Morphology and proliferation kinetics of early tumor stages induced by dimethylnitrosamine in rat kidneys. A total of 49 dimethylnitrosamine (DMN)-induced rat renal cell tumors were analyzed and classified cytomorphologically at an early stage of development. Of these, 17 were basophilic-tubular tumors, two of which showed a direct transition to proximal tubules of the P3-segment; 21 lesions were vacuolated and contained glycogen; these were defined cytomorphologically as a separate tumor type the histogenetic derivation of which from the collecting duct system was established by documentation of a direct transition. Morphological similarities point to the lipid-storing variant of the basophilic tumor, but a carcinoma of the ducts of Bellini is another possible human equivalent of this tumor type. Another seven lesions were clear and granular cell tumors. In two of these a direct transition from the collecting duct system was found, thus confirming that this only recently established origin of experimentally induced rat renal clear cell tumors also applies to lesions induced by DMN. The proliferation kinetics of DMN-induced lesions were studied in autoradiograms after pulse-labeling with tritiated thymidine. The basal proliferation of these early tumor stages displayed a marked proliferative advantage over the normal parenchyma. The lesions were still subject to physiological growth stimulation as determined by 3H-TdR-continuous-labeling with osmotic mini-pumps following unilateral nephrectomy. However, compared with normal kidney parenchyma, the 3H-TdR-labeling index of the lesions was even higher indicating a response modification during early neoplasia.


Proliferating cell nuclear antigen in breast lesions: correlation of c-erbB-2 oncoprotein and EGF receptor and its clinicopathological significance in breast cancer. Monoclonal anti-proliferating cell nuclear antigen (PCNA PC10), which is directed against a 36 kDa auxiliary protein for DNA polymerase delta specific for the S-phase of cell cycle, was used to measure tumour cell proliferation in 4 lactating breasts and 98 benign and malignant breast tumours. The percentage of PCNA-positive cells determined by point counting was significantly lower in the lactating breast [mean 3.6%, standard deviation (SD) 0.67, n = 5] than in fibroadenoma and mastopathy (mean 23.7, SD 5.0, n = 2). Primary breast carcinoma showed a PCNA index ranging from 2% to 36% (mean 12.3, SD 9.3, n = 50), whereas in recurrent carcinoma the index was mean 28.5, SD 4.0. A high index was correlated with c-erbB-2 and epidermal growth factor (EGF) receptor membrane reactivity, worsening histological grade, poor survival and disease-free survival. The expression of c-erbB-2 and EGF receptor was associated with poor survival and disease-free survival in primary breast cancer patients.


High levels of xanthine oxidoreductase in rat endothelial, epithelial and connective tissue cells. A relation between localization and function? The localization of xanthine oxidoreductase activity was investigated in unfixed cryostat sections of various rat tissues by an enzyme histochemical method which specifically demonstrates both the dehydrogenase and oxidase forms of xanthine oxidoreductase. High activity was found in epithelial cells from skin, vagina, uterus, penis, liver, oral and nasal cavities, tongue, esophagus, fore-stomach and small intestine. In addition activity was demonstrated in sinusoidal cells of liver and adrenal cortex, endothelial cells in various organs and connective tissue fibroblasts. Xanthine oxidoreductase produces urate which is a scavenger of oxygen-derived radicals. Because the enzyme is found in epithelial and endothelial cells which are subject to relatively high oxidant stress, it is postulated that in these cells xanthine oxidoreductase is involved in the antioxidant enzyme defense system. In addition, a possible role for the enzyme in proliferation and differentiation processes is discussed.


Expression of the protein kinase p-68 recognized by the monoclonal antibody TJ4C4 in human lung neoplasms. P68 is a protein kinase expressed by eukaryotic cells, which is inducible by alpha interferon, and is believed to be an important factor in the regulation of viral and cellular protein synthesis. We have previously reported on a monoclonal antibody, TJ4C4, which is able to specifically detect p68 in formalin-fixed, paraffin-embedded tissue. Because of its important role in regulating cellular protein synthesis, we hypothesized that p68 expression would vary among lung neoplasms with level of differentiation and degree of biosynthetic activity. A total of 246 untreated primary pulmonary and pleural neoplasms were studied. The frequency and relative intensity of p68 expression was determined by light microscopic evaluation of ABC immunoperoxidase stained specimens. All categories of tumors studied demonstrated a spectrum of p68 expression. Expression of p68 correlated well with degree of differentiation in squamous cell carcinomas (SQCC) and acinar adenocarcinomas (AAC). Papillary adenocarcinoma (PAC) and bronchioalveolar carcinoma (BAC) expressed low levels of p68, despite their well differentiated appearance. Expression of the antigen in large cell carcinoma (LCC) was higher than that seen in either poorly differentiated AAC or SQCC. Neuroendocrine tumors generally showed low levels of p68 expression with the intermediate variant of small cell carcinoma expressing higher levels of p68 than the classic "oat cell" form (SCC). Carcinoid tumors expressed higher levels of p68 than did atypical carcinoid tumors. Mesotheliomas showed weak expression of p68, limited primarily to areas of glandular differentiation in the epithelioid form.(ABSTRACT TRUNCATED AT 250 WORDS)


Establishment and characterization of a cell line of congenital primitive neuroectodermal tumor of soft tissue. A new human cell line, termed Muraoka, has been established from the recurrent tumor of a case of congenital primitive neuroectodermal tumor (PNET) arising at the temporofacial region of a male infant. The microscopic findings of this cell line were epithelioid, and the xenografted tumor in a nude mouse consisted of the malignant epithelioid cells. Immunohistochemically, the cells were positive for neuron-specific enolase, S-100 protein, carcinoembryonic antigen, cytokeratin, epithelial membrane antigen, and glial fibrillary acidic protein. These findings were quite similar to those of the epithelioid cells in the original tumor and of the xenografted tumor cells. Neither chromosomal abnormalities nor N-myc amplification were observed. Morphological differentiation after treatment with N6-2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (Bt2-cAMP), all-trans-retinoic acid (RA), prostaglandin E1 (PGE1), and 5-bromo-2'-deoxyuridine (BrdU) showed two different results. Bt2-cAMP and PGE1 induced neuronal differentiation with the extension of neurites, whereas RA and BrdU predominantly induced Schwannian differentiation (flat cells). In these respects, the cell line Muraoka seems to be useful for studying characteristics of PNET as well as for developing the new treatments against such tumors.


[The pathogenesis of the renal syndrome in hemorrhagic fever]. Lipid peroxidation was investigated in 89 patients suffering from hemorrhagic fever with renal syndrome. In addition to routine tests, measurements were made of plasma malonic dialdehyde and acyl hydroperoxides the levels of which were found increased 1.3-1.4-fold and 1.5-2-fold, respectively, in the severe disease compared to control values. The degree of lipid peroxidation intensification and aggravation of the symptoms proved to agree. It is suggested that abnormal lipid peroxidation contributes to development of renal syndrome which in hemorrhagic fever may progress to acute renal failure.


Detection of human papillomavirus types by the polymerase chain reaction and the differentiation between high-risk and low-risk cervical lesions. By means of a consensus polymerase chain reaction (PCR) method, the prevalence of HPV types was determined in cervical biopsies from 137 women referred to the gynecological outpatient clinic for colposcopy because of an abnormal cervical smear. The prevalence of HPV was 80.3%. There was a statistically highly significant rise in the prevalence of the oncogenic HPV types (16, 18, 31, 33) with increasing severity of cervical intraepithelial neoplasia (CIN I to III), indicating a role for these HPV types in the pathogenesis of cervical cancer. The prevalence of other HPV types decreased significantly with the severity of the lesion, suggesting that these HPV types play a less significant role in this process. These data indicate that HPV typing with PCR may be a valuable tool for distinguishing between high-risk and low-risk cervical lesions. Furthermore, our results suggest that the detection of HPV types by consensus PCR in the cervix of patients with an abnormal smear but without histologically detectable CIN is a useful tool for predicting which of these patients will eventually develop CIN. Finally, a relatively low percentage (3%) of HPV double infections is reported in this study.


Mouse liver regeneration after carbon tetrachloride injury as test system for hepatic growth regulators. A test system for growth regulators based on the time course of liver regeneration in male NMRI mice injected intraperitoneally (ip) with 50 nmol CCl4 at 12 is described. Regenerative DNA synthesis (labelling index) peaked at 36 h after CCl4 injury, and the Colcemid-assessed mitotic rate (MR) at 42 h, i.e., 6 h later. This response pattern was used to assess the effects of factors in liver extracts that regulate or modulate hepatocyte proliferation. The effect of one, two, four or eight ip injections of an aqueous mouse liver extract on MR was tested at 48 h. A 30-70% inhibition was seen only after single injections at 12 h, 29 h or 44 h after CCl4 treatment. A 30-80% stimulation was observed after a single injection of the liver extract at 0, 5 or 24 h, and after two or four injections. The assay system could thus detect the presence of growth modulators in the extract. The experiments also showed that the timing was crucial. We recently isolated and characterized a growth inhibitory pentapeptide from mouse liver extracts. Using a synthetic pentapeptide with the same structure we reassessed the timing for growth inhibition seen with the liver extract. The following test system for growth inhibitors seemed most expedient: inhibitor administration at 29 h to affect G1-S transition, measured as reduced DNA synthesis at 36 h, or inhibitor administration at 44 h to affect G2-M transition, measured as reduced MR at 48 h.


Intraglomerular fibronectin in rat experimental glomerulonephritis. To clarify the mechanisms of glomerular pericapillary fibronectin deposition in human membranous nephropathy and mesangial proliferative glomerulonephritis, intraglomerular fibronectin distribution was examined by light and electron microscopy using the experimental rat models of Heymann and nephrotoxic serum nephritis. As previously demonstrated by immunofluorescence microscopy (Pettersson and Colvin 1978; Ikeya et al. 1985, 1986), fibronectin was distributed in the mesangial areas and occasionally on percicapillary walls of normal glomeruli, while in nephrotoxic serum nephritis and Heymann nephritis, fibronectin was diffusely located along glomerular capillary walls as well as in the mesangium. By immunoelectron microscopy using the immunogold technique, fibronectin was also noted in the mesangial areas and the lamina densa of the glomerular basement membrane (GBM) in normal glomeruli. In nephrotoxic serum nephritis, fibronectin was seen around mesangial cells situated between endothelial cells and the GBM, suggesting that pericapillary fibronectin in nephrotoxic serum nephritis reflects mesangial extension. However, in Heymann nephritis, it was found uniformly in the lamina rara interna, lamina densa and lamina rara externa of the GBM, indicating no specific relation to glomerular cells. When sections of normal and both experimental nephritis kidneys were incubated with fluorescein isothiocyanate conjugated with rat plasma fibronectin, a linear pattern of fluorescein staining along the glomerular capillary walls was observed in Heymann nephritis but not in normal or nephrotoxic serum nephritic rats. The GBM in Heymann nephritis would thus appear to have an affinity for plasma fibronectin. Based on the above findings, fibronectin in the GBM of rats with Heymann nephritis may reasonably be concluded to originate from the plasma.


