S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial.

BACKGROUND: The ACTS-CC 02 trial demonstrated that S-1 plus oxaliplatin (SOX) was not superior to tegafur-uracil and leucovorin (UFT/LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) and subgroup analysis according to the pathological stage (TNM 7th edition) for treatment efficacy. PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, five cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2/day of S-1 on days 1-14, every 21 days, eight cycles). The primary endpoint was DFS and the patients' data were updated in February 2020. RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the final analysis. With a median follow-up time of 74.3 months, the 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group [stratified hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.76-1.11; P = 0.3973], and the 5-year OS rates were 78.3% and 79.1%, respectively (stratified HR 0.97; 95% CI 0.76-1.24; P = 0.8175). In the subgroup analysis, the 5-year OS rates in patients with T4N2b disease were 51.0% and 64.1% in the UFT/LV and SOX groups, respectively (HR 0.72; 95% CI 0.40-1.31). CONCLUSION: Our final analysis reconfirmed that SOX as adjuvant chemotherapy is not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer. The 5-year OS rate was similar in the UFT/LV and SOX groups.

Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug.

S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), which is a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD) activity; and potassium oxonate (Oxo), which reduces gastrointestinal toxicity. Phase I and early Phase II clinical trials have already been completed. On the basis of the results of these trials, 80 mg/m2/day, given daily in two divided doses after breakfast and supper, a 28-day consecutive oral regimen is recommended. In this study, we investigated the pharmacokinetics of 5-FU, intact FT, CDHP, and Oxo, after administration of S-1, at a standard dose of 80 mg/m2/day, in advanced cancer patients. Twelve patients were recruited to the study; 5 patients with gastric cancer, 4 with colorectal cancer, and 3 with breast cancer. Among them, analysis was conducted on 12 patients for single administration and on 10 patients for consecutive administration. The initial dose of S-1 for each patient was determined according to his/her body surface area (BSA) as follows: for BSA < 1.25 m2, 80 mg/body/day; for 1.25 m2 < or = BSA < 1.5 m2, 100 mg/day; and for 1.5 m2 < or = BSA, 120 mg/day. For single administration, half of the standard dose was used. For 28-day consecutive administration, the standard dose was given daily in two divided doses. The average single dose per BSA was 35.9 mg/m2 (31.7-39.7 mg/m2). Pharmacokinetic parameters of plasma 5-FU were as follows: Cmax, 128.5 +/- 41.5 ng/ml; Tmax, 3.5 +/- 1.7 h; AUC(0-14), 723.9 +/- 272.7 ng x h/ml; and T(1/2), 1.9 +/- 0.4 h. In the 28-day consecutive regimen, there were no fluctuations in pharmacokinetics nor any drug accumulation. Because the pharmacokinetics of orally administered S-1 is almost similar to that of continuous i.v. infusion of 5-FU, we concluded that S-1 may improve patients' quality of life.

Elevation of circulating plasma cytokines in cancer patients with high plasma parathyroid hormone-related protein levels.

Parathyroid hormone (PTH) and PTH-related protein/peptide (PTHrP) bind to the same PTH/PTHrP receptor and stimulate osteoblasts to secrete pro-inflammatory cytokines like interleukin (IL)-6. In patients with primary hyperparathyroidism, elevation of plasma levels of tumor necrosis factor (TNF)-alpha and IL-6 was also described. We, therefore, postulated that PTHrP secreted from cancer cells stimulates the secretion of cytokines and causes increases in their blood levels. Blood concentrations of several cytokines (TNF-alpha, IL-1beta, IL-5, IL-6, IL-8, IL-11 and IL-12) in cancer-bearing patients with or without elevation of blood PTHrP were measured by ELISA. The patients with high plasma PTHrP levels (n=29, intact PTHrP: 8.5 +/- 1.4 pmol/l, normal: <1.1) had higher serum type 1 collagen C-telopeptide (ICTP). Twenty of the patients were hypercalcemic. Plasma concentrations of TNF-alpha, IL-6 and IL-8 were significantly increased in patients with high PTHrP, in either the presence or absence of hypercalcemia. The concentrations of TNF-alpha and IL-6 were also significantly correlated with those of PTHrP. Our observations indicate that high plasma levels of PTHrP in cancer-bearing patients contribute not only to the development of hypercalcemia, but also to the development of the syndrome caused by an excess of pro-inflammatory cytokines.

Thymidylate synthase gene amplification in human colon cancer cell lines resistant to 5-fluorouracil.

