Longitudinal monitoring of CYP3A activity in patients receiving 3 cycles of itraconazole pulse therapy for onychomycosis.

WHAT IS KNOWN AND OBJECTIVE: Itraconazole, a CYP3A inhibitor, is used for the treatment for onychomycosis with a three-cycle pulse therapy over 3 months, but its effects on in vivo CYP3A activity during the entire course remain unknown. METHODS: Urinary 6ß-hydroxycortisol/cortisol ratios were determined in 19 patients with onychomycosis, before therapy, during three cycles of itraconazole pulse therapy (200 mg twice daily for a week in each monthly cycle) and at 3 month after completion of therapy. RESULTS AND DISCUSSION: The mean 6ß-hydroxycortisol/cortisol ratio was reduced by 68% from baseline (P < 0·05) after the 1st pulse dosing, but the inhibitory effect appeared to be resolved before the next pulse dosing and at 3 months post-treatment. The magnitude of inhibition appeared in proportion to the baseline CYP3A activity. WHAT IS NEW AND CONCLUSION: The inhibitory effect of itraconazole pulse therapy on the in vivo CYP3A activity appears clinically relevant at the end of each cycle, but the inhibition resolves, on average, within 3 weeks.

Lack of association of the interleukin-1 receptor antagonist gene with palmoplantar pustulosis in Japanese.

We analysed a polymorphism of the interleukin (IL)-1 receptor antagonist (IL1RN) gene in 93 Japanese patients with palmoplantar pustulosis (PPP). None of the IL1RN alleles was significantly increased in the patients compared with controls. Because PPP has been reported to be associated with the tumour necrosis factor (TNF) region, we examined the association between the TNF and IL1RN genes. There was a difference in IL1RN*2 positivity between patients with and without the AA genotype of the TNF gene. In contrast, such a difference was not found in controls. These data indicate a possible epistatic effect between TNF and IL1RN linked genes for susceptibility to the pathogenesis of PPP.

Additive effects of nicorandil on coronary blood flow during continuous administration of nitroglycerin.

OBJECTIVES: We examined whether patients with ischemic heart disease (IHD) should be treated with nicorandil, an adenosine triphosphate-sensitive potassium channel opener, in addition to the regular use of nitrates. BACKGROUND: It has been reported that nicorandil possibly has additive effects on nitroglycerin (NTG) treatment for angina, but the mechanism is not clear. METHODS: We directly measured anterograde coronary blood flow (CBF) with a Doppler guide wire to examine the effects of intravenous administration of NTG (0.3 mg) and nicorandil (6 mg) during continuous administration of NTG at a sufficient dose (25 microg/min) in subjects with normal and stenotic coronary arteries. RESULTS: Additional systemic administration of NTG decreased anterograde CBF (normal -19.7%; stenotic -21.2%). In contrast, nicorandil increased anterograde CBF in both normal (54.6%) and stenotic (89.6%) coronary arteries, without the coronary steal phenomenon. There was a tendency toward nicorandil-dilated diameters in the patients with stenotic arteries (p = 0.06). There were no effects of additional administration on pulmonary artery wedge pressure. There was no difference in changes in heart rate and mean aortic blood pressure between NTG and nicorandil therapy. CONCLUSIONS: These results suggest that in patients treated with nitrates, additional administration of nicorandil is more useful, in terms of increasing CBF, than additional administration of nitrates. Adjunctive use of nicorandil with nitrates may provide the further benefit of myocardial protection and may improve the prognosis of patients with IHD.

Lack of correlation between Mbo I restriction fragment length polymorphism of renin gene and essential hypertension in Japanese.

