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We describe three patients with congenital disorder of glycosylation (CDG) type Ia, all of whom had persistent hyperinsulinaemic hypoglycaemia responding to diazoxide therapy as a common feature. The first patient, an infant girl, presented with recurrent vomiting, failure to thrive, liver impairment, hypothyroidism and a pericardial effusion. The second patient, also female, had a milder disease with single organ involvement, presenting as isolated hyperinsulinaemic hypoglycaemia, not associated with any cognitive impairment. The third patient, a boy presented with multi-organ manifestations including congenital hypothyroidism, persistent hyperinsulinaemic hypoglycaemia, coagulopathy, olivopontocerebellar hypoplasia and recurrent pancreatitis. All three patients had a type 1 serum transferrin isoform pattern, and were subsequently found to have low phosphomannomutase activity, confirming the diagnosis of CDG type Ia. Our findings emphasize that CDG should be considered as a differential diagnosis in patients with persistent hyperinsulinaemic hypoglycaemia and that it may even occasionally be the leading symptom in CDG Ia. [ABSTRACT FROM AUTHOR]

Glutaric aciduria type I (GA I), a cerebral organic acidaemia with the potential for severe neurological consequences, can now be detected by tandem mass spectrometry newborn screening. Early detection with implementation of careful management strategies appears to lessen the likelihood of neurological damage. We assessed the outcome in all 10 GA I patients detected in New South Wales during the last decade. Three patients were detected clinically and 7 by newborn screening. Diagnosis was confirmed by detection of significantly elevated urinary 3-hydroxybutyrate and glutarate in urine, isolated elevation of glutarylcarnitine in plasma, typical clinical and MRI findings in several, and mutation analysis or enzyme analysis on cultured skin fibroblasts in 4 cases. The birth frequency was 1:90 000. Following diagnosis, treatment was initiated in all children with oral carnitine (100 mg/kg per day) and a low-protein diet supplemented with a lysine-free, low-tryptophan amino acid formula. Disability was assessed in fields of motor, cognitive and speech development and scored according to Kyllerman. Clinically diagnosed patients were all symptomatic, with severity scores (out of 9) of 3, 5 and 9. Six of seven patients detected by newborn screening are asymptomatic, 4 being aged 2–6 years. One patient had a severe decompensation at 7 months, despite full management advice and treatment, and later died. Our data support previous findings that early diagnosis reduces neurological complications, but show that even with early diagnosis and careful management severe complications may ensue in some. [ABSTRACT FROM AUTHOR]

Mass transfer across the gas--water interface is important in many fields, but the present understanding of the scalar transport as mediated by the complex near-surface turbulence is still far from complete. In this work, an innovative particle image velocimetry (PIV)--based measurement method was used to investigate the near surface turbulence. Turbulence measurement with respect to the fluctuating interface was performed and the gradient of the vertical fluctuating velocity (Hanratty's β) deemed as a critical controlling parameter was quantified. Several distinctly different but typical flow conditions were investigated and the associated mass-transfer velocity was measured. Based on these experimental works, an empirical relation, very similar to that proposed earlier by Law and Khoo, relating the mass transport across the turbulent interface to the turbulence parameter β, was determined in the midst of vastly different flow conditions where turbulence is induced simultaneously from above and beneath the gas--water interface. [ABSTRACT FROM AUTHOR]

We have screened 13 patients with neurological abnormalities and 3-methylglutaconic aciduria (3MGA) for mutations in the OPA3 gene, which are known to be the cause of Costeff syndrome (optic atrophy, chorea and spasticity; type III 3MGA). We aimed to explore whether mutations in the OPA3 gene are present in patients with 3MGA but without classic Costeff syndrome. OPA3 mutations (IVS1−1G>C) were identified in 2 patients with the classic phenotype of type III 3MGA, but not in the other 11 patients with differing non-Costeff phenotypes associated with developmental delay and neurological signs and symptoms as described. We identified a previously described sequence variation in the OPA3 gene (c.231T>C) in 12/13 patients. The alteration was homozygous in 8/12 and heterozygous in 4/12. This alteration was also found in 60 of 98 normal control alleles. In a single patient, a novel sequence variation in the 5′ UTR was identified, (c.−38A>G). Our studies suggest that the c.231T>C sequence variation is of no clinical significance, whereas the significance of the 5′ UTR sequence variation remains open to speculation. Our study of the OPA3 gene in patients with 3MGA without Costeff syndrome suggests that mutations in OPA3 are not a common cause of 3MGA in the absence of signs of Costeff syndrome. [ABSTRACT FROM AUTHOR]

