Biomedical subjects
S Brown
Publications and source records attributed to S Brown.
Case report. Neisseria meningitidis serogroup A in Ontario.
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Treatment of renal allograft rejection with T10B9.1A31 or OKT3: final analysis of a phase II clinical trial.
BACKGROUND: Treatment of acute renal allograft rejection with the monoclonal antibody (mAb) OKT3 has been shown to be superior to treatment with polyclonal antisera. To date, only OKT3 has demonstrated consistent efficacy in reversing rejection crisis. METHODS: From 1989 to 1993, a phase II trial comparing the mAb T10B9.1A31 (T10B9) with OKT3 for treatment of acute cellular rejection in renal allograft recipients was done at the University of Kentucky. We collected data from 178 patients potentially eligible to enter the study; 48 never rejected, 9 refused, 13 could not be biopsied, 16 received methylprednisolone, and 11 received antithymocyte globulin or OKT3. Altogether, 81 patients entered the study, 76 of whom were able to be evaluated. Patients with biopsy-confirmed acute rejection were randomly assigned to T10B9 or OKT3 for at least 10 days. RESULTS: Demographically, there was no difference between the T10B9 or OKT3 cohorts. Actuarial graft survival at 4 years was 87% for patients receiving T10B9, 79% for those receiving OKT3, and 89% for those receiving both mAbs (P=0.55). Patient survival at 4 years was 94% for T10B9, 100% for OKT3, and 89% for both mAbs (P=0.45). Mean creatinines of the cohorts were no different at 1, 6, 12, 24, and 36 months. There was less cytokine nephropathy (P<0.001) observed in patients receiving T10B9. Untoward gastrointestinal, neurological, respiratory, and febrile effects were significantly more frequent in the OKT3 cohort after the first dose (day 0) and with later (day 1-9) administration. Cytokine levels (tumor necrosis factor alpha and interferon gamma) measured 2 hr after the first dose were three to six times higher in patients treated with OKT3 than in those treated with T10B9 (P<0.005). Infectious complications were not significantly different, although serious infections occurred only in patients receiving OKT3. No cases of posttransplant lymphoproliferative disorder were seen in either cohort. Human anti-mouse antibody development was as follows: titer 1:100, 30% T10B9, 42% OKT3; titer 1:1000, 3% T10B9, 3% OKT3. There was no cross-reactivity with OKT3 in patients treated with T10B9, and there was only 9.7% cross-reactivity to T10B9 in patients treated with OKT3. CONCLUSIONS: T10B9 provides treatment for renal allograft acute cellular rejection as effective as that of OKT3 with fewer untoward effects, less cytokine release and nephropathy, fewer serious infections, and without increased development of human anti-mouse antibody. The lack of cross-reactivity offers an alternative therapy should the first mAb fail or re-rejection occur. A phase III trial should be initiated in renal allograft recipients, and phase I and phase II trials should be initiated in other solid-organ transplantations.
Aetiology of Parkinson's disease.
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In vivo interference of paromomycin with mitochondrial activity of Leishmania.
Paromomycin is an aminocyclitol aminoglycoside antibiotic used for the treatment of leishmaniasis. In view of the central role of mitochondria in cellular energetics and metabolism, its effect on in vivo mitochondrial activities of Leishmania donovani promastigotes-the parasite flagellate form-was investigated. The approach used flow cytometry, amperometric measure of O2 consumption, and, as a global estimate of mitochondrial dehydrogenases, thiazolyl blue reduction (MTT test); some in vitro controls were also made. When added to promastigote cultures for 24-72 h at 150-200 microM (= LC50), paromomycin doubled the generation time, inhibited respiration, and lowered its associated electric potential difference across mitochondrial membranes, as measured by rhodamine 123 fluorescence. The chemical analogue neomycin was ineffective. Furthermore, the in vivo mitochondrial dehydrogenase activities were lower, seemingly because of the shortage of respiratory substrates. Indeed, succinate addition to paromomycin-treated cultures partly restored mitochondrial membrane potential. However, no immediate effect of paromomycin on respiration was observed, neither inhibition of redox chain nor increase of membrane permeability (uncoupling). It is proposed that paromomycin acts at a metabolic level upstream of the respiratory chain itself. This would have the observed delayed consequence because the cell energy supply would progressively decline since it depends upon the proton gradient-viz., membrane potential-generated by respiration. In conclusion, paromomycin is an antibiotic affecting the cell's energetic metabolism; the respiratory dysfunction it induces may be a crucial aspect of its action against Leishmania and possibly other cells.
