Adherence to the infant vitamin D supplementation policy in Ireland.

PURPOSE: From September 2010 until November 2019, Ireland's infant vitamin D supplementation policy recommended administration of 5 µg/day of vitamin D3 from birth to 12 months to all infants, regardless of feeding method. This study aims to examine policy adherence. METHODS: In the prospective COMBINE birth cohort study (recruited 2015-2017), detailed longitudinal supplement data were examined in 364 infants across the first year of life, according to product type, dose, frequency, and duration. Vitamin D supplement use at 2, 6, and 12 months in COMBINE was compared with the BASELINE cohort (recruited 2008-2011, n = 1949). RESULTS: In COMBINE, 92% of infants initiated supplementation at birth. The median supplementation duration was 51 (40, 52) weeks, with a range of 3-52 weeks. While supplementing, most parents (92%) used an exclusive vitamin D supplement as recommended and 88% gave 5 µg/day. Half (51%) gave vitamin D daily and a further 33% supplemented at least 3-6 times/week. Overall, 30% adhered fully to the policy, providing 5 µg vitamin D3 daily from birth to 12 months. A further 16% were broadly compliant, giving 5 µg frequently for the full 12 months. Vitamin D supplement use at 2, 6, and 12 months in COMBINE was 93%, 89%, and 72%, considerably higher than our earlier BASELINE cohort at 49%, 64%, and 44% at the same time points (all P < 0.001). CONCLUSIONS: We report a high level of vitamin D supplementation initiation at birth, with full to broad policy adherence among more than half of infants. There is scope to improve overall compliance by focusing on supplementation frequency.

Vitamin D in pregnancy: Where we are and where we should go.

Vitamin D deficiency has been widely reported among pregnant women and infants around the world. Women with low sun exposure, high BMI, low vitamin D intakes and socioeconomic disadvantage with poor quality diets are at greatest risk of vitamin D deficiency, leading to very low serum concentrations of 25-hydroxyvitamin D (25(OH)D) in their offspring and an increased risk of nutritional rickets. Many observational studies, supported by compelling in vitro and in vivo data, have generated evidence suggesting that low vitamin D status in pregnancy may also contribute to the risk of adverse perinatal outcomes including hypertensive disorders (e.g., preeclampsia), fetal growth restriction, and preterm birth. However, the few large randomized controlled trials (RCTs) conducted to date have generated conflicting evidence for a role of vitamin D supplementation in improving perinatal outcomes. Vitamin D supplementation policies during pregnancy and implementation of policies vary within and between jurisdictions. Regulatory authorities have cited insufficient evidence to establish pregnancy-specific targets for serum 25(OH)D concentrations or prenatal vitamin D intake that effectively reduce the risks of adverse perinatal and infant outcomes. This paper arises from a Debate on Vitamin D Requirements during Pregnancy, held at the 22nd Vitamin D Workshop, 2019. From varied perspectives, our objectives were to evaluate the evidence for: vitamin D metabolism in pregnancy and the prevalence of gestational vitamin D deficiency worldwide; the translation of laboratory research findings to clinical studies on the role of vitamin D in perinatal health; the challenges of designing and conducting clinical trials to establish prenatal vitamin D requirements; and results to date of major large RCTs of prenatal vitamin D supplementation. Lastly, we explored potential next steps towards generating robust clinical data in this field to address both public health protection and patient care.

Impact of maternal, antenatal and birth-associated factors on iron stores at birth: data from a prospective maternal-infant birth cohort.

