Bleeding pattern and safety of consecutive use of the levonorgestrel-releasing intrauterine system (LNG-IUS)--a multicentre prospective study.

BACKGROUND: The LNG-IUS has increasingly been used for contraception, treatment of menorrhagia and endometrial protection during hormone replacement therapy since mid-1990s. Thus, many women use the LNG-IUS consecutively. However, published data on the bleeding pattern regarding consecutive use of the LNG-IUS is scarce. METHODS: We performed a prospective 15-month multicentre study on the bleeding profile, removal and insertion procedures and safety of the second LNG-IUS in fertile-aged women who had used their first LNG-IUS between 4 years 3 months and 4 years 9 months and who opted for the insertion of a second IUS immediately after removal of the first IUS. Bleeding data were reported descriptively starting from the last 90 days of the first IUS use and continuing for up to 1 year. RESULTS: Of the 234 subjects screened, 204 (87%) entered the trial. The median number of bleeding/spotting days during the last 90 days of the first LNG-IUS was 7 (25 and 75% percentiles 0 and 15). Due to bleeding associated with the insertion procedure, this increased to 8 days (4 and 18) during the first 90-day reference period, thereafter decreasing to 4 (0 and 10) days during the second to fourth reference periods. Only one expulsion and no pregnancies, pelvic inflammatory diseases or perforations occurred. A total of 12 subjects (5.9%) prematurely discontinued the study: five due to an adverse event and seven due to other reasons (inclusive of loss to follow-up). CONCLUSIONS: This study confirms the favourable bleeding profile and safety of consecutive use of the LNG-IUS.

Undiagnosed maternal phenylketonuria: the need for prenatal selective screening or case finding.

OBJECTIVES: The aims of this article are to report on a review of cases of maternal phenylketonuria in the International Maternal Phenylketonuria Collaborative Study that were initially diagnosed during or after a pregnancy, to alert health care practitioners to the possible existence of women with undiagnosed phenylketonuria whose fetuses are at risk, and to emphasize that not all adults with untreated phenylketonuria are mentally retarded. STUDY DESIGN: The study was conducted through retrospective database review. RESULTS: Of 414 women with live-born infants, 17 fulfilled our criteria. Six had phenylketonuria diagnosed after they had produced >/=1 affected offspring, 2 had phenylketonuria diagnosed as a result of transient postnatal hyperphenylalaninemia in an offspring, and 9 had phenylketonuria diagnosed by prenatal screening. Undiagnosed maternal phenylketonuria in North America and Europe is currently estimated at 1 case/100,000 births; this rate could be higher elsewhere. CONCLUSIONS: Physicians and midwives should consider a protocol of selective prenatal screening or case finding to detect undiagnosed phenylketonuria among their patients.

The present state of national animal welfare policy.

Animal welfare is expected to increase in importance as a political and marketing issue. There is a vigorous debate about what, besides the absence of physical pain, is necessary for acceptable animal welfare. This paper focuses on the present state of animal welfare policy at the national level.

Intellectual development in 12-year-old children treated for phenylketonuria.

Intelligence and achievement test scores were evaluated for 95 12-year-old children with phenylketonuria who had begun dietary therapy during the neonatal period. Dietary control of blood phenylalanine below 900 mumol/L was maintained beyond age 10 years in 23 children; 72 others had blood phenylalanine persistently above that level at ages ranging from 18 months to 10 years. Test scores at age 12 years were negatively correlated with the age at initiation of diet and with blood phenylalanine levels from ages 4 to 10 years, and positively correlated with parent IQ scores and the age at loss of dietary control. Children who maintained phenylalanine levels below 900 mumol/L beyond age 10 years showed no deficits in test scores, except for arithmetic, the scores of which declined between ages 6 and 12 years in 90% of the children in this study. These data strongly support a recommendation that dietary restriction of phenylalanine should be maintained through adolescence.

DOPA decarboxylase inhibition does not influence the diuretic and natriuretic response to exogenous alpha-atrial natriuretic peptide in man.

The role of dopamine synthesis in the renal actions of human alpha-atrial natriuretic peptide (alpha ANP) was investigated in six dehydrated volunteers using the DOPA decarboxylase inhibitor carbidopa. Each subject received oral placebo or carbidopa (100 mg) followed by an infusion of alpha ANP 10 pmol.kg-1.min-1 for 1 h. The responses to placebo alone and to carbidopa alone were investigated on separate occasions. alpha ANP produced a similar increase in plasma immunoreactive alpha ANP whether placebo or carbidopa pretreatment had been given. Urinary dopamine excretion was increased by alpha ANP. Carbidopa pretreatment substantially attenuated this increase without affecting the natriuretic or water-diuretic response to alpha ANP. Carbidopa also failed to alter the change in filtration fraction produced by alpha ANP. The results suggest that increased synthesis of intrarenal dopamine is not required for the renal effects of alpha ANP in man.

