The American Journal of Medicine

pital day 2), her blood pressure had decreased to 164/113 mm Hg and her heart rate had increased to 92 bpm. She then received 1 dose each of oral nifedipine XL (60 mg), clonidine (0.1 mg), hydralazine (10 mg), metoprolol (200 mg), and diltiazem 180 mg. Following these medications, the patient became confused and semi-comatose, and her blood pressure dropped to 90/62 mm Hg. An ECG taken at that time showed P waves occurring after the QRS complex (Figure 2, upper panel). Intravenous glucagon (7.5 mg) was administered to counteract the effects of both the betablockers and calcium channel blockers, 1 and the patient’s blood pressure improved to 120/72 mm Hg. A rhythm strip recorded 6 min after the administration of glucagon (Figure 2, middle panel) showed a small increase in the time interval between the QRS and the subsequent P waves. Normal sinus rhythm was obtained 4 min later (Figure 2, lower panel). Later that day, the patient’s blood pressure decreased again to 96/64 mm Hg. ECG rhythm strips showed a narrow QRS complex rhythm at 70 bpm with P waves of sinus morphology preceding the QRS complex, short and variable PR intervals, and periodically disappearing P waves (Figure 3). The administration of a second dose of intravenous glucagon (7.5 mg) resulted in the return of normal sinus rhythm and improved blood pressure (112/70 mm Hg).

Numerous studies have shown that effective control of elevated blood pressure has greatly reduced the risk of stroke and, to a lesser extent, the risk of coronary artery disease. Although the relationship between diastolic blood pressure and both stroke and coronary disease is significant, systolic blood pressure correlates more strongly with stroke, congestive heart failure, coronary artery disease, declining renal function, and left ventricular hypertrophy. Studies have also shown that the presence of a wide pulse pressure (>/=60-70 mm Hg) also has an independent and major impact on coronary disease mortality and is strongly correlated with increased risk for cardiovascular disease. Because many hypertensives have end-organ damage (cardiac, central nervous system, renal), and the majority also have a comorbid condition such as diabetes and hyperlipidemia, which also increases cardiovascular risk, it is necessary to view the risks and comorbidity of hypertension and antihypertensive therapy in light of these problems. Despite evidence that antihypertensive therapy reduces the risk of stroke and coronary events, and despite the availability of effective agents, roughly half of the hypertensives in the United States remain untreated and only 24% have blood pressure <140 mm Hg systolic and 90 mm Hg diastolic. To ensure that hypertensive patients receive adequate therapy, physicians should treat patients aggressively and appropriately, avoiding antihypertensive drugs that adversely affect comorbid conditions and selecting those that also exert favorable therapeutic effects on these conditions.

Purpose: For the patient-administered treatment of anogenital warts, 0.5% podofilox (podophyllotoxin), one of the active compounds of podophyllin, has been shown to be more effective than the vehicle alone. This study was designed to evaluate the safety and efficacy of 0.5% podofilox treatment followed by prophylaxis. Patients and methods: A total of 103 patients were entered in stage 1 of the study. Stage 1 was an open label study, and patients self-administered 0.5% podofilox twice daily for 3 consecutive days per week for 4 weeks. A total of 100 patients remained available for efficacy and safety analyses. At the end of stage 1, patients who had a complete response proceeded to stage 2 of the study. Patients who had a 50% to 99% reduction in measured total wart area were offered cryotherapy every 10 days, up to 5 times. If cleared of warts, they were also entered into stage 2. A total of 57 patients were enrolled into stage 2, a double-blind, randomized, placebo-controlled prophylactic study of 0.5% podofilox self-administered once daily for 3 days per week for 8 weeks, on the sites of healed warts. A total of 45 patients in stage 2 were available for efficacy analysis. Results: By the end of stage 1, 68% of the warts had disappeared, and 29 of 100 patients (29%) had a complete response. A total of 49 patients had a 50% or greater improvement in wart area and underwent cryotherapy. Rates of local side effects after 1 week of treatment were 57% for inflammation, 39% for erosion, 47% for pain, 48% for burning, and 44% for itching. However, these symptoms and signs were mostly mild to moderate in intensity and diminished over time. Therefore, overall treatment was well tolerated. In stage 2, only 4 of 21 patients (19%) in the podofilox group experienced a recurrence as opposed to 12 of 24 (50%) in the placebo group (P = 0.031). As in stage 1, the side effects were modest, and the drug was well tolerated. Conclusion: This study confirms the efficacy and good tolerance of 0.5% podofilox in the treatment of anogenital warts. It also establishes the safety and superior efficacy of patient-administered podofilox over the vehicle alone as prophylaxis against recurrence of lesions. Although long-term efficacy and tolerance remain to be established, podofilox appears to be a useful agent in the control of this disease.