BACKGROUND/OBJECTIVES: Low serum ferritin concentrations at birth, which reflect neonatal iron stores, track through to early childhood and have been associated with poorer neurodevelopmental outcomes. We aimed to identify maternal, antenatal and birth-associated factors that influence iron stores at birth in a prospective maternal-infant birth cohort. SUBJECTS/METHODS: In a population-based, longitudinal, birth cohort in Ireland, 413 maternal-infant dyads with prospectively collected lifestyle and clinical data from 15 weeks' gestation had umbilical cord serum ferritin concentrations measured. Regression models were developed to identify independent factors associated with cord ferritin concentrations. RESULTS: Median (IQR) cord ferritin concentrations were 185.7 (131.7, 385.5) µg/l, and 8% (n=33) of infants had low iron stores (ferritin <76 µg/l) at birth. Maternal obesity (BMI ⩾30 kg/m2) at 15 weeks' gestation (adj. estimate (95% confidence interval (CI)): -66.4 (-106.9, -25.9) µg/l, P<0.0001) and delivery by caesarean section (-38.8 (-70.2, -7.4) µg/l, P=0.016) were inversely associated with cord ferritin concentrations. In addition, maternal smoking at 15 weeks' gestation (adj. odds ratio (95% CI): 2.9 (1.2, 7), P=0.020) and being born small-for-gestational age (3.4 (1.3, 8.9), P=0.012) were associated with an increased risk of low iron stores (ferritin <76 µg/l) at birth. CONCLUSIONS: We have identified a number of potentially modifiable lifestyle factors that influence iron stores at birth, with the important role of overall maternal health and lifestyle during pregnancy highlighted. Public health policies targeting women of child-bearing age to improve nutrition and health outcomes should be prioritised for the health of the next generation.

CSF acetylcholinesterase in dementia and in sequential samples of lumbar CSF.

Acetylcholinesterase (AchE) activity (nmol/ml/min) was measured in lumbar CSF from 11 patients with dementia of the Alzheimer type (DAT), 8 patients with Korsakoff psychosis and 33 patients with low back pain who were undergoing myelography (controls). There was no significant difference in enzyme activity between the three groups. There was no significant correlation between age and AchE activity. AchE was also measured in 20 two-ml samples of CSF collected sequentially by lumbar puncture in two neurosurgical patients who had been recumbent for at least 8 hours. Variations in AchE between samples were small. In neither patient was there an increase in AchE activity with progressive sampling. These data indicate that (1) AchE is unchanged in Korsakoff psychosis (2) decreases in brain AchE which are found in DAT are not readily reflected in lumbar CSF (3) AchE in lumbar CSF has a diffuse origin including spinal cord (4) CSF AchE activity is unlikely to be a useful clinical marker for DAT.

Effect of ascorbic acid on brain amphetamine concentrations in the rat.

Ascorbic acid is reported to have antiamphetamine effects in rodents. The effect of ascorbic acid (1 g/kg ip) on the half-life of amphetamine (10 mg/kg) in rat brain using 3H-amphetamine and on amphetamine-induced stereotyped behaviour was investigated. Ascorbic acid had no effect on amphetamine-induced stereotyped behaviour or on the half-life of amphetamine in brain. If ascorbic acid antagonizes amphetamine-induced behavioural responses this is unlikely to be a result of altering the pharmacokinetics of amphetamine.

Cyclic GMP in sequential samples of lumbar CSF in man.

cGMP was measured in 15 and 20 sequential 2 ml samples of CSF withdrawn by lumbar puncture in two patients respectively who were recumbent for at least 8 hours. cGMP showed a significant linear increase in concentration with progressive sampling (r = 0.70, p less than 0.01; r = 0.59, p less than 0.01, respectively). These data indicate (a) the presence of a rostrocaudal gradient in CSF cGMP (b) recumbency and volume of CSF are important variables to consider in clinical studies (c) the cerebellum may be a source of cGMP in lumbar CSF.

Red cell choline in spasmodic torticollis and in a monozygotic twin pair with Tourette's syndrome.

1. Alterations in cholinergic function may play a role in the pathophysiology of idiopathic spasmodic torticollis (ST) and Gilles de la Tourette's syndrome (GTS). We measured red blood cell (RBC) choline in (i) ST (n = 24) and paired controls matched for age and gender (ii) a 20-year old pair of monozygotic twins with GTS, one of whom was moderately affected (CV) and the other virtually recovered (DV) (iii) both parents of the GTS twins, using gas chromatography-mass spectrometry. 2. RBC choline decreased with age in control men (r = -0.76; p less than 0.01) but not in control women. 3. RBC choline (nmol/ml) was higher in control men (18.3 +/- 4.8, X +/- SD) vs control women (13.1 +/- 4.3) (p = 0.025). 4. There was no significant difference in RBC choline (nmol/ml) between ST patients (16.6 +/- 5.0) and controls (15.5 +/- 5.2). 5. The RBC choline values (nmol/ml) in the twins and parents were: 56.6 (CV), 58.3 (DV), 89.8 (father), 38.3 (mother) and in the controls (age 20-24) (n = 5) 18.2 +/- 3.6. 6. These data suggest (i) RBC choline is affected by age and gender (ii) RBC choline is unchanged in ST (iii) the regulation of RBC choline is under genetic control (iv) elevated RBC choline is not a state marker for GTS.

