Paraoxonase status in coronary heart disease: are activity and concentration more important than genotype?

Human serum paraoxonase (PON1) hydrolyzes oxidized lipids in low density lipoprotein (LDL) and could therefore retard the development of atherosclerosis. In keeping with this hypothesis, several case-control studies have shown a relationship between the presence of coronary heart disease (CHD) and polymorphisms at amino acid positions 55 and 192 of PON1, which we associated with a decreased capacity of PON1 to protect LDL against the accumulation of lipid peroxides, but some other studies have not. However, the PON1 polymorphisms are only 1 factor in determining the activity and concentration of the enzyme. Only 3 of the previous 18 studies directly determined PON1 activity and concentration. Therefore, we studied PON1 activity, concentration, and gene distribution in 417 subjects with angiographically proven CHD and in 282 control subjects. We found that PON1 activity and concentration were significantly lower in subjects with CHD than in control subjects (activity to paraoxon 122.8 [3.3 to 802.8] versus 214.6 [26.3 to 620.8] nmol. min(-1). mL(-1), P<0.001; concentration 71.6 [11.4 to 489.3] versus 89.1 [16.8 to 527.4] microg/mL, P<0.001). There were no differences in the PON1-55 and -192 polymorphisms or clusterin concentration between patients with CHD and control subjects. These results indicate that lower PON1 activity and concentration and, therefore, the reduced ability to prevent LDL lipid peroxidation may be more important in determining the presence of CHD than paraoxonase genetic polymorphisms.

The effect of subcutaneous nerve stimulation (SCNS) on pain associated with osteoarthritis of the hip.

A novel form of subcutaneous nerve stimulation (SCNS) was recently introduced for the relief of chronic pain. We present a study using this form of SCNS applied over the radial, median and saphenous nerves in patients with clinically diagnosed osteoarthritis of the hip. Acceptable pain relief was obtained in 60% of patients receiving stimulation, however, comparable analgesia was achieved in a control group, who received no electrical stimulation through similarly placed needles. We suggest that these results may be explained by the ability of SCNS to evoke a placebo response. The efficacy of the placebo effect and the ethical implications of its use in clinical practice are discussed.

Troponin I, laboratory issues, and clinical outcomes in a district general hospital: crossover study with "traditional" markers of myocardial infarction in a total of 1990 patients.

AIMS: Review of the clinical outcomes and practical issues of replacing traditional cardiac enzymes with troponin I (cTnI) in a district general hospital. METHODS: Crossover study of three sequential three month stages during which serial cardiac enzymes were replaced with a single cTnI measurement available at three set times within 24 hours for the duration of the second three month stage. The study was carried out in a 630 bed district general hospital with 1990 admissions of suspected cardiac ischaemia over the study period as a whole. Account was taken of seasonal factors. RESULTS: The introduction of troponin was associated with 8.5% more patients with non-ischaemic heart disease (IHD) being discharged on the day after admission, saving approximately 107 bed days each year. Approximately 50% more patients were diagnosed with myocardial infarction during the cTnI stage. There was no increase in readmission within one month or early death with cTnI. Approximately 3% false positive and 1.5% false negative cTnI results were recorded. All false positive cTnI results were coding errors or attributable to known assay interference effects. All false negatives were potentially explained by sample timing factors. The lack of standardisation in troponin assay services impacts clinically. CONCLUSION: Younger patients without IHD were discharged earlier during the cTnI stage in apparent safety. Blood sample timing needs to be verified when cTnI is used as an adjunct to early discharge. There were no unexplained false positives or negatives. Standardisation related issues arose.

Inappropriate phosphate excretion in idiopathic hypercalciuria: the key to a common cause and future treatment?