A series of 5-fluorouracil (5-FU)-resistant human colon H630 cancer cell lines were established by continuous exposure of cells to 5-FU. The concentration of 5-FU required to inhibit cell proliferation by 50% (IC50) in the parent colon line (H630) was 5.5 microM. The 5-FU IC50 values for the resistant H630-R1, H630-R10, and H630-R cell lines were 11-, 29-, and 27-fold higher than that for the parent H630 cell line. Using both the radioenzymatic 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) binding and catalytic assays for measurement of thymidylate synthase (TS) enzyme activity, there was significantly increased TS activity in resistant H630-R1 (13- and 23-fold), H630-R10 (37- and 40-fold), and H630-R (24- and 34-fold) lines, for binding and catalytic assays, respectively, compared with the parent H630 line. The level of TS protein, as determined by western immunoblot analysis, was increased markedly in resistant H630-R1 (23-fold), H630-R10 (33-fold), and H630-R (26-fold) cells. Northern analysis revealed elevations in TS mRNA levels in H630-R1 (18-fold), H630-R10 (39-fold), and H630-R (36-fold) cells relative to parent H630 cells. Although no major rearrangements of the TS gene were noted by Southern analysis, there was significant amplification of the TS gene in 5-FU-resistant cells, which was confirmed by DNA slot blot analysis. These studies demonstrate that continuous exposure of human colon cancer cells to 5-FU leads to TS gene amplification and overexpression of TS protein with resultant development of fluoropyrimidine resistance.

Bone metabolic markers in bone metastases.

The efficacy and cost/performance benefit of radionuclide bone scintigraphy in monitoring metastatic bone activity remain controversial. Recently developed bone metabolic markers are expected to play an additional role in the diagnosis of bone metastasis. We measured osteoclastic and osteoblastic markers in 267 patients with breast cancer (100 with bone metastasis), 38 patients with prostatic cancer (25 with bone metastasis), 50 patients with lung cancer (12 with bone metastasis) and 33 patients with miscellaneous cancers (13 with bone metastasis) and compared the values in the presence and absence of bone metastasis. Bone metabolic markers, both osteoclastic and osteoblastic, increased significantly in patients with bone metastasis. In breast cancer (bone metastasis is mostly of the mixed type), osteoclastic markers were good in detecting bone metastasis. In prostatic cancer (bone metastasis is mostly osteoblastic), osteoclastic and osteoblastic markers were equally effective in detecting bone metastasis. In lung cancer (bone metastasis is mostly osteolytic), osteoclastic markers were elevated preferentially in bone metastasis. Over all, osteoclastic markers were more sensitive in the diagnosis of bone metastasis, and among osteoclastic markers, serum pyridionoline-cross-linked carboxyterminal telopeptide was the most efficient in both specificity (91.0%) and sensitivity (48.6%) for detecting bone metastasis.

The transient appearance of small blastoid cells in the marrow after bone marrow transplantation.

Of 14 patients who underwent allogeneic or syngeneic bone marrow transplantation, 6 had a transient appearance of small blastoid cells in the bone marrow after transplantation. Most of these patients (11) had leukemia, although 3 had severe aplastic anemia. The cells were 8-18 micron in diameter and had scant cytoplasm and dense nuclei with smooth, homogeneous chromatin. They often had distinct nuclear clefts. These cells constituted 4.0-21.3% of the total number of bone marrow cells. They were not reactive with peroxidase, alpha-naphtyl butylate esterase, naphthol AS-D chloroacetate esterase, or periodic acid-Schiff stains. Immunocytochemical analysis revealed that the small blastoid cells expressed terminal deoxynucleotidyl transferase, Ia-like, CD19, and CD10 antigens and cytoplasmic mu heavy chains, indicating a precursor B-cell phenotype. CD20 antigen was not expressed on these cells. The data suggest that cytoplasmic mu may be expressed earlier than CD20 antigen in the differentiation of B-cell lineage. The morphologic, cytochemical, and immunophenotypic characteristics did not distinguish these nonneoplastic cells distinctly from leukemic lymphoblastic cells. The increase of small blastoid cells was a transient and self-limited phenomenon, in contrast to that of neoplastic blasts. These cells should be recognized as a common component of the bone marrow of marrow transplant recipients. The significance and role of these cells in immune recovery and hematopoiesis remain uncertain.

