Role of prostaglandins in the metabolic responses of the fetus to hypoxia.

OBJECTIVE: The effect of inhibiting prostaglandin synthesis on the fetal metabolic response to hypoxemia was examined by infusing indomethacin during periods of reduced maternal uterine blood flow. STUDY DESIGN: In seven fetal sheep we administered a 6-hour infusion of either indomethacin (n = 5), indomethacin plus prostaglandin E2, or a vehicle solution (n = 5). The last 4 hours of each infusion period coincided with a period of fetal hypoxemia induced by reduced maternal uterine blood flow. RESULTS: During reduced maternal uterine blood flow indomethacin infusions caused a significantly greater reduction in pHA (reduced from 7.36 +/- 0.01 to 7.10 +/- 0.02) than both the vehicle (from 7.36 +/- 0.01 to 7.20 +/- 0.03) and indomethacin plus prostaglandin E2 infusions (from 7.36 +/- 0.01 to 7.18 +/- 0.02). Before reduced maternal uterine blood flow was induced, indomethacin significantly elevated fetal plasma glucose and lactate concentrations from 0.6 +/- 0.04 and 2.2 +/- 0.1 to 1.3 +/- 0.2 and 6.7 +/- 0.7 mmol/L, respectively. During reduced maternal uterine blood flow indomethacin caused a significantly greater increase in plasma glucose and lactate concentrations than the vehicle; plasma glucose and lactate concentrations increased to a maximum of 1.8 +/- 0.2 and 22.7 +/- 0.8 mmol/L, respectively, during indomethacin infusions compared with 1.1 +/- 0.1 and 15.7 +/- 1.7 mmol/L, respectively, during vehicle infusions. The addition of prostaglandin E2 to the indomethacin infusion prevented the enhanced increase in glucose and lactate concentrations during reduced maternal uterine blood flow and caused a significant increase in fetal plasma insulin concentrations from 12.6 +/- 0.7 to 60.9 +/- 28.1 microU/ml. CONCLUSION: The inhibition of prostaglandin synthesis during fetal hypoxemia alters the metabolic response of the fetus, leading to a severe metabolic acidosis.     

Effects of reduced uterine blood flow on electrocortical activity, breathing, and skeletal muscle activity in fetal sheep

Experiments were conducted in 11 unanesthetized fetal sheep during the last third of gestation to examine the effects of prolonged, reversible reduction in uterine blood flow on fetal electrocortical activity, breathing movements, and skeletal muscle activity. With an adjustable clamp placed around the maternal common internal iliac artery, uterine blood flow was restricted for 2 hours to produce a reduction in fetal arterial oxygen saturation from 56.1% +/- 1.9% to 28.8% +/- 0.7%. When blood flow was reduced, there was a decrease in the percentage of time that fetuses spent in low-voltage electrocortical activity, from 57.5% +/- 3.0% to 37.8% +/- 3.5%, and a decrease in the incidence of both breathing movements and integrated skeletal muscle activity. Younger fetuses (110 to 121 days' gestation) demonstrated a lesser degree of reduction in breathing movements when compared with older fetuses (125 to 140 days) whereas the effects of hypoxemia on electrocortical activity became less apparent with advancing gestational age.     

The lens in hereditary hyperferritinaemia cataract syndrome contains crystalline deposits of L-ferritin

BACKGROUND/AIM: Hereditary hyperferritinaemia cataract syndrome (HHCS) is an autosomal dominant disorder characterised by elevated serum L-ferritin and bilateral cataracts. The ocular manifestations of this disorder are poorly studied. This study therefore sought to determine the origin of cataracts in HHCS. METHODS: L-ferritin ELISA, immunohistochemical and ultrastructural analysis of a lens nucleus from an HHCS individual. RESULTS: The HHCS lens L-ferritin content was 147 microg/g dry weight of lens compared with <16 microg/g for a non-HHCS control cataract lens. The cataract comprised discrete crystalline inclusions with positive staining with anti-L-ferritin but not anti-H-ferritin. CONCLUSIONS: This unusual finding of crystalline opacities in the lens may be unique to HHCS and is likely to result from disturbed metabolism of L-ferritin within the lens or an abnormal interaction between L-ferritin and lens proteins.     

The effects of myometrial activity on fetal thoracic dimensions and uterine blood flow during late gestation in the sheep

We wished to investigate mechanisms by which non-labour contractions of the uterus influence fetal sleep states and respiratory activity during late pregnancy. The relationship between the dimensions of the fetal chest and uterine contractions was examined in 5 pregnant sheep. The dorso-ventral dimension at the level of the xiphisternum (3 fetuses) decreased, on average by 4.4-9.4% while increases of 16.6-18.7% were seen in the transverse dimension (4 fetuses). Blood flow in a middle uterine artery was monitored using a Doppler technique in 5 pregnant sheep. Non-labour uterine contractions were accompanied by mean reductions of 6.5-12.7% in blood flow. Postural adjustments by the ewe also influenced uterine blood flow. A mean increase in blood flow of 5.9-12.0% followed a change from standing to lying; standing caused a mean reduction of 5.9-11.8%. We conclude that the influence of uterine contractions on the fetus is likely to be complex, involving distortion of the body and alterations in utero-placental haemodynamics.     

