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Biomedical subjects

M Baines

Publications and source records attributed to M Baines.

At least 19 recordsLinked to original sources
PubMed2006

The association of homocysteine and its determinants MTHFR genotype, folate, vitamin B12 and vitamin B6 with bone mineral density in postmenopausal British women.

We studied the association between plasma total homocysteine (tHcy), its determinants folate, vitamin B(12), vitamin B(6) and MTHFR genotype, and bone mineral density (BMD) in 328 postmenopausal British women. When the subjects were assigned to one of 3 groups (control, osteopenic or osteoporotic) according to their BMD at the os calcis, those in the osteoporotic group had, compared with the controls, a significantly lower serum folate concentration, a significantly higher % of current smokers and a significantly higher incidence of recent fracture. In the population as a whole, we found significant associations of BMD with tHcy (r=-0.130, p=0.033, log tHcy) and folate (r=0.132, p=0.025, log folate). The association of folate with BMD was maintained after correction for age, weight and height (r=0.124, p=0.042, log folate), but the association of tHcy with BMD weakened after correction for age, weight, height and creatinine (r=-0.117, p=0.059, log tHcy). Vitamins B(12) and B(6) were not associated with BMD, but were significantly associated with tHcy, vitamin B(12) (r=-0.34, p<0.0001), vitamin B(6) (r=-0.16, p=0.007), as was folate (r=-0.41, p<0.0001). There was an increasing frequency of the MTHFR TT genotype across the 3 BMD groups, but this did not attain significance. Individuals with the TT genotype had significantly higher plasma tHcy but there was no difference between the genotypes (CC, CT, TT) for folate or BMD. Smoking was associated with a highly significant reduction in BMD and lower weight, and a significant reduction in circulating folate and vitamin B(6) concentrations, but no change in tHcy or vitamin B(12) concentrations when compared with non-smokers. We conclude that low serum folate is a significant risk factor for osteoporosis, with plasma tHcy having a lesser effect. Both vitamins B(12) and B(6), by acting through tHcy, may also have an effect on the skeleton, albeit a weaker one than folate. Cigarette smoking is a strong determinant of BMD, and may act through effects on folate and vitamin B(6).

Aged↗
PubMed2002

The management of gastric outlet obstruction secondary to inoperable cancer.

BACKGROUND: Historically, the distressing symptoms of malignant gastric outlet obstruction have been best managed by open gastrojejunostomy. We provide an assessment of an alternative laparoscopic technique. METHODS: We reviewed eight patients undergoing laparoscopic gastrojejunostomy. Patient data included age, sex, operation time, morbidity and mortality, length of stay, and outcome at 6 months where possible. RESULTS: There were six men and two women, their median age was 67 years. Median operating time was 135 min, median time to solid food was 4 days, and median postoperative stay was 7 days. Seven of our eight patients were palliated successfully using this technique. CONCLUSION: The risks inherent in operating on these patients, who are by definition in a poor state of health, has encouraged much interest in minimal access surgery. We conclude that laparoscopic gastrojejunostomy provides effective palliation of gastric outlet obstruction, and we recommend further evaluation of this technique.

Aged↗
PubMed2002

Lack of effectiveness of short-term intravenous micronutrient nutrition in restoring plasma antioxidant status after surgery.

BACKGROUND AND AIMS: Many patients recovering from surgery may be in a state of negative antioxidant balance. For those whose postoperative nutritional requirements are provided intravenously, this may not be adequate for antioxidant repletion. This study was undertaken to assess the total antioxidant status of these patients peri-operatively and prior to beginning intravenous nutrition (IVN), and to determine the adequacy of IVN, including daily micronutrients, in maintaining or restoring antioxidant status in the post-operative period. METHODS: Plasma total antioxidant status (TAS) was measured in 30 patients who were fed by standard IVN following surgery. Additionally, the 'antioxidant gap' (AOG, a measure of the contribution of antioxidants other than albumin and urate) was calculated. Blood samples were taken on beginning IVN and daily for the duration of IVN, which lasted for up to 26 days. RESULTS: Prior to IVN, 20 of the 30 patients had a plasma TAS below the reference range and 15 of these 20 remained deficient even after IVN of up to 19 days. A further 3 patients became deficient whilst on IVN. When the group of patients who were deficient was compared with the group who were not, it was found that this difference was predominantly due to a difference in the AOG, (518 (115) v 709 (68) micromol/L (mean (SD)), P<0.0001). The groups did not differ in terms of age, C-reactive protein level, duration of IVN or daily thiol intake/Kg body weight. CONCLUSIONS: The difference in the gap antioxidants was thought to be due to their utilization in opposing the extra oxidative burden of surgery. Consideration of the antioxidant provision of standard IVN, principally the thiol-containing amino acids, ascorbate, alpha -tocopherol and trace elements suggests that this is insufficient to counter the sum of the pre-existing oxidative stress and the additional oxidative burden imposed by the surgery.