Lateral growth and terminal differentiation during repeated epidermal regeneration in vitro. Age dependence and modulation by cholera toxin. By incubating multilayered primary cultures of human epidermal keratinocytes in a low calcium medium, the suprabasal layers can be stripped off leaving a basal cell monolayer. When this monolayer is refed normal calcium medium a reproducible series of cell kinetic, morphological and biochemical changes take place resulting in the regeneration of a multilayered tissue. The stripping procedure seems to induce the selective proliferation of a cohort of basal cells that is committed to vertical migration and rapid terminal differentiation. In contrast, when the basal cells are allowed to regenerate in the presence of the strong mitogen, cholera toxin, lateral growth and continued proliferation are favoured at the expense of the capacity of the cells to differentiate. Repeated stripping of the same cultures disclosed a considerable heterogeneity in the capacity of the basal cells to regenerate the suprabasal layers. The number of times the basal cells could restore the suprabasal layers after repeated stripping varied from four to nine times. A negative correlation between donor age and regenerative capacity was observed. The experiments with repeated stripping of the same cultures also showed that the capacity to proliferate and to restore the multilayering was fully retained for at least four cycles of stripping-regeneration, whereas the capacity to terminally differentiate was rapidly lost. It is suggested that the present system of regenerating epidermal tissue cultures may serve as an experimental model for the study of epidermal tissue homeostasis and cellular aging.


In vitro differentiation of the human osteosarcoma cell lines, HOS and KHOS. The osteogenic potential of the two human osteosarcoma cell lines HOS and KHOS; a cell line produced by the transformation of the HOS cells by the Kirsten murine sarcoma virus, was studied in vitro. HOS cells cultured more than 2 weeks formed nodules composed of two morphologically distinct layers, an epithelial-like surface cell layer and a collagen-rich inner cell layer. Alkaline phosphatase (ALPase) activity occurred in the plasma membrane of the surface cell layer, and calcified substances developing along collagen fibers were detected in the collagen-rich inner cell layer. The calcified substances were further examined by analytical electron microscopy and were shown to be hydroxyapatite crystals. In contrast, there was neither ALPase nor the deposition of a calcified substance in the KHOS cells.


[Hemodynamic effects of nitroglycerin and trimepranol in acute myocardial infarct]. The authors investigated the effect of intravenous nitroglycerin and trimepranol on the haemodynamics of patients with acute myocardial infarction. They found that nitroglycerin has a favourable effect on haemodynamics as it leads to a reduction of the pressure in the wedged pulmonary artery and to a reduction of oxygen requirement of the cardiac muscle, while the changes of the minute volume and pulse rate are insignificant. Trimepranol leads to a rise of pressure in the wedged pulmonary artery, sometimes to critical values, and to a decline of the cardiac minute output. The authors conclude that trimepranol is suitable for a selected group of patients with sinus tachycardia and without signs of cardiac failure while the pulmonary pressure is carefully monitored. Nitroglycerin can be administered to the majority of patients with acute myocardial infarction. To ensure safe administration it is sufficient to monitor the heart rate and in particular the systemic pressure. It is best to administer it to patients with extensive myocardial infarctions with a high filling pressure of the left ventricle.


Pancreatic tumors in multiple endocrine neoplasia type 1: clinical presentation and surgical treatment. Among 33 patients with endocrine pancreatic tumors due to multiple endocrine neoplasia type 1 (MEN-1), 19 (58%) patients had hypergastrinemia, 7 (21%) patients had hyperinsulinism, and 7 (21%) patients had clinically non-functioning lesions. At least one gross tumor was found in all patients undergoing pancreatic surgery, including those with negative localization studies prior to operation. The patients also had additional macroscopic tumors as well as numerous microadenomas, and the lesions frequently were positive for immunostaining with multiple hormones, mainly pancreatic polypeptide, insulin, glucagon, and somatostatin. Duodenal endocrine lesions were found in 4 of 5 investigated patients and stained with gastrin and somatostatin antibodies. Distal, mainly subtotal pancreatic resection, was performed in 18 patients, eventually combined with caput tumor enucleation or duodenotomy, while a few patients underwent only tumor enucleation or a Whipple procedure. The long-term outcome of operation was most favorable in patients with hyperinsulinism; only 1 patient had clinical recurrence. Patients with hypergastrinemia experienced only transitory lowering of serum gastrin values after pancreatic surgery and 47% of them had or developed metastases. Such tumor spread was seen in 57% of the patients with non-functioning lesions. Nine patients died from progressive tumor disease during follow-up. Consistent with previous studies, we found that surgery is indicated in MEN-1 patients with hyperinsulinism even if a lesion is not visualized by radiology. In addition, these indications should be extended to also include patients with only biochemical markers of disease, including elevations of gastrin, as these indicate the presence of gross tumors.(ABSTRACT TRUNCATED AT 250 WORDS)


Prominent corneal nerves in patients with multiple endocrine neoplasia type 2A: diagnostic implications. We examined corneal nerves of 22 patients from 10 families with multiple endocrine neoplasia type 2A (MEN-2A). According to the findings in slit-lamp biomicroscopic examination and photographic documentation, the increased visibility of corneal nerves were classified into 5 grades (Grade 0 = invisible to Grade 4 = as thick as in MEN-2B). All eyes of normal subjects, 19 of 20 eyes of patients with anterior keratoconus, and 11 of 12 eyes of patients with non-hereditary medullary thyroid carcinoma (MTC) were either grade 0 or 1, and the remaining 2 eyes were evaluated as grade 2. Of the 44 eyes of MEN-2A patients, 5 (11.4%) eyes were grade 0, 11 (25%) eyes were grade 1, 19 (43.2%) eyes were grade 2, 8 (18.2%) eyes were grade 3, and 1 (2.3%) eye was grade 4. Thus, more than 60% of eyes of MEN-2A patients showed pathologically thickened corneal nerves of varying degree (grade 2 or higher). There was no definite relationship between the grade of corneal nerve thickening and the patient's age or presence of pheochromocytoma. Differences in the grade of corneal nerve thickening were observed among affected members belonging to the same MEN-2A family, but unaffected members of the family never showed prominent corneal nerves of grade 2 or higher. Our findings suggest that MTC patients with thickened corneal nerves might actually be MEN-2A patients and should be carefully followed for other components of this syndrome.


The value of immunohistochemical detection of P-glycoprotein in breast cancer before and after induction chemotherapy. We have studied the patterns of P-glycoprotein expression before and after 3 cycles of induction chemotherapy (5-fluorouracil, adriamycin and cyclophosphamide) using immunohistochemically stained paraffin-embedded specimen of 28 patients with locally advanced breast cancer. The frequency of P-glycoprotein expression in untreated breast cancer turned out to be very low: only one out of 28 untreated, biopsy specimen at the time of diagnosis was positive. The frequency of P-glycoprotein expression was markedly increased from 9.1% before chemotherapy to 63.6% after induction chemotherapy (p = 0.006). After 3 cycles of induction chemotherapy, 25 patients had obtained clinical response to chemotherapy (4, CR; 21, PR). Eleven out of 25 tumors (44%) showing clinical response and all three tumors (100%) with minimal response have expressed P-glycoprotein. One out of 6 patients (16.7%) with microscopic residual tumor seen in mastectomy specimen expressed P-glycoprotein, whereas 13 of 22 patients (59.1%) with gross residual tumor showed the presence of P-glycoprotein (p = 0.08). The frequency of intrinsic P-glycoprotein expression in untreated breast cancer was quite low, but approximately half of the patients do acquire P-glycoprotein expression during the cycles of induction chemotherapy. Therefore, the results suggest that the immunohistochemical detection of P-glycoprotein on residual tumor cells after induction chemotherapy can predict acquired drug resistance in breast cancer.


Essential role of tumor necrosis factor and other cytokines in the pathogenesis of cerebral malaria: experimental and clinical studies. A natural body protein is probably a major cause of the deadliest complication of malaria, a finding that could point toward new methods of treatment. Studies in an experimental model indicate that tumor necrosis factor (TNF), a protein also known as cachectin, is an essential element in highly fatal cerebral malaria. This contention is supported by the following observations. First, during the course of an infection by P. berghei ANKA strain, mice of a CM-susceptible strain express markedly elevated levels of TNF in their serum at the time that neurological signs are evident. Second, in contrast, either mice from nonsusceptible strains, susceptible strains depleted of CD4+ T lymphocytes, or susceptible mice inoculated with malaria organisms incapable of producing CM all fail to express high serum TNF activity. Third, passive immunization against mouse TNF significantly prolong the survival of P. berghei-infected CBA/Ca mice, and prevented the development of neurologic signs to an extent that was highly significant. Treatment with the anti-TNF antibody also prevents the histopathological lesions that are characteristic of CM, i.e. plugging of cerebral vessels by macrophages, lymphoid and parasitized erythrocytes. We have recently shown that this increased TNF release and macrophage accumulation are schematically made of two components, each mediated by different cytokines presumably released by stimulated CD4+ T lymphocytes: (a) a quantitative component: increased accumulation of macrophages results from the concomitant release of IL-3 and GM-CSF, and (b) a qualitative component: macrophage number has not only to be raised, but macrophages need to be activated by IFN-gamma. Thus, CM appears to be the result of a cytokine cascade mediated by the immune response. TNF might also be involved in the pathogenesis of human cerebral malaria. Indeed, we have recently shown that in african children with falciparum malaria, elevated serum concentrations of this molecule are associated with severe neurological involvement and fatal outcome. Clinical trials of treatment with monoclonal anti-TNF antibodies are presently underway in an attempt to reduce mortality and morbidity in african children with cerebral malaria.


Effect of somatostatin on adenylate cyclase activity in normal and neoplastic thyroid tissue. Thyroid stimulating hormone (TSH) and other substances increase adenylate cyclase (AC) activity and growth of normal and neoplastic thyroid tissue. Factors that inhibit cAMP may provide targeted therapy to tumors dependent on cAMP for growth. Somatostatin has been reported to inhibit the growth of gastrinomas and carcinoid tumors. We therefore studied the effects of somatostatin on basal, TSH, pertussis toxin, and forskolin stimulated adenylate cyclase activity in normal and neoplastic thyroid tissue from 19 patients. Adenylate cyclase (AC) activity was determined by the conversion of alpha 32P-ATP to 32P-cAMP in pmoles/mg protein/30 minutes in an 8000 x g particulate fraction rich in thyroid plasma membranes. TSH (300 mU/ml) and forskolin (100 mM) (a diterpine that directly stimulates the catalytic unit of AC) increased AC activity in normal and neoplastic thyroid tissue. The AC stimulation was greater in the neoplasms (p less than 0.01). Somatostatin (5 x 10(-6)M) decreased basal and TSH stimulated AC activity below basal levels in both normal and neoplastic thyroid tissue (including papillary, follicular, and medullary carcinomas). The inhibition of AC by somatostatin was greater in neoplastic tissue (p less than 0.025). Pertussis toxin (which blocks the inhibitory guanyl nucleotide regulatory protein) was able to partially reverse the effect of somatostatin. Somatostatin partially inhibited forskolin stimulated AC activity. Somatostatin inhibits basal and TSH stimulated AC activity in both normal and neoplastic human thyroid tissue, with a greater effect on neoplasms. These studies establish that somatostatin blocks a major regulator of thyroid growth and provides the rationale for the use of somatostatin analogs in the treatment of thyroid cancers.


