Cutaneous vasculitis and glomerulonephritis associated with C4 deficiency.

Complete deficiency of the fourth component of complement (C4) is an extremely rare condition. However, it has been reported that partial C4 deficiency can occur in normal subjects, and is associated with several immune diseases. We report a 44-year-old woman who developed slight oedema and punctate purpura on her lower legs after a common cold. She was noted to have persistent microscopic haematuria and proteinuria, and her C4 level was undetectable. On histological examination of a skin biopsy specimen, leucocytoclastic vasculitis was seen, with granular deposition of IgG, IgM, C3 and C1q on the vessel walls in the upper dermis. A renal biopsy showed mild mesangial proliferative glomerulonephritis with slight damage to the capillary loops, and granular deposits of IgM and C4 mainly in the mesangium. The patient was systemically well and needed no medication. The C4 level remained low during the observation period, but neither genotyping nor allotyping analysis identified a C4 deficiency.

[Bronchogenic cyst with a high computed tomography number].

A 55-year-old man was diagnosed as having colon cancer. During the preoperative survey for metastasis, chest computed tomography (CT) revealed a well-defined tumor (33 mm) with a high CT value in the left hilum. We performed thoracoscopic resection for diagnosis and treatment. The contents of the lesion were yellowish, viscid, and creamy. Pathological examination revealed that the tumor was a bronchogenic cyst. This case is reported with a review of the literature.

Influence of concentration of fragrances on salivary alpha-amylase.

The objective is to reveal the influence of the concentration of fragrances on salivary biomarkers, which reflect the human stress system, in 15 female young healthy adults. Lavandula officinalis and Citrus aurantium were used as the test samples. Salivary biomarkers such as alpha-amylase activity (AMY), cortisol (CORT) and dehydroepiandrosterone (DHEA) were measured during baseline, inhalation and post-inhalation periods. Our results indicated that (i) a significant difference was not observed for the control and the 3 wt% test samples, however, the AMY was decreased by inhalation of the 1 wt% test samples (P < 0.05); (ii) AMY levels changed more significantly than did the hormone levels; (iii) a tendency of negative correlation was not observed between DHEA and CORT. It was considered that the time-course change of AMY might be a useful index of the inhalation of fragrances, which reflects the acute psychosomatic reactivity of humans.

[Metastatic lung tumor from uterine leiomyosarcoma; report of a case].

Endometrial leimyosarcoma is rare neoplasm of all the uterine malignancies. We herein present a case of metastatic pulmonary tumor derived from endometrial leiomyosarcoma She had undergone hysterectomy for leiomyosarcoma. About 10 years after the hysterectomy, metastatic hepatic tumors and peritoneal dissemination were pointed out. Following chemotherapy of cisplatin, ifomide and pirarubicine, right hepatectomy was performed. About 12 years after the hysterectomy, a metastatic lesion appeared in the right lower lung field and right S6 segmentectomy was performed. About 15 months after the pulmonary resection, another metastatic lesion appeared in the remaining right lower lobe. The mass grew so rapidly with involvement to adjacent organs that pericardial resection was necessary with completion right lower lobectomy. Postoperative chemotherapy was performed with the same regimen as previously performed. About 10 months after the second pulmonary resection, she died due to dissemination in the right haemithorax and malignant pericardial effusion. Careful follow up after the surgery for the uterine leiomyosarcoma is recommended because metastatic leiomyosarcoma possibly appears even after a long interval, and its progress can be so intensive that adjuvant chemotherapy is necessary if it can not be treated surgically alone.

Life threatening chronic expanding hematoma of the thorax.

A 73-year-old man presented with severe respiratory distress and systemic edema. Diagnosis of chronic expanding hematoma (CEH) was made through examination of past and present radiographic studies. A giant mass lesion with surrounding calcification occupying the left hemi-thorax on the chest was demonstrated via computed tomography on admission, and a chest X-ray from 8 years previously revealed evidence of tubercular pleurisy. The patient's condition deteriorated rapidly after admission, necessitating urgent operative resection of the mass. The mass consisted of fresh and organized blood and demonstrated a calcified fibrous capsule, findings that are consistent with the diagnosis of CEH. Although the patient's condition improved following operative removal of the mass, he was ultimately diagnosed with postoperative empyema secondary to bronchopleural fistula, necessitating additional surgery.

Comparison of SSR and QSART in early diabetic neuropathy--the value of length-dependent pattern in QSART.

