Microsomal Cytochrome P-450 Monooxygenase System and Its Drug-metabolizing Activity after Partial Portal Vein Ligation in the Rat

RID=" ID=" <E5>Correspondence to:</E5> K. Izuishi, M.D.     

PREVALENCE OF MICROALBUMINURIA IN NON-INSULIN-DEPENDENT DIABETES MELLITUS

The prevalence of microalbuminuria was assessed in 50 patients of non-insulin dependent diabetes mellitus. The mean age of patients was 52.1 ± 11.6 years and the duration of diabetes was 8.3 ± 6.8 years. Twenty (40%) patients had microalbuminuria. Microalbuminuria was more common in patients with a longer duration of diabetes (more than 5 years), a poor glycaemic control, and higher systolic blood pressure.KEY WORDS: Microalbuminuria, Diabetes mellitus, Diabetic nephropathy, Chronic renal failure     

Bone marrow stromal-B cell interactions in polycyclic aromatic hydrocarbon-induced pro/pre-B cell apoptosis.

Environmental polycyclic aromatic hydrocarbons (PAH) and related halogenated hydrocarbons are immunotoxic in a variety of systems. In a model system of B lymphopoiesis, PAH exposure rapidly induces apoptosis in CD43- pre-B and CD43+ pro/pre-B cells. Apoptosis induction by 7,12-dimethylbenzo[a]anthracene (DMBA) is dependent upon AhR+ bone marrow stromal cells and likely involves DMBA metabolism within the stromal cell. However, it is not known if PAH-treated stromal cells release free metabolites or soluble factors that may directly induce B cell death or if the effector death signal is delivered by stromal cell-B cell contact. Here, we demonstrate that supernatants from DMBA-treated bone marrow stromal cells contain an activity capable of inducing apoptosis in pro/pre-B cells cocultured with stromal cells. This activity (1) is not produced when stromal cells are cotreated with DMBA and alpha-naphthoflavone (alpha-NF), an aryl hydrocarbon receptor (AhR) and cytochrome P-450 inhibitor, (2) is > or = 50 kDa, (3) is trypsin and heat sensitive, and (4) is dependent on AhR+ stromal cells, which in turn deliver the effector death signal to pro/pre-B cells. The results (1) argue against a role for a soluble, stromal cell-derived cytokine as the effector of PAH-induced pro/pre-B cell death, (2) exclude the possibility of a free metabolite acting directly on AhR- pro/pre-B cell targets, and (3) suggest the elaboration by stromal cells of a relatively stable, DMBA metabolite-protein complex capable of acting on other stromal cells at some distance. Collectively, these studies suggest that, while stromal cell products, e.g., metabolite-protein complexes, may affect the function of distant stromal cells, the effector death signal delivered by stromal cells to bone marrow B cells is mediated by cell-cell contact.     

Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors.

PURPOSE: Constitutive mutational activation of c-kit has been found to be associated with the pathogenesis of gastrointestinal stromal tumors (GISTs). The prognostic significance of c-kit mutations, however, is still controversial. EXPERIMENTAL DESIGN: We examined 86 patients curatively resected for localized GIST. Genomic DNA was extracted from paraffin-embedded tumor tissues. Exons 9, 11, 13, and 17 of the c-kit gene were amplified by PCR and sequenced. RESULTS: Mutations in exon 11 were detected in 61 tumors, and mutations in exon 9 were observed in three tumors, whereas no mutations were detected in exons 13 or 17. The overall c-kit mutation frequency was 74%. Amino acid alterations in the 61 tumors with exon 11 mutations were deletion in 33 tumors, substitution in 20, both deletion and substitution in 4, insertion in 1, and duplication in 3. Histologically, tumors with c-kit mutations showed higher mitotic counts and higher cellularity. The 5-year relapse-free survival (RFS) in patients having GISTs with c-kit mutations was 21%, compared with 60% in those without c-kit mutations. Significantly higher RFS rates were observed in patients with tumors having mitotic counts < 5 mitoses/50 high power field, spindle-cell histology, tumor size < 5 cm, or gastric GISTs. Multivariate analyses indicated association of poorer RFS with a higher mitotic count > or = 5 of 50 high power fields; odds ratio (OR) = 3.0], presence of c-kit mutations (OR = 5.6), and a larger tumor size (> or = 5 cm; OR = 4.2). CONCLUSIONS: The presence of c-kit mutation, along with high mitotic count and larger tumor size, was an independent factor for poor prognosis in patients with localized GISTs.     

Profile of non-compliance in lymphoblastic leukaemia

A nationwide study of intracellular drug metabolite concentrations in children prescribed 6-mercaptopurine for the treatment of lymphoblastic leukaemia was carried out to assess interpatient variability at a standardised dose. Nine children (2% of the total) had completely undetectable metabolites, indicative of non-compliance. Five were adolescents, but otherwise they had no obvious distinguishing characteristics. Not taking any 6-mercaptopurine at all is uncommon, but the problem cannot be predicted. The total number of children who do not comply cannot be determined from this study, but the nine children described represent only a fraction of these.     

