Oxidative Stress Inhibits Endotoxin Tolerance and May Affect Periodontitis.

Periodontal disease is caused by dysbiosis of the dental biofilm and the host inflammatory response. Various pathogenic factors, such as proteases and lipopolysaccharides (LPSs) produced by bacteria, are involved in disease progression. Endotoxin tolerance is a function of myeloid cells, which sustain inflammation and promote tissue regeneration upon prolonged stimulation by endotoxins such as LPS. The role of endotoxin tolerance is gaining attention in various chronic inflammatory diseases, but its role in periodontal disease remains elusive. Oxidative stress, one of the major risk factors for periodontal disease, promotes disease progression through various mechanisms, of which only some are known. The effect of oxidative stress on endotoxin tolerance has not yet been studied, and we postulated that endotoxin tolerance regulation may be an additional mechanism through which oxidative stress influences periodontal disease. This study aimed to reveal the effect of oxidative stress on endotoxin tolerance and that of endotoxin tolerance on periodontitis progression. The effect of oxidative stress on endotoxin tolerance was analyzed in vitro using peritoneal macrophages of mice and hydrogen peroxide (H2O2). The results showed that oxidative stress inhibits endotoxin tolerance induced by Porphyromonas gingivalis LPS in macrophages, at least partially, by downregulating LPS-elicited negative regulators of Toll-like receptor (TLR) signaling. A novel oxidative stress mouse model was established using SMP30KO mice incapable of ascorbate biosynthesis. Using this model, we revealed that oxidative stress impairs endotoxin tolerance potential in macrophages in vivo. Furthermore, gingival expression of endotoxin tolerance-related genes and TLR signaling negative regulators was decreased, and symptoms of ligature-induced periodontitis were aggravated in the oxidative stress mouse model. Our findings suggest that oxidative stress may contribute to periodontitis progression through endotoxin tolerance inhibition.

Blood-brain barrier disruption is more severe in neuromyelitis optica than in multiple sclerosis and correlates with clinical disability.

OBJECTIVES: This study evaluated blood-brain barrier (BBB) integrity, using blood and cerebrospinal fluid (CSF) markers, and assessed the practicality of these markers in the differential diagnosis of neuromyelitis optica (NMO) and multiple sclerosis (MS). METHODS: This was a retrospective observational study of consecutive patients presenting with acute phase NMO or MS (first attack or relapse). Haematological tests (including antiaquaporin-4 antibody levels) and CSF parameters (using primary component analyses) were undertaken; the correlation between BBB permeability and disease severity (by Expanded Disability Status Scale [EDSS] score) was examined. RESULTS: Levels of several markers of BBB permeability were higher in patients with NMO (n=21) than in those with MS (n=52). The CSF:serum albumin ratio (AR) was the one of the main differentiators of NMO and MS. Additionally, there was a significant correlation between AR and clinical severity for NMO but not for MS. CONCLUSIONS: Markers of BBB permeability were significantly higher in NMO patients than in MS patients. AR was the best marker for differentiating NMO and MS. Thus, measurement of BBB disruption markers (such as AR) might help to differentiate the diagnosis of NMO and MS in acute clinical settings.

Varicose veins associated with CADASIL result from a novel mutation in the Notch3 gene.

No genetically diagnosed cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) pedigrees with venous insufficiency have been described. In a CADASIL pedigree with varicose veins, the authors have identified a novel heterozygous mutation in the 3' splice acceptor site of intron 15 of the Notch3 gene. This, based on mRNA analysis, resulted in skipping of exon 16 including eight cysteine residues of EGF-like repeats.

Chronic bird fancier's lung: histopathological and clinical correlation. An application of the 2002 ATS/ERS consensus classification of the idiopathic interstitial pneumonias.