We evaluated postganglionic sympathetic function using the sympathetic skin response (SSR) and quantitative sudomotor axon reflex test (QSART) on the feet of 31 patients with early diabetic neuropathy and 20 age-matched normal controls. The amplitude of SSR and the sweat volume of QSART were significantly decreased in the diabetic patients. We evaluated the sensitivity of the tests in detecting autonomic failure. Out of 31 patients, 14 (45%) had abnormal SSR (14 absent; 17 present), while 16 of 31 patients (52%) had abnormal QSART (1 absent; 5 absolutely reduced and 10 showed a length-dependent pattern of reduction). More important than differences in sensitivity is the specificity of QSART, which specifically evaluates the postganglionic axon (instead of polysynaptic pathways in SSR) and provides quantitative data on the severity and pattern of autonomic deficit. In normal controls under 65 years of age, there was a significant correlation between the amplitude of SSR and the sweat volume of QSART. However, there was no significant relationship between these in diabetic patients. These results suggest that QSART can evaluate early diabetic neuropathy more precisely than SSR.

[A case of mononeuritis multiplex associated with type I (monoclonal) IgG kappa cryogloblinemia].

We here reported a fifty-three year-old woman with mononeuritis multiplex, associated with type I cryoglobulinema induced IgG kappa MGUS (monoclonal gammopathy of undetermined significance). She first experienced numbness in the extremities, that showed stepwise deterioration for several weeks. The nerve conduction study revealed axonal neuropathy, and laboratory examination detected type I cryoglobulinema. The sural nerve biopsy demonstrated with severe axonal degeneration with focal accentuation, lacking any inflammatory response. Single cryofiltration definitely stopped the progression of the symptoms. The prompt clinical response to the removal of cryoglobulin, without the administration of anti-inflammatory drugs, confirmed the direct etiological correlation between type-1 cryoglobulin and the neuropathy, and may favor ischemic, rather than inflammatory nature of this rare type of neuropathy.

Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders.

OBJECTIVE: To identify antinuclear antibodies (ANA) specific for chronic fatigue syndrome (CFS), and in related conditions such as fibromyalgia (FM) or psychiatric disorders. METHODS: One hundred and fourteen CFS patients and 125 primary and secondary FM patients were selected based on criteria advocated by the Centers for Disease Control and Prevention and by the American College of Rheumatology, respectively. As controls, healthy subjects and patients with either various psychiatric disorders or diffuse connective tissue diseases were included. Autoantibodies were examined by immunoblot utilizing HeLa cell extracts as the antigen. RESULTS: Autoantibodies to a 68/48 kDa protein were present in 13.2 and 15.6% of patients with CFS and primary FM, respectively. In addition, autoantibodies to a 45 kDa protein were found in 37.1 and 21.6% of the patients with secondary FM and psychiatric disorders, respectively. Meanwhile, these two autoantibodies were not found at all in connective tissue disease patients without FM, nor in healthy subjects (P<0.05). As a group, the anti-68/48 kDa-positive CFS patients presented more frequently with hypersomnia (P<0.005), short-term amnesia (P<0.07) or difficulty in concentration (P<0.05) than those CFS patients without the antibodies. CONCLUSIONS: The presence of the anti-68/48 kDa protein antibodies in a portion of both CFS and primary FM patients suggests the existence of a common immunological background. These antibodies may find utility as possible markers for a clinicoserological subset of CFS/FM patients with hypersomnia and cognitive complaints.

Amiodarone stimulates interleukin-6 production in cultured human thyrocytes, exerting cytotoxic effects on thyroid follicles in suspension culture.

To investigate whether amiodarone increases interleukin-6 (IL-6) production in thyrocytes, human follicles obtained from subtotally thyroidectomized patients with Graves' disease were cultured in serum-free medium supplemented with various concentrations of bovine thyrotropin (bTSH) and amiodarone. The follicles gradually formed monolayer cells and secreted triiodothyronine (T3), thyroglobulin (Tg), and IL-6 for at least 14 days. TSH dose-dependently increased T3 and Tg but not IL-6 levels in the conditioned medium. Amiodarone exerted no significant effect on T3, Tg, or IL-6 concentrations at 0.1-1 microM. In contrast, at 10-20 microM, it decreased T3 and Tg, but increased IL-6 levels, and these changes were accompanied by increased expression of IL-6 mRNA. Amiodarone-induced IL-6 production was inhibited by prednisolone at 10(-7) M. Electron microscopic examination revealed that the thyroid follicles in the suspension culture remained intact at 1 microM, but that cytotoxic effects (decreased microvilli and increased onion-like inclusion bodies) occurred at higher concentrations (10-25 microM). These in vitro findings indicate that amiodarone does not impair thyroid function at clinically attainable serum levels (1 microM), but exerts cytotoxic effect by inducing the production of a proinflammatory cytokine (IL-6) at higher concentrations. Because amiodarone-induced IL-6 production was inhibited by prednisolone, it is reasonable to administer glucocorticoids to patients with amiodarone-induced destructive thyrotoxicosis (type II).

