Biomedical subjects

P Johnson

Publications and source records attributed to P Johnson.

At least 37 records · Page 2Linked to original sources

PubMed2003

Fatal chemotherapy-induced encephalopathy following high-dose therapy for metastatic breast cancer: a case report and review of the literature.

Chemotherapy-induced encephalopathies occur in a variety of clinical settings and the most detailed accounts have been described following combination methotrexate and radiation therapy. The case described herein developed severe encephalopathy following a high-dose chemotherapy protocol used in the treatment of metastatic carcinoma of the breast. Visual symptoms developed 3 weeks after completing high-dose chemotherapy and peripheral blood hematopoietic stem cell transplantation. Over the next several weeks, additional neurologic deficits developed and continued to progress despite various treatment interventions. Diffuse deep gray matter damage was identified on MR imaging and a brain biopsy revealed pathological findings similar in many respects to those described for methotrexate/radiation, cisplatin, BCNU and/or 5 FU/levamisole-related leukoencephalopathy. The patient succumbed to complications resulting from the CNS disorder, 8 weeks after the onset of symptoms. This case is unusual for two reasons. First, the patient developed severe encephalopathy following a high-dose chemotherapy protocol commonly used in the treatment of metastatic breast carcinoma and second, the encephalopathy involved primarily deep gray matter structures rather than white matter.

Adult↗

PubMed2003

To clip or not to clip? Noseclips for spirometry.

The use of noseclips for open-circuit spirometry is sporadic, despite guidelines encouraging their use. The authors aimed to evaluate whether noseclips significantly affected measurements of forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) in children attending a tertiary, paediatric respiratory centre. Children attending the asthma and cystic fibrosis (CF) clinics were asked to perform two sets of spirometry, one with and one without noseclips in random order, 20-min apart. Paired data was obtained on 62 patients (32 asthma, 30 CF) with a median age of 11.4 yrs (range 7.2-17.2 yrs). There were no systematic differences in FEV1 or FVC measured with and without noseclips, although seven children (11%) had clinically significant differences in FEV1 of >190 mL. There is no clear advantage to wearing noseclips when performing open-circuit spirometry. Individuals should be assessed to ascertain their optimal technique, which should then be used consistently in clinical practice. Noseclips should probably be retained for research protocols.

Adolescent↗

PubMed2002

Improving prostate cancer detection with an extended-core transrectal ultrasonography-guided prostate biopsy protocol.

OBJECTIVE: To investigate whether taking two transition zone (TZ) and four lateral peripheral zone (PZ) biopsies in addition to routine parasaggital sextant biopsies would improve detection rates in men with suspected prostate cancer. PATIENTS AND METHODS: The study included 493 consecutive men (mean age 68.7 years, sd 8.2) with elevated serum prostate-specific antigen (PSA) levels and/or abnormal findings on a digital rectal examination who underwent transrectal ultrasonography-guided prostate biopsy. In addition to sextant biopsies, six further biopsies were obtained, two from the TZ (mid-gland) and four from the lateral PZ (base and mid-gland). Pathological findings for the additional biopsies were compared with those of the sextant regions. RESULTS: Prostatic adenocarcinoma was diagnosed in 164 of the 493 (33%) men biopsied. Men with cancer were older, had smaller prostates and higher median PSA levels than men with negative biopsies. Sextant biopsies were positive for cancer in 133 of 164 (81%) men. All three sets of biopsies were positive in 53 (32%) cases. In 50 (30%) men both the sextant and lateral PZ biopsies were positive, while in six (4%) men, both sextant and TZ biopsies were positive. Thirty-one (19%) tumours were not detected by sextant biopsies, 10 (6%) where the lateral PZ biopsies alone were positive, 17 (10%) where the TZ biopsies alone were positive and four (3%) where both the TZ and lateral PZ together were positive. There were no differences in median PSA concentration, total prostate volume or TZ volume between men with an isolated TZ cancer and men with cancer elsewhere in the prostate. However, 77% of men with TZ cancer had a PSA of > 10 ng/mL, compared with 60% of men with cancer at other sites within the prostate (P = 0.015). CONCLUSION: An extended-core biopsy protocol significantly improves the detection rate for prostate cancer when compared with the standard sextant biopsy protocol alone. Routine TZ biopsies should be considered for men with serum PSA levels of >10 ng/mL.

Adenocarcinoma↗

PubMed2002

An improved assay for genotyping the common Alu insertion in the tissue-type plasminogen activation gene PLAT.

An improved assay for genotyping the common Alu insertion in the tissue-type plasminogen activator (PLAT) locus is described in this report. The assay is a valuable asset to clinical researchers interested in exploring disease associations with this allele. The automation and improved accuracy will facilitate future population-based studies, as well as clinical screening.

