Outcomes of neonatal chylous effusions: A 20-year west-Australian tertiary center experience.

Neonatal chylous effusions are rare entity with limited evidence-based management. We conducted a retrospective review of neonates admitted to King Edward Memorial and Princess Margaret/Perth Children's Hospital over 20 years with laboratory-confirmed chylous effusions. A total of 51 infants with chylous effusion were identified. Median gestational age and birth weight were 35.5 weeks and 2620 grams respectively. Congenital [27/ 51] and acquired [24/51] cases were included. Antenatal interventions were performed in 17/22 with antenatal hydrops and 50/51 needed postnatal drains. Effusions were monitored with serial (≥2) chest ultrasounds in 29/51 infants and multiple (≥5) x-rays in 45/51 infants. Median duration of mechanical ventilation, oxygen requirement, and hospital stay was 294.5 hours, 400 hours, and 49 days respectively. 39/51 received medium chain triglyceride (MCT) diet while 8/51 received octreotide. Six infants died during hospital stay. 12/19 had normal developmental assessment at one-year. The acquired group had higher number of xrays done, need for MCT diet and inotropes, and hospital stay vs congenital group. Duration of drains, radiological investigations and immunoglobulin administration were higher in neonates who received octreotide. Syndromic association, duration of ventilation and oxygenation were risk factors for mortality. In our setting, neonatal chylous effusions are associated with significant morbidity and mortality.

Congenital CLN8 disease of neuronal ceroid lipofuscinosis: a novel phenotype. / Enfermedad CLN8 congenita de lipofuscinosis neuronal ceroidea: un nuevo fenotipo.

INTRODUCTION: CLN8 disease is one of the thirteen recognized genetic types of neuronal ceroid lipofuscinosis, a group of neurodegenerative lysosomal storage disorders, most frequent in childhood. A putative 286 amino acids transmembrane CLN8 protein with unknown function is affected. Pathological variants in the CLN8 gene were associated with two different phenotypes: variant late-infantile in individuals from many countries worldwide, and epilepsy progressive with mental retardation, appearing in Finnish and Turkish subjects. CASE REPORT: The girl showed psychomotor delay and dementia since birth, tonic-clonic seizures, myoclonus, ataxia with cerebellar atrophy, and early death at 12 years old. Electron microscopy of the skin showed mixed GROD, curvilinear, fingerprint cytosomes and mitochondrial hypertrophy. Two pathological DNA variants in the CLN8 gene (exon 2 c.1A>G; p.?/ exon 3 c.792C>G; p.Asn264Lys) were found confirming a compound heterozygous genotype. CONCLUSION: This case is the Latin American index for a new congenital phenotype of the CLN8 disease. The congenital phenotype has to be added to the clinical spectrum of the CLN8 disease. The suspicion of CLN8 disease should be genetically sustained in challenging cases of a neurodegenerative syndrome with psychomotor delay since birth, speech difficulty and seizures. The course includes ataxia, cerebellar atrophy, and early death.

TITLE: Enfermedad CLN8 congenita de lipofuscinosis neuronal ceroidea: un nuevo fenotipo.Introduccion. La enfermedad CLN8 es uno de los 13 tipos geneticos reconocidos de lipofuscinosis neuronal ceroidea, un grupo de trastornos neurodegenerativos de acumulacion lisosomica, los mas frecuentes en la infancia. La causan mutaciones en la proteina transmembrana CLN8 de 286 aminoacidos, cuya funcion se desconoce. Las variantes patologicas en el gen CLN8 se asociaron con dos fenotipos diferentes: la variante infantil tardia en individuos de diversos paises alrededor del mundo, y la epilepsia progresiva con retraso mental, que aparece en pacientes finlandeses y turcos. Caso clinico. Niña que mostro retraso psicomotor y demencia desde el nacimiento, convulsiones tonicoclonicas, mioclonia, ataxia con atrofia cerebelosa y muerte temprana a los 12 años. La microscopia electronica de la piel mostro una mezcla de citosomas con patrones de depositos osmiofilicos granulares, curvilineos y de «huella digital¼, y mitocondrias hipertrofiadas. Se encontraron dos variantes patologicas de ADN en el gen CLN8 (exon 2 c.1A>G; p.?/ exon 3 c.792C>G; p.Asn264Lys), lo que confirmo un genotipo heterocigoto compuesto. Conclusion. Este es el caso indice en America Latina para el nuevo fenotipo congenito de la enfermedad CLN8. La sospecha de esta patologia deberia sustentarse geneticamente en casos de sindrome neurodegenerativo con retraso psicomotor desde el nacimiento, dificultad del habla y convulsiones. El curso clinico incluye ataxia, atrofia cerebelosa y muerte temprana.

