Which subgroup of patients with dilated cardiomyopathy would benefit from long-term beta-blocker therapy? A histologic viewpoint.

OBJECTIVES: The purpose of this study was to elucidate whether the effectiveness of long-term beta-blocker therapy could be predicted before this therapy is started. BACKGROUND: Long-term beta-blocker therapy has recently been reported to provide a favorable effect in treatment of congestive heart failure due to dilated cardiomyopathy. METHODS: Several measurements including histologic variables before administration of metoprolol were retrospectively compared among 18 good responders (showing improvement of at least one New York Heart Association functional class or an increase in ejection fraction > or = 0.10 12 months after drug administration) and 12 poor responders without such improvement. RESULTS: Although there were no significant differences between the two groups in age, gender, functional class, heart rate, blood pressure, pulmonary capillary wedge pressure, cardiac index, left ventricular end-diastolic dimension and ejection fraction, percent fibrosis estimated by the point-counting method in endomyocardial biopsy specimens was significantly lower in good than in poor responders (7.6 +/- 5.7 vs. 14.2 +/- 9.7%, p < 0.05). Moreover, when the types of fibrosis were classified as interfascicular and intercellular by the dominance of counted points, there were 13 cases of interfascicular fibrosis and 5 cases of intercellular fibrosis in good responders and 1 case of interfascicular fibrosis and 11 cases of intercellular fibrosis in poor responders (p < 0.001, sensitivity 72%, specificity 91%, predictive accuracy 80%). These results suggest that improvement with long-term beta-blocker therapy may be more likely to occur in patients with less myocardial fibrosis, with interfascicular fibrosis the dominant type. CONCLUSIONS: The extent and type of fibrosis may be important factors in the prediction of the effectiveness of long-term beta-blocker therapy for dilated cardiomyopathy.

Stimulatory effect of prolactin on luteinizing hormone-induced testicular 5 alpha-reductase activity in hypophysectomized adult rats.

Two pituitaries from 7-week-old female rats were grafted under the capsule of the left kidney of 50-day-old male rat to induce hyperprolactinemia. All of the pituitary-grafted and sham-operated rats were hypophysectomized at 56 days of age. The hypophysectomized rats in groups of 4 were given daily sc injections of saline or 9 micrograms NIADDK-ovine-(o)LH-23 for 4 and 5 days starting from days 58 and 70, respectively (short and long term hypophysectomized groups). The metabolism of [3H]progesterone or [14C]androstenedione by testicular homogenates, concentrations of testosterone and 5 alpha-androgens (androsterone plus 5 alpha-androstane-3 alpha, 17 beta-diol) in the serum and testes, and testicular LH receptors were estimated. Hypophysectomy caused significant decreases in testicular enzyme activities per gram of tissue, androgen production, and testicular LH receptors. In the testes of hypophysectomized rats, LH treatment significantly stimulated 5 alpha-reductase and 17-hydroxylase activities. Although pituitary grafts alone showed little or no effect on these testicular enzyme activities, hyperprolactinemia induced by the grafts markedly enhanced the LH-stimulated 5 alpha-reductase activity in both groups, especially in the long term hypophysectomized group. Therefore, androsterone and 5 alpha-androstane-3 alpha,17 beta-diol were shown to be the major C19-steroid products (immature type of testicular androgen production) in the LH- and PRL-stimulated testes of long term hypophysectomized adult rats. On the other hand, hyperprolactinemia was associated with a significant inhibition and a slight increase of the LH-stimulated 17-hydroxylase activities in the short and long term hypophysectomized groups, respectively. This difference can be attributed to both a PRL-induced increase in testicular LH receptors and a PRL-induced inhibition of 17-hydroxylase via a postreceptor mechanism(s). The present findings demonstrate for the first time that PRL directly stimulates LH-induced 5 alpha-reductase activity in the testes. It appears that PRL may play a role in the increased production of 5 alpha-C19-steroids and the parallel decrease of testosterone production in immature rat testes.