A chronic low dose infusion of insulin-like growth factor I alters placental function but does not affect fetal growth

Knowledge of the anabolic effects of insulin-like growth factor I (IGF-I) on fetal growth and feto-placental metabolism are derived from studies using large doses of IGF-I. Low doses of enteral IGF-I have trophic effects on the fetal gut, but there are no data on the effects of systemic low doses of IGF-I on fetal growth and feto-placental metabolism. We therefore compared the effects of a chronic infusion of low dose IGF-I (50 microg day(-1), n = 7) with vehicle-infused controls (n = 7) on fetal growth, metabolism and placental transfer capacity in the chronically instrumented late gestation ovine fetus (121-132 days of gestation; term = 145 days). Insulin-like growth factor I infusion did not affect fetal growth or the size of individual organs, including liver, spleen and bone. Placental morphology was altered, and placental clearances of 3-O-[methyl-3H]D-glucose (a non-metabolizable glucose analogue) and [methyl(14C)]aminoisobutyric acid (a non-metabolizable analogue of amino acids utilizing the system A transporter), were reduced in IGF-I-treated fetuses (P < 0.05 v. control). However, fetal and placental metabolite uptake was not significantly different between groups. We conclude that, despite altering placental transfer capacity and morphology, a chronic low dose infusion of IGF-I does not alter fetal growth or metabolism.     

The viral diarrhoea epidemic 2002 in the Marshall Islands: its impact on a small island pharmacy

This paper describes the increased demands on the pharmacy department of Majuro Hospital in the Marshall Islands during a recent viral diarrhoea epidemic. It discusses the increased number of patients, the increased usage of drugs and also the increased costs during this epidemic. The number of patients only rose 10%. However, the increase in workload of the outpatient department, laboratory and the pharmacy department was much greater. The percentage of children presenting to the outpatient department with diarrhoea increased from 10% to 80%. Oral rehydration solution (ORS) was the most common medication given during the epidemic in line with the World Health Organisation Guidelines.     

Cajal-Retzius cells,inhibitory interneuronal populations and neuropeptide Y expression in focal cortical dysplasia and microdysgenesis

Focal cortical dysplasia (FCD) and microdysgenesis (MD) are likely to represent abnormalities of radial neuronal migration during cortical development. We investigated the distribution of reelin-positive Cajal-Retzius cells, known to be important in the later stages of radial neuronal migration and cortical organization, in 12 surgical cases of both MD and FCD. Quantitation revealed significantly higher numbers of these cells in MD cases compared to controls. As the majority of cortical interneurones arise via tangential rather than radial migration, we studied the distribution and morphology of inhibitory interneuronal subsets immunolabelled for calbindin, parvalbumin and calretinin within these malformations. Frequent findings were a reduction of inhibitory interneurones in the region of FCD and abnormally localised hypertrophic or multipolar calbindin-positive interneurones in both FCD and MD. Neuropeptide Y immunostaining showed a striking increase in the density of the superficial plexus of fibres in both MD and FCD cases in addition to labelling of dysplastic neurones, which may represent an adaptive anti-convulsant mechanism to dampen down seizure propagation.     

Major vault protein, a marker of drug resistance, is upregulated in refractory epilepsy

PURPOSE: The molecular basis of drug resistance in epilepsy is being explored. Two proteins associated with drug resistance in cancer, P-glycoprotein and multidrug resistance-associated protein 1, are upregulated in human epileptogenic pathologies. Other proteins associated with resistance in cancer include major vault protein (MVP) and breast cancer resistance protein (BCRP). We hypothesized that these proteins would also be upregulated in human epileptogenic pathologies. METHODS: Hippocampal sclerosis (HS), focal cortical dysplasia (FCD), and dysembryoplastic neuroepithelial tumor (DNT) were studied by using immunohistochemistry for MVP and BCRP. Nonepileptogenic control and histologically normal brain adjacent to epileptogenic tissue were used for comparison. RESULTS: MVP and BCRP were expressed ubiquitously in brain capillary endothelium. Ectopic upregulation of MVP was seen in hilar neurons in HS, dysplastic neurons in FCD, and lesional neurons in DNT. Only in HS cases were rare extralesional neurons immunoreactive. Glial upregulation was not seen. There was no qualitative upregulation of BCRP. CONCLUSIONS: These results show that more than one resistance protein may be upregulated in a given epileptogenic pathology and may contribute to drug resistance. Determination of the types, amounts, and distribution of such proteins will be necessary for rational treatment for drug resistance in epilepsy.