Pharmacokinetic study of the oral fluorouracil antitumor agent S‐1 in patients with impaired renal function

Although dose reduction of S‐1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5‐fluorouracil, 5‐chloro‐2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S‐1 in patients with renal impairment. We classified patients receiving S‐1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S‐1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m²), 10 patients in cohort 2 (eGFR = 50‐79 mL/min/1.73 m²), 10 patients in cohort 3 (eGFR = 30‐49 mL/min/1.73 m²), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m²). Those in cohorts 3 and 4 treated with an adjusted dose of S‐1 showed a similar area under the curve for 5‐fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S‐1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S‐1 in patients with impaired renal function using eGFR is appropriate and safe.     

Case of autoimmune neutropenia with severe marginal periodontitis

Early onset periodontitis is rarely seen in infants, though often leads to an acute and serious clinical course when encountered in such patients. Autoimmune neutropenia presents systemic and dental symptoms, as depressed resistance to bacterial infection is caused by a disorder that reduces the number of neutrophils. This disease can result in not only gingival inflammation but also destruction of periodontal tissues, such as attachment loss, alveolar bone absorption, and early tooth loss in primary as well as mixed dentition. Here, we report treatment of a child with marginal periodontitis from the age of 3 years–7 years 9 months. No systemic manifestations were noted until 3 years of age, thus the patient had never received a detailed examination or medication related to the disease. Following examinations at our department, we referred the patient to a pediatrician at our university hospital for possible systemic disease, who made a diagnosis of autoimmune neutropenia. Although administration of antibiotics and professional dental care were continued, neutrophil count was not increased and progressive periodontal destruction was observed. Extraction of teeth with poor prognosis was performed and a prosthetic strategy for the missing teeth developed. It is important to recognize that periodontitis along with autoimmune neutropenia can appear in infants, even though the incidence is quite low. Early detection and early treatment of this disease is necessary for delaying progression of periodontitis and optimal occlusal induction of permanent teeth.     

Scintigraphic detection of recurrence of medullary thyroid cancer

A case of recurrent medullary thyroid cancer (MTC) was evaluated with¹²³I-MIBG,^99mTc(V)-dimercaptosuccinic acid (DMSA), and²⁰¹Tl scintigraphy. This patient had been operated on for MTC in the right thyroid. Recently a left neck mass was noticed, and was suspected of being a. recurrence of MTC based on increased plasma calcitonin (CT) and carcinoembryonic antigen (CEA). He was operated on for the neck mass which revealed MTC, and papillary thyroid cancer was incidentally found in the left thyroid, but the CT and CEA levels remained high, and remaining MTC tumor was suspected. But the location of the tumor was unknown. Although^99mTc(V)-DMSA scintigraphy is generally believed to be superior in sensitivity to¹²³I-MIBG scintigraphy, it did not demonstrate the tumor site but²⁰¹Tl and¹²³I-MIBG did. Furthermore,¹²³I-MEBG scintigraphy has greater specificity for tumors which arise in the neural crest. Judging from the results of this case and cases reported in the literatures, both¹²³I-MIBG and^99mTc(V)-DMSA should be performed in the detection of recurrent MTC.     

Research review: DNA polymerases as molecular markers of the regenerating capacity of hepatocytes

Hepatocyte regeneration has been widely investigated, with the mitotic index and the incorporation of [³H]thymidine being used as regeneration markers. We focused on the induction of DNA replication enzymes, particularly DNA polymerases (pol) α, δ, and ε. Using rat models, we have shown that the activity of pol α in crude liver extract well represents the regenerating capacity of hepatocytes. Using pol α as an indicator, we analyzed liver regeneration in rat models under various conditions: obstructive jaundice, external or internal biliary drainage, and the obstruction of portal vein branches. It has been revealed that the ligation of the common bile duct alone induces a certain amount of hepatocyte proliferation. It was striking that external biliary drainage suppressed regeneration capacity in cholestatic rat liver after partial hepatectomy. The strong regeneration in nonligated lobes induced by portal branch ligation was similar to the liver regeneration seen after partial hepatectomy with respect to the induction of DNA polymerases. Taken together, the aspects of DNA replication, particularly the induction of DNA polymerases, may contribute to shedding new light on the regeneration of human liver. This work was supported in part by a Grant-in-Aid for General Scientific Research and for Cancer Research from the Ministry of Education, Science and Culture, Japan, and by grants from the Uehara Memorial Foundation     