Clinicopathological study of livers from brain-dead patients treated with a combination of vasopressin and epinephrine.

Studies were made on the pathological lesions and biochemical indices of the livers of 22 patients in whom normal hemodynamics was maintained for 0-48 days after brain death by administration of vasopressin and epinephrine. Thirty-one specimens of liver tissues were obtained by percutaneous biopsy or at autopsy. The degrees of central venous congestion, central fibrosis, focal fibrosis, fatty metamorphosis, piecemeal necrosis, periportal fibrosis, and intrahepatic cholangitis in livers on various days after brain death were compared with those on the day of brain death (day 0). Central venous congestion was extensive on days 0-4, significantly less on days 5-14, and then again extensive on days 15-48. Central fibrosis and focal fibrosis showed no remarkable change during the 48-day period. Fatty metamorphosis, piecemeal necrosis, and periportal fibrosis showed no significant changes until day 16, but spread extensively on days 40-48. Intrahepatic cholangitis was scarcely observed on day 0 but began to increase after day 3, and spread extensively after day 5. The level of serum glutamic pyruvic transaminase did not increase in most patients until day 15. The mean value of prothrombin activity also did not decrease until day 15. However, the mean value of serum alkaline phosphatase increased gradually after day 3, and was correlated with cholangitis. The present study showed that during prolonged hemodynamic maintenance of brain-dead patients, pathological lesions did not spread or diminished and that biochemical indices did not become worse, or improved, in the first 2 weeks, except for increases in cholangitis and the serum alkaline phosphatase level.

Clear cell adenocarcinoma of the female urethra showing positive staining with antibodies to prostate-specific antigen and prostatic acid phosphatase.

A case of clear cell adenocarcinoma arising from the female urethra is described. Histologically, solid and glandular areas consisted of clear cells. The tumor cells stained positively with antibodies to prostate-specific antigen and prostatic acid phosphatase, suggesting that the clear cell adenocarcinoma arises from the female paraurethral duct, rather than embryonic remnants.

A heterozygous frameshift mutation of the PTEN/MMAC1 gene in a patient with Lhermitte-Duclos disease - only the mutated allele was expressed in the cerebellar tumor.

Lhermitte-Duclos disease is a rare disorder of the cerebellum which exhibits a focally indolent growth of the cerebellar cortex. The disease is sometimes associated with multiple hamartoma syndrome, or Cowden disease, an autosomal, dominantly inherited cancer syndrome. Germline mutations of the PTEN/MMAC1 gene, a gene recently discovered to be a tumor suppressor, have been documented in four families with Cowden disease. A family member in one of these families have had Lhermitte-Duclos disease, indicating that mutations of the gene are responsible for the development of Lhermitte-Duclos disease. However, the occurrence of Lhermitte-Duclos disease is mostly sporadic. It is unknown whether the PTEN/MMAC1 gene is involved in these cases. We performed a genetic analysis on a patient with Lhermitte-Duclos disease, as well as analyses on his family members, and found a germline mutation of the PTEN/MMAC1 gene. An insertion of A at nucleotide 83 in codon 28 was apparent in both the patient and members of his family. This mutation caused a frame shift that generated a premature stop codon in codon 43. The mutation was heterozygous, although only the mutated allele was expressed in the cerebellar tumor of the patient. A monoallelic expression of the mutated PTEN/MMAC1 gene may have been responsible for the development of a cerebellar tumor in the patient.

Perilobular pulmonary opacities: high-resolution CT findings and pathologic correlation.

This pictorial essay illustrates the high-resolution CT and histologic findings of various disease processes that involve the perilobular interstitium.

Malignant mesenchymoma of the spermatic cord with a brief review of the literature.

Sarcomas of the spermatic cord are rare, and malignant mesenchymomas are particularly rare. Only 8 cases of paratesticular mesenchymoma have been described previously. We report here the ninth case of malignant mesenchymoma of the spermatic cord, in which there was a local recurrence. We also briefly review the previously reported cases.

Deficiency of 5 alpha-steroid formation in guinea pig ovaries compared with immature rat and hamster ovaries.