Penicillin-resistant Streptococcus pneumoniae in Ontario, 1987-1995.
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The nuclear receptor homologue Ftz-F1 and the homeodomain protein Ftz are mutually dependent cofactors.
Nuclear hormone receptors and homeodomain proteins are two classes of transcription factor that regulate major developmental processes. Both depend on interactions with other proteins for specificity and activity. The Drosophila gene fushi tarazu (ftz), which encodes a homeodomain protein (Ftz), is required zygotically for the formation of alternate segments in the developing embryo. Here we show that the orphan nuclear receptor alphaFtz-F1 (ref. 3), which is deposited in the egg during oogenesis, is an obligatory cofactor for Ftz. The two proteins interact specifically and directly, both in vitro and in vivo, through a conserved domain in the Ftz polypeptide. This interaction suggests that other nuclear receptor/homeodomain protein interactions maybe important and common in developing organisms.
Impaired color vision in cocaine-withdrawn patients.
BACKGROUND: The main reinforcing effect of cocaine happens by altering dopaminergic neurotransmission in the brain reward systems. Dopamine is found in high concentrations in the retina in which it plays an important role in color vision. Therefore, we investigated whether cocaine-dependent patients might have impaired color vision. METHODS: We compared patients recently withdrawn from cocaine (n = 31) with matched normal controls (n = 31) on 2 color vision tests. RESULTS: Cocaine-withdrawn patients had significantly higher error scores than matched controls on the Farnsworth-Munsell 100-hue and Lanthony desaturated D-15 color vision tests. Also, 23 of the 31 cocaine-withdrawn patients had blue-yellow color vision losses on the Farnsworth-Munsell 100-hue test compared with 3 controls (P < .001, chi 2 test) and 15 had blue-yellow color vision loss on the Lanthony desaturated D-15 test compared with 2 controls (P < .001, chi 2 test). CONCLUSIONS: These significantly higher test error scores and blue-yellow color vision losses suggest that color vision is impaired in cocaine-withdrawn patients. Color vision testing may be useful in future studies of cocaine-dependent patients.
Biochemical alterations in paromomycin-treated Leishmania donovani promastigotes.
Paromomycin is used for the treatment of leishmaniasis in humans, but little is known about its mechanism of action. Investigating the effect of this antibiotic on promastigotes of Leishmania donovani, we showed that inhibition of the multiplication of these parasites could be related to its effect on RNA synthesis and to modifications of membranous polar lipids and membrane fluidity, leading to altered membrane permeability.
rhuIL-2 adjunctive therapy in multidrug resistant tuberculosis: a comparison of two treatment regimens and placebo.
SETTING: Low-dose recombinant human interleukin 2 (rhuIL-2) adjunctive immunotherapy in multidrug resistant tuberculosis (MDR-TB) patients. OBJECTIVE: Evaluation of the effects of daily versus pulse-administered rhuIL-2 compared to placebo. DESIGN: MDR-TB patients on best available antituberculous chemotherapy received rhuIL-2 for 30 consecutive days (daily therapy), or for 5 days followed by a 9-day 'rest', for three cycles (pulse therapy). Placebo control patients received diluent. The cumulative total dose of rhuIL-2 given to each patient in either rhuIL-2 treatment group was the same. Patient immunologic, microbiologic, and radiologic responses were compared. RESULTS: The three treatment schedules induced different results. Immune activation was documented in patients receiving daily rhuIL-2 therapy. Numbers of CD25+ and CD56+ cells in the peripheral blood were increased in these patients, but not in patients receiving pulse rhuIL-2 or placebo. In addition, 5/8 (62%) patients receiving daily rhuIL-2 demonstrated reduced or cleared sputum bacterial load while only 2/7 (28%) pulse rhuIL-2 treated and 2/8 (25%) controls showed bacillary clearance. Chest radiographs of 7/12 (58%) patients receiving daily rhuIL-2 indicated significant improvement over 6 weeks. Only 2/9 (22%) pulse rhuIL-2-treated patients and 5/12(42%) placebo controls showed radiologic improvement. CONCLUSION: Daily low dose rhuIL-2 adjunctive treatment stimulates immune activation and may enhance the antimicrobial response in MDR-TB.