Evidence of macrophage foam cell formation by very low-density lipoprotein receptor: interferon-gamma inhibition of very low-density lipoprotein receptor expression and foam cell formation in macrophages.

BACKGROUND: Expression of the VLDL receptor, primarily in macrophages, has been confirmed in human and rabbit atherosclerotic lesions. The high binding affinity of the VLDL receptor for remnant particles implicates the VLDL receptor pathway in the foam cell formation mechanism in macrophages. This study investigates the effect of interferon (IFN)-gamma on VLDL receptor expression in phorbol-12-myristate-13-acetate (PMA)-treated THP-1, HL-60 macrophages, and human monocyte-derived macrophages. METHODS AND RESULTS: THP-1 cells were induced to differentiate into macrophages by PMA treatment. IFN-gamma was added to the medium, and expression of the VLDL receptor was determined. (125)I-beta-VLDL degradation study and oil red O staining were examined. In THP-1 macrophages, VLDL receptor protein expression decreased at 2 days after PMA treatment but increased at 3 days and increased up to 5 days. Scavenger receptor proteins, which were not originally present, appeared at 3 days after PMA treatment. IFN-gamma inhibited VLDL receptor expression in a dose-and time-dependent manner in macrophages. However, no inhibitory effect was observed in monocytes. Moreover, IFN-gamma receptor mRNA increased during differentiation to macrophages. (125)I-beta-VLDL degradation study and oil red O staining showed that IFN-gamma significantly inhibited foam cell formation after the uptake of beta-VLDL. LDL receptor-related protein (LRP) and LDL receptor mRNAs were not expressed in macrophages. In PMA-treated HL-60 macrophages and human monocyte-derived macrophages, IFN-gamma also inhibited VLDL receptor expression and foam cell formation by beta-VLDL. CONCLUSIONS: VLDL receptor expression is upregulated during monocyte-macrophage differentiation. IFN-gamma inhibits VLDL receptor expression and foam cell formation only in macrophages. Remnant particles induce macrophage foam cell formation through the VLDL receptor pathway.

Thoracolithiasis.

Thoracolithiasis without any history of chest traumas or interventions is pathologically rare, with only 9 cases including our 2, reported thus far in the literature. Case 1: A 76-year-old man admitted to our hospital had an abnormal shadow in chest radiography that gradually enlarged. Serum carcinoembrionic antigen was slightly elevated during follow-up. A milky white tumor 1.5 cm in diameter with many projections was found in the thoracic cavity and removed by thoracoscopy. Histopathological examination showed the tumor to consist of fibrous tissue with fatty necrosis at the core. Case 2: A 54-year-old woman admitted to our hospital had an abnormal shadow in chest screening radiography in 1998. Transbronchial biopsy showed this shadow to be lung adenocarcinoma. A small trigonal pyramid-shaped milky white nodule 5 mm in diameter was found in the thorax during lobectomy for lung cancer. Histopathological examination showed this nodule also to consist of fibrous tissue with fatty necrosis.

Human thioredoxin attenuates hypoxia-reoxygenation injury of murine endothelial cells in a thiol-free condition.

The adult T cell leukemia-derived factor (ADF), or human thioredoxin (hTRX), has a radical scavenging effect similar to that of N-acetyl cysteine (NAC). We have recently shown that ADF/hTRX protects the lung and the heart from ischemia-reperfusion induced injury. To elucidate mechanisms of the protective effect, a hypoxia-reoxygenation (H-R) injury model was developed using a murine endothelial cell line, cultured in a thiol-free medium. In this condition, cells became much more vulnerable to H-R injury. The viability of cells decreased significantly after 1 h of hypoxic incubation followed by 1 h of reoxygenation. The injury was reduced by ADF/hTRX (100 microM) or NAC (10 mM). These two agents also demonstrated an additive protective effect. When cells were cultured in thiol-free medium for 2 h in a normoxic condition, intracellular hydrogen peroxide production was increased, which was associated with a decrease in glutathione level. NAC (10 mM) attenuated these changes whereas ADF/hTRX (100 microM) did not. These results suggest that although both ADF/hTRX and NAC protected cells from H-R injury, the underlying mechanisms are different. Because the cytoprotective effect of ADF/hTRX occurs in the thiol-free condition, it must be mediated via a novel mechanism other than enhancing thiol uptake. The additive cytoprotective effect between ADF/hTRX and NAC suggests that we should combine these two agents clinically.

