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Biomedical subjects

J L Johnson

Publications and source records attributed to J L Johnson.

At least 19 recordsLinked to original sources
PubMed2006

Comparison of intermittent ethambutol with rifampicin-based regimens in HIV-infected adults with PTB, Kampala.

BACKGROUND: The human immunodeficiency virus (HIV) is a key factor responsible for the high rates of tuberculosis (TB) in sub-Saharan Africa. Treatment of TB with rifampicin (R, RMP) containing short-course regimens is highly effective in HIV-infected adults. We conducted a study to compare the efficacy and safety of intermittent ethambutol (E, EMB) with two RMP-containing regimens to treat pulmonary TB in HIV-infected patients. SETTING: National Tuberculosis Treatment Centre, Mulago Hospital, Kampala, Uganda. DESIGN: This was a prospective cohort compared to two non-randomised control groups. The study group and the two control arms were treated with 2 months of isoniazid (H), RMP, pyrazinamide (Z) and EMB followed by 6 E3H3 for the study group and 4HR or 6HR for controls. RESULTS: Between April 1993 and March 2000, 136 patients were enrolled in the 2EHRZ/E3H3 arm, 147 in the 2EHRZ/4HR arm and 266 in the 2EHRZ/6HR arm. The relapse rate was 18.2 per 100 person-years observation (PYO) for the study regimen compared to 9.7/100 PYO (P = 0.0063) and 4.8/100 PYO (P = 0.0001) in patients treated with 2 EHRZ/4HR or 2EHRZ/6HR, respectively. CONCLUSION: The 2EHRZ/6E3H3 regimen is safe and effective but has a significant risk of relapse.

AIDS-Related Opportunistic Infections↗
PubMed2006

Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis.

OBJECTIVE: To evaluate the early bactericidal activity (EBA) of the new fluoroquinolones levofloxacin, gatifloxacin and moxifloxacin in patients with pulmonary tuberculosis (PTB). DESIGN: Randomized, open-label trial. Forty adults with newly diagnosed smear-positive PTB (10 per arm) were assigned to receive isoniazid (INH) 300 mg, levofloxacin 1000 mg, gatifloxacin 400 mg, or moxifloxacin 400 mg daily for 7 days. Sputum for quantitative culture was collected for 2 days before and daily during 7 days of monotherapy. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (EBA 0-2) and last 5 days of monotherapy (extended EBA, EBA 2-7). Laboratory staff were blinded to treatment assignment. RESULTS: The EBA 0-2 of INH (0.67 log10 cfu/ml/day) was greater than that of moxifloxacin and gatifloxacin (0.33 and 0.35 log10 cfu/ml/day, respectively), but not of levofloxacin 1000 mg daily (0.45 log10 cfu/ml/day) (P = 0.14). Bactericidal activity between days 2 and 7 was similar for all three fluoroquinolones. In a pooled comparison, the EBA 2-7 of the fluoroquinolones was greater than for INH. CONCLUSION: Moxifloxacin, gatifloxacin, and high-dose levofloxacin have excellent EBA, only slightly less than for INH, and greater extended EBA. These drugs warrant further study in the treatment of drug-susceptible TB.

Adult↗
PubMed2005

Bioactivation of latent transforming growth factor beta1 by Mycobacterium tuberculosis in human mononuclear phagocytes.

Biologically active transforming growth factor beta 1 (TGFbeta1) has been identified at sites of Mycobacterium tuberculosis (MTB) infection in the lung; however, the underlying mechanism(s) for its activation is not clear. Here using an enzyme-linked immunospot assay for TGFbeta1, we show that human blood monocytes (MN) and alveolar macrophages (AM) produce bioactive TGFbeta1 upon stimulation by MTB. However, only MTB-stimulated MN increased TGFbeta1 production on a per cell basis. The frequency of TGFbeta1-producing MN was reduced by an inhibitor of plasmin, bdellin, indicating a role for plasmin pathways in the bioactivation of cytokine. The expression of urokinase plasminogen activator receptor (uPAR) mRNA and both surface and soluble uPAR (CD87) was increased in MTB-activated MN. However, antibody neutralization of uPAR suppressed bioactive TGFbeta1 in MN alone. Thus, the more immature MN, which are continuously recruited to the lung during tuberculosis (TB), have a higher capacity to bioactivate TGFbeta1 by expression of components of the plasmin pathway. Excess production and bioactivation of TGFbeta1 at sites of MTB infection may undermine host immune responses during TB.

Adult↗
PubMed2005

Bioavailability of vitamin D from fortified process cheese and effects on vitamin D status in the elderly.

