Distribution of xanthine dehydrogenase and oxidase activities in human and rabbit tissues.

The activity of xanthine dehydrogenase in human postmortem tissues is surprisingly high in brain and heart; activity was found in most tissue samples, whereas many samples contained little or no oxidase activity. We have confirmed the high level of oxidase activity in liver in which tissue conversion of dehydrogenase to oxidase appears complete. We have also confirmed the virtual absence of either activity in fresh human placenta. Fresh rabbit tissues similarly show considerable dehydrogenase activity in brain and heart. In view of the stability and generalised distribution of dehydrogenase activity, our results suggest that some modification of existing ideas on the physiological and pathological roles of the enzyme may be needed.

Is inosine the physiological energy source of pig erythrocytes?

Pig erythrocytes are unable to metabolize glucose and their physiological energy source is unknown. These cells have a high-capacity nucleoside transport system with similar properties to that responsible for nucleoside transport in other species. Nucleoside transport is sufficiently rapid to allow the possibility that inosine and/or adenosine may represent major energy substrates for pig erythrocytes in vivo. Normal and adenosine deaminase-deficient pig erythrocytes have similar ATP levels, suggesting that adenosine is not important in this respect. However, it was calculated that an extracellular inosine concentration of only 40 nM could support the cells' entire energy requirement, a value 40-fold lower than plasma levels of this nucleoside.

Human placental mitochondrial respiration and its regulation by adenine nucleotides.

Respiratory parameters were studied in mitochondria from human placenta. Respiratory control and ADP/O ratios were low in this preparation. The adenine nucleotide content of placental mitochondria was found to be only one quarter of that found for adult uterine muscle tissue mitochondria prepared in the same way. Loading placental mitochondria with adenine nucleotides by incubation in the presence of ATP produced increased respiratory control ratios but no improvement in ADP/O ratios. Our evidence is consistent with the developmental changes shown to occur in rat liver, in which an increased concentration of adenine nucleotides is responsible for changes in respiratory parameters.

Effect of a failure of energy supply on adenine nucleotide breakdown in placentae and other fetal tissues from rat and guinea pig.

The effects of ischaemia on adenylate energy charge of tissues from fetal rats and fetal guinea pigs were measured. Adult rat and guinea-pig tissues, as well as human placentae, were also studied. The largest differences observed were between the fetuses from different pregnant animals (P = 4.74 X 10(-15). Reductions in energy charge in placentae were slower than in other defined fetal tissues, especially brain. In the rat, an immature species at birth, greater 'stability' was observed in placentae of 14 days of gestation than near term at 20 days of gestation. As contrast, in the guinea pig, a mature species at birth, there was no difference in 'stability' in placenta or other fetal tissues between about 40 days of gestation and near term, about 60 days of gestation. In addition to these tissue and maturity effects in the fetus, it has been confirmed that fetal tissues are more 'resistant' than adult tissues to failures of energy supply. Concentrations of adenosine, uridine, guanosine and cytidine nucleotides in placenta show similar patterns in rats and guinea pigs. Fetal liver contains more uridine nucleotides and brain more cytidine nucleotides. It is suggested that the placenta retains an early fetal ability to maintain itself during ischaemia; this might be advantageous during parturition. Possible endocrine and other mechanisms 'damping' fetoplacental metabolism are linked with a discussion of the large maternal effect.

The placenta in leprosy.

Eighty-one placentae from women with leprosy and 17 placentae from healthy controls were subjected to a detailed macroscopic, light microscopic, ultrastructural, immunopathological, microbiological and biochemical study. The placental morphology and immunohistology were normal, and there was no morphological evidence of infection of the placenta due to M. leprae. No acid-fast bacilli or acid-fast bacillary granules were seen on light microscopy of any of the placentae from leprous women, although homogenates from two out of seven placentae from women with very active lepromatous leprosy contained acid-fast bacilli in very small numbers. The small placental size of women with leprosy, most marked in those with lepromatous leprosy, appears to be due to a decrease in placental cell size, rather than to a reduced number of cells in the placenta. It is postulated that the small placenta and reduced fetal birth weight observed in lepromatous leprosy are a consequence of depressed maternal immune reactivity.

