Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients.

We investigated whether pediatric patients with sickle cell disease (SCD) (9 +/- 4 years; 27 homozygous SCD [HbSS]; 19 sickle-C disease [HbSC]) have different folate status compared with age-, sex-, and race-matched normal hemoglobin (HbAA) controls (n = 20), and whether their folate status can be improved by folate supplementation. The patients were supplemented with vitamins B6 and B12 during one week and with folate during the following week. Circulating folate, homocysteine, vitamin B6 and vitamin B12 levels were measured at baseline (patients and controls), after one week and after two weeks (patients). The patients had similar folate, vitamin B6, and vitamin B12, but higher homocysteine levels compared with HbAA controls (12.7 +/- 4.5 vs. 10.9 +/- 3.5 micromol/l; P = 0.04). Vitamin B6 and B12 supplementation did not change their homocysteine levels, but folate supplementation caused a 53% reduction (to 5.7 +/- 1.6). We conclude that patients with SCD have adequate vitamin B6 and B12 status, but suboptimal folate status, leading to elevated plasma homocysteine levels. They may therefore benefit from folate supplementation to reduce their high risk for endothelial damage.

Truncus arteriosus with anterior origin of a hypoplastic main pulmonary artery.

A newborn with an unusual form of truncus arteriosus is described, whose clinical presentation and certain features of her anatomy were more typical of pulmonary atresia with a ventricular septal defect. The morphological differentiation of certain types of truncus arteriosus and pulmonary atresia with ventricular septal defect remains an area of speculation among cardiac pathologists, and research in this area is being done using animal models. The anatomic features of the heart described in this report may assist in this discussion as the application of observations made in animal models to human cardiac development may be problematic.

Folic acid status of paediatric patients with sickle cell disease

We investigated whether paediatric patients with sickle cell disease (9ñ4 years; 27 HbSS; 19 HbSC) have different folic acid status compared with age-, sex-and race-matched HbAA controls (n=20), and whether their folic acid status can be improved by folic acid supplementation. The patients were supplemented with vitamins B6 and B12 during one week and with folic acid during the next week. Circulating folic acid, homocysteine, vitamin B6 and vitamin B12 levels were measured at baseline (patients and controls), after 1 and 2 weeks (patients). The patients had similar folic acid, vitamin B6 and vitamin B12, but higher homocysteine levels, compared with HbAA controls (12.7ñ4.5 vs 10.9ñ3.5 mmol/l;p=0.04). Vitamin B6 and B12 supplementation did not change their homocysteine levels, but folic acid supplementation caused a 52 percent reduction (to 5.7ñ1.6). We conclude that patients with sickle cell disease have adequate vitamin B6 and B12 status, but suboptimal folic acid status. They may benefit from folic acid supplementation to reduce their high risk for endothelial damage.(AU)

Topical ice slurry prevents brain rewarming during deep hypothermic circulatory arrest in newborn sheep.

OBJECTIVES: To measure the effect of ice slurry topical cooling on brain surface temperature during deep hypothermic circulatory arrest. DESIGN: This was a prospective, controlled experiment. SETTING: Animal laboratory at a university hospital. PARTICIPANTS: Five control lambs, five treatment (ice slurry) lambs. INTERVENTIONS: Animals were studied in two groups: the study group had topical cooling of the head with ice slurry started immediately before circulatory arrest and continued throughout the period of circulatory arrest; control group lambs received no supplemental topical cooling. MEASUREMENTS AND MAIN RESULTS: Brain surface temperature, scalp, nasopharyngeal, and rectal temperatures were measured at 5-minute intervals during 45 minutes of circulatory arrest. Lambs receiving topical cooling of the head with ice slurry had a statistically significant decrease in brain surface temperature of 2.2 +/- 1.2 degrees C during circulatory arrest, whereas brain surface temperature increased 1.2 +/- 0.3 degrees C, in control lambs. Equilibration of temperature between the scalp and brain in control lambs produced rewarming of the brain surface. CONCLUSIONS: Topical cooling of the head with ice slurry in newborn lambs lowers brain surface temperature during deep hypothermic circulatory arrest. Surrogate temperature monitoring locations such as nasopharyngeal and rectal temperatures varied significantly and do not accurately reflect changes in brain surface temperature.

Growth of the right heart after balloon valvuloplasty for critical pulmonary stenosis in the newborn.

Eight newborns with critical pulmonary stenosis and intact ventricular septum underwent successful percutaneous balloon dilation. Follow-up using echocardiography showed sustained relief of the obstruction across the pulmonary valve and excellent growth of the right heart structures.

