate time points commingled with one another and with current plasma sequences, consistent with an absence of time-dependent evolution. Four main groups of sequences can be discerned based on the presence of resistance mutations to zidovudine and ritonavir. One plasma clone (4.4) lacked any drug resistance mutations and showed a close phylogenetic relationship to a large group of previously isolated wild-type sequences present in the latent reservoir. Two other plasma clones (4.12 and 7.1) had a V82F substitution in protease and clustered with previously isolated latent reservoir sequences bearing the same mutation. Phenotypic analysis revealed only marginal resistance to ritonavir. A final plasma clone (1.1) had the characteristic V82A, I54V, V77I, and L63P mutations that confer high-level resistance to ritonavir. This clone clustered with a group of previously isolated latent reservoir sequences bearing the same mutations and having a high level of phenotypic resistance to ritonavir. The clone c22 7.1 (see Figure 4) was included for purposes of comparison. The scale indicates the expected number of substitutions per site.
  • JAMA July 11, 2001

    Figure 2: HIV-1 Reverse Transcriptase Sequences Amplified From Plasma

    HAART indicates highly active antiretroviral therapy; HIV-1, human immunodeficiency virus type 1; AZT, zidovudine; ddI, didanosine; 3TC, lamivudine; d4T, stavudine; ABC, abacavir; DLV, delavirdine; EFV, efavirenz; RTV, ritonavir; NFV, nelfinavir; SQV, saquinavir; and IDV, indinavir. For protease drug resistance color codes, see Figure 3. Accessory mutation refers to a genetic variant that alone does not confer high-level resistance but can occur in association with resistance mutations and may contribute to resistance or viral fitness. *Indicates insertion sequences.
  • JAMA September 22, 1999

    Figure 3: Longitudinal Determinations of Plasma HIV RNA, Plasma-Derived HIV-1 Genotypes, and Selected Phenotypes of Plasma-Derived Recombinant Viruses

    Data are from subject multidrug-resistant 1 with resistance to lamivudine at baseline who was treated with zidovudine-lamivudine-indinavir. Resistance of recombinant viruses to indinavir (circle), nelfinavir (square), and ritonavir (diamond) at days 0, 260, 400, and 730 of therapy are shown. HIV-1 indicates human immunodeficiency virus 1; RT, reverse transcriptase; PR, protease; and WT, wild type.
  • HIV-1 Drug Resistance in Newly Infected Individuals

    Abstract Full Text
    free access
    JAMA. 1999; 282(12):1135-1141. doi: 10.1001/jama.282.12.1135
  • JAMA June 24, 1998

    Figure: Antiretroviral Drug Resistance Testing in Adults With HIV Infection: Implications for Clinical Management

    Figure 2.—Schematic representation of a recombinant phenotypic assay. Total RNA is extracted from a small volume of plasma that generally contains at least 1000 copies/mL of human immunodeficiency virus (HIV) RNA. After complementary DNA (cDNA) synthesis using reverse transcriptase (RT) in vitro, the viral protease and reverse transcriptase genes are amplified by polymerase chain reaction (PCR). The resulting amplicons are either cloned or recombined into an HIV vector plasmid, from which the protease and/or RT gene have been deleted. Stocks of recombinant virus are assayed for drug susceptibility.
  • JAMA January 28, 1998

    Figure: To Die or Not to Die: An Overview of Apoptosis and Its Role in Disease

    Figure 2.—Apoptotic signaling pathways. Commitment to death: death ligand FasL binds to death receptor Fas to initiate intracellular signaling; the adaptor protein FADD (Fas-associated death domain protein) binds Fas and also binds to caspase-8 (also known as FLICE, a FADD-like interleukin 1β–converting enzyme). Execution: activation of caspase-8 leads to the activation of other caspases; caspases cleave each other's inactive procaspase precursors into active caspases, amplifying the death signal; active caspases mediate execution by cleaving polyadenosine diphosphate ribose polymerase, nuclear lamins, and other cellular proteins and by activating DNA fragmentation factor. Modulation of apoptotic signaling: in some cell types, cytochrome c is released from mitochondria, allowing activation of apoptotic protease activating factor-1 (Apaf-1), also leading to caspase activation;Bcl-2 family members may promote or suppress apoptosis by interacting with Apaf-1 and/or regulating mitochondrial permeability. Arrows do not necessarily imply direct interactions; homologous Caenorhabditis elegans gene products are shown in gray.
  • Society Proceedings

    Abstract Full Text
    JAMA. 1939; 112(4):362-362. doi: 10.1001/jama.1939.02800040080046
  • Studies on the "Mucous Barrier": Evaluation of Sialic Acid as a Protective Factor Against Degradation of Gastric Mucus by Pancreatic Endopeptidases

    Abstract Full Text
    JAMA. 1963; 184(7):221-221. doi: 10.1001/jama.1963.03700200157156
  • Sacubitril/Valsartan (Entresto) for Heart Failure

    Abstract Full Text
    JAMA. 2015; 314(7):722-723. doi: 10.1001/jama.2015.9398

    This Medical Letter on Drugs and Therapeutics article provides information about sacubitril/valsartan, a recently approved fixed-dose combination medication for patients with heart failure and reduced ejection fraction.