Effect of apomorphine, a dopamine receptor agonist, on penile tumescence in normal subjects.

Apomorphine HCl (Apo) (0.25, 0.5 or 0.75 mg sc), a dopamine (DA) receptor agonist, induced penile erections (PEs) (monitored by mercury strain gauges and continuous recording on paper strip charts) in 7 out of 9 normal subjects and placebo in 1 of these 9 (p less than 0.05). Apo-induced PEs recurred in each of the 6 subjects retested. Benztropine (2 mg iv) had no effect on Apo-induced penile tumescence (PT). These data suggest (a) DA mechanisms play a role in normal erectile function (b) DA-mediated PT is not modulated by cholinergic systems (c) evaluation of the erectile response to Apo may provide a simple ancillary test to the investigation of impotence and a way of identifying a subpopulation of impotent subjects with impaired DA function who may respond to long-acting DA agents (d) Apo-induced PT may provide a novel way of studying DA function in man.

Apomorphine: clinical studies on erectile impotence and yawning.

1. The erectile response to the short-acting dopamine (DA) receptor agonist, apomorphine (Apo) HCl (0.25, 0.5, 0.75 and 1.0 mg sc), and placebo was evaluated in 28 impotent patients and penile circumference monitored using a mercury strain gauge and strip chart recording. 2. A full erection (increment in penile circumference greater than 2 cm and lasting at least one minute) occurred in 17 patients with Apo; no erection developed after placebo. An erection occurred in 6/8 patients with impaired glucose tolerance, 2/6 patients with diabetes mellitus and in both patients on lithium. 3. Nine patients who responded to Apo were treated in an open trial with bromocriptine; 6 reported improvement in potency. 4. Impairment in DA function may play a role in idiopathic impotence and in impotence associated with impaired glucose tolerance and diabetes mellitus. 5. An erectile response to Apo may predict therapeutic response to bromocriptine or other long acting dopaminergic agents. 6. Lithium, which inhibits DA-sensitive adenylate cyclase, does not prevent Apo-induced erections. This provides further support indicating that Apo induces erections by an effect on D2 receptors. 7. The yawning response to placebo and four doses of Apo HC1 (3.5, 5.0, 7.0, and 10.5 ug/kg sc) was evaluated in five normal men using a polygraphic technique. The yawning response was also assessed in normal young (less than 30 yrs; N = 16) and elderly (greater than 60 yrs; N = 12) volunteers. 8. Under experimental conditions of study, placebo induced spontaneous yawning. This was antagonized by 3.5 and 5.0 ug/kg Apo HC1 but increased by 7.0 ug/kg Apo HC1. These observations are compatible with the view that Apo HC1 in doses of 3.5-5.0 ug/kg stimulates presynaptic DA receptors whereas 7.0 ug/kg stimulates postsynaptic DA receptors. 9. Spontaneous and Apo-induced yawning were significantly decreased in the elderly which suggests that D2 receptor function declines with normal aging.

Structural specificity of the carrier for L-tryptophan in rat cerebral cortex slices.

The effect of a number of commonly occurring amino acids as well as metabolites originating in the pyrrolase pathway of tryptophan catabolism and in the serotonin pathway have been studied with regard to their effect on the net flux of tryptophan into rat brain cerebral cortex slices. Phenylalanine, p-chlorophenylalanine, tyrosine, 3,4-dihydroxyphenylalanine and kynurenine as well as leucine, isoluecine and valine all inhibited the net uptake of tryptophan. It was concluded from these studies that tryptophan is transported into the cell via the large neutral amino acid carrier. Compounds lacking the aliphatic side chain carboxyl or alpha-amino group have no action on tryptophan transport.

Effect of L-tryptophan on spasmodic torticollis.