Activities of 4-ene-5 alpha-reductase and the metabolism of progesterone were estimated in ovaries of guinea pigs, rats and golden hamsters. In the ovaries of 20-90-day old guinea pigs, the major C21-17-hydroxysteroids and C19-steroids formed from progesterone were 4-ene-3-ketosteroids, such as 17-hydroxy-4-pregnene-3,20-dione and 4-androstene-3,17-dione, and 5 alpha-C21-17-hydroxysteroids and 5 alpha-C19-steroids were not produced. In contrast, the major steroids formed by the ovaries of immature rats and immature hamsters were 5 alpha-steroids, such as 3 alpha, 17-dihydroxy-5 alpha-pregnan-20-one and androsterone, and no 4-ene-3-ketosteroids were found. The 5 alpha-reductase activity (nmol/g tissue/h) in the ovaries of immature hamsters was approx 150 times higher than those in the ovaries of guinea pigs of different ages. In contrast to rats and hamsters, the ovaries of immature guinea pigs do not form a significant amount of 5 alpha-androgens.

17 alpha-oxidoreductase activity in kidneys of male and female mice of various ages.

Male and female mice at 0-120 days of age were used. Homogenates of kidneys were incubated with [14C]4-androstene-3,17-dione, and 17 alpha-oxidoreductase activity per g tissue was examined. The activities of 17 alpha-oxidoreductase in the kidneys of both sexes increased markedly with age during sexual development by up to 150-fold and reached the maximum values (2700 and 1500 nmol/g/h in male and female kidneys, respectively) at 60 days of age. In the adult male mouse kidney, the activity in isolated cortex fractions was 14 times as high as the activity in isolated medulla fractions; in the medulla fractions renal tubules from the cortex accounted for 3-15% of the total tissue. Furthermore, histochemical examination showed the activity present only in the cortex, at which much higher levels in the tubules than in the glomerulus. Activity at 35-120 days of age was significantly higher in male kidneys than in female kidneys. The difference appears to be induced by testicular androgens during sexual development, since neonatal castration in males resulted in decreases of activity to levels similar to those in female kidneys. However, castration at 60 days of age showed no significant effect on the activity. The present results show that the activity per g tissue of 17 alpha-oxidoreductase in the mouse kidney increases markedly with age, and that the activity is largely confined to the renal tubules of the cortex.

Alpha-1 antichymotrypsin is increased in human alveolar macrophages by phorbol myristate acetate or lipopolysaccharide and released from these activated macrophages by glucocorticoid.

Alveolar macrophages were obtained from 23 patients and the effects of phorbol myristate acetate (PMA), lipopolysaccharide (LPS), and dexamethasone (DEX) on the proportion of cells with intracellular alpha-1 antichymotrypsin (ACT), and concentrations of ACT in the culture medium were studied in vitro. The alveolar macrophages were obtained by bronchoalveolar lavage at autopsy or from resected lungs at operation and were cultured in suspension for 3 days in medium containing PMA, LPS, DEX, PMA+DEX, or LPS+DEX. Both PMA and LPS significantly increased the percentage of macrophages with intracellular ACT. Dexamethasone did not increase the number of ACT-positive cells and significantly suppressed the increase induced by PMA or LPS, releasing ACT into the culture medium. The release of ACT from macrophages may contribute to the anti-inflammatory effects of corticoids.

Thyroid nodules associated with Hashimoto thyroiditis: assessment with US.