BACKGROUND: Chronic bird fancier's lung (BFL) has often been misdiagnosed as one of the idiopathic interstitial pneumonias (IIPs). METHODS: To define the clinical and pathological characteristics of chronic BFL, 26 patients with chronic BFL from whom a surgical lung biopsy specimen was taken between October 1992 and June 2001 were evaluated. The histopathological characteristics of the surgical lung biopsy specimens were examined and correlations between the histopathology and clinical characteristics were analysed. The quality of chronic inflammatory and fibrotic changes was expressed according to the 2002 ATS/ERS consensus classification of IIPs. RESULTS: Two patients were diagnosed as having bronchiolitis obliterans organising pneumonia (BOOP)-like lesions, five as having cellular non-specific interstitial pneumonia (NSIP)-like lesions, and eight as having fibrotic NSIP-like lesions. The other 11 patients were considered to have usual interstitial pneumonia (UIP)-like lesions because of the temporal heterogeneous appearances of the fibrotic changes. However, fibrosis in these patients had developed in centrilobular as well as perilobular areas, suggestive of hypersensitivity pneumonitis. Nineteen patients (73.1%) had multinucleated giant cells, often with cholesterol clefts, while only five patients (19.2%) had granulomas. Patients with BOOP-like or cellular NSIP-like lesions tended to have recurrent acute episodes, whereas patients with UIP-like lesions had an insidious onset. Patients with BOOP-like or cellular NSIP-like lesions had a more favourable outcome than those with fibrotic NSIP-like and UIP-like lesions. CONCLUSIONS: The qualities of chronic inflammatory and fibrotic lesions vary significantly among patients with chronic BFL but correlate with clinical features and prognosis.

Mutation in the CHAC gene in a family of autosomal dominant chorea-acanthocytosis.

Although mutations in the CHAC gene have been identified in autosomal recessive chorea-acanthocytosis (AR-ChAc), the molecular basis of autosomal dominant ChAc (AD-ChAc) remains to be determined. The authors investigated abnormalities in the CHAC gene in an AD-ChAc family with mRNA and sequencing analyses of mRNA and genomic DNA. A novel single heterozygous mutation in the last nucleotide of exon 57 of the CHAC gene, which could cause skipping of the exon, was detected in affected siblings.

Rostral lateral pontine infarction: neurological/topographical correlations.

The authors correlated neurologic features of rostral lateral pontine infarct (rLPI) with lesion location on MRI. rLPI is a motor-sensory stroke presenting as crural monoparesis or crural dominant hemiparesis and segmental superficial or deep sensory disturbances. The dorsolateral pontine base causes crural paresis without supranuclear facial palsy.

Differences in biliary lipid excretion after major hepatectomy in obstructive jaundiced rats with preoperative internal, external, or no biliary drainage.

Necessity of preoperative biliary drainage for patients with obstructive jaundice is still controversial. We recently reported that liver regeneration after major hepatectomy was better restored in a rat model of obstructive jaundice with preoperative internal biliary drainage than that without biliary drainage or with external biliary drainage. The aim of this study was to investigate the differences in biliary lipid excretion after hepatectomy in obstructive jaundiced rats with or without preoperative internal or external biliary drainage. After bile duct ligation for 7 days, rats were randomly divided into the three groups; obstructive jaundice-hepatectomy (OJ-Hx), internal biliary drainage-hepatectomy (ID-Hx), and external biliary drainage-hepatectomy (ED-Hx) groups. 70% hepatectomy and internal biliary drainage were carried out 7 days after biliary decompression in the latter two groups and without biliary decompression in the OJ-Hx group. On the day of and on days 1, 2, 3 and 7 after hepatectomy, the liver weight, DNA synthesis rate, biliary lipids excretion rates, and bile acid composition were determined. In the ID-Hx group, the DNA synthesis rate and relative liver weight were significantly higher than those of the OJ-Hx and ED-Hx groups. The excretion rates of biliary lipids were disturbed in the ED-Hx group compared with those in the ID-Hx group and the values in the OJ-Hx group were in-between the ID-Hx and ED-Hx group. The liver regeneration rate was significantly correlated with bile flow and excretion rates of biliary lipids. The maintenance of enterohepatic circulation of biliary lipids before hepatectomy may be important for the liver regeneration.

