Repetitive transcranial magnetic stimulation in the treatment of resistant depression: changes of specific neurotransmitter precursor amino acids.

Repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depression offers an alternative therapy, since more than every third patient is not responding to adequate antidepressive treatment. In this interventional study safety, symptom development and changes of serum concentrations of neurotransmitter precursor amino acids, of immune activation and inflammation markers, of brain-derived neurotrophic factor (BDNF), nitrite as well as of salivary amylase were measured before and after a frontal polar cortex stimulation using rTMS as add-on treatment in 38 patients with treatment-resistant depression. Out of these, 17 patients received sham stimulation as a control. Treatment was well tolerated: with the exception of one patient of the verum group, who described discomfort during the second treatment, no serious adverse effects were observed. Improvement of depression with a significant decrease in the HAMD-7 scale (p = 0.001) was found in patients treated with rTMS, but not in sham-treated patients. Furthermore, serum phenylalanine and tyrosine dropped significantly (p = 0.03 and p = 0.027, respectively) in rTMS-treated patients. The kynurenine to tryptophan ratio (Kyn/Trp) tended to decrease under rTMS (p = 0.07). In addition, associations between concentrations of BDNF and neopterin as well as serum nitrite levels were found in patients after rTMS treatment, which indicates an influence of immune regulatory circuits on BDNF levels. In the sham-treated patients, no changes of biomarker concentrations were observed. Results show that rTMS is effective in the treatment of resistant depression. rTMS appears to influence the enzyme phenylalanine hydroxylase, which plays a central role in the biosynthesis of neurotransmitter precursors tyrosine and dihydroxyphenylalanine (DOPA).

Potential of genomic selection for improvement of resistance to ostreid herpesvirus in Pacific oyster (Crassostrea gigas).

In genomic selection (GS), genome-wide SNP markers are used to generate genomic estimated breeding values for selection candidates. The application of GS in shellfish looks promising and has the potential to help in dealing with one of the main issues currently affecting Pacific oyster production worldwide, which is the 'summer mortality syndrome'. This causes periodic mass mortality in farms worldwide and has mainly been attributed to a specific variant of the ostreid herpesvirus (OsHV-1). In the current study, we evaluated the potential of genomic selection for host resistance to OsHV-1 in Pacific oysters, and compared it with pedigree-based approaches. An OsHV-1 disease challenge was performed using an immersion-based virus exposure treatment for oysters for 7 days. A total of 768 samples were genotyped using the medium-density SNP array for oysters. A GWAS was performed for the survival trait using a GBLUP approach in blupf90 software. Heritability ranged from 0.25 ± 0.05 to 0.37 ± 0.05 (mean ± SE) based on pedigree and genomic information respectively. Genomic prediction was more accurate than pedigree prediction, and SNP density reduction had little impact on prediction accuracy until marker densities dropped below approximately 500 SNPs. This demonstrates the potential for GS in Pacific oyster breeding programmes, and importantly, demonstrates that a low number of SNPs might suffice to obtain accurate genomic estimated breeding values, thus potentially making the implementation of GS more cost effective.

Treatment of patients with geriatric depression with repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) has become a useful tool to treat different neuropsychiatric conditions such as depression, dementia and extrapyramidal syndromes insufficiently responding to conventional treatment. In this SHAM-controlled exploratory study safety, symptom improvement as well as changes in inflammation markers and neurotransmitter precursor amino acids availability were studied after a prefrontal cortex (PFC) stimulation using rTMS as add-on treatment in 29 patients with geriatric depression. Out of these, ten patients received SHAM treatment. Treatment was well tolerated, no serious adverse effects were observed. A clear improvement in symptoms of depression with a significant decrease in the HAMD-7 (U = 3.306, p = 0.001) was found by rTMS treatment. In parallel, serum phenylalanine dropped significantly (U = 2.340, p < 0.02), and there was a decline of tryptophan and of Phe/Tyr concentrations, both the effects, however, failed to reach the levels of statistical significance. In the patients who underwent SHAM treatment, no significant changes of HAMD-7 or the concentrations of any biomarker in the study could be found. In addition to the significant effect of rTMS on depression scores, these results point to a possible influence of rTMS on the enzyme phenylalanine hydroxylase (PAH), which plays a crucial role in the biosynthesis of neurotransmitter precursors related to geriatric depression.

