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H Jones

Publications and source records attributed to H Jones.

At least 73 records · Page 4Linked to original sources
PubMed1999

Effects of chronic anti-interleukin-5 monoclonal antibody treatment in a murine model of pulmonary inflammation.

The maturation of eosinophils in bone marrow, their migration to pulmonary tissue, and their subsequent degranulation and release of toxic granule proteins contributes to the pathophysiology observed in asthma. Interleukin-5 (IL-5) is essential for these processes to occur. Therefore, much emphasis has been placed on attempts to inhibit the production or activity of IL-5 in order to attenuate the inflammatory aspect of asthma. In this report, the immunological consequences of long-term exposure to an antibody recognizing IL-5 (TRFK-5) were studied in a murine pulmonary inflammation model. A single dose of TRFK-5 (1 mg/ kg, intraperitoneally) reversibly inhibited antigen-dependent lung eosinophilia in mice for at least 12 wk and inhibited the release of eosinophils from bone marrow for at least 8 wk. Normal responses to aerosol challenge were attained after 24 wk. In mice treated acutely with antibody (2 h before challenge), 50% inhibition of pulmonary eosinophilia occurred when 0. 06 mg/kg TRFK-5 was administered (intraperitoneally; ED50), resulting in 230 ng/ml (IC50) in serum. In mice treated with one dose of TRFK-5 (1 mg/kg) and rested before challenge, the antibody exhibited a half-life of 2.4 wk. After 18 to 19 wk, antigen challenge-induced eosinophilia was inhibited by 50% and serum levels of TRFK-5 were 25 ng/ml. TRFK-5 remaining in mice 8 wk after a single injection of TRFK-5 was sufficient to inhibit at least 50% of the eosinophilia induced in blood 3 h after injection of recombinant murine IL-5 (10 microg/kg, intravenously). To assess the biologic effect of long-term exposure of mice to antibody, several parameters of immune-cell function were measured. Throughout the extended period of activity of TRFK-5 (>/= 12 wk) there were no gross effects on antigen-dependent increases in T-cell recruitment into bronchoalveolar fluid (BALF), in IL-4 and IL-5 steady-state mRNA levels in lung tissue, or in immunoglobulin E (IgE) and IgG levels in serum. There was a small increase in IL-5 steady-state mRNA production in TRFK-5-treated mice after 2 h or 2 wk, but this was not observed at other times examined. In untreated mice, IL-5 steady-state mRNA production in response to antigen challenge decreased > 6-fold with age, although at all time points there was an increase in mRNA levels following challenge. Therefore, at later times, 25 ng/ml rather than 230 ng/ml of TRFK-5 inhibited BALF eosinophilia, probably because of reduced IL-5 levels. Twenty-four weeks after treatment with TRFK-5, when challenge-induced eosinophilia was restored, there was an excess of CD4(+) T cells in BALF from challenged mice. However, these T cells had no measurable effects on other responses to challenge, including cytokine production, B-cell accumulation, and immunoglobulin production in serum. Thus, the biologic duration of TRFK-5 was several months, and its activity was due to the presence of antibody above a therapeutic threshold rather than to any profound effect on the immune system.

Animals↗
PubMed1999

Differences in rates of glycation (glycation index) may significantly affect individual HbA1c results in type 1 diabetes.

Ten type 1 diabetic patients recorded their daily home blood glucose values, pre- and post-prandially, for 12 weeks. Blood was collected weekly for HbA1c and total haemoglobin measurement. A rolling 28-day mean of all blood glucose values and a glycation index (the ratio of the HbA1c to the rolling mean blood glucose) were calculated. In the pooled patients' data, there was a large scatter of results about the HbA1c versus mean blood glucose regression line. There was less variation in the results of individual patients. The glycation indices showed marked inter-individual variation, and in 60% of patients there was an inverse relationship between glycation index and mean blood glucose, suggesting a non-linear relationship between mean blood glucose and HbA1c. Patients should be monitored on the basis of their own previous results, and in some patients blood HbA1c may be a less sensitive index of mean blood glucose concentration at higher glucose levels.

Adult↗
PubMed1999

A novel human stress response-related gene with a potential role in induced radioresistance.