The induction of peroxisome proliferation in rat liver by perfluorinated fatty acids, metabolically inert derivatives of fatty acids.

The induction of peroxisome proliferation in rat liver was examined after administration of perfluoro-n-decanoic acid (PFDA, C10), perfluoro-n-octanoic acid (PFOA, C8), perfluoro-n-butyric acid (PFBA, C4), 1-H,1-H-pentadecafluoro-n-octanol (PFOL, C8) perfluorododecane (PFD, C12), and perfluorooctane (PFO, C8). The peroxisome proliferation in the liver was detected by the following methods; 1) measurement of liver weight, 2) assay of hepatic catalase activity, 3) analysis of 600 X g supernatant of liver homogenates by SDS-polyacrylamide gel electrophoresis to observe the induction of the bifunctional enoyl-CoA hydratase in peroxisomes (80K-protein) and 4) observation by electron microscopy. The oral administration of powdered chow containing 0.02%-PFOA and PFBA to male rats of the Sprague-Dawley strain for 2 weeks and the single intraperitoneal injection of corn oil mixed with PFDA, PFOA, and PFOL at the dose of 100 mg/kg induced peroxisome proliferation markedly. PFOL, which has two hydrogen atoms around the hydroxylated carbon, should be metabolized to PFOA, which is an active inducer. Perfluorinated paraffins, PFD and PFO, did not show any induction, indicating the importance of the carboxylic group in the molecule for the peroxisome proliferation. Although the participation of thyroid hormone cannot be excluded, PFOA appears to act directly on the liver.

Isoforms of gp138, a cell-fusion related protein in Dictyostelium discoideum.

Sexual development of Dictyostelium discoideum is a unique and useful system for the study of sexual phenomena. We have been studying molecular mechanisms of sexual cell fusion in D. discoideum and have identified several relevant cell-surface proteins. One of the proteins, gp138, was identified as a target molecule for fusion-blocking antibodies, and two genes for gp138, GP138A and GP138B, were cloned. The participation of gp138 in the sexual cell fusion was confirmed by antisense RNA mutagenesis, but it is unclear which of the genes encodes gp138. Moreover, the presence of a third gene for gp138 was indicated by gene disruption. In the present study, we generated strains of D. discoideum overexpressing either GP138A or GP138B to investigate the products of these genes. The transformants overexpressing GP138A and GP138B overproduced glycoproteins with molecular masses of 135 and 130 kDa, respectively. Although their molecular masses were different from that of gp138, the results of peptide mapping and amino acid sequencing showed that they are related to proteins, suggesting that the proteins encoded by GP138A and GP138B are isoforms of gp138 protein.

Interferon-alpha and 5-fluorouracil therapy in patients with metastatic renal cell cancer: an open multicenter trial. The Japanese Study Group Against Renal Cancer.

OBJECTIVES: Recent clinical trials have implied the cytotoxic and antiproliferative effects of combining 5-fluorouracil and interferon-alpha in the treatment of metastatic renal cell cancer. We therefore conducted an open multicenter trial to test the efficacy of such a combination on this cancer. METHODS: Human lymphoblastoid interferon (3 MIU per patient) was administered subcutaneously three times weekly for 12 weeks, while 5-fluorouracil was administered (600 mg/m2/day) as a continuous infusion for the first 5 days, followed by an intravenous bolus infusion of 600 mg/m2 once a week from the 3rd week until the 12th week. RESULTS: Of the 63 patients entered into the trial, 55 were eligible and evaluable for systemic toxicities, and 53 were evaluable for their response. All patients had undergone a prior nephrectomy, and their European Cooperative Oncology Group (ECOG) performance status ranged from 0 to 3 (median 0). Three complete and eight partial responses were induced, with an overall response rate of 20.0%. The median time to progression and the median survival time were 11 and 33 months, respectively. World Health Organization grade 3 toxicities were observed in 8 patients; however, no grade 4 toxicities or toxicity-related deaths were noted. CONCLUSIONS: Combination therapy of interferon-alpha plus 5-fluorouracil at the above-described dosage and schedule produced no better responses than interferon monotherapies. Prolongation of survival could be attributable to the fair performance status of the patients. This regimen has limited value for the treatment of patients with advanced renal cell cancer.

Epirubicin-containing high-dose chemotherapy followed by autologous hematopoietic progenitor cell transfusion for patients with chemotherapy-sensitive metastatic breast cancer: results of 5-year follow-up.