Hydroxyurea therapy in sickle cell anemia patients in Curaçao, The Netherlands Antilles.

We have treated 9 patients with sickle cell anemia (SS) with hydroxyurea (HU). All 9 patients carried 4 alpha-globin genes and the beta s-globin haplotypes 19/19 (Benin/Benin), except for 1 who had haplotype 19 together with type 3 (Benin/Senegal). Six patients received HU for 10 months and were again treated with the drug for 5 months after an interval of 1 year. One patient was given HU for 22 consecutive months. A record was kept of hematological and biochemical data, Hb F and G gamma levels, as well as possible clinical complications. Our data show that HU generally improves the hematological and biochemical values and the level of Hb F, and reduces painful crises in some patients. However, although the clinical symptoms improved in some patients during HU therapy, the older patients did not observe any changes in their general condition; the same is the case for the patient with haplotype 19/3. One patient also experienced life-threatening liver sequestration during treatment. We conclude that the selection of patients who may benefit from HU therapy needs further evaluation.

Depression of cardiac function after deep hypothermic circulatory arrest in deeply anesthetized neonatal lambs.

Cardiac dysfunction is common after neonatal cardiac operations. Previous in vivo studies in neonatal animal models however, have failed to demonstrate decreased left ventricular function after ischemia and reperfusion. Cardiac dysfunction may have been masked in these studies by increased endogenous catecholamine levels associated with the use of light halothane anesthesia. Currently, neonatal cardiac operations are often performed with deep opiate anesthesia, which suppresses catecholamine surges and may affect functional recovery. We therefore examined the recovery of left ventricular function after ischemia and reperfusion in neonatal lambs anesthetized with high-dose fentanyl citrate (450 micrograms/kg administered intravenously). Seven intact neonatal lambs with open-chest preparation were instrumented with left atrial and left ventricular pressure transducers, left ventricular dimension crystals, and a flow transducer. The lambs were cooled (< 18 degrees C) on cardiopulmonary bypass (22 +/- 6 minutes), exposed to deep hypothermic circulatory arrest (46 +/- 1 minutes), and rewarmed on cardiopulmonary bypass (30 +/- 10 minutes). Catecholamine levels and indexes of left ventricular function were determined before (baseline) and 30, 60, 120, 180, and 240 minutes after termination of cardiopulmonary bypass. Levels of epinephrine, norepinephrine, and dopamine were unchanged from baseline values. Left ventricular contractility (slope of end-systolic pressure-volume relationship) was depressed from baseline value (31.7 +/- 9.3 mm Hg/ml) at 30 minutes (15.7 +/- 6.4 mm Hg/ml) and 240 minutes (22.7 +/- 6.4 mm Hg/ml) but unchanged between 60 and 180 minutes. Left ventricular relaxation (time constant of isovolumic relaxation) was prolonged from baseline value (19.0 +/- 3.0 msec) at 30 minutes (31.4 +/- 10.0 msec) and 240 minutes (22.1 +/- 2.8 msec) but unchanged between 60 and 180 minutes. Afterload (left ventricular end-systolic meridional wall stress) was decreased at 30, 60, and 240 minutes. Indexes of global cardiac function (cardiac output, stroke volume), preload (end-diastolic volume), and left ventricular compliance (elastic constant of end-diastolic pressure-volume relationship) were unchanged from baseline values. In deeply anesthetized neonatal lambs exposed to ischemia and reperfusion, left ventricular contractility, relaxation, and afterload are markedly but transiently depressed early after reperfusion and mildly depressed late after reperfusion.

Filling characteristics of left ventricle in newborn lambs.

An integral component of increased cardiac performance during the immediate newborn period is an increased rate of left ventricular (LV) filling. To determine the factors that facilitate increased LV filling in newborns, we compared filling characteristics in chronically instrumented awake newborn (7 +/- 2 days old) and older lambs (55 +/- 5 days old). The studies were performed 4 +/- 2 days after surgery, during which pressure transducers, dimension crystals, a flow transducer, and vascular occluders were placed. Newborn lambs had an increased cardiac index (247 +/- 40 vs. 127 +/- 48 ml.kg-1.min-1; P < 0.01) due to an increased heart rate (223 +/- 24 vs. 120 +/- 9 beats/min; P < 0.01) despite a similar stroke volume index (1.1 +/- 0.1 vs. 1.1 +/- 0.5 ml/kg; not significant). In newborn lambs, indexed mean LV filling rates were more than twofold higher (10.5 +/- 2.5 vs. 4.6 +/- 1.7 ml.kg-1.s-1; P < 0.01), and a much greater percentage of filling occurred in the first 35 ms after mitral valve opening (52 +/- 7 vs. 23 +/- 8%; P < 0.01). In newborn lambs, early diastolic filling was facilitated by more rapid LV relaxation (tau: 17.2 +/- 2.2 vs. 23.3 +/- 1.2 ms; P < 0.01) and a higher left atrial (LA) pressure at the time of mitral valve opening (11.6 +/- 2.4 vs. 7.2 +/- 3.2 mmHg; P < 0.05). LV filling in newborn lambs also occurred at the expense of a higher mean LA pressure (8.4 +/- 2.4 vs. 5.1 +/- 2.6 mmHg; P < 0.05). These findings improve our understanding of LV diastolic function in newborns.