Adult↗
PubMed2001

Clinical-practice recommendations for the management of bowel obstruction in patients with end-stage cancer.

The paper highlights a series of questions that doctors need to consider when faced with end-stage cancer patients with bowel obstruction: Is the patient fit for surgery? Is there a place for stenting? Is it necessary to use a venting nasogastric tube (NGT) in inoperable patients? What drugs are indicated for symptom control, what is the proper route for their administration and which can be administered in association? When should a venting gastrostomy be considered? What is the role of total parenteral nutrition (TPN) and parenteral hydration (PH)? A working group was established to review issues relating to bowel obstruction in end-stage cancer and to make recommendations for management. A steering group was established by the (multidisciplinary) Board of Directors of the European Association for Palliative Care (EAPC) to select members of the expert panel, who were required to have specific clinical and research interests relating to the topic and to have published significant papers on advanced cancer patients in the last 5 years, or to have particular clinical expertise that is recognised internationally. The final constitution of this group was approved by the Board of the EAPC. This Working Group was made up of English, French and Italian physicians involved in the field of palliative care for advanced and terminal cancer patients; and of English, American and Italian surgeons who also specialized in artificial nutrition (Dr. Bozzetti) and a professor of health economics. We applied a systematic review methodology that showed the relative lack of RCTs in this area and the importance of retrospective and clinical reports from different authors in different countries. The brief was to review published data but also to provide clinical opinion where data were lacking. The recommendations reflect specialist clinical practice in the countries represented. Each member of the group was allocated a specific question and briefed to review the literature and produce a position paper on the indications, advantages and disadvantages of each symptomatic treatment. The position papers were circulated and then debated at a meeting held in Athens and attended by all panel members. The group reviewed all the available data, discussed the evidence and discussed what practical recommendations could be derived from it. An initial outline of the results of the review and recommendations was produced. Where there were gaps in the evidence, consensus was achieved by debate. Only unanimous conclusions have been incorporated. Subsequently the recommendations were drawn together by Carla Ripamonti (Chairperson) and Robert Twycross (Co-Chair) and refined with input from all panel members. The recommendations have been endorsed by the Board of Directors of the EAPC. It was concluded that surgery should not be undertaken routinely in patients with poor prognostic criteria, such as intra-abdominal carcinomatosis, poor performance status and massive ascites. A nasogastric tube should be used only as a temporary measure. Medical measures such as analgesics, anti-secretory drugs and anti-emetics should be used alone or in combination to relieve symptoms. A venting gastrostomy should be considered if drugs fail to reduce vomiting to an acceptable level. TPN should be considered only for patients who may die of starvation rather than from tumour spread. PH is sometimes indicated to correct nausea, whereas regular mouth care is the treatment of choice for dry mouth. A collaborative approach involving both surgeons and physicians can offer patients an individualized and appropriate symptom management plan.

Humans↗
PubMed2001

Homocysteine and thiol metabolites in vitamin B12 deficiency.