Alu Elements↗

PubMed2002

Does endothelial cell activation occur with intrauterine growth restriction?

It is possible that in fetal growth restriction without pre-eclampsia endothelial cell activation does not occur. This might be either because there is no release of 'factor X' or because of maternal resistance to its effects. To test this hypothesis, we took blood samples from 26 women with pre-eclampsia (without fetal growth restriction), 13 women with fetal growth restriction (without pre-eclampsia) and 24 normal pregnant controls, and measured the circulating levels of three markers of endothelial cell activation (soluble VCAM, ICAM and E-selectin) and three cytokines [tumour necrosis factor-a (TNF-alpha), interleukin-6 (IL-6) and -8 (IL-8)]. The levels of the markers of endothelial cell activation were raised in both pre-eclampsia and fetal growth restriction pregnancies compared with controls; however, the levels of TNF-alpha, IL-6 and IL-8 were significantly raised in pregnancies complicated by pre-eclampsia, but not in fetal growth restriction, compared with controls. These data show that endothelial cell activation is common to both pre-eclampsia and fetal growth restriction, but that the circulating levels of cytokines are elevated only in pre-eclampsia. Thus, it seems likely that endothelial cell activation is a consequence of a failure of trophoblast invasion and that a further step is required, possibly involving cytokine release, for the expression of the full clinical picture of pre-eclampsia.

Adult↗

PubMed2002

Is surgical mystique a myth and double standard the reality?

Clinically relevant attitudes and guidelines issued by a rational evidence based medicine (EBM) approach, integrate individual clinical expertise with the best available external clinical evidence from systematic research. Many surgeons, however, while considering the ultraliberal world they are practising in, and fearing that the primary goal of managed care in a market environment is reducing cost in order to make profit or decrease spending, remain suspicious of this kind of tentative protocol driven medicine when applied to surgical practice. If surgeons want to develop a health policy agenda that emphasises patient care issues above providers' or payers' interests, they should also enhance education programmes, improve continuing objective assessment of the way surgery is performed, face moral issues raised by innovation, and assume an increased leadership role in sound critical evaluation of non-validated new techniques. They should no longer consider EBM as a weapon turned against the surgical profession, but rather see it as a tool that may provide some answers to chronically unresolved questions in the evolving art of surgery.

Cholecystectomy↗

PubMed2002

A comparative study of a new wireless continuous cardiorespiratory monitor for the diagnosis and management of patients with congestive heart failure at home.

Congestive heart failure (CHF) is a major and increasing chronic disease in Western society, with a high mortality, morbidity and cost for unplanned hospital admissions. Continuous cardiorespiratory monitoring is required to detect Cheyne-Stokes respiration (CSR). We have tested a new wireless monitoring system and compared it with polysomnography (PSG) and respiratory inductance plethysmography (RIP) in six CHF patients with CSR in a sleep laboratory. The wireless system compared well with RIP for the detection of CSR but less well with PSG, which had unexpected but significant respiratory sensing errors that led to misclassification of the respiratory disorder present. The wireless system could be used to select CHF patients for better-customized treatment at home as part of a specialist-supported community telemedicine programme.

Heart Failure↗

PubMed2001

Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells.

It has been shown that serum levels of interleukin (IL)-6 are elevated in patients with various types of cancer. However, the exact source of IL-6 in these patients and its role in tumor progression remain unclear. Here we demonstrate that the autocrine production of IL-6 by tumor cells promotes resistance of the cells to chemotherapy, a novel function of IL-6 in cancer biology. Breast cancer cells that are sensitive to drug treatment do not express IL-6, whereas high levels of IL-6 are produced by multidrug-resistant breast cancer cells. Expression of the IL-6 gene in drug-sensitive breast cancer cells increases their resistance to drug treatment by activating the CCAAT enhancer-binding protein family of transcription factors and inducing mdr1 gene expression. Thus, the autocrine production of IL-6 by tumor cells is an important factor in determining the susceptibility or resistance of these cells to drug treatment. Because tumors from some breast cancer patients contain IL-6-producing cells, it is possible that IL-6 could potentially be used as a prognostic factor for chemotherapy resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

A method for identification of inhibitors of the phosphorylation reactions of bacterial response regulator proteins using (31)P nuclear magnetic resonance spectroscopy.