Unusual morphology of a virus which produces carbon dioxide sensitivity in mosquitoes. A virus, named Matsu, presumed to be the etiologic agent of hereditary sensitivity to carbon dioxide in Culex quinquefasciatus mosquitoes, was adapted to growth in the C6/36 line of Aedes albopictus cells. Though it was expected that the mosquito virus would be a rhabdovirus like sigma, the etiologic agent of hereditary carbon dioxide sensitivity in Drosophila melanogaster flies, that was not the case. The virion of Matsu was found to be unlike any previously described virus. It was pleomorphic, enveloped, from 200 to 550 nm in maximum diameter, and contained from three to several dozen virus-like polyhedral structures approximately 30 nm in diameter.


Urodynamics in patients with pheochromocytoma: a peri-operative study of 10 cases. Alpha receptors have been demonstrated in the bladder neck, and urinary retention may be the presenting symptom in an occasional pheochromocytoma patient. This prompted us to define the urodynamic profile in pheochromocytoma patients. Ten patients were studied. Except for 2 patients, all tumors secreted norepinephrine either alone (n = 4) or mixed (n = 4). Urodynamic studies (uroflowmetry, cystometry, profilometry, response to alpha-adrenergic agents) were performed with Urodyn 5000 chain (DANTEC) connected to a water perfused Bohler's catheter. Profilometry was done according to the Brown and Wickham technique. Normal values were those of the International Continence Society. Alpha blocker test was done by intravenous injection of thymoxamine (0.5 mg/kg) and was considered as positive if urethral closure pressure (UCP) decrease was greater than 30% after 10 minutes. Ten patients had a pre-operative study, omitting alpha-blocker test in 1 patient; 5 patients consented a postoperative study. Pre-operatively we could demonstrate: 1) Increased UCP in 8 of 10 patients, regardless of the secretory pattern; 2) Response to alpha-adrenolytic agents in 7 of 9 patients; and postoperatively: 3) Good correlation between a positive alpha-blocker test and a decrease in urethral pressure in 3 of 5 patients. Urodynamics in pheochromocytoma patients show a typical alpha-adrenergic pattern and may explain bladder dysfunction as a presenting symptom.


Clinical course and thyroid stimulating hormone (TSH) receptor antibodies during surgical treatment of Graves' disease. This study assessed the results of surgical treatment for Graves' disease in our hospital and examined the relationship between the values of thyroid stimulating hormone (TSH) receptor antibodies and postoperative thyroid function. From 1983 to 1988, subtotal thyroidectomy was performed in 313 patients with Graves' disease. The follow-up rate was 89.1% (278 of 313 patients). Thirteen (4.2%) patients required methimazole postoperatively for hyperthyroidism and 23 (7.3%) patients required L-thyroxine postoperatively for hypothyroidism. The relationship between the postoperative thyroid function and TSH receptor antibodies was examined. The pre-operative thyrotropin binding inhibitory immunoglobulin (TBII) value had no relationship to postoperative thyroid function. Only in the patients who were hyperthyroid postoperatively did the TBII value remain elevated, but the value decreased gradually in patients who were not hyperthyroid postoperatively. In 43 of 94 patients whose pre-operative TBII values were high, the postoperative TBII value normalized. The higher the preoperative TBII value, the longer time was required for it to normalize postoperatively. The postoperative thyroid stimulating antibody (TSAb) values were higher in patients who remained hyperthyroid than in the patients who were not hyperthyroid. In the patients who remained hyperthyroid postoperatively, there was a significant correlation between the postoperative TBII value and the TSAB value. In the patients who were hypothyroid postoperatively, the TSBAb values were negative. In patients undergoing surgical treatment of Graves' disease, the postoperative TBII and TSAb values were related to postoperative hyperthyroidism. The TSBAb value had no relationship to postoperative hypothyroidism.


[Behavioral assessment of neuroleptics (2)--stereotypy]. This paper describes the definition of stereotypy and the different methods available for measuring both the form and the invariance of stereotyped behavior. With respect to the use of stereotypy for screening antipsychotic drugs, commonly used techniques for observing dopamine agonist-induced oral stereotypy in rats and the relevant points to analyze in the results are discussed. Apart from the ways of visually analyzing stereotyped behavior, some approaches for quantifying the intensity of stereotypy by using automated systems are also discussed.


Clinical characteristics, treatment and survival in patients with pancreatic tumors causing hormonal syndromes. Eighty-five patients with endocrine pancreatic tumors associated with clinical syndromes of hormone excess were retrospectively analyzed regarding symptomatology, means of diagnosis, and results of surgical and medical treatment during follow-up of 3-18 years (median 8 years). The combination of angiography and computed tomography was most successful in pre-operative localization of both primary tumors and metastases. Surgery provided long term cure in 39 of 44 patients with benign islet cell lesions, the majority having insulinomas. Forty-one patients had malignant tumors, which at the time of diagnosis or operation were associated with liver and/or regional lymph gland metastases in 56% and 24%, respectively. Sixteen patients with metastatic disease and/or very large tumors were considered inoperable, 5 patients underwent palliative resection of their malignant tumors, while grossly radical tumor removal was accomplished in 20 patients. Long-term cure was achieved in 5 patients by excision of primary tumors and localized liver or lymph gland metastases. Half of the patients, particularly those with insulinoma, gastrinoma, or vipoma, showed response to streptozotocin, in combination with other cytostatics, for a median of 24 months or a response to interferon for a median of 10 months. The overall 5-year and 10-year survival among the patients with malignant islet cells tumors was 54% and 28%, respectively. Absence of liver metastases at time of operation/diagnosis, smaller size of the primary tumor, grossly radical tumor resection as well as response to medical therapy predicted the more favorable survival.


[Rat brain concentrations of monoamines and their metabolites after chronic administration of diazepam and tandospirone]. Tandospirone has been reported as a serotonergic antianxiety drug with a different pharmacological mechanism from benzodiazepines. In the present study, the brain concentrations of monoamines and their metabolites were measured, comparing control rats and two groups of rats which were given tandospirone (10 mg/kg, ip) and diazepam (5 mg/kg, ip) each for 14 days. After sacrifice, brains of all animals were cut and divided into three portions, i.e. the cortex (COR), cerebellum (CER) and subcortical structures and brain stem (SS & BS). The concentrations of COR and SS & BS were measured using a Neurochemicalanalyzer (NCA, ESA, Inc., USA) with a reverse-phase column (Neurocolumn, Niko Bioscience Inc.). In the COR, 3-O-MDOPA (3-O-methyldopa) increased in the tandospirone group. In the SS & BS, 3-O-MDOPA increased in the diazepam and tandospirone groups. 5HIAA (5-hydroxyindoleacetic acid), DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) decreased in the tandospirone group.


Findings and long-term results of parathyroid surgery in multiple endocrine neoplasia type 1. Forty-two patients with primary hyperparathyroidism (HPT) of multiple endocrine neoplasia type 1 (MEN-1) were evaluated a mean of 8.9 years after subtotal parathyroid resection (SPX, n = 34) or total parathyroidectomy with autotransplantation to the forearm (TPX, n = 23). TPX as the primary operation revealed asymmetric and mainly nodular enlargement of the parathyroid glands with the presence of at least one normal-size gland in half of the individuals. TPX and SPX were accompanied by resolution of the hypercalcemia in 78% and 38% of the patients. Persistent and recurrent HPT occurred in 22% and 61% of the patients, while hypoparathyroidism requiring oral supplements occurred in 30% and 12% of the patients, respectively. Intact serum parathyroid hormone (PTH) in the arm of parathyroid autograft was high in the normocalcemic patients, somewhat lower in the patients with recurrent HPT, and normal to very low in the hypoparathyroid patients. Ratios of intact PTH between the grafted and non-grafted arms varied from 1 to 56.3, with average of 28.1 in the normocalcemic individuals, 8.2 in the patients with recurrent HPT, and 3.3 in those requiring supplements to maintain normocalcemia. These findings substantiate an 80% to 92% reversal of hypercalcemia during long-term follow-up of MEN-1 patients undergoing total parathyroidectomy or subtotal resection of 3-4 parathyroid glands as primary operative procedures and demonstrate the usefulness of intact serum PTH for functional evaluation of parathyroid autografts.


Clinicopathological characteristics of duodenal microgastrinomas. Duodenal gastrinomas do not seem to behave as malignantly as sporadic pancreatic gastrinomas. Statistical analysis of 49 patients with sporadic pancreatic gastrinoma and 21 patients with sporadic duodenal gastrinoma reported since 1980 in Japan revealed that the incidence of hepatic metastasis was 57% in patients with sporadic pancreatic gastrinoma and only 9% in patients with sporadic duodenal gastrinoma (p less than 0.01). These findings suggest that there is an essential biological differences between duodenal and pancreatic gastrinoma. Five patients with sporadic duodenal microgastrinoma (tumor diameter less than 5mm) in our hospital had no hepatic metastases; however, 4 patients had lymph node metastases. Immunohistochemical study of 5 sporadic duodenal microgastrinomas and 6 sporadic pancreatic gastrinomas revealed that the sporadic duodenal gastrinomas contained significantly fewer insulin-producing or glucagon-producing cells than sporadic pancreatic gastrinomas. The cellular composition of the metastatic lymph nodes from duodenal microgastrinomas was similar to that of the primary tumor. This difference in cellular composition between the duodenal microgastrinomas and the pancreatic gastrinomas suggests that the process of development and differentiation of gastrinoma cells is different.


[In situ hybridization: a principle and method]. We describe the principle and method of in situ hybridization (ISH), detecting neurotransmitters or neuromodulators and their related enzyme or receptor. Furthermore, we overview recent research reports focused on the gene expression of dopamine receptors. ISH technique has been applied and is one of the most powerful strategies in the biological research field of psychiatry.