Arterial hypotension and prerenal failure in an extremely preterm infant associated with oral sildenafil.

We report significant hypotension and prerenal failure in an extremely preterm infant following two doses of oral sildenafil that warranted discontinuation of the drug and treatment with inotropes. Blood pressure and urine output normalized after 24 h of withdrawal of the oral drug. Sildenafil should be used cautiously in extremely preterm infants early in the neonatal course, where there is limited data on its efficacy and safety.

Evaluation of selection criteria for validating paired umbilical cord blood gas samples: an observational study.

OBJECTIVE: To compare six validation criteria for umbilical cord blood gas (UCBG) values in vigorous and nonvigorous neonates. DESIGN: Retrospective cohort study. SETTING: Single tertiary obstetric centre, King Edward Memorial Hospital (KEMH), Perth, Western Australia. SAMPLE: A total of 37,763 consecutive deliveries at >23 weeks of gestation. METHODS: Six validation criteria were compared to evaluate the proportion of deliveries with 'valid' UCBG data; and the proportion of vigorous and nonvigorous neonates with metabolic acidaemia. MAIN OUTCOMES: Proportion of deliveries with 'valid' UCBG values; proportions of vigorous and nonvigorous neonates with normal, borderline and abnormal UCBG values. RESULTS: The criteria based on KEMH 5th centile arteriovenous pH and Pco(2) differences resulted in a higher proportion of neonates with 'valid' UCBG values than the previously described Westgate and Kro criteria. The increase in 'valid' UCBG values occurred across the entire study population including vigorous and nonvigorous neonates. Among neonates with short-term neonatal complications there was an increase in nonvigorous neonates with umbilical artery metabolic acidaemia. There was no corresponding increase in vigorous neonates diagnosed with abnormal UCBG values. CONCLUSIONS: Use of the KEMH criteria results in an increase in the proportion of nonvigorous term neonates with UCBG data considered 'valid' to aid clinicians in the management of the neonate shortly after delivery. This change occurs without increasing the rate of false-positive diagnoses of acidaemia in vigorous neonates. The KEMH 'validation' criteria were developed from an entire presenting population and provide a simple algorithm that can be universally applied to identify neonates with nonphysiological UCBG values.

Therapeutic approaches to the challenge of neuronal ceroid lipofuscinoses.

The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 265 mutations and 38 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances.

Outreach obstetrics training in Western Australia improves neonatal outcome and decreases caesarean sections.

The objective of this study was to determine the effect of a multi-professional outreach obstetric training programme on perinatal and neonatal outcomes. This was a retrospective comparison of 5-min low Apgar scores, stillbirth, perinatal death and moderate/severe hypoxic ischaemic encephalopathy rates in 127,753 infants born in Western Australia before and after the introduction of training in rural and remote areas. Following the introduction of the training programme, there was a highly significant (p = 0.003) decrease in the rate of infants born with low 5-min Apgar scores (from 20.4 to 15.4/1,000 live births). While the changes in the other three outcomes were not significant, all three demonstrated a trend for improvement in the intervention area. This is the second study of an educational intervention in obstetrics to demonstrate improvement in neonatal outcome and the first to be associated with a decrease in caesarean sections.

An integrated strategy for the diagnosis of neuronal ceroid lipofuscinosis types 1 (CLN1) and 2 (CLN2) in eleven Latin American patients.

The neuronal ceroid lipofuscinoses (NCLs) are a family of progressive neurodegenerative diseases that are characterized by the cellular accumulation of ceroid lipofuscin-like bodies. NCL type 1 (CLN1) and type 2 (CLN2) are caused by deficiencies of the lysosomal enzymes palmitoyl-protein thioesterase 1 (PPT-1) and tripeptidyl peptidase 1 (TPP-1), respectively. In this study, 118 Latin American patients were examined for NCL using an integrated multidisciplinary program. This revealed two patients affected by CLN1 and nine by CLN2. Both CLN1 patients had a juvenile-onset phenotype with mutation studies of one patient demonstrating the known mutation p.Arg151X and a novel mutation in intron 3, c.363-3T>G. Six of the CLN2 patients presented with the 'classical' late-infantile phenotype. The remaining three patients, who were siblings, presented with a 'protracted' phenotype and had a higher level of residual TPP-1 activity than the 'classical' CLN2 patients. Genotype analysis of the TPP1 gene in the 'classical' CLN2 patients showed the presence of the known mutation p.Arg208X and the novel mutations p.Leu104X, p.Asp276Val, and p.Ala453Val. The siblings with the 'protracted' phenotype were heterozygous for two known TPP1 mutations, p.Gln66X and c.887-10A>G. This multidisciplinary program is also being used to diagnose other NCL types.