A case of familial amyloid polyneuropathy homozygous for the transthyretin Val30Met gene with motor-dominant sensorimotor polyneuropathy and unusual sural nerve pathological findings.

OBJECTIVE: To report a case of familial amyloid polyneuropathy homozygous for the amyloidogenic transthyretin (ATTR) Val30Met gene with motor-dominant sensorimotor polyneuropathy and unusual sural nerve pathological findings. METHODS: Mass spectrometry analysis and polymerase chain reaction-restricting fragment length polymorphism were performed. A right sural nerve biopsy specimen was obtained for histological investigation. SETTING: Academic medical center. RESULTS: A 56-year-old Japanese man living in a local town (Nakajima, Japan) in Ishikawa Prefecture, a nonendemic area of type I familial amyloidotic polyneuropathy, had vitreous amyloidosis, motor-dominant sensorimotor polyneuropathy, erectile dysfunction, and urinary incontinence. He had neither orthostatic hypotension nor indolent diarrhea. Restriction enzyme analysis with EcoT22 I of amplified DNA and mass spectrometry analysis revealed homozygosity for ATTR Val30Met. Of 8 family members, 5 were evaluated and found to be heterozygous for ATTR Val30Met; a family history found no relative with the similar neurologic disorders. The sural nerve biopsy specimen showed focal edema and an amyloid deposit in the subperineural tissue, associated with moderate loss of myelinated and unmyelinated fibers. CONCLUSIONS: In addition to the findings characteristic of homozygosity for ATTR Val30Met such as vitreous amyloidosis and relatively less autonomic involvements, this case had the unique findings of motor-dominant sensorimotor polyneuropathy and unusual sural nerve biopsy specimen results.

[A case of adult Wilms' tumor].

Wilms' tumor is very rarely found in adults and there are no established treatment guidelines for such tumors in adults. A 56-year-old woman was referred to our hospital for further examination of macroscopic hematuria. Computed tomography scan revealed a large right renal mass with enlarged lymph nodes. Angiography showed a hypovascular tumor. She underwent right nephrectomy and resection of lymph node metastasis with a diagnosis of malignant renal tumor. Histopathological examination revealed nephroblastoma with lymph node metastasis. The disease was classified as stage III according to the National Wilms' Tumor Study classification. The patient received adjuvant chemotherapy consisting of ifosfamide, cisplatin, and etoposide. This protocol was selected because of the published poor results with the standard Wilms' tumor chemotherapeutic agents when used in adults. She remained without tumor recurrence as of six months after surgery. Development of better therapeutic approaches to adult Wilms' tumor is awaited.

Amyotrophic lateral sclerosis associated with sarcoidosis.

We report a rare association of amyotrophic lateral sclerosis (ALS) with incidental pulmonary and muscle sarcoidosis. A 63-year-old woman presented with slowly progressive weakness and atrophy of the extremities starting from the left leg. The biopsy of a small mass in the left gastrocnemius revealed a typical sarcoid nodule. She was treated with corticosteroid for possible sarcoid neuromyopathy. In spite of the treatment, her clinical course was relentlessly progressive and she died of bulbar palsy. Autopsy revealed a loss of motor neurons in the anterior horn, vacuolar degeneration of the lateral funiculus, and noncaseating granulomas in paratracheal lymph nodes and lungs. No granulomatous lesion or cellular infiltration was found in the spinal cord.

Changes in serum hypoxanthine levels by exercise in obese subjects.