Isobutyramide therapy in patients with sickle cell anemia.

We have administered Isobutyramide as a suspension over a period of 3 months, from a starting dose of 50 mg/kg/day up to 150 mg/kg/day, to four adult sickle cell (SS) anemia patients. The maximum dose was maintained for 3 weeks. The blood counts remained stable and the Hb F levels decreased slightly. The G gamma levels increased at the end of the trial, suggesting activation of the G gamma gene at the highest dose of Isobutyramide. Three patients showed a stable rate of hemolysis, while in one patient, an increase of lactate dehydrogenase occurred. None of the patients experienced pain crisis or organ-specific crisis, but all four complained about mild epigastric burning and a bitter taste. After the first month of treatment one patient complained about intolerable epigastric discomfort which was relieved by Omeprazole. Another patient complained about increasing dyspepsia in the 12th week leading to the termination of the trial. Oral Isobutyramide administration does not qualify as an effective treatment of SS patients.

Low sickle-cell linoleic acid content is related to young erythrocyte age - abstract

Erythrocyte (RBC) fatty acids (FA) and polyamines were determined in subjects with HvM (n=29), HbAC (3), HbAS (41), HbSC (25) and HbSS (19). FA of plasma cholesterol esters (CE), plasma phosphatidylcholines (PC), RBC PC, and plasma and RBC PC-species were studied in subgroups. RBC of patients with HbSS and HbSC had abnormal FA, PC-FA, PC-species and polyamines. There were no major differences in plasma CE-FA, PC-FA and PC-species. Low 18:2U6 in RBC, RBC PC and RBC PC-species of patients with HbSC and HbSS are related to RBC polyamines. Low RBC 18:2U6 is almost stoichiometrically compensated for by higher stearic and palmitic acids. Circulating RBC from patients with HbSC and HbSS have normal total polyunsaturated FA with 20 carbons or more. Low RBC 18:2U6 of patients with HbSS and HbSC is rather related to young RBC-age (RBC polyamines) than to diet (plasma CE-FA). Their rapid RBC turnover causes incomplete RBC-FA exchange with plasma species (AU)

Milk of patients with tightly controlled insulin-dependent diabetes mellitus has normal macronutrient and fatty acid composition.

The composition of macro- and micronutrients in milk from six patients with tightly controlled insulin-dependent diabetes mellitus [median glycosylated hemoglobin concentrations at parturition of 5.2% (range 4.9-5.3%, reference range 4.9-6.6%) and 6 wk thereafter of 6.1% (range 5.0-6.3%, reference range 5.0-6.4%) was compared with that from five control subjects. Milk samples were collected halfway through a single breast-feeding at days 3-5 (colostrum); 7, 9, and 10 (transitional milk); and 12, 15, 17, 21, 25, 29, and 35 (mature milk). We found no abnormalities in macronutrient (triglycerides, lactose, and protein), cholesterol, glucose, and myoinositol concentrations or fatty acid composition. Two of three longitudinally studied patients showed rather constant ratios between glucose concentrations in milk and capillary blood. The present data suggest that tight control corrects a multitude of milk abnormalities associated with moderate and poor control.

Holzgreve syndrome: recurrence in sibs.

We report on 2 sibs with cardiac and renal abnormalities. The first had hypoplastic left heart sequence and renal hypoplasia; the second had a complex congenital heart defect, renal agenesis, and cleft lip and palate. We suggest that these cases represent the first familial examples of the Holzgreve syndrome. As such, they demonstrate the phenotypic variability seen in sibs, and may serve to further delineate the syndrome.

EDRF inhibition attenuates the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs.