We conducted 2 studies to determine the effect of vitamin D-fortified cheese on vitamin D status and the bioavailability of vitamin D in cheese. The first study was designed to determine the effect of 2 mo of daily consumption of vitamin D3-fortified (600 IU/d) process cheese on serum 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH), and osteocalcin (OC) concentrations among 100 older (> or =60 yr) men and women. Participants were randomized to receive vitamin D-fortified cheese, nonfortified cheese, or no cheese. Serum levels of 25-OHD, PTH, and OC were measured at the beginning and end of the study. There were no differences in 25-OHD, PTH, or OC after 2 mo of fortified cheese intake. The vitamin D-fortified cheese group had a greater decrease in 25-OHD than other groups, due to higher baseline 25-OHD. A second study was conducted to determine whether the bioavailability of vitamin D2 in cheese (delivering 5880 IU of vitamin D2/56.7-g serving) and water (delivering 32,750 IU/250 mL) is similar and whether absorption differs between younger and older adults. The second study was a crossover trial involving 2 groups of 4 participants each (younger and older group) that received single acute feedings of either vitamin D2-fortified cheese or water. Serial blood measurements were taken over 24 h following the acute feeding. Peak serum vitamin D and area under the curve were similar between younger (23 to 50 yr) and older (72 to 84 yr) adults, and vitamin D2 was absorbed more efficiently from cheese than from water. These studies demonstrated that vitamin D in fortified process cheese is bioavailable, and that young and older adults have similar absorption. Among older individuals, consuming 600 IU of vitamin D3 daily from cheese for 2 mo was insufficient to increase serum 25-OHD during limited sunlight exposure.

Absorption↗
PubMed2004

Control of H+/lactose coupling by ionic interactions in the lactose permease of Escherichia coli.

A combinatorial approach was used to study putative interactions among six ionizable residues (Asp-240, Glu-269, Arg-302, Lys-319, His-322, and Glu-325) in the lactose permease. Neutral mutations were made involving five ion pairs that had not been previously studied. Double mutants, R302L/E325Q and D240N/H322Q, had moderate levels of downhill [(14)C]-lactose transport. Mutants in which only one of these six residues was left unchanged (pentuple mutants) were also made. A Pent269(-) mutant (in which only Glu-269 remains) catalyzed a moderate level of downhill lactose transport. Pent240(-) and Pent 322(+) also showed low levels of downhill lactose transport. Additionally, a Pent240(-) mutant exhibited proton transport upon addition of melibiose, but not lactose. This striking result demonstrates that neutralization of up to five residues of the lactose permease does not abolish proton transport. A mutant with neutral replacements at six ionic residues (hextuple mutant) had low levels of downhill lactose transport, but no uphill accumulation or proton transport. Since none of the mutants in this study catalyzes active accumulation of lactose, this is consistent with other reports that have shown that each residue is essential for proper coupling. Nevertheless, none of the six ionizable residues is individually required for substrate-induced proton cotransport. These results suggest that the H(+) binding domain may be elsewhere in the permease or that cation binding may involve a flexible network of charged residues.

Biological Transport, Active↗
PubMed2004

In vitro activity of gemifloxacin and contemporary oral antimicrobial agents against 27247 Gram-positive and Gram-negative aerobic isolates: a global surveillance study.

This study was a multi-centre, multi-country surveillance of 27247 Gram-positive and Gram-negative isolates collected from 131 study centres in 44 countries from 1997 to 2000. MICs of gemifloxacin were compared with penicillin, amoxicillin-clavulanic acid, cefuroxime, azithromycin, clarithromycin, trimethoprim-sulphamethoxazole, ciprofloxacin, grepafloxacin and levofloxacin by broth microdilution. Penicillin resistance in Streptococcus pneumoniae was extremely high in the Middle East (65.6%), Africa (64.0%) and Asia (60.4%) and lower in North America (40.3%), Europe (36.9%) and the South Pacific (31.8%). Macrolide resistance in S. pneumoniae was highest in Asia (51.7%) but varied widely between laboratories in Europe (26.0%), North America (21.6%), the Middle East (13.7%), the South Pacific (10.6%) and Africa (10.0%). All the study quinolones were highly active against penicillin-resistant and macrolide-resistant S. pneumoniae. Overall, gemifloxacin had the lowest MIC(90) at 0.06 mg/l with MICs 4-64-fold lower than ciprofloxacin, levofloxacin and grepafloxacin against S. pneumoniae. Gemifloxacin MICs were more potent than grepafloxacin > levoflaxacin > ciproflaxin against the Gram-positive aerobes and shared comparable Gram-negative activity with ciprofloxacin and levofloxacin.

