Multiple lymphadenopathy as an initial sign of extramammary Paget disease.

Extramammary Paget disease (EMPD) often develops in external genitalia. Paget cells can, however, adopt an invasive phenotype and metastasize to regional lymph nodes and beyond, leading to poor patient outcomes. Based on this clinical observation, multiple lymphadenopathy may represent an initial sign of EMPD. To address the potential significance of multiple lymph node swelling in EMPD, we report two patients with cutaneous primary EMPD who showed multiple lymphadenopathy as an initial sign during the clinical course of the disease as well as tumour metastasis. Significantly, marked lymphatic vessel growth was observed in regional lymph nodes that underwent massive tumour cell invasion. Therefore, nodal lymphangiogenesis may promote tumour cell invasion and metastasis to distant organs, including the lymph nodes, emphasizing the clinical relevance of multiple lymphadenopathy.

An alkaline metallo-proteinase in the human uterine cervix an changes in its activity by cervical ripening.

Human uterine cervix at term pregnancy was found to contain an alkaline metallo-proteinase by use of a synthetic substrate, 2,4-dinitrophenyl-L-Pro-L-Gln-Gly-L-Ile-L-Ala-Gly-L-Gln-D-Arg. The enzyme (with a molecular weight of 3.8 . 10(4)) was most active around pH 9.2 toward casein and N alpha-benzoyl-DL-Arg-rho-nitroanilide. [14C]-Gelatin and proteoglycan subunit were also substrates for the enzyme, but [14C]collagen was not. In particular, the enzyme digested gelatin 70-times faster than the novel neutral proteinase in the cervix. Although EDTA was a potent inhibitor, 1,10-phenanthroline, human serum, diisopropylfluorophosphate and elastatinal had no effect on the enzyme. Alkaline proteinase in term pregnant cervices was significantly higher than in non-pregnant ones.

Presence of Vicia graminea lectin- and Vicia unijuga lectin-binding (Vgu) glycoprotein in human amniotic fluid and some of its chemical and serological properties.

Vicia graminea- and Vicia unijuga-binding glycoprotein (Vgu glycoprotein) has been reported as a malignant tumor-associated antigen, which is found in various kinds of malignant tumor-tissues and ascitic and cyst fluids of malignant tumor patients, but not found in 20 kinds of normal human tissues. The glycoprotein reacts with anti-N lectins of Vicia-graminea (VGA) and Vicia unijuga (VUA), but does not react with anti-blood group M and N sera. The existence of Vgu glycoprotein in human amniotic fluid is reported here. A perchloric acid-soluble glycoprotein fraction (PASF) was prepared from human amniotic fluid (AF-PASF). Sialoglycoprotein was then separated from AF-PASF by consecutive gel filtration on Sephacryl S-300, HPLC on Asahipak GS-710 and affinity chromatography in VUA-conjugated formyl-cellulofine columns. The sialoglycoprotein with 9.6% (w/w) carbohydrate content showed a molecular mass of 2940 kDa estimated by HPLC gel filtration. The sialoglycoprotein showed reactivity with VGA and VUA, but did not react with anti-M and -N sera. In addition, the sialoglycoprotein reacted with lectins of Ulex europeus, Arachis hypogaea, Maclura pomifera, Canavalia ensiformis, Ricinus communis, Phaseolus vulgaris, Sambucus nigra and Sophora japonica. These results show that Vgu glycoprotein exists in human amniotic fluid, and that Vgu glycoprotein obtained from human amniotic fluid has a similar serological property to Vgu glycoproteins found in malignant tumor-tissues, but its chemical property is significantly different from that of malignant-tumor associated Vgu glycoproteins.

Presence of Vicia graminea lectin- and Vicia unijuga lectin-binding (Vgu) glycoproteins in human fetal membranes and some of their biochemical properties.

