Effect of preoperative supplementation with alpha-tocopherol and ascorbic acid on myocardial injury in patients undergoing cardiac operations.

Augmentation of antioxidant defenses may help protect tissues against ischemia-reperfusion injury associated with operations involving cardiopulmonary bypass. In this study we examined the effect of pretreating patients with alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C) or placebo on injury to the myocardium. Seventy-six subjects undergoing elective coronary artery bypass grafting participated in a prospective, double-blind, placebo-controlled randomized trial, receiving either placebo or both 750 IU dl-alpha-tocopherol per day for 7 to 10 days and 1 gm ascorbic acid 12 hours before the operation. Plasma alpha-tocopherol concentrations, raised fourfold by supplementation, fell by 70% after the operation in the supplemented group and to negligible levels in the placebo group. There were no significant differences between the groups with respect to release of creatine kinase MB isoenzyme over 72 hours, nor in the reduction of the myocardial perfusion defect determined by thallium 201 uptake. Electrocardiography provided no evidence of a benefit from antioxidant supplementation. Thus the supplementation regimen prevented the depletion of the primary lipid soluble antioxidant in plasma, but provided no measurable reduction in myocardial injury after the operation.

Demonstration of late cardiotoxicity following bone marrow transplantation by assessment of exercise diastolic filling characteristics.

We evaluated the role of rest and exercise left ventricular diastolic filling parameters as a marker of cardiotoxicity in 25 consecutive patients 1 year following BMT. Ten age- and sex-matched subjects served as controls. Patients were evaluated in toto and in three sub-groups according to chemotherapy. Left ventricular ejection fraction (EF), peak filling rate (PFR) and time to peak filling (TTPF) were assessed at rest and at peak exercise. EF and PFR were similar at rest and at peak exercise in patients and controls. TTPF was significantly prolonged at rest in patients compared to controls (200 +/- 65 vs 131 +/- 26 ms, P = 0.003) and at peak exercise was markedly longer in patients (142 +/- 40 vs 54 +/- 19 ms, P < 0.001). Sub-group analysis demonstrated abnormal resting TTPF in those patients who had received either combination anthracycline and CY or anthracycline and melphalan, while those patients who received CY alone had normal resting TTPF. However, exercise TTPF was abnormally prolonged in all patient groups. While all controls demonstrated a normal decrease in TTPF during exercise, four of the 25 patients had a paradoxical increase in TTPF during exercise. Exercise diastolic function may provide evidence of cardiotoxicity in long-term survivors of BMT.

Failure of reflex venoconstriction during exercise in patients with vasovagal syncope.

BACKGROUND: In this study, we tested two hypotheses. First, we tested the hypothesis that reflex constriction of the venous capacitance beds in patients with vasovagal syncope is impaired during both subhypotensive lower-body negative pressure. Second, we proposed that splenic venoconstriction may be impaired during exercise in patients with vasovagal syncope. METHODS AND RESULTS: We evaluated 25 patients with vasovagal syncope (age, 45.0 +/- 15.9 years; 12 men, 13 women) and 24 control subjects (age, 41.3 +/- 13.7 years; 16 men, 8 women). A nuclear technique was used to assess changes in forearm venous tone during lower-body negative pressure and in splenic venous volume during cycle exercise. Changes in forearm vascular resistance (FVR) during cycle exercise were assessed with a strain-gauge plethysmography technique. The percentage reduction in unstressed forearm vascular volume during lower-body negative pressure was similar in patients and control subjects (9.0 +/- 8.0% versus 9.7 +/- 5.9%, P=NS). During exercise, splenic venous volume decreased less in patients than in control subjects (15.8 +/- 21.7% versus 42.6 +/- 12.6%, P < .0001). FVR decreased by 2 +/- 32% in patients but increased 108 +/- 90% in control subjects (P < .0001). There was no relation between percentage change in splenic volume and percentage change in FVR during exercise in either patients or control subjects (r= -.06, P=NS and r= -.18, P=NS, respectively). CONCLUSIONS: Patients with vasovagal syncope exhibit a failure of the normal increase in tone in the splenic capacitance bed and in forearm resistance vessels during dynamic exercise. Forearm venous tone increases normally during lower-body negative pressure.