Administration, Oral↗
PubMed2004

Determining incidence of extended spectrum beta-lactamase producing Enterobacteriaceae, vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus in 38 centres from 17 countries: the PEARLS study 2001-2002.

The PEARLS study prospectively monitored selected nosocomial pathogens from 38 centres in 13 European, three Middle Eastern countries and South Africa during 2001-2002. Extended spectrum beta-lactamase (ESBL) production rates among Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp. were 5.4% (142/2609), 18.2% (401/2,206) and 8.8% (204/2,328), respectively, for all study sites. The overall ESBL production rate for the combined Enterobacteriaceae was 10.5% (747/7,143), highest in Egypt, 38.5%, and Greece, 27.4%, and lowest in The Netherlands, 2.0%, and Germany, 2.6%. IEF, PCR and DNA sequencing determined 10.7% false positives among Enterobacter spp. when using NCCLS guidelines to screen for ESBL production. The prevalence of nosocomial methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium was 32.4% (294/908) and 8.7% (83/949), respectively. PEARLS provides baseline data against which prospective changes in resistant determinants and outcomes can be measured in this ongoing study.

Anti-Bacterial Agents↗
PubMed2004

Large volume polymerized haemoglobin solution in a Jehovah's Witness following abruptio placentae.

Severe anaemia, with haemoglobin (Hb) levels < or =3 g dL(-1), is associated with mortality rates of 50-95%. Although accepted transfusion targets have been debated in the literature (Carson et al., 2002; Practice guidelines for blood component therapy. 1996; Consensus Conference. 1988; Hebert et al., 1999), few would argue the risks associated with Hb levels less than 5 g dL(-1) in critically ill patients. In patients who are unable to receive red blood cell transfusions, the utility of Hb solutions is an attractive solution. We describe a Jehovah's Witness patient who exemplifies the marked physiologic derangements of severe anaemia and subsequent clinical resolution with large volume polymerized human Hb transfusion. The Hb-based oxygen carrier, PolyHeme, provided adequate oxygen transport, acting as a bridge until endogenous production could compensate for red cell loss. Practicing physicians need to be aware of current therapeutic options for use in these complicated patients.

Abruptio Placentae↗
PubMed2004

Effect of Mycobacterium vaccae (SRL172) immunotherapy on radiographic healing in tuberculosis.

OBJECTIVE: Controlled trials have failed to show an effect of Mycobacterium vaccae immunotherapy on treatment outcome and mortality in patients with tuberculosis (TB); however, several studies have suggested improvement in radiographic clearing and resolution of cavitary disease. METHODS: To assess the effect of M. vaccae immunotherapy on radiographic healing in pulmonary TB, chest X-rays from three randomized placebo-controlled trials of M. vaccae given as a single injection during the first 2 weeks of treatment were interpreted by a single, masked assessor using a standard scheme. Endpoints were the overall degree of radiographic improvement or deterioration and changes in cavitary disease at the end of antituberculosis treatment and follow-up. RESULTS: Of 1018 patients (478 HIV-infected; 540 HIV-uninfected) with an end of treatment or end of follow-up X-ray analyzed, 496 received M. vaccae and 522 received placebo. There was no difference in radiographic improvement or deterioration or cavitary disease at the end of treatment or follow-up comparing the M. vaccae and placebo groups. Results were similar comparing HIV-infected and HIV-uninfected patients. CONCLUSION: Adjunctive immunotherapy of drug-susceptible pulmonary TB with M. vaccae during the first 2 weeks of treatment did not improve radiographic responses to treatment or resolution of cavitary disease.

Adult↗
PubMed2003

Comparative in vitro surveillance of amoxicillin-clavulanic acid and four oral comparators against 21232 clinical isolates from europe.

The present study was conducted to determine the in vitro activity of amoxicillin-clavulanic acid compared to that of four newer antimicrobial agents (ampicillin, azithromycin, cefuroxime and trimethoprim-sulfamethoxazole). All of the agents were tested against 21232 recent clinical isolates encompassing 37 species submitted from 16 European countries between 1997 and 1999. After 20 years of clinical use, amoxicillin-clavulanic acid continues to retain much of its initial activity against targeted gram-positive organisms, selected gram-negative organisms and major respiratory pathogens.

Administration, Oral↗
PubMed2003

Comparative in vitro potency of amoxycillin-clavulanic acid and four oral agents against recent North American clinical isolates from a global surveillance study.