Cost-effectiveness of embryo transfer strategies: a decision analytic model using long-term costs and consequences of singletons and multiples born as a consequence of IVF.

STUDY QUESTION: What is the cost-effectiveness of elective single embryo transfer (eSET) versus double embryo transfer (DET) strategies from a societal perspective, when applying a time horizon of 1, 5 and 18 years? SUMMARY ANSWER: From a short-term perspective (1 year) it is cost-effective to replace DET with single embryo transfer; however when intermediate- (5 years) and long-term (18 years) costs and consequences are incorporated, DET becomes the most cost-effective strategy, given a ceiling ratio of €20 000 per quality-adjusted life years (QALY) gained. WHAT IS ALREADY KNOWN: According to previous cost-effectiveness research into embryo transfer strategies, DET is considered cost-effective if society is willing to pay around €20 000 for an extra live birth. However, interpretation of those studies is complicated, as those studies fail to incorporate long-term costs and outcomes and used live birth as a measure of effectiveness instead of QALYs. With this outcome, both multiple and singletons were valued as one live birth, whereas costs of all children of a multiple were incorporated. STUDY DESIGN, SIZE, DURATION: A Markov model (cycle length: 1 year; time horizon: 1, 5 and 18 years) was developed comparing a maximum of: (i) three cycles of eSET in all patients; (ii) four cycles of eSET in all patients; (iii) five cycles of eSET in all patients; (iv) three cycles of standard treatment policy (STP), i.e. eSET in women <38 years with a good quality embryo, and DET in all other women; and (v) three cycles of DET in all patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Expected life years (LYs), child QALYs and costs were estimated for all comparators. Input parameters were derived from a retrospective cohort study, in which hospital resource data were collected (n=580) and a parental questionnaire was sent out (431 respondents). Probabilistic sensitivity analysis (5000 iterations) was performed. MAIN RESULTS AND THE ROLE OF CHANCE: With a time horizon of 18 years, DETx3 is most effective (0.54 live births, 10.2 LYs and 9.8 QALYs) and expensive (€37 871) per couple starting IVF. Three cycles of eSET are least effective (0.43 live births, 7.1 LYs and 6.8 QALYs) and expensive (€25 563). We assumed that society is willing to pay €20 000 per QALY gained. With a time horizon of 1 year, eSETx3 was the most cost-effective embryo transfer strategy with a probability of being cost-effective of 99.9%. With a time horizon of 5 or 18 years, DETx3 was most cost-effective, with probabilities of being cost-effective of 77.3 and 93.2%, respectively. LIMITATIONS, REASONS FOR CAUTION: This is the first study to use QALYs generated by the children in the economic evaluation of embryo transfer strategies. There remains some disagreement on whether QALYs generated by new life should be used in economic evaluations of fertility treatment. A further limitation is that treatment ends when it results in live birth and that only child QALYs were considered as measure of effectiveness. The results for the time horizon of 18 years might be less solid, as the data beyond the age of 8 years are based on extrapolation. WIDER IMPLICATIONS OF THE FINDINGS: The current Markov model indicates that when child QALYs are used as measure of outcome it is not cost-effective on the long term to replace DET with single embryo transfer strategies. However, for a balanced approach, a family-planning perspective would be preferable, including additional treatment cycles for couples who wish to have another child. Furthermore, the analysis should be extended to include QALYs of family members. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant (grant number 80-82310-98-09094) from the Netherlands Organization for Health Research and Development (ZonMw). There are no conflicts of interest in connection with this article. TRIAL REGISTRATION NUMBER: Not applicable.

Hospital costs during the first 5 years of life for multiples compared with singletons born after IVF or ICSI.

