Loss of heterozygosity on chromosome 9q22.3 in microdissected basal cell carcinomas around the Semipalatinsk Nuclear Testing Site, Kazakhstan

A high incidence of skin cancers has been noted around the Semipalatinsk Nuclear Testing Site (SNTS) in Kazakhstan. Recently, basal cell carcinoma (BCC) susceptibility genes, human homolog of the Drosophila pathed gene (PTCH), and the xeroderma pigmentosa group A-complementing gene (XPA), have been cloned and localized on chromosome 9q22.3. To clarify the effect of low-dose irradiation on the occurrence of BCC, we used microdissection and polymerase chain reaction to identify loss of heterozygosity (LOH) at 9q22.3 using BCC samples obtained from this region. Ten Japanese samples were analyzed as controls. LOH with at least 1 marker was identified in 5 of 14 cases from around SNTS, whereas only 1 case with 1 marker was identified among the 10 Nagasaki cases. The total number of LOH alleles from SNTS (8 of 45) was significantly higher than the number from Nagasaki (1 of 26) (P = 0.03). The higher incidence of LOH on 9q22.3 in BCC from around SNTS suggests involvement of chronic low-dose irradiation by fallout from the test site as a factor in the cancers.     

Immunohistochemistry and angiography in adenomatous hyperplasia and small hepatocellular carcinomas

The sinusoidal structure and blood supply of 38 liver nodules less than 2 cm In diameter were Investigated. There were 18 cases of adenomatous hyperplasia (AH) and 20 cases of hepatocetlular carcinoma (HCC). Growth pattern, encapsulation and vascularity were examined, and Immunohistochemistry performed for factor VIII related antigen (factor VIII), type IV collagen (collagen IV), lamlnln and CD68. There were significant differences between AH and small HCC, except for the expression of CD68. There were differences In tumor size, vasculartty and the components of the basement membrane between AH and small, well differentiated HCC. The cases of AH were supplied by the portal system and maintained the sinusoidal structure, but small well-differentiated HCC were supplied by a mixture of portal and arterial vessels. In spite of their small size, moderately and poorly differentiated HCC had capillary and were supplied by branches of the hepatic artery.     

High-grade dysplasia associated with fundic gland polyposis in a familial adenomatous polyposis patient, with special reference to APC mutation profiles.

We report a patient with familial adenomatous polyposis who developed high-grade dysplasia against a background of fundic gland polyposis. Two large high-grade dysplasia lesions were found in the gastric body, where numerous fundic gland polyps were present. In both lesions, the dysplastic epithelium covered non-neoplastic oxyntic glands that occasionally exhibit cystic changes. A genetic analysis for APC (adenomatous polyposis coli) revealed a somatic 50-bp deletion involving codons 1502-1517 and 2-bp deletion at codon 1465 in each lesion of high-grade dysplasia. In contrast, six of the 18 fundic gland polyps were found to harbor an identical mutation: 1-bp insertion at codon 1556. Both lesions of high-grade dysplasia and the fundic gland polyps were similarly located in the fundic gland area and were caused by the inactivation of APC; however, their mutation profiles of APC were different. These results imply that fundic gland polyps and high-grade dysplasia of the stomach have distinct preferences for APC genotypes in their development.     

Temperature sensitive effects of alpha-adrenergic stimulation in mouse ventricular myocardia

The effects of alpha- and beta-adrenergic stimulation on the contractile force and L-type Ca2+ channel current were studied in mouse ventricular myocardia at two different temperatures. In ventricular tissue, at 35-36 degrees C, phenylephrine, in the presence of propranolol, produced a sustained negative inotropic response with no change in the time course of contraction and relaxation. These effects were greatly reduced at 22-23 degrees C. Isoproterenol produced marked positive inotropic responses accompanied by shortening of the time required for relaxation. In isolated ventricular myocytes, phenylephrine, in the presence of propranolol, significantly increased the L-type Ca2+ channel current (I(Ca)) at 35-36 degrees C, but the effect was small at 22-23 degrees C. Isoproterenol increased I(Ca) similarly at both temperatures. These results suggest that, in mouse ventricular myocardia, alpha-adrenoceptor mediated regulation of the contractile force and I(Ca) involve temperature-dependent mechanisms different from those of beta-adrenoceptor-mediated mechanisms.     

Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma

We examined alterations of the p16INK4, p14ARF, p15, TP53, and MDM2 genes in 30 osteosarcomas and 24 Ewing sarcomas. Among 21 osteosarcomas and 24 Ewing sarcomas, p16INK4, p14ARF, and p15 abnormalities were found in 4 (19%), 2 (9%), and 3 (14%) osteosarcomas, respectively, and in 4 (17%), 3 (13%), and 4 (17%) Ewing sarcomas, respectively. The alterations of p16INK4, p14ARF, and p15 included homozygous deletions spanning all 3 genes, methylation of p16INK4 or p15, and a nonsense mutation of p16INK4, which simultaneously caused a missense mutation of p14ARF. Alterations of TP53 were found in 15 (50%) of 30 osteosarcomas and 1 (3%) of 24 Ewing sarcomas. None of the sarcomas showed MDM2 amplification. While TP53 abnormalities were far more frequent in osteosarcoma than in Ewing sarcoma, alterations of p16INK4, p14ARF, and p15 were present at similar frequencies in the two types of sarcoma. The event-free survival (EFS) was worse in Ewing sarcoma patients with p16INK4 and p14ARF mutation/deletion than in those without the mutation/deletion (P = 0.019), and EFS was worse in osteosarcoma patients with TP53 alterations than in those without TP53 alterations (P = 0.048). The different incidence of TP53 abnormalities in the 2 types of sarcoma may reflect differences of the molecular processes through which the 2 types of tumor develop.     

Prenatal diagnosis of short-rib polydactyly syndrome type 3 (Verma-Naumoff type) by three-dimensional helical computed tomography

We present a case of short-rib polydactyly syndrome (SRPs) type 3 in which accurate prenatal diagnosis was feasible using both ultrasonography and 3D-CT. SRP encompass a heterogeneous group of lethal skeletal dysplasias. However, the phenotypes overlap with those of nonlethal skeletal dysplasias (i.e. Ellis-van Creveld syndrome and Jeune syndrome). As accurate prenatal diagnosis of SRP is helpful for parents, we used 3D-CT in the early third trimester to examine a fetus suggested to have phenotypes of 'short-rib dysplasia group' on ultrasonography. 3D-CT showed mild modification of the vertebral bodies, small ilia with horizontal acetabula and triangular partial ossification defects, and subtle metaphyseal irregularities of the femora. These CT findings and an extensive literature search regarding the phenotypes of various diseases categorized as short-rib dysplasia group led to a correct prenatal diagnosis of SRP type 3. This case exemplified the usefulness of 3D-CT for the precise prenatal diagnosis of skeletal dysplasias.     

Effect of aging on heart rate and blood pressure variabilities in healthy men and women

OBJECT: To clarify the effect of aging and gender on heart rate and blood pressure variability in healthy men and women. SUBJECT AND METHODS: One hundred ninety four healthy subjects aged from 20 to 70(97 men and 97 women) were examined. Heart beat and blood pressure during 5 minutes in the supine and standing positions were measured under a respiration rate of 15/min. Blood pressure and heart were measured with Finapres and Biotop, respectively. Data entry and spectral analysis were carried out by the Fast Fourier Transform(FFT) method with BIMUTAS-II, after correcting 256 data with Hanning window function and resampling at 200 Hz. RESULT AND DISCUSSION: High frequency power(HF: 0.15-0.50 Hz) of heart rate variability decreased with age in both men and women, Low frequency power (LF: 0.05-0.15 Hz) of systolic blood pressure(SBP) variability in the standing posture decreased with age in men. The HF of SBP variability in the standing posture was decreased with age in both men and women. These findings suggest that aging and gender affected heart rate and blood pressure variability.     

