Decreased level of interleukin-10-producing B cells in patients with pemphigus but not in patients with pemphigoid.

BACKGROUND: While the frequency of interleukin (IL)-10-producing B (B10) cells is reported to have an inverse correlation with disease activity in some human autoimmune diseases, the association between B10 cells and autoimmune blistering diseases (AIBD) has not been well evaluated. Although several phenotypes of human regulatory B cells have been proposed, the most appropriate one in AIBD has not been established. OBJECTIVE: To evaluate B10 cells in AIBD including their phenotypes. METHODS: Peripheral blood mononuclear cells were isolated from 39 patients with AIBD, including 14 with pemphigus and 25 with pemphigoid, and 10 healthy controls. We investigated the frequencies of B10 cells and CD19+ CD24hi CD38hi B cells using flow cytometry. RESULTS: The frequencies of B10 cells and CD19+ CD24hi CD38hi B cells were significantly lower and higher, respectively, in patients with pemphigus compared with healthy controls. Comparing patients with pemphigoid and healthy controls, no significant difference in the frequencies of B10 cells and CD19+ CD24hi CD38hi B cells was observed. B10-cell level in pemphigus was not associated with disease severity but inversely correlated with the required dose of steroid for treatment. While no significant difference in the frequency of IL-10-producing cells among CD19+ CD24hi CD38hi B cells was observed, in CD9+ and CD27- B-cell subsets it was significantly decreased in patients with pemphigus compared with healthy controls. CONCLUSIONS: Our results suggest the association of B10 cells with pemphigus but not with pemphigoid. The decrease in B10-cell level in pemphigus is partly caused by the lower production of IL-10 in CD9+ and CD27- B-cell subsets.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Fish intake and serum levels of organochlorines among Japanese women.

This study evaluates background serum levels of selected organochlorine compounds among Japanese women of reproductive age and investigates whether lifestyle factors, especially dietary factors, may be associated with these levels. A cross-sectional study was performed on 80 Japanese women, aged 26-43 years, who complained of infertility and were confirmed not to have endometriosis. The serum levels of total toxic equivalency (TEQ), 18 polychlorinated dibenzo-p-dioxins (PCDDs)/polychlorinated dibenzofurans (PCDFs), 4 coplanar polychlorinated biphenyls (cPCBs), 36 ortho-substituted polychlorinated biphenyls (PCBs), and 13 chlorinated pesticides or their metabolites were measured and data were collected on the women's age, residence, occupation, body mass index (BMI), smoking and alcohol habit and 6 dietary intakes (fish, meats, rice, vegetables, fruits and dairy products). The serum median level of total TEQ was 25.1 pg TEQ/g lipid, that of PCDDs/PCDFs/cPCBs was 11.5 pmol/g lipid, that of PCBs was 0.46 nmol/g lipid, and that of total pesticides was 1.32 nmol/g lipid. The serum levels of total TEQ, PCDDs/PCDFs/cPCBs, PCBs and pesticides were positively associated with age (P for trend=0.003, 0.01, 0.005 and 0.01, respectively) and frequent fish consumption (P for trend=0.002, 0.003, 0.0003 and 0.006, respectively). Other lifestyle factors were not associated with serum organochlorine levels. The present study suggests that Japanese women who consume fish frequently in their reproductive period tend to accumulate organochlorines in their bodies.

A prospective study of estradiol and breast cancer in Japanese women.

Few studies have prospectively examined endogenous hormone levels as risk factors for breast cancer. The present study compares prediagnostic hormone levels using stored serum from breast cancer cases and controls selected from the Life Span Study population of the Radiation Effects Research Foundation in Hiroshima and Nagasaki, Japan. Stored serum samples collected in 1968-1970 were assayed for 72 women subsequently diagnosed with breast cancer and 150 control subjects in 72 case-control sets matched on age, date of blood collection, exposure, radiation dose, and city. Serum levels were determined for sex hormone binding globulin, total estradiol (E2), bioavailable E2, dehydroepiandrosterone sulfate, and prolactin. Matched case-control comparisons of hormone levels were carried out by conditional logistic regression and were adjusted for menopausal status at the time of blood drawing. The odds ratio per unit log change in bioavailable E2 was 2.2 [95% confidence interval (CI), 1.02-5.31 for all subjects, and 2.3 (95% CI, 0.55-6.8) and 2.1 (95% CI, 0.55-9.7), respectively, based only on premenopausal or postmenopausal serum. The estimated odds ratios in each quintile of bioavailable E2 level, using the lowest quintile as referent, were 1.00, 1.89, 1.43, 3.45, and 3.37 (P for trend = 0.035). For sex hormone binding globulin, the overall odds ratio was 0.58 (95% CI, 0.14-2.26), and 1.00 (95% CI, 0.19-5.45) and 0.21 (95% CI, 0.02-1.88) based on premenopausal and postmenopausal serum, respectively. This study offers further prospective support for the hypothesis that a high level of biologically available E2 is a risk factor for the subsequent development of breast cancer.

