Sex related differences in therapy and outcome of patients with intermittent claudication in a real-world cohort.

BACKGROUND AND AIMS: The prevalence of lower extremity artery disease (LEAD) is increasing worldwide and sex-related differences are a current matter of debate. METHODS: We analysed claims data on unselected patients with in-patient treatment for LEAD with intermittent claudication (IC; Rutherford grade 1-3) from 01.01.2014 to 31.12.2015. Data files included diagnostic and procedural information from two years before index, and a five-year follow-up. RESULTS: Our analysis comprised 42,197 IC patients, thereof 28,520 (68%) male. Male patients were younger (median: 66.4 years vs. 72.6 years) but presented with higher frequency of cardiovascular risk factors such as diabetes (40% female vs. 46% male), atrial fibrillation (13% vs. 17%), chronic coronary syndrome (41% vs. 53%), chronic heart failure (23% vs. 27%), or chronic kidney disease (29% vs. 32%; all p < 0.001; age adjusted). Revascularisation applied in 80% of patients, thereof endovascular approach predominantly in female and surgery in male patients. Concomitant pharmacotherapy with statins (74% at 2 years) and platelet inhibitors (75% respectively) were long lasting below guideline recommendation, under-use being more pronounced in women. Two years after index, one-third of IC patients had subsequent revascularisation, one-quarter progressed to chronic limb threatening ischemia (CLTI), and 2% underwent amputation. Male sex was an independent risk factor for long-term mortality (female HR 0.75; 95%-CI 0.72-0.79; p < 0.001) and CLTI (female HR 0.89; 95%-CI 0.86-0.92; p < 0.001) during follow-up. CONCLUSIONS: The majority of in-patient treated patients for IC are male, presenting with worse cardiovascular risk profiles. In view of a general under-supply with statins and platelet inhibitors, women received somewhat less often preventive medication. Despite low LEAD stages at index, serious prognosis was observed in the long term. Particularly male patients were at high risk for all-cause mortality and the combined endpoint CLTI and death.

Assessment of current serum levels of PCDD/Fs, dl-PCBs and PBDEs in a Dutch cohort with known perinatal PCDD/F exposure.

As part of a longitudinal cohort study, now in its second decade, we determined PCDDs/Fs dl-PCBs and PBDEs in serum of adolescents with known perinatal PCDD/F exposure. Of the original cohort, 33 adolescents aged 14-19 years, who had been studied previously during their neonatal (n=60), toddler and pre-pubertal period (n=41) agreed to participate in the current follow-up. PCDD/F-, dl-PCB- and PBDE congeners were measured using GC/MS. Current serum levels of PCDD/Fs determined in our cohort were relatively low (mean of 2.2 pg/g) compared to the perinatal exposure. No correlation between perinatal exposure and current serum PCDD/F was found. Planar PCB TEQ levels were 2.2 pg/g. Current summation operatorPBDE levels were 8.7 ng/g lipid. There was one outlier with a summation operatorPBDE of 74 ng/g lipid. The presence of this high value indicates that the exposure pathway is different from PCDD/F and PCB, most likely by dust and food contaminated with dust. Concluding we can say that current PCDD/F levels are quite low compared to the perinatal PCDD/F exposure of the cohort. PBDE levels however are relatively high compared to other European countries, more research on possible health effects of these levels, especially for subjects with outlier concentrations, should be performed.

Psychological development of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome.

Potential side effects of antenatal administration of corticosteroids to prevent neonatal respiratory distress syndrome were studied in 10- to 12-year-old children whose mothers had participated in a randomized, double-blind, placebo-controlled trial of betamethasone. Aspects of the children's intellectual and motor development, school achievement, and social-emotional functioning were investigated. There were no differences between the corticoid group and the placebo group on these variables, nor were there more children with learning difficulties and behavioral disturbances in either of the groups.

Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10- to 12-year follow-up.

Potential side effects of antenatal administration of corticosteroids to prevent neonatal respiratory distress syndrome were studied in 10- to 12-year-old children whose mothers had participated in a randomized, double-blind, placebo-controlled trial of betamethasone. The children had a general physical examination; parents were interviewed about the medical history of their child with special attention to infectious diseases; growth data were collected; and a developmental neurological examination, an ophthalmological examination, and a lung function test were conducted. In the corticosteroid group significantly more hospital admissions because of infectious diseases during the first years of life were reported. On the other variables no differences between the corticoid and the placebo groups were found.

Influence of short-term dietary measures on dioxin concentrations in human milk.

Breast-feeding may expose infants to high levels of toxic chlorinated dioxins. To diminish intake of these lipophilic compounds by the baby, two diets were tested for their ability to reduce concentrations of dioxins in human milk. The diets were a low-fat/high- carbohydrate/low-dioxin diet. (about 20% of energy intake derived from fat) and a high fat /low-carbohydrate/low-dioxin diet. These diets were tested in 16 and 18 breast-feeding women, respectively. The test diets were followed for 5 consecutive days in the fourth week after delivery. Milk was sampled before and at the end of the dietary regimen, and dioxin concentrations and fatty acid concentrations were determined. Despite significant influences of these diets on the fatty acid profiles, no significant influence on the dioxin concentrations in breast milk could be found. We conclude that short-term dietary measures will not reduce dioxin concentration in human milk.

