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Biomedical subjects

P Marshall

Publications and source records attributed to P Marshall.

At least 55 records · Page 3Linked to original sources
PubMed1996

Double-blind placebo-controlled study of the efficacy of oral terfenadine in the treatment of chronic fatigue syndrome.

BACKGROUND: There is no established treatment for chronic fatigue syndrome (CFS), an illness characterized by disabling fatigue exacerbated by physical activity. A variety of immunologic abnormalities have been reported, including a high incidence of atopy and hypoergy or anergy. OBJECTIVE: Because of anecdotal reports and uncontrolled trials showing antihistamine efficacy in CFS, we evaluated the clinical efficacy of the antihistamine terfenadine (60 mg twice daily) in a placebo-controlled study. METHODS: Thirty patients with CFS were enrolled in a 2-month, double-blind, placebo-controlled trial of terfenadine. Participants underwent a battery of both immediate- and delayed-type hypersensitivity skin tests and completed a self-assessment questionnaire used to measure severity of symptoms, physical and social functioning, health perceptions, and mental health before each of six biweekly visits. RESULTS: Twenty-eight patients completed the trial. History of atopy and positive immediate skin test results were prevalent, 73% and 53%, respectively. No evidence for hypoergy or anergy after delayed-type hypersensitivity skin testing was found. No therapeutic benefit from terfenadine could be detected in terms of symptom amelioration, improved physical or social functioning, health perceptions, or mental health. A high incidence of atopy in patients with CFS was confirmed. CONCLUSION: Although this trial involved a small number of patients, the results suggest that terfenadine is unlikely to be of clinical benefit in treating CFS symptoms.

Administration, Oral↗
PubMed1996

Nutritional supplementation in elderly medical in-patients: a double-blind placebo-controlled trial.

The aim of this study was to assess the effect of vitamin and/or glucose energy supplementation in elderly medical patients on an intention-to-treat basis. One hundred and six elderly medical in-patients were entered into a double-bind placebo-controlled factorial trial of glucose energy and vitamin supplementation. Supplementation was given for 1 month. This trial was designed to detect a > 2 kg increase in weight and > 3 g/l increase in serum albumin between active and placebo supplementation in 100 patients with 90% power (p < 0.05). Other outcome measures included changes in Barthel activities of daily living, length of stay, and mental test score (MTS). No interaction between vitamin and glucose supplementation was demonstrated. Active energy supplementation with glucose alone was associated with a +0.6 kg change in weight and +0.7 g/l change in albumin [95% confidence interval (CI) -0.8, +2.0 and -1.3, +2.8, respectively]. The respective changes for active vitamin supplementation were -0.6 kg for weight and +0.5 g/l for albumin (95% CI -2.1, +0.8 and -1.5, +2.6, respectively). There were no significant differences in mental test score, Barthel score, or length of stay between the two groups. Compliance with the glucose energy supplementation was poor with only one-third of patients consuming more than 50% of the offered drink. We conclude that the giving of glucose alone and/or vitamin supplementation in elderly patient is of no benefit on an intention-to-treat basis.

Aged↗
PubMed1996

Heart failure: can it be defined?

Unlike hypertension, heart failure is not readily identified, defined and evaluated. Research and clinical management of heart failure has been handicapped by the absence of a clear definition. In other branches of medicine, e.g. renal or pulmonary failure can be clearly defined with the help of direct measures of organ function. Unfortunately such a parameter does not exist in cardiology to help us with defining cardiac function or failure. Representative definitions of heart failure hitherto proposed are reviewed. A common error in these 'definitions' is the confusion between formulating a definition and giving instructions on how to identify or diagnose heart failure. Other short-comings are also recognised. From these it is possible to compile criteria which a definition of heart failure should possess. When formulating any definition, in order to avoid unnecessary detail, the importance of including only the essence and not the contingents is recognised. To find a new definition which complies best with these criteria is an important challenge facing cardiologists.

Cardiac Output↗
PubMed1995

Comparison of recombinant cyclooxygenase-2 to native isoforms: aspirin labeling of the active site.