Predisposition to essential hypertension is associated with gene polymorphisms of the renin angiotensin system (RAS). Gene polymorphisms of the angiotensinogen and angiotensin converting enzyme genes are known to be risk factors for hypertension, while few studies concerning the renin gene polymorphism have been published. In the present investigation, we carried out a case control study using a Japanese population to examine the genetic influence of the renin gene on the predisposition to hypertension. Patients (n=235) recruited from outpatients at Osaka University Hospital and diagnosed with essential hypertension or receiving long-term antihypertensive medication participated in the study. Normotensive control subjects (n=510) without a history of hypertension and without diabetes mellitus were recruited from the same population, and were sex-matched with experimental subjects. A polymorphism in intron 9 of the human renin gene was determined as the Mbo I restriction fragment length polymorphism (Mbo I-RFLP). There was no significant association between Mbo I-RFLP of the renin gene and predisposition to essential hypertension in Japanese (p>0.05, chi2=2.1). These results suggest that the Mbo I (+) allele of the renin gene does not increase the risk for hypertension in Japanese.

Low potentiality of angiotensin-converting enzyme gene insertion/deletion polymorphism as a useful predictive marker for carotid atherogenesis in a large general population of a Japanese city: the Suita study.

BACKGROUND AND PURPOSE: Some previous studies, almost all western, have investigated whether there is a relationship between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) and carotid atherosclerosis. The results, however, have not been consistently positive. Further, there have been few investigations based on a large, general population. Therefore, the present study aimed to clarify whether ACE gene deletion polymorphism was associated with carotid atherosclerosis in a large Japanese general population with a more homogeneous genetic background than Caucasian populations. METHODS: Subjects aged 30 to 86 years were randomly selected from Suita City, located in Osaka, the second largest urban area of Japan, and included 1894 men and 2137 women. With the aid of high-resolution ultrasonography, carotid atherosclerosis was evaluated using our atherosclerotic indexes of intimal-medial thickness (IMT), plaque number (PN), plaque score (PS), and percentage of stenosis of the carotid artery assessed using high-resolution B-mode ultrasonography. ACE gene I/D polymorphism was detected by polymerase chain reaction. RESULTS: There were no significant differences among the ACE genotypes for age and conventional cardiovascular risk factors, except for systolic blood pressure (SBP) and the percentage of hypertension in men. The values of IMT, PN, and PS as carotid atherosclerotic indexes were not significantly different among genotypes for either sex. After adjusting for age, body mass index, smoking habit, high-density lipoprotein cholesterol, triglycerides, presence of hypertension, presence of diabetes mellitus, and presence of hyperlipidemia, the estimated ORs for the presence of IMT >/=1.10 mm (defined as thickened IMT), according to ACE genotype (DD versus II, DD+ID versus II, and DD versus ID+II), for men were 0.80 (95% CI 0.60 to 1.23), 0.89 (0.62 to 1.29), and 0.89 (0.70 to 1.28), respectively. On the other hand, the ORs for women after the same adjustment were 0.92 (95% CI 0.58 to 1.35), 0.93 (0.59 to 1.45), and 0.91 (0.59 to 1.27), respectively. CONCLUSIONS: Our present data suggest that ACE I/D polymorphism is not potentially a useful predictive marker for carotid atherogenesis when investigated in a large and homogeneous general Japanese population of 4031 subjects, a finding similar to that in a Caucasian population study, the Perth Carotid Ultrasound Disease Assessment Study, an Australian study based on a general population using 1111 subjects.

Arteriovenous haemangioma in chronic liver disease: clinical and histopathological features of four cases.

Chronic liver diseases are known to cause several skin manifestations, including cutaneous vascular changes such as spider naevus and palmar erythema. Arteriovenous haemangioma (AVH), a benign acquired cutaneous vascular lesion, has also been reported to be associated with chronic liver disease. We report here four cases of AVH in patients with chronic liver disease: (i) a 59-year-old man who had suffered from chronic active hepatitis associated with hepatitis C virus for 15 years; (ii) a 48-year-old man who had suffered from alcoholic hepatitis for 3 years and was diagnosed with liver cirrhosis 1 year ago; (iii) a 69-year-old female who had had chronic active hepatitis associated with hepatitis C virus infection for 20 years and was diagnosed with liver cirrhosis 7 years ago; and (iv) a 48-year-old man who had had chronic active hepatitis associated with hepatitis B virus infection for about 20 years. All patients showed an asymptomatic solitary dome-shaped reddish papule, 5-10 mm in diameter, on the face (first, second and third patients) or chest (fourth patient). Histopathological examination of the tumours revealed features of AVH, namely a well-circumscribed lesion composed of vascular structures of various sizes reminiscent of arteries and veins. In all four cases, elastic-van Gieson stain showed the absence of an internal elastic lamina in the thick-walled vessels as well as the thin-walled vessels. Examination of multiple sections demonstrated glomus cells and an ascending artery feeding the tumour vessels in only one case. Slight inflammatory cell infiltration was seen in the stroma of three patients while Toluidine blue staining revealed an increased number of mast cells in the stroma in all lesions. The present cases suggest that the occurrence of AVH associated with chronic liver disease is not related to any specific liver disease, but may be related to chronic liver dysfunction itself.