AIMS: To present experimental evidence in support of a proposed common cause for absorptive hypercalciuria, renal hypercalciuria, renal phosphate leak and enhancement of 1,25-(OH)2-vitamin D concentrations in patients presenting with renal stone disease; and to suggest further investigation with a view to new management. METHODS: An oral calcium loading test was administered to 15 patients with renal stones and 10 normal controls in the fasting state: urine and blood were collected hourly. After the second urine sample, 400 mg calcium dissolved in water was administered orally. Serum calcium, albumin, parathyroid hormone (PTH), and phosphate were measured together with urine calcium clearance and urinary phosphate from which the TmPO4/glomerular filtration rate (GFR) ratio was calculated. Serum 1,25-(OH)2-vitamin D was measured in the first serum sample. In addition, 24 hour urine calcium results were collected retrospectively from the patients' case notes over the previous 18 months. RESULTS: In the basal state, renal stone patients had an overall greater phosphaturia (lower TmPO4/GFR: median 1.72 compared with 2.10 in controls) and increased calcium clearance. Serum corrected calcium and PTH concentrations did not differ between the groups. After calcium loading, serum calcium and urine calcium clearance rose in both groups, with patients with renal stones experiencing a greater percentage fall in phosphaturia. In both groups TmPO4/GFR fell (greater phosphaturia) with increased serum corrected calcium, with the patients showing notably greater phosphaturia for any given calcium concentration. Patients also had notably greater phosphaturia compared with the serum calcium concentration for any given PTH value. Serum 1,25-(OH)2-vitamin D was higher in patients than controls and for any 1,25-(OH)2-vitamin D concentration phosphaturia measured against serum calcium was greater in patients than controls. 1,25-(OH)2-vitamin D did not correlate with phosphaturia relative to serum calcium concentrations within the patient and control groups. CONCLUSIONS: It is proposed that patients with idiopathic hypercalciuria have an "inappropriately' high phosphate excretion for any given serum calcium concentration. Loss of phosphate may induce increased activation of 1,25-(OH)2-vitamin D. Some of the commonly described causes of stone formation may be manifestations of a single mechanism.

Why oral calcium supplements may reduce renal stone disease: report of a clinical pilot study.

AIMS: To investigate whether increasing the daily baseline of gut calcium can cause a gradual downregulation of the active intestinal transport of calcium via reduced parathyroid hormone (PTH) mediated activation of vitamin D, and to discuss why such a mechanism might prevent calcium oxalate rich stones. To demonstrate the importance of seasonal effects upon the evaluation of such data. METHODS: Within an intensive 24 hour urine collection regimen, daily calcium supplementation (500 mg) was given to five stone formers for a 10 week period during a six month crossover study. In a further population of patients on follow up for previous renal stone disease, observations were made on 1066 24 hour urine samples collected over five years in respect of seasonal effects relevant to the interpretation of the study. RESULTS: In the group of patients on calcium supplements the following results were found. During calcium supplementation, the proportion of urine calcium to oxalate was higher (increased calcium to oxalate molar ratio), the 24 hour urine product of calcium and oxalate did not rise, and urine oxalate was lower during the first six weeks of supplementation. Twenty four hour urine calcium was 10.2% higher than baseline in the final four weeks of the 10 weeks of supplementation. Twenty four hour urine phosphate was 11.4% lower during the first six weeks of supplementation, but then rose while the patients were still on supplementation; renal tubular reabsorption of phosphate (TmP/GFR) mirrored the urine phosphate changes inversely. PTH was higher after stopping supplementation, but 1,25-(OH)2-cholecalciferol changes were not detected. In the 1066 urine samples collected over five years the following results were found. Calcium and oxalate excretion correlated positively and not inversely. Urine calcium and phosphate excretion were 5.5% and 2.5% higher, respectively, in "light" months of the year compared with "dark" months. A post summer decline in both urine calcium and urine phosphate was relevant to the interpretation of the study. CONCLUSIONS: Regular calcium supplementation does not raise the product of calcium and oxalate in urine and the proportion of oxalate to calcium is reduced. The underlying mechanisms of the changes seen in phosphate, calcium, and PTH and the observations on 1,25-(OH)2-cholecalciferol are not clear. Observed changes in phosphate could possibly be part of a calcium regulating feedback loop operating over a period of weeks. In evaluating these mechanisms background seasonal effects are important. It is possible that "programming" of the gut mucosa in terms of calcium transport is a major determinant of the relation between calcium and oxalate concentrations in urine and their relative abundance. Increased oral calcium, in association with a reduction of the relative proportion absorbed, may be pertinent to the prevention of calcium oxalate rich stones.