Bacterial response regulators are attractive targets for antibacterial drug development, yet random screening against these targets has failed as yet to identify chemicals that constitute viable leads. Alternative methods to provide leads for drug development based on identification and optimization of low affinity ligands from NMR screens have been described. However, leads from these processes still require verification in a bioassay, which is often problematic if compounds have unfavorable optical and solubility properties. A simple method, based on using NMR to observe the activity of the target, is described. It has the advantages of being able to characterize both low affinity leads and a wider selection of compounds in a structure activity relationships series, without the problems affecting a fluorescence assay. In this example we use (31)P to monitor the turnover of a bacterial response regulator, but the generic approach could be applied to other nuclei and thus a range of biological systems.

Anti-Bacterial Agents↗

PubMed2001

Role of sulfation in CD44-mediated hyaluronan binding induced by inflammatory mediators in human CD14(+) peripheral blood monocytes.

Activation of T cells by Ag or stimulation of monocytes with inflammatory cytokines induces CD44 to bind to hyaluronan (HA), an adhesion event implicated in leukocyte-leukocyte, leukocyte-endothelial cell, and leukocyte-stromal cell interactions. We have previously shown that TNF-alpha induces CD44 sulfation in a leukemic cell line, which correlated with the induction of HA binding and CD44-mediated adhesion. In this study, we establish that TNF-alpha and IFN-gamma induce HA binding and the sulfation of CD44 in CD14(+) PBMC, whereas no induced HA binding or CD44 sulfation was observed in CD14(-) PBMC stimulated with TNF-alpha. Treatment of cells with NaClO(3), an inhibitor of sulfation, prevented HA binding in a significant percentage of CD14(+) PBMC induced by TNF-alpha, LPS, IL-1beta, or IFN-gamma. Furthermore, stimulation with TNF-alpha or IFN-gamma in the presence of NaClO(3) reduced the ability of isolated CD44H to bind HA, demonstrating a direct effect of CD44H sulfation on HA binding. In contrast, the transient induction of HA binding in T cells by PHA was not affected by NaClO(3), suggesting that activated T cells do not use sulfation as a mechanism to regulate HA binding. Overall, these results demonstrate that inducible sulfation of CD44H is one mechanism used by CD14(+) peripheral blood monocytes to induce HA binding in response to inflammatory agents such as TNF-alpha and IFN-gamma.

Humans↗

PubMed2001

Biogeography and ecological setting of Indian Ocean hydrothermal vents.

Within the endemic invertebrate faunas of hydrothermal vents, five biogeographic provinces are recognized. Invertebrates at two Indian Ocean vent fields (Kairei and Edmond) belong to a sixth province, despite ecological settings and invertebrate-bacterial symbioses similar to those of both western Pacific and Atlantic vents. Most organisms found at these Indian Ocean vent fields have evolutionary affinities with western Pacific vent faunas, but a shrimp that ecologically dominates Indian Ocean vents closely resembles its Mid-Atlantic counterpart. These findings contribute to a global assessment of the biogeography of chemosynthetic faunas and indicate that the Indian Ocean vent community follows asymmetric assembly rules biased toward Pacific evolutionary alliances.

Animals↗

PubMed2001

Role of alpha(2)-adrenoceptors in the sympathetic inhibition of motility reflexes of guinea-pig ileum.

1. Sympathetic regulation of the motility of guinea-pig ileum was investigated using mesenteric nerve (MN) stimulation to inhibit motility reflexes, in vitro. 2. Transmural electrical stimulation (5 Hz, 1 s) in intact intestinal segments, or inflation of a balloon against the mucosa in opened segments, evoked contractions of the circular and longitudinal muscles oral to the stimulus. 3. MN stimulation (10 Hz, 5 s) usually abolished contractions of the longitudinal and circular muscles evoked by either electrical or mechanical stimuli. 4. The inhibition was mimicked by UK14,304 (70-100 nM) and abolished by idazoxan (100 nM), revealing an enhancement of circular muscle contractions. There was no evidence for alpha(2)-receptors on the muscle, suggesting sympathetic inhibition was via the myenteric plexus. 5. Possible sites of action of noradrenaline released from sympathetic nerves were investigated using intracellular recordings from the circular muscle in a multichambered organ bath. 6. When in the stimulation chamber, UK14,304 depressed (by 50 %) excitatory junction potentials (EJPs) recorded oral to a distension stimulus, but did not affect inhibitory junction potentials (IJPs) recorded anal to the stimulus. When added to a chamber between the stimulus and recording chambers, UK14,304 depressed EJPs by 40 %, but did not alter IJPs. When in the recording chamber, UK14,304 depressed EJPs by 20 %, but had no effect on IJPs. IJPs were inhibited, however, when UK14,304 was applied to the whole bath. 7. It is concluded that sympathetic activity inhibits intestinal motility mainly via alpha(2)-adrenoceptors on ascending interneurons and intrinsic sensory neurons of the orally directed reflex pathway.

