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Biomedical subjects

S Johnson

Publications and source records attributed to S Johnson.

At least 163 records · Page 9Linked to original sources
PubMed1999

Effect of gradual accumulation of iron, molybdenum and sulfur, slow depletion of zinc and copper, ethanol or fructose ingestion and phlebotomy in gout.

Gout affects mostly males over 40 years old and, occasionally, postmenopausal women. This pattern coincides with the pattern of iron accumulation. On the other hand, menstruating women are seldom afflicted by gout, because the monthly blood loss causes them to accumulate iron to a much lesser degree. Gout involves seven aspects: (1) uric acid overproduction from increased purines in the diet; (2) uric acid overproduction from ATP degradation; (3) uric acid overproduction from increased de novo synthesis of purines; (4) uric acid overproduction from increased DNA breakdown from cell damage; (5) decreased uric acid elimination, caused by molybdenum and sulfur binding to copper in the kidneys; (6) precipitation of sodium urate-iron crystals in the joints due to high ferritin and saturated transferrin and low CuZn-SOD and Cu-thionein in the joint; (7) development of inflammation, triggered by tyrosine bonding to the sodium-urate-iron crystals and being transformed by tyrosine kinase. Alcohol and iron greatly affect most of these aspects. Therefore, phlebotomy is suggested as therapy for gout patients, in order to eliminate the accumulated Fe. Furthermore, yearly blood donation is recommended for males with a family history of gout, so as to prevent Fe accumulation and avoid gout.

Copper↗
PubMed1999

A direct comparison of the activities of two humanized respiratory syncytial virus monoclonal antibodies: MEDI-493 and RSHZl9.

Two humanized monoclonal antibodies, MEDI-493 and RSHZ19, were developed independently as potential improvements over RSV-IGIV for prevention of respiratory syncytial virus (RSV) infection. RSV-IGIV is a polyclonal human antibody preparation for intravenous infusion enriched for RSV neutralizing activity. A phase III clinical trial showed that MEDI-493 significantly reduced hospitalizations due to RSV infection. In a separate trial, RSHZ19 failed to show significant efficacy. In new studies, the in vitro and in vivo activities of MEDI-493 and RSHZ19 were compared to determine whether the different clinical results are related to differences in biologic activity. MEDI-493 was consistently 4- to 5-fold more potent than RSHZ19 in antigen binding, RSV neutralization, and fusion inhibition assays. Although both MEDI-493 and RSHZ19 were effective against A and B subtypes of RSV in the cotton rat model of RSV infection, 2- to 4-fold higher doses of RSHZ19 were required for similar protection. The enhanced activity of MEDI-493 compared with RSHZ19 may, in part, explain its better clinical effect.

Animals↗
PubMed1999

Vinorelbine (Navelbine) in the treatment of non-small-cell lung cancer: studies with single-agent therapy and in combination with cisplatin.

Initial studies of vinorelbine (Navelbine) given as a single agent to patients with operable non-small-cell lung cancer (NSCLC) showed that overall response rates of the order of 30% could be obtained with a schedule of 30 mg/m2 given weekly. Although such high levels of response have seldom been obtained when vinorelbine is given alone in one arm of a comparative study, the level of activity is clearly worthwhile and represents a significant improvement over supportive care. Combination therapy with cisplatin has been highly successful, establishing Vinorelbine as a safe well-tolerated agent which provides considerable activity, and experience from large phase III studies suggests that the combination of vinorelbine and cisplatin could represent a reference schedule against which other therapy should be compared.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Vinorelbine (navelbine) in the treatment of non-small-cell lung cancer: recent developments in combination chemotherapy and radiotherapy.

The investigation of the activity of vinorelbine in non-small-cell lung cancer (NSCLC) has continued beyond the initial studies which established its single agent activity and defined the combination of vinorelbine and cisplatin as one of the standard treatments for inoperable NSCLC. Alternative partners to cisplatin have been evaluated in combination therapy with vinorelbine with promising results emerging from combinations with carboplatin, ifosfamide, mitomycin C and gemcitabine. Three drug combinations such as vinorelbine, cisplatin and ifosfamide can clearly produce high response rates in patients with good performance status at the time of treatment. The ability of vinorelbine to contribute to disease reduction either alone or in combination with other cytotoxic drugs has made it possible to consider its use in neo-adjuvant therapy, while the synergistic action of vinorelbine with radiotherapy has encouraged the use of sequential or concomitant chemoradiotherapy producing high response rates after completion of both modalities. The possible role of post-operative adjuvant treatment with Vinorelbine either alone or in combination with cisplatin is being assessed in a prospective trial.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Emergency department observation of poisoned patients: how long is necessary?