The search for isoform-specific enzyme inhibitors has been the focus of much recent research effort. Towards this goal, human recombinant cyclooxygenase-2 (EC 1.14.99.1, prostaglandin H synthase) was expressed in insect cells and purified to > 98% purity. Recombinant enzyme was characterized both by physical methods and activity measurements and shown to be fully active with kinetic properties similar to native COX-2 and COX-1. After detergent extraction, the enzyme had hydrodynamic properties indistinguishable from native bovine COX-1 and corresponded to the enzyme dimer as measured with size-exclusion chromatography. Peptide mapping via Lys-C protease identified a site of N-linked glycosylation and the aspirin covalent modification site. In the presence of heme, aspirin-specifically acetylated Ser-516. The enzyme will be suitable for biophysical studies and may lead to isoform-specific enzyme inhibitors.

Amino Acid Sequence↗
PubMed1994

The I-CeuI endonuclease: purification and potential role in the evolution of Chlamydomonas group I introns.

During genetic crosses between the interfertile green algae Chlamydomonas eugametos and Chlamydomonas moewusii, the I-CeuI endonuclease encoded by the fifth group I intron (CeLSU.5) in the C. eugametos chloroplast large subunit rRNA gene mediates the mobility of this intron by introducing a double-strand break near the insertion site of the intron in the corresponding C. moewusii intronless allele. To characterize the biochemical properties of this endonuclease, we have purified I-CeuI and determined the optimal reaction conditions for cleavage. I-CeuI activity is maximal at 50 degrees C, pH 10.0, 2.5 mM MgCl2 and in the absence of NaCl. Unlike the well-characterized I-SceI endonuclease, I-CeuI remains stable following preincubation in the absence of substrate. We discuss the role that homing endonucleases may have played in the evolution of Chlamydomonas chloroplast group I introns.

Animals↗
PubMed1994

How appropriate are commercially available human milk fortifiers?

A preliminary investigation was made into the effectiveness of two breastmilk fortifiers on the Australian market (FM-85 [Nestlé, Vevey, Switzerland] and Enfamil Human Milk Fortifier [EHMF; Mead Johnson, Evansville, IN, USA]). Infants < 1800 g and < 34 weeks gestation at birth, who were receiving breast milk, were randomized to receive either of the fortifiers (n = 14 for FM-85, n = 10 for EHMF), until a weight of 2 kg was reached. Infants not receiving breast milk (n = 9) were fed a preterm formula (Prenan, Nestlé). The two fortifier groups were similar in most parameters examined: (i) weight gain (17.9 +/- 3.0 vs 17.4 +/- 3.5 g/kg per day); (ii) head circumference growth (1.02 +/- 0.28 vs 1.03 +/- 0.25 cm/week); (iii) arm muscle area growth (32.6 +/- 20.0 vs 33.5 +/- 13.7 mm2/week); (iv) arm fat area growth (14.0 +/- 8.7 mm2/week); (v) plasma calcium (2.52 +/- 0.08 vs 2.58 +/- 0.15 mmol/L); (vi) plasma phosphate (2.02 +/- 0.21 vs 2.13 +/- 0.32 mmol/L); (vii) plasma copper (5.28 +/- 2.83 vs 5.66 +/- 3.07 mumol/L); and (vii) plasma zinc (13.3 +/- 5.5 vs 15.8 +/- 9.2 mumol/L). The FM-85 group had a higher alkaline phosphatase level (355 +/- 110 vs 231 +/- 70 iu/L) than the EHMF group; however, no values were outside the normal range. The Prenan group had a higher rate of weight gain (23.6 +/- 3.3 g/kg per day) and higher arm fat area growth rate (25.2 +/- 7.6 mm2/week) than the fortifier groups while all other parameters were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1993

Cells lacking glycan phosphatidylinositol-linked proteins have impaired ability to vesiculate.