Cloning of a WD-repeat-containing gene from alfalfa (Medicago sativa): a role in hormone-mediated cell division?
Rhizobium meliloti can interact symbiotically with Medicago plants thereby inducing the formation of root nodules. Screening of a young nodule cDNA library led to the isolation of a cDNA from Medicago sativa, Msgbl, that comprises a new member of the RACK1 (Receptor of Activated C Kinase) subfamily of WD-repeat proteins. This subfamily shows homology to the beta-subunit of heterotrimeric G proteins. Besides RACK1, this subfamily contains several plant genes including the well characterized auxin-inducible ArcA of tobacco. The Msgbl gene is strongly expressed in young embryos and in leaves, and is induced upon cytokinin treatment of roots. Whereas northern analysis failed to reveal differences in expression between total RNA from roots and nodules, in situ hybridization demonstrated that the transcript was most abundant in dividing cells of nodule primordia and in the nodule meristem. Msgbl may be related to the signal transduction acting in response to hormone-mediated cell division.
Metal-recognition by repeating polypeptides.
Attachment of proteins to metal surfaces has the potential to improve our understanding of protein adhesion and has applications in sensor technology. Repeating polypeptides able to bind to metallic gold or chromium were selected from a population of approximately 5 million different polypeptides. Each polypeptide contained several direct repeats of identical peptide units 14 or 28 amino acids long. The metal-recognizing polypeptides were found to retain their binding properties when freed from the protein used to select them. One gold-binding polypeptide's avidity for gold was found to be dependent on the number of repeats and the presence of salt.
A second dose of a CFTR cDNA-liposome complex is as effective as the first dose in restoring cAMP-dependent chloride secretion to null CF mice trachea.
Phase I clinical trials have provided encouraging data suggesting that gene transfer could provide a treatment for cystic fibrosis (CF). However, for all the current viral and nonviral vectors used to deliver the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the duration of CFTR expression is limited, necessitating a repeat dosing regimen to provide a long-term treatment. This study was performed to determine whether a second delivery of a CFTR cDNA-liposome complex could result in a similar level of functional CFTR expression observed after a single delivery and to assess whether the deliveries produced adverse inflammatory responses. CFTR functional expression was assessed by short circuit current measurements of tracheas taken from CF null mice (Cftrtm1Cam) treated with a CFTR cDNA-liposome complex in the upper airways. Mice receiving two deliveries of this complex, the second after the response to the first had declined, showed cAMP-stimulated chloride currents which were not significantly different from normal tracheas or tissues assayed after a single dose of the complex. This double treatment was well tolerated with no discernible inflammation of lung tissue.
The impact of the commissioning agenda upon nursing practice: a proactive approach to influencing health policy.
The commissioning aspect of purchasing, in the context of health care, has been heralded as an activity that will effect a shift towards a health service. According to the Department of Health (DoH), England, it will be a key factor in ensuring the ideals of the reforms; i.e. efficiency, equity and effectiveness move from being rhetoric to reality. The importance being placed upon commissioning has implications for the functioning of each professional group. Nursing has historically been identified as relatively naive in matters outside the immediate province of patient care and has suffered from a lack of any real influence in the health policy arena. This paper attempts to describe the impact that the current emphasis on commissioning will have on nursing practice and proposes that unless nurses understand and engage in debate around the purchasing and commissioning function in health care, nursing's capacity to influence the future development of patient services will be severely limited. A framework is outlined for addressing this, thereby ensuring that nursing can proactively inform present and future commissioning agendas.
A carbonic anhydrase gene is induced in the nodule primordium and its cell-specific expression is controlled by the presence of Rhizobium during development.