The in vitro activity of amoxycillin-clavulanic acid was compared with four comparator oral antimicrobial agents; ampicillin, azithromycin, cefuroxime and trimethoprim-sulphamethoxazole against 4536 recent clinical isolates covering 29 species isolated in the US and Canada between 1997 and 1999. Based upon Minimum inhibitory concentrations (MICs), amoxycillin-clavulanic acid was the most active agent against many Gram-positive species and phenotypes including methicillin susceptible Staphylococcus aureus (MSSA) Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae including penicillin intermediate and macrolide resistant strains and was as active as ampicillin against Streptococcus agalactiae, penicillin resistant S. pneumoniae and viridans streptococci. Against Enterobacteriaceae amoxycillin-clavulanic acid in general, displayed weak activity with only Proteus mirabilis and Proteus vulgaris displaying levels of susceptibility above the 90th percentile. Amoxycillin-clavulanic acid had significant activity against many species of Gram-negative non-Enterobacteriaceae including Haemophilus influenzae, Haemophilus parainfluenzae and Moraxella catarrhalis but negligible activity against Burkholderia cepacia, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. Amoxycillin-clavulanic acid continues to retain excellent activity against the majority of targeted pathogens despite 20 years of clinical use.

Administration, Oral↗
PubMed2003

BCL-2 in prostate cancer: a minireview.

Prostate cancer progression and the development of androgen-independent prostate cancer have been largely related to a number of genetic abnormality that affect not only the androgen receptor but also crucial molecules involved in the regulation of survival or apoptotic pathways. One of these molecules, the pro-survival protein BCL-2, has been associated with the development of androgen-independent prostate cancer due to its high levels of expression in androgen-independent tumors in advanced stages of the pathology. The upregulation of BCL-2 after androgen ablation in prostate carcinoma cell lines and in a castrated-male rat model further established a connection between BCL-2 expression and prostate cancer progression. This review focuses on the experimental evidence that associates BCL-2 expression with prostate carcinogenesis and cancer progression, and analyzes the evidence that links the phosphatidylinositol 3-kinase (PI 3-kinase)/nuclear factor kappa B (NF-kappaB) survival pathway with the upregulation of BCL-2. The way in which hormone ablation influences this survival pathway and the potential application of novel therapeutic strategies to overcome this anti-apoptotic mechanism is examined.

Androgens↗
PubMed2002

Isolated sulfite oxidase deficiency: mutation analysis and DNA-based prenatal diagnosis.

Isolated sulfite oxidase deficiency is an autosomal recessive, neurological disorder resulting from a defect in SUOX, the gene encoding the enzyme that catalyzes the terminal reaction in the sulfur amino acid degradation pathway. In its classical, severe form, sulfite oxidase deficiency leads to intractable seizures, severe and progressive brain pathology and death at an early age. We report here on clinical features and mutational analysis of the genetic defect in a newborn with sulfite oxidase deficiency. Cultured fibroblasts from this patient exhibited no detectable sulfite oxidase activity, and a unique four base pair deletion was present in the cDNA isolated from the same source. Identification of the same genetic defect in a heterozygous state in each of the parents and the monitoring of subsequent pregnancies in this family by DNA-based prenatal diagnosis are also described. The deletion mutation was identified in a homozygous state in uncultured chorionic villus tissue from the second pregnancy that was subsequently terminated. In the third pregnancy, the presence of sulfite oxidase activity and identification of the mutation in a heterozygous state suggested that the fetus was not affected. This pregnancy resulted in the birth of a normal child.

Brain↗
PubMed2002

Mycobacterium africanum subtype II is associated with two distinct genotypes and is a major cause of human tuberculosis in Kampala, Uganda.

The population structure of 234 Mycobacterium tuberculosis complex strains obtained during 1995 and 1997 from tuberculosis patients living in Kampala, Uganda (East Africa), was analyzed by routine laboratory procedures, spoligotyping, and IS6110 restriction fragment length polymorphism (RFLP) typing. According to biochemical test results, 157 isolates (67%) were classified as M. africanum subtype II (resistant to thiophen-2-carboxylic acid hydrazide), 76 isolates (32%) were classified as M. tuberculosis, and 1 isolate was classified as classical M. bovis. Spoligotyping did not lead to clear differentiation of M. tuberculosis and M. africanum, but all M. africanum subtype II isolates lacked spacers 33 to 36, differentiating them from M. africanum subtype I. Moreover, spoligotyping was not sufficient for differentiation of isolates on the strain level, since 193 (82%) were grouped into clusters. In contrast, in the IS6110-based dendrogram, M. africanum strains were clustered into two closely related strain families (Uganda I and II) and clearly separated from the M. tuberculosis isolates. A further characteristic of both M. africanum subtype II families was the absence of spoligotype spacer 40. All strains of family I also lacked spacer 43. The clustering rate obtained by the combination of spoligotyping and RFLP IS6110 analysis was similar for M. africanum and M. tuberculosis, as 46% and 49% of the respective isolates were grouped into clusters. The results presented demonstrate that M. africanum subtype II isolates from Kampala, Uganda, belong to two closely related genotypes, which may represent unique phylogenetic branches within the M. tuberculosis complex. We conclude that M. africanum subtype II is the main cause of human tuberculosis in Kampala, Uganda.