OBJECTIVE: To compare the emergency physician disposition decisions after observation periods of two, four, and six hours in a single cohort of ED patients with acute intentional ingestion to determine the accuracy of disposition decisions at two and four hours relative to the six-hour period of observation. METHODS: This was a prospective observational study at two university hospital EDs. Study participants were patients with potentially toxic oral ingestions occurring less than six hours prior to ED presentation. Patients with isolated recreational drug or ethanol use were excluded. Structured data forms were completed at presentation, and two, four, and six hours later. Data included signs and symptoms consistent with toxic ingestion, physical examination, laboratory determinations, medications ingested, treatment, and suicide risk. At two and four hours, physicians were asked to determine whether they thought the patient was safe for medical clearance. These patients continued to be observed for six hours. The main outcome was whether patients initially thought to be appropriate for early medical clearance were ultimately cleared at six hours. RESULTS: There were 260 patients enrolled: 28 were immediately admitted to the hospital and 17 were immediately discharged; 215 entered ED observation. Patients had a mean age of 24 years; 55% were female; 50% were suicidal; 17% had toxidromes. Of the 215 observed patients, 106 (49%) were deemed safe for early medical clearance at two hours. All 106 were ultimately cleared at six hours (100%, 95% CI = 97% to 100%). Of the 109 not safe for early medical clearance at two hours, 61 (56%) were deemed safe for early medical clearance at four hours; all 61 were subsequently discharged at six hours (100%; 95% CI = 95% to 100%). Overall, 167 of 215 (77%) observed overdose patients were deemed safe for early medical clearance after two or four hours of observation. All 167 were ultimately cleared at six hours (100%; 95% CI = 98.2% to 100%). CONCLUSIONS: A large subset of overdose patients who are medically cleared after six hours of observation can be identified within two to four hours of presentation. No patient who was believed to be safe for medical clearance at either two or four hours had a complication within the six-hour time period (95% CI = 0% to 1.8%). These data suggest that asymptomatic patients with selected acute intentional ingestions can be released from medical observation in less than six hours.

Adolescent↗
PubMed1999

Outcomes and costs of a community support worker service for the severely mentally ill.

There has recently been an expansion of paraprofessional staff involved in the provision of care for the severely mentally ill. In this paper we shall evaluate the effects of a community support worker (CSW) service in South London. A sample of patients with severe mental illness receiving the service was assessed over a 6-month period in order to examine the effects of continuing use of CSWs on outcomes, service use and costs. During the study period there were improvements in outcome reflecting service satisfaction, needs, quality of life and social behaviour. Whilst provision of the CSW service did not lead to extra total service costs, service use and cost data suggest that CSWs are associated with the substitution of in-patient use by community-based services.

Adult↗
PubMed1999

The abundance of cell cycle regulatory protein Cdc4p is controlled by interactions between its F box and Skp1p.

Posttranslational modification of a protein by ubiquitin usually results in rapid degradation of the ubiquitinated protein by the proteasome. The transfer of ubiquitin to substrate is a multistep process. Cdc4p is a component of a ubiquitin ligase that tethers the ubiquitin-conjugating enzyme Cdc34p to its substrates. Among the domains of Cdc4p that are crucial for function are the F-box, which links Cdc4p to Cdc53p through Skp1p, and the WD-40 repeats, which are required for binding the substrate for Cdc34p. In addition to Cdc4p, other F-box proteins, including Grr1p and Met30p, may similarly act together with Cdc53p and Skp1p to function as ubiquitin ligase complexes. Because the relative abundance of these complexes, known collectively as SCFs, is important for cell viability, we have sought evidence of mechanisms that modulate F-box protein regulation. Here we demonstrate that the abundance of Cdc4p is subject to control by a peptide segment that we term the R-motif (for "reduced abundance"). Furthermore, we show that binding of Skp1p to the F-box of Cdc4p inhibits R-motif-dependent degradation of Cdc4p. These results suggest a general model for control of SCF activities.

Binding Sites↗
PubMed1999

Autocrine production of matrix metalloproteinase-2 is required for human airway smooth muscle proliferation.

Airway smooth muscle proliferation is important in asthma and is dependent on pro- and antimitogenic factors and cell-matrix interactions. Here we show an antiproliferative effect of protease inhibitors on human airway smooth muscle due to inhibition of autocrine-derived matrix metalloproteinase (MMP)-2. Proliferation in response to fetal bovine serum, thrombin, and platelet-derived growth factor was inhibited by the broad-spectrum protease inhibitor Complete and the MMP inhibitors EDTA and Ro-31-9790 but not by cysteine or serine protease inhibitors. Conditioned medium from airway smooth muscle cells contained 72-kDa gelatinase that was secreted by growth-arrested cells and increased by fetal bovine serum but not by thrombin or platelet-derived growth factor. Immunostaining of cultured human airway smooth muscle cells and normal lung biopsies confirmed this gelatinase to be MMP-2. Our results suggest a novel role for MMP-2 as an important autocrine factor required for airway smooth muscle proliferation. Inhibition of MMPs could provide a target for the prevention of smooth muscle hyperplasia and airway remodeling in asthma.

