Familial amyloidotic polyneuropathy (ATTR Ser50Ile): the first autopsy case report

We report an autopsy case of a pedigree of familial amyloidotic polyneuropathy (FAP) with a mutation of isoleucine-50 transthyretin (ATTR Ser50Ile). A 47-year-old man started developing severe diarrhea and weight loss at age 41 years, followed by urinary incontinence, autonomic-nervous-system abnormalities and serious heart failure; the diagnosis of FAP (ATTR Ser50Ile) was made on the basis of genetic, histochemical and immunohistochemical analysis. Six years after the initial symptoms, he died of septic shock. Autopsy revealed suppurative peritonitis, perforation of the sigmoid colon and marked systemic amyloid deposition. The total amount of amyloid deposited in the heart was greatly increased and was much lower in the thyroid gland and kidneys compared with amyloid deposits in ordinary FAP (ATTR Val30Met). Amyloid deposition in peripheral vessel walls was prominent, particularly in lymphatics and veins. His elder sister, 54 years old, started to develop orthostatic hypotension at age 49 years, followed by dysesthesia, diarrhea and severe congestive heart failure. Endomyocardial biopsy revealed severe TTR–amyloid deposition; ultrastructural examination demonstrated that amyloid fibrils were deposited disproportionately and extended radially around microvessels. These characteristic patterns of systemic amyloid deposition and distinct clinical manifestations, especially in the cardiovascular system, are considered to be a characteristic feature of ATTR Ser50Ile amyloidosis. Received: 31 August 1999 / Accepted: 19 October 1999     

Autosomal linkage analysis of a Japanese single multiplex schizophrenia pedigree reveals two candidate loci on chromosomes 4q and 3q.

We analyzed a large multiplex schizophrenia pedigree collected in mid-eastern Japan using 322 microsatellite markers distributed throughout the whole autosome. Under an autosomal-dominant inheritance model, the highest pairwise LOD score (LOD = 1.69) was found at 4q (D4S2431: theta = 0.0), and LOD scores at two other loci 3q (ATA34G06) and 8q (D8S1128) were 1.62 and 1.46, respectively. In multipoint analysis, LOD scores of the regions on 4q and 3q remained at a similar level; however, the LOD score of the region on 8q apparently decreased. Additional dense map analysis revealed haplotypes on 4q and 3q regions shared by affected individuals. On chromosome 4q, the haplotype spanning about 8 centiMorgans (cM) was shared by four of six genotyped individuals with schizophrenia and one affected individual whose haplotype was estimated. On 3q, the haplotype spanning about 20 cM was shared by five genotyped individuals with schizophrenia. We obtained two candidate regions of major susceptibility loci for schizophrenia on chromosomes 3q and 4q.     

Intra-uterine physical growth in schizophrenia: evidence confirming excess of premature birth

BACKGROUND: Many studies have suggested a possible aetiological role for obstetric complications in the development of schizophrenia. We focused on prenatal physical growth in schizophrenia, a contentious issue in the literature. METHODS: We compared gestational age at birth, birth weight (BW) and birth head circumference (BHC) between 312 schizophrenics and 517 controls, and between 187 schizophrenics and their matched healthy siblings. Information on obstetric histories was obtained from the Maternal and Child Health Handbooks (i.e. contemporaneous records). RESULTS: Gestational age at birth was significantly earlier in the schizophrenics than in the controls (P = 0.017). Pre-term birth (gestational age of 36 weeks or less) was more common in schizophrenics than in controls (8.0% v. 3.4%, P = 0.005, odds ratio 2.5). Low BW (2500 g or less) was more frequent in schizophrenics than in controls (9.6% v. 4.6%, P = 0.005, odds ratio 2.2). The schizophrenics had significantly lighter BW (P = 0.0003) and tended to have smaller BHC (P = 0.081) compared with controls. However, multiple regression analysis showed that there was no significant difference in BW or BHC between the schizophrenics and controls when gestational age and maternal weight were controlled. There was no significant difference in BW or BHC between schizophrenics and their siblings, although the schizophrenics tended to be born at earlier gestational age than their siblings. CONCLUSIONS: Our results suggest that prematurity at birth is associated with a risk of developing schizophrenia in adulthood. When gestational age and maternal body weight were allowed for, there was no evidence that schizophrenics tend to have lower mean BW or smaller BHC.     