Transfer of metformin into human milk.

AIMS/HYPOTHESIS: The aim of this study was to characterize the milk-to-plasma ratio and infant dose for metformin in breastfeeding women, and to measure plasma concentrations and assess any effects in their infants. We hypothesized that metformin used by mothers is safe for their breastfed infants. METHODS: Seven women taking metformin (median dose 1500 mg orally daily) and their infants were studied. Metformin concentrations in plasma and milk were measured by high performance liquid chromatography. Infant exposure was estimated as the product of estimated milk production rate and the average concentration of the drug in milk and also expressed as a percentage of the weight-normalized maternal dose. RESULTS: The mean milk-to-plasma ratio for metformin was 0.35 (95%CI 0.2-0.5). The mean of its average concentrations in milk over the dose interval was 0.27 mg/l (0.15-0.39 mg/l). The absolute infant dose averaged 0.04 mg x kg(-1) x day(-1) (0.02-0.06 mg x kg(-1) x day(-1)) and the mean relative infant dose was 0.28% (0.16-0.4%). Metformin was present in very low or undetectable concentrations in the plasma of four of the infants who were studied. No health problems were found in the six infants who were evaluated. CONCLUSIONS/INTERPRETATION: The concentrations of metformin in breast milk were generally low and the mean infant exposure to the drug was only 0.28% of the weight-normalized maternal dose. As this is well below the 10% level of concern for breastfeeding, and because the infants were healthy, we conclude that metformin use by breastfeeding mothers is safe. Nevertheless, each decision to breastfeed should be made after conducting a risk:benefit analysis for each mother and her infant.

Alpha-interferon therapy induces improvement of platelet counts in children with chronic idiopathic thrombocytopenic purpura.

PURPOSE: To investigate alpha-interferon (IFN) therapy for children with chronic idiopathic thrombocytopenic purpura (ITP). PATIENTS AND METHODS: Patients with refractory ITP lasting more than 12 months from diagnosis were included if they had platelet counts <50 x 10(9)/L and had received no treatment during the past month. Patients received IFN (3 x 10(6) U/m2 per dose), three times per week for 4 weeks; if partial (<150 x 10(9)/L) or no response was obtained, the same dose was continued for another 8 weeks. In patients with favorable response and subsequent decrease to pre-treatment values, an additional 4 weeks of treatment could be administered. RESULTS: Fourteen patients (ages 4-20 y) receiving 17 IFN courses were included. Mean initial platelet count was 29 +/- 15 x 10(9)/L. A significant increase was achieved during 14 of 17 courses (82.4%). All but two responses were transitory, and platelets returned to initial values after IFN discontinuation (mean 44 +/- 26 days). Considering the best response achieved by each patient, we observed: 1) 10 patients who achieved a sustained improvement of platelet count throughout the treatment period, decreasing to initial values after therapy was stopped; 2) one patient who achieved platelet count >150 x 10(9)/L, remaining with normal platelets at 18 months; 3) one patient who achieved platelet count >150 x 10(9)/L, remaining with platelets between 100 and 140 x 10(9)/L at 48 months; 4) one patient who had no response; and 5) one patient in whom therapy worsened the thrombocytopenia. A mild to moderate flu-like syndrome and a moderate decrease of the absolute neutrophil count were the only side effects observed. CONCLUSION: Interferon therapy induces a significant increase of platelet count and seems to be a valid alternative therapy to attempt the achievement of prolonged remission in refractory ITP, to defer splenectomy in younger children, or to improve platelet count before planned splenectomy.

Increased endometrial thickness in women with hypertension.

