Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data.

OBJECTIVE: In heart failure, digitalis increases exercise capacity and reduces morbidity, but has no effect on survival. This raises the suspicion that the inotropic benefits of digitalis may be counteracted by serious adverse effects. Patients with atrial fibrillation (AF) were studied to clarify this. DESIGN: In the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V studies, 7329 patients with AF at moderate-to-high risk were randomised to preventive treatment of thromboembolism, either with warfarin or the oral direct thrombin inhibitor ximelagatran. The survival of users and non-users of digitalis was investigated. RESULTS: At baseline, 53.4% of the study population used digitalis, and these patients had a higher mortality than non-users (255/3911 (6.5%) vs 141/3418 (4.1%), p<0.001; hazard ratio (HR) = 1.58 (95% CI 1.29 to 1.94)). Digitalis users also had more baseline risk factors. After multivariate risk factor adjustment, the increased mortality persisted (p<0.001; HR = 1.53 (95% CI 1.22 to 1.92 vs 1.23 to 1.92)). CONCLUSIONS: The results suggest that digitalis, like other inotropic drugs, may increase mortality. This may be concealed in heart failure, but be revealed in patients with AF, who need the rate-reducing effect of digitalis, but do not benefit much from an increased inotropy. Cautious interpretation of the data is mandatory since the patients were not randomised with respect to digitalis use.

Effects of tamoxifen on cardiovascular risk factors in postmenopausal women after 5 years of treatment.

BACKGROUND: Adjuvant tamoxifen therapy for breast cancer has been given for a period of several years. Cardiovascular diseases increased in incidence rapidly in women older than 60 years. Favorable changes in cardiovascular risk factors have been seen with 2 years of tamoxifen therapy, and lower rates of myocardial infarction and of hospitalization for heart disease have been observed in tamoxifen-treated women. PURPOSE: We sought to evaluate changes in risk factors for cardiovascular diseases in postmenopausal women after therapy with tamoxifen for 5 years. METHODS: Five years after their initial entry in a 2-year randomized, placebo-controlled toxicity study, we re-examined 62 of the original 140 disease-free, axillary node-negative postmenopausal breast cancer patients. These 62 patients were women available for study because they had not suffered major illness and had continued on either the tamoxifen or no-tamoxifen regimen to which they had been originally randomly assigned for the entire 5 years. Patient and control blood samples were analyzed for total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and subfractions, triglycerides, apolipoprotein AI, apolipoprotein B, lipoprotein(a), fibrinogen, glucose, and platelets. RESULTS: At base line for all measurements except atherogenic lipoprotein [lipoprotein(a)], the 30 long-term tamoxifen recipients and the 32 long-term no-tamoxifen recipients were not significantly different. After 5 years, levels of total serum cholesterol (P < .001), LDL cholesterol (P < .001), and lipoprotein(a) (P = .001) were significantly lower, and apolipoprotein AI levels were significantly higher (P < .001) in the tamoxifen-treated group compared with the no-tamoxifen group. Apolipoprotein B levels increased to a greater extent in the no-tamoxifen than in the tamoxifen group (P < .001). After 5 years, fibrinogen level decrease and triglyceride level increases in the tamoxifen group compared with the no-tamoxifen group were of borderline statistical significance and HDL cholesterol levels were not different in the two groups. CONCLUSION: Favorable changes in lipid, lipoprotein, and fibrinogen levels seen early in tamoxifen therapy in postmenopausal women persist with treatment of 5 years. IMPLICATIONS: The types and magnitude of changes in cardiovascular risk factors seen here with tamoxifen are similar to a certain extent with those seen with estrogen supplements. Further risk-factor and ethnic-group data are needed to estimate the magnitude of expected benefits of tamoxifen treatment on incidence of heart disease.

Protein S and protein C level changes with adjuvant tamoxifen therapy in postmenopausal women.