PURPOSE: Conventional chemotherapy for metastatic breast cancer results in very few long-term survivors. With a view to overcoming this problem, we hypothesized that a higher rate of complete response (CR) would lead to more long-term survivors. Therefore, we conducted a phase II study of epirubicin-containing high-dose chemotherapy (HDC) followed by autologous hematopoietic progenitor cell transfusion in patients who were sensitive to induction chemotherapy. METHODS: The induction chemotherapy consisted of doxorubicin 60 mg/m2, cyclophosphamide 750 mg/m2 and fluorouracil 750 mg/m2 on day 1. Supported by G-CSF, this chemotherapy was repeated for at least three cycles at intervals of 2 weeks until the achievement of > 50% tumor regression. The HDC comprised epirubicin 120 mg/m2 on day 1, cyclophosphamide 60 mg/kg on days 1 to 3 and thiotepa 6 mg/kg on days 1 to 3, followed by autologous bone marrow transplantation and peripheral blood stem cell transfusion. RESULTS: Of 25 patients who achieved a partial response to the induction chemotherapy, 17 were treated with the HDC. Of the 15 patients evaluable for response, 10 achieved a CR (67%), giving an overall CR rate of 43% (10/25). The disease-free survival rate at 5 years was 27%. The median duration of overall survival was 21 months and the overall survival rate at 5 years was 31%. However, the survival curves were not significantly different from those of the historical controls who achieved a CR or PR to conventional chemotherapy. There were three early deaths, one as a consequence of disease progression and two treatment-related (sepsis and heart failure). Diarrhea (grade 3, 76%) and stomatitis (grade 3-4, 29%) were the dose-limiting toxicities. CONCLUSIONS: The present study suggests that epirubicin-containing HDC is able to induce a high rate of CR, but its benefit in terms of survival is still unclear. To determine whether HDC can achieve a cure in some patients, further studies in a larger number of patients, with a longer follow-up, are necessary.

The analysis of the innate pathways of 5-fluorouracil phosphorylation in human gastrointestinal cancer cell lines in vitro and in vivo.

Possible pathways of the phosphorylation of 5-fluorouracil (FUra) were investigated in vitro and in vivo, using certain xenografts, of human gastric and colorectal cancer cell lines. The oxonic acid (Oxo), an inhibitor of orotate phosphoribosyltransferase (OPRTase) that catalyzes the direct production of 5-fluorouridine 5'-monophosphate from FUra (the first pathway) and 2, 6-dihydroxypyridine (DP), an inhibitor of uridine phosphorylase (UPase), the enzyme converting FUra to 5-fluorouridine (the second pathway), were employed to estimate a contribution of these two metabolic pathways in the anabolism of FUra. Ten out of 13 cancer cell lines tested were found to utilize the first route for the phosphorylation of FUra, as revealed by marked inhibition of the phosphorylation of FUra by Oxo in 4 of 5 and in 6 of 8 gastric and colorectal cancer cell lines, respectively. The phosphorylation of FUra in the xenografts of human AZ521 gastric adenocarcinoma and SNU-C2A colorectal carcinoma was also regulated by Oxo, the production of 5-fluoro-nucleotides after i.v. injection of FUra with the Oxo significantly decreased from 0.587 to 0.311 nmol/g and from 1.75 to 0.40 nmol/g in respective xenografts, suggesting that the nature of an anabolic pathway of FUra in the tumor cells in vitro reflects the metabolic pattern found in the in vivo conditions. Moreover, the intracellular concentrations of phosphoribosylpyrophosphate (PPRibP) in DLD-1 and SNU-C(2)A cells were much higher than those found in HCT-15 and MKN-28 cells, leading to the findings that FUra was phosphorylated by OPRTase in the former and by UPase and uridine kinase in the latter cells. These results also may suggest that the intracellular levels of PPRibP in the tumor cells are importantly related to the selection of a proper metabolic pathway of FUra by the cell.

Detection and quantitation of thymidylate synthase mRNA in human colon adenocarcinoma cell line resistant to 5-fluorouracil by competitive PCR.