A novel five-microlitre capillary system for home glucose monitoring.

Improvement in the control of diabetic patients is aided by a knowledge of blood glucose levels during a 'normal' (non-hospitalised) day. We have devised a 5 microliter capillary tube collection system as a 'kit' for home use by diabetics. Blood collected into 5 microliter capillary tubes is washed into a protein precipitant by the patient. The completed kit is posted to the laboratory for analysis. The technique has achieved a high degree of patient acceptability. Subsequent analysis involves the addition of a single reagent. Reagents, patient samples, and standards are stable, and the precision of the technique compares favourably with our routine glucose procedure.

The evaluation of liquid crystal thermography in the investigation of nerve root compression due to lumbosacral lateral spinal stenosis.

The role of liquid crystal thermography (LCT) in the investigation of nerve root compression due to lumbosacral lateral spinal stenosis was evaluated using a quantitative analysis technique. In 28 healthy volunteers, normal lower limb dermatomal asymmetry was found to follow a Gaussian distribution, with a normal range of less than 1.0 degree for the lower limbs and less than 1.9 degrees for the feet. The results of LCT from a patient group were compared with those from other investigations, with the following results: clinical assessment (107 patients), 53% agreement; myelography (60 patients), 45% agreement; computerized tomography (35 patients), 46% agreement; electromyography (27 patients), 41% agreement; and surgical findings (19 patients), 53% agreement. Each method of investigation was compared against the surgeon's final overall assessment. Clinical assessment agreed in 76%, myelography in 71%, computerized tomography in 71%, and electromyography in 70%. However, agreement could be demonstrated in only 48% of cases using LCT; therefore, it would appear that LCT is by far the least reliable of these techniques in the diagnosis of nerve root compression.

Minor procedures in the accident and emergency department: can Entonox help?

The efficacy of Entonox as a supplement to local anaesthesia for minor surgical procedures was studied. Eighty-five patients undergoing surgery for the incision and drainage of a subcutaneous abscess using a local anaesthetic were involved in a trial to ascertain the level of pain associated with such procedures and to investigate the possibility of using on-demand Entonox to supplement the local anaesthesia provided. Patients received either the standard local anaesthesia, or, alternatively, the local anaesthesia was supplemented with oxygen or Entonox via on-demand apparatus. Patients indicated on three linear visual analogue scales their pain, anxiety and total discomfort, and also on a cartoon pain rating scale, at different stages during the operation. Results showed that there was no statistically significant reduction in pain provided by the Entonox, despite general patient approval. Both oxygen and Entonox showed some anxiolytic properties. Pure oxygen was also seen to produce a rise in heart rate, while both gases (pure oxygen and Entonox) caused an increase in diastolic blood pressure. It was also seen that the patient's short term memory of the pain experienced was unaffected by pure oxygen or Entonox.

A prospective study of diagnostic epidural blockade in the assessment of chronic back and leg pain.

A consecutive series of 100 patients with back and leg pain were evaluated prospectively. All had a detailed clinical assessment together with radiculography and computed tomography (CT) of the lumbosacral spine. In addition, each patient underwent diagnostic epidural blockade that identified three kinds of response. Injection of local anaesthetic into the epidural space relieved the symptomatic pain--the positive result (51 patients). Local anaesthetic injection had no effect on the symptomatic pain--the negative result (30 patients). In 19 patients, saline injection into the epidural space relieved the symptomatic pain--the placebo result. The results of this investigation were assessed in the light of the number of inappropriate physical signs found on clinical examination, together with the result of the radiculogram and CT scan. No statistical correlation was found with any of these parameters.