Homocysteine metabolism is increasingly implicated in a diverse group of clinical disorders, including atheromatous vascular disease. We studied the disposition of homocysteine via the trans-sulphuration pathway, plasma glutathione peroxidase (GPx) activity and plasma levels of the sulphated hormone dehydro-epiandrosterone sulphate (DHEAS) in six vitamin B(12)-deficient human subjects before and after 2 weeks of vitamin B(12) repletion, both in the fasting state and following an oral methionine load (0.1 g/kg body weight). Fasting plasma total homocysteine concentrations fell (P=0.03) and total cysteine concentrations rose significantly (P=0.048) after treatment for 2 weeks with vitamin B(12) injections. The magnitude of the mean fall in the fasting concentration of homocysteine (38.8 micromol/l) was similar to the mean rise in cysteine levels (36.0 micromol/l) following vitamin B(12) therapy. Circulating levels of homocysteine were increased at 4 h after a methionine load when compared with fasting levels, both before and after vitamin B(12) repletion (P=0.003 for both). Total cysteinyl-glycine was lower post-methionine than in the fasting state following vitamin B(12) therapy (P=0.007). Fasting plasma GPx fell significantly after 2 weeks of vitamin B(12) therapy (P=0.05). The change in plasma GPx between the fasting state and 4 h after methionine loading was significantly different pre- and post-vitamin B(12) therapy (P=0.05). The present study provides indirect support to the hypothesis that defects in the trans-sulphuration and remethylation of homocysteine produce hyperhomocysteinaemia in vitamin B(12) deficiency in human subjects. Elevated homocysteine levels directly or indirectly may up-regulate GPx. Sulphation status, as measured by plasma DHEAS, was unchanged.

Aged↗
PubMed1998

Does total antioxidant status relate to outcome in very preterm infants?

1. In healthy humans, a balance exists between oxygen-derived free-radical production and their removal by antioxidants. In preterm infants inadequate antioxidant defences may contribute to the pathogenesis of some of the complications of prematurity. 2. Plasma total antioxidant status and malondialdehyde concentration were measured during the first 11 days of life in 25 infants to determine whether increased lipid peroxidation is associated with low extracellular antioxidant status. In a second group of infants, total antioxidant status was quantified within 12 h of birth, and subsequently on days 4 and 10 to investigate the hypothesis that adverse neonatal outcome is associated with low antioxidant status. 3. There may be a weak negative correlation between the total antioxidant status of infants and the lipid peroxidation marker malondialdehyde in plasma (r = -0.24, P = 0.056, n = 89) during the first 11 days of life. In the second group of infants, total antioxidant status was found to be significantly related to plasma urate and bilirubin levels, but not to adverse neonatal outcomes such as chronic lung disease, intraventricular haemorrhage, retinopathy of prematurity or death. 4. If adverse neonatal outcomes are due to inadequate antioxidant defences, these are likely to be intracellular or localized rather than general extracellular deficiencies.

Antioxidants↗
PubMed1997

Modulation of cathepsin D activity in retinal pigment epithelial cells.

This project used retinal pigment epithelial (RPE) cells to investigate the effects of up- and down-regulation of cathepsin D expression on the processing of cathepsin D and on the normal phagocytic and digestive function of these cells. RPE cells were transfected with a pHbetaApr-1-neo vector construct carrying the full-length sequence of the translated region of human cathepsin D in sense and antisense directions. Transfected cells were characterized for the presence and expression of the transgene by PCR amplification using transgene-specific primers. Total aspartic proteinase activity present in transformed RPE cells was measured by an enzyme assay using haemoglobin as substrate. Flow cytometry was used to quantify phagocytosis of fluorescein isothiocyanate-labelled rod outer segments (ROS), and lysosomal digestion of ROS was monitored by immunofluorescence. A 435 bp fragment was present in RPE cells carrying the cathepsin D transgene in sense and antisense orientations after PCR amplification. Expression of both 52 kDa procathepsin D and 34 kDa active cathepsin D was significantly up-regulated in sense cathepsin D-transfected RPE cells and down-regulated in RPE cells transfected with antisense cathepsin D. No other forms of cathepsin D were detected in the transfected cells, suggesting that, if pseudo-cathepsin D exists in RPE cells in vivo, it requires the presence of unknown specific regulatory elements. The up- and down-regulation of cathepsin D expression was further confirmed by enzyme assay. Transfected cells retained their phagocytosing ability after ROS challenge and maintained their ability to process ROS. The processing of ROS was significantly slower in RPE cells transfected with antisense than control vector or in sense-cathepsin D-transfected cells. These results demonstrate that cathepsin D is a major proteolytic enzyme participating in the lysosomal digestion of photoreceptor outer segments.