[The hemagglutinating properties of Pseudomonas aeruginosa strains isolated from patients with nonspecific lung diseases]. To detect d-mannose-sensitive (MS) pili in 31 P. aeruginosa strains isolated from the respiratory tract of patients with inflammatory and purulent destructive pulmonary diseases, the hemagglutination (HA) test was used. The isolated Pseudomonas under study differed in the degree of manifestation of their MS adhesins. Among them microorganisms with pronounced HA activity (high HA titer) occurred, as well as those whose HA activity was less pronounced (low HA titer). P. aeruginosa strains with pronounced HA activity were more frequently isolated from patients with purulent destructive processes in the lungs. A correlation between the state of the patient at the moment of bacteriological examination and the degree of manifestation of MS pili in the P. aeruginosa strain isolated from this patients was established. The value of HA titer in the presence of d-mannose is indicative of the presence of MS adhesins in a P. aeruginosa strain.


[Preliminary study on RFLPs for dystrophin gene in Chinese]. We have studied the RFLPs distribution and frequency of dystrophin gene in Chinese by using 14 subclones of complete 14 kb cDNA for the dystrophin gene as hybridization probes. Allelic fragments are detected in hybridization patterns of Pvu II/1a, Taq I/2b-3, Taq I/5b-7, Xba I/10. Among them, the allelic fragments (26 kb and 3.8 kb) in Pvu II/2b-3 patterns and the allelic fragments (10 kb and 8.4 kb) in Taq I/5b-7 patterns are the new RFLPs which have never been reported. From the comparison of our data with those of Caucasian and Japanese respectively and their statistical analysis, we can obtain the results as follows: There is remarkable difference (p less than 0.01) of the allelic fragment frequency in Taq I/2 b-3 (A1 = 3.4 kb, fre. 0.04; A2 = 3.2 kb, fre. 0.96) and Xba I/10 (A1 = 7.4 kb, fre. 0.41; A2 = 6.7 kb, fre. 0.59) between Chinese and Caucasian. The frequency of the allelic fragments A2 in Taq I/8 (A1 = 6.5 kb, A2 = 5.6 kb) and EcoR V/9 (A1 = 11.8 kb, A2 = 10.7 kb) are high in Caucasian, but have not been detected in Chinese. These differences are also highly significant. But the B1B2 allelic frequencies in Taq I/5 b-7 (B1 = 3.2 kb, B2 = 1.6 kb) are the same. There is no significant difference in the frequency of the allelic fragments A1A2 and B1B2 in Pvu II/1 a between Chinese and Japanese. Preliminary results suggest that there probably are high frequencies for spontaneous neutral mutations in the evolution process of the huge dystrophin gene (about 2,300 kb). In the meantime, the neutral mutation frequencies of various sectional sequences have remarkable differences, and that of some sectional sequences of the gene between Chinese and Caucasian may also have remarkable differences.


[Effective operations of the foot. Report of experiences after 25 years of administration of the orthopedic department]. Report on proven methods of operation for the typical foot diseases. Particular emphasis is put on the possibilities for correction of many deformities of the foot through Chopart-arthrodesis by corresponding wedge-removal from the root of the foot, as underlined by Imhäuser. The Chopart-arthrodesis is especially suitable for treating weight-bearing complaints of mal-healed fractures of the calcaneum, because this procedure stabilizes the hindfoot and sets the mid- and forefoot plantarly. For post-operative recurrences of toe deformities, syndactily-operations are recommended.


Abnormal expression of Ki-67 antigen in hair follicle of alopecia areata. The monoclonal antibody Ki-67 was used to determine the numbers of cycling cells in hair follicles both in alopecia areata and in normal scalp skin. Pronounced nuclear staining was limited to the area below the critical line of Auber and the exterior part of the outer root sheath. In alopecia areata there is reduced nuclear Ki-67 binding in the bulb of anagen hair follicles. These findings indicate that inhibition of keratinocyte proliferation might be a pathogenetic mechanism in alopecia areata.


Interleukin-6 in normal skin and psoriasis. Interleukin-6 (IL-6 or BSF-2/IFN beta 2) is a component of normal human skin. IL-6 was immunologically detected in basal keratinocytes, endothelial cells and in a number of mononucleated cells and fibroblasts in normal skin and sudoriparous ducts. In psoriasis, intense labelling of the cytoplasm in the vicinity of keratinocyte membranes was detected in all epidermal layers and other skin appendages. The fact that this interleukin acts synergistically with respect to IL-1 and Tumour Necrosis Factor (TNF) strengthens the hypothesis whereby IL-6 may contribute via its receptor action to EGF function in modulating cell hyper-proliferation in psoriasis.


[The interaction of mediators with protein synthesis processes in the visual cortex neurons in the goal-directed behavior of cats]. The chemical sensitivity was studied of the neurones of cats visual cortex at successive stages of food-procuring instrumental behaviour, formed in conditions of intraventricular administration of the blocker of protein synthesis the cyclohexamide. Animals with cyclohexamide had a low chemical sensitivity of the cortical neurones to microionophoretically applied solutions of acetylcholine and noradrenaline. In comparison with the intact animals, in animals with cyclohexamide the number of neurones reacting with change of the impulse activity at the stages of instrumental behaviour as well as the number of areactive cells, did not depend on the nature of the applied neurotransmitter.


Expression of beta-2 integrin molecules on human keratinocytes in cytokine-mediated skin diseases. Integrins are cell surface molecules of importance in a wide variety of cellular functions, including morphogenesis, cell migration and cell matrix interactions. The beta-2 (B2) integrin (leukocyte integrin, CD11/CD18) subfamily comprising three members, each consisting of a shared beta subunit (CD18) non-covalently associated with unique alpha subunits (CD11a, CD11b, CD11c). In the present study, we have analysed the expression pattern of B2 integrins on the surface of human keratinocytes (HKs) in biopsies obtained from healthy volunteers, from positive tuberculin skin tests and from patients with acute urticaria (AU), lichen planus (LP), psoriasis vulgaris (PV), mycosis fungoides (MF) or purpura pigmentosa chronica (PPC). In biopsies obtained from positive tuberculin tests and from the clinically involved skin of patients with LP, PV, MF or PPC, a multifocally occurring, suprabasal peroxidase-positive reaction was observed on the membranes of the HKs when the monoclonal antibodies (MABs) Dako CD11a, Dako-p150, 95 or Dako CD18 were used. In contrast, no specific staining of the HKs was observed with the same MABs in biopsies from healthy volunteers, from patients with AU and in the uninvolved skin specimens obtained from the other patients. The HKs from PV, LP, MF, PPC and AU patients and those from the healthy subjects failed to give a positive reaction when the MAB against CD11b (OKM1) was used. Our present findings provide further evidence that HKs may be actively involved in cell adhesion processes.


A study of bone formation in osteoma cutis employing biochemical, histochemical and in situ hybridization techniques. A female presenting multiple osteoma cutis lesions without underlying endocrinological disturbance was studied. Histologically, lesions revealed true bone formation with multiple osteoblastic cells. This was confirmed by demonstrating high alkaline phosphatase activity and osteonectin expression in osteoma cutis lesions. Interestingly, tenascin and type III procollagen were in close association to bony lesions, indicating that these matrix proteins may be somehow involved in bone formation. In situ hybridization revealed fibroblastic cells around bony lesions, which actively deposited type I collagen and osteonectin. One of the activators of bone formation, TGF beta, was also present in some osteoblastic cells. The results thus indicate that in osteoma cutis, fibroblasts have the ability to differentiate into osteoblastic cells, which have some properties of osteoblasts, such as high alkaline phosphatase activity and a high expression of osteonectin.


Langerhans' cell distribution in drug eruption. The number in and distribution of Langerhans' cells were studied in 11 patients with a maculopapular drug eruption. The Langerhans' cells (LC) were identified with a monoclonal antibody to OKT6 antigen, by employing an immunofluorescence technique. Skin biopsies were taken from lesional and non-lesional skin during the acute stage of the disease. LC in the lesional biopsies increased in number by 66% (p less than 0.001) and displayed more intense staining and more prominent dendrites than did LC from non-lesional skin. Control biopsies, taken from identical sites at least 4 weeks after the eruption disappeared, exhibited a cell distribution similar to the non-lesional acute stage (p = N.S.). Delivery of drugs via the circulation and their distribution into the skin may cause a type IV immune reaction due to LC activation by a drug-carrier complex.


Effect of doxycycline on the generation of reactive oxygen species: a possible mechanism of action of acne therapy with doxycycline. On the basis of a recent report that minocycline is effective in the treatment of acne inflammation by acting directly as an antioxidant on infiltrating neutrophils, we investigated whether doxycycline might also be capable of reducing the generation of reactive oxygen species, using human neutrophils and a cell-free, xanthine-xanthine oxidase system. The species investigated are superoxide radical anion (O2-), hydrogen peroxide (H2O2) and hydroxyl radical (OH.). Doxycycline significantly reduced the levels of O2-, H2O2 and OH. generated by both systems. Our results seem to suggest that the clinical effectiveness of doxycycline in the treatment of acne inflammation is due partly to its antioxidant effect on neutrophils.


The skin as the possible reservoir for Candida albicans in the oculocutaneous candidiasis of heroin addicts. We describe 2 patients who injected themselves with the same brown heroin a few days before hospitalization. The first patient presented with characteristic oculo-cutaneous candidiasis. Blood samples remained sterile during the so-called 'septicemic syndrome' which represents the first phase of this syndrome and were positive for Candida albicans only when cutaneous nodules developed. The second patient was hospitalized for a stomach perforation and had no cutaneous or ocular candida involvement. Both patients were unusually colonized by C. albicans on their skin (particularly on hairy zones). These observations support the hypothesis that the skin may constitute the reservoir for C. albicans in oculo-cutaneous candidiasis.


Cutaneous cryptococcosis resembling molluscum contagiosum in a homosexual man with AIDS. Report of a case and review of the literature. A 43-year-old homosexual man with the Acquired Immunodeficiency Syndrome (AIDS) developed cutaneous molluscum contagiosum-like lesions on face, ears, neck, hands and feet. He was admitted to our unit with fever, malaise and headache. Cytologic examination of skin brushing revealed numerous encapsulated budding yeasts, identified as Cryptococcus neoformans. Such a finding calls for a cytologic examination of skin lesions in patient with AIDS who present with fever and headache, in order to rule out a potentially life-threatening fungal infection.


Follow-up of men with genital papilloma virus infection. Psychosexual aspects. Genital papilloma virus infection (GPVI) is in many patients a longlasting, relapsing disease for which no effective treatment is available. This fact and the association between the virus and cancer puts much stress on the afflicted patient. Of 41 men with GPVI interviewed, 17 (40%) reported a negative effect of the disease on their sexual life. Most distressing was the fear of transmitting the disease to their partner. After 18 months, 15 (37%) of the 41 men still exhibited signs of GPVI. In the care of patients with GPVI, more attention needs to be paid to the psychosexual effects of the disease.