906 variations among 27 genes encoding cytochrome P450 (CYP) enzymes and aldehyde dehydrogenases (ALDHs) in the Japanese population

 We screened DNAs from 48 Japanese individuals for single-nucleotide polymorphisms (SNPs) in genes encoding 13 cytochrome P450 (CYP) enzymes and 14 aldehyde dehydrogenases (ALDHs) by directly sequencing their entire genomic regions except for repetitive elements. This approach identified 810 SNPs and 96 insertion/deletion polymorphisms among the 27 genes. Of the 810 SNPs, 229 were identified among the CYP genes and 581 in the ALDH genes; of the total, 48 SNPs were located in 5′ flanking regions, 619 in introns, 91 in exons, and 52 in 3′ flanking regions. These variants should contribute to studies designed to investigate possible correlations between genotypes and phenotypes of disease susceptibility or responsiveness to drug therapy. Received: April 23, 2002 / Accepted: April 25, 2002     

Kidney enlargement and multiple liver cyst formation implicate mutations in PKD1/2 in adult sporadic polycystic kidney disease

Distinguishing autosomal‐dominant polycystic kidney disease (ADPKD) from other inherited renal cystic diseases in patients with adult polycystic kidney disease and no family history is critical for correct treatment and appropriate genetic counseling. However, for patients with no family history, there are no definitive imaging findings that provide an unequivocal ADPKD diagnosis. We analyzed 53 adult polycystic kidney disease patients with no family history. Comprehensive genetic testing was performed using capture‐based next‐generation sequencing for 69 genes currently known to cause hereditary renal cystic diseases including ADPKD. Through our analysis, 32 patients had PKD1 or PKD2 mutations. Additionally, 3 patients with disease‐causing mutations in NPHP4, PKHD1, and OFD1 were diagnosed with an inherited renal cystic disease other than ADPKD. In patients with PKD1 or PKD2 mutations, the prevalence of polycystic liver disease, defined as more than 20 liver cysts, was significantly higher (71.9% vs 33.3%, P = .006), total kidney volume was significantly increased (median, 1580.7 mL vs 791.0 mL, P = .027) and mean arterial pressure was significantly higher (median, 98 mm Hg vs 91 mm Hg, P = .012). The genetic screening approach and clinical features described here are potentially beneficial for optimal management of adult sporadic polycystic kidney disease patients.     

Initial experience in Japan with HeartWare ventricular assist system

We describe the first clinical experiences in Japan with the HeartWare ventricular assist device (HVAD: HeartWare Inc., Miami Lakes, FL, USA) in patients awaiting heart transplantation. Nine patients (6 males, 3 females; mean 33.5 ± 7.8 years; New York Heart Association class III or IV) received the HVAD as a bridge to transplantation between 2011 and 2012. Six had dilated cardiomyopathy, 2 secondary cardiomyopathy, and 1 dilated phase hypertrophic cardiomyopathy. All operations were uneventful, with a mean operation time of 269 ± 77 min and cardiopulmonary bypass time of 121 ± 40 min. One required a temporary right ventricular assist device and was weaned on postoperative day 20, while another required pump exchange due to foreign tissue in the inflow. Mean support duration was 245 ± 162 days (range: 50–535 days) and mean pump blood flow at 1 month postoperatively was 4.8 ± 0.8 l/min. There was no mortality after 30 days, though 1 patient died during support due to cerebral hemorrhage. Presently, the others are waiting for heart transplantation without problems, except 1 who suffered from an active infection. There was no pump mechanical failure in any case. The HeartWare pump enables quick implantation with acceptable morbidity and mortality. Our preliminary results indicate that this left ventricular assist device is safe for circulatory assistance for heart transplant candidates in Japan.