STUDY QUESTION: Do in vitro fertilization (IVF) multiples generate higher hospital costs than IVF singletons, from birth up to age 5? SUMMARY ANSWER: Hospital costs from birth up to age 5 were significantly higher among IVF/ICSI multiple children compared with IVF/ICSI singletons; however, when excluding the costs incurred during the birth admission period, hospital costs of multiples and singletons were comparable. WHAT IS KNOWN ALREADY: Concern has risen over the long-term outcome of children born after IVF. The increased incidence of multiple births in IVF as a result of double-embryo transfer predisposes children to a poorer neonatal outcome such as preterm birth and low birthweight. As a consequence, IVF multiples require more medical care. Costs and consequences of poorer neonatal outcomes in multiples may also exist later in life. STUDY DESIGN, SIZE, DURATION: All 5497 children born from IVF in 2003-2005, whose parents received IVF or ICSI treatment in one of five participating Dutch IVF centers, served as a basis for a retrospective cohort study. Based on gestational age, birthweight, Apgar and congenital malformation, children were assigned to one of three risk strata (low-, moderate- or high-risk). PARTICIPANTS/MATERIALS, SETTING, METHODS: To enhance the efficiency of the data collection, 816 multiples and 584 singletons were selected for 5-year follow-up based on stratified (risk) sampling. Parental informed consent was received of 322 multiples and 293 singletons. Individual-level hospital resource use data (hospitalization, outpatient visits and medical procedures) were retrieved from hospital information systems and patient charts for 302 multiples and 278 singletons. MAIN RESULTS AND THE ROLE OF CHANCE: The risk of hospitalization (OR 4.9, 95% CI 3.3-7.0), outpatient visits (OR 2.6, 95% CI 1.8-3.6) and medical procedures (OR 1.7, 95% CI 1.2-2.2) was higher for multiples compared with singletons. The average hospital costs amounted to €10 018 and €2093 during the birth admission period (P < 0.001), €1131 and €696 after the birth admission period to the first birthday (not significant (n.s.)) and €1084 and €938 from the second to the fifth life year (n.s.) for multiples and singletons, respectively. Hospital costs from birth up to age 5 were 3.3-fold higher for multiples compared with singletons (P < 0.001). Among multiples and singletons, respectively, 90.8 and 76.2% of the total hospital costs were caused by hospital admission days and 8.9 and 25.2% of the total hospital costs during the first 5 years of life occurred after the first year of life. LIMITATIONS, REASONS FOR CAUTION: Resource use and costs outside the hospital were not included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the increased use of healthcare resources by IVF/ICSI multiples compared with IVF/ICSI singletons. Single-embryo transfer may result in substantial savings, particularly in the birth admission period. These savings need to be compared with the extra costs of additional embryo transfers needed to achieve a successful pregnancy. Besides costs, health outcomes of children born after single-embryo transfer should be compared with those born after double-embryo transfer. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant (grant number 80-82310-98-09094) from the Netherlands Organization for Health Research and Development (ZonMw). There are no conflicts of interest in connection with this article. TRIAL REGISTRATION NUMBER: Not applicable.

Follow-up of children born after ICSI with epididymal spermatozoa.

BACKGROUND: To evaluate the safety of ICSI with epididymal sperm, this study compared children born after ICSI treatment with epididymal sperm and children conceived after IVF and ICSI with ejaculated sperm. Additionally, the results of a multidisciplinary, multicentre follow-up of the children conceived with epididymal sperm at 2 years of age are described. METHODS: This follow-up study included 378 children conceived after ICSI with epididymal sperm (percutaneous epididymal sperm aspiration: PESA group) and a control group of 1192 IVF and 1126 ICSI (with ejaculated sperm) children, all with a gestational age of 20 weeks or more. Questionnaires were sent at birth, 1 year and 4 years of age, collecting data on parental, pregnancy and child factors. A total of 148 PESA children were assessed at 2 years of age for motor performance, mental- and language development and compared with the Dutch norms. RESULTS: PESA children showed no increased risks for stillbirths, total deaths and malformations. They also did not differ from IVF and ICSI children in gender rate, birthweight and gestational age. The mental Bayley score was higher (P < 0.05) for PESA singletons and parents reported fewer (P < 0.05) behavioural problems in the PESA group than the Dutch reference group. The scores for syntactic and lexical development for the PESA singletons were better (P < 0.05) than the Dutch standards. CONCLUSIONS: ICSI with epididymal sperm does not lead to more stillbirths or congenital malformations in comparison to IVF and ICSI with ejaculated sperm and does not lead to poor development in comparison with the Dutch reference group.

Iron stores, liver transaminase levels and metabolic risk in healthy teenagers.