Bacterial Typing Techniques↗
PubMed2001

Molybdopterin synthase mutations in a mild case of molybdenum cofactor deficiency.

Molybdenum cofactor deficiency is a rare inborn error of metabolism with generally severe symptoms, most often including neonatal seizures and severe developmental delay. We describe a patient with an unusually mild form of the disease. Two mutations in MOCS2A (molybdenum cofactor synthesis enzyme 2A) were identified: a single base change, 16C > T, that predicts a Q6X substitution on one allele and a 19G > T transversion that predicts a valine to phenylalanine substitution, V7F, on the second. It is postulated that the milder clinical symptoms result from a low level of residual molybdopterin synthase activity derived from the 19G > T allele.

Alleles↗
PubMed2001

Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults.

BACKGROUND: Treatment of latent infection is needed to protect HIV-infected individuals against tuberculosis. A previous report addressed short-term efficacy of three regimens in HIV-infected adults. We now report on long-term efficacy of the study regimens. METHODS: Three daily self-administered regimens were compared in a randomized placebo-controlled trial in 2736 purified protein derivative (PPD)-positive and anergic HIV-infected adults. PPD-positive subjects were treated with isoniazid (INH) for 6 months (6H), INH plus rifampicin for 3 months (3HR), INH plus rifampicin and pyrazinamide for 3 months (3HRZ), or placebo for 6 months. Anergic subjects were randomized to 6H or placebo. RESULTS: 6H initially protected against tuberculosis in PPD-positive individuals; however, benefit was lost within the first year of treatment. Sustained benefit was observed in persons receiving 3HR and 3HRZ. In a Cox regression analysis, the adjusted relative risk for tuberculosis compared with placebo was 0.67 [95% confidence interval (CI), 0.42-1.07] for 6H, 0.49 (95% CI, 0.29-0.82) for 3HR, and 0.41 (95% CI, 0.22-0.76) for 3HRZ. When the rifampicin-containing regimens were combined, the adjusted relative risk for tuberculosis compared with placebo was 0.46 (95% CI, 0.29-0.71). Among anergic subjects, a modest degree of protection with 6H was present (adjusted relative risk, 0.61; 95% CI, 0.32-1.16). Treatment of latent tuberculosis infection had no effect on mortality. CONCLUSION: Six months of INH provided short-term protection against tuberculosis in PPD-positive HIV-infected adults. Three month regimens including INH plus rifampicin or INH, rifampicin and pyrazinamide provided sustained protection for up to 3 years.

AIDS-Related Opportunistic Infections↗
PubMed2001

Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer.

This work presents direct evidence that the bcl-2 gene is transcriptionally regulated by nuclear factor-kappa B (NF-kappa B) and directly links the TNF-alpha/NF-kappa B signaling pathway with Bcl-2 expression and its pro-survival response in human prostate carcinoma cells. DNase I footprinting, gel retardation and supershift analysis identified a NF-kappa B site in the bcl-2 p2 promoter. In the context of a minimal promoter, this bcl-2 p2 site 1 increased transcription 10-fold in the presence of the p50/p65 expression vectors, comparable to the increment observed with the consensus NF-kappa B site, while for the full p2 promoter region transcriptional activity was increased sixfold by over-expression of NF-kappa B, an effect eliminated by mutating the bcl-2 p2 site 1. The expression of Bcl-2 has been linked to the hormone-resistant phenotype of advanced prostate cancer. Here we show that an increase in the level of expression of Bcl-2 in the human prostate carcinoma cell line LNCaP observed in response to hormone withdrawal is further augmented by TNF-alpha treatment, and this effect is abated by inhibitors of NF-kappa B. Concomitantly, bcl-2 p2 promoter studies in LNCaP cells show a 40-fold increase in promoter activity after stimulation with TNF-alpha in the absence of hormone.

Adenocarcinoma↗