Pityrosporum ovale and atopic dermatitis in children and young adults. Children aged 0-21 years, 60 children with atopic dermatitis (AD), 40 children with rhinoconjunctivitis and or asthma (RA) and 40 children with no atopic history (HC) were studied to evaluate the relationship between skin colonisation with Pityrosporum ovale and the occurrence of specific IgE antibodies to P. ovale. The following studies were done: culture for P. ovale, measurement of IgE antibodies to P. ovale (skin prick test, RAST), Candida albicans, and Cladosporium herbarum (RAST) and IgG antibodies to P. ovale. P. ovale could be cultured with about the same frequency in children and young adults with AD and age-matched children with or without other atopic manifestations. In spite of similar colonisation, IgE antibodies against P. ovale occur only in atopy and more frequently in children with AD than in those with other types of atopic disease.


Immediate and delayed hypersensitivity reactions to birch pollen in patients with atopic dermatitis. We investigated immediate and delayed hypersensitivity to birch pollen in 10 patients with atopic dermatitis (AD) who had experienced a worsening of their eczema during the birch pollen season. The patients were prick- and patch-tested and antigen-induced basophil histamine release and lymphocyte proliferation were measured. 9/10 birch pollen-allergic patients proved positive in the histamine release test and the results correlated with specific IgE levels measured by RAST. Birch pollen antigen induced lymphocyte proliferation in 6/10 patients, but a positive patch test result was obtained in only one case. Both peripheral blood monocytes and purified epidermal Langerhans' cells were able to present birch pollen antigen to T cells, although Langerhans' s cells seemed to function less efficiently in this respect.


Effects of antihistamines on cutaneous reactions and influx of eosinophils after local injection of PAF, kallikrein, compound 48/80 and histamine in patients with chronic urticaria and healthy subjects. The effects of one week's daily treatment with dexchlorpheniramine (3 + 3 mg x 2) and loratadine (10 mg x 2) on the cutaneous reactions to putative mediators of urticarial reactions were studied in healthy subjects and in patients with chronic urticaria. Biopsy specimens were taken from skin with delayed reactions and studied immunohistochemically for the presence of eosinophilic cationic protein (ECP). In healthy subjects both antihistamines significantly decreased the weal and flare induced by histamine and the histamine releaser compound 48/80. They also reduced the flare seen after injection of PAF (platelet activating factor) and kallikrein. In patients with chronic urticaria the delayed reactions to PAF and kallikrein were larger than in healthy subjects. The immediate flare seen after injection of histamine, 48/80 and PAF, and the delayed reaction to 48/80, were significantly decreased by treatment with loratadine. No correlation was found between the clinical response and test reactions. In the group of healthy subjects, eosinophils were increased in the skin of all subjects after intradermal injection of 100 micrograms of PAF and in 50% after 1 microgram of PAF, but no eosinophils were seen after injection of 1 ng of PAF. In patients with chronic urticaria the eosinophils were increased at all sites where 1 ng of PAF had been injected and also at a limited number of sites of injection of histamine, 48/80, kallikrein and saline. Treatment with the antihistamines had no effect on the influx of eosinophils in the skin.


Allergic granulomatosis and angiitis of Churg-Strauss. A case of high serum level of eosinophil cationic protein. We report a case of allergic granulomatosis and angiitis of Churg-Strauss. The patient is a 40-year-old woman who satisfied the clinico-pathological triad of asthma, tissue and blood eosinophilia, and granulomatous vasculitis. We also measured serum eosinophil cationic protein (ECP) levels in this patient. In the active stage, the serum ECP level was higher than in healthy controls, declining in the remission stage, a finding suggesting that ECP is involved in the pathogenesis and course of Churg-Strauss disease.


Red lunulae in severe alopecia areata.

Red lunulae in severe alopecia areata. The development of red nail lunulae has been extremely rarely described in alopecia areata. We observed 2 patients, a 30-year-old woman and a 61-year-old man, both suffering from severe alopecia areata, and having red lunulae. The colour changes, which developed a few weeks after the acute onset of hair loss, disappeared slowly, leaving horizontal fissures (Beau's lines).


Psoriasiform acral dermatitis. Report of three cases. The authors report 3 patients affected by psoriasiform acral dermatitis, a distinctive clinical entity characterized by a chronic dermatitis of the terminal phalanges, associated with marked shortening of the nail beds of the affected fingers. The skin biopsy showed in all cases the pathological features of a subacute spongiotic dermatitis. X-ray examination of affected fingers showed no bone or soft tissue changes. Differential diagnosis of psoriasiform acral dermatitis included psoriasis, atopic or contact dermatitis and corticosteroid-induced distal phalangeal atrophy.


Alcohol and smoking: risk factors for infectious eczematoid dermatitis? Risk factors for infectious eczematoid dermatitis (IED) were analyzed in a study of males aged 19-50 years. The subjects were 43 IED patients and 226 controls with other skin diseases from the dermatological outpatient clinics of three University Hospitals in Finland. The patients' lifestyles were assessed by a self-administered questionnaire pertaining to two specified periods: the period 12 months before the onset of the skin disease and the period 12 months before the examination date. Recalled mean alcohol intake before the onset of the skin disease was 39.2 g/day for the IED patients and 17.1 g/day for the controls (p = 0.04). The average number of cigarettes smoked daily was 17.7 for the IED patients and 10.4 for the control patients (p = 0.001). The IED patients significantly reduced their alcohol intake after the onset of the skin disease. In logistic regression analysis, IED associated with alcohol intake and smoking but not with coffee consumption, life events, age, marital status, or social group. The odds ratio for IED at an alcohol intake of 50 g/day as against no intake, was 1.7 (95% confidence interval 1.03-2.7), and the odds ratio at a tobacco consumption rate of 20 cigarettes/day as against no use of tobacco, was 2.1 (1.2-3.7). We conclude that alcohol intake and smoking appear to be risk factors for infectious eczematoid dermatitis among males.


Significance of tubuloreticular structures in infants with neonatal lupus erythematosus and their mothers with Sjögren's syndrome. Four infants with neonatal lupus erythematosus who had annular erythema on the trunk and face reacted positively to tests for anti-Ro(SS-A)/La(SS-B) antibodies. Electron microscopic examination of vascular endothelial cells in the annular erythema revealed the presence of tubuloreticular structures. Once anti-Ro(SS-A)/La(SS-B) antibodies had turned negative, these tubuloreticular structures were no longer evident in the vascular endothelial cells in the same area where annular erythema had been present. Mothers of these 4 infants reacted positively to anti-Ro(SS-A)/La(SS-B) antibodies, but had no sicca syndrome. A biopsy taken from the minor salivary gland of the lip of each mother revealed marked periductal mononuclear cell infiltration. Primary subclinical Sjögren's syndrome was confirmed. Tubuloreticular structures were also observed in the vascular endothelial cells in the region of the minor salivary gland. These findings suggest that the presence of tubuloreticular structures may be related to anti-Ro(SS-A)/La (SS-B) antibodies.


Topical glucocorticoids of the non-fluorinated double-ester type. Lack of atrophogenicity in normal skin as assessed by high-frequency ultrasound. With the advent of non-fluorinated double esters the spectrum of topical dermatotherapy with glucocorticoids seems to have broadened to include safer congeners. To assess the atrophogenicity potential of glucocorticoids, high-frequency ultrasound has been proposed. In a comparative trial using the DUB 20 system, 24 healthy volunteers applied hydrocortisone aceponate, the corresponding vehicle, prednicarbate ointment and betamethasone-17-valerate ointment over a period of 6 weeks. While both hydrocortisone aceponate and prednicarbate ointment induced no significant reduction in skin thickness, the onset of epidermal-dermal thinning with betamethasone-17-valerate was early and the extent marked. These findings imply an increased therapeutic index with the non-fluorinated double esters.


Serum levels of vitamin D metabolites in isotretinoin-treated acne patients. Serum levels of vitamin D metabolites were determined in 11 patients treated for cystic acne with a four-month course of isotretinoin (Roaccutane). The levels were measured before treatment and after two months of medication. We found a significant fall in the level of 1,25-dihydroxyvitamin D (p less than 0.01) and a significant increase in the molar ratio of 24, 25-dihydroxyvitamin D to 25-hydroxyvitamin D (p less than 0.05). No significant changes were found for the vitamin D metabolites 25-hydroxyvitamin D or 24,25-dihydroxy-vitamin D, for serum calcium, phosphorus, alkaline phosphatase or parathyroid hormone. Our data indicate early changes in the metabolism of vitamin D in patients on retinoid treatment.


Delayed hypersensitivity reactions following allergic and irritant inflammation. Delayed hypersensitivity retest reaction 3 and 6 weeks after induction of allergic and irritant inflammation, was studied in 13 females with known hypersensitivity to nickel. An increased retest reaction compared to controls was observed only in sites of earlier specific allergic inflammation. Also a general down-regulation of the degree of hypersensitivity was observed at retesting.


Effect of drugs on the early and late phase UV erythema. The inhibition of erythema by drugs applied topically after irradiation with 0.2-0.8 J of 313 nm has been studied in healthy volunteers. Indomethacin and piroxicam markedly inhibited the erythema at 6 to 24 h after irradiation but erythema reappeared at 45 h. The results reported suggest that the UVB response is biphasic with an early phase responsive to nonsteroid anti-inflammatory drugs and a late phase which is not responsive. No effect on the intensity of the erythema was seen with betamethasone chloroquine and cetirizine. Oral intake of aspirin before and/or after irradiation did not influence the UV response.


