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Biomedical subjects

L P McMahon

Publications and source records attributed to L P McMahon.

At least 19 recordsLinked to original sources
PubMed2004

Modulation of the protein kinase activity of mTOR.

mTOR is a founding member of a family of protein kinases having catalytic domains homologous to those in phosphatidylinositol 3-OH kinase. mTOR participates in the control by insulin of the phosphorylation of lipin, which is required for adipocyte differentiation, and the two translational regulators, p70S6K and PHAS-I. The phosphorylation of mTOR, itself, is stimulated by insulin in Ser2448, a site that is also phosphorylated by protein kinase B (PKB) in vitro and in response to activation of PKB activity in vivo. Ser2448 is located in a short stretch of amino acids not found in the two TOR proteins in yeast. A mutant mTOR lacking this stretch exhibited increased activity, and binding of the antibody, mTAb-1, to this region markedly increased mTOR activity. In contrast, rapamycin-FKBP12 inhibited mTOR activity towards both PHAS-I and p70S6K, although this complex inhibited the phosphorylation of some sites more than that of others. Mutating Ser2035 to Ile in the FKBP12-rapamycin binding domain rendered mTOR resistant to inhibition by rapamycin. Unexpectedly, this mutation markedly decreased the ability of mTOR to phosphorylate certain sites in both PHAS-I and p70S6K. The results support the hypotheses that rapamycin disrupts substrate recognition instead of directly inhibiting phosphotransferase activity and that mTOR activity in cells is controlled by the phosphorylation of an inhibitory regulatory domain containing the mTAb-1 epitope.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies.

The role and control of the four rapamycin-sensitive phosphorylation sites that govern the association of PHAS-I with the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E), were investigated by using newly developed phospho-specific antibodies. Thr(P)-36/45 antibodies reacted with all three forms of PHAS-I that were resolved when cell extracts were subjected to SDS-polyacrylamide gel electrophoresis. Thr(P)-69 antibodies bound the forms of intermediate and lowest mobility, and Ser(P)-64 antibodies reacted only with the lowest mobility form. A portion of PHAS-I that copurified with eIF4E reacted with Thr(P)-36/45 and Thr(P)-69 antibodies but not with Ser(P)-64 antibodies. Insulin and/or amino acids increased, and rapamycin decreased, the reactivity of all three antibodies with PHAS-I in both HEK293 cells and 3T3-L1 adipocytes. Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1. Interestingly, the phosphorylation of Thr-69 and Ser-64 was much more sensitive to inhibition by rapamycin-FKBP12 than the phosphorylation of Thr-36/45, and the phosphorylation of Ser-64 by mTOR was facilitated by phosphorylation of Thr-36, Thr-45, and Thr-69. In these respects the phosphorylation of PHAS-I by mTOR in vitro resembles the ordered phosphorylation of PHAS-I in cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Effects of haemoglobin normalization on quality of life and cardiovascular parameters in end-stage renal failure.

BACKGROUND: The optimal haemoglobin concentration ([Hb]) for patients with end-stage renal failure is uncertain. In particular, it is unclear whether Hb normalization may be an advantage to such patients who are otherwise well. METHODS: A prospective, randomized, double-blind cross-over study was completed in 14 haemodialysis patients (12 male) aged between 23 and 65 years over a period of 18 months, using a variety of measures to examine the effect of epoetin at target [Hb] of 10 g/dl ([Hb](10)) and 14 g/dl ([Hb](14)). Patients were randomized to maintain one or other of the target levels for 6 weeks before being crossed over to the alternative [Hb]. Baseline data (mean [Hb]: 8.5+/-0.2 g/dl) were also included selectively. Six patients were known to be hypertensive. Comparisons were made between 24-h ambulatory blood pressure levels (ABP), echocardiographic findings and estimates of blood volume (BV), plasma volume (PV) and Hb mass. Quality of life estimates were obtained using the Sickness Impact Profile (SIP), and epoetin dosage requirements at target [Hb] were assessed. RESULTS: Daytime and nocturnal ABP (systolic and diastolic) were not different at the respective target [Hb], although nocturnal diastolic levels were higher compared with baseline (73+/-4 mmHg) at both [Hb](10) (83+/-3, P:<0.01) and [Hb](14) (81+/-6, P:<0.05). Significant reductions in cardiac output (5.2+/-0.3 vs 6.6+/-0.5 l/min, P:<0.01) and left ventricular end-diastolic diameter (4.8+/-0.2 vs 5.2+/-0.2 cm, P:<0. 001) were found at [Hb](14) compared with [Hb](10). Left ventricular mass index was correlated with both PV (P:<0.001) and BV (P:<0.01), but not with Hb mass. The PV decreased as the [Hb] rose (P:<0.001) but BV remained unchanged. Quality of life was significantly improved at [Hb](14) compared with [Hb](10) for both total score (6. 5+/-1.7 vs 13.4+/-3.0, P:=0.01) and psychosocial dimension score (5. 4+/-1.9 vs 15.4+/-4.0, P:<0.01). The maintenance weekly dose of epoetin required was 80% higher at [Hb](14) compared with [Hb](10) (P:<0.001). CONCLUSION: These data suggest there may be a significant haemodynamic and symptomatic advantage in maintaining a physiological [Hb] in haemodialysis patients. Although untoward effects were not identified in this study at [Hb](14), a substantially higher dose of epoetin is required to maintain this level.