Off-pump resection of a coronary arterial fistula using the Harmonic Scalpel

Off-pump surgery was performed in a patient with post-infarction angina complicated with aneurysmal coronary-pulmonary arterial fistula. Epicardial echocardiography localized the artery feeding the fistula in the myocardium, which had not been revealed by visual inspection, palpation, or transesophageal echocardiography. The patient underwent off-pump coronary artery bypass grafting concomitant with aneurysmectomy. The feeding arteries were dissected easily using a Harmonic Scalpel and ligated. The flow in the aneurysm disappeared immediately and aneurysmectomy was performed without bleeding.     

Rapid isolation and characterization of 118 novel C2H2-type zinc finger cDNAs expressed in human brain

C2H2-type zinc finger genes comprise one of the largest genefamilies in the human genome. These proteins are involved ingenetic regulation and development and are quite conserved throughoutevolution. The finger domains commonly contain the small linkerpeptide TGEKP between some finger units. Here, we report theisolation of 133 human zinc finger cDNAs, of which 118 are novel.These clones were isolated from human brain cDNA libraries usingoligonucleotide hybridization followed by expressed sequencetag (EST) analysis, sequencing from the conserved linker regionusing degenerate oligonucleotide primers. This directed partialsequencing approach to cDNA isolation and characterization,signature sequencing, combines the speed of EST automatic sequencingwith the focus of specific cDNA family analysis. Signature sequencingminimizes the generation of less informative random EST sequencesand provides a unique relative position for sequence comparison.We also show that there is an even distribution of these RNA5from this brain cDNA library, and that these cDNAs contain N-terminaldomains found in other zinc finger genes. This rapid focusedsequencing approach should be applicable to any family of cDNAscontaining short conserved signature peptide sequences.     

Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome.

BACKGROUND: Gitelman's syndrome (GS) is an autosomal recessive disorder resulting from inactivating mutations in the thiazide-sensitive Na-Cl co-transporter (NCCT) gene. To date, almost 90 mutations have been identified. It is possible that there is a population-specific distribution of mutations. In this study, we analysed mutations in the NCCT gene of seven Japanese patients with GS. METHODS: Peripheral blood mononuclear cells were isolated from patients with GS, their family members and healthy control subjects. A mutation analysis of the NCCT gene was performed completely by direct automated sequencing of polymerase chain reaction-amplified DNA products. In patients with a deletion or splice site mutation, we undertook cDNA sequence analysis. RESULTS: We identified nine mutations. Five of them [c.185C>T (Thr60Met), c.1712C>T (Ala569Val), c.1930C>T (Arg642Cys), c.2552T>A (Leu849His) and c.1932delC] have been reported in Japanese patients, but not in GS patients from other ethnic groups. The remaining four mutations [c.7A>T (Met1Leu), c.1181_1186+20del26, c.1811_1812delAT and IVS16+1G>A] were novel. In cDNA derived from a patient with c.1181_1186+20del26, a deletion of exon 9 and a frameshift at the start of exon 10 were observed. In cDNA derived from patients with IVS16+1G>A, an additional 96 bp insertion between exons 16 and 17 was observed. Six out of seven patients were compound heterozygotes, and the remaining one carried a single heterozygous mutation. CONCLUSIONS: We found four novel mutations in the NCCT gene in seven Japanese patients with GS. Moreover, our study suggests that the distribution of mutations in the NCCT gene in Japanese GS patients potentially differs from that in other populations.