The number of unexpected HbA variants may be a greater problem in routine practice than is generally realized.

BACKGROUND: The majority of variant and abnormal haemoglobins are clinically silent but may not be biochemically silent when it comes to HbA1c estimation. CASE REPORT: We describe several cases in which there were problems in the determination of HbA1c for monitoring diabetes in patients that would not normally be classified as being at risk. Four of these cases were sufficiently unusual to warrant individual publication but all came from a very restricted geographical area with a population of only approximately 500,000. The significance of this is not that variant haemoglobins affect HbA1c analysis but that the occurrence of unexpected/unusual variant haemoglobins may be more frequent than most clinicians would expect, considering that only a small proportion of the basal population are diabetic and have their HbA1c monitored. Differences will exist between different areas due to differences in both the prevalence of variants and the analytical methods employed. CONCLUSIONS: Consequently, we propose greater interaction between diabetologists and the laboratory in an attempt to identify these clinically but not biochemically silent variants to achieve a true estimation of the glycaemic control in affected patients.

Hormonal and biochemical normalization and tumor shrinkage induced by anti-parathyroid hormone immunotherapy in a patient with metastatic parathyroid carcinoma.

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism, and the efficacy of medical therapy and chemo- and radiotherapy is poor in recurrent or metastatic disease. We report the first case of PTH immunization in which tumor shrinkage accompanied hormonal, biochemical, and clinical improvements in a patient with metastatic parathyroid carcinoma.A 50-yr-old woman with refractory parathyroid carcinoma and pulmonary metastases was immunized eight times between February 2001 and December 2003 with bovine and modified human PTH fragments and intact human PTH, mixed with Freund's adjuvant. Total and ionized calcium and PTH levels were assayed weekly for 6 months and regularly thereafter. Thoracic computed tomography scans were performed regularly. Antibodies to all PTH fragments were detected after two immunizations. Baseline PTH and total calcium were 213.0 ng/liter and 13.96 mg/dl, respectively, and remained elevated during the first three immunizations. From the fourth immunization onward, PTH and calcium decreased, and the patient's clinical condition improved markedly. PTH and calcium levels have remained controlled for more than 24 months, and the sizes (surface area) of pulmonary metastases decreased from baseline by 39-71%. This is the first evidence that PTH immunization not only can improve clinical, hormonal, and biochemical measures in parathyroid carcinoma but also has an antitumor effect.

Effects of breathing air containing 3% carbon dioxide, 35% oxygen or a mixture of 3% carbon dioxide/35% oxygen on cerebral and peripheral oxygenation at 150 m and 3459 m.

The effects of gas mixtures comprising supplementary 3% carbon dioxide, 35% oxygen or a combination of 3% CO(2) plus 35% O(2) in ambient air have been compared on arterial blood gases, peripheral and cerebral oxygenation and middle cerebral artery velocity (MCAV) at 150 m and on acute exposure to 3459 m in 12 healthy subjects. Breathing 3% CO(2) or 35% O(2) increased arterial blood oxygen at both altitudes, and the CO(2)/O(2) combination resulted in the most marked rise. MCAV increased on ascent to 3459 m, increasing further with 3% CO(2) and decreasing with 35% O(2) at both altitudes. The CO(2)/O(2) combination resulted in an increase in MCAV at 150 m, but not at 3549 m. Cerebral regional oxygenation fell on ascent to 3459 m. Breathing 3% CO(2) or 35% O(2) increased cerebral oxygenation at both altitudes, and the CO(2)/O(2) combination resulted in the greatest rise at both altitudes. The combination also resulted in significant rises in cutaneous and muscle oxygenation at 3459 m. The key role of carbon dioxide in oxygenation at altitude is confirmed, and the importance of this gas for tissue oxygenation is demonstrated.

Pericardial tamponade caused by Pasteurella multocida infection after a cat bite.

An unusual case of meningitis and pericardial tamponade caused by Pasteurella multocida after a cat bite is reported. The patient was successfully treated by antibiotics and pericardiocentesis and made an uneventful recovery from a life threatening condition. This case illustrates the potential dangers that can arise from a seemingly trivial and commonplace injury.

Carbon dioxide contributes to the beneficial effect of pressurization in a portable hyperbaric chamber at high altitude.