Prediagnostic serum selenium and zinc levels and subsequent risk of lung and stomach cancer in Japan.

Serum samples were collected in Hiroshima and Nagasaki, Japan, from 1970 to 1972 for 208 persons who in 1973-1983 developed stomach cancer; for 77 who in 1973-1983 developed lung cancer; and for controls matched for age, sex, city, and season of blood collection. Average serum levels of selenium and zinc were slightly (< 5%) but not significantly lower among the cancer cases than among controls. Smoking-adjusted risks of lung cancer were elevated only among those in the lowest quartiles of serum selenium [odds ratio (OR) = 1.8] and zinc (OR = 1.3); the trends in risk of this cancer with decreasing serum levels were neither linear nor significant. Little or no excess risk of stomach cancer was observed among those with lowest levels of selenium (OR = 1.0) or zinc (OR = 1.2). These exploratory findings add to limited data available from other reports showing slightly increased risks of lung cancer associated with low blood levels of selenium, but suggest little association with either lung or stomach cancer across normal selenium or zinc ranges in this Japanese population.

Isotope cisternography in patients with intracranial hypertension.

Cerebrospinal fluid flow (CSF) was studied using isotope cisternography in 52 patients with increased intracranial pressure (ICP), all of whom showed acute transient rises of ICP, i.e., plateau waves, in their continuous ICP recordings. The patients were assigned to two groups. Group I was comprised of 23 patients without hydrocephalus and high ICP resulting from brain tumors, benign intracranial hypertension, and superior sagittal sinus thrombosis. Group II included 29 patients with either communicating hydrocephalus or high ICP resulting from rupture of intracranial aneurysm. Plateau waves were frequently observed in patients with baseline pressures ranging from 21 to 40 mmHg in both groups. The isotope cisternographic pattern in the Group I patients showed a large accumulation of radioactivity over the cerebral convexities, while that in the Group II patients revealed a complete obstruction of the subarachnoid space over both cerebral convexities. The isotope clearance from the intracranial CSF showed a marked delay in both groups of patients with one exception. The results suggest that, in the limited range of increased ICP caused by delayed CSF absorption, plateau waves are most evident regardless of the isotope cisternographic pattern.

A population study on risk factors for insomnia among adult Japanese women: a possible effect of road traffic volume.

In an effort to identify risk factors for insomnia and determine the contribution of nightime road traffic volume to insomnia in the general population, a questionnaire survey was carried out among 3,600 adult Japanese women living in eight urban residential areas. The crude prevalence rate of insomnia was 11.2%. Multivariate analysis revealed that aging, living with a child/children aged six or younger, undergoing medical treatment, experiencing major life events, having an irregular bedtime, having a sleep apnealike symptom, and living near a road with a heavy volume of traffic are risk factors for insomnia. Taking into account other risk factors, there was a level-response relationship between the nighttime traffic volume of main roads and the risk of insomnia in the subjects living in the zones 0-20 m from these roads. These results suggest that road traffic noise raises the sound level in bedrooms in such zones, and consequently the prevalence rate of insomnia among the residents, and that noise-induced insomnia is an important public health problem, at least in highly urbanized areas. To confirm this, a further study on noise exposure is needed.

Factors associated with serum levels of estradiol and sex hormone-binding globulin among premenopausal Japanese women.