The effect of L-tryptophan, a precursor of serotonin, and placebo were studied in eight patients with spasmodic torticollis. L-Tryptophan (5 g po as a single dose) which increased free plasma tryptophan 20-53 fold improved only one out of six patients. Two out of three patients, including the subject who improved following an oral load of tryptophan, improved with L-tryptophan combined with nicotinamide, a tryptophan pyrrolase inhibitor, when administered for 1-3 weeks. However, the magnitude of clinical improvement was not impressive. Our findings suggest that impairment of serotonergic function is not a general finding in spasmodic torticollis though it may play a minor role in the manifestation of this movement disorder in some patients. The present study emphasizes therapeutic response, namely, the intrinsic variability of the disorder, the response to placebo in some subjects and the limitations of methods for measuring change.

Effect of blood sampling on apomorphine-induced penile tumescence in erectile impotence: a case report.

Apomorphine HCl (Apo) (0.5 mg sc), but not placebo, induced an erectile response (monitored with a mercury strain gauge) lasting 40 min in an impotent hyperprolactinemic patient. Serial blood sampling modified the 40 min erectile response. Prompt detumescence followed by complete or partial restoration of tumescence occurred each time blood was drawn. This observation points to the sensitivity of the Apo-erectile response to experimental procedures subjectively perceived as anxiogenic.

Effect of oral melatonin administration on melatonin, 5-hydroxyindoleacetic acid, indoleacetic acid, and cyclic nucleotides in human cerebrospinal fluid.

Melatonin was given orally to patients undergoing diagnostic pneumoencephalography and various compounds were measured in the lumbar and cisternal CSF. Melatonin markedly increased plasma and CSF melatonin concentrations. The plasma: CSF melatonin ratios were similar in patients who received, and in those who did not receive, melatonin. This supports the idea that melatonin is released from pineal to blood and gets into the CSF via the blood. Melatonin did not affect CSF 5-hydroxyindoleacetic acid, which indicates that it has no effect on 5-hydroxytryptamine metabolism. Melatonin increased CSF indoleacetic acid significantly, indicating increased metabolism of tryptamine. Melatonin did not affect CSF cAMP levels, but increased cGMP levels. The effect on indoleacetic acid and cGMP was seen in both lumbar and cisternal CSF, suggesting that melatonin can have generalized actions throughout the CNS.

Effect of bromocriptine in patients with apomorphine-responsive erectile impotence: an open study.

An open pilot study was undertaken to investigate the therapeutic effect of the dopaminergic agent, bromocriptine (BC), in impotent patients who developed an erectile response to the dopamine receptor agonist, apomorphine. Eight out of 17 patients reported improvement in ability to obtain an erection; five of these 8 subjects were able to achieve penetration. The optimum dose of BC was 2.5 - 11.25 mg/day. A double-blind placebo-controlled study is merited.

Effect of sleep deprivation on the growth hormone response to the alpha-3 adrenergic receptor agonist, clonidine, in normal subjects.

One night's sleep deprivation (SD) increased the growth hormone (GH) response to clonidine (20 ug/kg i.v.) in 11 normal men ( p < 0.005). This finding may indicate that SD enhances alpha-2 adrenergic receptor function or that the GH response to GH releasing factor in increased by SD.

Hypothalamic-pituitary dopaminergic function in hepatic failure in man.

The growth hormone (GH) response to apomorphine HCl (Apo) (0.75 mg sc), a dopamine (DA) receptor agonist, was assessed in healthy chronic alcoholics without cirrhosis (N = 20) and in patients with alcoholic cirrhosis both with (N = 5) and without (N = 14) hepatic encephalopathy (HE). A significant number of cirrhotic patients with (P less than 0.004) and without (P less than 0.002) HE had an impaired GH response (peak increment less than 5 ng/ml) compared with non-cirrhotic individuals. An impaired GH response was independent of the presence of HE. The magnitude of the GH response was unrelated to plasma oestrone, oestradiol, or progesterone concentrations but was significantly correlated with plasma testosterone levels (P less than 0.01). None of the patients with an abnormally low testosterone concentration showed a normal GH response. None of the subjects with HE showed an arousal response to Apo. These results suggest that DA receptor sensitivity is decreased in liver cirrhosis and that this decrease is related to inadequate circulating levels of testosterone. The occurrence of HE is independent of impaired DA function. The present study only evaluates DA function in the hypothalamic-pituitary axis and therefore may not reflect changes in other regions of brain.