BACKGROUND: Iron overload may contribute to the pathogenesis of insulin resistance. We aimed to investigate the relationship among iron stores, liver transaminases and components of the metabolic syndrome in healthy teenagers in a cross-sectional study. MATERIAL AND METHODS: We determined body mass index (BMI), waist-to-hip-ratio (WHR), blood pressure, liver ultrasound, serum lipids, insulin, fasting glucose, liver transaminase levels, hsCRP, iron parameters in 325 of 341 (95.3%) students (234 men, 16.7 +/- 1.7 years; 91 women, 16.5 +/- 1.7 years) of one single high school. Male and female study participants were allocated to increasing quartiles of body iron stores as assessed by sTfr/ferritin and alanine aminotranspeptidase (ALT) levels, and the distribution of cardiometabolic risk factors along quartiles was analysed. Regression analysis was performed to confirm the independent relationship between parameters. RESULTS: In male students, BMI, WHR, systolic and diastolic blood pressure, serum triglyceride levels and hsCRP were higher in the top sTfR/ferritin and ALT quartiles compared with the lowest quartiles (P < 0.01 for all parameters). In female students, sTfR/ferritin were not associated with antropomorphic cardiometabolic risk factors but with insulin resistance (HOMA-IR, P = 0.046). Moreover, ALT levels were independently related to BMI, waist and hip circumference, systolic blood pressure, serum triglyceride and insulin concentrations (P < 0.05 for all parameters) in female students. CONCLUSION: These results provide evidence for linkage among body iron stores, transaminase activity and the prevalence of cardiometabolic risk factors in apparently healthy, non-obese adolescents even within the range of normal laboratory and anthropomorphic values and suggest that iron stores should be investigated as a potentially modifiable risk factor in healthy teenagers.

Lack of cerebellar tDCS effects on learning of a complex whole body dynamic balance task in middle-aged (50-65 years) adults.

BACKGROUND: Cerebellar transcranial direct current stimulation (tDCS) is widely considered as a promising non-invasive tool to foster motor performance and learning in health and disease. The results of previous studies, however, are inconsistent. Our group failed to provide evidence for an effect of cerebellar tDCS on learning of a complex whole body dynamic balance task in young and healthy participants. Ceiling effects in the young study population are one possible explanation for the negative findings. METHODS: In the present study, we therefore tested 40 middle-aged healthy participants between the ages of 50 to 65 years. Participants received either anodal or sham cerebellar tDCS using a double-blinded study design while performing a balance task on a Lafayette Instrument 16,030 stability platform®. Mean platform angle and mean balance time were assessed as outcome measures. RESULTS: Significant learning effects were found in all participants. Balancing performance and learning rate was significantly less in the group of middle-aged adults compared to our previous group of young adults. No significant effects of cerebellar tDCS were observed. CONCLUSIONS: Our findings are in line with other studies that have failed to prove robust effects of cerebellar tDCS on motor learning. The present findings, however, do not exclude cerebellar tDCS effects. tDCS effects may be more prominent after repeated stimulation, using other stimulus parameters, in patient populations, or in other motor learning tasks. TRIAL REGISTRATION: Not applicable.

Parent views on enhancing the quality of health care for their children with fragile X syndrome, autism or Down syndrome.

BACKGROUND: International research in recent years has begun to focus on the medical problems of individuals with intellectual disabilities and on family stress in accessing health services for persons with developmental disabilities. Less is known about the needs of individuals in different diagnostic groups, or about their experiences of systems of care. Therefore, we report the results of focus groups with parents of children or adults with fragile X syndrome, autism or Down syndrome. METHODS: Semi-structured group interviews with parents of children, youth or adults from each of three diagnostic groups probed perceptions of challenges and successes in obtaining and negotiating healthcare services in Ontario, Canada. RESULTS: Parents described diverse barriers to care, the need for advocacy in securing services, perceptions of service delivery and the role of healthcare professionals in regulating access to a wide range of services. Diagnostic services represented one area of central concern to parents from all three groups. DISCUSSION: Focus group data yielded a wide range of concerns. Suggestions for enhancing the system included expanding syndrome-specific education for medical students and health professionals and creating a centre that could offer service-related information for parents.

Computational Analysis of Nonuniform Expansion in Polyurethane Foams.