Erythrocytes shed membrane vesicles in response to many stimuli. It has been previously demonstrated that glycan phosphatidylinositol-linked (GPI-linked) proteins such as decay accelerating factor and acetylcholinesterase are concentrated in these vesicles relative to the erythrocyte membrane. We have examined the requirement for GPI-linked proteins for the process of vesiculation. Erythrocytes that do not express GPI-linked proteins, obtained from patients with paroxysmal nocturnal hemoglobinuria (PNH), release between 10% and 50% of the quantity of vesicles as normal cells in response to the Ca2+ ionophore A23187. Platelets from the same patients produced 10% to 20% of the amount of vesicles as normal platelets. In addition, a mutant B-lymphoblastoid cell line that lacks GPI-linked molecules produces about half of the number of vesicles as compared with the wild-type cell line in response to the Ca2+ ionophore. Prior findings indicate that vesiculation is one of the mechanisms that the cell uses to remodel the plasma membrane, as well as protect itself from membrane-damaging agents such as the terminal complement components C5b-9. On the basis of the present results, we conclude that GPI-linked proteins play an important role in membrane vesiculation.

Acetylcholinesterase↗
PubMed1992

The I-CeuI endonuclease recognizes a sequence of 19 base pairs and preferentially cleaves the coding strand of the Chlamydomonas moewusii chloroplast large subunit rRNA gene.

The I-CeuI endonuclease is a member of the growing family of homing endonucleases that catalyse mobility of group I introns by making a double-strand break at the homing site of these introns in cognate intronless alleles during genetic crosses. In a previous study, we have shown that a short DNA fragment of 26 bp, encompassing the homing site of the fifth intron in the Chlamydomonas eugametos chloroplast large subunit rRNA gene (Ce LSU.5), was sufficient for I-CeuI recognition and cleavage. Here, we report the recognition sequence of the I-CeuI endonuclease, as determined by random mutagenesis of nucleotide positions adjacent to the I-CeuI cleavage site. Single-base substitutions that completely abolish endonuclease activity delimit a 15-bp sequence whereas those that reduce the cleavage rate define a 19-bp sequence that extends from position -7 to position +12 with respect to the Ce LSU.5 intron insertion site. As the other homing endonucleases that have been studied so far, the I-CeuI endonuclease recognizes a non-symmetric degenerate sequence. The top strand of the recognition sequence is preferred for I-CeuI cleavage and the bottom strand most likely determines the rate of double-strand breaks.

Animals↗
PubMed1991

Influx of extracellular calcium is required for the membrane translocation of 5-lipoxygenase and leukotriene synthesis.

Our studies assessed the effects of increases in intracellular calcium concentrations [( Ca2+]i) on leukotriene synthesis and membrane translocation of 5-lipoxygenase (5LO). The calcium ionophore ionomycin and the tumor promoter thapsigargin stimulated leukotriene production and translocation of 5-lipoxygenase to the membrane. Both agents elicited prolonged rises in [Ca2+]i. Leukotriene C4 production associated with [Ca2+]i in cells stimulated with various concentrations of ionomycin and thapsigargin suggests that a threshold [Ca2+]i level of approximately 300-400 nM is required. In the absence of extracellular Ca2+, both the ionomycin- and thapsigargin-induced rises in [Ca2+]i were transient, indicating that the prolonged [Ca2+]i elevation is due to an influx of extracellular Ca2+. Addition of EGTA to the external medium before, or at different times during, the treatment with ionomycin or thapsigargin instantaneously inhibited 5LO translocation and leukotriene synthesis, indicating that Ca2+ influx plays an essential role in 5LO membrane translocation and leukotriene synthesis. No leukotriene production was detected when cells were stimulated by a physiological stimulus of leukotriene D4. The addition of 100 nM leukotriene D4 triggered peak rises in [Ca2+]i that were comparable to those achieved by the ionomycin and thapsigargin. However, the leukotriene D4 induced rise was transient and rapidly declined to a lower but still elevated steady-state level, which was attributed to Ca2+ influx. Stimulation with 100 nM leukotriene D4 for 15 s increased the cellular levels of 1,4,5-inositol triphosphate (IP3), 1,3,4-IP3, and 1,3,4,5-inositol tetraphosphate (IP4).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Cleavage pattern of the homing endonuclease encoded by the fifth intron in the chloroplast large subunit rRNA-encoding gene of Chlamydomonas eugametos.