At birth, pulmonary vasodilation occurs during rhythmic distension of the lungs and oxygenation. Inhibition of prostaglandin synthesis prevents pulmonary vasodilation during rhythmic distension of the lungs but not during oxygenation. Because endothelium-derived relaxing factor (EDRF) modulates pulmonary vascular tone at birth, at rest, and during hypoxia in older animals, we hypothesized that EDRF may modulate pulmonary vascular tone during oxygenation in fetal lambs. We studied the responses to N omega-nitro-L-arginine, a competitive inhibitor of EDRF synthesis, in nine near-term fetal lambs and to drug vehicle in six of these lambs and the subsequent responses to in utero ventilation with 95% O2 in these fetal lambs. In all fetal lambs, prostaglandin synthesis was prevented by meclofenamate. N omega-nitro-L-arginine increased pulmonary and systemic arterial pressures by 28% (P < 0.05) and 31% (P < 0.05), respectively, and decreased pulmonary blood flow by 83% (P < 0.05). In the controls, ventilation with 95% O2 increased pulmonary blood flow by 1,050% (P = 0.05) without changing pressures, thereby decreasing pulmonary vascular resistance by 88% (P = 0.05). During N omega-nitro-L-arginine infusion, ventilation with 95% O2 increased pulmonary blood flow by 162% (P = 0.05) and decreased pulmonary vascular resistance by 74% (P = 0.05). This suggests that EDRF may play an important role in modulating resting pulmonary vascular tone in fetal lambs and in the vasodilatory response to ventilation with O2 in utero.

Adhesive knob formation by conidia of the nematophagous fungus Drechmeria coniospora.

We studied conidiogenesis and adhesive knob formation (maturation) by newly developed conidia of the nematophagous fungus Drechmeria coniospora. Upon conidiogenesis on infected nematodes or during saprophytic growth of the fungus in axenic cultures compact clusters of conidia developed. Less than 10% of such clustered conidia matured; mature conidia were invariably located on the periphery of the clusters. The kinetics and rate of maturation of conidia were studied in in vitro systems and in soil. In both cases adhesive knobs were formed; the rate at which knobs were formed appeared to be determined by the age of the conidia, the temperature and the soil moisture. In addition, knob formation was suppressed at increasing conidial densities. Under favorable conditions, however, over 90% of the conidia matured within a period of 3 days. The rate of knob formation was neither influenced by the presence of nematodes nor by that of exogenous nutrients, which suggests that maturation is an autonomous process. Electron-microscopical analysis indicated that budding of the conidia at the initial stage of maturation occurred simultaneously with the deposition of the sticky, adhesive layer around the wall of the developing knob. The ecological significance of the time- and spatially separated maturation of conidia after conidiogenesis is discussed with respect to survival of the conidia.

Prostaglandin inhibition prevents the fall in pulmonary vascular resistance as a result of rhythmic distension of the lungs in fetal lambs.

Prostaglandins (PG) are vasoactive factors involved in the regulation of pulmonary vascular resistance at birth. However, their physiologic importance is unclear. We hypothesized that PG are important regulators of pulmonary vascular resistance during static and rhythmic distension of the lungs. To test this hypothesis, we studied seven near-term fetal lambs treated with meclofenamate (a PG synthetase inhibitor) and six controls. The fetal lambs were instrumented on a long-term basis with vascular catheters to measure pulmonary arterial pressures, left atrial pressures, and pulmonary blood flow (radionuclide-labeled microsphere method). The fetal airway was intubated, and the ductus arteriosus wall was infiltrated with formalin to assure full patency during the study period. Pulmonary vascular resistance was calculated during baseline and during sequential in utero static distension of the fetal lungs, rhythmic distension, and ventilation with oxygenation. We found that during rhythmic distension, inhibition of PG synthesis abolished the 4-fold decrease in pulmonary vascular resistance seen in the control group. In contrast, during static distension, pulmonary vascular resistance did not change in either group, and during ventilation with oxygenation, pulmonary vascular resistance decreased 12-fold in both groups. We conclude that PG are important regulators of pulmonary vascular resistance during rhythmic distension but are not essential for the regulation of pulmonary vascular resistance during static distension or during ventilation with oxygenation.

Leukotrienes C4, D4, and E4 in fetal lamb tracheal fluid.