Animals↗
PubMed1997

Descriptive epidemiology of sweating in a hospice population.

Sweating can be a distressing and difficult problem to manage in patients with advanced cancer. Despite this, new published data exist on the frequency, nature, and severity of sweating in cancer patients. This prospective survey describes the epidemiology of sweating in patients with advanced cancer on admission to a London hospice. 153 consecutive admissions were assessed. Of these, 100 were suitable for inclusion into the study. A general symptom enquiry was performed on all patients. Age, sex, primary diagnoses, extent of diseases, relevant secondary diagnoses, and concurrent medication were also recorded. 16 patients volunteered sweating as a problem. For 12 of these 16 patients, sweating had been severe (drenching sweats requiring change of clothing or bedlinen or both) in nature. This survey highlights sweating as a significant problem in this group of patients.

Adult↗
PubMed1996

Correlation between autofluorescent debris accumulation and the presence of partially processed forms of cathepsin D in cultured retinal pigment epithelial cells challenged with rod outer segments.

The purpose of the present study was to investigate the accumulation of rod outer segment (ROS)-derived debris in cultured human retinal pigment epithelial cells (RPE). The RPE cell layer is responsible for the phagocytosis and digestion of photoreceptor outer segments. Due to the immense volume of photoreceptor-derived material processed by the RPE cells, even minor changes in the efficiency of ROS processing may cause the accumulation of lipofuscin and photoreceptor derived debris. In this work, 17 RPE cultures were established from the globes of eye bank donors whose ages ranged from 18 to 79 years. Third passage cultures were challenged with bovine ROS and the accumulation of an autofluorescent debris was quantified using a flow cytometer. It was demonstrated that ROS challenge greatly increased the rate of autofluorescent debris accumulation. The accumulation of autofluorescent debris varied significantly from culture to culture. This variation was independent of the phagocytosing capacity of individual cultures and was not age dependent. To further investigate the factors which may be responsible for these differences, the presence of cathepsin D, an aspartic protease responsible for 80% of proteolysis of rhodopsin, was analysed by Western blot. Although the 34 kDa active form of cathepsin D was found in all cultures, in 41% of the cultures higher-molecular-weight forms of cathepsin D were additionally present, thus providing a multimer form of cathepsin D in these cultures. The rate of autofluorescent debris accumulation in cultures possessing a multimer form of cathepsin D was significantly greater (mean 42.3, S.D. +/- 19.8) than those in cultures having a singlet active form (mean 18.8, S.D. +/- 5.5) at 34 kDa (Student's t-test, DF = 15, t = 6.834, P < 0.001). The former cultures included one from a donor with age related macular degeneration, the latter cultures included one from a donor with diabetic retinopathy. This study demonstrates that the rate of autofluorescent debris accumulation in cultured RPE cells is not age dependent, but is an intrinsic property of the donor RPE cells that is possibly related to the presence of a multimer form of the lysosomal enzyme cathepsin D.

Animals↗
PubMed1995

Antigen processing and presentation by a murine myoblast cell line.

The ability of non-professional antigen-presenting cells (APC) to process and present antigen to the immune system has been the subject of debate in autoimmunity and tumour immunology. The role of muscle cells in the processing and presentation of antigen to T cells via class I and class II MHC pathways is of increasing interest. Muscle cells are the targets of autoimmune attack in the inflammatory muscle diseases, and direct intramuscular injection of antigen-expressing DNA constructs is under scrutiny as a means of vaccination. Furthermore, the immunological properties of muscle cells are of relevance in attempts to transfer myoblasts as replacement cells in dystrophic diseases or as depot cells for the secretion of certain molecules in deficiency states. Using class I and class II MHC transfectant clones of the C2C12 myoblast cell line, myoblasts have been shown to be capable of presenting antigen to, and stimulating secretion of IL-2 by, T cell hybridomas via both of these pathways. The epitopes which are dominantly presented by professional APC after processing of native antigens were also presented by the myoblast cell line after processing of either ovalbumin (class I) or hen egg lysozyme (class II). Further, antigen processing and presentation via the class II pathway were enhanced by pretreatment of the myoblasts with interferon-gamma (IFN-gamma). Up-regulation of invariant chain expression by this treatment may have contributed to this enhanced presentation, but an effect of IFN-gamma on the expression of other molecules such as H-2 DM may have also played a role. The demonstration of the antigen-presenting properties of these myoblasts is of relevance to all three areas mentioned above. In each situation myoblasts comprise a significant population within muscle. In the case of inflammatory muscle diseases the process of muscle degeneration and regeneration is on-going, while in the vaccination procedure some muscle damage occurs, and vaccination is more effective when muscle damage has preceded inoculation.