Effects of pre- and postnatal exposure to chlorinated dioxins and furans on human neonatal thyroid hormone concentrations.

Animal studies have shown that dioxins influence plasma thyroid hormone concentrations. To investigate the effect of chlorinated dioxins and furans on thyroid hormone concentrations in humans, we studied 38 healthy breast-fed infants. The study population was divided into two groups according to the dioxin concentrations in milk fat of their mothers. Blood samples were taken at birth and at the ages of 1 and 11 weeks. At birth a tendency to higher total thyroxine (tT4) concentrations was found in the high exposure group. At the ages of 1 and 11 weeks the increase of mean tT4 concentrations and tT4/thyroxine-binding globulin ratios in the high exposure group reached significance as compared to the low exposure group. At birth and 1 week after birth, mean thyrotropin (TSH) concentrations were similar in both groups, but at the age of 11 weeks the mean TSH concentrations were significantly higher in the high exposure group. We postulate that the observed plasma tT4 elevation in infants exposed to dioxins before and after birth is the result of an effect on the thyroid hormone regulatory system.

Threatened preterm labor: the influence of time factors on the incidence of respiratory distress syndrome.

The interval between the first symptoms of threatened preterm labor and delivery was studied and found to be correlated with the incidence of respiratory distress syndrome (RDS), independent of treatment with corticosteroids or betamimetics and the state of the membranes. The incidence and severity of RDS decreased when labor was postponed for a period ranging from 12 hours to three weeks after admission. The decrease was most marked in a steroid-treated group but also occurred in the placebo-treated and untreated groups. The combination of orciprenaline and betamethasone was more effective in postponing delivery in early pregnancies than was the combination of orciprenaline and placebo. Treatment with betamimetics and corticosteroids is therefore indicated in cases of active preterm labor.

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin or 2,2',4,4',5,5'-hexachlorobiphenyl on vitamin K-dependent blood coagulation in female germfree WAG/Rij-rats.

Newborn infants are susceptible to bleeding disorders caused by a vitamin K deficiency, so called 'haemorrhagic disease of the newborn' (HDN). These bleedings often occur in infants after medication of the mother with antiepileptics, such as phenobarbital or phenytoin. It has been suggested that an increase in the late type of HDN in exclusively breast-fed infants might be related to the presence of cytochrome P450-inducing polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) in human milk. In order to study this possible mechanistic relationship 5-week-old, germfree, female WAG/Rij-rats were exposed to a single oral dose of either 1 microgram 2,3,7,8-tetrachlorodibenzo-p-dioxin/kg body weight (TCDD) or 30 mg 2,2',4,4',5,5'-hexachlorobiphenyl/kg body weight (HxCB), representing cytochrome P-450 1A (3-methylcholanthrene type) and 2B (phenobarbital type) inducers. During the experiment blood coagulation time from each rat was measured. Also, hepatic 7-ethoxy-(EROD) and 7-pentoxyresorufin O-dealkylating (PROD) activities and total cytochrome P450 content were measured. Blood coagulation time (Thrombotest) in the HxCB-treated rats was significantly prolonged and positively correlated to PROD activity and total P450 content. No clear effect of TCDD on coagulation time could be observed under these experimental conditions. These results suggest involvement of P450 2B isoenzymes in vitamin K metabolism.

Severe asphyxia and outcome of survivors.

Fifty-four infants born severely asphyxiated with birth weights of more than 2500 g and gestational ages older than 37 weeks were studied with help of careful review of the case files. To establish a relationship between the time elapsed after birth to spontaneous regular active respiration and later outcome, the infants were divided into three groups: group A of 34 children, established spontaneous active respiration within 15 min; group B of 7 children recovered in 15-30 min, and group C of 13 children recovered 30 min after birth. The outcome in group C, in which the infants also had a history of prolonged intrapartum asphyxia, was uniformly bad. The absence or presence of an audible heart beat at birth was not a reliable clinical sign for a prognosis. The time that elapsed between the start of resuscitation and the first gasp had to be doubled to indicate the likely start of regular active respiration in one third of our babies. The results indicated that the combination of prolonged intrapartum asphyxia and a delay in onset of spontaneous regular respiration of more than 30 min following birth predicted a uniformly bad prognosis. Attempts at resuscitation after this interval did not appear to be warranted.

Circadian rhythms in preterm infants: a preliminary study.

A method has been developed for long-term continuous recordings of several physiological variables in humans, including body movements, core temperature, heart rate and respiratory rate. This method enabled us to study circadian rhythms of body temperature and rest-activity in preterm infants. In 5 out of 9 infants (recorded at 28-34 weeks conceptional age) circadian rhythms were found in body temperature. We conclude that circadian rhythmicity is present during the early neonatal period in certain physiological variables (body temperature) but not in others (rest-activity).

Nutrition and breast-feeding.

