Clinical assessment of microscopic polyangiitis in elderly patients]

OBJECTIVE: To evaluate the influence of the age at disease onset on the clinical symptoms, laboratory findings, treatment, and complications of microscopic polyangiitis (MPA). PATIENTS: From 1999 to 2001, we encountered 4 MPA patients with disease onset at age 65 or older (average 77.3, all were female: the elderly group). For comparison, 4 MPA patients with disease onset a 64 years or younger (average 44.7, two were male: the non-elderly group) were used. RESULTS: There was no statistically significant difference in clinical features between the two groups. All patients in the elderly group were referred to our hospital, because of fever of unknown origin or suspicion of connective tissue disease. The elderly group had a longer duration from the first admission to the start of treatment. Renal biopsies were done in all of the non-elderly group and one of the elderly group. The diagnosis of the other 3 patients of the elderly group was based on muscle or nerve biopsy, showing necrotizing vasculitis. At the time of diagnosis, antibodies to myeloperoidase (MPO-ANCA) were positive in 7 of 8 patients (87.5%). 2 patients of the non-elderly group were died of heart failure and hepatic failure by cyclophosphamide (CYC). The other 6 patients achieved substantial improvement. CONCLUSIONS: Muscle or nerve biopsy helped clinical management of elderly patients when renal biopsies could not be done. IVCY was relatively safe and effective treatment for MPA in elderly as well as non-elderly patients.     

Inhibition of inward rectifier K+ currents by angiotensin II in rat atrial myocytes: lack of effects in cells from spontaneously hypertensive rats.

We examined the effects of angiotensin II (Ang II) on inward rectifier K+ currents (IK1) in rat atrial myocytes. [125I]Ang II-binding assays revealed the presence of both Ang II type 1 (AT1) and type 2 (AT2) receptors in atrial membrane preparations. Ang II inhibited IK1 in isolated atrial myocytes with an IC50 of 46 nmol/l. This inhibition was abolished by the AT, antagonist RNH6270 but not at all by the AT2 antagonist PD123319. Treatment of cells with pertussis toxin or a synthetic decapeptide corresponding to the carboxyl-terminus of Gialpha-3 abolished the inhibition by Ang II, indicating the role of a Gi-dependent signaling pathway. Accordingly, Ang II failed to inhibit IK1 in the presence of forskolin, dibutyryl-cAMP or protein kinase A catalytic subunits. In spite of the increased binding capacities for [125I]Ang II, Ang II failed to affect IKI in cells from spontaneously hypertensive rats (SHR). AT, immunoprecipitation from atrial extracts revealed decreased amounts of Gialpha-2 and Gialpha-3 proteins associated with this receptor in SHR as compared with controls. The reduced coupling of AT, with Gialpha. proteins may underlie the unresponsiveness of atrial IK1 to Ang II in SHR cells.     

The trajectory of the sympathetic nerve fibers to the rat cochlea as revealed by anterograde and retrograde WGA-HRP tracing

Wheat germ agglutinin-horseradish peroxidase conjugate was injected in the unilateral superior cervical ganglion (SCG), and the projection pathways of postganglionic sympathetic nerve fibers innervating the cochlea were traced in the rat. The labeled axons advanced along the internal carotid artery (ICA), and a few advanced caudally in the major petrosal nerve (MPN) and entered the facial nerve, while the majority ran rostral to the pterygopalatine ganglion at the point where they crossed the MPN in the carotid canal. The rest of the labeled fibers remained on the surface of the ICA and advanced to the cranial cavity. Most of the labeled fibers along the facial nerve joined the cochlear nerve and finally reached the osseous spiral lamina through the spiral ganglion. Some of the labeled fibers ran along the anterior inferior cerebellar artery from the basilar artery which was previously thought to have been the only pathway. We could not find any labeled fiber on the modiolar artery from anterior inferior cerebellar artery in the cochlea. These observations are consistent with our hypothesis that the sympathetic fibers innervating the neural tissues or related structures follow nerve fibers and meninges as matrices of projection pathways rather than arteries.     