Sonographic findings in 109 thyroid nodules in 104 patients with Hashimoto thyroiditis were retrospectively analyzed. Sixty patients underwent ultrasound (US)--guided fine-needle aspiration (FNA) biopsy (65 nodules, 24 palpable, 27 surgically confirmed), 14 of whom also underwent palpation-guided FNA (14 nodules, all palpable, all surgically confirmed). Forty-four patients (44 nodules, 25 palpable) underwent diagnostic US followed up with surgery. US-guided FNA helped differentiate between benign (n = 11) and malignant (n = 16) diseases (sensitivity, 100%). Two papillary carcinomas were falsely diagnosed as Hashimoto thyroiditis with palpation-guided FNA. Eight malignancies were not palpable, and correct diagnosis was obtained with US-guided FNA. Hyperechoic nodules were usually benign, and isoechoic nodules had a low frequency (13%) of malignancy. Most carcinomas were found in hypoechoic masses, and almost all lymphomas were found in markedly hypoechoic masses. Lymphoma was indistinguishable from pseudotumor in Hashimoto thyroiditis or adenomatous hyperplasia at US. US-guided FNA is helpful in making the histologic diagnosis in thyroid nodules associated with Hashimoto thyroiditis. US-guided FNA is clinically beneficial because it can help select patients who need surgery, avoiding unnecessary surgery for patients with nonneoplastic disorders.

Hyperprolactinemia enhances LH-stimulated 4-ene-5 alpha-reductase activity but inhibits LH-induced 17-hydroxylase activity in testes of hypophysectomized immature rats.

Two pituitaries from 7-week old female rats (Sprague-Dawley strain) were grafted under the capsule of the left kidney of 21-day old male rat. The pituitary grafted and sham-operated rats were hypophysectomized at 27 days of age. The hypophysectomized rats, in groups of 4, were given daily injections of 9 micrograms NIAMDD-oLH-23 (minimum effective dose) or saline for 3 days starting from day 29. Testicular homogenates were incubated with [3H]progesterone or [14C]4-androstene-3,17-dione, and enzyme activities per testes were estimated. Testicular HCG-binding sites were also measured. Hypophysectomy caused significant decreases in activities of testicular 5 alpha-reductase, 17-hydroxylase, and 17 beta-hydroxysteroid oxidoreductase. These decreased enzyme activities were significantly stimulated by LH treatment. Although pituitary grafts alone showed no effects on these enzyme activities in the testes of the hypophysectomized rats, the grafts significantly enhanced LH-stimulated 5 alpha-reductase activities but inhibited LH-stimulated 17-hydroxylase activity. Testicular LH/HCG receptors were significantly increased by the grafts, especially in the presence of LH, without affecting affinity for HCG. The present results demonstrate for the first time that hyperprolactinemia directly stimulates LH-stimulated 5 alpha-reductase activity in rat testes. The results also show that the same grafts directly inhibit LH-stimulated 17-hydroxylase activity, probably via postreceptor mechanisms.

Effects of chronic administration of LH releasing hormone on age-dependent activities of testicular 4-ene-5 alpha-reductase and 17 beta-ol-dehydrogenase in mice.

Male (WB X C57BL/6)F1 hybrid mice of 16, 26 and 66 days of age, 4 in each group, were injected daily with 0.2 micrograms/10 g body weight of LH releasing hormone (LHRH) or saline for 14 days. Testicular homogenates were incubated with [14C]4-androstene-3,17-dione and enzyme activities were examined. In mice treated with saline, testicular 17 beta-ol-dehydrogenase activity increased with age but 4-ene-5 alpha-reductase (5 alpha-reductase) activity decreased with age. LHRH treatment for 14 days starting from day 26 resulted in a delay in sexual maturation, as evidence by significant decreases (P less than 0.05) in seminal vesicle weight and testicular 17 beta-ol-dehydrogenase activity and by a significant increase (P less than 0.05) in 5 alpha-reductase activity. However, LHRH treatment starting from day 66 had no significant effect on these testicular enzyme activities.

Effects of hyperprolactinemia on activities of 17-hydroxylase, 17 beta-ol-dehydrogenase and 5 alpha-reductase in neonatally grafted and host testes in mice.