Tamoxifen citrate is a synthetic antiestrogen that provides survival benefit when given as adjuvant treatment in postmenopausal women with breast cancer. Venous thrombophlebitis may complicate tamoxifen treatment at a rate of approximately one per 800 treatment-years. To explore the possible procoagulant effects associated with tamoxifen therapy we evaluated changes in protein S and C activity levels in 58 postmenopausal women with surgically resected breast cancer who were disease-free and participating in a double-blind, placebo-controlled, randomized toxicity study of tamoxifen. The changes in protein C activities for the tamoxifen group (mean level = 113%) compared to those in the placebo group (mean level = 115%) were not significant (p = 0.45). Protein S activity levels increased while protein C activity levels decreased from baseline at 24 months in both tamoxifen and placebo groups. We conclude that the possible thrombophlebitis-promoting effect of tamoxifen in postmenopausal women is unlikely to be explained on the basis of protein S and protein C activity level changes.

Metastatic basal cell carcinoma. Report of five cases.

BACKGROUND: Metastatic basal cell carcinoma (MBCC) is rare. Risk factors for the development of MBCC include a history of persistent basal cell carcinoma (BCC) for many years, refractory to conventional methods of treatment and previous radiation treatment either in early adulthood or for localized cancer. Most MBCC originate from large tumors. METHODS: The authors report five patients with basal cell carcinomas (BCC) of the ear (two patients), scalp, inner canthus, and nasolabial fold that metastasized to the regional lymph nodes, skin, and submandibular gland. In addition, the authors reviewed more than 40 reports of MBCC (n = 65) from 1981 to 1991 and tabulated the primary tumors by size and depth of invasion according to TNM classification, a classification that previously has not been used for BCC. RESULTS: The authors tabulated the size distribution of tumors of 45 patients with MBCC. The overall mean and median diameters of the primary BCC were 8.7 and 7.0 cm, respectively. The mean area of the primary MBCC lesion that originated on the face and trunk was 62 and 217 cm2, respectively. Using the TNM classification, approximately 9% of MBCC originate from tumors smaller than 10 cm2. In addition, the authors found that large (T2 and T3) and deep (T4) BCC account for approximately 75% of the metastatic tumors. Metastatic BCC from primary tumors smaller than 1 cm in diameter are exceptionally rare. CONCLUSIONS: Approximately 67% of MBCC (n = 238) originate from facial sites. Using the data base of the Mohs Surgery Clinic, the authors found that BCC greater than 3 cm in diameter have approximately a 1.9% incidence of metastasis, and the overall rate of metastases for morpheaform BCC is less than 1%. Patients with tumors classified as T3 and T4 lesions ideally should be followed up for 10 or more years for the remote possibility of the development of MBCC.

Effects of tamoxifen on cardiovascular risk factors in postmenopausal women.

OBJECTIVE: To determine the effects of tamoxifen on risk factors for cardiovascular disease in disease-free postmenopausal women. DESIGN: Double-blind, placebo-controlled, randomized 2-year clinical trial. SETTING: University health sciences center. PATIENTS: Clinically postmenopausal women (140) with a diagnosis of axillary node-negative breast cancer, who were disease-free by laboratory and clinical evaluations. MEASUREMENTS: Levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein A-I, apolipoprotein B, glucose, weight, blood pressure, and reported exercise and work activity were measured. MAIN RESULTS: Postmenopausal women receiving tamoxifen were evaluated at 3- or 6-month intervals during a 2-year assessment period and showed a mean decrease of 12% in total cholesterol levels (at 24 months -0.672 mmol/L; 95% CI, -0.839 to -0.505 mmol/L) and a mean decrease of 20% in calculated low-density lipoprotein (LDL) cholesterol levels (at 24 months, -0.725 mmol/L; 95% CI, -0.868 to -0.583 mmol/L) (P less than 0.001). Women with greater baseline cholesterol levels had greater decreases with tamoxifen treatment. Levels of HDL cholesterol decreased in patients treated with tamoxifen, but this decrease was only statistically significant at one of five measurement times. Apolipoprotein A-I levels increased significantly at the two time points at which it was measured (P = 0.02), and apolipoprotein B levels decreased significantly at these times (P less than 0.01) in patients treated with tamoxifen. Plasma glucose levels, reported exercise and work activity, reported smoking, weight, and systolic and diastolic blood pressures did not change with treatment. CONCLUSION: During 2 years of treatment, tamoxifen showed generally favorable effects on the lipid and lipoprotein profile of treated postmenopausal women. These effects may partially explain the decrease in adverse events and in mortality related to coronary heart disease seen in patients receiving adjuvant tamoxifen treatment.