Adult↗
PubMed2000

Management of essential thrombocythaemia during pregnancy.

Essential thrombocythaemia is a rare myeloproliferative disorder that often presents with haemorrhagic or thrombotic complications. It may be detected incidentally in an asymptomatic younger adult and there are only a few case reports of essential thrombocythaemia in pregnant women. The risks posed by essential thrombocythaemia during pregnancy and its optimal management are uncertain. To determine if there is increased incidence of obstetric complications seen in women who have essential thrombocythaemia, we collected a large case series from a number of tertiary obstetric units in Australia and New Zealand. There were 30 pregnancies in 12 women who had essential thrombocythaemia. There were 17 live births (57%), 7 stillbirths (23%), 5 miscarriages (17%) and 1 ectopic (3%). Five pregnancies were complicated by placental abruption. When the outcomes of those women who received treatment with aspirin or interferon were compared to those that did not receive any treatment, there was a trend towards a higher livebirth rate (79% v. 38%, p = 0.06). Seven women were treated with aspirin and 5 had successful outcomes with no fetal complications. Four women were treated with alpha-interferon which reduced their platelet counts and all had successful outcomes with no fetal complication. These findings suggest that there is a high incidence of miscarriage, stillbirth and abruption in women with essential thrombocythaemia. Their pregnancies should be carefully monitored. Treatment with low dose aspirin and/or the use of alpha-interferon may be associated with an improved pregnancy outcome.

Adult↗
PubMed2000

Heroin overdose and myoglobinuric acute renal failure.

BACKGROUND: Heroin abuse is an increasing problem in Australia. In our hospitals we have noted an apparent increase in drug-related admissions. In this study we aimed to examine the incidence of renal failure due to heroin-related rhabdomyolysis and to determine any predisposing factors to the requirement for dialysis in these patients. PATIENTS AND METHODS: We identified a group of 27 patients who developed renal failure after recent intravenous heroin use. There was a significant rise in the incidence during 1997-1998 compared with the previous seven years (p < 0.05). RESULTS: Rhabdomyolysis was the likely cause of renal failure in all cases. Eight patients required dialysis for an average of 14 days (range 3-26). Patients who required dialysis had a higher admission creatine kinase (115 x 10(3) U/l (1-316), median (range), versus 9 x 10(3) (0-91 ), p < 0.05 ), a higher admission creatinine (3.8 mg/dl (2.1- 6.7) versus 2.4 (1.4-8.1), p < 0.05 ), a higher peak creatinine kinase (129 x 10(3) U/l (2-316) versus 22 x 10(3) (3-197), p < 0.05), a lower urine output in the initial 24 hours (0.91/24 hrs (0.1-1.5) versus 3.9(1.0-11.1), p < 0.005) and a longer length of hospitalization (37 days (17-112) versus 12 (5-87), p < 0.05). No patient died and all patients had independent renal function at last review. The majority of patients had significant comorbidities. The incidence of serological evidence of exposure to blood-borne viruses was HIV 5% (n = 1), hepatitis B 10% (n = 2) and hepatitis C 74% (n = 17) of patients tested. Pneumonia occurred in 52% (n = 14) and 26% (n = 7) developed respiratory failure requiring intubation. 22% (n = 6) developed a compartment syndrome requiring fasciotomy and 37% (n = 10) had significant residual limb weakness at discharge. CONCLUSION: There is an increase in patients admitted with rhabdomyolysis-induced renal failure associated with heroin use in our hospitals. We found a varied approach to an increasing clinical problem and suggest that a consistent investigative and therapeutic approach be introduced. Although renal recovery can be expected, long-term disability may occur due to potential serious complications.