To study on effect of obesity on changes in serum hypoxanthine with exercise, exercise stress testing with treadmill was performed on 7 obese subjects (body mass index [BMI], 30.6 +/- 3.2 kg/m(2)) and 16 healthy volunteers (BMI, 21.5 +/- 2.10 kg/m(2)). Expiratory gas analysis during exercise showed that peak Vo(2) was significantly lower in the obese group than in the control group (28.1 +/- 4.0 v 37.1 +/- 4.7 mL/kg/min; P <.001). Furthermore, the obese group had lower anaerobic threshold (AT) values (P <.005), respiratory quotient at AT (P =.003), and exercise capacity reserve (P =.002) than the control group. Baseline serum hypoxanthine levels were significantly higher in the obese group than in the control group (3.46 +/- 3.70 v 1.23 +/- 1.16 micromol/L; P <.05). Exercise induced a pronounced increase in serum hypoxanthine level in the obese group compared with the control group (10.65 +/- 6.81 v 43.86 +/- 4.56 micromol/L; P <.01). Serum levels of uric acid before and after load were also higher in the obese group than in the control group (404 +/- 43 v 302 +/- 77 micromol/L; P <.005). A pronounced increase in hypoxanthine with exercise may result in organ damage caused by free radicals, and intermittent training from mild intensity may be less hazardous for exercise treatment of obesity.

[A case of clinically multifocal renal cell carcinoma].

A 61-year-old woman was diagnosed with a renal tumor of the left kidney by ultrasound sonography during a health check-up. Computerized tomography (CT) and colored Doppler ultrasound sonography demonstrated two hypervascular tumors as typical renal cell carcinomas. A radically nephrectomized specimen was step-sectioned. Four tumor nodules were detected macroscopically, and 47 small nodules were detected microscopically, showing the clear cell type and alveolar growth pattern. Then all nodules including the 47 small nodules were diagnosed renal cell carcinoma.

[Transformation of the fungus ball type pulmonary aspergillosis].

Though the concept of semi-invasive pulmonary aspergillosis was advocated in 1981 by Gefter et al., its histopathological appearance has not yet been reported in detail. Pathological studies on fungus ball type pulmonary aspergillosis (PA) were originally made mainly in regard to related bronchi. Chronic-progressive destructive changes cannot be completely explained from this viewpoint alone. Clinically, since bloody sputum and hemoptysis appeared frequently, further studies on the pulmonary vasculature were considered necessary. In the resected lungs of 3 cases of semi-invasive pulmonary aspergillosis, the pathological features of pulmonary vasculature were characterized by numerous fungal clots within pulmonary arteries and veins, marked destruction of pulmonary blood vessels and extensive intravascular fibrin deposition. Intravascular fibrin deposition causes stasis of blood flow, promotes intravascular proliferation of aspergilli and probably accelerates pulmonary destruction caused by blood stasis. Important pathological findings of fungus ball type pulmonary aspergillosis of the semi-invasive subtype with clinical aspects of chronic-progressive lung destruction caused by severe inflammation, were reported for both the vascular and the bronchial system.

[Two cases of thalamic infarction presenting with "thalamic astasia"].

We report two cases of so-called 'thalamic astasia', associated with thalamic infarction. A 76-year-old-man suddenly noted to fall down to the left side without severe hemiparesis. An MRI showed an infarction in the superolateral portion of the right thalamus. Over eight weeks, his astasia gradually disappeared. A 69-year-old-man suddenly noted inability to stand with loss of balance. He showed mild hemiparesis, hypesthesia and cerebellar signs on the right side. Although right hemiparesis was slight, he was unable to stand by himself. An MRI demonstrated an infarction in the ventrolateral to ventroposterior portion of the left thalamus. Three weeks later, his symptoms except for cerebellar ataxia remarkably disappeared. The overlapped MRI lesions of these two cases were localized in the ventrolateral thalamus, such as Vimi (nucleus ventrointermedii internus), Vci (nucleus ventrocaudalis internus), Cemc (nucleus centralis thalami magnocellularis). These lesions are so-called 'vestibular thalamic nuclei', in which fibers from vestibulocerebellum are terminated. Involvement of the thalamic connectivity explains that two patients noted inability to stand. Thus we concluded that these two patients had thalamic astasia, described by Masdeu and Gorelick.

