Effect of CYP2D6 genotypes on the metabolism of haloperidol in a Japanese psychiatric population.

We investigated the effect of CYP2D6 genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.14+/-0.69 ng/ml/mg) and RHAL (1.10+/-1.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL=0.68+/-0.31 ng/ml/mg, RHAL=0.28+/-0.37 ng/ml/mg), those with one CYP2D6*10 (HAL=0.70+/-0.23 ng/ml/mg, RHAL=0.31+/-0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL=0.69+/-0.14 ng/ml/mg, RHAL=0.40+/-0.09 ng/ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (<10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43+/-0.23 ng/ml/mg, 0.34+/-0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18+/-0.16 ng/ml/mg). The results of this study indicate that CYP2D6*10 allele plays significant but modest role in HAL metabolism in Japanese; nevertheless, we should not lump CYP2D6*10 allele with CYP2D6*5 allele because these two mutated alleles seem to have different impacts in the metabolism of HAL.     

Early expression of interferon-gamma inducible protein 10 and monokine induced by interferon-gamma in cardiac allografts is mediated by CD8+ T cells

BACKGROUND: Our goal was to test the intragraft mRNA expression and production of two chemokines that are potent chemoattractants for antigen-primed T cells, interferon-gamma inducible protein 10 (IP-10) and monokine-induced by IFN-gamma, (Mig), in allogeneic heart grafts. METHODS: Syngeneic or allogeneic A/J (H-2a) hearts were heterotopically transplanted to wild-type, CD4-/-, CD8alpha-/-, or IFN-gamma-/- C57BL/6 (H-2b) recipients. To test expression of IP-10 and Mig, grafts were removed 1-8 days posttransplant for RNA isolation and Northern blot analysis. To test the potential recipient leukocyte populations mediating intraallograft expression of IP-10 and Mig, recipients were treated with anti-NK 1.1, anti-CD4, and/or anti-CD8 monoclonal antibodies before transplantation. RESULTS: Allogeneic heart grafts transplanted to wild-type, but not IFN-gamma-/-, recipients expressed IP-10 and Mig at day +2 posttransplant that increased thereafter until rejection was completed. Expression of IP-10 and Mig in isografts was low or undetectable. Cardiac allografts from CD8+ T cell depleted, but not NK cell or CD4+ T cell depleted, recipients had low to undetectable expression of IP-10 and Mig on day +2 posttransplant. Similarly, cardiac allografts from CD8-/-, but not CD4-/-, recipients had low to undetectable expression of IP-10 and Mig on day +2 posttransplant. CONCLUSIONS: Early intraallograft expression of Mig and IP-10 during primary rejection of cardiac allografts is dependent on the activities of recipient CD8+ T cells.     

Early increased chemokine expression and production in murine allogeneic skin grafts is mediated by natural killer cells

BACKGROUND: Increased expression of chemokine mRNA is observed in allogeneic but not syngeneic skin grafts 3-4 days after transplantation. The recipient cells mediating this early inflammatory response in allografts remain unidentified. METHODS: Isogeneic and allogeneic skin grafts were transplanted to euthymic and athymic nude mice. mRNA expression and protein production of macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and the murine homolog of Gro(alpha), i.e. KC, from graft homogenates retrieved 3-4 days posttransplantation was tested by Northern blot hybridization and ELISA. To deplete NK cells, recipients were treated with antiasialo GM1 (ASGM1) antisera or with anti-NK1.1 mAb before transplantation. RESULTS: Expression of KC, MIP-1alpha, and MIP-1beta mRNA was equivalent in C57BL/6 allogeneic skin grafts and BALB/c isografts at day 2 posttransplant. At day 3 posttransplant, chemokine mRNA levels decreased in isografts but were maintained at high levels in the allografts. Increased early chemokine mRNA was also observed in C57BL/6, but not BALB/c++ grafts on BALB/c athymi(nu/nu) recipients. Treatment of allograft recipients with ASGM1 or with anti-NK1.1 antibody eliminated NK cells from the spleen and allograft infiltrating cell populations and decreased early chemokine mRNA levels in allografts 60-70%. Analyses of allograft homogenates indicated increased levels of KC, MIP-1alpha, and MIP-1beta protein at day 4 posttransplant that were decreased in recipients depleted of NK cells. Early chemokine mRNA levels were equivalent in isogeneic and semiallogeneic F1 grafts. CONCLUSIONS: Early chemokine mRNA expression and protein production in allogeneic skin grafts is amplified by recipient natural killer (NK) cells. These results indicate a novel function for infiltrating NK cells in mediating early increased intra-allograft chemokine production and inflammation during the initiation of acute rejection.     