Increase in choroidal blood flow in rabbits with endothelin-1 induced transient complete obstruction of retinal vessels

Background: In a previous paper, we reported that retinal blood flow (RBF) ceased immediately after injection of 1 nmol endothelin-1 (ET-1) and no recovery of RBF was detected for at least 50 min. In this study, we confirmed the same duration of RBF cessation and measured choroidal blood flow (CBF) for 180 min. Methods: We measured CBF in a rabbit model of transient complete obstruction of retinal vessels induced by intravitreal injection of a high dose of ET-1, using the hydrogen clearance method. We also investigated the effects of intravitreal injection of ET-1 on intraocular pressure (IOP), blood pressure, pulse rate and blood gases. Results: CBF was significantly greater in the ET-1-injected eyes than in the control eyes 40–130 min after injection of ET-1 (P < 0.05). The maximal CBF ratio in the ET-1-injected eyes was 128 ± 7.4% at 40 min. CBF decreased to the pre-injection level at 140 min after the injection of ET-1. There was no significant change in blood pressure, pulse rate and blood gases throughout this experiment, and there was no significant difference in IOP between ET-1-injected eyes and control eyes. Conclusion: It seems likely that the increase in CBF resulted from some local mechanisms of control that compensated for the decrease in RBF induced by intravitreal injection of ET-1. This model may be useful for investigation of the regulatory system of intraocular circulation, including endothelin receptors.     

Use of a pericardial fat pad flap for preventing bronchopleural fistula: An experimental study focusing on the angiogenesis and cytokine production of the fat pad

An experimental study was conducted to determine whether pericardial fat tissue could induce neovascularization and produce cytokines related to tissue repair. Neovascularization was examined using chick chorioallantoic membranes. Pieces of pericardial fat tissue, omentum, and intercostal muscle were individually placed on a number of chorioallantoic membranes and neovascularization induced by each material was assayed 6 days after the implantation. The intensity of neovascularization was in the order of pericardial fat omentum > muscle. Cytokines, such as interleukin 1 (IL-1) and , tumor necrosis factor- (TNF), interferon- (IFN-), and interleukin 6 (IL-6) were assayed in a culture supernatant of pericardial fat tissue. The latter was obtained 24h after the addition of lipopolysaccharide (LPS) following various incubation times. All cytokines other than IFN are known to play a part in tissue repair, whereas IFN is negatively related to tissue repair because it inhibits fibroblast growth. The pericardial fat tissue incubated with LPS produced a certain amount of IL-1 on day 1, and TNF on days 1 and 8, whereafter these values decreased to an undetectable level. Irrespective of the addition of LPS, a large amount of IL-6 was observed in the supernatant of pericardial fat tissue and it was detectable until day 29. On the contrary, INF was not detected at any assay time. These observations suggest that a pericardial fat pad flap could possibly be beneficial in the prevention of bronchopleural fistula after pulmonary resection.     

Urbanization and risk for schizophrenia: does the effect operate before or around the time of illness onset?