BACKGROUND: Thymldylate synthase (TS) is an important target of cancer chemotherapeutic agents, such as 5-fluorouracil (FU). To investigate mechanisms of resistance to FU, we tried to detect TS mRNA in the human colon adenocarcinoma cell lines. MATERIALS AND METHODS: SNU-C1 (C1) and its FU-resistant cell line, SNU-C1/FU (C1/FU) were used for this study. Total RNA was isolated by the AGPC method, then competitive PCR and northern blot were done to detect TS mRNA. RESULTS: Using sets of primers covering the 3'-untranslated region of TS mRNA, PCR products were amplified from cDNA prepared from both C1 and C1/FU in their logarithmic growth phases. However, only cDNA prepared from C1/FU was amplified in the stationary phase. The amount of mRNA was quantified by competitive PCR technique in both cell lines, using another set of primer to amplify the product in the stationary phase. The amount of TS mRNA in C1/FU was found to be four times more than that found in C1. In addition, TS catalytic activity of C1/FU was approximately 2-times higher than that of C1. Southern blot analysis revealed that no TS gene amplification or rearrangement in genomic DNA was detected in these cell lines. CONCLUSIONS: This PCR technique is applicable for detecting TS mRNA, and the TS mRNA level was found to be increased 1.5-fold (as detected by northern blot analysis) and 4-fold (measured by competitive PCR), leading to enhanced TS catalytic activity in C1/FU in contrast to its parent cell line, C1; thus accounting for one possible resistant mechanism to FU.

A case with athetosis, mental retardation, deafness, and pachygyria.

A 6-year-old girl with pachygyria was presented. Regions of pachygiria were seen in the frontal, temporal, and parietal areas in vivo by magnetic resonance imaging. She showed athetosis, mental retardation, deafness, short stature, and microcephalus, but did not show epilepsy. A combination of these symptoms may be a new clinical entity, caused by undetermined prenatal events.

A case of ataxic diplegia, mental retardation, congenital nystagmus and abnormal auditory brain stem responses showing only waves I and II.

A three-year-old boy who had ataxic diplegia, mental retardation, horizontal pendular nystagmus with head nodding and abnormal auditory brain stem responses showing only waves I and II was presented. His clinical features coincided with recent reports in the Japanese literature of cases of a new syndrome that is congenital in origin and seen only in boys.

New antibiotics, enaminomycins A, B and C. III. The structures of enaminomycins A, B and C.

The structures of enaminomycins A and B were determined by their physico-chemical properties and X-ray crystallographic analyses to be 4-amino-2,5-dioxo-7-oxa-bicyclo[4,1,0]hept-3-ene-3-carboxylic acid and 2-oxo-4-amino-5-hydroxy-5-acetonyl-7-oxa-bicyclo[4,1,0]hept-3-ene-3-carboxylic acid, respectively. The structure of enaminomycin C was also determined by the analysis of NMR spectrum and other physico-chemical properties to be 2-oxo-4-amino-5-hydroxy-7-oxa-bicyclo[4,1,0]hept-3-ene-3-carboxylic acid.

Pilot study of continuous low-dose 5-fluorouracil and cisplatin (FP regimen) for the treatment of metastatic breast cancer.

Background. The effect of low-dose 5-fluorouracil (FU) and cisplatin therapy (FP regimen) against metastatic breast cancer was investigated. Methods. A pilot study of the FP regimen was performed in 11 patients with metastatic breast carcinoma who had previously received chemotherapy, including adriamycin, and/or hormonal therapy. Their median age was 56 years (range, 48-72 years). Visceral metastases were present in all patients. FU, at a dose of 170 mg/m(2) per day, was administered for 28 days by continuous intravenous infusion. Cisplatin (7 mg/m(2) per day) was given intravenously on days 1-5, 8-12, 15-19, and 22-26. After a 2-week interval, this treatment was repeated. Results. Of the 11 patients assessable for tumor response to the FP regimen, 4 patients (36%; 95% confidence intervals [CI], 8%-64%) achieved an objective response, with 1 showing a complete response and 3 showing a partial response. Median time to progression was 6.5 months (range, 4-25 months). The median survival time from the initiation of the FP regimen was 11 months (range, 3-25 months). Gastrointestinal and hematologic toxicity was mild. Conclusion. The FP regimen is promising for and has acceptable tolerance in patients with metastatic breast carcinoma refractory to previous anthracycline-containing chemotherapy.

Reliability of data obtained by radionuclide angiocardiography in follow-up studies with special reference to intra- and interobserver variations.