We have isolated a novel gene, DIR1, from L132 cells that is transiently repressed after exposure to low radiation doses and has a potential role in induced radioresistance. Molecular and cellular characterization of this gene reveals that it is unique but has similarities to a family of heat-shock-related proteins known as immunophilins. These have been implicated in various cellular functions including general stress responses and control of the cell cycle. Antisense strategies have demonstrated that the DIR1 gene also appears to have some involvement in the control of the cell cycle. Furthermore, there appears be a potential role for this gene product in the phenomenon of induced radioresistance through a mechanism that increases the rate of DNA repair in cells exposed to X rays and subsequently increases the cells' resistance to radiation. This is the first description of an immunophilin-like gene that has a possible role in adaptive/inducible responses to X rays in mammalian cells.

Amino Acid Sequence↗
PubMed1998

The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen.

Genetic susceptibility to multiple sclerosis is implicated on the basis of classical family studies and phenotype analyses. The only reproducible legacy from the candidate gene approach has been the discovery of population associations with alleles of the major histocompatibility complex. Systematic genome scanning has since been applied using a panel of anonymous markers to identify areas of linkage in co-affected siblings. Here, we describe the principles of genome screening and update the UK survey of multiple sclerosis. This identified 20 regions of potential interest, but in none was there unequivocal linkage. In theory, attempting to replicate these findings in a second set of sibling pair families is the most appropriate way to distinguish true from false positives, but unfortunately the number of families required to do this reliably is prohibitively large. We used three approaches to increase the definition achieved by the screen: (i) the number of sibling pairs typed in an identified region of potential linkage was extended; (ii) the information extraction was increased in an identified region; and (iii) a search was made for missed regions of potential linkage. Each of these approaches has considerable limitations. A chromosome-by-chromosome account is given to direct future searches. Although an additional marker placed distal to the 'hit' on chromosome 14q increased linkage in this area, and typing extra sibling pairs increased linkage on chromosomes 6p and 17q, evidence for linkage was more commonly reduced and no additional regions of interest were found. A further refinement of the genome screen was undertaken by conditioning for the presence of HLA-DR15. This produced a surprising degree of segregation among the regions of interest, which divided into two distinct groups depending on DR15 sharing: the DR15-sharing cohort comprised loci on chromosomal areas 1p, 17q and X; and the DR15-non-sharing cohort was made up of loci on 1cen, 3p, 7p, 14q and 22q. This result further highlights the genetic complexity of multiple sclerosis. What can now be inferred is that a gene of major effect is excluded from 95% of the genome and one with a moderate role from 65%, whereas genes which make a very small biological contribution cannot be discounted from any region. The available results suggest that multiple sclerosis depends on independent or epistatic effects of several genes each with small individual effects, rather than a very few genes of major biological importance.

Genetic Linkage↗
PubMed1998

Risperidone is associated with blunting of D-fenfluramine evoked serotonergic responses in schizophrenia.

The high 5-HT affinity of some atypical antipsychotic agents is thought to contribute to their clinical efficacy. We examined central 5-HT responses in two groups of ten schizophrenic patients by measuring serum prolactin and cortisol responses to the neuroendocrine challenge D-fenfluramine. One group of patients with schizophrenia was tested after a 2-week neuroleptic free period. A similar group were tested after a mean of 12 weeks treatment with the atypical antipsychotic risperidone. A significant elevation of baseline serum prolactin levels, consistent with dopaminergic antagonism was seen after risperidone treatment. Significantly reduced 5-HT mediated serum prolactin responses were seen in risperidone treated patients. D-fenfluramine evoked serum prolactin responses were positively correlated with positive but not negative schizophrenic symptoms for all 20 patients. Risperidone treatment was associated with a significant functional in-vivo 5-HT antagonism similar to clozapine. 5-HT antagonism may contribute to the efficacy of risperidone against positive schizophrenic symptoms.

Adult↗
PubMed1998

High-protein diets augment albuminuria in rats with Heymann nephritis by angiotensin II-dependent and -independent mechanisms.

