Cerebrotendinous xanthomatosis in a Saudi Arabian family-genotyping and long-term follow-up

A Saudi Arabian family is described in which there were 2 siblings with typical features of cerebral xanthomatosis CTX including premature cataracts, xanthomata of the Achilles tendons, neuro-psychiatric disturbances, and atherosclerosis. The 2 patients were homozygous for a point mutation in the mitochondrial 27-hydroxylase gene CYP27A1, OMIM 606530 located in the splice site of intron 6, where G was exchanged for A IVS6+1G>A. Their parents were cousins, 5 siblings were healthy, 2 were heterozygous for the mutation, and one showed the wild-type genotype. The father was heterozygous for the mutation, while the other family members were not tested. The progress of the 2 CTX patients over 14 years is described; firstly when they were receiving treatment with chenodeoxycholic acid; when this medication was not available, and later when it was restored. A hereditary hyperlipidemia was also present in this family. It is suggested that when this occurs with CTX, a more serious illness results that merits more aggressive dual therapy.     

Subcellular Distribution of 3H-noradrenaline in Adrenergic Nerves of Mouse Atrium — Effect of Reserpine,Monoamine Oxidase and Tyrosine Hydroxylase Inhibition

The subcellular distribution of exogenously administered ³H-noradrenaline in adrenergic nerves of mouse atria after pretreatment with nialamide, reserpine and nialamide, or the methylester of a-methyl-p-tyrosine (H44/68) has been investigated. Parallel fluorescence histochemical studies have been performed. Both reserpine and H44/68 cause a pronounced decrease in the endogenous noradrenaline stores. The subcellular distribution was practically identical in untreated, nialamide-pretreated and H44/68-pretreated animals; approximately 30 %³H-noradrenaline was recovered in the particulate fraction which in all probability contains the amine storage granules. In the reserpine-nialamide pretreated mice, however, most of the ³H-noradrenaline was found in the supernatant iraction, and about 10 % in the particulate fraction. These studies thus confirm earlier investigations that reserpine is a potent inhibitor of the noradrenaline uptake in the amine storage granules, although there is a small reserpineresistant uptake. Furthermore, after tyrosine hydroxylase inhibition both the ‘membrane pump’ and the granular uptake mechanism seem to operate. The morphological studies disclosed differences in the adrenergic nerves when the noradrenaline taken up is mainly granularly or extragranularly stored, since the varicosities are in the former case distinct and the latter case less distinct, while the pre-terminals are more prominent. Methodological studies of the homogenization procedure for subcellular distribution studies have also been performed, the results of which are discussed in view of the experimental data obtained. It is now well established, based on both biochemical and electronmicroscopic evidence. that the peripheral adrenergic transmitter NA^I is mainly stored in special intraneuronal storage granules (Euler and Hillarp 1956. Schümann 1958. Camps and Shideman 1962. Potter and Axelrod 1962, Lundborg 1967, Hokfelt 1969). Exogenously administered NA is rapidly taken up by the axonal membrane of the adrenergic neuron and subsequently incorporated into the storage granules, mainly by means of an ATP-Mg++-dependent uptake mechanism. This latter process can be efficiently-blocked by reserpine (Carlsson et al. 1963, Euler and Lishajko 1963.     

Indications for contralateral carotid endarterectomy: Role of the noninvasive laboratory

In 1,733 patients, 2,054 carotid phonoangiographic and oculoplethysmographic studies were performed. Seventy of these patients required carotid endarterectomy either for symptoms or for severely ulcerated plaques. Of these, 12 had bilateral procedures. This review suggests that noninvasive studies can be helpful in determining which patients should undergo contralateral carotid endarterectomy and when. The decision to correct the other side was based on generally accepted indications, development of symptoms and the presence of severely ulcerated plaques. In addition, positive results on carotid phonoangiography and oculoplethysmography, whenever they develop, are a strong indication for the contralateral procedure. The stenotic lesion that appears significant on arteriography may not be hemodynamically significant on noninvasive studies. These patients may be followed expectantly with serial carotid phonoangiographic and oculoplethysmographic studies until hemodynamically significant flow delays appear or symptoms develop.     

Lp(a) phenotypes, other lipoprotein parameters, and a family history of coronary heart disease in middle-aged males

In a study of 95 presumably healthy, 40-42-year old males from Northen Sweden, the Lp(a) phenotype distribution differed between those who had, and those who did not have one or more close relatives (parent or sib) with coronary heart disease. In the former group, 60% of the males were Lp(a+), as opposed to 28% in the latter group. Thus, in the homogeneous population sample studied, analysis of the normal inherited Lp(a) variation permitted the identification of distinct subpopulations, with respect to familial occurrence of coronary heart disease. None of a series of other parameters distinguished such sub-populations. The results reported are in agreement with our previous finding of a close association between phenotype Lp(a+) and risk of contracting coronary heart disease.     