One thousand unselected patients admitted to large urban medical centers were examined for the presence of a diagonal ear lobe crease and evaluated for the presence of coronary artery disease. A high degree of correlation between the two was seen, using both clinical and angiographic criteria for the diagnosis of coronary artery disease. The association between the ear lobe crease and coronary artery disease was independent of patient age. Prospective analysis of single risk factors in 112 consecutive patients subjected to coronary cineangiography revealed that demonstrable coronary artery disease was correlated only with the ear lobe crease and with previous acute myocardial infarction (although less strongly with the latter). These conclusions are consistent with those of the world's literature, which also finds a strong correlation between coronary artery disease and the ear lobe crease, with the exception of Oriental patients, native American Indian patients, and children with Beckwith's syndrome.

Two-hundred-sixty-nine otherwise healthy persons experiencing periodic, moderately severe headache of a type that had previously responded to nonprescription medications completed this randomized, parallel, double-blind study. The three demographically similar subgroups took either 1,000 mg acetaminophen, 650 mg aspirin, or an identical placebo, for headache. Headache intensity and relief scores over the following six hours were obtained and assessed by sums of pain intensity difference and values of pain relief scores analyses. Responses for the group, and for the subgroup with tension headaches (107 persons) showed no differences between the effects of the active medications. The effects of each medication were strongly superior to placebo. There were no differences in side effects among the three treatment modalities. In persons experiencing tension-vascular headaches (162), only aspirin, at two hours, was superior to placebo, but direct comparison with acetaminophen suggested no real difference. Acetaminophen (1,000 mg) and aspirin (650 mg) are clinically similar in treating the headaches for which they are commonly taken. Recommendations for their use in treating headache should be based on individual patient suitability and on cost factors.

The contribution of M-mode echocardiography to cardiac diagnosis was evaluated in a series of 1,000 successive patients. Among subjects in whom a presumptive clinical diagnosis had been made, echocardiography demonstrated totally unexpected findings in 10 per cent, supported the clinical diagnosis in 50 per cent and was entirely within normal limits in 19 per cent. Among patients with evidence of heart disease but no firm clinical diagnosis, echocardiography established the diagnosis in 23 per cent, including 20 per cent of all patients referred for evaluation of chest pain or arrhythmia of unclear etiology. "Missed" clinical diagnosis frequently involved patients with mitral valve prolapse, congestive cardiomyopathy, pericardial disease or asymmetrical septal hypertrophy of the heart. This study quantifies the amount of independent information contributed by echocardiography to cardiac diagnosis and demonstrates that this technic provides data of important clinical relevance in a surprisingly large number of cardiac patients.

Three patients are described in whom there was no simple correlation between plasma 1,25(OH)2D3 concentration and the occurrence of osteomalacia. One patient had severe osteomalacia with high plasma 1,25(OH)2D3 and normal mineral ion product; the second had a normal mineral ion product and no evidence of osteomalacia even though plasma 1,25(OH)2D3 was undetectable; and the third had osteomalacia, low plasma 1,25(OH)2D3 and a reduced mineral ion product. In considering these data in the light of presently available information, it is concluded that osteomalacia can occur as a consequence of a lack of a vitamin D metabolite other than 1,25(OH)2D3, or a consequence of a reduced mineral ion product, but not as a consequence of 1,25(OH)2D3 lack if the mineral ion product is normally maintained and other D metabolites are present. However, a deficiency of 1,25(OH)2D3 normally leads to a reduction in the mineral ion product hence 1,25(OH)2D3 deficiency may play a role in the development of certain forms of osteomalacia.