This paper computationally investigates heterogeneity in the distribution of foam fraction in chemically expanding blown polyurethane foam. The experimentally observed disparity in the volumes of expanded foam when an equal mass of the foaming mixture was injected into tubes of different dimensions motivated this study. To understand this phenomenon, attributed to local variations in the thermal and rheological properties of the expanding system, we explore available data from free-rise foam-expansion experiments in different geometries. Inspired by the mathematical framework for the microstructure modelling of bubble growth in viscous liquids, we study the reacting mixture as a continuum and formulate appropriate mathematical models that account for spatial inhomogeneity in the foam-expansion process. The nonlinear coupled system of partial differential equations governing flow was numerically solved using finite-volume techniques, and the associated results are presented and discussed with graphical illustrations. The proximity of the foaming-mixture core to the external environment and the thickness of a thermal-diffusion layer formed near the bounding geometry was seen to influence the distribution of the foam fraction. Our simulations showed an average spatial variation of about 1.1% in the distribution of solid foam fraction from the walls to the core, as verified with data from µ CT scan analysis of the expanded foam. This also reflects the distribution of void fraction in the foam matrix. The models were validated with experimental data, and our results favourably compared with the experiment observations.

Effect of early nutritional intake on long-term growth and bone mineralization of former very low birth weight infants.

BACKGROUND: Preterm infants are at risk for impaired bone mineralization and growth in length later in life due to inadequate nutritional intake in the early postnatal period. OBJECTIVE: To investigate whether increased nutritional supplementation of calcium, phosphate and protein in Very Low Birth Weight (VLBW) infants during the first 14days after birth was associated with improvement in length and bone development until 9-10years of age. DESIGN: Observational follow-up study of VLBW infants (birth weight<1500g or gestational age<32weeks) born in two consecutive years (eligible infants: 2004 n: 63 and 2005: n: 66). Cohort 2005 received higher intake of calcium, phosphate and protein with parenteral nutrition compared to Cohort 2004. Anthropometric data were collected during standard follow-up visits until five years, and additionally at 9-10years of age including measurements of bone mineral content, bone mineral density of the whole body and lumbar spine determined by dual-energy X-ray absorptiometry. Long-term growth trajectories of both cohorts were evaluated separately for participants born appropriate (AGA) and small for gestational age (SGA), stratified by gender. Multivariate linear regression was used to examine the effect of nutritional intake and clinical covariates on length and bone mineralization. RESULTS: Both cohorts achieved a catch-up in length to SDS within the normal range by 6months (length SDS: estimated mean (95% confidence interval (CI): 6months: Cohort 2004: -0.7 (-1.1, -0.3) Cohort 2005: -0.5 (-0.8, -0.2)). Bone mineral content and density were within the normal range and not different between the cohorts. SGA children achieved a catch-up in length at 5years with bone mineralization comparable to AGA children. Only for girls birth weight was significantly associated with length SDS (per gram: ß 0.001; 95% CI (0.000, 0.003); p=0.03) There was no evidence of an association between early nutritional intake and bone mineralization. CONCLUSION: Children born as appropriate or small for gestational age preterm infants are able to catch up in length after the postnatal period, and achieve a normal length and bone mineralization at age nine-ten years. An improvement of calcium and phosphate intake during the first 14days after birth was not associated with improvement in length and bone development.

Effects of morphine on glucose homeostasis in the conscious dog.

This study was designed to assess the effects of morphine sulfate on glucose kinetics and on glucoregulatory hormones in conscious overnight fasted dogs. One group of experiments established a dose-response range. We studied the mechanisms of morphine-induced hyperglycemia in a second group. We also examined the effect of low dose morphine on glucose kinetics independent of changes in the endocrine pancreas by the use of somatostatin plus intraportal replacement of basal insulin and glucagon. In the dose-response group, morphine at 2 mg/h did not change plasma glucose, while morphine at 8 and 16 mg/h caused a hyperglycemic response. In the second group of experiments, morphine (16 mg/h) caused an increase in plasma glucose from a basal 99 +/- 3 to 154 +/- 13 mg/dl (P less than 0.05). Glucose production peaked at 3.9 +/- 0.7 vs. 2.5 +/- 0.2 mg/kg per min basally, while glucose clearance declined to 1.7 +/- 0.2 from 2.5 +/- 0.1 ml/kg per min (both P less than 0.05). Morphine increased epinephrine (1400 +/- 300 vs. 62 +/- 8 pg/ml), norepinephrine (335 +/- 66 vs. 113 +/- 10 pg/ml), glucagon (242 +/- 53 vs. 74 +/- 14 pg/ml), insulin (30 +/- 9 vs. 10 +/- 2 microU/ml), cortisol (11.1 +/- 3.3 vs. 0.9 +/- 0.2 micrograms/dl), and plasma beta-endorphin (88 +/- 27 vs. 23 +/- 6 pg/ml); all values P less than 0.05 compared with basal. These results show that morphine-induced hyperglycemia results from both stimulation of glucose production as well as inhibition of glucose clearance. These changes can be explained by rises in epinephrine, glucagon, and cortisol. These in turn are part of a widespread catabolic response initiated by high dose morphine that involves activation of the sympathetic nervous system, the endocrine pancreas, and the pituitary-adrenal axis. Also, we report the effect of a 2 mg/h infusion of morphine on glucose kinetics when the endocrine pancreas is clamped at basal levels. Under these conditions, morphine exerts a hypoglycemic effect (25% fall in plasma glucose, P less than 0.05) that is due to inhibition of glucose production (by 25-43%, P less than 0.05). The hypoglycemia was independent of detectable changes in insulin, glucagon, epinephrine and cortisol, and was not reversed by concurrent infusion of a slight molar excess of naloxone. Therefore, we postulate that the hypoglycemic effect of morphine results from the interaction of the opiate with non-mu receptors either in the liver or the central nervous system.