We measured serum levels of estradiol (E(2)) and sex hormone-binding globulin (SHBG) among 50 healthy premenopausal Japanese women in 1994 in Gifu, Japan, to investigate the relationships between potential risk factors for breast cancer and hormone levels. Using a self-administered questionnaire, we collected data on body size, physical activity, and previous disease history, as well as menstrual and reproductive histories of the woman and her mother. Blood samples were drawn from each subject on the 11th and 22nd days of her menstrual cycle. Higher serum E(2) levels were observed for women with shorter menstrual cycles. Age as well as cycle length were included in the regression models to determine the associations between hormone levels and study variables. Body mass index (BMI) was inversely related to SHBG level measured at the 11th day of the cycle, after adjusting for age and cycle length (r = -0.33; p = 0. 03). Women born in spring/summer had higher levels of E(2) on the 22nd day (p = 0.07) and higher levels of SHBG on both the 11th and 22nd days of the cycle (p = 0.01 and p = 0.06, respectively) than those born in other seasons. Physical activity at 13-15 years of age was inversely related to E(2) level on the 11th day of the cycle after controlling for age, cycle length, BMI, and birth month (r = -0.35; p = 0.04).

Helicobacter pylori infection and atrophic gastritis in middle-aged Japanese residents of São Paulo and Lima.

BACKGROUND: Helicobacter pylori infection and atrophic gastritis (AG) are markedly more prevalent in Japan than in other industrialized countries, however, the reasons for such a high prevalence are not fully understood. To add to information on H. pylori infection and its association with AG, the authors studied Japanese living in less developed countries. METHODS: Cross-sectional surveys were conducted of randomly selected Japanese residents aged 40-59 years in São Paulo, Brazil and Lima, Peru. Serum IgG antibody to H. pylori and pepsinogen I (PGI) and II (PGII) were measured as markers of AG. RESULTS: The prevalence of H. pylori infection was similar in both populations, 77% (95% CI: 70-83) in São Paulo and 75% (95% CI: 65-82) in Lima, and was within the range of five populations in Japan from our previous study. However, the prevalence of AG, defined by PGI < 70 ng/ml and PGI/PGII < 3.0 was more prevalent among Japanese in São Paulo (39% [95% CI: 32-47]), than Japanese in Lima (18% [95% CI: 12-27]). This difference was not explained by sex, age, generation or H. pylori infection. CONCLUSIONS: Helicobacter pylori infection among Japanese in less developed countries was similar to Japanese in Japan, although prevalence of AG varied. Factors other than H. pylori infection are important in the development of AG among Japanese.

MR imaging of cerebrospinal fluid rhinorrhea after operation for acoustic neurinoma.

MR was useful in verifying CSF rhinorrhea following removal of an intracanalicular acoustic neurinoma via the occipital route in a 29-year-old man. MR accurately identified the location of the CSF leak.

Ruptured suprasellar dermoid cyst presenting olfactory delusion (Eigengeruchs erlebnis).

A 24-year-old man sought treatment of a long-standing olfactory delusion (Eigengeruchs erlebnis) and associated psychotic symptoms, which disappeared after the removal of a suprasellar dermoid cyst. The pathophysiology of the phenomenon is discussed.

Giant aneurysm of an azygos anterior cerebral artery: report of two cases and review of the literature.

The authors present two cases of a largely thrombosed giant aneurysm of an azygos anterior cerebral artery. An aneurysm of an azygos artery is rare, and a giant aneurysm in this location is extremely rare.

The antitumor effect of MX2, a new morpholino anthracycline, against malignant glioma cell lines and its subcellular distribution.

The chemotherapeutic effect of MX2 (3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin), a new lipophilic morpholino anthracycline, against rat C6 and human T98G glioma cells, was examined in vitro and in vivo. The subcellular distribution of MX2 was also studied. The drug concentrations of MX2 required for the 50% inhibition of cell growth (IC50) for C6 and T98G cells were 25.5 +/- 1.3 ng/ml and 70.6 +/- 6.8 ng/ml, respectively, which were much lower than the IC50 values for nimustine (ACNU). A C6 subline resistant to ACNU, C6/ACNU, was established by continuous exposure to graded concentrations of ACNU. The IC50 of MX2 for C6/ACNU was 28.3 +/- 2.2 ng/ml, indicating no cross-resistance to MX2. In the rats bearing the intracerebral C6 tumors, the life span was increased by about 40 to 100% after intravenous administration of MX2 at doses ranging from 1 to 3 mg/kg of body weight. Confocal laser scanning microscopy demonstrated visually the good accumulation of MX2 in the implanted intracerebral C6 tumors, as well as its predominant distribution in the cytoplasm over the nucleus in both cell lines in vitro. Ultrastructural studies also demonstrated the cytotoxic effects of MX2 against glioma cells. Our results suggest that MX2 may be a useful chemotherapeutic agent in the treatment of malignant gliomas and that confocal laser scanning microscopy is useful for the study of the cellular pharmacokinetics of anthracycline derivatives, such as MX2.