The fifth group-I intron in the chloroplast large subunit rRNA-encoding gene of Chlamydomonas eugametos (CeLSU.5) is mobile during interspecific crosses between C. eugametos and Chlamydomonas moewusii. Like the six other mobile introns that have been well characterized so far, CeLSU.5 contains a long open reading frame (ceuIR) coding for a site-specific endonuclease (I-CeuI) that cleaves the C. moewusii intronless gene in the vicinity of the intron-insertion site. This stimulates gap repair and mediates efficient transfer of the intron at its cognate site. By expressing the ceuIR gene in the Escherichia coli vectors pKK233-2 and pTRC-99A, we recently demonstrated that the endonuclease is highly toxic to E. coli [Gauthier et al., Curr. Genet. 19 (1991) 43-47]. To eliminate this problem and characterize the cleavage pattern and recognition sequence of the I-CeuI endonuclease, we have expressed the ceuIR gene in E. coli under the control of a bacteriophage T7 promoter in a tightly regulated M13 system, and developed an in vitro system to assay partially purified I-CeuI activity. This allowed us to determine that I-CeuI recognizes a sequence of less than 26 bp centered around the insertion site and produces a staggered cut 5 bp downstream from this site, yielding 4-nucleotide (CTAA), 3'-OH overhangs.

Animals↗
PubMed1991

Analgetic activity of SK&F 105809, a dual inhibitor of arachidonic acid metabolism.

The analgetic activity of inhibitors of 5-lipoxygenase (5-LO) and cyclooxygenase (CO) was investigated using rat Randall-Selitto (RS) hyperalgesia and mouse phenylbenzoquinone (PBQ)-induced abdominal constriction assays. Using the RS assay, the CO inhibitors indomethacin, naproxen, and ibuprofen all effectively reduced hyperalgesia; whereas, the inhibitors of leukotriene production, MK886 and phenidone were inactive. SK&F 105809, a dual inhibitor of 5-LO/CO, significantly reduced hyperalgesia. In the PBQ assay, CO inhibitors were active, SK&F 105809 was nearly as potent as naproxen, and MK886 and phenidone were found to be active. Thus, improved analgetic activity appeared to result from inhibition of 5-LO and CO; whereas, in the RS assay, only CO inhibitors and SK&F 105809 were clearly effective. These results suggest that dual inhibitors, and in particular, SK&F 105809 may be more efficient analgesic agents than selective CO inhibitors in clinical situations in which 5-LO products play a significant role.

Analgesics↗
PubMed1991

Action of peptidoleukotrienes on ion transport in rabbit distal colon in vitro.

Serosal but not mucosal addition of the peptidoleukotrienes, leukotriene (LT) C4 (LTC4), LTD4 and LTE4 transiently (maximal response within 2 min) increased short-circuit current (Isc) and transepithelial conductance across stripped rabbit colonic mucosa mounted in Ussing chambers. All three peptidoleukotrienes elicited their responses in the presence of amiloride (10 microM) and were inhibited by serosal addition of the NaCl cotransport inhibitors bumetanide (100 microM) and furosemide (1 mM). The effects of the peptidoleukotrienes on Isc and transepithelial conductance were concentration-dependent with maximal effects occurring at 10 microM. Half-maximal effects were produced at 30 nM for LTC4, 50 nM for LTD4 and 450 nM for LTE4. The secretory responses to both LTD4 and LTE4 were antagonized in a concentration-dependent manner by the LTD4/LTE4 receptor antagonist, SK&F 104353 (2(S)-hydroxy-3-(R)-[(2-carboxyethyl)thio]-3-[2-(8 phenyloctyl)phenyl]propanoic acid). Complete inhibition of the LTD4 and LTE4 effects were observed at 0.1 microM SK&F 104353 and half-maximal effects were achieved at 0.6 nM SK&F 104353. At 10 microM SK&F 104353 only 50% inhibition of the LTC4-induced increase in Isc was observed. These results suggest the peptidoleukotrienes stimulate colonic Cl- secretion by receptor-mediated mechanisms and that receptors for LTC4 are distinct from those mediating the action of LTD4/LTE4.

Animals↗