Frontal mucocele presenting as a subcutaneous tumour on the forehead.

A 57-year-old Japanese woman had a 3-month history of an asymptomatic subcutaneous tumour on the forehead. The patient presented a slightly elevated, elastic soft subcutaneous mass, 3 cm in diameter, on the mid to left-side forehead. Slight swelling of the left upper eyelid was observed. CT scanning and magnetic resonance images revealed a sharply demarcated cystic mass from the subcutaneous area on the forehead expanding into the frontal sinus and intracranial space. The tumour was diagnosed as a frontal mucocele and combined external and endoscopic approaches were performed. It is rare that a patient with a frontal mucocele is initially referred as a case of a subcutaneous tumour because most of the patients complain primarily of the ophthalmic symptoms. However, the present case reminds us that frontal mucocele is one of the differential diagnoses for a subcutaneous mass on the forehead.

[Bilateral homonymous hemianopsia with atrial fibrillation].

We encountered an 80-year-old man with sudden bilateral visual disturbance. When he was admitted to the hospital, his blood pressure was 138/70 mmHg, and an ECG revealed atrial fibrillation. Neurological examination showed only bilateral homonymous hemianopsia with no nystagmus or impairment of eye movement. He did not have paralysis cerebellar ataxia, or speech disturbance. Therefore, there was no evidence of obstruction of the thalamogeniculate or thalamoperforating artery. Magnetic resonance imaging of the brain showed cerebral infarctions in both occipital lobes. Perimetry showed bilateral homonymous hemianopsia; the left side of the macula was spared. The lack of neurological deficit other than bilateral homonymous hemianopsia indicates that only the right and left cortical branches of the posterior cerebral artery were occluded.

Malignant histiocytosis presenting as multiple erythematous plaques and cutaneous depigmentation.

We report on a patient with malignant histiocytosis (MH) presenting as multiple erythematous plaques and cutaneous depigmentation on her neck and chest. In a biopsy of an erythematous plaque, atypical large, foamy histiocytes infiltrated the dermis and positively stained with antibodies to lysozyme, leukocyte common antigen, and KP-1 (CD68). A few similar atypical cells were present in the superficial dermis focally in the depigmented areas. With use of immunohistochemical studies, most cases previously diagnosed as MH have been reclassified as T-cell lymphoma, B-cell lymphoma, or Ki-1-positive anaplastic large cell lymphoma. However, a few cases of "true" MH characterized by authentic histiocytes have been reported, presenting usually as red nodules. To our knowledge, our patient is the first with MH to present with erythematous plaques and vitiligo-like depigmentation.

Malignant melanoma and squamous cell carcinoma forming one tumour on a burn scar.

Malignant melanoma occurring in burn scars is rare and cases of malignant melanoma and squamous cell carcinoma arising in a burn scar are extremely rare. We report a case of malignant melanoma and squamous cell carcinoma arising in one tumour on a stable thermal burn scar on the right leg of a 55-year-old man after a long latent period of about 50 years. The case was unique in that the malignant melanoma and squamous cell carcinoma occurred synchronously next to each other and produced one tumour. Immunohistochemical stainings with keratin, S-100 protein and HMB 45 clearly distinguished the two kinds of atypical tumour cells. Following the total resection of the original tumour, metastasis of malignant melanoma in the inguinal lymph node was found. This case underlines the possibility that another tumour may co-exist even if pathological observation reveals one kind of tumour.