Effect of preoperative portal vein embolization on liver volume and hepatic energy status of the nonembolized liver lobe in humans.

Clinically portal vein embolization (PVE) is presently preferred to extended hepatectomy. Nevertheless, its effect on hepatic adenosine triphosphate (ATP) and energy charge levels, which are essential for organ viability, has been little studied in humans. Fourteen patients with (n = 7) and without (n = 7) preoperative right PVE participated in this study. Changes in hepatic lobar volume and serum liver function tests were examined before and after percutaneous transhepatic right PVE. Liver volume (cm(3)) was calculated on computed tomograms before and 20+/-3 days after PVE. At the time of surgery (mean of 25 days after PVE), small liver specimens were obtained from portal vein (PV) nonembolized left lobes immediately after laparotomy without any ischemic procedures. Concentrations of adenine nucleotides were measured by high performance liquid chromatography, and hepatic energy charge levels were calculated. These values were compared with those in control patients who had not undergone preoperative PVE. Serum liver function tests including the indocyanine green retention rate did not differ significantly before and after PVE. The volume of the PV-nonembolized left lobe significantly increased after right PVE (from 473+/-32 to 624+/-66 cm(3)), with a significant increase in the percentage of the left lobe to total liver volume. The concentrations of AMP, ADP, and ATP, and hepatic energy charge levels in the PV-nonembolized left lobe were similar to those of the control liver. These results suggest that preoperative right PVE increases the volume of the nonembolized left lobe, keeping the hepatic engery charge and ATP levels similar to the control liver, thereby increasing the total amount of ATP and hepatic energy reserve of the PV-nonembolized lobe in proportion to its volume increase at the time of surgery.

[Arteriovenous fistula associated with Staphylococcus aureus sepsis in a patient with Rendu-Osler-Weber syndrome].

A 58-year-old man with a history of cerebral infarction and bleeding due to duodenal ulcer was admitted with fever and arthralgia. Methicillin-sensitive Staphylococcus aureus (MSSA) was isolated from his peripheral blood. Bacteremia with MSSA was diagnosed, and antibiotic therapy was started. However, chest X-ray films and computed tomographic scans disclosed mass shadows in both lungs accompanied by dilated vascular markings. Pulmonary arteriography and magnetic resonance angiography revealed the existence of arteriovenous fistulas in both lungs. Ga scintigraphy disclosed a hot spot in the left lower lobe, consistent with the location of one fistula. This indicated that the fistula might be the focus of MSSA sepsis. Because the patient also had telangiectasia in his gastric mucosa, oral cavity, and nasal cavity, he was given a diagnosis of Rendu-Osler-Weber syndrome.

[Analysis of deep mycoses in autopsy cases].

The deep mycosis in compromised patients is increasing. We examined 40 cases (3%) of the deep mycoses out of 1170 autopsy cases experienced in Saint Luke's International Hospital from 1987 to 1996. The deep mycosis was highly associated with hematologic malignancies(23%) but not with solid tumors(2%). The common mycoses were aspergillosis and candidiasis, which were observed in 27(68%) and 14 (35%) cases, respectively. Most of the patients received broad-spectrum antibiotics, anticancer agents and corticosteroids, and showed granulocytopenia. The symptoms of deep mycoses were non-specific, for example, pyrexia and/or respiratory symptoms. The clinical diagnosis was established in 8 cases and the appropriate antifungal agents were used in 12 cases(30%). Thus, empiric amphotericin-B therapy should be started early in-patients with granulocytopenia, respiratory symptoms, and pyrexia.

Non-N-methyl-D-aspartate glutamate receptors mediate oxygen--glucose deprivation-induced oligodendroglial injury.