Acute Kidney Injury↗
PubMed1999

Physical performance and associated electrolyte changes after haemoglobin normalization: a comparative study in haemodialysis patients.

BACKGROUND: To determine the effects of different haemoglobin (Hb) levels on exercise performance and associated electrolyte changes, a prospective, randomized, double-blinded crossover study was completed in 14 haemodialysis patients. METHODS: Performance and changes in arterial [K+] and lactate were compared at rest and during a maximal incremental cycling exercise at a Hb concentration ([Hb]) of 10 g/dl ([Hb]10) and 14 g/dl ([Hb]14) following an initial baseline test (Hb: 8.3 +/- 0.2 g/dl, mean +/- SEM). Ages ranged from 23 to 65 years and patients were divided into younger (age 23-45 years, n = 9) and older (aged 55-65 years, n = 5) groups. RESULTS: Peak work rate and VO2 peak were higher at [Hb]14 than at [Hb]10. 145 +/- 9 vs 134 +/- 9 W, mu +/- SEM, P < 0.01, and 1.90 +/- 0.11 vs 1.61 +/- 0.11 l/min, P < 0.01, respectively. Improvements were demonstrated in both younger and older groups at the higher target [Hb], with an improved aerobic performance evident particularly in younger patients. However, performance remained below that predicted for comparable sedentary controls. Resting plasma [K+] was raised at both [Hb]10 and [Hb]14 compared with baseline (P < 0.01) although the change in [K+] from rest to peak exercise (delta[K+]) was similar at each level. The delta[K+] per unit work performed (used as a marker of K+ regulation) was, however, inversely related to the [Hb] (baseline: 80 +/- 12 micromol/l/kJ vs [Hb]10, 61 +/- 8, P < 0.01, vs [Hb]14. 49 +/- 7, P < 0.05). Exercise induced a significant but similar rise in lactate concentration at both target [Hb] (P < 0.001), which remained markedly elevated for at least 10 min after exercise in both younger and older groups. CONCLUSIONS: These data demonstrate that a physiological [Hb] improves, but does not normalize, exercise performance in end-stage renal failure. Both younger and older patients appear to benefit similarly from the enhanced oxygen transport. Impaired K+ regulation is apparently related to [Hb] and could well contribute to the observed limitations in performance.

Adult↗
PubMed1999

Does early anemia correction prevent complications of chronic renal failure?

Anemia is a common complication of chronic renal failure (CRF). With the availability of recombinant human erythropoietin (rhEPO) over the last decade, much progress has been made in the management of anemia in patients with end-stage renal disease (ESRD) [Eschbach 1995, Gimenez and Scheel 1994, Muirhead et al. 1995, Winearls 1995]. The clearest benefit of rhEPO in ESRD is a substantial reduction in transfusion dependency, which reduces the need for hospital admission and the risk of viral transmission. Improvements in hemostasis and a decrease in human leucocyte antigen (HLA) antibodies have also been reported. Beneficial effects of rhEPO on the cardiovascular system in ESRD include regression of left ventricular hypertrophy (LVH), improvement of angina, and a modest increase in aerobic work capacity. Treatment of anemia with rhEPO has also been shown to improve cognitive function, socialization and quality of life in dialysis patients, although this has not led to better vocational rehabilitation or employment status. It has also been reported that a lower hemoglobin (Hb) content is an independent risk factor for increased mortality in hemodialysis patients [Harnett et al. 1995]. Clearly, therefore, treatment of anemia associated with ESRD is required and beneficial. The optimum treatment of anemia prior to dialysis, however, is still a matter for debate.

Anemia↗
PubMed1995

N5-methylasparagine and energy-transfer efficiency in C-phycocyanin.