Two boys aged six and four with the syndrome of hereditary resistance to 1,25-dihydroxyvitamin D3 with rickets alopecia and growth retardation are presented. After unsuccessful therapeutic trials with pharmacologic doses of vitamin D or its active metabolites, the patients were treated by long-term intracaval infusions of calcium through an implantable catheter. A total of 0.5 to 0.9 g of elemental calcium was infused daily for 18 months and the serum calcium concentration was maintained at 9 to 10 mg/dl. Bone pain subsided within one week of treatment. Serum phosphorus, immunoreactive parathyroid hormone, and 1,25-dihydroxyvitamin D concentrations and alkaline phosphatase activity were normalized within four to nine months. Radiographs of the knees and hands revealed progressive healing of rickets with complete resolution after one year of treatment. The patients gained 12 cm and 8 cm per year in height as compared with 3 cm and 2 cm, respectively, in the previous year. A transilial bone biopsy obtained from one patient prior to treatment revealed severe osteomalacia associated with osteitis fibrosa. A follow-up biopsy examined after 12 months of therapy showed almost complete healing of osteomalacia and normal mineralization. These observations indicate the following: (1) Long-term intracaval calcium infusions are an effective mode of therapy for these patients, and (2) When adequate serum calcium and phosphorus concentrations are maintained, healing of rickets and normal growth rate could be achieved even in the absence of a normal 1,25-dihydroxyvitamin D3 receptor-effector system.

The short-term effects of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) on disordered calcium metabolism were studied in 15 trials in patients with advanced renal failure and, for comparison, in 20 trials in normal persons. The steroid was given orally in doses of 0.027, 0.14, 0.68 and 2.7 μg/day for 7 to 15 days. Calcium absorption and urinary calcium increased after the administration of 0.14 to 2.7 μg/day in normal subjects, but 0.68 to 2.7 μg/day was needed to augment calcium absorption in the patients with uremia. Fecal calcium decreased significantly during metabolic balance studies. Serum calcium increased markedly only in the patients with uremia, and hypercalcemia occurred at a dosage level of 2.7 μg/day. With the increase in serum calcium, the blood levels of immunoreactive parathyroid hormone (iPTH) decreased. Urinary calcium increased substantially only in normal subjects. The steroid corrected the "vitamin D resistance" of uremia, suggesting that the renal production of 1,25-(OH)2D3 in uremia is defective.

Principal among the many relationships involving the metabolism and function of vitamin D is the central role of the kidney in the production of the biologically active steroid, 1,25-dihydroxychole-calciferol. Three important topics under intensive investigation in many laboratories are (1) the role of the kidney as an endocrine organ producing the biologically active form of vitamin D, (2) the regulation of the endocrine organ and its integration in the process of calcium homeostasis, and (3) reevaluation of the wide variety of vitamin D-related disease states as they relate to the central role of the kidney in vitamin D action.

In calcium deficiency states such as chronic renal failure, 1,25-dihydroxyvitamin D3 increases calcium and magnesium absorption toward normal levels. In the present study, the ability of exogenous 1,25-dihydroxyvitamin D3 to increase calcium and magnesium absorption above normal rates in healthy subjects was investigated. Steady-state perfusion studies were performed in 30 cm segments of jejunum and ileum before and after one week of 1,25-dihydroxyvitamin D3 administration (2 micrograms per day, 10 subjects). Serum 1,25-dihydroxyvitamin D concentration increased from 25.8 +/- 2.5 pg/ml to 56.4 +/- 6.6 (mean +/- SEM, p less than 0.05). In the basal state, calcium absorption was significantly higher in the jejunum than in the ileum. Vitamin D administration resulted in a significant increase in calcium absorption which was quantitatively similar in both the jejunum and ileum. The changes in net movement were due to an increase in lumen-to-plasma flux of calcium; the plasma-to-lumen flux remained unchanged. Jejunal magnesium absorption also was enhanced by 1,25-dihydroxyvitamin D3. These studies demonstrate that in healthy persons, exogenous 1,25-dihydroxyvitamin D3 increases calcium absorption in both the jejunum and the ileum, and increases magnesium absorption in the jejunum.