Implicit and explicit motor sequence learning in children born very preterm.

BACKGROUND: Motor skills can be learned explicitly (dependent on working memory (WM)) or implicitly (relatively independent of WM). Children born very preterm (VPT) often have working memory deficits. Explicit learning may be compromised in these children. AIMS: This study investigated implicit and explicit motor learning and the role of working memory in VPT children and controls. METHODS: Three groups (6-9 years) participated: 20 VPT children with motor problems, 20 VPT children without motor problems, and 20 controls. A nine button sequence was learned implicitly (pressing the lighted button as quickly as possible) and explicitly (discovering the sequence via trial-and-error). RESULTS: Children learned implicitly and explicitly, evidenced by decreased movement duration of the sequence over time. In the explicit condition, children also reduced the number of errors over time. Controls made more errors than VPT children without motor problems. Visual WM had positive effects on both explicit and implicit performance. CONCLUSION: VPT birth and low motor proficiency did not negatively affect implicit or explicit learning. Visual WM was positively related to both implicit and explicit performance, but did not influence learning curves. These findings question the theoretical difference between implicit and explicit learning and the proposed role of visual WM therein.

[Two-year follow-up of infants born at 24 weeks gestation; first outcomes following implementation of the new 'Guideline for perinatal policy in cases of extreme prematurity']. / Follow-up na 2 jaar van kinderen geboren bij 24 weken.

OBJECTIVE: Since 2010 the guideline 'Guideline for perinatal policy in cases of extreme prematurity' has advised an active policy in infants born at 24 weeks gestation. We investigated how infants born at 24 and 25 weeks gestation in the first year following the implementation of the guideline had developed by the age of 2 years. DESIGN: Retrospective national cohort study. METHOD: The study population consisted of all surviving infants born in the Netherlands at 24 or 25 weeks gestation in the period from 1 October 2010 to 1 October 2011. At a corrected age of 2 years the children underwent a general physical and neurological examination, and their cognitive scores were determined on the 'Bayley scales of infant and toddler development' (Bayley III). Examinations took place in the 10 neonatal intensive care units (NICU's) in the Netherlands. RESULTS: Of 185 extremely premature infants, 166 were admitted to a NICU. A total of 95 survived to a corrected age of 2 years; 78 (82%) children were examined. Their average cognitive score on the Bayley III scale was 88 (SD: 16). Among the children born at 24 weeks gestation, 20% had mild disabilities and 20% had moderate to severe disabilities. Among the children born at 25 weeks gestation, 17% had mild disabilities and 12% had moderate to severe disabilities. CONCLUSION: Of the children born at 24 weeks gestation in the first year after the introduction of active policy in the Netherlands and surviving to 2 years of age (46%), more than half had developed without disabilities. This was comparable to children born at 25 weeks gestation. Of all children born at 24 weeks gestation, 25% survived to 2 years of age without disabilities.

Lack of effect of somatostatin on the stimulation of hepatic glycogenolysis by epinephrine in isolated canine hepatocytes.