Male and female (WB X C57BL/6)F1 hybrid mice were used. Two pituitaries from 60-80-day-old female mice were grafted under the capsule of the left kidney of 60-80-day-old male mice. One week after grafting, 2 testes from neonatal mice were grafted under the capsule of the right kidney of the grafted mice and 70-90-day-old intact male mice. The grafted and host testes, in groups of 10-26, were removed 15, 30, 40, 60 and 120 days after transplantation of the neonatal testes. Testicular homogenates were incubated with [3H]progesterone or [14C]4-androstene-3,17-dione, and enzyme activities per g tissue were estimated. Significantly elevated prolactin levels, slightly lower LH levels and normal testosterone levels were found in the mice with pituitary grafts, compared with those in the mice without pituitary grafts. Activities of 17-hydroxylase and 17 beta-ol-dehydrogenase increased clearly with age in the grafted testes in the mice without pituitary grafts, though the increases were inhibited significantly by the pituitary grafts. However, the pituitary grafts had no significant effect on activities of 17-hydroxylase and 17 beta-ol-dehydrogenase in the host testes under similar gonadotrophic stimulation. 5 alpha-Reductase activities in the grafted and host testes were unaffected by the pituitary grafts. These results show that hyperprolactinemia may directly inhibit increases in activities of 17-hydroxylase and 17 beta-ol-dehydrogenase with testicular age in neonatally grafted testes in mice.

Solitary glomus tumour with mucinous degeneration.

Four cases of solitary glomus tumour are reported, three of the angiomatous type, and one of the epitheliomatous type. In all cases, mucinous degeneration was seen, the extent of which correlated with the number of glomus cells.

Metastatic pulmonary calcification: early detection by high-resolution CT.

A 41-year-old man with a renal transplant was admitted with cough, fever, and dyspnea. Although chest radiography was normal, high-resolution CT demonstrated small hazy round opacities in the centrilobular regions throughout both lungs. The biopsy specimen revealed metastatic calcification in the alveolar septa and the walls of the bronchioles and arterioles. High-resolution CT may be useful for the early detection of metastatic pulmonary calcification when plain radiography is negative and therapy has the potential to reverse the process.

Nonamyloidotic nephrotic syndrome in Waldenström's macroglobulinemia.

Severe nephrotic syndrome developed in an 83-year-old Japanese man with Waldenström's macroglobulinemia. Treatment with corticoid remarkably improved the proteinuria. Autopsy disclosed no deposit of amyloid in the kidneys but a slight infiltration of atypical lymphocytes. A considerable number of glomeruli showed mesangial cell proliferation and global or segmental thickening of the basement membrane with occasional double tracks. Immunofluorescent studies revealed deposits of IgM but not IgG, IgA and C3 along the basement membrane in most glomeruli. Electron microscopy disclosed the splitting glomerular basement membrane and scattered electron-dense deposits.

Fractal analysis for classification of ground-glass opacity on high-resolution CT: an in vitro study.

PURPOSE: Fractal analysis based on the fractional Brownian motion model was applied ground-glass opacity on high-resolution CT (HRCT) to investigate its usefulness in distinguishing ground-glass opacity caused by nonfibrotic disease processes and that caused by fibrotic disease processes, confirming pathology. METHOD: Twenty-one postmortem lungs inflated and fixed by Heitzman's method were evaluated. By correlating HRCT and pathology, the lungs were classified into nonfibrotic disease processes and fibrotic disease processes. Fractal analysis based on the fractional Brownian motion model provides the parameter H, which is a statistical measure related to the psychophysical perception of roughness. For regions of interest positioned over ground-glass opacities on HRCT, conventional statistics (mean value and SD) and the estimated H values were calculated using a workstation. RESULTS: Pathologically, 10 lung specimens were categorized as nonfibrotic disease processes and 11 as fibrotic disease processes. Whereas the conventional statistics had considerable overlap in two disease processes, the overlapping was drastically reduced in the H values. The H values of fibrotic disease processes (mean +/- SD, 0.423 +/- 0.064) were significantly greater than those of nonfibrotic disease processes (0.297 +/- 0.036) (p < 0.001). CONCLUSION: Fractal analysis based on the fractional Brownian motion model may provide a new promising scheme for assessing ground-glass opacity on HRCT caused by either nonfibrotic or fibrotic disease processes.