A posttranslationally methylated asparagine residue, N5-methylasparagine, is found at the beta-72 site in many phycobiliproteins. Two mutations (Asp and Gln) in the beta-72 position of Agmenellum quadruplicatum C-phycocyanin were investigated to clarify the role of the wild-type N5-methylasparagine near the beta-84 "fluorescing" bilin tetrapyrrole chromophore. Chemical analysis for amide modification revealed that the beta-72Q protein was partially methylated with a stoichiometry of 0.27, suggesting that either the asparagine methyltransferase is nonspecific or a glutamine methyltransferase exists. Urea denaturation studies could detect no difference in protein stability for any of the C-phycocyanin species. Steady-state spectroscopic measurements demonstrate that Asp and Gln substitution for the C-phycocyanin beta-72 NMA affects both the ground to excited state transition and the excited-state characteristics of the beta-84 chromophore, while the rate of radiative energy transfer is unaffected. Energy-transfer efficiency within phycobilisomes (represented by steady-state fluorescence quantum yields) was also negatively impacted by the beta-72 substitutions. Time-resolved fluorescence emission spectroscopic studies with C-phycocyanin reveal three distinguishable fluorescence lifetimes. The longest fluorescence lifetime is diminished 7-10% by the Asp and Gln mutations in comparison to a control sample where beta-72 is NMA. Molecular dynamics calculations implicate a change in the bilin tetrapyrrole chromophore ring geometry as a likely source of the altered photophysics induced by the mutations. We conclude that N5-methylasparagine plays a special role in establishing the environment surrounding the beta-84 chromophore which minimizes the rates of nonradiative energy losses that would otherwise defeat the high quantum yield for energy transfer within the phycobilisomes.

Asparagine↗
PubMed1993

Expression of the three endothelin genes and plasma levels of endothelin in pre-eclamptic and normal gestations.

1. Maternal vasoconstriction and fetal growth retardation are part of the syndrome of pre-eclampsia and are thought to be related to placental insufficiency. There is evidence to suggest that the powerfully vasoactive endothelin peptides might be involved in the pathogenesis. 2. The production of endothelins appears to be regulated mainly by modulation of mRNA levels, and they are thought to exert their effects locally, rather than systemically. Hence, the measurement of endothelin mRNA levels in tissues would be expected to reflect the activity of the endothelin systems. 3. RNAase protection assays, using specific antisense probes capable of distinguishing between the endothelin mRNA isoforms, have been used to examine the expression of the three endothelin genes in placental villous tissue, amniotic membrane and myometrium. Samples were taken from 15 pre-eclamptic women and from 14 women with normal gestations. Myometrium was taken at hysterectomy from five non-pregnant women as an additional control. Plasma concentrations of immunoreactive endothelin [endothelin-1, endothelin-2 and big endothelin (not distinguished)] were measured in samples taken concurrently from uterine vein and peripheral blood during surgery in ten patients. 4. The level of endothelin-1 mRNA in placental villous tissue was significantly higher in pre-eclamptic women (32 weeks gestation) than in control subjects (38 weeks gestation) (1.85 +/- 0.26 versus 0.52 +/- 0.09 arbitrary units, means +/- SEM, P < 0.001) and in gravid than in non-gravid myometrium (P < 0.001). Endothelin-2 was not expressed in villous tissue, but was expressed in amniotic membrane and myometrium, with relatively little difference between pre-eclamptic and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Haemodynamic changes and physical performance at comparative levels of haemoglobin after long-term treatment with recombinant erythropoietin.

Physical performance and haemodynamic parameters at rest and with exercise were compared in a prospective, cross-over fashion in 12 anaemic haemodialysis patients (Hb 6.4 +/- 0.5, mean +/- SEM) at two levels of haemoglobin (Hb 9 and 12 g/dl) before and after long-term treatment with recombinant human erythropoietin (rHuEpo). Patients were divided into two groups and measurements made prior to treatment, upon reaching, and after 4 months at the first target Hb (9 g/dl group A, 12 g/dl group B), and after 4 months at the alternative target Hb. Tests included an exercise radionuclide ventriculogram, Doppler echocardiogram, and respiratory function exercise test. Compared to pretreatment, there was a significant reduction in resting pulse rate (P < 0.001), and in pulse rate (P < 0.001) and arterial lactate (P < 0.01) concentrations at specified levels of exercise. Work capacity improved 60% (P < 0.001), and left ventricular mass fell by 26% (P < 0.001). Although cardiac output (CO) during and after exercise was reduced (P < 0.05), resting CO, cardiac index, stroke volume and ejection fraction (rest and exercise) were not significantly altered. There appeared little benefit in having the higher target Hb: no significant difference could be found between target levels for almost any measure. In addition, despite marked improvement from pretreatment levels, performance parameters were still below those of non-uraemic age-matched controls. These results demonstrate the beneficial but incomplete effect of rHuEpo on resting and exercise-related factors, and suggest that most improvement is achieved with modest increments in haemoglobin.

Anemia↗
PubMed1992

Subjective quality of life assessment in hemodialysis patients at different levels of hemoglobin following use of recombinant human erythropoietin.

