The study of developmental pharmacology (I). Effect of pentazocine HCl on the physiology of rats given the drug during perinatal and postnatal periods (author's transl)

The effects of drug administration on the dams (F0) and their offspring (F1), particularly on the central nervous and reproductive functions of F1, were studied by oral administration of pentazocine HCl to rats during the perinatal and postnatal periods. No significant differences were observed between administered and control rats regarding body weight changes and food intake during perinatal and postnatal periods in F0 at all dosages, but temporary salivation was observed in the 200 and 100 mg/kg groups, and decline of spontaneous activity and respiratory rate, disappearance of righting reflex, clonic convulsion were observed in some of the 200 mg/kg group. No significant differences were observed regarding litter size, birth rate, state and timing of differentiation as postnatal development, sex maturity, reproductive function in F1, although some groups were slightly inferior in body weight at birth and during the nursing period. Furthermore, no differences were observed in respect to the nervous functions of balance, exercise and psychotic related activity in the open-field test.     

Clonal T cells of pure red-cell aplasia

This study detected clonal T cells in patients with acquired pure red-cell aplasia (PRCA) by Southern blotting and polymerase chain reaction (PCR). Twenty-nine adult patients with acquired PRCA were enrolled in this study. Seventeen patients had primary acquired PRCA, while 12 patients had the secondary form. Twenty-two of 29 (76%) patients demonstrated TCR rearrangement by at least one method. We divided the patients into three groups depending on T-cell clonality. The CD4/8 ratio of patients who were positive on Southern blotting was significantly lower than that of other groups. Except for the CD4/8 ratio, other laboratory findings did not significantly differ among the three groups. The CD4/8 ratio should be a useful surrogate marker to detect T-cell clonality.     

Histopathogenesis of early-stage mitral annular calcification

Mitral annular calcification (MAC) is a common condition in elderly subjects that sometimes causes degenerative mitral valvular diseases. To investigate the early histopathogenesis of MAC, we examined 180 consecutive autopsies of elderly subjects. After a macroscopic and radiological examination, 5-mm-thick serial tissue blocks obtained from the mitral annulus were examined in all MAC cases. Five cases without MAC were also studied using histology, immunostaining, electron microscopy, analytical electron microscopy and the TUNEL method. The incidence of MAC in females (23%) was higher than that in males (15%). Most MAC was located at the posterior cusp (91%). The mitral annulus showed signs of microscopic calcification and lipid-deposition in some degenerated areas in all of the cases without MAC. The interstitial cells were positive for vimentin and partially positive for smooth muscle actin, indicating the myofibroblastic differentiation. Ultrastructural studies showed an abundance of cellular degradation products and foci of calcium- and phosphorus-deposition on these products in the interstitium. Several interstitial cells tested positive for both single-stranded DNA immunostaining and the TUNEL reaction. In conclusion, the microscopic calcification of mitral annulus is an early stage of MAC and caused by calcium-deposition on cellular degradation products, probably released from apoptotic or necrotic interstitial cells.     

Association of estrogen receptor alpha gene polymorphisms with neurofibrillary tangles

Estrogen receptor alpha (ERalpha) may be implicated in the pathogenesis of Alzheimer's disease (AD). The aim of this study was to clarify the association between ERalpha gene polymorphisms and AD-related pathologic changes. The staging of neurofibrillary tangles (NFT) and senile plaques (SP) was performed according to the method by Braak and Braak and two polymorphisms, PvuII (P or p) and XbaI (X or x), of the ERalpha gene were typed in 551 Japanese cadavers (294 men and 257 women; mean age, 80.8 years). Distributions of the NFT and SP stages significantly correlated with age (NFT: r = 0.306, p < 0.0001; SP: r = 0.237, p < 0.0001) and were significantly higher in patients with the apolipoprotein E epsilon4 allele (p < 0.0001). Possession of the P allele showed a trend to be associated with a more serious NFT stage, but had no relationship with the SP stage. In men, a significant association between PvuII polymorphism and the NFT stage (p = 0.002) was found, revealing a gene- dose effect of the P allele. Similar results were obtained in the men without the epsilon4 allele (p = 0.011). Multiple regression analyses demonstrated that age was the strongest determinant of the NFT stage, possession of the epsilon4 allele was the next strongest, and PvuII polymorphism was the third strongest (p < 0.0001, R(2) = 0.144). The XbaI polymorphism did affect neither the NFT stage nor the SP stage. In conclusion, the PvuII polymorphism of the ERalpha gene is associated with Braak NFT stages and possession of the P allele may act as a risk factor for AD in Japanese men, especially in those without the epsilon4 allele.     