Acute effects of physiological increments of alpha-atrial natriuretic peptide in man.

Seven dehydrated volunteers received three hour infusions of 0.8 pmol kg-1 min-1 of human alpha-atrial natriuretic peptide (h-alpha ANP) or vehicle alone (Ve) in a single-blind, randomized cross-over design. H-alpha ANP infusion increased plasma h-alpha ANP from 4.2 +/- 0.4 to 20.3 +/- 6.4 pm. H-alpha ANP suppressed plasma renin activity from 3.30 +/- 0.48 to 1.37 +/- 0.35 ng ml-1 hr-1 (P less than 0.001 vs. Ve). Plasma aldosterone was unaltered by h-alpha ANP. Fractional excretion of filtered sodium (FENa) changed from 0.92 +/- 0.09 to 1.13 +/- 0.16% with h-alpha ANP, and from 1.02 +/- 0.09 to 0.69 +/- 0.11% with Ve (P less than 0.01 h-alpha ANP vs. Ve). FEK was unchanged. FEpo4 increased from 7.2 +/- 1.2 to 9.2 +/- 1.2% and FELi from 22.1 +/- 1.4 to 24.9 +/- 3.0% with h-alpha ANP (both P less than 0.05 vs. Ve). H-alpha ANP decreased mean urinary osmolality by approximately 150 mOsmol kg-1 compared to Ve (P less than 0.01). GFR, RPF and filtration fraction were unchanged by h-alpha ANP, H-alpha ANP was associated with a significant tachycardia (P less than 0.01 vs. Ve) but with no significant change in arterial pressure. These results suggest that small increments of plasma h-alpha ANP, mimicking physiological changes, are natriuretic at least partly by reducing proximal tubular reabsorption of sodium, and also impair urinary concentration.

Development of a solid-phase extraction technique for alpha-human atrial natriuretic peptide in human plasma.

A reliable extraction method was developed for alpha-human atrial natriuretic peptide (alpha-hANP) using Bond Elut C8 columns in tandem. This involved activation of the columns using methanol followed by a water wash to remove the excess methanol. Plasma (1 ml) was then added and a vacuum applied until all was drawn through. Excess protein and other endogenous compounds were removed by washing the columns with water and elution of the alpha-hANP was achieved with 0.75 ml acetonitrile-water-trifluoroacetic acid (80:19.8:0.2, v/v/v). Samples were evaporated under nitrogen and reconstituted in radioimmunoassay buffer ready for analysis. The recovery of alpha-hANP from plasma using this method was found to be 90% +/- 0.6% [mean +/- standard error of the mean (S.E.M.); coefficient of variation (C.V.) = 1.5%] which will allow more precise measurement of the peptide than is presently available. With this high precision of analysis available, having a limit of detection of 0.4 fmol/ml and a range of 0 to 32 fmol/ml, a low-dose infusion of alpha-hANP was conducted and the changes in plasma concentration were followed.

Vascular responses to local atrial natriuretic peptide infusion in man.

1. The effect on skin and muscle blood flow of arterial infusion of atrial natriuretic peptide (ANP) directly into the forearm circulation, and on venous tone of direct infusion into a dorsal hand vein, was studied in normal subjects. 2. ANP produced a dose-dependent increase in both skin and muscle blood flow, but at equivalent doses, produced no dilatation of noradrenaline-preconstricted dorsal hand veins. These findings indicate that ANP acting locally, is an arterioselective dilator in the upper limb circulation in normal man. 3. Measurements of ANP in venous plasma during arterial infusion suggest marked clearance of ANP across the forearm vascular bed. Such peripheral clearance may, at least in part, account for the short plasma half-life of this peptide. 4. The lowest dose of ANP infused was calculated to produce plasma levels similar to those found in patients with heart failure. The findings with this dose suggest that, in heart failure, circulating levels of ANP may be within a range capable of influencing peripheral vascular resistance directly.

Folinic acid therapy in treatment of dihydropteridine reductase deficiency.

We gave folinic acid to three siblings, and to a fourth child, who have or had dihydropteridine reductase (DHPR) deficiency. The youngest began folinic acid therapy in addition to neurotransmitter precursors and a phenylalanine-restricted diet at age 2 months, and at 2 years of age has near normal development without evidence of neurologic impairment. His older brother began similar treatment at 5 1/2 months of age, when early neurologic findings were evident. At age 6 years his mental retardation and neurologic impairment are less severe than reported in most patients with DHPR deficiency. Little improvement occurred in their sister, who first received treatment at 2 years of age, when she already had severe neurologic impairment. An unrelated boy with profound neurologic impairment showed subtle signs of improvement after he began treatment with folinic acid alone at age 9 years. These results provide evidence that folinic acid is important in the treatment of DHPR deficiency and, if begun early in infancy, may prevent irreversible neurologic damage. The mechanism of folinic acid action in DHPR deficiency may be to increase indirectly the synthesis of 5-methyltetrahydrofolate.