The quality of life of 12 hemodialysis (HD) patients was assessed in a prospective, blinded, cross-over fashion before treatment with recombinant human erythropoietin (r-HuEPO) and at two different levels of hemoglobin (Hb, 9 and 12 g/dl) by means of an interviewer-based questionnaire, the sickness impact profile (SIP). Patients were matched into two groups with no significant difference for age, weight, Hb (6.3 +/- 0.5, mean +/- SEM, group A, vs. 6.4 +/- 0.9 group B), length of hemodialysis or number of years of prior transplantation. SIP was assessed prior to treatment, after reaching the first target Hb (Hb 9 g/dl group A, 12 g/dl group B), after 4 months at that target Hb and after 4 months at the alternative target Hb for each group. For all patients, there was a highly significant improvement in quality of life as assessed by lower SIP scores between the initial and second assessments. This was evident for the physical (8.9 +/- 1.4 vs. 2.8 +/- 1.0; p less than 0.001) and psychosocial (14.9 +/- 3.9 vs. 4.4 +/- 1.1; p less than 0.01) dimensions. Total scores (16.3 +/- 2.4 vs. 5.7 +/- 0.9; p less than 0.001) showed similar changes, reflecting significant improvement in 10 of 12 possible categories between the first two assessments (p less than 0.05 to p less than 0.001). Improved scores were maintained but did not change appreciably after the 2nd assessment. There was no significant difference in any score (category, dimensional or total) obtained after 4 months at Hb 9 g/dl compared to those after the same period at Hb 12 g/dl.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia↗
PubMed1991

Shoulder ultrasound in dialysis related amyloidosis.

Ultrasonographic changes around the shoulder joint were compared in ten symptomatic patients with dialysis related amyloid (DRA) and seventeen patients without symptoms. All patients had been on long-term (greater than 7 years) hemodialysis (HD). Three control groups were used: 8 predialysis patients, 10 continuous ambulatory peritoneal dialysis (CAPD) and 9 HD patients who had been on dialysis for less than two years. Dry bodyweight, sex, handedness, length of hemodialysis and fistula side were not significantly different between the study groups. Proven amyloid patients were significantly older than other groups (p less than 0.001). Parameters assessed included cross-sectional area of long head of biceps tendon (LHB), diameter of supraspinatus tendon (SS), and general features (bursae, deposits) around the joint. Results demonstrated significant differences in all parameters in patients with symptomatic amyloid compared with other long-term patients: [SS: 7.4 mm +/- 0.7, mean +/- SEM, vs 5.1 +/- 0.2 (right, R), p = 0.001; 6.7 +/- 0.7 vs 4.9 +/- 0.2 (left, L), p = 0.01. LHB: 140.0 mm2 +/- 11.1 vs 79.6 +/- 5.1 (R), p less than 0.001; 114.5 +/- 10.5 vs 80.8 +/- 5.4 (L), p = 0.004. Bursae: 5 vs 1 (patients), p = 0.006]. Compared with controls changes in the amyloid group were less marked though in most cases still significant. There was no significant difference between control groups nor between controls and asymptomatic long-term HD patients in any parameter. We conclude that shoulder ultrasound may have a role in identifying patients with dialysis related amyloid. Serial measurements may also help to elucidate the pathogenesis of the tendon changes.

Adult↗
PubMed1990

Experience with low dose intravenous and subcutaneous administration of recombinant human erythropoietin.

Twelve stable haemodialysis patients were divided into two groups and given recombinant human erythropoietin (r-HuEPO) for 14 weeks either intravenously (i.v.) or subcutaneously (s.c.). Dosage was 25 units/kg either thrice (i.v.) or twice (s.c.) per week for 7 weeks, and then 50 units/kg for a further 7 weeks. Response to s.c. therapy was comparable to i.v. despite a 33% lower weekly dosage, and was significant at both 7 (i.v.: 1.1 +/- 0.3, mean +/- SEM, p = 0.02; s.c.: 0.8 +/- 0.3 g/dl, p = 0.03) and 14 weeks (i.v.: 2.8 +/- 0.5, p = 0.003; s.c.: 2.6 +/- 0.6 g/dl, p = 0.009). A correlation was observed between response to r-HuEPO and initial ferritin levels (r = 0.63, p = 0.04). One patient required an increase in antihypertensive medication and there was one arteriovenous fistula thrombosis. Results suggest that overall s.c. therapy is as effective as i.v. therapy, and that a good response with few side effects can be obtained using relatively low doses of r-HuEPO.

Anemia↗