Two unrelated kindreds with four affected children having 1,25-dihydroxyvitamin D resistance, rickets, and alopecia are described. The children exhibited early onset of severe rickets with hypocalcemia, hypophosphatemia, elevated serum alkaline phosphatase levels, and secondary hyperparathyroidism. Radiography showed diffuse demineralization and classic changes of rickets. All affected children had total-body alopecia. Serum levels of 1,25-dihydroxyvitamin D3 were elevated and rose to extremely high values during treatment, with no apparent change in the mineral disorder. However, secondary hyperparathyroidism and hypophosphatemia did remit during treatment despite persistently low calcium levels. Skin biopsy was performed in the parents and affected children in one kindred. Analysis of 1,25-dihydroxyvitamin D3 receptors in cultured fibroblasts indicated apparent normal receptors in the parents and undetectable receptors in both affected children. After long periods of treatment with vitamin D metabolites and mineral replacement, healing took place in the older child in each kindred. These data suggest that the healing occurred spontaneously as the children reached seven to nine years of age rather than as a result of the treatment. The biochemical lesion in these children appeared to be a genetically transmitted defect in the 1,25-dihydroxyvitamin D3 receptor. The mechanisms by which healing was initiated and maintained remain to be elucidated.

Hypercalcemia has been infrequently associated with Hodgkin's disease. When seen, most cases have been attributable to skeletal invasion by disease. Herein is described a 40-year-old man with a 15-year history of Hodgkin's disease. Each of four disease recurrences was heralded by hypercalcemia occurring in the absence of bone disease or elevation of parathyroid hormone levels. Marked elevations of 1,25-dihydroxyvitamin D levels were observed that paralleled his disease course and response to therapy. The repetitive association of hypercalcemia with an elevation of 1,25-dihydroxyvitamin D in this case provides further evidence of lymphoma-associated production of this vitamin.

Six long-term hemodialysis patients with progressive skeletal deterioration during long-term pharmacologic vitamin D2 therapy were treated for six to 12 months with oral 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) to determine its therapeutic effectiveness in vitamin D2-unresponsive osteodystrophy. On bone biopsy, three of the patients had severe osteomalacia and three showed predominant osteitis fibrosa. Previous therapies, including phosphate binders and dialysis schedules, were maintained. The three patients with osteomalacia and the two with osteitis fibrosa showed clinical deterioration. There was no significant change in serum calcium, phosphate, alkaline phosphatase, bone densitometry, immunoreactive parathyroid hormone levels or bone histology. Roentgenograms showed multiple new fractures of ribs and femoral necks in the patients with osteomalacia and increased bone resorption in two of three patients with osteitis fibrosa. 1,25-(OH)2D3 dosage had to be decreased in all patients because of hypercalcemia with a mean tolerated dose of 0.22 microgram/day. In these patients, 1,25-(OH)2D3 was not effective therapy for progressive osteodystrophy unresponsive to pharmacologic vitamin D2.

Two patients with lepromatous leprosy and hypercalcemia are presented. Serum immunoreactive parathyroid hormone and urinary cyclic adenosine monophosphate concentrations were suppressed. Serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations were elevated in one patient and normal in the other. Urinary hydroxyproline excretion was slightly high in both patients. Hypercalcemia resolved excretion was slightly high in both patients. Hypercalcemia resolved with prednisone therapy. Abnormal 1,25-(OH)2D production and/or metabolism may play a role in the pathogenesis of hypercalcemia in some patients with leprosy.