Effect of endothelin on the canine basilar artery.

Endothelin, a recently discovered peptide produced by endothelial cells, has been shown to have potent constrictor effects on major arteries in vitro. This experiment was performed to determine whether endothelin plays a physiological role in cerebral vasospasm after subarachnoid hemorrhage. A cisternal injection of endothelin (10(-8) mol or 10(-9) mol) caused severe vasoconstriction of the canine basilar artery. The degree of vasoconstriction was dose related and long lasting, persisting for more than 24 hours. This constriction was prevented completely by pretreatment with nicardipine (10(-8) mol). Endothelin produced a marked and transient elevation in blood pressure and might play an important role in cerebral vasospasm. Further investigation will be needed to determine the role of endothelin in the pathogenesis of vasospasm.

Phosphorus-31 magnetic resonance spectroscopy of cerebral ischemia in cats.

The energy metabolism of the brain was measured in three types of ischemic models in the cat using phosphorus-31 magnetic resonance spectroscopy. The cerebral ischemia was produced as follows. In Group 1, two balloons were inflated in the left subclavian artery and the brachiocephalic trunk. In Group 2, the left middle cerebral artery was occluded through a transorbital approach. A combination of the two was employed in Group 3. Phosphorus-31 magnetic resonance spectra were obtained serially during 2 hours of ischemia. Immediately after occlusion, peaks of phosphocreatine and adenosine triphosphate decreased, whereas the peak of inorganic phosphate increased and split in two. Intracellular pH determined by chemical shift of the inorganic phosphate peak decreased. These changes were more pronounced in Group 3 when compared with the other groups. Histological study showed no infarction in Group 1 and infarcted areas in Groups 2 and 3. The size of the infarcted area in Group 3 was larger than that in Group 2. These results suggest that the model of middle cerebral artery occlusion potentiated with the occlusion of the brachiocephalic trunk and the left subclavian artery by balloon catheters is a reliable stroke model and that phosphorus-31 magnetic resonance spectroscopy is useful to understand the pathophysiological state of cerebral ischemia in vivo.

Cerebral vasospasm and vasoconstriction caused by endothelin.

We investigated the histological changes between arteries constricted by endothelin for 7 days and vasospastic arteries induced by the double injection of autologous blood. Group 1 was a sham-operated group. Group 2 animals received a continuous cisternal injection of endothelin-1 (1.7 x 10(-9) mol/7 days) by a miniosmotic pump implanted in the neck musculature for 7 days. Group 3 received double injections of cisternal blood administered 48 hours apart. Angiography showed severe constriction of the basilar artery, 34.6% and 43% in Groups 2 and 3, respectively, on Day 7. Histological study showed marked constriction of the basilar artery in both Group 2 and Group 3. Degenerative changes in endothelial cells and smooth muscle cells were observed in both Group 2 and Group 3. Immunohistochemical study demonstrated endothelin-1 in the endothelial cells in Group 2, but not in Group 1 or in Group 3. It is suggested that endothelin-1 may play an important role in the pathogenesis of cerebral vasospasm.

The correlation between immunological reaction in the arterial wall and the time course of the development of cerebral vasospasm in a primate model.

To investigate the role of immunological reactions in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH), the authors studied the correlation between immune/inflammatory reactions in the arterial wall and the time course of vasospasm in primates. Twenty monkeys were divided into four groups of 5 animals each: 1) a control group of sham-operated animals, 2) animals subjected to angiography 3 days after the induction of SAH (3-day SAH), 3) animals subjected to angiography 7 days after SAH (1-week SAH), and 4) animals subjected to angiography 7 and 14 days after SAH (2-week SAH). To induce SAH, the main cerebral arteries on the right were dissected free of the arachnoid, and an autologous blood clot was placed around the arteries. To evaluate vasospasm, all animals underwent a baseline angiogram before SAH; angiography was repeated at different intervals in each group, as outlined above. Histopathological changes and the deposition of the immunoglobulin IgG in the arterial wall were evaluated immunohistochemically in each group. The cerebral arteries on the side of the clot showed evidence of mild vasospasm (-24.6% reduction) on the angiogram performed on Day 3, severe vasospasm (-51.7%) on Day 7, and mild vasospasm (-12.8%) on Day 14. The infiltration of inflammatory cells was most marked in the spastic arterial wall in the 1-week SAH group. In the 2-week SAH group, severe myonecrosis and intimal disruption were observed, even in the vessels that showed only mild vasospasm, and the inflammatory reactions had almost abated.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cyclosporine on the development of cerebral vasospasm in a primate model.