We have previously reported that Vicia graminea lectin (VGA)- and Vicia unijuga lectin (VUA)-binding glycoproteins (Vgu glycoproteins), malignant tumor-associated antigens, exist in human meconium and amniotic fluid. To examine the origin of Vgu glycoprotein, their presence, some of their chemical and serological properties and their biosynthesis in the human fetal membrane, amnion and chorion laeve and accompanying membrane cells were examined. Perchloric acid-soluble fractions were prepared from human amnion and chorion laeve, after which VUA-binding components (Vgu glycoproteins) were separated by HPLC and affinity chromatography using immobilized VUA. Biosynthesis of the antigens in primary cultured cells prepared from the amnion and chorion laeve were examined by pulse-labeling and immunoprecipitation using immobilized VUA and compared with those in cultured human cancer cells. The results indicated that the serological properties of VUA-binding components in fetal membranes were similar to those of meconium and amniotic fluid, that many molecular species of VUA-binding components were synthesized in amnion and chorion laeve cells and that about 40-50% of antigens synthesized are secreted from cells while antigens synthesized in cultured cancer cells human were hardly secreted with more than 95% of the antigens remaining in the cells. From these results, we concluded that a large part of Vgu glycoproteins found in amniotic fluid is synthesized in cells of the amnion and chorion laeve and secreted into the fluid, and that Vgu glycoproteins synthesized in cancer cells were not secreted, rather they were retained in the cells.

Cytophilic antithyroglobulin antibody and antibody-dependent monocyte-mediated cytotoxicity in Hashimoto's thyroiditis.

Antithyroglobulin (anti-Tg) antibodies cytophilic for human monocytes were detected in the serum of 30 of 45 patients with Hashimoto's thyroiditis using the passive rosette technique. These antibodies conferred on normal monocytes the ability to form rosettes with Tg-coated erythrocyres (E-Tg) in vitro. The percentage of E-Tg rosette-forming monocytes was correlated with serum anti-Tg antibody titers measured by tanned sheep red cell hemagglutination. Most serum cytophilic activities were recovered in the immunoglobulin G fraction and were not affected by heating to 56 C for 30 min or ultracentrifugation at 105,000 X g for 60 min. Passive E-Tg rosette formation by monocytes was immunologically specific and was inhibited by the addition of small amounts of free Tg into the medium but was not inhibited by the addition of normal human serum. The anti-Tg antibody-armed monocytes became cytotoxic against Tg-coated chicken erythrocytes and lysed target erythrocytes by an extracellular mechanism. It was suggested that monocytes might be armed by cytophilic antibodies in vivo, since monocytes of patients with Hashimoto's thyroiditis showed increased E-Tg binding (rosette formation) relative to monocytes from control subjects. These findings support the possible pathogenetic involvement of monocytes in human autoimmune thyroiditis.

Human recombinant interleukin-1 alpha increases biosynthesis of collagenase and hyaluronic acid in cultured human chorionic cells.

The influence of human recombinant interleukin-1 alpha (hrIL-1) on biosynthesis of collagenase and glycosaminoglycans was investigated with fibroblast-like cells of human chorionic membrane. hrIL-1 stimulated cells to produce procollagenase in a dose-dependent manner. Furthermore, it similarly accelerated both biosynthesis and secretion of hyaluronic acid in chorionic cells, but did not modulate the biosynthesis of sulfated glycosaminoglycans. Therefore, the relative concentration of hyaluronic acid vs total glycosaminoglycans increased significantly. These results are connected with the decrease in tensile strength observed in ruptured fetal membranes. Thus, it is proposed that IL-1 from effused leukocytes in fetal membranes plays an important role in connective tissue metabolism, especially in premature rupture of membranes with chorioamnionitis.

Oral contraceptive steroids: effects on iron and zinc levels and on tryptophan pyrrolase and alkaline phosphatase activities in tissues of iron-deficient anemic rats.