Cells of oligodendroglial lineage are susceptible to oxygen and glucose deprivation. When oligodendrocyte-like cells differentiated from CG-4-immortalized rat O-2A progenitor cells were exposed to hypoxia alone or glucose deprivation alone for 48 h, release of lactate dehydrogenase (LDH) into the culture medium did not increase. However, when cells were deprived of both oxygen and glucose for 6 or 12 h preceding reoxygenation for 2 h, LDH release increased. Adding glucose to the medium protected against cell death and increased lactate production in a concentration-dependent manner. Cell damage induced by deprivation of oxygen and glucose was prevented by calcium-free medium or by non-N-methyl-D-aspartate glutamate receptor (GluR) antagonists, such as 6-cyano-7-nitroquinoxaline-2,3-dione or LY293558, but not by the voltage-dependent calcium channel blocker, nimodipine, or by the N-methyl-D-aspartate GluR antagonist, MK-801. The glutamate concentration in the medium from cells exposed to oxygen-glucose deprivation for 12 h was 49.70+/-3.04 microM/l, which is sufficient to activate GluRs during deprivation of oxygen and glucose. Apoptotic cells detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL) or Hoechst 33258 staining did not increase in cells exposed to oxygen-glucose deprivation for 12 h and subsequent reoxygenation for 2 h. No DNA laddering was detected by agarose gel electrophoresis from cells exposed to deprivation of oxygen and glucose. Neither acetyl-YVAD-CHO, an inhibitor of caspase-1-like proteases, nor acetyl-DEVD-CHO, an inhibitor of caspase-3-like proteases, prevented oxygen-glucose deprivation-induced injury. Thus, oxygen and glucose deprivation causes calcium-influx-induced necrotic cell damage in cells of oligodendroglial lineage via non-N-methyl-D-aspartate GluR channels.

Cyclic GMP/cyclic GMP-dependent protein kinase system prevents excitotoxicity in an immortalized oligodendroglial cell line.

Previously, we have demonstrated that excitotoxicity of oligodendrocyte-like cells (OLC), differentiated from immortalized rat O-2A progenitor cells (CG-4 cells), is prevented by cyclic AMP-elevating agents. We now report that some agents that elevate cyclic GMP prevent OLC excitotoxicity. Kainate-induced injury was prevented by cyclic GMP analogues (8-bromo-cyclic GMP and dibutyryl cyclic GMP), a guanylate cyclase activator [atrial natriuretic peptide (ANP)], and phosphodiesterase inhibitors [3-isobutyl-1-methylxanthine (IBMX), ibudilast, propentofylline, and rolipram]. When both forskolin and 8-bromo-cyclic GMP were added, kainate-induced injury was additively prevented. There was a strong positive correlation between suppression of kainate-induced Ca2+ influx and prevention of injury by these chemicals. The measurement of intracellular cyclic AMP and cyclic GMP by radioimmunoassay demonstrated the following: an increase of cyclic GMP with treatment with 8-bromo-cyclic GMP, dibutyryl cyclic GMP, and ANP; an increase of cyclic AMP with treatment with ibudilast and rolipram; and an increase of both cyclic AMP and cyclic GMP with treatment with IBMX and propentofylline. Kainate-induced Ca2+ influx was decreased by 8-(4-chlorophenylthiol)-guanosine-3',5'-monophosphate, an activator of cyclic GMP-dependent protein kinase (PKG), or okadaic acid, an inhibitor of protein phosphatases 1 and 2A. RT-PCR and westem blotting of OLC demonstrated transcription of PKG II gene and translation of PKG Ibeta mRNA, but no translation of PKG Ialpha mRNA. Therefore, we concluded that the cyclic GMP/PKG system prevents OLC excitotoxicity.

Incidence rate of satellite tumors in renal cell carcinoma.

BACKGROUND: Nephron-sparing surgery for incidentally detected small renal tumors has been performed. The main objection to such surgery concerns the incidence rate of satellite renal tumors. In this study, the authors analyzed the rate of incidence and proliferative potential of satellite renal tumors. METHODS: The tumors of 124 renal cell carcinoma patients with a clinically identified unilateral and single tumor measuring