Correlation between epidermal growth factor receptor concentration and the growth of human gastric cancer xenografts in nude mice.

Seven human gastric cancer xenografts with different concentrations of EGF receptor were established in nude mice. The expression of EGF receptor in the tumors was demonstrated by Western blotting with anti-EGF receptor antibody, binding assay with 125I-EGF and immunohistochemistry with anti-EGF receptor antibody. Western blotting revealed EGF receptor doublet bands at molecular masses of 150 KDa and 170 KDa in all of the samples. The concentration of 125I-EGF binding activity in the tumors ranged from 36.0 to 11,000 fmol/mg protein, with a mean of 345 fmol/mg protein. EGF receptor was also demonstrated immunohistochemically on the apical border of the glands and the cell membrane of the tumor cells. There seemed to be a close correlation between the concentration of 125I-EGF binding activity and the doubling time of these tumors in nude mice (gamma = -0.68). However, no definite correlation was observed between EGF ligand binding and histological features of intestinal type or diffuse type. The expression of EGF receptor appears to facilitate the growth of human gastric cancer xenografts in nude mice.     

Relationship between the thromboxane A2 receptor gene and susceptibility to cerebral infarction.

The risk of cerebral infarction (CI) in an individual is dependent on the interplay between genetic risk factors and environmental influences. Binding of thromboxane A2 (TXA2) to its receptor (TP) modulates thrombosis/hemostasis and plays a significant role in the pathogenesis of CI. The aim of the present study was to investigate the relationship between human TP gene single nucleotide polymorphisms (SNPs) and haplotypes and CI in a Japanese population. A genetic association study was performed in 194 CI patients and 365 non-CI subjects by specifically characterizing 6 SNPs in the human TP gene (rs2271875, rs768963, rs2238634, rs11085026, rs4523 and rs4806942). Analysis demonstrated that there were significant differences in the overall distribution of genotypes and dominant or recessive models of rs2271875 and rs768963 between the CI and the non-CI groups. Multiple logistic regression analysis revealed that the C allele of rs768963 was significantly associated with CI (p = 0.029), even after adjusting for confounding factors (odds ratio: 2.41). Further, the C-T-C haplotype of rs768963-rs2238634-rs4806942 was significantly more frequent in the CI group (23.0%) than in the non-CI group (17.7%). These results suggest that specific SNPs and haplotypes may have utility as genetic markers for the risk of CI and that TP or a neighboring gene is associated with the increased susceptibility to CI.     

Enhancement of the intrinsic defecation reflex by mosapride, a 5-HT4 agonist, in chronically lumbosacral denervated guinea pigs.

The defecation reflex is composed of rectal distension-evoked rectal (R-R) reflex contractions and synchronous internal anal sphincter (R-IAS) reflex relaxations in guinea pigs. These R-R and R-IAS reflexes are controlled via extrinsic sacral excitatory nerve pathway (pelvic nerves), lumbar inhibitory nerve pathways (colonic nerves) and by intrinsic cholinergic excitatory and nitrergic inhibitory nerve pathways. The effect of mosapride (a prokinetic benzamide) on the intrinsic reflexes, mediated via enteric 5-HT(4) receptors, was evaluated by measuring the mechanical activity of the rectum and IAS in anesthetized guinea pigs using an intrinsic R-R and R-IAS reflex model resulting from chronic (two to nine days) lumbosacral denervation (PITH). In this model, the myenteric plexus remains undamaged and the distribution of myenteric and intramuscular interstitial cells of Cajal is unchanged. Although R-R and R-IAS reflex patterns markedly changed, the reflex indices (reflex pressure or force curve-time integral) of both the R-R contractions and the synchronous R-IAS relaxations were unchanged. The frequency of the spontaneous R and IAS motility was also unchanged. Mosapride (0.1-1.0 mg/kg) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indices (maximum: 2.76) from that of the control (1.0) 6-9 days following chronic PITH. The dose-response curve was similar to that in the intact guinea pig, and had shifted to the left from that in the guinea pig after acute PITH. A specific 5-HT(4) receptor antagonist, GR 113808 (1.0 mg/kg), decreased both reflex indices by approximately 50% and antagonized the effect of mosapride 1.0 mg/kg. This was quite different from the result in the intact guinea pig where GR 113808 (1.0 mg/kg) did not affect either of the reflex indices. The present results indicate that mosapride enhanced the intrinsic R-R and R-IAS reflexes and functionally compensated for the deprivation of extrinsic innervation. The actions of mosapride were mediated through endogenously active, intrinsic 5-HT(4) receptors which may be post-synaptically located in the myenteric plexus of the anorectum.     