Determinants of exercise capacity in patients with coronary artery disease and mild to moderate systolic dysfunction. Role of heart rate and diastolic filling abnormalities.

BACKGROUND: To test the hypothesis that diastolic filling abnormalities are an important cause of exercise limitation in some patients with coronary artery disease we assessed the factors limiting exercise capacity in a group of patients with coronary artery disease in whom exercise limitation was greater than expected from the degree of resting left ventricular systolic dysfunction. METHODS AND RESULTS: We assessed the relationship between exercise capacity (maximal oxygen consumption) during erect cycle ergometry, heart rate, radionuclide indices of left ventricular systolic function (ejection fraction) and diastolic filling (peak filling rate, and time to peak filling) during semi-erect cycle ergometry in 20 patients (15 male, five female) who were aged 42-72 years (mean 61 years) and had angiographically proven coronary artery disease and evidence of reversible myocardial ischaemia on thallium scintigraphy. All patients exhibited marked exercise limitation (maximal oxygen consumption 8.7- 22.4 ml.min-1.kg-1--mean 15.9 ml.kg-1.min-1, which was 61.1 +/- 16% of age and gender predicted maximum) due to breathlessness or fatigue rather than angina, in spite of a mean ejection fraction for the group of 46.5% (range 30-67%). We also compared the diastolic filling characteristics of these patients during exercise with 10 healthy controls (age 38-66, mean 58 years; eight male, two female). Comparing diastolic filling characteristics, peak filling rate was higher and time to peak filling shorter both at rest and at peak exercise in controls than patients (peak filling rate 3.1 +/- 0.5 vs 2.2 +/- 0.9 EDV.s-1, P = 0.01 at rest and 8.3 +/- 0.8 vs 5.2 +/- 1.9 EDV.s-1, P < 0.0001 on exercise; time to peak filling 115.2 +/- 29.8 vs 228.9 +/- 71.7 ms, P < 0.0001 at rest and 52.8 +/- 16.2 vs 139.6 +/- 44.8 ms, P < 0.0001 on exercise respectively). On univariate analysis in the patients studied, maximal oxygen consumption was correlated with peak heart rate (r = 0.45 P = 0.04), peak exercise time to peak filling (r = -0.85 P < 0.0001), peak exercise peak filling time rate (r = 0.51 P = 0.019), and the relative increase in cardiac output i.e. cardiac output peak/cardiac output rest (r = 0.58, P = 0.008). There was no correlation between maximal oxygen consumption and resting indices of diastolic filling (peak filling rate and time to peak filling) or with resting or peak exercise ejection fraction. On multiple regression analysis, only peak exercise time to peak filling was significantly related to maximal oxygen consumption. CONCLUSION: We have observed a strong correlation between exercise capacity and indices of exercise left ventricular diastolic filling, and have confirmed previous studies showing a poor correlation with resting and exercise indices of systolic function and resting diastolic filling, in patients with coronary artery disease.

Mechanism of exercise hypotension in patients with ischemic heart disease. Role of neurocardiogenically mediated vasodilation.

BACKGROUND: Exercise-induced hypotension in patients with coronary artery disease (CAD) has been considered to be due to an inability to achieve an adequate increase in cardiac output to match the demands of exercise. We investigated 10 consecutive patients (9 men and 1 woman; age, 38 to 71 years; mean, 52 years) with angiographically documented CAD and exercise-induced hypotension (EIH) (BPPeak < BPRest). Ten approximately age- and sex-matched patients with documented CAD and normal exercise blood pressure response (NBP) served as control subjects. METHODS AND RESULTS: Nine patients with EIH and all 10 control subjects underwent forearm plethysmography and radionuclide ventriculography (RNV) during semierect cycle exercise. Forearm vascular resistance (FVR) fell by 35 +/- 21% in exercise-induced hypotension patients versus an increase of 78 +/- 65% in patients with an NBP response (P < .0001). Left ventricular ejection fraction increased by 5.1 +/- 7.5% in the group with EIH versus a fall of 4.1 +/- 6.2% in the control group (P = .004). Cardiac output at peak exercise (RNV) increased by 2.2 +/- 0.89-fold in the group with EIH versus 1.49 +/- 0.47-fold in the control group (P = .04). The tenth patient in the group with EIH underwent invasive hemodynamic evaluation during erect exercise. Systolic blood pressure fell (136/80Rest to 50/40Peak) and cardiac output (Fick) tripled, whereas calculated systemic vascular resistance decreased by a factor of 10. Successful angioplasty to an isolated circumflex lesion resulted in resolution of symptoms and abnormal hemodynamic responses during exercise. CONCLUSIONS: Abnormal vasodilation associated with a normal or even increased rather than decreased cardiac output response appears to be an important mechanism underlying EIH in some patients with CAD. In the present study, this appears to have been the dominant mechanism in 8 and contributory in 2 of the consecutive patients studied.