The effects of somatostatin on epinephrine's ability to stimulate glucose output have been examined in hepatocytes isolated from dogs fasted overnight. Half-maximal stimulation of phosphorylase a activity and glucose output occurred at an epinephrine concentration of approx. 5 X 10(-9) M. Somatostatin at 10, 100 or 1000 ng/ml had no effect on the ability of a maximal (1 X 10(-7) M) and a submaximal (1 X 10(-8) M) dose of epinephrine to activate phosphorylase at 2 min, or to stimulate glucose output over 20 min. Since the doses of somatostatin used in the present study are up to 50-fold higher than the blood concentrations commonly found when somatostatin is used in vivo to inhibit pancreatic hormone secretion, it seems unlikely that use of somatostatin in this way would affect stimulation of hepatic glycogenolysis by epinephrine in vivo.

The role of phosphorylation in the alpha-adrenergic-mediated inhibition of rat hepatic pyruvate kinase.

Phenylephrine in the presence of 1-methyl-3-isobutylxanthine and propanolol caused a 40-50% inhibition of pyruvate kinase (type L) activity in isolated hepatocytes, which was accompanied by a 2-3-fold increase in the phosphate content of the enzyme. These changes were blocked by the alpha-adrenergic antagonist dihydroergocryptine and could not be accounted for by the slight increase in cyclic AMP-dependent protein kinase activity generated by the alpha-adrenergic agonist. It is concluded that a significant component of the inhibition of hepatic pyruvate kinase mediated by alpha-adrenergic agonists can be attributed to a cyclic AMP-independent alteration in the phosphorylation state of the enzyme.

Altered ability of the liver to produce glucose following a period of glucagon deficiency.

It is known that the effectiveness of a physiologic increment in glucagon to stimulate glucose production wanes with time even when counterregulatory insulin secretion is prevented. The aim of the present study was to establish whether the converse is true: does glucagon become a more effective stimulus of glucose production following a period of acute hypoglucagonemia? To determine this, somatostatin was infused along with basal replacement amounts of glucagon (0.65 ng/mg x min) and insulin (228 microU/kg x min) into five postabsorptive conscious dogs. After 1.5 h of basal hormone replacement, the glucagon infusion was terminated and a selective fall in the plasma glucagon level (75 +/- 6 to 30 +/- 4 pg/ml) occurred. This resulted in a drop in tracer (3H-glucose)-determined glucose production from 3.0 +/- 0.4 to 1.5 +/- 0.3 mg/kg x min. The plasma insulin level remained unchanged at 10 +/- 1 microU/ml throughout the experiment. Euglycemia (110 +/- 4 mg/dl) was maintained by exogenous glucose infusion. After 3 h of glucagon lack, restoration of the glucagon infusion returned the IRG level to control values (78 +/- 6 pg/ml) but restored glucose output only partially (42 +/- 9%), necessitating continued glucose infusion to preserve euglycemia. Repetition of the experiment in dogs whose pancreatic glucoregulatory feedback loops were broken surgically (two-stage pancreatectomy) rather than pharmacologically resulted in similar findings. It is concluded that glucagon deficiency of 3-h duration leads to a decrease, rather than an increase, in hepatic sensitivity to glucagon.

Relative importance of first- and second-phase insulin secretion in glucose homeostasis in conscious dog. II. Effects on gluconeogenesis.

The normal pancreatic response to an exogenous glucagon infusion is a biphasic release of insulin. In our study the ability of each component of insulin release to counter the effects of the glucagon on gluconeogenesis and alanine metabolism was assessed by mimicking first- and/or second-phase insulin release with infusions of somatostatin and intraportal insulin. When a fourfold increase in glucagon was brought about in the presence of fixed basal insulin release, there was a large increase in overall glucose production and gluconeogenesis. The increase in the conversion of [14C]alanine into [14C]glucose (169 +/- 42%, P less than .05) was accompanied by an increase in the fractional extraction of alanine by the liver (FEA 0.32 +/- 0.06 to 0.66 +/- 0.10, P less than .05) and net hepatic alanine uptake (NHAU 2.97 +/- 0.45 to 4.61 +/- 0.48 mumol . kg-1 . min-1, P less than .05). Simulated first-phase insulin release had no effect on the ability of glucagon to increase FEA (0.32 +/- 0.03 to 0.66 +/- 0.03, P less than .05) or NHAU (3.69 +/- 0.80 to 5.10 +/- 0.69 mumol . kg-1 . min-1, P less than .05) but did limit the increase in overall gluconeogenic conversion (114 +/- 37%). Second-phase insulin release had no effect on either the glucagon-induced increase in FEA (0.35 +/- 0.08 to 0.73 +/- 0.04) or NHAU (3.35 +/- 0.92 to 5.13 +/- 0.85 mumol . kg-1 . min-1) but completely inhibited the increase in overall gluconeogenic conversion.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of ketogenesis by epinephrine and norepinephrine in the overnight-fasted, conscious dog.