Adrenergic alpha-Agonists↗

PubMed2001

Pharmacokinetic study of intralesional cisplatin for the treatment of hepatocellular carcinoma.

BACKGROUND: In the current study the authors examined the pharmacokinetics of direct intralesional injection of cisplatin/epinephrine/bovine collagen gel in patients with hepatocellular carcinoma and cirrhosis. METHODS: Six patients with cirrhosis and unresectable hepatocellular carcinoma received a direct intralesional injection (range, 6.7-26.7 mg) into their tumors under ultrasonographic guidance. The authors determined the total cisplatin (Pt) concentration in the plasma and urine and nonprotein-bound free Pt in plasma ultrafiltrate using flameless atomic absorption spectrometry. Data from individual patients were analyzed to calculate the pharmacokinetic parameters via a noncompartmental method for constant infusion. To demonstrate that the changes in pharmacokinetics are not related to the underlying cirrhosis, a similar methodology was applied to measure the pharmacokinetic parameters of four similar patients who were treated with cisplatin, 75 mg/m(2), as a 1-hour intravenous infusion. RESULTS: The time to attain maximum concentration of total Pt after intralesional injection was dose-dependent and ranged from 2-13 hours. The concentration-time curve was biphasic in nature. The initial half-life of total Pt in patients who received an intralesional injection varied with the cisplatin dose. The initial half-life for cisplatin doses < 15 mg was approximately 9 hours and the initial half-life at higher cisplatin doses (> 15 mg) was approximately 25 hours. The area under the curve (AUC) was dose-dependent with values ranging from 38-150 microm/mL x hour. Pharmacokinetic parameters for free Pt (ultrafiltrate) were significantly different. The time to attain maximum concentration (t-max) and terminal half-life were shorter and the average AUC was approximately 100-fold lower than total Pt. After the intravenous infusion of cisplatin, the t-max for total and free Pt was 1.3 hours and 1.1 hours, respectively. The terminal half-life and average AUC for total Pt was 194 hours and 247 microg/mL per hour, respectively, and its corresponding parameters for free Pt after intravenous infusion were much lower, similar to the findings for the intralesional injection. CONCLUSIONS: The prolonged t-max and initial half-life noted with the intralesional injection of cisplatin/epinephrine/collagen gel are consistent with its proclaimed ability to retain cisplatin at the tumor and delay its release in systemic circulation. The kinetics of intralesional cisplatin injection also suggest local sequestration of the drug in the injected site. Parameters of intravenous cisplatin infusion in cirrhotic patients are similar to those of patients from the historic control group.

Aged↗

PubMed2001

CD44-initiated cell spreading induces Pyk2 phosphorylation, is mediated by Src family kinases, and is negatively regulated by CD45.

CD44 is a cell adhesion molecule implicated in leukocyte adhesion and migration, co-stimulation of T cells, and tumor metastasis. CD45 is a leukocyte-specific protein tyrosine phosphatase that dephosphorylates the Src family kinases, Lck and Fyn, in T cells. Positive regulation of Lck by CD45 is required for its effective participation in T cell receptor signaling events. Here, immobilized CD44 antibody induced a distinctive cell spreading in CD45(-), but not CD45(+), T cells, and this correlated with the induction of tyrosine-phosphorylated proteins. Two focal adhesion family kinases, Pyk2 and, to a lesser extent, FAK were inducibly phosphorylated, as was a potential substrate, Cas. CD44-mediated cell spreading and induced tyrosine phosphorylation were prevented by the Src family kinase inhibitor, PP2. Furthermore, 2-fold more Lck associated with CD44 in the low density sucrose fraction from CD45(-) T cells compared with CD45(+) T cells, suggesting that CD45 may regulate the association of Lck with CD44 in this fraction. Therefore, in CD45(-) T cells, CD44 signaling is mediated by Src family kinases, and this leads to Pyk2 phosphorylation, cytoskeletal changes, and cell spreading. This implicates CD45 in the negative regulation of Src family kinase-mediated CD44 signaling leading to T cell spreading.

Animals↗

PubMed2001

Pineal transplantation after pinealectomy in young chickens has no effect on the development of scoliosis.