Urinary albumin excretion (U(alb)V) increases following dietary protein augmentation (DPA) in nephrotic humans and rats. Angiotensin-converting enzyme inhibitors (ACEI) blunt, but do not entirely prevent, increased U(alb)V at doses that reduce blood pressure and entirely block the pressor effect of exogenously administered angiotensin I (Ang-I), suggesting that angiotensin II (Ang-II) might not mediate the effect of DPA on U(alb)V. We determined the effect of losartan (Los), a specific Ang-II receptor antagonist, and compared its effect to that of enalapril (En), an ACEI, on DPA-induced increase in U(alb)V in rats with passive Heymann nephritis (HN). When Los was administered to HN rats for 48 h prior to DPA from 8.5 to 40% casein. U(alb)V increased in an identical fashion in treated and untreated rats, even though Los caused hypotension and prevented the pressor effect of infused Ang-II. Only on day 6 after DPA did U(alb)V decrease. We then measured the effect of duration of pretreatment with Los on Ang-II binding to isolated glomeruli. Maximal inhibition of Ang-II binding required treatment with Los for 6 days. We then pretreated HN rats with either En or Los for 6 days prior to DPA. In contrast to administration of Los for 2 days prior to DPA, pretreatment with either Los or En for 6 days entirely prevented any increase in U(alb)V. We then increased dietary NaCl from 0.2% to 2% (HS) to determine whether En or Los would modulate U(alb)V after DPA when Ang-II activity was suppressed. En reduced the DPA-mediated increase in U(alb)V regardless of dietary NaCl, while Los was effective only in when dietary NaCl was reduced (0.2%), suggesting that under these conditions ACEI reduces U(alb)V by a mechanism that is independent of inhibition of Ang-II and that high protein diets augment U(alb)V by both Ang-II-independent and Ang-II-dependent mechanisms.

Albuminuria↗
PubMed1998

Neuroendocrine evidence that clozapine's serotonergic antagonism is relevant to its efficacy in treating hallucinations and other positive schizophrenic symptoms.

OBJECTIVE: The authors examined the effect of prolonged clozapine treatment on central serotonergic (5-HT) function in schizophrenia. METHOD: Prolactin responses to the 5-HT releasing agent d-fenfluramine were measured in two groups of 10 schizophrenic subjects. The first group was tested twice, before and after a mean of 10 weeks of clozapine treatment. The second group was tested after a mean of 20 months of clozapine treatment. RESULTS: The prolactin response was significantly blunted in these 20 patients treated with clozapine. There was a significant positive correlation between d-fenfluramine-evoked prolactin release and the overall positive symptom score and the hallucination and delusion subscores of the Scale for the Assessment of Positive Symptoms. CONCLUSIONS: Blunted 5-HT-mediated prolactin responses in schizophrenic patients receiving clozapine monotherapy for up to 20 months were correlated with reductions in positive symptoms. This suggests that 5-HT antagonism is relevant to clozapine's efficacy in alleviating hallucinations and other positive schizophrenic symptoms.

Adult↗
PubMed1998

The laboratory's role in outcome assessment.

How does the laboratorian influence patient outcome, and how is this influence measured? The clinical laboratory gives vital support to decisions about diagnosis, treatment, and management. Outcome assessment must include a structured approach to performance improvement, proper test utilization, and defining best practices.

Benchmarking↗
PubMed1998

Anti-inflammatory activity of inhaled mometasone furoate in allergic mice.

Mometasone furoate (CAS 83919-23-7, Sch 32088) is a new inhaled corticosteroid that is being developed to treat allergic inflammatory airway disorders such as rhinitis and asthma. In this study, we investigated the effects of inhaled mometasone furoate in allergic mice that, after antigen challenge, develop an influx of eosinophils and T cells and display an increased mRNA expression of proinflammatory cytokines in the lungs. Mometasone furoate aerosol was generated from metered dose inhalers and delivered into an animal exposure chamber. The mice were exposed to mometasone furoate by nose-only inhalation at respired doses ranging from 0.5-33 micrograms/kg given 24, 18 and 2 h before aeroallergen challenge. The elevated eosinophil numbers in the bronchoalveolar lavage fluid and lung tissues of sensitized, ovalbumin challenged mice were dose-dependently inhibited by inhaled mometasone furoate. Increased numbers of Thy1+ T cells and CD4+ (T-helper) and CD8+ (T-cytotoxic) T cell subsets were seen in the bronchoalveolar lavage fluid of ovalbumin-challenged mice. Pretreatment of these animals with mometasone furoate (33 micrograms/kg) reduced the number of Thy1+ T cells and the T-helper subset. Furthermore, mometasone furoate (33 micrograms/kg) reduced the percentage of CD44+ T-helper cells (activated/memory cells) to the levels observed in non-sensitized, ovalbumin-challenged mice. There were increased levels of steady-state mRNA for interleukin-4, interleukin-5, and to a lesser extent, gamma-interferon in the lungs of sensitized mice after ovalbumin challenge and pretreatment with mometasone furoate reduced the steady-state mRNA levels of these cytokines. Our results demonstrate a potent lung anti-inflammatory effect of inhaled mometasone furoate and identify that inhibition of T cell influx, eosinophil accumulation and modulation of cytokine activity are important components of this response.