The effects on ketogenesis and lipolysis of a norepinephrine (0.04 microgram/kg-min), epinephrine (0.04 microgram/kg-min), or saline infusion were examined in the overnight-fasted, conscious dog. Plasma insulin and glucagon levels were maintained constant by means of a somatostatin infusion (0.8 microgram/kg-min) and intraportal replacement infusions of insulin and glucagon. In saline-infused dogs, plasma epinephrine (62 +/- 8 pg/ml), norepinephrine (92 +/- 29 pg/ml), blood glycerol (87 +/- 10 microM), and plasma nonesterified fatty acid (NEFA) (0.82 +/- 0.17 mM) levels did not change. Total blood ketone body levels tended to rise (62 +/- 10 to 83 +/- 11 microM) by 3 h as did total ketone body production (1.5 +/- 0.4 to 2.2 +/- 0.4 mumol/kg-min) over the same time interval. Norepinephrine infusion to produce plasma levels of 447 +/- 86 pg/ml caused a sustained 50% rise in glycerol levels (66 +/- 17 to 99 +/- 15 mumol/L, P less than 0.05) and 53% rise in nonesterified fatty acids (0.53 +/- 0.07 to 0.81 +/- 0.15 mumol/L, P less than 0.05). Total ketone body levels rose by 43% (51 +/- 8 to 73 +/- 10 mumol/L) and ketone body production rose by a similar proportion (1.5 +/- 0.2 to 2.2 +/- 0.3 mumol/kg-min), changes that did not differ significantly from control animals. A similar increment in plasma epinephrine levels (75 +/- 15 to 475 +/- 60 pg/ml) caused glycerol levels to rise by 82% (105 +/- 23 to 191 +/- 26 mumol/L) in 30 min, but this rise was not sustained and the level fell to 146 +/- 14 mumol/L by 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Similar dose responsiveness of hepatic glycogenolysis and gluconeogenesis to glucagon in vivo.

This study was undertaken to determine whether the dose-dependent effect of glucagon on gluconeogenesis parallels its effect on hepatic glycogenolysis in conscious overnight-fasted dogs. Endogenous insulin and glucagon secretion were inhibited by somatostatin (0.8 micrograms X kg-1 X min-1), and intraportal replacement infusions of insulin (213 +/- 28 microU X kg-1 X min-1) and glucagon (0.65 ng X kg-1 X min-1) were given to maintain basal hormone concentrations for 2 h (12 +/- 2 microU/ml and 108 +/- 23 pg/ml, respectively). The glucagon infusion was then increased 2-, 4-, 8-, or 12-fold for 3 h, whereas the rate of insulin infusion was left unchanged. Glucose production (GP) was determined with 3-[3H]glucose, and gluconeogenesis (GNG) was assessed with tracer (U-[14C]alanine conversion to [14C]glucose) and arteriovenous difference (hepatic fractional extraction of alanine, FEA) techniques. Increases in plasma glucagon of 53 +/- 8, 199 +/- 48, 402 +/- 28, and 697 +/- 149 pg/ml resulted in initial (15-30 min) increases in GP of 1.1 +/- 0.4 (N = 4), 4.9 +/- 0.5 (N = 4), 6.5 +/- 0.6 (N = 6), and 7.7 +/- 1.4 (N = 4) mg X kg-1 X min-1, respectively; increases in GNG (approximately 3 h) of 48 +/- 19, 151 +/- 50, 161 +/- 25, and 157 +/- 7%, respectively; and increases in FEA (3 h) of 0.14 +/- 0.07, 0.37 +/- 0.05, 0.42 +/- 0.04, and 0.40 +/- 0.17, respectively. In conclusion, GNG and glycogenolysis were similarly sensitive to stimulation by glucagon in vivo, and the dose-response curves were markedly parallel.