The use of etomidate infusions during anaesthesia for cardiopulmonary bypass.

The effects of cardiopulmonary bypass and hypothermia were studied on the plasma concentration and metabolism of a continuous infusion of etomidate in six patients. Continuous etomidate infusions (20 micrograms/kg/minute) with analgesic cover may be a suitable anaesthetic for cardiac surgery. This rate of infusion provides adequate plasma concentrations, and it would appear unnecessary from the results to alter the rate of infusion during cardiopulmonary bypass and hypothermia.

Respiratory depression after intrathecal narcotics.

Three out of six patients who had received 1 mg of morphine and 0.22 ml plain bupivacaine 0.5%/segment as a subarachnoid spinal anaesthetic developed serious and delayed respiratory depression on several occasions. This was reversed by intravenous naloxone. It is postulated that the morphine had diffused to the level of the cisterna magnum and thence through brain tissue around the fourth ventricle. Naloxone did not reverse the analgesia.

Electrical stimulation therapy in the treatment of cigarette smoking.

In this study electrical stimulation therapy (EST) is explored as a possible new treatment for smoking cessation within a randomized controlled trial. The investigation follows reports of several authors that electrical stimulation applied to specific acupuncture points is effective in treating a variety of drug dependencies, including cigarette smoking. Three key features of treatment (electrical stimulation, frequency modulation, and electrode placement), were investigated in a 2 x 2 x 2 factorial design, resulting in eight treatment combinations. Out of 265 smokers recruited into the trial 216 completed the one-week treatment. Outcome was assessed in terms of complete abstinence from smoking and symptomatic relief of withdrawal symptoms. Smokers receiving active electrical stimulation obtained higher abstinence rates than those in the inactive groups although the difference did not achieve statistical significance (all active vs. all placebo groups: lambda 1,1(2) = 0.50, p > 0.10, 95% confidence interval = -8.04 to +17.44%; most effective vs. least effective group: lambda 1,1(2) = 3.11, p = 0.08, CI0.95 = -2.2 to +48.8%). The efficacy of electrical stimulation therapy for smoking is not supported.

The effect of oral folic acid on glutathione, glycaemia and lipids in Type 2 diabetes.

Plasma homocysteine is an established risk factor for vascular disease and precursor of the anti-oxidant glutathione. This study was designed to investigate the relationship of changes in homocysteine (Hcy) induced by oral folate to glutathione and measures of glycaemia and lipid metabolism in Type 2 diabetes (T2DM). Twenty-seven patients (26 male, 1 female, aged 48-68 years) with T2DM and microalbuminuria were treated with folic acid 10 mg daily for 3 months. During the study, diastolic blood pressure (p=0.04), HbA1c (p=0.04), serum triglycerides (p=0.04) and serum total/HDL-cholesterol ratio (p=0.004) all increased and serum HDL-cholesterol fell (p=0.006). The increased red cell folate correlated with a reduction in microalbuminuria (p=0.001). Overall, plasma glutathione increased (p=0.016) despite reduction in its precursor Hcy (p<0.001). Change in glutathione correlated inversely with change in HbA1c (p<0.02), total cholesterol (p=0.003) and triglycerides (p<0.02) and positively with HDL-cholesterol (p=0.033). Increase in glutathione correlated with levels of vitamin B6 (p<0.05). Metformin treatment protected against the rise in blood pressure (BP) (p=0.02), independently of changes in plasma glutathione. In summary, oral folic acid supplementation in T2DM reduced plasma Hcy and increased glutathione levels. HbA1c, triglycerides and HDL-cholesterol deteriorated during the trial: their levels correlated inversely with changes in glutathione. The increase in glutathione may depend on an adequate supply of B6, as changes in glutathione correlated with vitamin B6 levels. Reduced Hcy and increased glutathione may both mediate improvement in vascular function and outcome. Some aspects of the response to folate may be different in patients on metformin.