Mitochondrial injuries in rat lungs preserved for 17 h: An ultrastructural study.

Mitochondria of the small vasculature endothelial cells were examined in preserved rat lungs before and after reperfusion, and the ultrastructural changes were correlated with pulmonary function after reperfusion. Rat lungs were flushed with perfusate and prostaglandin E1 and divided into five groups (n = 5 in each group): group A, normal control group; group B, University of Wisconsin solution; group C, Euro-Collins solution; group D, ET-Kyoto solution, and group E, new ET-Kyoto solution. After preservation at 4 degrees C for 17 h, the left lungs were reperfused at 37 degrees C for 60 min. Tissue was sampled and mitochondria of the small vasculature endothelial cells were ultrastructurally analyzed by transmission electron microscopy before and after reperfusion. The ultrastructure of the mitochondria was well maintained in groups A, B and E before and after reperfusion. In group C, the number of severely degenerated mitochondria in the sectional area of 100 microm2 before reperfusion was 18.0 +/- 3.9, which was significantly larger than in the other groups (p < 0.01), and the total number of mitochondria significantly decreased with reperfusion (from 24.8 +/- 3.5 to 8.2 +/- 2.4, p < 0.05). In group C, the shunt fraction, mean pulmonary arterial pressure and the wet-dry ratio of the lung tissue after reperfusion C were significantly higher than in the other groups (p < 0.05; 76.3 +/- 1.5%, 54.8 +/- 4.2 mm Hg, and 20.6 +/- 2.5, respectively). A positive correlation was found between the percentage of the mitochondrial degeneration before reperfusion and the physiological parameters after reperfusion. Mitochondrial damage associated with cold ischemia is probably involved in lung injury caused by cold preservation and reperfusion.

Hyperhomocysteinemia is a risk factor for coronary arteriosclerosis in Japanese patients with type 2 diabetes.

OBJECTIVE: An increased plasma homocysteine level is an important risk factor for vascular disease, including coronary atherosclerosis, in the general population. However, the role of hyperhomocysteinemia in the development of coronary artery disease (CAD) in patients with type 2 diabetes is unknown. Therefore, we have endeavored to determine the relationship between plasma homocysteine levels and the presence of coronary arteriosclerosis in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The study group consisted of 145 Japanese patients (95 men and 50 women) who underwent routine coronary angiography to assess chest pain or suspected CAD. Plasma total homocysteine level, lipid level, and parameters of fibrinolytic activity were measured. All patients were identified as diabetic or nondiabetic by the new American Diabetes Association (ADA) criteria. The diagnoses of all patients studied were confirmed by coronary angiography. The severity of coronary artery stenosis was quantified using CAD scoring on the basis of prior reports, and subjects were graded as nonstenotic, stenotic single-vessel, stenotic two-vessel, or stenotic three-vessel based on the number of stenotic coronary arteries. Patients were classified into two groups: those with stenotic vessels and those without stenotic vessels. RESULTS: The plasma homocysteine level was significantly higher in patients with than in patients without stenotic vessels (13.8 +/- 3.9 vs. 11.7 +/- 3.9 mumol/l, respectively; P = 0.0009). The number of stenotic coronary arteries, which was used to grade each case as nonstenotic, stenotic single-vessel, stenotic two-vessel, or stenotic three-vessel, was related only to the total homocysteine level in the diabetic (diabetes mellitus [DM]) group, but it was associated with lipoprotein(a) in the nondiabetic (non-diabetes mellitus [non-DM]) group. Spearman's rank correlation test demonstrated that the plasma homocysteine level was strongly correlated with CAD score, both in the entire study group and in the DM group (P = 0.003 for the entire group and P = 0.011 for the DM group). Hyperhomocysteinemia, which was defined as total homocysteine level > 14.0 mumol/l, was seen in 57 (39.3%) of the patients. The CAD score was highest in diabetic patients with hyperhomocysteinemia (P < 0.05). CONCLUSIONS: There seems to be a clear relationship between hyperhomocysteinemia and an increased risk of coronary arteriosclerosis in Japanese patients with type 2 diabetes.

Expression of thrombomodulin in atherosclerotic lesions and mitogenic activity of recombinant thrombomodulin in vascular smooth muscle cells.