The authors studied the effect of the immunosuppressive drug cyclosporine (CS) on the development of cerebral vasospasm after subarachnoid hemorrhage (SAH) using a primate model of vasospasm. Eighteen monkeys were randomly divided into three groups: a sham-operated control group, an SAH group, and a CS-treated group. To induce SAH, the right side of the circle of Willis was dissected free of the arachnoid and an autologous blood clot was placed around the arteries. In the CS group, CS (5 mg/kg/day) was administered intramuscularly for 7 days after the induction of SAH. The vessel caliber was evaluated on angiograms before the induction of SAH (Day 0) and 7 days after SAH (Day 7). Histological changes and the deposition of IgG in the arterial wall were studied in the three groups. The combined values of the average reduction of the right cerebral arteries at Day 7 was significant (P less than 0.05) in the SAH group (-43.3%) and in the CS group (-31.3%) as compared with the Sham group (-0.7%); however, there was no significant difference between the values in the SAH and the CS groups. In the CS group, the average reduction in vessel caliber of the right middle and anterior cerebral arteries was significantly (P less than 0.05) less than in the SAH group; this did not prove true for the internal carotid artery, however. Although the deposition of IgG in the media and an inflammatory reaction were observed in the spastic arterial wall in both the SAH and CS groups, there was no definitive difference in these immune/inflammatory reactions between the two groups. It is suggested that CS may be helpful in reducing the severity of vasospasm, but may not have a major therapeutic effect, considering its systemic toxicity.

Brain blood volume and blood flow in patients with plateau waves.

Plateau waves, characterized by acute transient rises of the intracranial pressure (ICP), are accompanied by a marked decrease of the cerebral perfusion pressure. Patients with plateau waves, however, often show no clinical symptoms of ischemia of the brain stem, such as vasopressor response or impairment of consciousness during the waves. The authors studied brain blood volume and blood flow with dynamic computerized tomography using rapid-sequence scanning in patients with plateau waves identified during continuous ICP recording. Following an intravenous bolus injection of contrast medium, density-versus-time curves were obtained for the regions of interest; that is, the frontal lobe, the temporal lobe, the caudate nucleus, the putamen, and the pons. The dynamic studies were undertaken when the ICP was high during a plateau-wave phase and when it was low during an interval phase between two plateau waves. The results indicate that, in the cerebral hemisphere (frontal lobe, temporal lobe, caudate nucleus, and putamen), plateau waves were accompanied by an increase in blood volume and, at the same time, a decrease in blood flow. In the pons, however, both the blood volume and blood flow showed little change during plateau waves as compared with the intervals between two plateau waves. These observations may explain why there is no rise in the systemic blood pressure and why patients are often alert during plateau waves.

An artificial blood vessel with an endothelial-cell monolayer.

An artificial blood vessel with an endothelial-cell monolayer was used as an arterial substitute in rats. Endothelial cells were isolated from the aorta of a Wistar rat by the digestion method. The cell identification was established by the cobblestone appearance of a confluent cell monolayer, by an expression of factor VIII-related antigen, and by the presence of Weibel-Palade bodies. The luminal surface of the thin-walled polytetrafluoroethylene (PTFE) graft (4 mm in diameter and 10 mm in length) was coated with an endothelial-cell monolayer for 7 days in vitro. An interpositional graft was placed using the endothelial cell-coated PTFE prosthesis on the right common carotid artery in seven rats. A total of 10 rats received an interpositional graft with the noncoated PTFE prosthesis as a control. The patency rate at 1 month after implantation was significantly higher in the coated group than in the control group. The vascular prosthesis with an endothelial-cell monolayer is a promising technique to inhibit the development of thrombosis.