Administration, Inhalation↗
PubMed1997

Stimulatory effect of a specific substance P antagonist (RPR 100893) of the human NK1 receptor on the estradiol-induced LH and FSH surges in the ovariectomized cynomolgus monkey.

Utilizing a human NK1 receptor antagonist (RPR 100893), the present in vivo study was designed to test the hypothesis that endogenous substance P (SP) modulates the action of 17beta-estradiol in inducing luteinizing hormone (LH) and follicle stimulating hormone (FSH) surges in ovariectomized cynomolgus monkey. Plasma concentrations of LH and FSH as well as NK1 receptor antagonist and SP were measured during the development of the negative and positive feedback phases which follow a single administration of estradiol benzoate (50 microg/kg) to long-term ovariectomized monkeys. Daily administration by gastric intubation of 1 mg/kg or 10 mg/kg of the NK1 receptor antagonist (RPR 100893) leads to detectable levels of the antagonist in the blood of treated animals for at least 6 hr after its administration. These levels are in agreement with the experimentally determined IC50 value of the antagonist. The most striking finding of this study is that LH and FSH releases are enhanced during the descending arm of the estradiol benzoate-induced LH and FSH surges, which suggests that endogenous SP normally has an inhibitory role during this time. The enhancement of LH release is approximately 50%, regardless of the amount of the NK1 antagonist used. However, the enhanced FSH release is more important. Furthermore, blockade of the NK1 receptor with the smaller dose of the antagonist leads to a small, but significant, increase in plasma levels of SP, indicating that blockade of SP receptors leads to an increased release of SP. Collectively, these results further substantiate the link which exists between the ovarian steroid 17beta-estradiol and SP systems. Also, for the first time, these results demonstrate an inhibitory involvement of the human NK1 receptor in the 17beta-estradiol-induced pseudo-ovulatory gonadotropin surges in the ovariectomized monkey.

Animals↗
PubMed1997

Intracorneal, aqueous humor, and vitreous humor penetration of topical and oral ofloxacin.

OBJECTIVES: To investigate the intracorneal, aqueous, and vitreous penetration of ofloxacin, and to assess the concentration of the drug after topical administration alone and after combined topical and oral administration. METHODS: Twenty consecutive patients undergoing penetrating keratoplasty with vitrectomy for bullous keratopathy received 2 drops of 0.3% ofloxacin every 30 minutes starting 4 hours before surgery. Group A (10 patients) received topical therapy alone. Group B (10 patients) received an additional 3 doses of oral ofloxacin, 400 mg, every 12 hours starting 26 hours before surgery. Aqueous humor, vitreous humor, and corneal specimens were analyzed for ofloxacin levels. RESULTS: For group A, the mean intracorneal ofloxacin level was 4.51 micrograms/mL (range, 0.58-8.77 micrograms/mL; 10 specimens), the mean aqueous humor level was 1.34 micrograms/mL (range, 0.07-4.98 micrograms/mL; 8 specimens), and the mean vitreous humor level was 0.37 micrograms/mL (range, 0.05-0.90 micrograms/mL; 8 specimens). For group B, the mean intracorneal ofloxacin level was 8.59 micrograms/mL (range, 1.18-23.24 micrograms/mL; 10 specimens), the mean aqueous humor level was 2.77 micrograms/mL (range, 0.25-5.80 micrograms/mL; 10 specimens), and the mean vitreous humor level was 2.55 micrograms/mL (range, 0.28-4.97 micrograms/mL; 9 specimens). CONCLUSIONS: Topically applied ofloxacin achieves therapeutic levels in the cornea and aqueous. Mean levels achievable are well above the 90% minimal inhibitory concentration (MIC90) for the majority of bacteria responsible for endophthalmitis and corneal ulceration. The addition of oral ofloxacin to topical therapy increased vitreous penetration 7-fold in this assay trial.