Weanling Wistar-strain female rats were fed a normal or an iron-deficient diet for 8 weeks and oral contraceptive steroids (OCS) were added for the last 4 weeks. Hemoglobin content, serum iron and zinc levels, liver iron levels, and tryptophan pyrrolase activities, and liver, kidney, and brain zinc levels and alkaline phosphatase activities were determined. Compared to control rats given the normal diet (N group), elevated liver zinc levels and tryptophan pyrrolase activity were found in rats fed the normal diet containing OCS ( + S group), but other parameters did not alter. In rats fed the iron-deficient diet alone (D group), only liver zinc levels were significantly higher, while other parameters were in general lower than those in the N group. In rats fed the iron-deficient diet containing OCS (D + S group), all hematological values, tissue mineral contents with the exception of liver zinc levels, and liver tryptophan pyrrolase and kidney alkaline phosphatase activities were lowered, compared to the N or N + S group. However, compared to the D group, the values of most parameters in the D + S group did not differ significantly, apart from an increase in serum zinc levels. These observations suggest that OCS does not greatly influence the various changes caused by iron-deficient anemia.

Age-related increase in systolic fraction of pulmonary vein flow velocity-time integral from transesophageal Doppler echocardiography in subjects without cardiac disease.

The pulmonary vein flow velocity-time profile would be equivalent to the pulmonary vein flow volume-time profile, provided that the cross-sectional area of the pulmonary vein remains unchanged during 1 cardiac cycle. The systolic fraction of the pulmonary vein flow velocity-time integral, a ratio of velocity-time integral of the S wave to the sum of velocity-time integrals of the S and D waves, represents the ratio of left atrial storage volume to left ventricular stroke volume. This systolic fraction may help early filling of the left ventricle through an appropriate storage of blood and generation of driving pressure in the left atrium. Because early filling of the left ventricle is progressively impaired with age, it was hypothesized that this systolic fraction is increased with age. Forty-four noncardiac surgical patients (age range 17 to 70 years) who underwent transesophageal Doppler echocardiography under general anesthesia were studied, and left upper pulmonary vein flow and mitral inflow velocities were recorded. The ratio of peak velocity of the E wave to that of the A wave of mitral inflow velocity-time profile (y) decreased with age (y = -0.0245 x age + 2.41; r = -0.672, p < 0.01). Systolic fraction (y) increased with age (y = 0.00373 x age + 0.514; r = 0.656, p < 0.01). The age-related increase in the systolic fraction of pulmonary vein flow velocity-time integral may account for the compensation for impaired early filling of the left ventricle in elderly patients.

Prognostic significance of posturally induced crackles. Long-term follow-up of patients after recovery from acute myocardial infarction.

We found that on pulmonary auscultation, fine crackles could be induced by changing the posture from sitting to supine and/or from supine to supine with passive leg elevation in patients without obvious congestive heart failure. We named these crackles "posturally induced crackles (PIC)." To investigate the relationship between PIC and long-term prognosis after myocardial infarction, we followed up 262 patients who recovered from acute myocardial infarction for a mean period of six years. Cardiac death occurred in three of 78 PIC-negative patients and in 28 of 143 PIC-positive patients. PIC-negative patients had a significantly better long-term prognosis than PIC-positive patients according to the Kaplan-Meier survival curves for cardiac death (p < 0.01). In a multilogistic model based on 70 appropriate cases, PIC was the third most important prognosticator after recovery from myocardial infarction and the number of diseased coronary vessels and the pulmonary capillary wedge pressure ranked first and second, respectively.

Electron microscopic pathological patterns of alveolar septum in acute dextran-induced and alloxan-induced pulmonary edema in dogs.

We studied the incidence of electron microscopic pathological patterns of the alveolar septum observed 30 min after induction of pulmonary edema by dextran-70 infusion (6 dogs, dextran group) and by alloxan injection (6 dogs, alloxan group). For comparable amounts of extravascular lung water in both dextran and alloxan groups, which were twice as much as control group (6 dogs), we characterized the pathological changes. The incidence of the electron microscopic pathological patterns that appeared in dextran group compared with that in control group was significantly high in terms of the widening of the interstitial space, dispersion and disarray of collagen fibrils, and erythrocytes in the interstitial space. The incidence in alloxan group compared with that in control group was significantly high in terms of the swelling of epithelial cells and endothelial cells as well as the widening of the interstitial space, and dispersion and disarray of collagen fibrils. We conclude that dextran causes interstitial changes exclusively and alloxan causes cellular changes primarily coupled with secondary interstitial changes in acute pulmonary edema.