Asthmatic airway remodelling is characterized by myofibroblast hyperplasia and subbasement membrane collagen deposition. We hypothesized that cytokines and growth factors implicated in asthmatic airway remodelling are increased in bronchoalveolar lavage (BAL) fluid of asthmatics after segmental allergen challenge (SAC), and that these growth factors and cytokines increase α-smooth muscle actin (α-SMA) and collagen III synthesis by human lung fibroblasts (HLFs). Transforming growth factor (TGF)-β1, TGF-β2, IL-4 and IL-13 levels were measured in BAL fluid from 10 asthmatics and 9 non-asthmatic controls at baseline and then 1 day, 1 week and 2 weeks after SAC. Confluent cultures of HLFs were stimulated by exogenous addition of TGF-β1, TGF-β2, IL-4 or IL-13 (concentration range 0.01–10 ng/mL) over 48 h. Collagen III was measured in culture supernates and α-SMA in cell lysates by Western blot. At baseline, there was no difference in BAL fluid concentrations of TGF-β1, IL-4 and IL-13 between asthmatics and controls; however, non-asthmatics had higher concentrations of total TGF-β2. In asthmatics, BAL fluid concentrations of all four factors increased significantly 1 day after SAC. TGF-β1, TGF-β2 and IL-13 concentrations returned to baseline by 1 week after SAC, but BAL fluid IL-4 concentration remained elevated for at least 2 weeks. TGF-β1, TGF-β2 and IL-4 significantly increased α-SMA in fibroblasts, but only IL-4 caused corresponding increases in collagen III synthesis. IL-13 had no direct effects on collagen III synthesis and α-SMA expression. Because IL-4 caused a dose-dependent increase in α-SMA and collagen III synthesis, it may be an important cytokine mediating asthmatic airway remodelling. TGF-β1 and TGF-β2 may also play a role in airway remodelling by stimulating phenotypic change of fibroblasts to myofibroblasts. Additionally, collagen III synthesis appears to be independent of myofibroblast phenotype and is apparently regulated by different growth factors and cytokines. [ABSTRACT FROM AUTHOR]

Three patients with ketosis had increased excretion of 3-hydroxyglutarate (21.8–37.9 μmol/mmol creatinine; controls 2.3 ± 1.6), an indicator of glutaryl-CoA dehydrogenase deficiency (GDHD), which normalized when the patients were nonketotic. Clinical assessment of all three patients and enzyme studies in one patient were not consistent with GDHD. These findings were compared with those of other ketotic patients, who showed statistically significant increases in 3-hydroxyglutarate excretion (9.4 ± 5.0 μmol/mmol creatinine; p < 0.01), and with those of a child with confirmed GDHD when she was both ketotic and nonketotic. Secondary increase in 3-hydroxyglutarate excretion during ketosis is a potential confounder in the diagnosis of GDHD. [ABSTRACT FROM AUTHOR]

A neonate at risk for hepatic carnitine palmitoyltransferase I (L-CPT I) deficiency was investigated from birth. The free carnitine and acylcarnitine profile in dried whole blood filter paper samples collected at ages 1 and 4 days showed a markedly elevated concentration of free carnitine (141 and 142 μmol/L, respectively), normal concentrations of acetyl- and propionylcarnitine, with the near absence of all other species. The diagnosis was confirmed by in vitro fatty acid oxidation screening assays and enzyme assay in cultured skin fibroblasts. Retrospective study of the newborn whole blood sample of the index case showed a similar profile (free carnitine 181 μmol/L). The newborn population distribution of free carnitine ( n=143981) showed that only three samples had free carnitine >140 μmol/L (>99.9th centile), two were from L-CPT I-deficient neonates and one from a baby with sepsis. While there are other conditions that can cause elevated concentrations of free carnitine, an isolated elevation of free carnitine only in an apparently healthy term neonate warrants further investigation to exclude L-CPT I deficiency. [ABSTRACT FROM AUTHOR]