Thrombomodulin (TM), a thrombin receptor protein found on the endothelial cell surface, contains 6 tandem epidermal growth factor (EGF)-like structures. Recombinant human TM peptide containing these 6 EGF-like domains (rTME1-6) exhibits mitogenic activity in Swiss 3T3 cells. We examined the localization of TM in atherosclerotic lesions and the effects of rTME1-6 on the growth of cultured rat vascular smooth muscle cells (SMCs). Immunohistochemical analysis demonstrated that TM antigen was localized on monocytes, macrophages, and vascular SMCs. In cultured vascular SMCs, rTME1-6 accelerated [3H]thymidine uptake into DNA in a dose-dependent manner up to 3.4 times the control level. This mitogenic activity was abolished by addition of polyclonal anti-human TM antibody. The rTME1-6-induced mitogenesis was enhanced by EGF. However, a neutralizing monoclonal antibody against the EGF receptor (monoclonal antibody 225) did not inhibit the mitogenic activity of rTME1-6. Calphostin C, a specific protein kinase C inhibitor, and lavendustin-A, an inhibitor of EGF receptor-specific protein tyrosine kinase, inhibited the mitogenic activities of both rTME1-6 and EGF. Finally, rTME1-6 treatment increased the level of phosphorylated mitogen-activated protein kinase in SMCs. Together, these results suggest that TM expression in atherosclerotic lesions may be associated with promotion of atherosclerosis through its mitogenic activity in vascular SMCs.

L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol stimulates ganglioside biosynthesis, neurite outgrowth and synapse formation in cultured cortical neurons, and ameliorates memory deficits in ischemic rats.

To address the role of brain gangliosides in synaptic plasticity, the synthetic ceramide analog, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) was used to manipulate the biosynthesis of gangliosides in cultured cortical neurons. Spontaneous synchronized oscillatory activity of intracellular Ca2+ between the neurons, which represents synapse formation, was suppressed by the depletion of endogenous gangliosides by D-threo-PDMP, an inhibitor of glucosylceramide synthase. The decreased functional synapse formation was normalized by supplementation of GQ1b but not by the other gangliosides, suggesting that de novo synthesis of ganglioside GQ1b is essential for the synaptic activity (Mizutani A. et al., Biochem. Biophys. Res. Commun. 222, 494-498, 1996). On the other hand, the enantiomer of the inhibitor, L-threo-PDMP, could elevate cellular levels of glycosphingolipids including gangliosides. This paper presents our recent findings on the neurotrophic actions of L-threo-PDMP in vitro and in vivo. We found that L-PDMP could up-regulate neurite outgrowth, functional synapse formation and ganglioside biosynthesis through activating GM3, GD3 and GQ1b synthases. Simultaneously, the activity of p42 mitogen-activated protein kinase was also facilitated by L-PDMP. To evaluate the efficacy of this drug on long term memory, rats were trained for 2 weeks using an 8-arm radial maze task, and then forebrain ischemia was induced by 4-vessel occlusion (for 10 min x 2 with a 60 min interval). Repeated treatment of L-threo-PDMP (40 mg/kg, i.p. for 6 days, twice a day) starting 24 h after the ischemia, improved the deficit of the well-learned spatial memory, demonstrating the potential therapeutic use of the ceramide analog for treatment of neurodegenerative disorders.

Relationship between fluctuations in the cerebral hemoglobin oxygenation state and neuronal activity under resting conditions in man.

Simultaneous measurements by near-infrared spectroscopy and electroencephalography were performed during 15-min resting periods in nine healthy adult brains. The peak frequencies of the frontal and occipital rhythms varied with the time course like the hemoglobin oxygenation state. Changes in the amount of oxygenated hemoglobin in the frontal region by more than 50% of the maximum resting variation range were accompanied by changes in peak frequency at the electrode position between two optodes. The results suggest that spontaneous neuronal activity is responsible for fluctuations in the hemoglobin oxygenation state in the resting state.

Patients' understanding and opinion about informed consent for coronary angiography in a rural Japanese hospital.

Based on an anonymous questionnaire obtained from 102 Japanese in-patients at a rural Japanese hospital who underwent coronary angiography, the patients understanding of information about the procedure, their perception of consent and their attitude toward it were investigated. The patients were able to recall 63.8% of the contents of the information. There was a statistically significant correlation between the patients' educational status and the recall test score of the information. Older (65 years old and above) patients had a tendency to entrust decision making to their physicians. Only 19.6% of the patients made the decision to undergo a coronary angiography by themselves. After being informed of the risks 40.2% of the patients felt more anxious. In conclusion, our patients could not recall the contents of the information sufficiently. There still existed a tendency to entrust important decisions to the physician especially in older patients. The patients had a tendency not to face difficult problems solely by themselves but with the support of family members.