Animals↗
PubMed1995

Evidence that continuous normothermic blood cardioplegia offers better myocardial protection than intermittent hypothermic cardioplegia.

OBJECTIVES: To compare transmyocardial ischaemia and oxidative stress, as well as non-infarction myocardial injury, in patients randomised to intermittent hypothermic cardioplegia or continuous normothermic blood-potassium cardioplegia. DESIGN: Prospective randomised trial. SETTING: Tertiary cardiac referral centre. METHODS: 24 patients undergoing elective coronary artery bypass surgery were randomised to hypothermic (13 patients, mean (SEM) age 59.5 (2.6) years) or normothermic (11 patients, mean (SEM) age 59.7 (3.3) years) cardioplegia. Transmyocardial oxidative stress and ischaemia were assessed by the difference in plasma concentrations of oxidised glutathione and lactate respectively, from samples taken simultaneously from the coronary sinus and aortic root. Blood samples were taken just before cross clamp application and at intervals up to 15 min after cross clamp release. Non-infarction myocardial injury was assessed by measurement of creatine kinase MB isoenzyme activity from peripheral venous blood taken 2 and 18 h after surgery. RESULTS: Intermittent hypothermic cardioplegia resulted in a significant increase in transmyocardial ischaemia (P < 0.001) and oxidative stress (P < 0.001). Evidence of significantly increased myocyte damage was also present (P < 0.01). No significant corresponding changes were present with normothermic cardioplegia. CONCLUSIONS: Normothermic blood cardioplegia seems to avoid significant changes in myocardial ischaemic status and consequent oxidative stress. This study provides direct evidence that normothermic cardioplegia offers enhanced myocardial protection compared with that of hypothermic cardioplegia. Certain subsets of patients may derive more benefit from normothermic cardioplegia, although it is unclear whether this would be the case for all patients.

Cardiopulmonary Bypass↗
PubMed1994

Renal function and proteinuria after cardiopulmonary bypass: the effects of temperature and mannitol.

We studied three groups of patients without previous renal impairment, undergoing elective coronary artery bypass surgery. Group H (n = 7) underwent open heart surgery using moderate hypothermia (28 degrees C); Groups N and M (n = 8, each) were managed at normothermia. The extracorporeal circuit was primed with Hartmann's solution 2.5 L with the addition of mannitol 0.5 g/kg in Group M. Serum concentrations of sodium and creatinine, and the urinary concentrations of microalbumin and N-acetyl-beta-D-glucosaminidase (NAG) were measured in each patient at six different time intervals: T0, 6 h prior to surgery; T1, between sternotomy and 45 min into cardiopulmonary bypass (CPB); T2, in the interval from 45 min into, to prior to weaning off CPB; T3, from coming off CPB to skin closure; T4, in the first 6 h in the intensive care unit; and T5, at 6 days postoperatively. Creatinine clearance (CCR) and fractional sodium excretion (FENA) were calculated at each time point. Urine output during CPB at Interval T2 was significantly higher in Group H compared to Group N (P = 0.03) but not Group M. We found no significant differences in CCR, FENA, microalbuminuria, and urinary NAG among the three groups at any time. However, there were overall significant changes in measured variables over time compared to baseline. We conclude that CPB is associated with a significant alteration in renal function as shown by increased FENA, microalbuminuria, and urinary NAG. The use of hypothermic or normothermic CPB and the use of prophylactic mannitol did not produce any significant modification of these changes.

Coronary Artery Bypass↗
PubMed1993

Differential free-radical activity after successful and unsuccessful thrombolytic reperfusion in acute myocardial infarction.