The reproducibility of the data obtained by radionuclide angiocardiography was studied in terms of the intra- and intervariations of three technicians. Three parameters were chosen: the left ventricular ejection fraction (LVEF), the 1/3 filling fraction (1/3FF), and the ratio of the time from end systole to the point of peak filling rate against the entire diastolic period (TRPFR). First, each technician studied an independent consecutive series of 40 patients for the initial analysis. The original data of each patient, composed of 26 frames for one beat, were stored on an optical disc for the intra- and intervariation studies. In this study, analysis of the volume curve was performed by using both 3rd order and 4th order Fourier series. The region of interest (ROI) for the left ventricle, which was set for the initial analysis, was recorded by Polaroid photography to be used as a reference for the later analyses for the variation studies. The least variation was noted in the LVEF not only for the intravariation study but also for the intervariation study, no matter which order of the Fourier series was used. However, the 3rd order Fourier series seemed to give better curve fitting to avoid fluctuation of the diastolic parameters. The results indicate that we can expect more steady and reliable information from LVEF than from the diastolic parameters, even when various technicians perform the follow-up study of a particular patient.

Intrahepatic interleukin-2 with chemotherapy for unresectable liver metastases: a randomized multicenter trial.

BACKGROUND/AIMS: A pilot study of Interleukin-2 (IL-2) with chemotherapy for unresectable colorectal liver metastases revealed a favorable response rate (76%). This prospective, randomized, multicenter study was conducted to evaluate the efficacy of this treatment protocol. METHODOLOGY: Over a period of 32 months, 46 patients with unresectable liver metastases were randomly assigned to 1 of 3 treatment groups: group A: chemotherapy alone, group B: chemotherapy plus high-dose, intermittent IL-2 (2.1 x 10(6) U twice weekly) or group C: chemotherapy plus low-dose, continuous IL-2 (7 x 10(5) U daily). Treatment continued for 4 weeks in the hospital and on an outpatient basis according to the clinical response. No crossover between treatment arms was permitted. RESULTS: IL-2 combined with chemotherapy produced a higher complete and partial response rate of 40% in group A, 60% in group B, and 78% in group C. Toxicity related to IL-2 included fever, chills, malaise, and eosinophilia. CONCLUSIONS: Hepatic arterial infusion of chemotherapy plus IL-2 resulted in an increased tumor response when compared with chemotherapy alone. To confirm the efficacy of this treatment protocol, we have started a large-scale, randomized, multi-institution trial.

Minute findings of inner ear anomalies by three-dimensional CT scanning.

In actual clinical situations, inner ear anomalies must be diagnosed by image diagnosis such as high resolution CT-scanning of the temporal bone before three dimensional (3D) CT-scanning was introduced. In this paper, the usefulness of 3D-CT was investigated in some anomaly cases. It was found that 3D-CT was useful in observing the minute structure of the inner ear in that it could ascertain spatial relationships and minute constrictions and protrusions that could not be detected by 2D analysis. This CT was also capable of assessing the stage of embryological injuries and evaluating anomalies in cochlear turning that are the hidden factors of hearing impairment.

Cosinor analysis of feed intake cycle of rats fed a zinc-deficient diet and the effect of zinc supplementation.

Rats fed a Zn-deficient diet develop a characteristic cyclic variation in feed intake (Mills et al., Am J Clin Nutr 22: 1240-1249 (1969). A preliminary analysis (Tamaki et al., Br J Nutr 73: 711-722 (1995)) of the cyclic variations was followed with a personal computer. Cosinor analysis revealed that the cyclic period of the feed intake of male rats was 3.5 +/- 0.05 d. The mesor, amplitude and acrophase value were 10.0 +/- 0.3 g/d, 4.4 +/- 0.2 g/d and 3.5 +/- 0.3 radian, respectively. The cycle of body-weight change of the Zn-deficient rats was well synchronized with that of feed intake. The parameters of the feed intake cycle had a high correlation to the corresponding parameters of body-weight change (mesor: r = 0.846; amplitude: r = 0.771; period: r = 0.925; acrophase: r = 0.452). With the supplementation of Zn (0.95-3.80 mg/kg of the Zn-deficient diet), cyclic variations in feed intake and body-weight change were also found. The mesor, amplitude and period of feed intake cycle were is good correlation with Zn intake (r = 0.856, p < 0.001, r = 0.804, p < 0.001 and r = 0.613, p < 0.01, respectively). The cycle of feed intake of the rats fed a Zn-free diet was simulated to be: mesor 9.7 +/- 0.1 g/d, amplitude 6.5 +/- 0.1 g/d and period 3.4 +/- 0.02 d. The concentration of Zn intake given the half-maximal value of the amplitude was assumed to be 56 +/- 1 microgram/d.