Marked decrease of intracranial atherosclerosis in contrast with unchanged coronary artery stenosis in Japan

We conducted comparative studies on intracranial atherosclerosis and coronary artery stenosis over the past 28 years. Two-year consecutive autopsy case studies from an urban geriatric hospital between 1974-1975 (Group I. 484 cases). 1986-1987 (Group II, 504 cases) and 2000-2001 (Group III, 273 cases) were employed. Atherosclerotic changes of the bilateral middle cerebral arteries and basilar artery were semiquantitatively evaluated as none (0), mild (1), moderate (2) and severe (3) and values of the 3 arteries were totalled to give a value of 0-9 which was taken as the intracranial atherosclerotic index (ICAI). The coronary stenotic index was calculated as previously reported (Sugiura et al 1969). ICAI and CSI were directly compared with each other, together with risk factors for each, including mean blood pressure (BP), serum level of total cholesterol (Tch) and the history of diabetes mellitus (DM+). Chronologically ICAI decreased dramatically but CSI did not change at all. There was continuous lowering of BP, elevation of Tch and increased incidence of DM+. There was a significant positive correlation in BP in relation to both ICAI and CSI (p < 0.01). DM+ vs. CSI (p < 0.01) and ICAI (p < 0.05), and Tch vs. CSI (p < 0.01) but not ICAI. Regression analysis highlighted age and BP as major risk factors for ICAI. Our study provides the first morphological confirmation of marked decrease of the intracranial atherosclerosis in the recent 28 years, in contrast with unchanged coronary stenosis in Japanese elderly subjects.     

Frequent chromosome arm 13q deletion in aggressive non-Hodgkin's lymphoma.

To clarify the role of allelic loss on chromosome arm 13q in lymphomagenesis, we performed fluorescence in situ hybridization (FISH) analysis of a total of 43 primary lymphomas, including both indolent and aggressive non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD), using the specific probes at RB1 and D13S319 loci on the centromeric portion of chromosome arm 13q. Monosomy at either or both RB1 and D13S319 loci was detected in 15 of 43 (35%) lymphomas (14 of 43 cases at RB1 locus and seven of 43 cases at D13S319 locus); the 13q deletion was frequently detected in the aggressive NHLs (40%; 12 of 30 cases) compared with that in indolent NHL (17%; one of six cases) and a subset of HD (29%; two of seven cases). There are only six cases of 43 which have total monosomy 13q14, all aggressive NHL, 14% of total or 20% of this subgroup. In addition, we analyzed the loss of heterozygosity in 15 of the 43 primary lymphoma samples for several polymorphic microsatellite loci (D13S168, RB1 and D13S272) on the chromosome arm 13q, and confirmed the 13q deletion in four of five cases that were positive on FISH analysis. The subchromosomal region frequently altered in lymphoma on 13q14 is the region around RB1 locus and centromeric to D13S319 locus, which is an overlapped region frequently deleted in chronic lymphocytic leukemia. Together, our data indicate that the 13q alterations are present in a variety of types of lymphoma and occur in a significant proportion of aggressive NHLs, suggesting the possible presence of common candidate gene(s) on the 13q14 region, whose alteration may play an important role in the formation or development of a wide variety of mature lymphoid malignancies.     

Elastic fibers in scar tissue: scanning and transmission electron microscopic studies

Cutaneous scar tissue (atrophic and hypertrophic) and normal dermis were examined using scanning (SEM) and transmission electron microscopy (TEM) as well as light microscopy (LM). Although LM revealed only a few Weigert stain-positive elastic fibers in scar tissue, SEM and TEM disclosed the presence of a large number of fine elastic fibers which was not present in normal dermis. Atrophic scar tissue contained more Weigert stain-positive fibers and fewer fine elastic fibers than hypertrophic scar tissue. In addition, finding suggestive of newly synthesized elastic fibers were seen in some hypertrophic scar tissue. These results indicate that there is elastogenesis in scar tissue.     

Isolation of Helicobacter cinaedi from blood of an immunocompromised patient in Japan

We report the isolation of Helicobacter cinaedi (previously called Campylobacter-like organism) from the blood of an immunosuppressed Japanese patient receiving immunosuppressive therapy after renal transplantation. The identification of H. cinaedi was based on the findings of microscopic examinations, biochemical properties, and 16S rRNA gene nucleotide sequences. H. cinaedi bacteremia should be considered as one of the critical infectious diseases in immunocompromised patients, and the sequencing of 16S rRNA may be a useful method to confirm the identification of this organism.     

Normal mortality in the elderly with diabetes under strict glycemic and blood pressure control: outcome of 6-year prospective study

Mortality, macroangiopathic events and end-stage renal disease (ESRD) in the elderly under long-term, intensive multifactorial diabetes control were prospectively investigated. Three hundred and eighty-eight elderly patients (> or =65 years) with type 2 diabetes (the mean age 72.9 years, men/women ratio 176/212) were followed-up for 6 years with HbA1c 7.0%, BP 145/80 mmHg and total cholesterol<240 mg/dl as targets. The mean baseline HbA1c was 6.8%, BP 137/74 mmHg and total cholesterol 196 mg/dl, and corresponding values upon closing 6.9%, 134/72 mmHg and 188 mg/dl respectively. Mortality rate was 19.6%/6 years (1.01 times that of age- and sex-matched general population), and macroangiopathic events developed in 142 (36.6%) and ESRD in 9 (2.3%). Independent risk factors: low glomerular filtration rate (GFR) (P<0.001), prior stroke (P=0.002), age (P=0.001) and DeltaBMI (P=0.001) for mortality; prior stroke (P<0.001) and coronary events (P=0.042), high LDL-cholesterol (P=0.004), low GFR (P=0.028), and past maximum BMI (P=0.032) and age (P=0.019) for macroangiopathy; low GFR (P<0.001) for ESRD. No smoking was an independent protective factor for mortality (P=0.008). In conclusion, normal mortality was attained in the elderly under intensive mutifactorial diabetes control. Renal dysfunction, prior stroke, high LDL-cholesterol, and prior obesity were prominent risks for mortality, macroangiopathy and/or ESRD.