Administration, Oral↗
PubMed1997

Rat liver transcript profiling in normal and disease states using a kinetic polymerase chain reaction assay.

Synthesis of a number of rat liver proteins, including albumin, fibrinogen, apolipoprotein AI, and transferrin, is elevated in the nephrotic syndrome (NS). Increased synthesis of these proteins is regulated at the transcriptional level and occurs in the context of increased mRNA encoding each protein. Changes in albumin, fibrinogen, apolipoprotein AI, and transferrin mRNA levels in total cellular RNA isolated from the livers of normal rats and rats with passive Heymann nephritis were measured using a kinetically monitored, reverse transcriptase-initiated PCR (kRT-PCR) assay. The kRT-PCR assay rapidly quantitated changes in rat liver mRNA levels with an accuracy comparable to that of more labor-intensive mRNA quantitation methods. The relative levels of beta-actin, apolipoprotein AI, fibrinogen, and albumin mRNAs were very similar in total cellular RNA isolated from rat liver versus H4C3 hepatocytes in culture, suggesting that the H4C3 hepatocyte is an appropriate model for studying expression of genes encoding proteins secreted by the liver. Taken together, the results demonstrate the feasibility of using the kRT-PCR assay for isolation and characterization of a soluble factor responsible for elevated synthesis of hepatocyte mRNAs associated with the nephrotic syndrome.

Animals↗
PubMed1997

Cloning of cold-inducible dehydrin-like genes from the blackcurrant (Ribes nigrum L.) using RT-PCR.

A method is described for the identification of conserved genes in one plant species by using sequence information on internal motifs from well-characterized clones from another species. This sequence information is used to design primers for reverse transcriptase polymerase chain reaction (RT-PCR) and to design oligonucleotide probes to identify genuine positive amplification products. The approach was successfully used to clone cDNAs encoding cold-inducible dehydrin-like genes from the woody perennial blackcurrant, Ribes nigrum L. The strategy described can accelerate the cloning of heterologous cDNAs and is a convenient alternative to direct screening of cDNA libraries.

Amino Acid Sequence↗
PubMed1997

Preoptic area infusions of morphine disrupt--and naloxone restores--parental-like behavior in juvenile rats.

As in the adult lactating female, opioids disrupt (and naloxone restores), parental behavior in juvenile rats (approximately 25 days of age). Because the preoptic area regulates the display of parental behavior in lactating females, we examined its parental behavior role in the juvenile rat. At 21 days of age, juvenile rats were implanted with bilateral cannulae aimed at the preoptic area using a modified Kopf stereotaxic and extrapolating from a developing-rat brain atlas [58], and divided into two groups: Initiation and maintenance. On day 25, the initiation group received bilateral infusions of either morphine (0.50 microgram), saline (0.25 microliter), or morphine plus naloxone (0.25 microgram). Thirty minutes later, they were exposed to three 1-6-day-old pups; the maintenance group was exposed to pups until they displayed 2 consecutive days of parental behavior, then infused. Morphine disrupted parental behavior in both the initiation and Maintenance groups, and naloxone restored the behavior to control/ saline levels. Parental behavior in the juvenile animal of both sexes, therefore, is under opioid regulation that parallels the adult female.

Animals↗
PubMed1997

A modified form of low-density lipoprotein with increased electronegative charge is present in rheumatoid arthritis synovial fluid.

Reactive oxygen species (ROS) are pro-inflammatory factors in the pathogenesis of rheumatoid arthritis. During inflammation, the amount of low-density lipoprotein (LDL) in the inflamed joint is increased. LDL is known to be susceptible to oxidation by ROS. Oxidized LDL may serve as a mediator for joint damage, further exacerbating the inflammatory process. LDL isolated from synovial fluid and plasma from individual patients (paired samples) with rheumatoid arthritis or osteoarthritis was characterized by crossed immunoelectrophoresis. On analysis by this technique, synovial fluid LDL from most patients with rheumatoid arthritis contained two peaks: one corresponding to normal plasma native LDL, and the other having an increased electrophoretic mobility associated with oxidized LDL. Paired plasma LDL samples contained native LDL alone, as did paired synovial fluid and plasma LDL from patients with osteoarthritis. Thus, in addition to native LDL, a second form of LDL was shown to be present in rheumatoid synovial fluid, which had properties consistent with those of oxidized LDL.

Aged↗