We have used a low-calcium diet providing only 2 mg/kg (body weight) per 24 hours of calcium to distinguish between "renal" and "absorptive" idiopathic hypercalciuria. Sixteen of 27 hypercalciuric subjects excreted calcium in excess of intake during days seven, eight and nine of he diet, suggesting some element of renal hypercalciuria; however, all patients had low or normal serum PTH and urine cAMP levels. In general, fasting urine calcium was elevated in these 16 subjects and normal in the remaining 11, who conserved calcium more normally. SErum 1,25(OH)2D3 levels were the same in patients and normal subjects, even though PTH levels of the patients were below those of he normal subjects. Urine magnesium excretion and phosphorus excretion were both increased in the patients who excreted calcium in excess of intake. Our findings suggest that renal and absorptive hypercalciuria may not be distinct entities but rather the two extremes of a continuum of behavior. A uniform elevation of intestinal calcium absorption and a variable defect of renal calcium reabsorption could explain our results far better than the hypothesis of distinct absorptive and renal forms of hypercalciuria.

Hypoparathyroidism was diagnosed in nine members of a kindred of three generations. This study investigated why these persons were asymptomatic and without developmental abnormalities, in contrast to the common presentation of idiopathic hypoparathyroidism. In the hypocalcemic subjects, serum calcium level was 7.4 +/- 0.8 mg/dl (mean +/- SD) and ionized serum calcium level was 3.48 +/- 0.21 mg/dl. Immunoreactive parathyroid hormone values were inappropriately low. Injection of EDTA in one patient lowered ionized calcium levels, but immunoreactive parathyroid hormone values did not rise. Serum levels of 1,25-dihydroxyvitamin D and other vitamin D metabolites were normal or elevated and substantially higher than in other hypoparathyroid states. The normally observed positive correlation between the fasting urinary calcium/creatinine ratio and serum 1,25-dihydroxyvitamin D that reflects the dependence of net bone resorption on 1,25-dihydroxyvitamin D was upheld in hypoparathyroid patients. It is proposed that the subjects with familial hypoparathyroidism in this kindred had moderate asymptomatic hypocalcemia without developmental abnormalities because normal or elevated serum 1,25-dihydroxyvitamin D levels enhanced intestinal calcium absorption. This may represent one point in the spectrum of idiopathic hypoparathyroidism. Alternately, both the moderate degree of hypocalcemia and the normal serum calcitriol values could have been related to mild, partial hypoparathyroidism, which could have been inherited in this kindred.

The impact of strenuous exercise and environmental hypoxia on sickle cell trait (SCT) remains controversial. To determine if these factors induce cardiopulmonary and gas exchange abnormalities in SCT, healthy, young black male volunteers, 25 with SCT (HbAS) and 16 control subjects (HbAA), were evaluated during incremental and steady-state exercise tests using a cycle ergometer at 1,270 meters and 24 degrees C. Peak incremental exercise values for power (242 +/- 7 versus 253 +/- 10 watts), oxygen consumption (3.08 +/- 0.1 versus 3.26 +/- 0.14 liters/minute), heart rate (188 +/- 2 versus 189 +/- 3 beats/minute), minute ventilation (129 +/- 4.6 versus 144 +/- 7.7 liters/minute), oxygen pulse (16.4 +/- 0.5 versus 17.3 +/- 0.8 ml/beat), and respiratory exchange ratio (1.31 +/- 0.01 versus 1.33 +/- 0.02) revealed no significant differences (p less than 0.05) between the SCT and control groups, respectively. Peak incremental exercise values for arterial oxygen tension (82 +/- 1.7 versus 82 +/- 2.2 mm Hg), arterial carbon dioxide tension (32 +/- 0.7 versus 31 +/- 0.9 mm Hg), and alveolar-arterial oxygen pressure differences (19 +/- 1.4 versus 21 +/- 1.9 mm Hg) were similar for the SCT and control groups, respectively. Steady-state exercise results corroborate incremental exercise findings. It is concluded that cardiopulmonary and gas exchange responses to a brief period of strenuous exercise performed at low altitude at 24 degrees C in a well-characterized SCT sample of recruits were within normal limits and comparable to those of a carefully selected control sample.