Increased skeletal uptake of Tc-99m methylene diphosphonate in milk-alkali syndrome.

A case of milk-alkali syndrome is described in a 34-year-old man taking an over-the-counter antacid preparation for gastroesophageal reflux. A Tc-99m MDP bone scan performed in the initial investigation of the hypercalcemia was markedly abnormal with a "metabolic" pattern of tracer uptake similar to that seen in hyperparathyroidism and humoral hypercalcemia. Following withdrawal of the antacid and calcium, the bone scan appearance returned to normal, as did the biochemical markers of his disease.

Aerosol deposition in cystic fibrosis using an aerosol conservation device and a conventional jet nebulizer.

The deposition of technetium radiolabelled aerosol within the lungs of 12 stable cystic fibrosis patients (mean age 12.7 years) was compared using the Acorn nebulizer and mouthpiece alone, and the Acorn nebulizer attached to the Mizer Aerosol Conservation Device (MACD). The total activity delivered to the patient using the MACD was 11.1% (+/- 7.8% s.d.) of the initial dose, compared to 5.8% (+/- 4.2% s.d.) with the nebulizer and mouthpiece alone (P < 0.05). With the MACD, 84% of the intrapulmonary dose was delivered to the peripheral regions, compared to 76.5% with the nebulizer and mouthpiece (P < 0.05). No significant correlation was found between aerosol deposition and pulmonary function. The Mizer Aerosol Conservation Device significantly increases both total intrapulmonary aerosol deposition and peripheral aerosol distribution.

The validity of the geometric mean method for estimating internal activities in nuclear medicine.

The activity of an internal radioactive source may be calculated by comparing the geometric mean of the regional counts in a pair of conjugate gamma camera images with the geometric mean of the counts from a small surface reference source of known activity. Allowance must be made for the effects of differential forward scatter in the detector count rates from the internal and reference sources. The magnitude of these can be predicted, and a suitable correction factor for a given collimator and energy acquisition window calculated by applying a simple count rate build-up model to the observed count rate-depth data for a point and plate source in a water tank. Using a high resolution collimator with 99mTc sources in three sets of phantom trials, the model shows that a scatter build-up correction factor of 1.20-1.22 is suitable for an internal 99mTc source in a typical adult chest or abdomen.

Blunted parathyroid response to correction of hypercalcemia in subjects with squamous cell carcinoma.

In malignancy-associated hypercalcemia (MAH) elevated plasma calcium levels are believed to inhibit parathyroid secretion independently of the underlying tumor. This predicts that correction of hypercalcemia should disinhibit circulating parathyroid hormone (PTH) levels, irrespective of the underlying disease. We have tested this hypothesis in subjects with multiple myeloma (MM) and squamous cell carcinoma (SCC) treated with pamidronate. In the MM group, PTH levels returned to normal as hypercalcemia was corrected. In contrast, PTH levels remained low in the SCC group despite a similar fall in plasma calcium. Calcitriol levels were significantly higher and magnesium levels slightly lower in the SCC group than those in the MM group. We conclude that the parathyroid response to the correction of hypercalcemia is blunted in subjects with SCC but not MM. In addition to hypercalcemia, other factors, perhaps related to tumor secretion of PTH-related protein, may therefore contribute to suppressing PTH secretion in MAH due to SCC.