Plasma adrenocorticotropic hormone in the rat demonstrates three different rhythms within 24 h.

Secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary is rhythmic and episodic, as reflected by fluctuations in plasma concentrations of ACTH. The present work was designed to further characterize the patterns of ACTH secretion that occur simultaneously within a 24-hour period in the rat. To accomplish this, blood collection protocols with sampling intervals of 2 min, 15 min, and 4 h were used in awake, chronically cannulated rats. Plasma samples were assayed for immunoreactive ACTH, and resultant data were analyzed for significant pulsatile secretory episodes. We observed three different patterns of ACTH secretion within a 24-hour period. Circadian variation occurred with peak plasma ACTH levels in the early evening. In addition, plasma ACTH exhibited two types of episodic variation: (1) episodic bursts with variable amplitudes that occurred approximately three times per hour which have been referred to as 'micropulses', and (2) prolonged elevations of plasma ACTH that occurred approximately 14 times in 24 h which have been referred to as 'larger ultradian' secretory episodes. These latter episodes appeared to consist of groups of relatively high amplitude micropulses. The physiological significance, functional interactions, and location of the controlling oscillator(s) of these different rhythms remain to be determined.

Immunoneutralization of corticotropin-releasing hormone prevents the diurnal surge of ACTH.

To determine whether CRH is required for the evening rise in plasma ACTH, rats were injected at 0800 hr with CRH antiserum (anti-CRH) or normal rabbit serum (NRS). Blood samples were taken through venous catheters at 0800 hr before treatment and at 1300, 1700, and 2100 hr. Plasma was assayed for immunoreactive ACTH and corticosterone. There was no significant difference in pretreatment values between the two groups. Immunoneutralization of CRH abolished the rise in plasma ACTH seen at 1700 hr in the NRS group but had little effect on earlier levels. The diurnal elevation in plasma corticosterone continued after anti-CRH treatment, but peak levels occurred earlier. Plasma ACTH and corticosterone were significantly correlated at the time of the diurnal surge, but not at 0800 hr or 1300 hr in the NRS controls or at any time point in the anti-CRH group. These results suggest that CRH is required for the diurnal surge of plasma ACTH. They also confirm previous observations by others that the adrenal cortex does not require active CRH or a diurnal surge of ACTH in order to exhibit a significant diurnal increase in secretion of corticosterone, and that factors other than CRH may be relatively more active than CRH in regulation of ACTH secretion during the time of circadian inactivity.

Risk factors for sensitization by blood transfusions. Comparison of the UW/Madison and UC/San Francisco donor-specific transfusion experience.