Nucleotide, nucleoside and purine base concentrations in human placentae.

Nucleotides, nucleosides and purine bases in trichloroacetic acid extracts of freeze clamped samples of human placenta have been measured by high-pressure liquid chromatography. The concentrations of the nucleotides concerned with energy transduction, ATP, ADP and AMP, and especially the energy charge, are stable over periods of ischaemia of 30 min. Concentrations of 14 nucleotides, including UDPAG, GDP Man, UDP and CTP, have now been defined. In addition, the concentrations of hypoxanthine, xanthine, uridine, adenine and inosine are indicated. Concentrations of the vasodilator adenosine are similar to the apparent Michaelis constants of its main metabolizing enzymes adenosine kinase and adenosine deaminase. The availability of 'normal' values of adenine nucleotide concentrations in human placenta should permit the detection of 'placental insufficiency' of energy supply, if this condition exists.

Clinical biochemistry of the neonatal period: immaturity, hypoxia, and metabolic disease.

This review attempts to provide practical information on common problems in the laboratory medicine of newborn infants and also considers unresolved problems in achieving neonatal diagnoses. A common cause of upset in the newborn--intrapartum asphyxia--can now be positively diagnosed. This leaves a small group whom it is necessary to investigate because they may have metabolic disease. The initial investigation of metabolic disease at the district general hospital should be limited to the commoner conditions.

Cerebrospinal fluid concentrations of hypoxanthine, xanthine, uridine and inosine: high concentrations of the ATP metabolite, hypoxanthine, after hypoxia.

CSF obtained for clinical purposes from newborn, children and adults has been analysed by high pressure liquid chromatography for hypoxanthine, xanthine, inosine, uridine and urate. Large rises in hypoxanthine and to a lesser extent xanthine occur for about 24 h after hypoxia. High concentrations were associated with later evidence of brain damage or subsequent death. Changes in CSF could be independent of those in plasma. Small or negligible rises were associated with localised and generalised infections including bacterial meningitis, fits, or both. Marked and rapid rises were found after death. These estimations may "predict" the extent of brain damage or brain death.

Clinical and biochemical assessments of damage due to perinatal asphyxia: a double blind trial of a quantitative method.

Using conventional criteria, a series of 26 infants was selected for intrapartum asphyxia from about 4000 deliveries over one year at a single hospital to assess the efficacy of a new biochemical method. Tissue damage was estimated from urinary excretion of hypoxanthine, an important and central intermediate in purine metabolism. The overall pattern showed agreement between the grading (by previously accepted methods) of asphyxia in the perinatal period and our new biochemical approach. The association with handicap at one year of age following asphyxia was complex. This biochemical technique could be used to exclude postasphyxial damage as a cause of clinical disturbances and to select a small group (0.1% of all births) who require further investigation for rarer disorders which may also cause long term handicap.

Intrapartum hypoxia: the association between neurological assessment of damage and abnormal excretion of ATP metabolites.

A series of 29 newborn infants had been studied after intrapartum hypoxia defined as meconium aspiration, an Apgar score of less than or equal to 6 at 5 min or a peripheral blood pH of 7.2 or less after resuscitation. Two independent sets of techniques were used; one concerned with the critical system in hypoxic damage, the central nervous system, the other assessing the central biochemical events in hypoxia. Both sets of data were assembled, then graded separately and only then combined. In this way detailed neurological assessment has been combined with measurement of urinary excretion of the ATP metabolites, hypoxanthine and xanthine. The essential metabolic consequence of hypoxia is a reduction in the synthesis of the energy currency of cells, ATP. This is associated with an outflow of ATP metabolites from cells. The extent of neurological damage was related to the magnitude of the hypoxanthine and xanthine excretion; neither were closely related to the initial blood pH. Infants who were normal neurologically had normal oxypurine excretion. Infants with neurological abnormalities for less than 48 h had lower excretion than those who were abnormal for more than 48 h. The duration of abnormal oxypurine excretion after an acute episode of hypoxia was studied in two infants with respiratory distress and in two other infants with apnoeic attacks. Severe hypoxia was followed by abnormal oxypurine excretion for at least 40 h after an acute episode. It is justifiable to suggest that abnormalities of oxypurine excretion should indicate intrapartum hypoxia in newborn infants. This excretion should also quantify the metabolic damage.