Thermosoftening treatment of the nasotracheal tube before intubation can reduce epistaxis and nasal damage

We evaluated whether a thermosoftening treatment with warm saline of a nasotracheal preformed tube can improve navigability through the nasal passageways and reduce epistaxis and nasal damage. A total of 150 patients were randomly allocated to three groups: Group I (untreated tube group, n = 50), Group II (35 degrees C treated tube group, n = 50), and Group III (45 degrees C treated tube group, n = 50). In Groups II and III, the tubes were softened at 35 +/- 2 degrees C and 45 +/- 2 degrees C with warm saline, respectively. In Group I the tube was prepared at room temperature (25 +/- 2 degrees C). The incidence of epistaxis and nasal damage in Groups II and III was significantly less than that of Group I (P: < 0.05). Despite the more frequent incidence of smooth passage in Group III, no statistical difference was found among the groups. Logistic regression analysis also confirmed that epistaxis was more likely to be reduced when the tube had been thermosoftened (odds ratio = 1.46, 95% confidence interval = 1.02, 2.11). We conclude that simple thermosoftening treatment of the nasotracheal tube with warm saline helps to reduce epistaxis and nasal damage. IMPLICATIONS: Thermosoftening treatment of a nasotracheal tube with warm saline before intubation can effectively reduce epistaxis and nasal damage. This technique is safe, easy, and suitable for all types of tubes and does not require additional implements.     

Trapeziometacarpal joint instability affects the moment arms of thumb motor tendons

This study measured the changes in moment arm length of thumb motor tendons after simulated ligamentous instability and subsequent reconstruction of the trapeziometacarpal joint. Excursions of thumb motor tendons were measured simultaneously with the trapeziometacarpal joint angulation during flexion to extension and abduction to adduction motion. Tendon moment arms were calculated based on joint and tendon displacement techniques in the intact joint, after sequential sectionings of the capsuloligamentous restraints, and after the reconstruction procedure of Eaton and Littler. The results showed that moment arms of the abductor pollicis longus and extensor pollicis brevis tendons increased significantly as compared with those for normal joints during flexion to extension motion after sectioning the palmar capsuloligamentous components. After the ulnopalmar structures were cut, the moment arm of the extensor pollicis longus tendon had a statistically significant increase during abduction to adduction motion, and those of the extensor and flexor pollicis longus tendons decreased significantly during flexion to extension motion. Changed moment arms were restored to a normal level after the ligamentous reconstruction. These results indicate that ligamentous disruptions alter the mechanical balance of thumb motor tendons, which may contribute to joint deformities observed in trapeziometacarpal joint arthritis. Restoring joint stability is important to correct mechanical imbalance of the tendons.     

Frequent genotype changes at -308, and 488 regions of the tumor necrosis factor-alpha (TNF-alpha) gene in patients with prostate cancer

PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is involved in oncogenesis of several cancers. The purpose of this study was to investigate whether genotype changes of TNF-alpha promoter regions (-238, -308) and at the 488 region are associated with human prostate cancer. MATERIALS AND METHODS: The DNA from 73 cases of human prostate cancer was analyzed by allele-specific polymerase chain reaction to characterize the genotype changes of three regions of the TNF-alpha gene in prostate cancer patients. We also determined the genotype frequency in these patients. The relative risk of variant genotype was calculated by comparing with our previous data from healthy controls. RESULTS: Genetic changes were detected in 15.1% (11/73) of prostate cancer samples at 488 region of TNF-alpha. Seventy-three percent (53/73) of the patients showed genotype GA at -308 region of TNF-alpha. Genotype GA at 488 region in TNF-alpha was observed in 73% (53/73) of the cancer and 71% (52/73) of the normal tissue. The relative risks of incidence for prostate cancer was 14-fold higher in people with genotype GA at -308 region of TNF-alpha. The relative incidence for prostate cancer was a 17-fold higher in-patient with genotype GA at 488 region of TNF-alpha. Genotype GA at -308 of TNF-alpha was related to higher clinical tumor stage of prostate cancer than genotype G (p <0.05). CONCLUSIONS: The present study demonstrates, for the first time, that the genotype changes in -308 and 488 regions of TNF-alpha are associated with prostate cancer.     

Immune responses against SARS-coronavirus nucleocapsid protein induced by DNA vaccine

The nucleocapsid （N） protein of SARS-coronavirus （SARS-CoV） is the key protein for the formation of the helical nucleocapsid during virion assembly. This protein is believed to be more conserved than other proteins of the virus, such as spike and membrane glycoprotein. In this study, the N protein of SARS-CoV was expressed in Escherichia coli DHSalpha and identified with pooled sera from patients in the convalescence phase of SARS. A plasmid pCI-N, encoding the full-length N gene of SARS-CoV, was constructed. Expression of the N protein was observed in COS1 cells following transfection with pCI-N. The immune responses induced by intramuscular immunization with pCI-N were evaluated in a murine model. Serum anti-N immunoglobutins and splenocytes proliferative responses against N protein were observed in immunized BALB/c mice. The major immunoglobulin G subclass recognizing N protein was immunoglobulin G2a, and stimulated splenocytes secreted high levels of gamma interferon and IL-2 in response to N protein. More importantly, the immunized mice produced strong delayed-type hypersensitivity （DTH） and CD^8＋ CTL responses to N protein.