Histopathological study on the effects of aging in myocardium of hypertrophied hearts

To clarify the effects of aging in myocardium of hypertrophied hearts, 555 autopsied hearts were studied histopathologically. Degrees of myocyte hypertrophy, disarrangement and fibrosis and lipofuscin deposits were estimated light-microscopically in tissue specimens taken from the anterior wall of the left ventricle. Myocyte hypertrophy was assigned to one of four classes from 0 to 3+ according to size. Other findings were estimated using the conventional three classes. All cases were divided according to heart weight, into the following groups: severe hypertrophy (Group I; more than 450 g for males and 400 g for females), mild hypertrophy (Group II; 450 greater than HW greater than 350 g for males and 400 greater than HW greater than 300 g for females) and no hypertrophy (Group III: less than 350 g for males and 300 g for females). Lipofuscin deposits increased with aging, but in Group I the increase was delayed in comparison to that in other groups. As a rule, myocyte size in the outer layer was equal to or smaller than that in the inner layer (outer-layer-selective atrophy). This was particularly true in pressure-overloaded hypertrophy and less so in volume-overloaded hypertrophy. Myocyte disarrangement was observed in the inner and median layers in the oldest group. Peri-vascular fibrosis became thick with aging, and perimysial fibrosis increased with age. The fibrotic process was accelerated in hypertrophied myocardium. As to the mode of hypertrophy, aging appears to result in a kind of myocardial asymmetry of layer-selective atrophy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ketamine Suppresses Platelet Aggregation Possibly by Suppressed Inositol Triphosphate Formation and Subsequent Suppression of Cytosolic Calcium Increase

Background: Ketamine has been shown to suppress platelet aggregation, but its mechanisms of action have not been defined. The purpose of the current study is to clarify the effects of ketamine on human platelet aggregation and to elucidate the underlying mechanisms of its action.

Methods: Platelet aggregation was measured using an eight-channel aggregometer, and cytosolic free calcium concentration was measured in Fura-2/AM-loaded platelets using a fluorometer. Inositol 1,4,5-triphosphate (IP3) was measured with use of a commercially available IP3 assay kit. To estimate thromboxane A2 (TXA2) receptor binding affinity and expression, Scatchard analysis was performed using [3H]S145, a specific TXA2 receptor antagonist. TXA2 agonist binding assay was also performed. The membrane-bound guanosine 5'-triphosphatase activity was determined using [[gamma]-32P]guanosine triphosphate by liquid scintillation analyzer.

Results: Ketamine (500 [mu]m) suppressed aggregation induced by adenosine diphosphate (0.5 [mu]m), epinephrine (1 [mu]m), (+)-9,11-epithia-11,12-methano-TXA2 (STA2) (0.5 [mu]m), and thrombin (0.02 U/ml) to 39.1 +/- 30.9, 46.3 +/- 4.3, -2.0 +/- 16.8, and 86.6 +/- 1.4% of zero-control, respectively. Ketamine (250 [mu]m-1 mm) also suppressed thrombin- and STA2-induced cytosolic free calcium concentration increase dose dependently. Although ketamine (2 mm) had no effect on TXA2 receptor expression and its binding affinity, it (1 mm) suppressed intracellular peak IP3 concentrations induced by thrombin and STA2 from 6.60 +/- 1.82 and 4.39 +/- 2.41 to 2.41 +/- 0.98 and 1.90 +/- 0.86 pmol/109 platelets, respectively, and it suppressed guanosine triphosphate hydrolysis induced by thrombin (0.02 units/ml) and STA2 (0.5 [mu]m) to 50.3 +/- 3.2 and 67.5 +/- 5.5%versus zero-control, respectively.     

Neutrophil elastase inhibitor reduces hepatic metastases induced by ischaemia-reperfusion in rats.

OBJECTIVE: To investigate the possibility in rats that ONO-5046 Na, a new recombinant inhibitor of neutrophil elastase, can reduce hepatic metastases induced by ischaemia-reperfusion. DESIGN: Laboratory experimental study. SETTING: Research laboratory, Japan. SUBJECTS: Male Fischer rats. INTERVENTIONS: Rats underwent 60 min of 70% partial hepatic ischaemia, after which rat colon adenocarcinoma cells (RCN-H4) were injected into the spleen. The animals were divided into two test groups and a control group. One group was given ONO-5046 Na intravenously at 10 mg/kg/hour. A second group was given a saline solution for the same period, while the controls were not made ischaemic. MAIN OUTCOME MEASURES: Three weeks after inoculation, the number of tumour nodules on the liver surface was counted. The anti-cancer effect of ONO-5046 Na was measured by monotetrazolium assay. RESULTS: Hepatic ischaemia-reperfusion increased the number of liver metastases of RCN-H4 in both clamped and unclamped hepatic lobes. ONO-5046 Na significantly inhibited this in unclamped lobes, but had no anti-cancer effect. CONCLUSION: Neutrophil elastase may have an important role in increasing haematogenous liver metastases by ischaemia-reperfusion, particularly in unclamped lobes.     