Aprotinin↗
PubMed1999

Phase I trial of multiple cycles of high-dose chemotherapy supported by autologous peripheral-blood stem cells.

PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin and paclitaxel with hematopoietic peripheral-blood stem cell (PBSC) support. PATIENTS AND METHODS: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with cyclophosphamide, etoposide, and granulocyte-macrophage colony-stimulating factor (GM-CSF). After one cycle of conventional-dose carboplatin and cyclophosphamide with GM-CSF, patients received multiple cycles of high-dose carboplatin (area under the concentration-time curve [AUC], 12 to 20) and paclitaxel (250 mg/m(2)) with PBSC and GM-CSF repeated every 28 days. RESULTS: Twenty-four of 28 patients were assessable for toxicity and clinical outcome. Dose-limiting toxicities were dehydration, diarrhea, and electrolyte imbalances. The maximum-tolerated dose of carboplatin was AUC 16 (equivalent to a median of 1,189 mg/m(2)). The relationship of target AUC to measured AUC was linear (r(2) =. 29; P =.0011). The overall response rate was 96%, with a complete clinical response rate of 67%. The median time to progression from the first PBSC reinfusion was 49.5 weeks (range, 8 to 156+ weeks). CONCLUSION: Multiple cycles of high-dose carboplatin (AUC 16) and paclitaxel (250 mg/m(2)) can be safely administered with GM-CSF and PBSC support. Although this regimen is safe, feasible, and active, the use of multiple cycles of high-dose chemotherapy as front-line treatment remains experimental and should only be used in the context of a clinical trial.

Adult↗
PubMed1999

Globular domains of agrin are functional units that collaborate to induce acetylcholine receptor clustering.

Agrin, an extracellular matrix protein involved in neuromuscular junction formation, directs clustering of postsynaptic molecules, including acetylcholine receptors (AChRs). This activity resides entirely in the C-terminal portion of the protein, which consists of three laminin-like globular domains (G-domains: G1, G2 and G3) and four EGF-like repeats. Additionally, alternate mRNA splicing yields G-domain variants G2(0,4) with 0- or 4-amino-acid inserts, and G3(0, 8,11,19) with 0-, 8-, 11- or 19-amino-acid inserts. In order to better understand the contributions of individual domains and alternate splicing to agrin activity, single G-domains and covalently linked pairs of G-domains were expressed as soluble proteins and their AChR clustering activity measured on cultured C2 myotubes. These analyses reveal the following: (1) While only G3(8) exhibits detectable activity by itself, all G-domains studied (G1, G2(0), G2(4), G3(0) and G3(8)) enhance G3(8) activity when physically linked to G3(8). This effect is most pronounced when G2(4) is linked to G3(8) and is independent of the order of the G-domains. (2) The deletion of EGF-like repeats enhances activity. (3) Increasing the physical separation between linked G1 and G3(8) domains produces a significant increase in activity; similar alterations to linked G2 and G3(8) domains are without effect. (4) Clusters induced by two concatenated G3(8) domains are significantly smaller than all other agrin forms studied. These data suggest that agrin G-domains are the functional units which interact independently of their specific organization to yield AChR clustering. G-domain synergism resulting in biological output could be due to physical interactions between G-domains or, alternatively, independent interactions of G-domains with cell surface receptors which require spatially localized coactivation for optimal signal transduction.

Agrin↗
PubMed1999

Changes in the morphology and the distribution of rat intestinal eosinophils during infection with the nematode Nippostrongylus brasiliensis.

Increases in the numbers of eosinophil leukocytes present in the lamina propria of intestines infected with nematodes is a well described phenomenon, yet the role of these leukocytes and their actions in this situation are not yet fully understood. Morphologic changes in these cells occur with the course of the infection, as do alterations in their location within the gut; these findings may give important clues to the function of this prominent cell. We observed changes in intestinal eosinophils in the August rat during infection with the nematode Nippostrongylus brasiliensis and found, together with the well known increases in number infiltrating the lamina propria at Day 20 (three times the levels in normal animals), a distinct change in the morphology of individual cells which included increase of the cell's overall size and changes in shape, as well as a dissemination of cytoplasmic granules in relationship to the cell's nucleus. No ultrastructural evidence of extracellular degranulation or intact eosinophil cytoplasmic granules outside the bounds of cell cytoplasmic membranes was seen. This finding is important considering the light microscopic appearance of individual eosinophil granules apparently distributed extracellularly, and lying in the connective tissue of the lamina propria, a common histopathologic observation in eosinophilic conditions. Eosinophils within the lamina propria changed their location as the infection progressed, tending to move to line up along the subepithelial zones. In addition, eosinophils were observed both at the light and electron microscopic levels to be passing through the basement membrane and into the epithelial layer. This latter phenomenon was confirmed using confocal optical slicing where eosinophils were commonly observed on the luminal side of the nuclei of the gut epithelium. These observations strongly suggest that morphologic alterations occur in eosinophils in the lamina propria and these changes may be associated with functional alterations in these cells akin to the putative phenomenon of "activation." Our findings indicate that eosinophils have the capacity to enlarge and extend their cytoplasmic processes between various components of the lamina propria and move toward the basement membrane during an active infection, as well as into, and possibly through, the intestinal epithelium. These findings emphasize the need for careful consideration of the changing morphologic status of eosinophils when investigating biologic changes associated with the activation of these cells in tissue inflammatory responses.