Previously, we demonstrated that either putative leukotriene receptor antagonists or a synthesis inhibitor markedly decreased pulmonary vascular resistance in the near-term fetal lamb and concluded that leukotrienes may play a role in maintaining the high pulmonary vascular resistance in the fetus. To further investigate the role of leukotrienes, we measured concentrations of leukotriene (LT) C4, LTD4, and LTE4 in 17 tracheal fluid samples from 8 of 9 near-term (129-139 days, term = 145 days), chronically-catheterized, fetal lambs during normoxia to evaluate their possible role in regulating resting tone and in seven of the nine before and during hypoxia to evaluate their possible role in hypoxic vasoconstriction. The tracheal fluid samples collected by gravity over 1-3 min, on ice, were immediately treated with cold ethanol, centrifuged, and the supernatant covered with N2 and stored in a -70 degrees C freezer for a maximum of 3 weeks. Purification and separation of leukotrienes was done by reverse-phase high performance liquid chromatography using a gradient elution method, and fractions corresponding to LTC4, LTD4, and LTE4 standards were quantified immediately by radioimmunoassay. During normoxia (descending aortic PaO2 2.9 +/- 0.3 kPa [21.5 +/- 2.5 mmHg]; mean +/- SD), all 3 leukotrienes were detected in 16 of the 17 samples: LTC4 29 +/- 28 pg/ml (range 0-119 pg/ml); LTD4 66 +/- 51 pg/ml (range 9-177 pg/ml); and LTE4 43 +/- 50 pg/ml (range 0-204 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Successful transcatheter ablation of congenital junctional ectopic tachycardia in a ten-month-old infant using radiofrequency energy.

Congenital junctional tachycardia is a difficult-to-control rhythm in children which has a high mortality rate with current management. A 10-month-old child followed since birth with the diagnosis of congenital junctional ectopic tachycardia is reported. He failed treatment with multiple antiarrhythmic agents, and underwent an electrophysiology study. The junctional focus was successfully ablated using transcatheter radiofrequency energy. This technique may be safer than high voltage DC shock ablation, particularly in small children.

Weight loss in full-term negroid infants: relationship to body water compartments at birth?

The possible influence of the body fluid compartments at birth on postnatal weight loss was studied in normal term negroid infants when on a standardized oral fluid, sodium and energy regimen during the first three days of life. Measurements of plasma volume (PV), total body water (TBW), and extracellular water (ECW) were performed simultaneously on vaginally-born infants on the first day of life, by using a triple indicator (Evans blue, deuterium oxide and sucrose) single injection dilution technique. PV was 54 +/- 7 ml/kg (N = 9), TBW was 751 +/- 50 ml/kg (N = 13) and ECW was 311 +/- 61 ml/kg (N = 13) (mean +/- S.D.). Postnatal weight loss (3.7% of birth weight) occurred during the first two days. The postnatal weight loss was not related to any of the body water compartments. However, there was a highly significant correlation with the (cumulative) urine water excretion (r = 0.833, P less than 0.001 on day 1, with similar values for days 1 and 2).

Alpha- and gamma-tocopherol in plasma, red blood cells, and platelets during plasma exchange.

The effect of a rapid reduction of plasma lipoproteins on the alpha- and gamma-tocopherol levels in plasma, erythrocytes, and platelets was studied. Sixteen successive plasma exchange procedures performed weekly in an adult with heterozygous familial hypercholesterolemia were evaluated. Plasma exchange was done by intermittent flow centrifugation, exchanging one plasma volume against a 4% human albumin solution. Plasma exchange reduced in plasma alpha-tocopherol from 41.5 +/- 8.9 to 23.6 +/- 4.8 mumol/L and gamma-tocopherol from 4.9 +/- 4.1 to 2.4 +/- 2.1 mumol/L, without changing their ratios to total lipids. It diminished alpha-tocopherol in platelets from 12.97 +/- 4.37 to 10.03 +/- 1.78 mumol/10(13) cells and gamma-tocopherol from 1.43 +/- 0.55 to 1.06 +/- 0.41 mumol/10(13) cells, but did not affect erythrocyte tocopherols. The total amount removed per procedure was 47.57 +/- 13.65 mumol for alpha-tocopherol and 4.70 +/- 3.59 mumol for gamma-tocopherol. Plasma exchange increased the number of erythrocytes from 3.67 +/- 0.10.10(12) to 4.05 +/- 0.13.10(12) cells/L, without affecting their volume. Platelet count did not change, but mean platelet volume decreased from 7.7 +/- 0.5 to 6.9 +/- 0.5 fl and platelet distribution width from 15.1 +/- 0.4 to 14.9 +/- 0.5. Thus, plasma exchange reduces plasma alpha- and gamma-tocopherol to the same extent as total lipids, and decreases these tocopherols in circulating platelets, along with a reduction in platelet size and, compared to the change in erythrocyte count, a fall of platelet number.(ABSTRACT TRUNCATED AT 250 WORDS)