Genetic alteration in carcinoid tumors of the lung.

Surgically resected specimens of 13 carcinoid tumors of the lung including nine typical carcinoids and four atypical carcinoids, and eight salivary gland type carcinomas (six mucoepidermoid carcinomas and two adenoid cystic carcinomas) were analyzed regarding p53 expression, loss of heterozygosity (LOH) in chromosome 3p, 9p, and K-ras mutation. The overexpression of p53 was identified in four atypical carcinoid tumors, one mucoepidermoid carcinoma, and one adenoid cystic carcinoma, however, none of typical carcinoids showed p53 immunoreactivity. LOH in 3p14 was demonstrated in three of seven informative cases in all tumors. LOH in 9p was demonstrated in two of five informative cases in all tumors. Two of three cases with LOH at 3p14 had a poor prognosis, one of which also had LOH at 9p. No mutation of the K-ras gene was observed in any of these tumors. These data thus indicate that p53 overexpression might distinguish atypical carcinoid tumors from typical tumors and might therefore be useful as an adjunct modality in the differential diagnosis of pulmonary carcinoid tumors. The presence of LOH at 3p14 or 9p may thus help to identify lung cancer patients with a poor prognosis.     

Intrinsic healing capacity and tearing process of torn supraspinatus tendons: In situ hybridization study of α1(I) procollagen mRNA

To determine the healing potential and healing process of torn supraspinatus tendons, in situ hybridization was used to localize cells containing α1 type-I procollagen mRNA. Biopsy specimens of torn supraspinatus tendons from 19 patients with complete-thickness tears and 13 patients with incomplete-thickness tears were obtained during surgery. Four macroscopically normal supraspinatus tendons were obtained to serve as normal controls. Specimens were fixed in 10% buffered formalin and embedded in paraffin. A 22-mer oligonucleotide probe was labeled with digoxigenin and used as an in situ marker. The labeled cells were mainly composed of tenocytes and undifferentiated mesenchymal cells. In complete-thickness tears, the labeled cells at the proximal tendon stumps in the specimens that were obtained less than 4 months after trauma were significantly more abundant than in the specimens obtained 4 months or more after trauma. However, the number of labeled cells was maintained at the torn portion even in long-standing incomplete-thickness tears. The labeled cells at the margins of concomitant intratendinous extensions of the tears were detected even in the long-standing tears. The intratendinous extensions exhibited more labeled cell than were bursal-side or joint-side layers of the tendon substance in the incomplete-thickness tears (p < 0.05). The torn supraspinatus tendon may possess an intrinsic healing capability in the intermediate and late phases of tendon healing. Incomplete-thickness tears and concomitant intratendinous extensions can continue to rupture after the initial injury.     

The relationship between cerebral white matter changes, mental function and blood pressure in normal elderly

The authors examined the relationship between cerebral white matter changes and mental function, blood pressure in 39 neurologically normal aged (21 males, 18 females, mean age 75.0 years) who had no latent lesions on MRI images. The severity of cerebral white matter changes was estimated by T1 value images on MRI and was measured in the bilateral frontal lobe on an axial slice at the level of the basal ganglia and in the bilateral anterior, middle, and posterior portions on axial slices at the level of the body of the lateral ventricle. Mental function was measured by the Hasegawa's dementia rating scale (HDS) and Kohs' block design test (Kohs' test). The severity of cerebral frontal white matter changes increased significantly with age (p less than 0.05). However there was no significant correlation between the severity of cerebral white matter changes and HDS, Kohs' test. The severity of frontal white matter changes correlated with the mean arterial blood pressure (p less than 0.02). These results suggest that the severity of cerebral white matter changes is not related with mental function in the normal elderly, and that the severity of frontal white matter lesions is related with mean arterial blood pressure.     