Proton-nuclear-magnetic-resonance studies of serum, plasma and urine from fasting normal and diabetic subjects.

Resonances for the ketone bodies 3-D-hydroxybutyrate, acetone and acetoacetate are readily detected in serum, plasma and urine samples from fasting and diabetic subjects by 1H n.m.r. spectroscopy at 400 MHz. Besides the simultaneous observation of metabolites, the major advantage of n.m.r. is that little or no pretreatment of samples is required. N.m.r. determinations of 3-D-hydroxybutyrate, acetoacetate, lactate, valine and alanine were compared with determinations made with conventional assays at six 2-hourly intervals after insulin withdrawal from a diabetic subject. The n.m.r. results closely paralleled those of other assays although, by n.m.r., acetoacetate levels continued to rise rather than reaching a plateau 4h after insulin withdrawal. The 3-D-hydroxybutyrate/acetoacetate ratio in urine during withdrawal gradually increased to the value observed in plasma (3.0 +/- 0.2) as determined by n.m.r. The acetoacetate/acetone ratio in urine (17 +/- 6) was much higher than in plasma (2.5 +/- 0.7). Depletion of a mobile pool of fatty acids in plasma during fasting, as seen by n.m.r., paralleled that seen during insulin withdrawal. These fatty acids were thought to be largely in chylomicrons, acylglycerols and lipoproteins, and were grossly elevated in plasma samples from a non-insulin-dependent diabetic and in cases of known hyperlipidaemia.

Neurotransmitter defects and treatment of disorders of hyperphenylalaninemia.

The disordered biosynthesis of dopamine, norepinephrine, and serotonin in brain in untreated PKU is corrected by dietary restriction of phenylalanine. Low levels of biogenic amine metabolites were measured in cerebrospinal fluid from three patients with classical PKU; metabolite concentrations increased after dietary treatment. In a variant of hyperphenylalaninemia caused by deficiency of dihydropteridine reductase, there is defective metabolism of biogenic amines despite dietary restriction of phenylalanine. Two siblings with DHPR deficiency had low amine metabolite values in CSF; in one patient the metabolic defect was corrected by administration of hydroxylated amino acid precursors. Defective biosynthesis of biogenic amines in brain in disorders associated with hyperphenylalaninemia and evaluation of specific dietary treatments can be determined by analysis of neurotransmitter metabolites in CSF.

The diagnosis of phenylketonuria: a report from the Collaborative Study of Children Treated for Phenylketonuria.

One hundred ninety-five infants who met diagnostic criteria for enrollment in the Collaborative Study of Children Treated for Phenylketonuria (PKU) underwent a standard three-day challenge with 180 mg/kg/day of phenylalanine for confirmation of diagnosis. A sustained rise in serum phenylalanine levels of greater than 20 mg/dl was observed in 166 infants (85.1%), compatible with the diagnosis of classical PKU. In the remaining 29 infants (14.9%), the serum phenylalanine concentration either did not reach 20 mg/dL or, having achieved this level, subsequently declined below this point by 72 hours. It was agreed that these 29 patients had variant PKU and they were dropped from the Collaborative Study. We recommend that all infants diagnosed as having classic PKU undergo a challenge to confirm the diagnosis and need for continued treatment.

Insecticide resistance in field strains of Lucilia cuprina.

A survey was conducted in 1977-78 to determine the level of insecticide resistance in field strains of Lucilia cuprina from a wide area of Queensland. Discriminating dose data showed that all 19 strains tested were resistant to diazinon, dichlofenthion, fenthion-ethyl and chlorfenvinphos, but resistance factors in all strains were low, the highest being 18.9 for diazinon. Six strains showed no resistance to butacarb. A strain collected in 1967 and selected with diazinon for 117 generations, attained resistance factors of organophosphorus compounds far higher than those of the present field strains.

Hyperphenylalaninemia due to dihydropteridine reductase deficiency. Assay of the enzyme in fibroblasts from affected infants, heterozygotes, and in normal amniotic fluid cells.

Two infant siblings with modest elevations of serum phenylalanine concentrations had seizures and developmental regression: they died in their second year. Dihydropteridine reductase activity, which can be measured in normal cultured skin fibroblasts, was measured in the younger sibling and was absent. Parents of the two siblings and parents of a previously reported patient all showed 50% or less of the normal dihydropteridine reductase activity in their cultured fibroblasts. Dihydropteridine reductase activity is also present in normal cultured amniotic fluid cells, offering the possibility of prenatal diagnosis. Absence of dihydropteridine reductase results not only in a defect in the conversion of phenylalaning to tyrosine, but also in the biosynthesis of the neurotransmitters, dopamine, norephinephrine, and serotonin. Since deficiencies in these neurotransmitters would not be alleviated by a phenylalanine-restricted diet, it is important to establish the nature of the enzymatic defect in all suspected variants of phenylketonuria.