Changes in patterns of left ventricular hypertrophy after aortic valve replacement for aortic stenosis and regurgitation with St. Jude Medical cardiac valves

In this study, we analyzed the extent and pattern of regression of left ventricular (LV) hypertrophy after aortic valve replacement in patients with aortic stenosis (AS) and compared the results with those of another group of patients with aortic regurgitation (AR). Seventy patients who underwent isolated aortic valve replacement were divided into 2 groups. Group 1 was comprised of 29 patients who underwent aortic valve replacement for aortic stenosis, and Group 2 of 41 patients who underwent aortic valve replacement for aortic regurgitation. A third group of 10 healthy subjects served as a healthy control group. Echocardiographic studies were done before the operation and 5 years postoperatively. At follow-up, a significant reduction in the left ventricular mass was found in both groups, but it remained significantly greater than in the healthy control group. The ratio of LV wall thickness to radius (th/r) in Group 1 decreased significantly, and at follow-up it was within the normal value. In Group 2, the th/r ratio increased, and at follow-up it was within the normal value. After aortic valve replacement, the wall thickness remained significantly greater than normal for patients with AS, and the chamber radius remained significantly greater than normal for patients with AR. For these reasons, LV hypertrophy still existed in both groups at postoperative follow-up. The actuarial survival rate was 85.3% at 16 years for Group 1 and 83.4% at 18 years for Group 2. There was no significant difference in the long-term survival rates between the 2 groups. Actuarial freedom from valve-related events was 91.9% at 16 years for Group 1 and 82% at 18 years for Group 2. There was no significant difference in the valve-related event free curves between groups. After 5 years of follow-up, th/r reached normal for both groups, indicating remodeling of the LV geometry after aortic valve replacement.     

Treatment of Lethal Midline Granuloma Type Nasal T-Cell Lymphoma

Nasal T-cell lymphoma of the LMG type (LMG-NTL) is characterized by progressive, unrelenting ulceration, and necrosis of the nasal cavity and midline facial tissues. The clinical behavior of this tumor in 16 patients is compared with that of a nasal lymphoma of non-LMG-NTL type (non-LMG-NTL) in 8 patients and a paranasal sinus lymphoma (PSL) in 6 patients. All patients had stage I or II disease. Fourteen of the 16 patients with LMG-NTL received chemotherapy before and/or after radiotherapy. Cause-specific 5-year survival rates for patients with LMG-NTL, non-LMG-NTL, and PSL were 22%, 75%, and 67%, respectively. Seven patients with LMG-NTL, had complete response, although 3 recurred, whereas it was incomplete in 9 patients. The data indicates that it is desirable to deliver 50 Gy or more to achieve in-field control of LMG-NTL.     

Radiotherapy of Vertebral Hemangiomas

Between 1975 and 1996, 14 patients (11 females, 3 males) with vertebral hemangioma received treatment with radiotherapy. Thirteen patients had a history of back pain or lumbago and 2 patients had neurological symptoms such as sensory impairment or paraplegia. The standard dose administered was 36 Gy in 18 fractions (five treatments per week). In the 13 patients with pain, this was completely or partially relieved. The condition of a man with hypesthesia of the legs deteriorated and a woman with paraplegia who was treated with decompressive laminectomy followed by radiotherapy recovered completely after irradiation. CT scan before irradiation showed thickened trabeculae as small punctate areas of sclerosis in all patients. At MR imaging before irradiation, T2-weighted MR images showed areas of high intensity in all patients and MR images demonstrated lesion enhancement. However, none of the patients who were treated successfully with radiation demonstrated any changes of the affected vertebra in the conventional radiographic films, CT scan or MR imaging, even 5 years after irradiation. Radiological imaging is indispensable for the diagnosis of vertebral hemangiomas but does not appear to be useful for evaluating the effects of radiotherapy.     

Effect of facial affect stimuli on auditory and visual P300 in healthy subjects

This study investigated whether or not P300 components are influenced by emotional affect such as sadness and pleasure in twenty healthy subjects and whether or not the P300 effects of facial affect stimuli are influenced by auditory and visual stimulus modalities. Written informed consent was taken from each subject before the study. Each subject was asked to stare at a simple picture of a facial expression (crying or smiling faces) during the auditory and visual oddball tasks. P300 amplitude and area were significantly larger when viewing a crying face (sadness) than a smiling face (pleasure) under both conditions with auditory and visual stimulus. P300 latency was significantly longer while viewing sadness than while viewing pleasure only with auditory stimuli. Reaction time was not changed by facial stimuli. Amplitude and area of P300 were significantly larger in women than men in their modalities, but the effects of facial affect on P300 amplitude and area in women were similar to those in men. These results suggest that amplitude and area of P300 with both modalities recorded while viewing sadness may induce larger attentional resource than pleasure. Gender was a less potent influence of facial expression on P300 parameters. The influence of facial emotion may be important to investigate the recognition processes of subjects.     

Characteristics of incidentally detected renal cell carcinoma by ultrasonography at health check-up

BACKGROUNDS: The prognosis of patients with incidentally detected renal cell carcinoma is better than that of patients with symptomatic renal cell carcinoma. These incidentalomas include those discovered by ultrasonography at health check-up and those found during examinations for unrelated disease. In this study, we investigated the prognosis of the patients of the health check-up group and the unrelated disease group. METHODS: From April 1987 to March 1997, 263 patients with renal cell carcinoma were treated in our department including 166 incidentalomas (63.1%). The occasion of incidental detection was divided into 2 groups; 90 cases as health check-up group and 76 cases as unrelated disease group. RESULTS: The mean age was 52.9 +/- 9.7 years for health check-up group and 65.1 +/- 11.4 years for unrelated disease group (p < 0.01). The mean evaluated tumor size was 3.6 +/- 1.6 cm for health check-up group and 4.4 +/- 2.6 cm for unrelated disease group (p < 0.05). The survival rates were significantly different in the two groups (p < 0.01); the 5- and 10-year survival rate for health check-up group was 91.5% and 55.9%, respectively and for unrelated disease group 79.4% and 66.1%, respectively. CONCLUSION: These results suggested that examination by ultrasonography at health check-up lead to detection of smaller renal cell carcinoma and improve the prognosis further.