Regional cerebral oxygenation (rSO2) and peripheral oxygen saturation (SpO2) have been studied in subjects inside a portable hyperbaric chamber at altitude during pressurization. The effects of the accumulation of carbon dioxide within the chamber on rSO2 and SpO2 have also been investigated. Three studies of cerebral regional oxygenation were undertaken, using near-IR spectroscopy, in subjects who had ascended to 3475 m in the Alps, 4680 m in the Andes or 5005 m in the Himalayas. At 3475 m and 5005 m the effects of the removal of inspired carbon dioxide by a soda lime scavenger were also studied. On pressurization of the chamber to 19.95 kPa, inspired carbon dioxide rose within the chamber from 0.03% (0.06 kPa) ambient to over 1% (1.3 kPa). At 5005 m, SpO2 rose from a baseline of 79.5% (S.D. 4.5%) to 95.9% (2.0%) (P<0.0001), and cerebral rSO2 rose from 64.6% (3.4%) to 69.4% (3.6%) (P<0.0001). The introduction of a soda lime CO2 scavenger into the breathing circuit resulted in a drop in SpO2 from 95.9% (2.03%) to 93.6% (2.07%) (P<0.001) and a fall in rSO2 from 69.4% (3.64%) to 68.5% (3.5%) (P<0.01). Chamber pressure was maintained throughout at 19.95 kPa. Similar changes were seen at the other altitudes. Cerebral rSO2 increased rapidly following pressurization at all three altitudes. Scavenging of inspired carbon dioxide was associated with a significant fall in cerebral rSO2 and SpO2, and we estimate that the contribution of carbon dioxide may account for up to one-third of the beneficial effect of the portable hyperbaric chamber.

Control of hypercalcaemia of parathyroid carcinoma by immunisation.

BACKGROUND: Patients with parathyroid tumours can develop extreme hypercalcaemia and osteitis fibrosa cystica. Clinical features result from the action of parathyroid hormone (PTH) on bone receptors. Because this hormone is produced in microgram quantities, inhibition of its metabolic effects with potent PTH antibodies should be possible. We tested whether an immunisation with synthetic human and bovine PTH peptides could stimulate autoantibodies against PTH. METHODS: A patient with metastatic parathyroid carcinoma in the lungs and pleura developed severe bone disease and extreme hypercalcaemia that proved resistant to conventional therapy. She was immunised with 200 microg human and bovine PTH peptides and 50 microg human PTH. Booster doses were also given at 4 weeks and 11 weeks. The patient was then seen every week. FINDINGS: Antibodies against PTH were produced within 4 weeks of initial immunisation and titres increased with repeated doses of immunogens. Total serum calcium concentrations, which had ranged from 3.5 mmol/L to 4.2 mmol/L over the previous 18 months, fell to between 2.5 mmol/L and 3.0 mmol/L over 6 months of therapy. This fall was accompanied by striking clinical improvement. INTERPRETATION: We believe this is the first use of immunotherapy to control remote, non-metastatic complications of malignant disease. B-cell tolerance to human PTH was broken by immunisation with PTH peptides in adjuvant. This therapeutic approach could be used to control excess hormone production in several types of endocrine tumour and may have applications in other diseases.

Clinical and neurophysiological studies of aldose reductase inhibitor ponalrestat in chronic symptomatic diabetic peripheral neuropathy.

Increased flux through the polyol pathway mediated by the enzyme aldose reductase may be associated with the development of diabetic neuropathy. Fifty-four diabetic patients (median age 56 yr, range 25-65 yr) with chronic neuropathic symptoms were randomly allocated to placebo or aldose reductase inhibition (300 or 600 mg ponalrestat ICI 128436) groups for 24 wk. Patients with vibration perception thresholds (VPTs) greater than 35 V at the great toe or thermal difference thresholds (TTs) greater than 10 degrees C on the dorsum of the foot were excluded from the trial. No significant changes were observed in symptoms of pain, numbness, or paresthesia between ponalrestat and placebo groups, and there were no improvements in VPT or TT at several sites. Posterior tibial nerve conduction velocity changed from 35.3 +/- 4.9 m/s at baseline to 33.4 +/- 4.0 m/s at 24 wk (NS) with placebo compared with 37.6 +/- 5.6 vs. 37.2 +/- 8.7 m/s (NS) with 300 mg ponalrestat and 34.5 +/- 6.1 vs. 36.2 +/- 6.8 m/s (NS) with 600 mg ponalrestat. Further studies are indicated with intervention at an earlier stage in the evolution of neuropathy and for longer periods.