STUDY DESIGN: Three experimental groups and one control group of chickens underwent different surgical procedures to determine the effects of pineal gland transplantation on the development of scoliosis. OBJECTIVE: To determine whether transplantation of the pineal gland to the body wall musculature maintains serum melatonin levels at normal values and prevents the development of scoliosis. SUMMARY OF BACKGROUND DATA: Scoliosis occurs consistently after pinealectomy in young chickens. Many characteristics of this scoliosis are similar to those seen in patients with adolescent idiopathic scoliosis. It is not clear whether the underlying mechanism is dependent on reduced levels of serum melatonin or some other aspect of the extensive surgery. METHODS: Four groups of chickens were selected: normal chickens, pinealectomized chickens, chickens that underwent simple cutting of the pineal stalk, and chickens that underwent transplantation of the pineal gland into the body wall. Development of scoliosis was determined from measurement of the Cobb angle from weekly radiographs. RESULTS: All of the experimental groups showed the same levels of incidence and the same patterns of scoliosis development. Serum melatonin levels were reduced to nearly zero in all the experimental groups for the duration of the experiment. Scoliosis developed in none of the normal chickens. CONCLUSIONS: Neither transplantation of the pineal gland into the body wall musculature nor simple cutting of the pineal stalk was able to maintain normal levels of serum melatonin because both procedures reduced levels to nearly zero. The incidence and pattern of scoliosis development in these groups were the same as those for the pinealectomized group. Reduction of serum melatonin levels remains a prerequisite for scoliosis development in young chickens.

Animals↗

PubMed2001

Primary fibroblast cell cultures from transbronchial biopsies of lung transplant recipients.

BACKGROUND: Survival after lung transplantation is limited by the development of bronchiolitis obliterans (BO) that is a fibroproliferative process and regarded as the histological marker of chronic rejection. To study further the pathogenesis of BO we attempted to establish primary fibroblast cell cultures from transbronchial lung biopsies (TBBs)of lung transplant recipients. METHODS: One to two TBB samples from each patient were collected in sterile phosphate-buffered saline. Biopsies were cut into small pieces and placed onto 25-cm2 culture flasks for cell culture and kept under standard cell culture conditions (21% O2, 5% CO2, 37 degrees C). Culture medium consisted of RPMI 1640, 10% fetal calf serum, L-glutamine, HEPES, and antibiotics. After reaching confluence, fibroblasts were passaged into 75-cm2 flasks. RESULTS: The success rate of establishing fibroblast cultures from transbronchial lung biopsies was 54% (27/50). Cell growth was independent of patient age, transplant type, underlying lung disease, indication for transbronchial lung biopsies, grade, or type of re jection and infection. CONCLUSIONS: We have established a novel method of culturing fibroblasts from lung transplant recipients. We consider this method as an unique human in vitro model to study the pathogenetic mechanisms leading to BO.

Adult↗

PubMed2001

CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling.

The regulation of tyrosine phosphorylation and associated signalling through antigen, growth-factor and cytokine receptors is mediated by the reciprocal activities of protein tyrosine kinases and protein tyrosine phosphatases (PTPases). The transmembrane PTPase CD45 is a key regulator of antigen receptor signalling in T and B cells. Src-family kinases have been identified as primary molecular targets for CD45 (ref. 4). However, CD45 is highly expressed in all haematopoietic lineages at all stages of development, indicating that CD45 could regulate other cell types and might act on additional substrates. Here we show that CD45 suppresses JAK (Janus kinase) kinases and negatively regulates cytokine receptor signalling. Targeted disruption of the cd45 gene leads to enhanced cytokine and interferon-receptor-mediated activation of JAKs and STAT (signal transducer and activators of transcription) proteins. In vitro, CD45 directly dephosphorylates and binds to JAKs. Functionally, CD45 negatively regulates interleukin-3-mediated cellular proliferation, erythropoietin-dependent haematopoieisis and antiviral responses in vitro and in vivo. Our data identify an unexpected and novel function for CD45 as a haematopoietic JAK phosphatase that negatively regulates cytokine receptor signalling.

Animals↗

PubMed2001

Nonradiochemical DNase I footprinting by capillary electrophoresis.

A new application for DNase I footprinting using capillary electrophoresis (CE) has been developed in order to decrease analysis time and to eliminate the use of radiochemicals. An additional advantage of the new method over the traditional radioactive methods is that the DNA probe can be labeled on both ends with different fluorescein dyes. This provides an internal check of the identification of protein-binding sites on DNA, because the binding region can be observed from both DNA strands. The initial parameters for the CE method were developed using the Promega Core Footprinting Kit for analysis of AP-2 binding sites in the SV40 enhancer sequence. After optimization of the method, the protocol was found to be effective for footprint analysis of the immediate upstream region (bases -1 to -370) of the rat glutathione peroxidase (GPX) and it permitted identification of a previously unknown binding site in the upstream sequence of the GPX gene.

Animals↗