BACKGROUND: Higher level of urbanicity of place of birth and of place of residence at the time of illness onset has been shown to increase the risk for adult schizophrenia. However, because urban birth and urban residence are strongly correlated, no conclusions can be drawn about the timing of the risk-increasing effect. The current study discriminated between any effect of urbanization before and around the time of illness onset. METHODS: All individuals born between 1972 and 1978 were followed up through the Dutch National Psychiatric Case Register for first admission for schizophrenia until 1995 (maximum age 23 years). Exposure status was defined by a combination of place of birth and place of residence at the time of illness onset in the three most densely populated provinces of the Netherlands (the 'Randstad', exposed) or in all other areas (the 'non-Randstad', non-exposed). The risk for schizophrenia was examined in four different exposure groups: non-exposed born and non-exposed resident (NbNr, reference category), non-exposed born and exposed resident (NbEr), exposed born and non-exposed resident (EbNr) and exposed born and exposed resident (EbEr). RESULTS: The greatest risk for schizophrenia was found in the EbNR group, without evidence for any additive effect of urban residence (rate ratio (RR) for narrow schizophrenia in EbNr group, 2.05 (95 % CI 1.18-3-57); in EbEr group, 1.96 (95% CI, 1.55-2.46)). Individuals who were not exposed at birth, but became so later in life, were not at increased risk of developing schizophrenia (RR for narrow schizophrenia in NbEr group, 0.79 (0.46-1.36)). CONCLUSION: The results suggest that environmental factors associated with urbanization increase the risk for schizophrenia before rather than around the time of illness onset.     

Fluorescence automatic cell sorter and immunohistochemical investigation of CD68-positive cells in meningioma

Infiltration of brain neoplasms by mononuclear cells including monocytes/macrophages has attracted little attention since they have marked morphological heterogeneity. Twenty-seven meningiomas were studied by anti-CD68 antibody-gated flow cytometry and by immunohistochemical analysis using the anti-CD68 antibodies. Flow cytometric analysis divided cells contained within tumor tissues into CD68-positive and -negative cells. In addition, eight gliomas, eight metastatic brain tumor, and 12 pituitary adenomas were investigated in the same way to compare meningiomas. The mean contents of CD68-positive cells were 24.0±3.7% in meningiomas, 4.4±1.4% in gliomas, 9.5±3.9% in metastatic brain tumors, and 4.5±1.8% in pituitary adenomas. Immunohistochemically, CD68-positive cells showed significant heterogeneity and were detected as round, rod-shaped, ameboid and ramified cells in meningiomas. Although the infiltrated mononuclear cells in gliomas have been investigated to some degree and showed that they express cytokines and/or growth factors, these infiltrated cells in meningioma have barely been studied. The CD68-positive cells detected in this study are likely to be monocytes, macrophages and microglias, and are presumed to be in various functional stages and to play important roles in growth regulation in meningioma.     

Z-350, a new chimera compound possessing α1-adrenoceptor antagonistic and steroid 5α-reductase inhibitory actions

The effects of Z-350, (S)-4-[3-(4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy} benzoyl)indole-1-yl]butyric acid hydrochloride, a newly synthesized compound possessing α₁-adrenoceptor antagonistic and steroid 5α-reductase inhibitory actions, were studied in vitro. In functional experiments, Z-350 shifted the concentration/response curve for the phenylephrine-induced contraction of rabbit prostate, urethra and aorta to the right with pA₂ values of 8.04, 7.57 and 7.13, respectively. The binding affinity of Z-350 for α₁-adrenoceptors in rabbit prostate, urethra and aorta were estimated by the displacement of [³H]prazosin. The pK _i values for this action of Z-350 were 7.53, 7.95 and 7.62 for the prostate, urethra and aorta, respectively. α₁-Adrenoceptor subtype selectivities were studied in the submaxillary gland (α_1A) and liver (α_1B) of rat. Z-350 inhibited the specific binding of [³H]prazosin to α_1A and α_1B-adrenoceptors with pK _i values of 7.82 and 7.29, respectively. Z-350 inhibited rat prostatic steroid 5α-reductase non-competitively with a pIC₅₀ of 8.42. These results indicate that Z-350 is a α₁-adrenoceptor antagonist and is a steroid 5α-reductase inhibitor. It is expected that Z-350 will be a candidate drug for the treatment of benign prostatic hyperplasia. Received: 26 January 1999 / Accepted: 2 March 1999