We have tested the predictive model for risk of sensitization by donor-specific transfusions developed at the University of California, San Francisco for its applicability to the DST experience at UW/Madison. Patient sample sizes between the two groups were similar (n = 249 for UW/Madison, n = 261 for UCSF) and the two groups of patients had similar compositions in terms of mean age, ABO type, baseline panel-reactive antibody, and pregnancy rate. The two groups differed in that the UW/Madison group had a higher percentage of males, diabetic patients, previously transplanted patients, and 0 haplotype-matched (2 HLA-mismatched related and unrelated) recipients. In addition, all the UW/Madison patients received azathioprine (AZA) whereas only half the UCSF group was given AZA. Despite these differences, application of the UCSF model for prediction of sensitization by DST gave remarkably similar results in our patient population, with pregnancy, prior transplant, baseline PRA, and HLA antigen sharing giving similar odds ratios and P values. However, when female sex was included in the model along with the other variables, the significance of pregnancy risk disappeared. We have developed an alternative multivariate model using stepwise logistic regression that identifies baseline PRA greater than 40%, female sex, and prior transplant as significant risk factors for sensitization, while number of HLA (A, B, DR) antigens shared and increasing recipient age significantly decreased risk of sensitization by DST.

Intracavernous self-injection for impotence: a long-term therapeutic option? Experience in 78 patients.

A total of 78 patients 17 to 84 years old reported their experience via questionnaire with the papaverine-phentolamine injection technique for impotence. The mean number of injections used was 30.7. Penile induration occurred in 13 patients (16 per cent) and it was generally of limited extent. A higher incidence of induration was observed in those with vasculogenic impotence. Prolonged erection was reported by 23 per cent of the patients, 8 per cent of whom experienced erection for more than 12 hours. Priapism occurred exclusively in diabetic patients and patients with a neurological etiology of impotence. A total of 22 per cent of the patients reported moderate to severe pain with injection, 35 per cent indicated decreased quality of erection with time in response to the vasoactive agents and 28 per cent believed this therapy to be unsatisfactory. Among those who discontinued the injections 5 cited variability of erectile response (duration or quality) as the reason for discontinuation. A decrease in the effectiveness of the injections with time may be anticipated among some patients. For patients who face a penile implant without other options penile self-injection with vasoactive drugs is a reasonable alternative in that complications do not prevent successful prosthetic implantation.

Relating cerebral ischemia and hypoxia to insult intensity.

The contributions of five variables believed to influence the brain's metabolism of O2 during hypoxia [duration, PaO2, delta CMRO2 (the difference between normal and experimental oxygen uptake), O2 availability (blood O2 content.CBF), and O2 deficit (delta CMRO2.duration)] were assessed by stepwise and multiple linear regression. Levels of brain tissue carbohydrates (lactate, glucose, and glycogen) and energy metabolites [ATP, AMP, and creatine phosphate (CrP)] were significantly influenced by O2 deficit during hypoxia, as was final CMRO2. After 60 min of reoxygenation, levels of tissue lactate, glucose, ATP, and AMP were related statistically to the O2 deficit during hypoxia; however, CMRO2 changes were always associated more significantly with O2 availability during hypoxia. Creatine (Cr) and CrP levels in the brain following reoxygenation were correlated more to delta CMRO2 during hypoxia. Changes in some brain carbohydrate (lactate and glucose), energy metabolite (ATP and AMP) levels, and [H+]i induced by complete ischemia were also influenced by O2 deficit. After 60 min of postischemic reoxygenation, brain carbohydrate (lactate, glucose, and glycogen) and energy metabolite (ATP, AMP, CrP, and Cr) correlated with O2 deficit during ischemia. We conclude that "O2 deficit" is an excellent gauge of insult intensity which is related to observed changes in nearly two-thirds of the brain metabolites we studied during and following hypoxia and ischemia.

Changes in mean plasma ACTH reflect changes in amplitude and frequency of secretory pulses.

ACTH is secreted in an episodic manner from the anterior pituitary. Unanesthetized rats with indwelling jugular and femoral venous cannulae were continuously bled and simultaneously infused with isotonic fluid by peristaltic pump. Two-minute blood samples were collected for up to five hours in 8 male rats. ACTH was measured by radioimmunoassay. The resulting time series were analyzed for significant secretory pulses with the PULSAR program. Elevations or declines in mean plasma ACTH levels were associated with significant changes in amplitude and frequency of secretory pulses.