Since 1998, the NSW Newborn Screening Program has used electrospray tandem mass spectrometry (MS/MS) to analyse samples from all babies born in NSW and the ACT (approximately 95 000 per year) for selected amino acids and acylcarnitines. The software rules editor initially interprets all results where ratio of analyte to internal standard is modified by input from the external standard curves per analyte. The numerical results are then downloaded to the NSW Newborn Screening database, which provides automatic, analyte specific follow-up test cascade. We have analysed samples from 137 120 consecutive newborns received by the program, requested repeat samples from 122 babies, and found abnormal levels in 17 babies with phenylketonuria, 1 tetrahydrobiopterin deficiency, 3 hyperphenylalaninaemia, 1 maple syrup urine disease, 1 tyrosinaemia type II, 1 congenital lactic acidosis, 2 medium-chain acyl CoA dehydrogenase deficiency, 1 short-chain acyl CoA dehydrogenase deficiency, 1 β-ketothiolase deficiency, 2 vitamin B12 deficient babies of vegan mothers and 1 glutaric aciduria type I. Using population data plus that obtained from retrospective samples with proven disorders we have established cut-off levels for each analyte tested. This coupled with the ability of the database to provide ratios of various analytes gives excellent screening specificity and sensitivity for the detection of at least 40 rare inborn errors of metabolism. [ABSTRACT FROM AUTHOR]

We report a male infant with cobalamin C defect whose clinical course was complicated by diarrhoea suggestive of a protein-losing enteropathy, failure to thrive, macrocytosis and thrombocytopenia which resolved with hydroxocobalamin treatment. Protein-losing enteropathy has not previously been reported in association with cobalamin C defect and, if unrecognized, could cause considerable morbidity. [ABSTRACT FROM AUTHOR]

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Unlabelled: We report on a favourable case of MCAD deficiency (homozygous 985A > G) that presented as lethargy, poor feeding, pulmonary haemorrhage and cardiac arrest without hypoglycaemia. The cessation of intralipid and the commencement of carnitine supplementation were associated with a rapid clinical improvement.Conclusion: Mild carnitine depletion and secondary impairment of long-chain fatty acid metabolism may have contributed to post-asphyxial myocardial dysfunction and ventricular arrhythmias. Metabolic disorders must be kept in mind as a differential diagnosis in acutely ill infants, but it must also be emphasized that carnitine therapy is not uniformly effective in all MCAD patients. [ABSTRACT FROM AUTHOR]

Background: N2O irreversibly inhibits the vitamin B12-dependent enzyme, methionine synthase, and has the potential to cause hematological, neurological and cardiovascular adverse effects [1–5]. Repeated exposure to N2O is common in certain pediatric settings (burns dressing and radiotherapy). There are no published clinical studies investigating the effects of nitrous oxide anesthesia on vitamin B12 and folate metabolism in a pediatric population. Aims: To study the effect of repeated exposure to N2O on metabolic indices in a cohort of children predisposed to metabolic and nutritional disturbance. Method: In an on-going, prospective study of children undergoing radiotherapy for cancer, homocysteine, methylmalonic acid, vitamin B12, folate and red cell indices were measured at regular intervals. Results were correlated with cumulative N2O exposure in those children who required repeated general anesthesia. Results: Forty children have been studied so far. Fifteen required general anesthesia to complete therapy. Median exposure to N2O was 28 min per exposure for an average of 13 exposures. The median cumulative exposure to N2O in this cohort was 397 min. Four children each had a cumulative exposure of more than 15 h. In these cases, nitrous oxide was delivered in 30 or more anesthetics over periods ranging from 6 to 11 weeks. Preliminary results show that homocysteine levels are not consistently correlated with N2O exposure. No clinical or biochemical adverse effects related to the gas have been detected. Conclusion: This interim analysis suggests that repeated N2O has a marginal effect on vitamin B12 metabolic indices in predisposed children. The study is on-going. This study is supported by a grant from SPANZA. References 1 Nunn JF. Clinical aspects of the interaction between nitrous oxide and vitamin B12. British Journal of Anaesthesia 1987; 59:3-13 2 Myles PS, Leslie K, Chan MTV, Paech MJ, Peyton P, Pascoe E. Avoidance of nitrous oxide for patients undergoing major surgery: a randomised controlled trial. Anesthesiology 2007; 107:221-231. 3 Nagele P, Zeugswetter B, Wiener C, Burger H, Hupfl M, Mittlbock M et al. Influence of methylenetetrahydrofolate reductase gene polymorphism on homocysteine concentration after nitrous oxide anesthesia. Anesthesiology 2008; 109:36-43. 4 Badner NH, Beattie WS, Freeman D, Spence JD. Nitrous oxide induced increased homocysteine concentrations are associated with increased postoperative myocardial ischemia in patients undergoing carotid endarterectomy. Anesthesia and Analgesia 2000; 91:1073-1079. 5 Badner NH, Drader K, Freenab D, Spence JD. The use of intraoperative nitrous oxide leads to postoperative increases in plasma homocysteine. Anesthesia and Analgesia 1998; 87:711-713 [ABSTRACT FROM AUTHOR]

The article presents an abstract of a medical research related to a major neuronal energy source called lactate. The metabolic fate of lactate has been examined by researchers in guinea pig brain cortical slices in the presence of alternative fuels, glucose using NMR spectroscopy and GCMS. Label from the energy source was rapidly incorporated into glutamate and citrate.