Cerebral blood flow in acute mountain sickness.

Changes in cerebral blood flow (CBF) were measured using the radioactive xenon technique and were related to the development of acute mountain sickness (AMS). In 12 subjects, ascending from 150 to 3,475 m, CBF was 24% increased at 24 h [45.1 to 55.9 initial slope index (ISI) units] and 4% increased at 6 days (47.1 ISI units). Four subjects had similar increases of CBF when ascending to 3,200 m 3 mo later, indicating the reproducibility of the measurements. In nine subjects, ascending from 3,200 to 4,785-5,430 m, CBF increased to 76.4 ISI units, 53% above estimated sea-level values. CBF and increases in CBF were similar in subjects with or without AMS. In six subjects, CBF was measured before and after therapeutic intervention. At 2 h CBF increased 22% (71.3 to 87.3 ISI units) above pretreatment values in three subjects given 1.5 g acetazolamide, while three subjects given placebo showed no change. Symptoms remained unaltered in all subjects during the 2 h of the study. Overall, the results indicated that increases in CBF were similar in subjects with or without AMS while acetazolamide-provoked increases of CBF in AMS subjects caused no acute change in symptoms. Alterations in CBF cannot be directly implicated in the pathogenesis of AMS.

Effect of carbon dioxide in acute mountain sickness: a rediscovery.

The effect of adding CO2 to inhaled air in six subjects with acute mountain sickness was investigated during a medical expedition to 5400 m.3% CO2 in ambient air increased ventilation and resulted in a rise in PaO2 of between 24% and 40%. There was a 9-28% increase in PaCO2 and a reduction of the respiratory alkalosis normally seen at high altitude. Symptoms of acute mountain sickness were rapidly relieved. In three subjects cerebral blood flow increased by 17-39%, so that oxygen delivery to the brain would have been considerably improved. This study confirms earlier suggestions of the beneficial effect of CO2 inhalation at high altitude.

The release rate of 37Ar from human subjects following intravenous injection.

Two measurements of the exhalation rate of 37Ar following an intravenous bolus injection have been made on a volunteer, and compared with the exhalation rate of 133Xe for the same subject. The results are also compared with a previously reported pilot 37Ar injection study on a second volunteer. During the first 100 min following injection, the 37Ar washout rate was shown to resemble closely the 133Xe washout rate. This result shows that for short time periods after injection, the behaviour of 133Xe may be used to predict 37Ar behaviour.

Congenital adrenal hyperplasia in a 66-year-old female.

A 66-year-old genotypically female patient was reared as a man. Investigations showed a partial adrenal 21-hydroxylase deficiency, and pituitary gonadotrophin secretion typical of a post-menopausal woman.

Cadmium-induced osteomalacia.

The detailed study of a battery plate maker, who had worked with cadmium for 36 years, showed that proteinuria, typical of renal tubular dysfunction, had been observed for 25 years and during the last 12 years of his life the patient had suffered increasing disability from gross bone disease. Several bone biopsies and detailed metabolic studies showed typical severe osteomalacia, which responded well initially to calcium and vitamin D treatment. Examination of the liver both in life and after death showed a gross excess of cadmium. This was also found in the kidneys after death. Previously unreported changes were present in the bones, especially the lumbar vertebrae which were probably more the result of gross bone deformity than cadmium deposition. The mechanism of development of the severe acquired Fanconi syndrome was thought to be a combination of dietary calcium and vitamin D deficiency and impaired calcium absorption from abnormal vitamin D synthesis, related to the cadmium deposition in the renal tubules, which also caused the defect in renal tubular reabsorption.

Birmingham Medical Research Expeditionary Society 1977 Expedition: effect of a Himalayan trek on whole body composition, nitrogen and potassium.

The body composition of the 17 members of the BMRES was studied using body weight and fat fold calipers, with measurements of whole body potassium and nitrogen. The full assessment was made just before departure from Birmingham and immediately on return. Daily observations of body weight and fat folds were made during the trek to high altitude. During the ascent all subjects lost body fat but there was little change in lean body mass. After return it was found that there had been further loss of body fat and some loss of lean tissue also. One subject who took methandienone retained potassium but had no increase in body nitrogen. There was no correlation between changes in body composition and acute mountain sickness.