Under nitrogen starvation, Rhizobium meliloti is able to induce nitrogen-fixing nodules on alfalfa roots. Certain alfalfa cultivars spontaneously develop pseudonodules in the absence of bacteria. A transcript, Msca1, expressed in spontaneous and R. meliloti-induced nodules, that codes for a carbonic anhydrase (CA), an enzyme catalyzing the hydration of CO2 has been identified. This is the first CA gene cloned from a non-photosynthetic tissue in plants. Msca1 was activated initially in all cells of the bacterium-induced nodule primordium and was also induced by cytokinin treatment of alfalfa roots. The presence of CA enzymatic activity in different nodule types was demonstrated. Thus, Msca1 is a new early nodulin gene with a function possibly related to the increased amyloplast deposition of the dividing cortical cells. Msca1 transcripts were subsequently found mainly in a peripheral envelope of cells in developing and mature nodules. This novel pattern of gene expression is controlled by the presence of the bacterium inside the nodule. Sucrose synthase and phosphoenol pyruvate carboxylase (PEPC), other genes of the carbon fixation metabolism, were expressed in the same peripheral cells and even more strongly in the nitrogen-fixing region. Analysis of expression patterns of these genes indicated that early CA function may not be related to carbon fixation through PEPC. CA might be acting in pH regulation and/or CO2/HCO3-transport during nodule initiation. Thus, carbonic anhydrase may play different roles at several stages of nodule development and function.
Pyloric stenosis: is over-reliance on ultrasound scans leading to negative explorations?
AIM: To see whether increasing use of ultrasound scans in pyloric stenosis is leading to false-positive diagnoses, and even negative laparotomies. METHODS: Over a 2-year period, 76 neonates underwent laparotomy with a preoperative diagnosis of pyloric stenosis (PS). There were 57 males and 19 females, age ranged from 10 days to 7 weeks. RESULTS: Six patients proceeded straight to surgery after undergoing a test feed. The remaining 70 patients had one or more imaging investigations. Of these; 56 patients had an ultrasound only, 5 had a barium meal only while 9 patients had both investigations. Ultrasound showed evolving lesions in 2 patients. It was equivocal or falsely negative in 8 - all were diagnosed correctly after undergoing barium meals. Fifty-two patients were diagnosed correctly on ultrasound. There were, however, 3 false-positive ultrasonic diagnosis--i.e., at laparotomy the pylorus was found to be normal. One of these patients even had a "diagnostic" barium meal. The factors leading to these negative explorations are discussed. CONCLUSION: Pyloric "tumours" can be difficult to palpate early in the evolution of the disease. Reliance upon the ultrasound appearance of the pylorus without taking into account other important diagnostic evidence will increase the risk of false-positive diagnoses and unnecessary laparotomy. The importance of clinical examination and test feed is emphasised.
A profile of UK unemployment: regional versus demographic influences.
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High-level tetracycline-resistant Neisseria gonorrhoeae in Ontario, Canada--investigation of a cluster of isolates, showing chromosomally mediated resistance to penicillin combined with plasmid-mediated resistance to tetracycline.
Between 1991 and 1994, plasmid-mediated, tetracycline-resistant Neisseria gonorrhoeae (TRNG) increased from 61.8% to 85.96% of all resistant isolates in Ontario, Canada. Ninety-nine isolates with tetracycline MICs >32 mg/L were characterized by auxotype/serovar (A/S) class, plasmid profile, hybridization with eight tetracycline-resistant probes, and pulsed-field gel electrophoresis (PFGE) of genomic DNA after digestion with NheI and SpeI restriction endonucleases. A cluster of 82 isolates with penicillin MICs of 2-4 mg/L and tetracycline MICs of 128 mg/L (chromosomally mediated resistance) belonged to A/S class NR/IB-1 and had identical or closely related PFGE profiles. Seventeen isolates, TRNG (10) and penicillinase-producing TRNG (7), with tetracycline MICs of 64-256 mg/L, belonged to eight A/S classes and displayed 12 different PFGE profiles. The 99 isolates hybridized only with the TetM probe. Phenotypic and molecular characterization indicated a diverse population throughout the Province of Ontario.