OBJECTIVE: We noticed an increase in endometrial thickness in women with hypertension who were treated with a combination of medications, including beta-blockers. The purpose of this study was to examine whether the endometrium of hypertensive women is thicker than that of healthy women and to determine whether endometrial thickening in hypertensive women is directly related to the antihypertensive beta-blocker treatment. STUDY DESIGN: We compared 3 groups of postmenopausal patients as follows: (1) women with a history of essential hypertension treated with a combination of medications, including beta-blockers; (2) women with a history of hypertension treated with a combination of medications that did not include beta-blockers; and (3) healthy women without hypertension. All patients were interviewed and examined, blood tests were performed, and endometrial thickness in the anterior-posterior diameter was measured by vaginal ultrasonography. Among the exclusion criteria were diabetes or an abnormal fasting blood glucose level, obesity, hormonal medication or replacement hormonal therapy during the previous 6 months, and a history of hormonal disturbances, infertility, or polycystic ovary syndrome. RESULTS: Of 45 hypertensive women enrolled in the study, 22 were treated with a beta-blocker combination medication and 23 were treated with other antihypertensive medications. They were compared with 25 healthy women. There was no statistically significant difference in endometrial thickness between women treated with medications, including beta-blockers, and those who were treated with other hypotensive agents. Twenty percent of women with hypertension and none of the healthy women had endometrium >5 mm thick (P <.017; odds ratio, 8.22; 95% confidence interval, 1.22-infinity). CONCLUSION: Twenty percent of hypertensive postmenopausal women were found to have increased endometrial thickness. However, we were unable to substantiate an association between the type of treatment administered, whether beta-blockers were included, and the increase in endometrial thickness.

Citalopram and demethylcitalopram in human milk; distribution, excretion and effects in breast fed infants.

AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for citalopram and demethylcitalopram, in breast-feeding women taking citalopram for the treatment of depression, and to determine the plasma concentration and effects of these drugs in their infants. METHODS: Seven women (mean age 30.6 years) taking citalopram (median dose 0.36 mg kg(-1) day(-1)) and their infants (mean age 4.1 months) were studied. Citalopram and demethylcitalopram in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval. Infant exposure was estimated (two separate methods) as the product of milk production rate and drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/PAUC values of 1.8 (range 1.2-3) and 1.8 (range 1.0-2.5) were calculated for citalopram and demethylcitalopram, respectively. The mean maximum concentrations of citalopram and demethylcitalopram in milk were 154 (95% CI, 102-207) microg l(-1) and 50 (23-77) microg l(-1). Depending on the method of calculation, mean infant exposure was 3.2 or 3.7% for citalopram and 1.2 or 1.4% for demethylcitalopram. Citalopram (2.0, 2.3 and 2.3 microg l(-1)) was detected in three of the seven infants. Demethylcitalopram (2.2 and 2.2 microg l(-1) was detected in plasma from two of the same infants. No adverse effects were seen in the infants, all were within appropriate percentile limits for weight and all had normal Denver developmental quotients. CONCLUSIONS: The mean combined dose of citalopram and demethylcitalopram (4.4-5.1% as citalopram equivalents) transmitted to infants via breast milk is below the 10% notional level of concern. Plasma concentrations of these drugs in the infants were very low or absent and there were no adverse effects. These data support the safety of the use of citalopram in breast feeding women. Nevertheless, each decision to breast feed should always be made as an individual risk:benefit analysis.

Experimental use of raffinose as an osmotic agent for peritoneal dialysis.

Conventional glucose-based solutions for peritoneal dialysis fluids have been shown to raise problems of biocompatibility. We therefore evaluated the ultrafiltration capabilities of raffinose as an alternative osmotic agent in a non-uremic rat model. Animals were divided into four groups and injected intraperitoneally with solutions containing raffinose (4.5%, 345 mOsm/kg; 16.7%, 518 mOsm/kg) or glucose (1.5%, 346 mOsm/kg; 4.25%, 489 mOsm/kg). Data obtained from animals exposed to 16.7% raffinose were excluded because of precipitation of the osmotic agent. Low-osmolality raffinose solution induced higher ultrafiltered volume than the low-osmolality glucose-enriched fluid at 120 minutes of dwelling time. No significant differences were observed in effluent sodium and potassium concentration and protein dialysate-to-plasma (D/P) ratio. The D/P ratio of phosphate was higher in the low-osmolality raffinose-based fluid than in the low-osmolality glucose solution. The osmolality of the solutions was significantly decreased after a dwelling time of 120 minutes. We conclude that 4.5% raffinose is an effective osmotic agent. Total or partial replacement of glucose by raffinose for clinical peritoneal dialysis could be eventually considered after appropriate evaluation of its biocompatibility and general side effects.