Ultrastructural substrates for increased lung water content in experimental pulmonary edema.

We examined the relationship between the incidence of ultrastructural changes in the alveolar septum and the extravascular lung water content. Pulmonary edema was induced in 18 mongrel dogs by either dextran (n = 12) or alloxan (n = 6) administration. Six other dogs served as controls. Extravascular lung water content was measured by the thermal-dye double indicator dilution method. Specimens of lung tissue were examined with an electron microscope, and the incidence of 13 types of pathological changes in the alveolar septum was studied. For each type of pathological change, the incidence was correlated with the magnitude of lung water content. The following results were obtained. The incidence of edematous changes in the alveolar interstitium (widening of the interstitial space, and dispersion and disarray of collagen fibres in the interstitial space) was well correlated with lung water content (r = 0.78, p < 0.01, and r = 0.84, p < 0.01, respectively). The correlation was not significant in the remaining types of changes. We conclude that the incidence of the pathological changes in the alveolar septum is increased along with the increase in the content of lung water in both dextran- and alloxan-induced experimental pulmonary edema in dogs.

Effect of superior vena caval hypertension on alloxan-induced lung injury in dogs.

To investigate how fast and to what extent superior vena caval hypertension (SVCH) increases lung water in acute increased-permeability state, we studied the time course of lung water accumulation for 3 h in anesthetized dogs under different treatments: 1) controls without intervention (5 dogs), 2) SVCH alone (5 dogs), 3) mild lung microvascular injury induced by low-dose alloxan (75 mg/kg) alone (5 dogs), and 4) SVCH coupled with low-dose alloxan (5 dogs). Neither low-dose alloxan alone nor SVCH alone [superior vena caval pressure (Psvc) = 11.0 +/- 3.1 (SD) mmHg] increased lung water significantly. The SVCH coupled with low-dose alloxan (Psvc = 11.3 +/- 2.7 mmHg) doubled extravascular lung thermal volume measured by the thermal-dye dilution technique within 1 h (5.3 +/- 0.9 ml/kg at base line and 10.9 +/- 4.7 ml/kg at 1 h), then remained unchanged (12.5 +/- 5.7 ml/kg at 3 h). This increase in lung water was confirmed by gravimetric method (5.69 +/- 1.71 g/g blood-free dry wt). We conclude that SVCH is one of the factors that may promote lung water accumulation in increased-permeability state.

The treatment of unruptured tubal pregnancy with intratubal methotrexate injection under laparoscopic control.

Nine patients with unruptured tubal pregnancies of 6-9 weeks' duration were treated with methotrexate intratubal injection under laparoscopic control. Urinary hCG levels decreased immediately after completion of the procedure, with a median time of 11 days (range 1-29) to resolution. Tubal patency on the side of the ectopic gestation was confirmed by hysterosalpingography 1-3 months after the procedure in all cases. This method requires a reduced methotrexate dosage compared with intramural or intravenous therapy. The indications are unruptured tubal pregnancy of 4 cm or less in diameter and urinary hCG levels of 8000 mIU/mL or lower.

Human pulmonary vascular and venous compliances are reduced before and during left-sided heart failure.