Leg and foot ulcers. Nursing care in Malmö, Sweden. Questionnaires concerning nursing care of leg and foot ulcer patients in three major care-giving sectors of the national health service, namely the Department of Dermatology, general hospital wards/clinics, and primary care, have been analysed. The overall response rate was 88% (primary care: 100%). Forms regarding 193 patients with leg ulcers and 64 patients with foot ulcers were analysed. Substantial differences in nursing care were noted between the three sectors. In 55% of the leg ulcers and 45% of the foot ulcers fibrin slough was present in the ulcer. Black, necrotic tissue was present in 8% of the leg ulcers and 22% of the foot ulcers. Profuse ulcer-exudation was most commonly reported for leg ulcer patients treated at the Department of Dermatology, while the majority of foot ulcers had only a mild exudation. Frequency of dressing changes varied between 1.4 times/week for leg ulcers at the Department of Dermatology and 9.2 times/week (foot ulcers 11.6) at general hospital clinics. Local wound dressings were exclusively chosen by physicians at the Department of Dermatology, mainly by physicians at general hospital clinics, and equally often by physicians and nurses in primary care. Time since last evaluation of the ulcer by a physician varied. At the general hospital clinics, 89% of the patients with leg ulcers had been seen by a physician within the last 2-month period. At the Department of Dermatology, 89% and in primary care 61% of the patients were examined within this period. 11% of the patients in primary care had never consulted a physician for their ulcers.(ABSTRACT TRUNCATED AT 250 WORDS)


A demographic survey of leg and foot ulcer patients in a defined population. By means of a questionnaire sent to all medical units in Malmö, including primary care, homes for the elderly, and industrial health clinics, 275 patients with leg and foot ulcers were identified. With a population of 232,908 in Malmö, this corresponds to a prevalence of 0.12%, which is lower than reported by others. Since the response rate was high (88% total, Primary Care: 100%), the prevalence of 0.12% is, however, believed to be real and might be explained by the urban area investigated, with easy access to care and proximity to one somatic hospital. 50% of the patients with leg and foot ulcers were treated in Primary Care, and 30% of the leg ulcer patients were treated at the Department of Dermatology. 88% of leg and foot ulcer patients were over 75 years of age. Median age was 79.5 years, with 80 for women and 76.5 for men. In Primary Care the median age was 82. There was a predominance of women in the study population with an overall sex ratio of 3:1. A higher proportion of patients living alone was found in Primary Care. The etiology of the ulcers was considered to be "unknown" or "other" or else no statement was given in 36% of the leg ulcer- and 22% of the foot ulcer patients. This might reflect an overall uncertainty about the underlying etiological cause. Medially and laterally located leg ulcers were reported equally often, but there was also a great proportion of wholly or partially circumferential ulcers. 76% of the foot ulcers were located on the toes.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of psoriasis heliotherapy on epidermal urocanic acid isomer concentrations. A noninvasive Finn Chamber sampling method and HPLC analysis were used to determine epidermal urocanic acid (UCA) concentrations of psoriasis patients during 4 weeks of heliotherapy on the Spanish Canary Islands and a follow-up period of 8 weeks. During heliotherapy the epidermal cis-UCA concentration increased from a mean initial value of 0.2 nmol/cm2 to a mean final value of 2.9 nmol/cm2. The total UCA concentration decreased during the first week of heliotherapy from an initial value of 5.5 nmol/cm2 to a nadir of 2.0 nmol/cm2. Thereafter, a steady increase was recorded in the total UCA level, with a maximum of 10.2 nmol/cm2 in week 2 of the post-treatment follow-up period. Suberythemal sun exposures caused near-maximal UCA isomerization, and during heliotherapy the cis isomer constituted 63.7-74.3% of the total UCA concentration. Clinical response of psoriasis to heliotherapy, however, seemed to be independent of UCA isomer levels.


The fate of individual organisms during clearance of experimental cutaneous Candida albicans infections in mice. A mouse model of acute cutaneous Candida albicans infections was used to study the manner in which these infections are cleared. Results of histological examination were correlated with determinations of the viability by acridine orange staining of superficial C. albicans pseudohyphae retrieved from the surface of the infected skin. The number of organisms retrieved from the skin surface was highest on the third and fourth day after inoculation, a finding which appeared to relate to a loss of Candida foci observed histologically to occur after the second day. Viability was high (approximately 80%) for at least 1-2 days after the organisms were seen histologically to have become associated with neutrophils and extruded from the stratum Malpighi into the stratum corneum; however, at later time points (fourth and fifth day after inoculation), the viability of the retrieved organisms did decline. Pseudohyphae germinated in vitro and applied to the skin of mice were found to be non-viable when retrieved 24 h later. These data suggest that the microbicidal processes of neutrophils may not be required for resolution of these infections. They are most consistent with clearance through an epidermal proliferative response which relocates the infecting organisms to a very superficial site, from which they can be either lost in a viable state, or subjected to killing by other factors at the skin surface.


Purification of bullous pemphigoid IgG subclasses and their capability for complement fixation. The antibody reactivity and complement fixing capability of circulating IgG subclass antibodies of patients with bullous pemphigoid (BP) were investigated. Four subclasses of polyclonal IgG were purified from the sera of BP patients. The first stage of purification was a combination of chromatographies on DEAE Affi-Gel Blue and protein A-Cellulofine columns. The four polyclonal IgG subclasses were then isolated from the above-mentioned semi-purified subclass fractions using IgG subclass-specific immuno-affinity chromatographies. Using an immunohistopathological technique, IgG deposits were detected at the basement membrane zone (BMZ) in the normal skin incubated with IgG subclasses other than IgG3. C3 deposits were detected at BMZ in the skin incubated with IgG1. Neither IgG nor C3 deposits were in skin incubated with IgG3. These findings suggest that the subclasses of circulating BP antibodies are IgG1, IgG2 and IgG4, but not IgG3. Moreover, only the BP IgG1 subclass appears to fix complement.


Zinc salts effects on granulocyte zinc concentration and chemotaxis in acne patients. To explore the mechanism by which zinc acts on cutaneous inflammatory lesions, we studied granulocyte zinc levels and in vitro polymorphonuclear leukocyte chemotaxis in 20 acne patients before and after 2 months of zinc therapy (200 mg/day zinc gluconate). The zinc level was assayed by flame absorption spectrophotometry and chemotaxis was performed by agarose assay. After 2 months of treatment, a significant decrease in granulocyte zinc level associated with inhibition of chemotaxis (r = 0.69) was observed in 16 patients. This suggests that zinc anti-inflammatory action is related to inhibition of polymorphonuclear leukocyte chemotaxis induced by a decreased granulocyte zinc level.


A defective purine nucleotide synthesis pathway in psoriatic patients. Purine nucleotide concentrations in skin- and blood-cells of psoriatic patients are abnormal: The increase in the steady state level of cGMP and the decrease in the cAMP concentrations are associated with an enhanced rate of cellular proliferation. Concomitantly we found in the present study decreased ADP and ATP concentrations in blood cells (p less than 0.0001). The change in nucleotide concentrations suggests a defective purine nucleotide synthesis pathway. Stimulation of the Krebs cycle with fumaric acid raises ATP (p less than 0.0001) and most probably cAMP levels and at the same time slows down the purine nucleotide synthesis through end-product inhibition. Both effects can inhibit DNA and protein synthesis activity, which results in inhibition of cellular proliferation. Fumaric acid seems therefore a useful treatment for psoriatic lesions if liver and kidney functions (purine nucleotide and urea cycle) are controlled during treatment.


Alterations of skin microcirculatory rhythmic oscillations in different positions of the lower extremity. Microcirculatory vasomotion is considered to be an important mechanism promoting and facilitating the transfer of blood cells through skin capillaries. Since skin vulnerability of the leg is closely associated with gravitational factors and skin micro-circulation, we investigated by a laser Doppler apparatus influence of postural changes on skin blood flow oscillations in lower limbs of healthy volunteers. Our data show a marked decrease in microcirculatory oscillation amplitudes at a frequency 7.6 (+/- 0.6) min-1 after lowering the leg. This could be reversed by the application of compressive bandage. Our study points toward a potentially important mechanism of microcirculatory impairment during orthostasis.


Objective prick test evaluation: non-invasive techniques. Prick test reactions are evaluated and quantified, comparing visual assessment with two non-invasive techniques: remittance spectroscopy and pulsed ultrasound for erythema and skin thickness measurements. Different information is provided by the two methods. Remittance spectroscopy discriminates well between negative and positive reactions (+ or ++), while failing to differentiate stronger reactions, where edema is a prominent feature. The latter reactions are better evaluated by skin thickness measurements, which, on the contrary, are less sensitive in revealing small skin thickness increases in weak reactions.


Skin sensitization to cinnamic alcohol: the role of skin metabolism. Cinnamic alcohol and cinnamic aldehyde are a cause of allergic contact dermatitis in man and give rise to similar rates of positive reactions in routine patch testing. However, data from animal models indicates that the aldehyde is the stronger sensitizer of the two. Circumstantial evidence has pointed to the conversion of alcohol to aldehyde in skin as the cause of cinnamic alcohol sensitization. This report discusses the subject in the light of studies of skin metabolism of cinnamic alcohol. Evidence of limited cross reactivity between cinnamic alcohol and cinnamic aldehyde is supported by data showing conversion of cinnamic alcohol to cinnamic aldehyde by an epidermal enzyme.


In vitro assessment of 'T' lymphocyte functioning in vitiligo. Support for autoimmune hypothesis concerning the disease. Ten patients with vitiligo in the active state of the disease and an equal number of age- and sex-matched controls were selected for certain immunological markers. A significantly high production of leukocyte migration inhibition factor was observed in these patients when compared with controls. Levels of immunoglobulin G were found to be significantly elevated. Eighty percent of the cases showed elevated levels of circulating immune complexes. Our investigation supports the autoimmune hypothesis for the disease, showing an increased release of LMIF with a subsequent activation of B-cells which might have led to the observed hypergammaglobulinaemia and elevated levels of circulating immune complexes in these patients.


Abnormalities of lymphocyte function and phenotypic pattern in a case of toxic epidermal necrolysis. We examined the blood lymphocyte function and phenotypic pattern in a patient with toxic epidermal necrolysis after taking salazopyrin. We studied cell surface markers, natural killer cell activity and mitogen-induced lymphocyte transformation. Our results point to temporary immunosuppression as evidenced by lymphopenia with a large "null cell" population, reduced natural killer cell activity, and impaired lymphocyte response to mitogens.


Expression of the high affinity IgE-receptor on human Langerhans' cells. Elucidating the role of epidermal IgE in atopic eczema. Epidermal Langerhans' cells have previously been shown to bear IgE molecules, particularly in atopic dermatitis skin. Using two highly specific antibodies against the antibody-binding chain of the high affinity IgE-receptor, 29C6 and 6F7, we here provide evidence that Langerhans' cells express this receptor in both normal skin (foreskin) and in lesional skin of patients with atopic and stasis eczema. A specific antibody against the low affinity IgE-receptor, Tü1, showed only a low expression of this receptor. This finding has important potential functional implications for the role of Langerhans' cells in transepidermal, IgE-mediated allergy.