Misoprostol at a dose of 200 micrograms inhibits gastric acid secretion and protects the gastric mucosa against the injurious effects of a single 1,300-mg dose of aspirin. The purpose of this study was to determine whether lower subantisecretory doses of misoprostol protect the gastric mucosa in this single-dose aspirin model. Protection was defined as no more than 10 hemorrhagic spots and no more than two hemorrhagic streaks. A total of 140 men participated in the two phases of the study. In the first phase, groups of 10 subjects each received placebo or misoprostol in doses of 200 micrograms, 100 micrograms, 50 micrograms, or 25 micrograms in a double-blind design. All misoprostol doses protected 50 to 70 percent of subjects as compared with 20 percent of subjects in the placebo group. To expand the number of observations, 90 additional subjects in groups of 30 each were evaluated after receiving misoprostol 50 micrograms or 25 micrograms or placebo. Misoprostol 50 micrograms protected 14 of 30 subjects (47 percent), 25 micrograms protected 11 of 30 (37 percent), and placebo protected six of 30 (20 percent). The dose-response trend was statistically significant (p less than 0.05). It is concluded that misoprostol protects the gastric mucosa against a single 1,300-mg dose of aspirin and that there is a significant dose-response relationship.

This report from the Canadian survey of thyroid cancer describes 1,074 patients with papillary thyroid cancer and 504 with follicular thyroid cancer followed for four to 24 years. The study groups included more patients with "advanced" disease and fewer with "early" disease than in the general population because these patients were referred to radiotherapy cancer centers, sometimes routinely, but often because referring physicians believed that certain clinical features indicated the need for additional treatment. Although this report is subject to all the problems of retrospective studies, a careful assessment of the pretreatment extent of disease combined with a long follow-up period has allowed an analysis of prognostic factors with considerable confidence. Univariate analysis of 12 possible prognostic factors (excluding treatment) demonstrated that nine of them were of statistical significance: postoperative status, age at diagnosis, extrathyroidal invasion, distant metastases, nodal involvement, differentiation, sex, tumor size, and pathologic type (in descending order of importance). Multivariate analysis was carried out using cause-specific survival rates. Independently important prognostic factors at initial treatment were age at diagnosis, extrathyroidal invasion, and degree of differentiation histologically for papillary cancers; and extrathyroidal invasion, distant metastases, primary tumor size, nodal involvement, age at diagnosis, and postoperative status for follicular cancers. The prognostic factors for tumor recurrence were quite different for the papillary and follicular cancers and ranked differently for the two groups.

A review of 1,997 patients to whom carinamide was administered has demonstrated that the drug possesses a low order of toxicity. Exclusive of nausea (12.1 per cent) and vomiting (5.5 per cent) the incidence of toxic manifestations was less than 2 per cent. True drug sensitivity was confirmed in fourteen patients and may be assumed in twenty-three additional cases although the concurrent administration of penicillin raises some questions as to the etiologic role of carinamide in all of the latter cases. Nausea may preclude therapy with the drug but this symptom may in large measure be ascribed to the mechanical factor of swallowing a large and oft-repeated dose of drug rather than to toxicity of the drug itself. From the observations recorded there is no indication that carinamide interfered with the elimination of normal nitrogenous metabolites or permanently impaired renal functions. Carinamide should be withheld in the presence of renal disease not because it is damaging to the kidneys but because its administration is unnecessary. Since carinamide is excreted almost entirely by glomerular filtration and sub-clinical grades of renal impairment cause accumulation of the drug in the circulation, dosage should be individualized and controlled by plasma carinamide estimations. It is possible that carinamide, by exerting its pharmacologic action upon the renal tubules, may inhibit the tubular excretion of some commonly employed medications. Few drugs in common use, even those that are granted to have little or no toxicity, can be given in the large doses, 18 to 32 Gm. per day, over periods of time up to sixty days, that are recorded here for carinamide.