A Biochemical Study of Erythrocytes in Swedish Families with p -Thalassaemia Minor

In three ‘aboriginal’ Swedish families with β-thalassaemia minor the contents of Ery-Hb A₂ and Ery-Hb F seem not to vary with time (age). The results were entirely the same in both young and adult β-thalassaemic individuals. The erythrocyte contents of hexokinase, phosphofructokinase, pyruvate kinase, aldolase, lactate dehydrogenase, glucose-6-phosphate dehydrogenase and glutathione reductase expressed per unit volume of cells were increased in accordance with findings in β-thalassaemia minor from the Mediterranean area. The erythrocyte concentrations of ATP and ADP, also calculated as per cent volume of cells, were decreased, the concentrations of G6P + F6P and DPG increased. These findings are not specific for the disease, as they have also been registered in iron deficiency anaemia. There are indications, however, that the glycolytic system of β-thalassaemic erythrocytes can increase the oxygen releasing capacity of the haemoglobin mass to the same extent as in other types of anaemia.     

DNA content determination of micronucleated polychromatic erythrocytes induced by clastogens and spindle poisons in mouse bone marrow and peripheral blood

The frequencies and DNA distributions of micronuclei (MN) inpolychromatic erthrocytes (PCEs) from bone marrow (BM) and peripheralblood (PB) of mice after four different treatments were determinedby flow cytometry. PCEs were differentiated from normochromaticerythrocytes (NCEs) using the fluorescent RNA stain Thiazoleorange, while MN in erythrocytes were detected with the DNAstain Hoechst 33342. The treatments were X-irradiation (1 Gy)cyclophosphamide (CPA; 30 mg/kg) vincristine sulphate (VCR;0.08 mg/kg) and cholchicine (COL; 1 mg/kg). All treatments showedincreased frequencies of micronucleated PCEs at 30 h after treatmenthi BM and at 50 h in PB. The clastogens(X-irradiation and CPA)and the spindle poisons (VCR and COL) could be grouped accordingto the fluorescent characteristics of the induced MN as wellas the relative frequency of small (0.5—2% of the diploidDNA content) and large (2—10%) MN. In PB the relativefrequency of large MN was lower than in BM indicating that theywere partly eliminated before entrance into the peripheral circulation. ³To whom correspondence should be addressed     

Effects of N-nitrosomorpholine and phenobarbital on UDPglucuronyltransferase in putative preneoplastic foci of rat liver

Effects of initiators and promoters of hepatocarcinogenesison UDP-glucuronyltransferase and arylhydrocarbon hydroxylasewere investigated in foci of altered hepatocytes. A single admhktrationof N-nitmmorpholine (75 mg/kg, 24 h after partial hepatectomy)was used for initiation and chronic administration of phenobarbital(0.1% in tap water) for promotion. Histological evidence indicatedthat ATPase-negative, y-glutamyltranspeptidase-positive, andUDP-glucuronyltransferase-positive foci were highly correlated.Based on this evidence ATPase-negative foci were used as a guideto monitor early lesions and to microdissect lyophilized fociand extrafocal tissue. It was found that treatment with N-nitrosomorpholineled to a permanent increase of UDP-glucuronyltransferase activityin foci tissue (3- to 5-fold, detected 180 and 330 days afterinitiation). In contrast, arylhydrocarbon hydroxylase activitywas decreased by 50%. Administration of phenobarbital furtherincreased UDP-glucuronyltransferase activity in focal tissue(up to 9-fold, compared with control liver). However, this furtherincrease of enzyme activity by phenobarbital was reversible.The results suggest that (i) initiation by chemical carcinogensleads to permanent alterations of drug metabolizing enzymes,consistent with increased toxin-resistance of initiated hepatocytes,and (ii) chronic administration of phenobarbital markedly enhancesgene expression of UDP-glucuronyltransferase in initiated hepatocytes.     

Altered growth control of rat hepatocytes after treatment with 3,4,3',4'-tetrachlorobiphenylin vivo and in vitro

Alterations of hepatocyte growth control by inducers of drugmetabolizingenzymes were investigated using 3,4,3',4'-tetrachlorobiphenyl(TCB) as the inducing agent. TCB was chosen as a selective 3-methylcholanthrene-typeinducer and liver tumor promoter which probably exerts its biologicalactions through binding to the aryl hydrocarbon (Ah) receptor.In vivo treatment of rats with TCB (200 mg/kg) markedly stimulatedgrowth of enzyme altered liver foci and [³H]-thymidine incorporationinto nuclear DNA. Hepatocyte cultures from TCB-treated ratswere more sensitive to exogenous growth factors such as EGFthan those from untreated controls. In vitro TCB exposure ofhepatocyte cultures also altered hepatocyte growth control ina dose-dependent manner and induced drug-metabolizing enzymes.TCB treatment in vivo enhanced EGF-stimulated autophosphorylationof the EGF receptor in liver plasma membranes. The results suggestthat altered growth control is due to a direct effect of TCBon hepatocytes. The proposed model may be useful to elucidatea possible linkage between the functional stress imposed onhepatocytes by sustained overexpression of an adaptive programand modulation of hepatocyte growth control.