Animals↗
PubMed1998

Evidence that C1q binds specifically to CH2-like immunoglobulin gamma motifs present in the autoantigen calreticulin and interferes with complement activation.

Calreticulin (CRT) is located predominantly in the endoplasmic reticulum (ER) of cells, where it functions as a quality control controller of protein folding. However, CRT is also a prevalent autoantigen in patients with systemic lupus erythematosus (SLE), where its release from the cell may arise as a results of dysfunctional apoptosis and inefficient removal of ER vesicles, which are an abundant source of CRT and other autoantigens. Indicative of this is the presence of autoantibodies against CRT in the sera of 40-60% of all SLE patients. Once released into the circulation, CRT might bind directly to C1q and we have suggested that this association may result in a defect in C1q-mediated clearance of antigen-antibody complexes. It has been previously shown that CRT under physiological salt conditions binds to the globular head of C1q. It is known that the globular head region of C1q binds to the CH2 domain in the Fc portion of immunoglobulin gamma (IgG). The N-terminal half of CRT contains a number of short regions of 7-10 amino acids that show sequence similarity to the putative C1q binding region in the CH2 domain of IgG. By use of a series of 92 overlapping CRT synthetic peptides, a number of C1q binding sites on the CRT molecule have been identified, including several containing a CH2-like motif similar to the ExKxKx C1q binding motif found in the CH2 domain of IgG. A number of these peptides were shown to inhibit binding of C1q to IgG and reduce binding of native CRT to C1q. Moreover, several of the peptides were capable of inhibiting the classical pathway of complement activation. These studies have identified specific binding sites on the CRT molecule for C1q and lend support to the hypothesis that interaction of CRT with C1q may interfere with the ability of C1q to associate with immune complexes in autoimmune-related disorders.

Amino Acid Sequence↗
PubMed1998

Acquisition of Clostridium difficile and Clostridium difficile-associated diarrhea in hospitalized patients receiving tube feeding.

BACKGROUND: Clostridium difficile is the most common infectious cause of nosocomial diarrhea, but its role in diarrhea associated with tube feeding has not been rigorously investigated. OBJECTIVE: To determine the incidence of C. difficile acquisition and C. difficile-associated diarrhea in tube-fed and non-tube-fed patients. DESIGN: Prospective cohort study. SETTING: A university-affiliated Veterans Affairs Medical Center. PATIENTS: 76 consecutive hospitalized, tube-fed patients and 76 hospitalized, non-tube-fed patients. The two cohorts were matched for age, unit location, duration of hospitalization before surveillance, and severity of illness. MEASUREMENTS: Incidence of C. difficile acquisition, incidence of C. difficile-associated diarrhea, and C. difficile restriction endonuclease analysis typing results. RESULTS: More tube-fed patients than non-tube-fed patients acquired C. difficile (15 of 76 patients [20%] compared with 6 of 76 patients [8%]; P=0.03) and developed C. difficile-associated diarrhea (7 of 76 patients [9%] compared with 1 of 76 patients [1%]; P=0.03). The mean proportion (+/-SD) of surveillance days with diarrhea was greater for tube-fed patients after the development of C. difficile-associated diarrhea than for tube-fed patients without this diarrhea (0.68+/-0.4 compared with 0.22+/-0.2 [95% CI for the mean difference, 0.08 to 0.84]). Postpyloric tube feeding (odds ratio, 3.14 [CI, 1.008 to 9.77]) and duration of surveillance (odds ratio, 1.08 [CI, 1.0009 to 1.16]) were risk factors for the acquisition of C. difficile. Nineteen restriction endonuclease analysis types of C. difficile were identified from 20 patients. CONCLUSIONS: Hospitalized, tube-fed patients, especially those receiving postpyloric tube feeding, are at greater risk for the acquisition of C. difficile and the development of C. difficile-associated diarrhea than are hospitalized, non-tube-fed patients. Clinicians should test for C. difficile in tube-fed patients with diarrhea.

Aged↗