HLA-DQA1, -DQB1 and -DRB1 genotyping in Japanese pemphigus vulgaris patients by the PCR-RFLP method.

We performed HLA-DQA1, -DQB1 and -DRB1 genotyping using the PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) method for 32 Japanese pemphigus vulgaris (PV) patients. There was a significant association of either DQB1*0503 or DRB1*1405 with PV, and a negative association of either DQA1*0103 or DQB1*0601 with PV was found. Since the DQB1*0503+ patients had various DR14-related alleles, we concluded that the association with DQB1 is primary and that the association with DRB1 is simply due to linkage disequilibrium between the DQ and DR genes. These results may indicate that specific HLA class II antigens confer the susceptibility to PV among Japanese.

A case of pemphigus foliaceus after interferon alpha-2a therapy.

We present here a 63-year-old man with chronic hepatitis C who developed bullous lesions and anti-intercellular antibodies when he received interferon (IFN) alpha-2a, 9 MU subcutaneously, 3 times a week for 3 months. The direct immunofluorescence was consistent with pemphigus features. The indirect immunofluorescence showed negative before IFN treatment, but it became positive after 3 months. The immunoblot study showed no specific bands. This is the third report of the bullous lesions with anti-intercellular antibodies following IFN therapy.

Is tubular apocrine adenoma a distinct clinical entity?

A 75-year-old Japanese man developed a tubular apocrine adenoma (TAA) (tubulopapillary hidradenoma with apocrine differentiation, a rare skin tumor), within a long-standing organoid nevus on the parietal area of his scalp. Histologically, the tumor consisted of dilated ductlike areas with some atypism and apocrine glandlike areas surrounded by myoepithelial cells. The superficial part of the tumor was connected to the epidermis and showed some of the characteristics of syringocystadenoma papilliferum (SCAP). The close relationship between TAA, SCAP, and papillary eccrine adenoma (PEA) is discussed. According to 19 reported cases of TAA, SCAP might occur together with TAA when they are preceded by an organoid nevus, and they might represent a spectrum of disease. Although TAA and PEA may represent another spectrum (designated as tubulopapillary hidradenoma), the relationship to SCAP should be considered in understanding and diagnosing an intermediate case.

Two cases of clear cell acanthoma: an immunohistochemical study.

Two cases of clear cell acanthoma are reported. The expression of carcinoembryonic antigen (CEA), involucrin and keratin proteins in the tumors was investigated immunohistochemically. In 1981, Penneys et al. reported that this tumor was not of sweat gland origin because of the absence of CEA. This study confirmed this, further, the pattern of positive reaction of involucrin also indicated that this tumor is not of sweat duct origin.

Involucrin expression in skin appendage tumours.

The expression of involucrin was examined in 23 skin tumours of hair follicle origin, 17 tumours of sweat gland origin and three tumours of unknown origin, using an immunoperoxidase technique. All tumours from the hair follicle showed a positive reaction for involucrin. In particular keratoacanthoma and the squamous eddies in various tumours stained strongly. Trichofolliculoma, trichilemmoma and pilomatrixoma exhibited characteristic staining patterns which resembled those in the normal hair follicle. On the other hand the majority of the tumours of sweat gland origin did not stain, with restricted positive reactions in areas showing lumen formation or squamous metaplasia. In contrast to the lack of staining in syringoma, a positive reaction was observed in desmoplastic trichoepithelioma, which is histologically similar to syringoma. Clear cell acanthoma, the origin of which is still controversial, showed a staining pattern which indicated that its origin may not be in the sweat gland. These results suggest that testing for involucrin in skin appendage tumours may be very useful for understanding the kinetics of maturation as well as in determining the origin of the tumours.

Intercellular IgA dermatosis with clinical features of subcorneal pustular dermatosis.

In a patient whose clinical features resembled subcorneal pustular dermatosis, IgA deposits in the intercellular space of the upper epidermis were found on direct immunofluorescence study. Furthermore, by indirect immunofluorescence, IgA autoantibodies against the same area of the epidermis were demonstrated in the patient's serum.