Effects of genetic defects in the CYP2C19 gene on the N-demethylation of imipramine, and clinical outcome of imipramine therapy

Abstract  The relationship between the genetic polymorphism of S-mephenytoin 4'-hydroxylation catalyzed by CYP2C19 and the N-demethylation of imipramine was examined in 10 Japanese depressed patients. Five patients, who were poor metabolizers of S-mephenytoin, were determined to be either homozygous for a mutation in exon 5 or heterozygous for mutations in exon 4 and exon 5 of the CYP2C19 gene. In contrast, five patients, who were extensive metabolizers, had no mutations. The demethylation index (the desipramine/imipramine ratio) was significantly lower in patients with genetic defects. Plasma levels of imipramine and 2-hydroxyimipramine normalized by the daily dose (mg) per weight (kg) were significantly higher in patients with genetic defects. This suggests that the N-demethylation of imipramine is impaired in patients with genetic defects in the CYP2C19 gene, and that genotype determination may be useful in preventing side effects induced by unexpectedly elevated levels of imipramine.     

Color Doppler ultrasonography as a routine clinical examination in male infertility

AIM: We assessed the value of scrotal color Doppler ultrasonography as a routine examination in infertile men. METHODS: Color Doppler ultrasonography was performed in 545 infertile men with a mean age of 35.8 years to detect intrascrotal abnormalities. Findings were compared with those of physical examination. RESULTS: Intrascrotal abnormalities were detected by ultrasonography in 65.3% of patients. Of 374 abnormalities, 58.3% were undetected by physical examination. Left varicocele was found in 313 patients (57.4%); testicular microlithiasis in 30 (5.5%); epididymal cyst in 21 (3.9%); right varicocele in 4 (0.8%); and testicular cysts in 3 (0.6%). One occurrence each (0.2%) was found for testicular tumor, intrascrotal hemangioma, and hydrocele of the spermatic cord. Compared to ultrasonography, sensitivity in detecting left varicocele by physical examination was 58.4%; specificity, 79.3%; accuracy, 67.3%; and positive predictive value, 79.3%. Venous diameters in the pampiniform plexus were 3 mm or more in 61.5% of 130 subclinical left varicoceles. Of 30 patients with testicular microlithiasis, 14 had varicocele, 2 had epididymal cyst,s 3 had a history of mumps orchitis, 1 had retractile testis, and 1 had a history of orchiectomy for contralateral testicular tumor. CONCLUSIONS: The routine Color Doppler ultrasonography is valuable for diagnosing scrotal abnormalities in infertile men, frequently detecting non-palpable lesions.     

Electrophysiological Demonstration of Anterograde Concealed Conduction in Accessory Atrioventricular Pathways Capable Only of Retrograde Conduction

Anterograde concealed conduction into the concealed accessory atrioventricular (AV) pathway has been postulated to be one of the factors preventing the reciprocating process via the accessory pathway in patients with the concealed Wolff-Parkinson-White(WPW) syndrome but its presence has not been documented. To demonstrate the occurrence of anterograde concealment, 12 patients with the concealed WPW syndrome were selected for study. A pacing protocol was designed in which the retrograde conduction of the ventricular extrastimulus over the accessory pathway was assessed during ventricular pacing aione (conventional method) and during the AV simultaneous pacing (simultaneous method); the results were then compared. When the high right atrium was simultaneously paced, the effective refractory period of the concealed accessory pathway shortened as compared with the conventional method in five of 12 patients (from 341.7 ± 110.8 to 312.5 ± 108.2 msec, n = 12), whereas, it decreased in all patients studied when the coronary sinus near the accessory pathway was simultaneously paced (from 375.7 ± 135.0 to 287. ± 116.1 msec, n = 7). These results demonstrate that the AV simultaneous pacing frequently shortens the refractoriness of the concealed accessory AV pathway and such facilitation seems to he well explained by the probable anterograde concealment in it and peeling back of the refractory barrier.     

Mexiletine and Propafenone: A Comparative Study of Monotherapy, Low, and Full Dose Combination Therapy

The electrophysiological effects of combination therapy of mexiletine and propafenone were assessed using standard 12-Iead electrocardiogram (standard ECG), signal-averaged EGG (SAECG), and ambulatory ECG in 31 patients with ventricular arrhythmias. All patients underwent mexiletine monotherapy (M-mono), propafenone monotherapy (P-mono), low dose combination therapy (low M 4- P), and full dose combination therapy (full M + P). Full M + P increased the PQ interval and QRS duration to the same extent as P-mono did. Low M + P increased PQ interval and QRS duration to a lesser extent than P-mono and full M + P did. P-mono and full M + P significantly decreased root mean square (RMS) and increased f-QRS in SAECG, while M-mono and low M + P showed only a weak trend. SAECGs with late potentials increased in number with treatments; 9 in predrug control, 11 on M-mono, 15 on P-mono, 10 on low M + P, and 14 on full M + P. The percent suppression of frequent premature ventricular contractions (PVCs) (> 1,000/day) with M-mono, P-mono, low M + P, and full M + P were 46.4 ± 9.0,56.6 ± 10.4,64.4 ± 9.2, and 71.4 ± 7.1, respectively, and those of frequent couplets (> 10/day) were 58.3 ± 17.7, 62.6 ± 23.6, 87.5 ± 6.2, and 92.1 ± 4.0, respectively. Thus, full dose combination of mexiletine and propafenone exhibited the maximum antiarrhythmic efficacy without enhancement of effects on standard ECG and SAECG. Low dose combination therapy showed better antiarrhythmic efficacy in association with lesser effects on standard ECG and SAECG compared with propafenone monotherapy.     