Postnatal lung function after prenatal steroid treatment in sheep: effect of gender.

The effect of fetal gender on postnatal lung function and response to prenatal steroid exposure were examined retrospectively in a group of 115 preterm lambs. Fetuses received a single intramuscular injection of 0.5 mg/kg betamethasone alone or in conjunction with L-thyroxine 48 h before delivery at 128-d gestational age. Control animals received an equivalent volume of saline. After delivery, respiratory mechanics and blood gas parameters were recorded for 40 min. Deflation pressure volume curves were constructed in excised lungs. Right upper lobes from a randomly selected subgroup of control animals were examined morphometrically. Control (saline-treated) females were able to be ventilated at lower ventilatory pressures with equivalent tidal volumes and more efficient gas exchange. There were no gender differences in compliance, conductance, or excised lung volumes for saline-treated animals. More efficient gas exchange in females could not be explained by thinner alveolar septa or greater alveolar surface area. After hormone treatment, both males and females exhibited significant improvements in respiratory mechanics, gas exchange, and an increase in alveolar surfactant concentration. However, female exhibited a significantly greater improvement than males for compliance, conductance, excised lung volume, and arterial oxygen partial pressure. These data provide a comprehensive description of gender differences in postnatal lung function and response to steroid treatment in preterm animals, and support clinical findings of sexual dimorphism.

Effects of severe hemorrhage on plasma ANP and glomerular ANP receptors.

Atrial natriuretic peptide (ANP) plays an important role in blood volume and electrolyte homeostasis in normovolemia and in hypervolemic states. The currently available information on the effects of hypovolemia on plasma ANP is contradictory. Moreover, possible regulation of ANP receptors during severe hemorrhagic hypovolemia has not been investigated. This study evaluated the effects of severe hemorrhage on plasma ANP and on the regulation of glomerular ANP receptor subtypes in anesthetized rats. Constant rate bleeding of 50% of total blood volume within 2 h induced a reproducible shock state characterized by marked decreases in blood pressure, heart rate, and hematocrit and an increase in plasma renin activity and aldosterone. Hemorrhaged rats exhibited a gradual significant increase in plasma ANP from 39.3 +/- 2.9 to 114.7 +/- 20.0 pmol/l 1 h after the bleeding (P < 0.001 from the initial value and P < 0.02 from the final value of sham-shock rats). Hemorrhage induced a significant decrease in total glomerular ANP binding sites (172 +/- 25 vs. 363 +/- 39 fmol/mg protein in hemorrhaged and sham-shock rats, respectively, P < 0.05). This decrease was mainly due to a significant decrease in ANPC receptors (132 +/- 22 vs. 312 +/- 40 fmol/mg protein in hemorrhaged and sham-shock rats, respectively, P < 0.05). Hemorrhage did not change glomerular ANPA receptor density. No significant differences in the affinity of the glomerular receptor subtypes for ANP were detected. Our data indicate that plasma ANP increases after prolonged severe hemorrhage. It is suggested that downregulation of renal ANPC receptors leads to reduced clearance of ANP and contributes to elevation of its plasma level after severe hemorrhage.

Preterm lung function after retreatment with antenatal betamethasone in preterm lambs.

OBJECTIVE: We hypothesized that two doses of betamethasone administered 1 week apart would further enhance postnatal pulmonary function in preterm lambs (compared with a single dose). STUDY DESIGN: Fetal sheep (121 days' gestation) randomly received saline solution or betamethasone (0.5 mg/kg) as a single injection. Six days later fetal sheep were retreated with either saline solution or corticosteroid, and postnatal lung function was evaluated 1 day later. RESULTS: Betamethasone improved compliance and ventilation efficiency index nearly 50%, and total lung volume increased twofold. No effects of treatment-to-delivery interval (1 vs 7 days) or corticosteroid retreatment on pulmonary function were apparent. Although surfactant pool sizes increased as a function of duration of exposure, no additional effect of corticosteroid retreatment was noted. Antenatal betamethasone increased messenger ribonucleic acid levels for the surfactant proteins A and C, and retreatment augmented surfactant protein B messenger ribonucleic acid levels but suppressed surfactant protein A and C messenger ribonucleic acid. CONCLUSION: Improved postnatal lung function resulting from antenatal betamethasone was not augmented by retreatment.