Binding and uptake of Trichophyton rubrum mannan by human epidermal keratinocytes: a time-course study. Trichophyton rubrum infects skin. This fungus or its products might affect the function of epidermal cells. We previously reported that T. rubrum mannan (TRM) exhibits a suppressive effect on proliferation of human lymphocytes. The goal of the present study was to investigate the possibility of direct interaction of TRM with cultured normal human epidermal keratinocytes (EK). Mannan, a cell wall glycoprotein, was extracted from T. rubrum by precipitation with cetyltrimethylammonium bromide and conjugated with fluorescein isothiocyanate (FITC-TRM). After incubation of EK with 50 micrograms/ml FITC-TRM for 30 min, the surface of EK showed bright fluorescent staining. EK cultures pretreated with non-labelled TRM remained unstained. The fate of TRM bound to EK surface was determined in a time-course study. After pulse exposure to FITC-TRM, EK cultures were washed and incubated for various time periods. The EK moved surface mannan to the one area of cell membrane, so that at 4-6 h, the homogeneous staining of the entire cell surface was replaced by staining in a "cap" pattern. By 12 h, FITC-TRM was taken up into the cell, brought to the nuclear area and concentrated in the EK nucleoli. During the next 3 days nucleolar and cytoplasmic staining of the cells was observed. The intensity of fluorescence gradually diminished. On the 4th day, the sharp staining of organelles disappeared; instead, a large number of small fluorescent granules were seen intra- and extracellularly. By the 6th day after exposure, no EK staining remained. Thus, EK specifically bound, internalized and apparently catabolized TRM.(ABSTRACT TRUNCATED AT 250 WORDS)


Non-Hodgkin malignant lymphoma in the nails in the course of a chronic lymphocytic leukaemia. We describe a 70-year-old woman with B-cell chronic lymphocytic leukaemia without nodal involvement, who developed non-Hodgkin malignant lymphoma in the toe-nails. Clinically, the affected nails looked like a typical mycotic infection, but later small tumours developed which affected the nails, and biopsy established the diagnosis. Treatment with chlorambucil (Leukeran) and prednisolone had a striking effect. Malignant infiltration of B lymphocytes in the nails is very rare, but should be considered in patients with malignant haematologic disease.


Can alopecia areata be triggered by emotional stress? An uncontrolled evaluation of 178 patients with extensive hair loss. One hundred and seventy-eight patients with severe alopecia areata were asked at interview whether they attributed their first attack of hair loss to an emotional trauma. Twelve patients (6.7%) reported a severely disturbing event during the 6 months preceding the first symptoms of their disease. No patient reported that episodes of hair loss coincided with stressful life events. Emotional triggers were not especially correlated with any particular type of alopecia areata. The present study does not therefore provide evidence of a significant role of emotional stress in the pathogenesis of alopecia areata.


The analgesic effect of EMLA cream on facial skin. Quantitative evaluation using argon laser stimulation. The hypoalgesic effect of EMLA cream (Eutectic Mixture of Local Anesthetics) applied for 5, 15, and 30 min on facial skin was evaluated. Hypoalgesia was assessed by changes in pain thresholds to brief argon laser stimuli 0, 2, 5, 10, 15, 20, 25, 30, 45, and 60 min after removal of EMLA cream. The local cutaneous vascular changes induced by EMLA cream was evaluated by Erythema Index determined by reflectance spectroscopy and by laser Doppler blood flowmetry. A large inter-individual variability in analgesic efficacy was observed. The volunteers could be divided into two groups, one group of 6 persons where EMLA induced analgesia or considerable hypoalgesia, and one group of 4 persons where EMLA had no or only slight hypoalgesic effect. This great variability should be considered when EMLA cream is used for facial application in the clinic. Differences in local blood flow probably contribute to the variability. Application of EMLA cream for 5 and 15 min did not change erythema of the skin, while 30 min of application caused minor blanching.


Topical ketoconazole does not potentiate oral cyclosporin A in allergic contact dermatitis. Cyclosporin A is an effective drug but its use is limited by its side effects. Since oral ketoconazole inhibits the metabolism of oral cyclosporin, we set out to find out whether topical ketoconazole would enhance the effect in the skin of oral cyclosporin. Five patients with contact allergic dermatitis (CAD) were given a 6-day course of cyclosporin (1 mg/kg/day) and applied 2% ketoconazole cream to an area on one arm and the inert base to the other. Serial dilutions of the relevant allergen were applied to the arms at 3 days for 48 hours, and the responses were measured objectively a day later. There was no significant difference between responses at the two sites, indicating that topical ketoconazole does not enable the dose of oral cyclosporin to be reduced in CAD.


A new kind of skin lesion in Behçet's disease: extragenital ulcerations. A new skin lesion was encountered in 29 of 970 Behçet's patients. The lesions resembled oral aphthae clinically, were recurrent and left a scar tissue like genital ulcers but were located extragenitally. Skin biopsies could be done in only 4 cases and they all showed vasculitis.


Extraskeletal osteochondroma in the finger. Mimicking the fourth phalangeal bone. A 36-year-old Japanese woman with an extraskeletal osteochondroma in the left thumb is reported. A roentgenogram showed a calcified tumor, located at the distal portion of the left distal phalanx, which mimicked the fourth phalangeal bone. The pathogenesis might in this case be hamartomatous.


Rheumatoid arthritis: an association with pemphigus foliaceous. We have observed a high incidence of pemphigus foliaceous, in the absence of therapy with penicillamine, within a small population of patients with rheumatoid arthritis. We suggest that penicillamine as well as inducing autoimmune disease might exacerbate subclinical pemphigus foliaceous in this group, accounting for those few patients whose skin disease fails to resolve following drug withdrawal. Pemphigus and rheumatoid arthritis have both been associated with HLA DR4, which was present in all three of our patients who were tested.


Familial occurrence of fixed drug eruptions. Fixed drug eruptions following the use of pyrazolone derivatives occurred in 4 members of the same family: a 12-year-old girl, her grandmother, and two of her great aunts. Although the pathophysiologic events leading to this type of reaction are unknown, these cases of familial occurrence suggest that genetic predisposition might be an important causal factor.


Acute mercury intoxication with lichenoid drug eruption followed by mercury contact allergy and development of antinuclear antibodies. A 31-year-old black man was examined for evaluation of a suspected occupational disease. Three years earlier he had been suffering from acute mercury intoxication during work in a mercury recycling factory. Skin symptoms then had been a lichenoid drug eruption, patchy alopecia and stomatitis, which had all disappeared rapidly after systemic glucocorticosteroid treatment. The examination revealed positive patch test reactions to metallic mercury and inorganic mercury compounds, an elevated titre of serum antinuclear antibodies and normal IgE levels. The induction of antinuclear antibodies by mercury has been shown in animal experiments. It can be hypothesized that this patient, who may have had an increased individual susceptibility, became allergic to mercury by the mercury intoxication.


Roxithromycin in Lyme borreliosis: discrepant results of an in vitro and in vivo animal susceptibility study and a clinical trial in patients with erythema migrans. A new semisynthetic macrolide roxithromycin was evaluated for its potential use in the treatment of Lyme borreliosis. Using a macro-dilution broth technique, Borrelia burgdorferi was shown to be susceptible to roxithromycin with a minimal bactericidal concentration (MBC) of 0.06-0.25 microgram/ml. A systemic B. burgdorferi infection was established in gerbils; a dosage of greater than or equal to 25 mg/kg/day roxithromycin for 10 days eliminated the infection. A single blind, randomized multicenter study was performed to evaluate the efficacy of roxithromycin 150 mg b.i.d. versus phenoxymethyl-penicillin 1 g b.i.d. for 10 days in patients with uncomplicated erythema migrans. The study was interrupted when 19 patients had enrolled because of five treatment failures. All 5 patients had received roxithromycin; three patients had persisting or recurrent erythema migrans, one developed a secondary erythema migrans-like lesion and severe arthralgia and one developed neuroborreliosis. B. burgdorferi was isolated from skin biopsies after roxithromycin therapy from two patients with persistent erythema migrans and both isolates were still highly susceptible to roxithromycin (MBC = 0.03 microgram/ml). No treatment failures were seen in 10 patients treated with phenoxymethyl-penicillin. Roxithromycin is thus not recommended for treatment of Lyme borreliosis.


Subcorneal pustular dermatosis in a patient with Crohn's disease. A case of subcorneal pustular dermatosis (Sneddon-Wilkinson disease) is reported in a patient with a one-year history of Crohn's disease. Subcorneal pustular dermatosis has been described in association with monoclonal gammopathy, but to our knowledge it has not been associated with Crohn's disease. This new association reinforces the hypothesis of a possible common pathogenesis for neutrophilic dermatoses and inflammatory bowel diseases.


Digital verrucous fibroangioma: a new variant of verrucous hemangioma. In this article, we report on 4 cases of a dome-shaped nodule on the dorsum of the finger, which had been present since birth and slowly enlarged. On light microscopic examination, these nodules showed similarities to verrucous hemangioma. However, they were characterized by distinct clinical features and proliferation of dermal connective tissue. We consider these tumors to be a variant of verrucous hemangioma and propose to term them digital verrucous fibroangioma.


PUVA treatment of vitiligo: a retrospective study of 59 patients. We have performed a retrospective study of 59 patients with vitiligo who received PUVA therapy from 1972 to 1986. Sixteen patients had generalized vitiligo and 43 vitiligo in four locations (focal vitiligo). In both groups there were repigmentation in 44% of the patients. Half of the repigmented patients had improved more than 50%. None developed hypertrichosis, actinic keratosis, lentigines, or skin cancer within the observation period. Regardless of the results of PUVA therapy half of the patients thought PUVA was an acceptable therapy.


Hemolytic uremic syndrome in a patient with systemic sclerosis treated with cyclosporin A. The case is presented of a 48-year-old female suffering from diffuse cutaneous systemic sclerosis (diffuse scleroderma) since 8 years, who went into renal failure as part of hemolytic uremic syndrome following 3 weeks' treatment with 3.8 mg/kg cyclosporin A. Hemolytic uremic syndrome has previously been described in transplant patients receiving cyclosporin A. There are also four cases reported in the literature of renal failure developing in middle aged females with diffuse cutaneous systemic sclerosis after short-term use of low dosage cyclosporin A treatment. It is suggested, that it may be wise not to use cyclosporin A to this category of patients, in which it can not be ruled out, that even a low dose therapy may trigger the rapid onset of scleroderma renal crisis or as in our case provoke hemolytic uremic syndrome.


Escherichia coli cellulitis: two cases.

Escherichia coli cellulitis: two cases. We report two cases of cellulitis of the legs occurring in adults where Escherichia coli (E. coli) was, or probably was, the causative bacterial agent. E. coli and other gram-negative bacilli cellulitis are rarely reported. However, in cellulitis, the causative microorganism is rarely identified, and some cases of E. coli cellulitis could be unrecognized. Furthermore, classical risk factors for gram-negative sepsis are characterized by a state of leucocyte dysfunction which could explain the possibility of a severe, even lethal, course of gram-negative cellulitis. Therefore, the occurrence of cellulitis in patients with risk factors should prompt attempts at isolating the pathogenic microorganism, and a broad spectrum of antibiotic therapy should be initiated.


Hormonal modulation of prolyl endopeptidase and dipeptidyl peptidase IV activities in the mouse uterus and ovary. Prolyl endopeptidase and dipeptidyl peptidase IV are proline-specific peptidases, and are ubiquitously distributed in various tissues in mammals. The specific activities of these peptidases in both uterus and ovary were examined in the SHN strain of mice at estrus or diestrus. A marked change in prolyl endopeptidase activity was found in the uterus and ovary in intact mice during the estrous cycle, the activity being high at estrus and low at diestrus. In ovariectomized mice, prolyl endopeptidase activity was significantly higher in the uterus treated with progesterone or estradiol than in the uterus treated with vehicle oil only or a dopamine antagonist (perphenazine) which stimulates prolactin secretion. On the other hand, notable change in dipeptidyl peptidase IV activity during the estrous cycle was found only in the uterus of intact mice. The activity was low at estrus and high at diestrus. In ovariectomized mice, the uterus exposed to estradiol showed a lower dipeptidyl peptidase IV activity than the uteri treated with progesterone, the dopamine antagonist or vehicle oil. These findings reveal that there is a close correlation between the circulating level of ovarian steroids and the activities of these proline-specific enzymes.