Thyroid nodules in the population living around Chernobyl.

OBJECTIVE: To determine the baseline incidence, prevalence, and characteristics of thyroid nodules in the population living around the Chernobyl nuclear power plant and to compare the findings with unexposed populations. DESIGN: Prevalence study. Population samples from seven highly contaminated villages were compared with six nearby control villages of the same size and type. The data were obtained as part of the International Chernobyl Project conducted in 1990. SETTING: The study was conducted 4.5 years after the Chernobyl reactor accident that released large quantities of radionuclides, including radioiodine. PATIENTS OR OTHER PARTICIPANTS: Population samples of approximately 100 persons residing in both highly contaminated villages and control villages since the accident were compared. Individuals were selected on the basis of birth date as being 5, 10, 40, or 60 years old at the time of the study. All persons selected underwent a thyroid examination. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Two main outcome measures were used, both for thyroid nodularity: clinical palpation and high-resolution ultrasonography. RESULTS: There was no significant difference in thyroid nodularity between the study groups. Nodules were palpated in 0.7% of children and 2.9% of adults. Discrete nodules were found by ultrasonography in 0.5% of children and 14.9% of adults. Multinodular goiter was found in 3% of adults. Nodules were more common in females. CONCLUSIONS: Four and a half years after the Chernobyl accident, the incidence, prevalence, and characteristics of thyroid nodules were the same in population samples from both highly contaminated and control settlements and similar to results reported for unexposed populations in other countries.

Clinical significance of the large adrenal mass.

Current clinical teaching indicates that large (greater than 5 cm in diameter) adrenal masses are often malignant. In a retrospective analysis of patients studied between 1977 and 1988 with computed tomography (CT), adrenal scintigraphy, and when available, magnetic resonance imaging (MRI) 45 were found to have adrenal masses greater than 5 cm (range 5-19 cm) in diameter. Thirty were benign (16 phaeochromocytomas, six adrenocortical adenomas, four adrenal cysts, two myelolipomas, an adrenal hematoma and a ganglioneuroma). Of 15 malignant masses, there were seven adrenocortical carcinomas, five adrenal metastases and three adrenal lymphomas. With the exception of the adrenal myelolipomas, cysts, and the ganglioneuroma neither CT nor MRI demonstrated sufficient diagnostic specificity to distinguish benign from malignant lesions. Functional scintigraphy with 131I-6-beta-iodomethyl-19-norcholesterol for suspected adrenocortical lesions and 131I-metaiodobenzylguanidine for suspected phaeochromocytomas frequently provided useful information.

Single-dose intravenous pamidronate is effective alternative therapy for Paget's disease refractory to calcitonin.

We have conducted an open, prospective study to investigate the efficacy of a single 60 mg infusion of pamidronate as alternative therapy in 15 subjects with severe Paget's bone disease refractory to calcitonin. Disease activity was assessed with a visual-analogue score of symptom severity, plasma alkaline phosphatase and quantitative estimation of 99mTc-methylene biphosphonate uptake on bone scan. All indices of disease activity fell after pamidronate, reaching a nadir at 3 months. Although disease activity increased thereafter, only 3 subjects required retreatment within 12 months. Plasma calcium fell after 3 days and remained below baseline levels for 6 months associated with evidence of secondary hyperparathyroidism. Pamidronate was well tolerated; femoral neck fractures occurred in 2 subjects with severe local Paget's disease but were unlikely to be due to the drug. We conclude that pamidronate is an effective and promising alternative for treatment of patients with severe Paget's disease no longer adequately controlled by calcitonin. Calcium supplementation may be prudent to prevent secondary hyperparathyroidism associated with the use of this agent.

Phaeochromocytoma and functioning paraganglioma in childhood and adolescence: role of iodine 131 metaiodobenzylguanidine.