This study replicated and extended previous research on the effectiveness of brief habit reversal, consisting of awareness training and competing response training (silent pause) in reducing the rate of speech disfluencies during public speaking. Nine university students, divided into 3 groups, delivered short speeches on a novel topic. Brief habit reversal combined with an interdependent group contingency resulted in a meaningful reduction in speech disfluencies with only 1 group requiring booster sessions. Relative to baseline, competing responses increased for all participants but only remained high for 1 participant following training. Reductions in speech disfluencies maintained during follow-up when participants presented in front of a small audience., (© 2021 Society for the Experimental Analysis of Behavior (SEAB).)

D-2-hydroxyglutaric aciduria (D2HGA) is a rare autosomal recessive disorder with variable clinical expression. The biochemical defect is unknown at present. Previously reported cases have either followed a severe clinical course characterized by neonatal epileptic encephalopathy, cortical blindness, and profound developmental delay, or a mild course characterized by mild developmental delay, manageable epilepsy, and mild hypotonia. To date there has been a clear distinction between these two groups. We report the second case of a child with D2HGA who has followed an intermediate course. She presented in infancy with hypotonia, manageable epilepsy and developed moderate to severe developmental delay, and cortical visual impairment. The proposita had a coarse facial appearance, flat face, broad nasal bridge, up-turned nose, and simple, anteverted ears. These facial anomalies have been noted in other children with D2HGA and this case strengthens the proposed association between this facial phenotype and D2HGA. We also report the third and fourth instances of prenatal diagnosis for D2HGA. At each prenatal diagnosis, an affected fetus was diagnosed on the basis of markedly increased levels of D-2-hydroxyglutaric acid in amniotic fluid., (Copyright 2003 Wiley-Liss, Inc.)

Questions about usual drinking play an important role in the construction of alcohol consumption measures. However, little is known about difficulties in answering these questions for respondents with variability in their drinking patterns. We investigated this in a community sample of 945 drinkers and in a clinical sample of 400 patients treated for alcohol and/or drug problems. Demographic variables were not consistently related to self-reported difficulty in answering, but a diagnosis of current DSM-IV alcohol dependence was significantly related in both samples. In modeling the relationship between alcohol consumption and DSM-IV alcohol dependence, the fit of the model to the data was significantly improved by the addition of a variable indicating respondents' difficulty answering the usual drinking questions. Using this information in the development of alcohol consumption questions may provide more precise estimates of the risk from alcohol consumption to outcomes such as alcohol dependence.

The present study examined the effects of substance use history and depressive symptomatology on the cognitive functioning of 149 male and 72 female dually diagnosed inpatients. Logistic regression models examined the effects of life-time alcohol and cocaine use, previous month's alcohol and cocaine use and depression on abstract reasoning as assessed by the Shipley Institute of Living Scale (SILS) and neuropsychological functioning as measured by the Screening Test for the Luria-Nebraska Neuropsychological Battery (ST-LNNB). Results indicated differential effects of substance use across the two cognitive outcome measures. Specifically, a significant relationship was demonstrated for previous month's alcohol use on Shipley classification. However, after adjusting for possible borderline cases, previous month's alcohol use dropped to non-significance and in its stead an association between Shipley classification and life-time use was demonstrated. No significant effects were demonstrated for cocaine use, recent alcohol use, depressive symptoms or any of the interaction terms. The Luria-Nebraska performance classifications were significantly associated with both educational level and life-time cocaine use. No significant relationships were obtained for previous month's cocaine use, the alcohol use variables, depressive symptoms, or any of the interactions terms. The degree of classification agreement between the two outcome measures was slightly better than chance (kappa = 0.24 for ST-LNNB and traditional or full scale SILS; kappa = 0.35 for ST-LNNB and modified SILS). These kappa coefficients suggest that the SILS and ST-LNNB assess partially independent dimensions of cognitive functioning. The findings are discussed in light of previous research and implications for clinical assessment and treatment are outlined.