Alpha-2 adrenergic agonism stimulates islet glucagon release from perfused rat pancreas: possible involvement of alpha-2A adrenergic receptor subtype. Although insulin release is known to be inhibited by alpha-2 adrenergic agonism, the effect of alpha adrenergic agonism on islet glucagon release remains controversial. Alpha-2 adrenoceptors are subdivided into alpha-2A and alpha-2B subtypes using receptor binding methods or cloning methodology. This study was designed to confirm the involvement of the alpha-2 adrenoceptor and its subtypes in glucagon release from the isolated, perfused rat pancreas. Both the alpha-2A preferential agonist oxymetazoline and the non-subtype-selective alpha-2 agonist clonidine induced concentration-dependent stimulation of glucagon release, starting at 10(-8) and 10(-7) mol/l, respectively (p < 0.01). In contrast, neither of the two alpha-1 selective agonists, methoxamine and phenylephrine, at concentrations up to 10(-6) mol/l affected glucagon release. Furthermore, the non-subtype-selective alpha-2 antagonist rauwolscine at concentrations of 10(-6) and 10(-5) mol/l and the alpha-1 and alpha-2A selective antagonist WB-4101 at 10(-5) mol/l showed significant antagonism of 10(-7) mol/l clonidine-induced glucagon release versus corresponding controls. Neither the alpha-1 and alpha-2B selective antagonist prazosin nor the alpha-2B preferential antagonist chlorpromazine, at concentrations up to 10(-5) mol/l, antagonized the effects of clonidine. None of the eight drugs, at the concentrations tested, affected insulin release with 5.5 mmol/l glucose. These results suggest that in rats islet glucagon release induced by alpha adrenoceptor agonism is mediated through alpha-2 adrenoceptors, possibly the alpha-2A subtype.


[Therapy of silent ischemia].

[Therapy of silent ischemia]. Treatment of silent ischemia is still controversial, because of the lack of studies showing improvement of prognosis with therapy. However, silent ischemia is an independent predictor of poor prognosis. Therefore significant ischemia has to be investigated to determine the therapeutic strategies as for patients with angina pectoris. The medical therapy has been reported successful with nitrates, beta-blockers and calcium canal blockers. The same applies for surgical therapy and PTCA. The target has to be to reduce myocardial ischemia and to ameliorate the prognosis.


[Pathophysiology of left heart failure with reference to hemodynamic and neurohumoral changes]. Myocardial pump deficiency is regarded to be the hemodynamic hallmark of congestive heart failure. A decline of arterial pressure in the systemic circulation is counter-regulated by vasoconstriction in the arteriolar vascular bed; the compensatory vasoconstriction, however, results in an increased afterload that in turn aggravates myocardial pump deficiency. As part of the counterregulatory systems the sympathetic nervous system is activated (increase of neuronal activity, increased plasma norepinephrine) and the renin-angiotensin-aldosterone system is stimulated as well (increased plasma renin activity, elevated angiotensin II serum levels, hyperaldosteronism). In parallel, serum levels of antidiuretic hormone (ADH) is despite a serum hypoosmolarity increased and only poorly compensated by release of the atrial natriuretic peptide. On the cellular level, congestive heart failure leads to a shift of the expression of contractile proteins towards to fetal forms (for instance myosin-isoenzymes). Although the counterregulatory activation of the neuroendocrine systems vasoconstricts the peripheral arteries thereby maintaining perfusion of vital organs, the rise in afterload ultimately leads to a progression of congestive heart failure. Consequently, vasodilators (such as ACE-inhibitors) that not only induce vasodilation in the peripheral arteries, but also inhibit progressive neuroendocrine stimulation evolved as excellent compounds for treating congestive heart failure.


Clinical evaluation and pharmacological treatment of Gilles de la Tourette's syndrome and other hyperkinesias. The clinical evaluation and pharmacological treatment of Gilles de la Tourette's syndrome (TS) and other hyperkinesias in Hvidovre Hospital is reviewed. Pimozide still seems to be the most effective single drug in the treatment of Tourette symptoms. Anticholinergics most often in combination with one or two other drugs are still the most effective drug in the treatment of dystonia. Clozapine is an effective alternative in the treatment of tremor.


Stereology: the fast lane between neuroanatomy and brain function--or still only a tightrope? Precise and unbiased quantitation of the key element of nervous tissue has solved some long-standing problems in neuroscience and the new stereological methods are now very efficient tools for experimental testing of new (and old!) ideas and concepts. Technically, the "zipless" combination of new stereological methods with certain essential principles for observation and recognition is only beginning to be made.


Apraclonidine and early postoperative intraocular hypertension after cataract extraction. The efficacy of topical 1% apraclonidine in controlling early postoperative IOP rise after cataract extraction was evaluated. Topical 1% apraclonidine was applied to 20 patients who underwent extracapsular cataract extraction with posterior intraocular lens implantation. On another 20 patients, who acted as control group a placebo (artificial tears) was given. The IOP was measured before preoperative medication and postoperatively at 6, 12 and 24 h, using the Perkins hand-held applanation tonometer. In the control group, 9 patients (45%) developed intraocular hypertension and in the treated group only 2 (10%) showed hypertension, but with short duration and a moderate IOP rise. The difference in frequency of intraocular hypertension between the groups was statistically significant (p less than 0.02). The statistical analysis showed that the postoperative IOP of operated treated eyes was significantly smaller than the IOP of operated control eyes. Furthermore, the postoperative IOP and the initial IOP did not differ statistically. The results of this study demonstrate the efficacy of topical apraclonidine 1% in controlling the early and transient intraocular hypertension following cataract extraction.


Circulatory effects of denopamine in newborn piglets. Denopamine is an orally active beta 1 agonist whose cardiovascular action in the newborn is unknown. We evaluated its circulatory effects during normoxia in newborn piglets less than 7 days of age. The piglets were acutely instrumented under general anesthesia with an electromagnetic flow probe around the main pulmonary artery and catheters in the main pulmonary artery, aorta, left ventricle, and the right and left atria. A Millar high-fidelity catheter was used to measure left ventricular dp/dt. The ductus arteriosus was ligated. Denopamine was administered in the right atrium as a continuous infusion of 2, 4, and 8 micrograms/kg per min for 10 min each. Although cardiac index, heart rate and left ventricular dp/dt increased dose-dependently by 46.0 +/- 18.2%, 87.1 +/- 34.9% and 159.9 +/- 42.4%, respectively, stroke index was not significantly altered. Unlike pulmonary artery pressure (which increased dose-dependently), aortic pressure increased with 2 and 4 micrograms/kg per min denopamine, respectively, it fell with 8 micrograms/kg per min denopamine. Similarly, the systemic vascular resistance decreased with the high dose (8 micrograms/kg per min). There was no significant change in pulmonary vascular resistance. Denopamine is potently inotropic in the adult. However, its circulatory effect in the neonate is dependent on its chronotropic action. Furthermore, denopamine is a systemic vasodilator at high doses in the neonatal circulation.


Paranoid schizophrenics may not use irrelevant signals. The use of measures of blocking and of urinary dopamine. Conditioned blocking tests for the use of superfluous (irrelevant) information in task-solving. Paranoid psychotic, obsessive-compulsive and healthy subjects usually showed normal blocking, but non-paranoid subjects tended to learn about the superfluous stimulus. Attenuated blocking was usually associated with increased dopamine utilization measured in 24h urine samples. This may reflect poor stabilization of response to neuroleptic medication.


Breast carcinoma in patients receiving neuroleptic therapy. Morphologic and clinicopathologic features of thirteen cases. We report 13 cases of breast carcinoma in patients treated with neuroleptics (prolactin-releasing drugs). Twelve of the patients were female and one was male. Nine patients had unicentric carcinoma, one had multicentric tumors arising synchronously, and three had bilateral tumors (synchronous in one case and metachronous in two cases). Thirteen tumors in ten patients were invasive ductal carcinomas, two tumors in one patient were mucinous carcinomas, and the two other patients had lipid-secreting carcinomas. Immunohistochemical staining showed alpha-lactalbumin (alpha-LA) in the lipid-secreting carcinomas at sites exhibiting active lipid secretion. A precise cause-effect relationship is difficult to elucidate, since the patients ranged in age from 40 to 64 years (mean: 51 years) when cancer was first diagnosed. However, the relatively high incidence of multiple tumors and the production of lipid and alpha-LA by the cancer cells were unusual features suggesting an association with neuroleptic therapy.


A case of adult T-cell leukemia/lymphoma, histologically presenting CD30-positive large cell lymphoma. A 48-year-old Japanese woman with adult T-cell leukemia/lymphoma (ATLL), histologically presenting CD30-positive large cell lymphoma is reported. The patient, who was from an ATLL endemic area in Japan, had cutaneous nodules in the head, trunk, and extremities, and cervical lymph node swelling; these had been found three months before her admission to our hospital. A biopsy specimen of a skin lesion showed diffuse large cell lymphoma; the lymphoma cells were positively stained with CD30 (Ki-1/Ber H-2), CD4 (helper-T), and CD25 (interleukin-2 receptor) antibodies. Anti HTLV-1 antibody (ATLA) was detected in the serum, and molecular cytogenetic studies of lymphoma cells showed both positive T-cell receptor rearrangement and HTLV-1 specific DNA sequences.


Loss of constitutional heterozygosity in human astrocytomas. Inactivation of tumour suppressor genes or anti-oncogenes as well as activation of dominant acting oncogenes seem to be important mechanisms in the pathogenesis of gliomas. We compared constitutional and tumoural genotypes at different restriction fragment length polymorphism loci (RFLP) on chromosomes 10 and 17 in 15 unrelated individuals. Loss of heterozygosity (LOH) pointing to chromosomal loss or deletions was detected for at least one chromosome 17 marker in 11 gliomas (astrocytomas grades I-III and glioblastoma multiforme), whereas LOH for chromosome 10 loci was only detected in 3 out of 9 cases of glioblastoma multiforme and was not detected in low grade gliomas. Since LOH for chromosome 10 loci seems to be restricted only to glioblastoma multiforme, it is possible that recessive mutations on chromosome 10 are engaged in tumour progression from astrocytomas to glioblastoma multiforme. As LOH of chromosome 17 markers occurs in astrocytomas as in glioblastoma multiforme, chromosome 17 loci probably are involved in early tumour development.