Phaeochromocytomas and functioning paragangliomas are rare tumours in childhood and adolescence. We review our experience of 43 cases (24 men, 19 women) who were first diagnosed at the age of less than or equal to 18 years. All patients were evaluated at some point in their illness with iodine 131 metaiodobenzylguanidine (131I-mIBG) scintigraphy. Eight patients (19%) had bilateral adrenal tumours, 12 (28%) had solitary extra-adrenal tumours, and 8 (19%) had multiple tumours. In 10 patients (23%), the tumours were associated with a familial neurocristopathic syndrome. Thirteen of 24 (54%) unifocal tumours which were initially considered to be benign ultimately proved to be multi-focal and/or malignant. The final prevalence of malignancy was 60%--26 patients, of whom only 15 (57%) had obviously malignant tumours at the time of diagnosis. Primary tumour size greater than or equal to 5 cm was more commonly associated with a malignant course in adrenal but not extra-adrenal tumours. No other clinical, biochemical or morphological characteristic was significantly associated with malignancy. Although the high prevalence of malignancy in this series at least partly reflects referral bias, the need for lifelong follow-up of these patients is underscored. 131I-mIBG scintigraphy was positive in 36 patients (84%), with a somewhat lower false-negative rate (12%) than X-ray computed tomography (20%). Eight patients with malignant tumours received therapeutic doses of 131I-mIBG, with partial tumour responses in 3. Thus, 131I-mIBG is an efficacious, non-invasive, localising agent and may be considered as a palliative therapeutic agent when alternatives have failed.

Use of aminohydroxypropylidene bisphosphonate (AHPrBP, "APD") for the treatment of hypercalcemia in patients with renal impairment.

Aminohydroxypropylidene bisphosphonate (AHPrBP, "APD") is a relatively new bisphosphonate which has been shown to be effective for control of hypercalcemia due to a variety of causes. Renal impairment has been reported following the use of other bisphosphonates and pre-existing renal impairment has been regarded as a contraindication to the use of AHPrBP. We report the successful use of intravenous AHPrBP to control hypercalcemia in three patients with renal impairment, one of whom was dialysis-dependent. No significant side effects were noted; in particular, there was no further deterioration in renal function. Intravenous AHPrBP may be a safe and effective agent for the control of hypercalcemia in patients with renal impairment.

Multiple endocrine neoplasia type 2b: long-term follow-up of a case.

Multiple endocrine neoplasia type 2b is a rare inherited syndrome which comprises the association of medullary thyroid carcinoma, phaeochromocytoma, widespread neuromatous proliferation and a characteristic body habitus. In this report we present the late clinical course and autopsy findings of the first patient with this syndrome described in Australia. At presentation she was found to have a right adrenal phaeochromocytoma and medullary thyroid carcinoma which were resected in separate operations. No clinical or biochemical evidence of residual medullary thyroid carcinoma was identified in life. However, in spite of serial vanillylmandelic acid estimations, which showed normal or only mildly elevated levels, and normal results of urinary catecholamine studies, a left adrenal phaeochromocytoma was identified in a metaiodobenzylguanidine (MIBG) study performed 14 years after presentation. Her late clinical course was dominated by progressive dysphagia, intestinal dysmotility and megacolon associated with unrelenting malnutrition. After her death due to an intracerebral haemorrhage, an autopsy confirmed the presence of a left adrenal phaeochromocytoma and revealed diffuse intestinal ganglioneuromatosis to be the cause of her intestinal dysmotility. No residual medullary thyroid carcinoma was found. This case emphasises the propensity for multiple endocrine tumours in these patients and highlights the potentially significant role of intestinal ganglioneuromatosis in the natural history of this condition.

Insensitivity of Tc-99m pertechnetate for detecting metastases of differentiated thyroid carcinoma.

To evaluate the use of Tc-99m pertechnetate whole body scanning for the detection of metastases of differentiated thyroid carcinoma, the authors performed sequential Tc-99m pertechnetate and I-131 scans in five patients with known or suspected metastatic thyroid cancer. All five patients had abnormal I-131 uptake, but only two patients had abnormal Tc-99m pertechnetate uptake. A total of 33 abnormal foci were located with I-131; Tc-99m pertechnetate detected only 3 of these foci, and did not demonstrate any foci that were not apparent with I-131. Despite the theoretical advantages of Tc-99m pertechnetate, it cannot be recommended as a substitute for I-131 for locating thyroid cancer metastases.