Increased accumulation of iodine-123-IMP in the pulmonary inflammatory lesion surrounding a lung cancer

In a patient with primary lung cancer, increased accumulation of I-123-IMP was observed in a pulmonary inflammatory lesion surrounding a lung cancer which was delineated as a photon deficient area. Ga-67-citrate uptake was observed in both the inflammatory and cancerous areas. These findings suggest that I-123-IMP may have the potential to accumulate differently in a variety of pathological conditions of the lung and thus may be a clinically useful lung imaging agent.     

Preliminary Report on Teratogenic Effects of Zonisamide in the Offspring of Treated Women with Epilepsy

Summary: Purpose: We wished to assess the risk of terato-genicity of zonisamide (ZNS) in humans.
Methods: Pregnant epileptic women treated with ZNS and their offspring were prospectively monitored from June 1989 to December 1994. The outcome of pregnancy and status of neonates were examined based on the same standardized protocol.
Results: Twenty-six offspring exposed to ZNS with or without other antiepileptic drugs (AEDs) were studied. Malformations were detected in 2 offspring (7·7%) exposed to ZNS polypharmacy. Anencephaly was detected in one case at 16 weeks of gestation (case 1, artificial abortion), and atrial septa1 defect was detected in another case at 37 weeks of gestation (case 2, delivery by cesarean section). Serum concentrations of ZNS during the first trimester of pregnancy were 6·1 μg/ml in case 1 and 6·3μ/ml in case 2; in both cases, the levels were below the therapeutic concentration range of ZNS.
Conclusions: Teratogenic effects of ZNS were not clearly defined from these results since malformations were detected in two polypharmacy cases but not in four monopharmacy cases. The present data do not indicate that the risk of ZNS teratogenicity is greater than that of other conventional AEDs. However, such risk cannot be neglected even at therapeutic dosages or concentrations of ZNS, especially in patients receiving polypharmacy.     

Primary Adenocarcinoma in the Urethrorectal Fistula

A 60-year-old Japanese man was hospitalized because of urinary leakage from the anus on October 3, 1994. Retrograde urethrography detected a fistula between the bulbous urethra and the rectum. Urethrocystoscopy revealed a tumor on the urethrorectal fistula. Tumor biopsy showed a well differentiated adenocarcinoma. Cystourethrectomy with fistulectomy, and ileal conduit urinary diversion were performed. Pathological examination revealed primary adenocarcinoma in the fistula with invasion to the prostatic urethra and bladder wall. The patient showed no evidence of a recurrence as of August, 1996.     

The efficacy of fluconazole in treating prosthetic valve endocarditis caused byCandida glabrata: Report of a case

A case of active prosthetic valve infective endocarditis (PVE) due toCandida glabrata was successfully treated by the systemic administration of fluconazole. A 66-year-old Japanese man with infective endocarditis of unknown etiology underwent aortic and mitral valve replacement to treat severe aortic and mitral regurgitation associated with multiple organ failure. Postsurgical cultures of arterial blood were repeatedly positive forC. glabrata, and therefore fluconazole was administered either intravenously or orally at a dose of 400 mg/day for 46 days. During that time the signs of inflammation including fever such as an elevated white blood cell count and the presence of C-reactive protein (CRP) all improved while the blood cultures became negative. Fluconazole is thus considered to be effective in treating PVE caused byC. glabrata. When administering this treatment, it is also important to monitor the patient's renal and liver function.