Laparoscopic adrenalectomy in patients with large adrenal tumors

OBJECTIVES: The maximum size of adrenal tumors that should be removed by laparoscopic adrenalectomy is controversial. We conducted a retrospective comparison of the results of laparoscopic adrenalectomy between patients with adrenal tumors > or =6 cm ('large tumors') and patients with adrenal tumors <6 cm ('small tumors'). METHODS: The participants in the study were 16 patients with large tumors and 111 patients with small tumors. The patients comprised 59 men and 68 women (mean age, 49.0 years; age range, 23-79) with varying diagnoses. Of the 16 patients with large tumors, five had Cushing's syndrome, four had pheochromocytomas, six had a non-functional tumor and one had malignant lymphoma. Adrenal tumors were confirmed by hormonal assays, biochemical tests and computed tomography. Of the 16 large tumors, five tumors were on the right and 11 were on the left. RESULTS: We found no significant differences in general demographic parameters between patients with large and small tumors. The mean duration of surgery was not significantly different between two groups. (large tumors, 210 min; small tumors,175 min). The mean volume of blood loss was 212 mL for large tumors and 30 mL for small tumors (P < 0.001, significant difference). There was no significant difference in time until walking, duration of hospitalization or number of using analgesics used. The time to first oral intake of group 1 (<6 cm) was significantly shorter than group 2 (> or =6 cm). Tumor size (> or =7.5 cm) was an independent predictor of a longer operation and greater blood loss in large tumors. CONCLUSIONS: Laparoscopic adrenalectomy for large tumors was safe and minimally invasive.     

A study of prognosis in 52 cases with juvenile rheumatoid arthritis

The prognosis in 52 patients with juvenile rheumatoid arthritis (JRA) was studied. There were 35 cases of systemic onset, 12 of polyarticular onset and 5 of pauciarticular onset. Thirteen systemic cases developed a polycyclic course with chronic polyarthritis. Many monocyclic JRA in systemic cases subsided within 1 year. There were no instances of polyarticular cases or pauciarticular cases that shifted to other type. However, there were many cases with a long active polyarticular JRA and with remission at an early stage in the pauciarticular type. The stage and class were I or II in 90% of cases with a good prognosis for the joints, but there were some serious cases. Transient carditis or iritis which developed at an early stage subsided later. The intractable systemic cases had drug-induced complications. The cases with steroid-induced complications tended to be chronic. One death in a systemic case was caused by hepatic failure.     

RENAL CELL CARCINOMA IN CHILDREN: EXPERIENCE AT A SINGLE INSTITUTION IN JAPAN

PURPOSE: We analyzed the presentation, treatment and survival of 4 children with renal cell carcinoma. MATERIALS AND METHODS: We retrospectively reviewed the pathological and hospital records of 4 Japanese children diagnosed with renal cell carcinoma at our hospital from 1970 to 1998. RESULTS: In the 1 boy and 3 girls with an average age of 8 years 7 months at diagnosis the most common presenting complaints were gross hematuria in 75% and a palpable abdominal mass in 50%. Computerized tomography revealed characteristic calcification within the tumor in 3 of the 4 patients (75%). In the remaining case the lesion had high density areas with microcalcification, as confirmed by histopathological study. In 2 patients with regional lymph node metastasis calcification was also observed in the metastatic lesions. Disease was stages I to III in 1, 1 and 2 patients, respectively. All patients underwent transabdominal nephrectomy with regional lymphadenectomy. One patient with stage I disease had multiple metastases 15 months later and died of disease 55 months postoperatively. However, the remaining 3 patients received adjuvant interferon therapy and they are without evidence of recurrence a mean of 51.3 months postoperatively. CONCLUSIONS: Calcification within the tumor and/or metastatic lesions or high density areas in the tumor on screening computerized tomography are characteristic findings suggestive of pediatric renal cell carcinoma. Adjuvant therapy with interferon may provide some benefit in select pediatric patients. Further studies of a larger number of pediatric renal cell carcinoma cases may be necessary to establish the optimal diagnostic and therapeutic regimen.     

Pathological improvement of IgA nephropathy and Henoch-Schönlein purpura nephritis with urokinase therapy

The pathological findings of 13 patients with immunoglobulin A (IgA) nephropathy or Henoch-Schönlein purpura nephritis before and after urokinase (UK) administration were investigated retrospectively. The mean activity index value decreased significantly at the time of the second biopsy compared with that of the biopsy before UK treatment. The mean chronicity index value, which was considered to reflect the renal outcome, before and after UK treatment did not change significantly, although it improved significantly in six patients. Immunofluorescence microscopy showed that the immune deposition of C3 decreased, but that of IgA and fibrin-related antigen were unchanged, by UK therapy. These results suggest that UK may prevent the mesangial proliferation associated with IgA nephropathy and Henoch-Schönlein purpura nephritis not only by its fibrinolytic action, but also by other mechanisms, such as digestion of the mesangial matrices.