Role of p53 mutations in endocrine tumorigenesis: mutation detection by polymerase chain reaction-single strand conformation polymorphism.

To elucidate the molecular basis for endocrine tumorigenesis, p53 mutations in human endocrine tumors were analyzed by using polymerase chain reaction-single strand conformation polymorphism. Exons 5 through 10 of the p53 gene were studied in genomic DNAs from 134 primary endocrine tumors and 6 human endocrine cancer-derived cell lines. Mutations were detected and identified in 4 endocrine tumors, including one parathyroid adenoma and three thyroid carcinoma cell lines. The sites of these mutations were in exons 5 (codon 151 and 152) and 7 (codon 248 and 255). In all of three tumor cell lines, but not in a parathyroid adenoma, the normal allele encoding the p53 gene was lost. However, p53 mutations were not found in any other endocrine tumors or cell lines. Based upon these results, we concluded that the p53 gene may play a role in the tumorigenesis of a limited number of parathyroid adenoma and thyroid cancers, and that the p53 mutation with an allelic loss of the p53 gene is an important factor in malignant tumorigenesis of the thyroid gland.     

Detection limit in low-amplitude EEG measurement.

Electrocerebral inactivity for the determination of cerebral death is defined as no findings of EEG greater than the amplifier's inherent internal noise level when recording at increased sensitivity. A surface biopotential electrode contains two interfaces composed of skin gel (electrolyte) and gel electrode (metal), each forming a noise source. The power spectral density, S(f), of extremely low noise signals was obtained by means of autocorrelation and fast Fourier transformation. Interelectrode resistance, R(f), was measured with synchronous rectification. The formula of equivalent noise resistance R(n) = S(f)/4kT, where k is the Boltzmann constant and T is room temperature in Kelvin, gives a resistance that generates the thermal noise corresponding to the measured S(f). Rn/R is a parameter derived from normalization by R. When Rn/R = 1, measured noise contains thermal noise only. Meanwhile, Rn/R > 1 indicates presence of excess noise, such as 1/f, and tissue noise in addition to the thermal noise. Mean square root (Rn/R) of the scalp noise was 10.8 at 10 Hz, showing existence of excess noise. The study results suggest that it is necessary to take excess noise into consideration in the measurement of low-amplitude EEG for the determination of cerebral death.     

T Cell Receptor Vβ Repertoires of Angioimmunoblastic Lymphadenopathy-like T Cell Lymphoma

To elucidate the pathogenesis of angioimmunoblastic lymphadenopathy-like T cell lymphoma (AILD-T) we investigated the T cell receptor Vβ gene repertoires of four AILD-Ts and compared them with those of other histological types of lymphomas and three cases with reactive disorders. All lymphoma patients had rearrangement bands detected by Southern blot analysis. Only 1 of the 4 cases of AILD-T showed a single predominant usage of Vβ 20 gene by PCR with 20 different Vβ specific primers and the others had repertoires somewhat restricted but similar to reactive lesions. Subsequent sequencing of this PCR product revealed that only 2 of 7 clones were identical. These results suggest the monoclonal malignant cells in AILD-T are scant and that the infiltrating T cells show a reactive pattern. In the only AILD-T case with a single dominant Vβ usage, the relationships of this repertoire and lymphoma cells seems to be of some consequence.     

Late Effects of Childhood Acute Leukemia and Its Treatment

Late effects of childhood acute leukemia and its treatment were studied in 766 patients (684 ALL, 73 ANLL, and 9 others) in Japan who had remained in remission for more than 1 year after their first complete remission. Delayed adverse sequelae involve a wide variety of organs and their functions. Short stature was present in 2.61%, obesity in 3.79%, abnormalities of growth hormone secretion in 1.5%, delayed secondary sex characteristics in 1.5% of males and 0.6% of females, motor disturbances in 1.17%, sensory disturbances in 0.91%, intellectual and learning disabilities in 2.48%, abnormal findings in routine neurologic examinations in 1.31%, EEG abnormalities in 4.30%, brain CT abnormalities in 5.09% and cardiac dysfunction in 1.07%. Various other disorders were seen in 20 patients. Many of these delayed adverse sequelae are caused by or related to central nervous system prophylaxis and systemic combination chemotherapy. The results suggest that it is needed to improve therapeutic methods through the stratification of patients by risk factors and detailed analysis of prognostic factors. Moreover it is important to render medical and psychosocial support to long-term survivors of childhood leukemia through interactions between the patient, parents and medical staff.