Neonatal spongioform myelinopathy after restricted application of hexachlorophane skin disinfectant.

At least four out of 97 low birth weight (less than 1750 g) newborn infants who had received only limited skin disinfection with 3% hexachlorophane (HCP) emulsion developed spongioform myelinopathy in association with detectable amounts of HCP in their brains. These four cases were found in a post-mortem survey of 20 out of the 27 infants who died. Another nine of these infants had detectable amounts of HCP in the brain but no myelinopathy. It is at present not possible to define a 'safe" level of exposure to 3% HCP emulsion for small preterm infants in the first 2 weeks of life.

Sea-blue histiocytosis associated with hyperlipidaemia.

A patient with sea-blue histiocytosis in spleen and bone marrow with an accompanying hyperlipidaemia is described. The hyperlipidaemia was due to an increase in "free" cholesterol, lecithin, and triglycerides. Despite these findings lecithin-cholesterol acyl transferase activity was normal. Although the precise biochemical defect was not identified, there was a failure of transport of cholesterol from chylomicrons in vitro. We propose that the sea-blue histiocyte is a marker, in some cases, of abnormal lipid metabolism.

Cot deaths in Edinburgh: infant feeding and socioeconomic factors.

One hundred and twenty-six consecutive cases of sudden infant death syndrome (SIDS) in the Edinburgh area have been studied with particular reference to the interrelationship of feeding, associated biochemical changes, and social status. There was an excess of cases born to parents in Social Classes IV and V: the effect was maximal in children who dies beyond 12 weeks of age. A low-grade uraemia was discovered in approximately one-fifth of the cases; analysis showed this to be related most strongly to bottle-feeding. Feeding habits were found to be associated with social class and this accounted for the relationship between bottle-feeding and the youth of mothers and also for an apparent relationship between uraemia in the infant and social class of the mother. Mothers of SIDS children were younger than expected and SIDS was found to be electrolyte imbalance is common in SIDS cases, nor did the findings support the suggestion that cross-infection due to overcrowding is an important aetiological factor. The significant factors of young motherhood, low social status, bottle-feeding, and mild uraemia in the babies are interrelated and seem to focus attention on unwitting 'mothering problems'. It is, however, not easy to see how this, or any other hypothesis, can account for all cases of SIDS.

ATP, ADP and AMP in plasma from peripheral venous blood.

ATP, ADP and AMP in concentrations at least 1 mumol/l have been found by high pressure liquid chromatography (HPLC) in plasma from peripheral venous blood. Total adenine nucleotide concentrations of about 15-20 mumol/l can be found in some conventional clinical samples of blood using EDTA as an anticoagulant. EDTA prevented adenine nucleotide conversion to inosine in plasma. In order to estimate concentrations in vivo, the contribution derived from the cell breakage inherent even in careful venous blood sampling has been estimated by extrapolation to zero 'haemoglobin' concentration in plasma and minimum values in samples of small volume. Available results appear to be consistent with the release of small amounts of ATP in or near the peripheral circulation at the time of venepuncture. In CSF, ATP, ADP and AMP concentrations were less than 0.05 mumol/l suggesting that membrane activity in the central nervous system is not associated with non-specific leakage. The high Km variant of lymphocyte ecto-5'-nucleotidase was not associated with a significantly higher concentration of its substrate AMP in plasma. However, this enzyme may function on the lymphocyte in the thymus and spleen.

Oestrogens and host resistance.

PIP: The literature is searched for references to studies dealing with the immunobiological effects of pregnancy and other instances of increased estrogenic production in humans and various animal species. In the human female, the estrogen-related metabolic changes associated with pregnancy and reproduction have widespread effects on host tolerance of the fetus and diseases where host resistance is involved. These changes facilitate fetal survival. They also lower bodily resistance to viral and bacterial infections. Acute inflammation may be stimulated and chronic inflammation inhibited by pregnancy, both of which effects are mediated by estrogens. It is speculated that some aspects of host resistance are increased while others are decreased, maintaining an overall balance.^ieng