Human pulmonary vascular and venous compliances were measured in 41 patients with or without left-sided heart failure. Two methods were used. Method 1 was based on analysis of pulmonary capillary wedge (PCW) pressure tracings according to Cv,PCW = (SF/100)(0.075PCW + 0.90)SV/[(v - d)PCW + 1], where Cv,PCW is compliance of pulmonary venous system, SF is systolic fraction of pulmonary venous flow [related to pulmonary capillary wedge pressure (PCW) as SF = 82 - 2.01PCW], (v - d)PCW is pulse pressure in PCW position, and SV is stroke volume. The (0.075PCW + 0.90) term equals k", i.e., systolic run-off ratio. Method 2 was used to measure to pulmonary vascular volume-pressure (V-P) relationship and pulmonary vascular compliance (Cvasc) and is based on measurement of pulmonary blood volume (PBV) and its increase with passive elevation of the legs to calculate Cvasc. Assuming the proportion of blood entering pulmonary venous system (in increase of PBV) during passive leg elevation to be 0.8, pulmonary venous compliance (Cv,PBV) was calculated as Cv,PBV = 0.8Cvasc. Cv,PCW correlated fairly closely with Cv,PBV (r = 0.81, coefficient of variation = 31%). This fair agreement between two independent methods suggests strongly that both methods may be valid, although other interpretations are possible. Cv,PCW, Cvasc, and Cv,PBV decreased going from New York Heart Association class I to classes II and III. When PBV was plotted vs. PCW, average V-P line for class II patients was flatter and shifted downward to the right compared with that for class I. This suggests pulmonary vasoconstriction as well as other factors. Average V-P line for class III patients is flatter but not displaced compared with that for class II. Another previously reported series of 50 patients, most of whom had ischemic heart disease, are included in this study.

Pretreatment with catalase or dimethyl sulfoxide protects alloxan-induced acute lung edema in dogs.

We tested the preventive effects of catalase, an enzymatic scavenger of hydrogen peroxide, or dimethyl sulfoxide (DMSO), a hydroxyl radical scavenger, on intravenous alloxan-induced lung edema in four groups of pentobarbital sodium-anesthetized, ventilated dogs for 3 h: saline (20 ml.kg-1.h-1) infusion alone (n = 5), alloxan (75 mg/kg) + saline infusion (n = 5), catalase (150,000 U/kg) + alloxan + saline infusion (n = 5), or DMSO (4 mg/kg) + alloxan + saline infusion (n = 5). Catalase or DMSO significantly prevented the increase in plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha over 3 h after alloxan and the accumulation of extravascular lung water after 3 h [3.95 +/- 0.52 (SE) g/g with catalase, 3.06 +/- 0.42 g/g with DMSO] but not early pulmonary arterial pressor response. An electron microscopic study indicated that catalase or DMSO significantly reduced the endothelial cellular damages after alloxan. These findings strongly suggest that hydrogen peroxide and hydroxyl radical are major mediators responsible for intravenous alloxan-induced edematous lung injury in anesthetized ventilated dogs.

PZ-peptidase activity in human uterine cervix in pregnancy at term.

PZ-peptidase (EC 3.4.--) was detected in human uterine cervix distributed in the soluble fraction after 100 000 x g centrifugation. Optimum pH for PZ-peptidase was observed to be pH 7.2--7.4, except for two of the preparations examined. PZ-peptidase activity was found to significantly increase in pregnancy at term as compared with that in a control group.

Disturbances of cross-localization of fingertips in a callosal patient.

If defective cross-localization of fingertips (CLF) in callosal patients is due to a deficit in the interhemispheric transfer of somesthetic information, when the patient's eyes are open, CLF should be affected when the stimulated hand is excluded from vision, not when the responding hand is excluded from vision. In order to investigate this hypothesis, a patient with a callosal lesion was subjected to CLF with eyes closed and open. With eyes closed, the CLF score in the left-to-right direction was significantly lower than that in the right-to-left direction. With eyes open, the CLF performance in the right-to-left direction was impaired when it was the responding hand to be excluded from vision, not when it was the stimulated hand to be excluded from vision. It would, therefore, appear that the patient's CLF disturbance was not due to a somesthetic transfer deficit, but to left unilateral apraxia for the right-to-left direction errors and to left tactile finger anomia for the left-to-right direction errors.