BACKGROUND: Free-radical generation after successful thrombolysis in acute myocardial infarction may jeopardize ischaemic but viable myocardium, thus limiting the optimal benefits of reperfusion. METHODS: Circulating free-radical activity was assessed in 25 consecutive patients with acute myocardial infarction. Those who successfully reperfused (Group A) were compared with those who did not (Group B). We also compared patients who had or had not developed Q waves and patients with and without previous angina or myocardial infarction. All patients presented within 6 h of the onset of chest pain and received standard intravenous streptokinase therapy. Free-radical activity in serial serum samples collected over 72 h was measured using the percentage molar ratio (PMR) of the concentrations of 9,11-linoleic acid to 9,12-linoleic acid, and malonaldehyde concentration. RESULTS: Throughout the study period Group A (n = 11) showed significantly greater change in serum PMR and malonaldehyde levels compared with Group B (n = 14) (P < 0.01). PMR differences between the two groups were most pronounced at 3 and 12 h (P < 0.001). Patients with non-Q-wave myocardial infarction (n = 5) showed significantly greater changes in serum PMR and malonaldehyde levels (P < 0.01) compared with those with Q-wave infarction (n = 20). A history of previous infarction or angina had no apparent effects on the changes in serum free-radical activity. CONCLUSIONS: Successful early reperfusion and non-Q-wave myocardial infarction are both associated with a significantly greater increase in the levels of markers of serum free-radical activity immediately after infarction. The results support present concepts of free-radical-mediated reperfusion injury. Use of these assays may identify those patients who may be at risk from free-radical-mediated reperfusion injury.

Aged↗
PubMed1992

HLA and disease.

Many human diseases are associated with HLA class I, class II and class III antigens. It appears that the class III antigen disease associations can be explained by a direct defect operating at the level of either the class III gene or its gene product. The mechanism underlying class I and class II antigen disease associations is at present unknown. In this review we have considered thirty diseases which have been ranked according to their relative risk as defined by the frequency of a given HLA antigen in patient and control populations. The chronic inflammatory disorder, ankylosing spondylitis and its association with HLA B27 has been used as a model to study the HLA linked diseases. We have suggested that the disease may be caused by the Gram-negative microorganism Klebsiella which has antigenic similarity to HLA B27. It is proposed that some antibodies made against Klebsiella bind to HLA B27, thereby acting as autoantibodies leading to the pathological sequelae of chronic inflammatory arthritis. This is the crosstolerance hypothesis or molecular mimicry model and it has been compared to the receptor model. It is further suggested that the crosstolerance hypothesis can be utilised as a general theory to explain the association of other diseases with the class I and class II antigens, and offer a possible explanation for the polymorphism of HLA.

Antigen-Presenting Cells↗
PubMed1990

Modulation of the biological activity of thyrotrophin by anti-human thyrotrophin monoclonal antibodies.

The mechanism by which monoclonal antibodies enhance the biological activity of a number of hormones is poorly understood. One such antibody (GC73), which binds to human but not bovine TSH, enhances the bioactivity of human TSH in vivo. We have investigated whether GC73 enhancement of TSH bioactivity involves potentiation of hormone-receptor activation assessed by the cyclic AMP (cAMP) responses of both primary human thyrocyte cultures and a TSH-responsive human thyrocyte cell line (SGHTL-45). GC73 had no effect on basal cAMP production. In contrast to its enhancement of the bioactivity of human TSH in vivo, it markedly inhibited the cAMP response to 1 and 10 mU human TSH/ml in primary thyrocytes. This effect was dose-dependent with neutralization of the bioactivity of TSH occurring at 2 mg GC73/ml. GC73 had no effect on the bioactivity of bovine TSH. In contrast, a second anti-TSH monoclonal antibody (TC12), which binds to both human and bovine TSH, inhibited the bioactivity of both species of TSH. Similar results were obtained using SGHTL-45 cells, although the peak concentrations of cAMP were lower. We conclude that binding of GC73 to human TSH resulted in inhibition rather than enhancement of the in-vitro biological activity of human TSH. We suggest that GC73 enhancement of human TSH bioactivity seen in vivo does not result from a mechanism involving potentiation of receptor activation by human TSH.

Antibodies, Monoclonal↗