In the western industrialized world, malnutrition of the lactating mother is not a problem any more. However, new problems, the chemical pollutants in breastmilk, have given rise to concern. Since the seventies, pollution of breastmilk with PCBs and dioxins has taken place. After World War II, more and more PCBs and dioxins entered the environment. Because of the low half-life of these chemicals, persistence leading to accumulation in animal and human fat has taken place. The baby, before birth and when breast-fed, is the highest animal in the food chain, consuming the most concentrated amount of PCBs and dioxins in his/her daily fat intake. Exposure before and after birth has given rise to subtle abnormalities in approximately 10% of the newborns in the Netherlands. These subtle abnormalities are a disturbed cognitive development and a delayed motor-development. Severe vitamin K deficiency can be caused by these contaminants as well. Because of the very threatening situation, a study was performed to look for the possibilities of prevention by influencing the diet of the lactating mother. Two diets were tested for their ability to reduce concentrations of dioxins in human milk. The diets were a low-fat/high-carbohydrate/low-dioxin diet (about 20% of energy intake derived from fat) and a high-fat/low-carbohydrate/low-dioxin diet. Despite significant influences of these diets on the fatty acid profiles, no significant influence on the dioxin concentrations in breast milk could be found. We conclude that short-term dietary measures will not reduce dioxin concentrations in human milk. A lowering of intake of these chemicals must take place years before the mother becomes pregnant.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of glucocorticoids during pregnancy on the outcome of the children directly after birth and in the long run.

We studied 17 mothers and the outcome of their 34 pregnancies. The purpose of this retrospective study was to determine possible adverse effects on growth of prolonged use of glucocorticoids, which have been recommended for short-term use in the prevention of respiratory distress syndrome (Liggins). There was no effect on duration of pregnancy; no congenital abnormalities were seen in this small group of children when corticoids were used during the whole pregnancy. There was a slight decrease in birth weight and placenta weight and, when known, also in length in almost every case. However, after long-term follow-up all of these children except 1 showed a catch-up growth and were slightly above normal. Their neurological and mental development was also normal except in 1 child who was born severely asphyxiated. We conclude from these results that there appears to be no adverse effect on later growth in the use of glucocorticoids during pregnancy. Therefore, it is unlikely that the short-term use of glucocorticoids as recommended by Liggins would have any influence on later growth.

Breast milk, dioxins and the possible effects on the health of newborn infants.

The concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the fat of breast milk of 14 Dutch mothers varied from 5.35 to 17.0 ng kg-1 (nanograms per kilogram fat). Expressed as toxic equivalents the concentrations of the 17 different congeners of dioxin and furans in the fat of the breast milk were between 29.85 and 92.88 ng kg-1. These levels are sufficient to induce enzyme formation in the livers of infants. (The acceptable daily intake is 4 pg/kg bodyweight/day). Dioxin induces the same enzyme production in the liver as phenobarbital; therefore, because phenobarbital affects fat-soluble vitamins, such as vitamins D and K, a similar response was anticipated in response to exposure to dioxin. Consequently, one aim of this study was to investigate blood coagulation parameters. We found a statistically significant relationship with the mean concentration of TCDD in the breast milk of mothers whose babies suffered from bleeding problems. This association was not found for 2,3,4,7,8-pentachlorodibenzofuran concentrations, nor for the remaining congeners expressed as toxic equivalents. A simple laboratory test for measuring dioxins and furans is urgently needed.

Open chemical combustions resulting in a local increased incidence of orofacial clefts.

HYPOTHESIS: The open chemical combustions in Zeeburg, Amsterdam, The Netherlands, during the years 1961 up to and including 1969, resulted in a local increased incidence of orofacial clefts during this period. STUDY: A retrospective observational epidemiological study was performed, comparing the trend of the incidence of non-syndromal orofacial clefts during the sixties, for the Zeeburg maternity with that of the Wilhelmina Gasthuis. Both clinics were situated in Amsterdam, but varying in distance and compass direction from the incineration works. Thereafter, the addresses of the mothers giving birth to infants with orofacial clefts were plotted on a map of Amsterdam. RESULTS: Of the 8803 children born in the Zeeburg clinic during this period, 21 had a non-syndromal orofacial cleft, producing an average incidence of 2.4 per 1000 births. For the years 1963 through 1965 the incidence rose dramatically to peak at 7.1 per 1000, before plateauing at an average incidence of 1.68 per 1000 births, still 155% higher than in the Wilhelmina clinic (average incidence of 0.66 per 1000 during the years 1966 through 1969). During the 10 year period the Wilhelmina clinic exhibited no such rise. The incidence of non-syndromal orofacial clefts at the Wilhelmina clinic at no time exceeded 2.3 per 1000 births during the 10 year period. The addresses of the mothers of the Zeeburg clefts were grouped primarily to the northwest (and a smaller group to the west) of the incineration works. CONCLUSION: A relation between the open incineration of the chemicals and a local increased incidence of orofacial clefts seems very likely.

Signs of enhanced neuromotor maturation in children due to perinatal load with background levels of dioxins. Follow-up until age 2 years and 7 months.

We investigated psychomotor development (Bayley-test) and neuromotor functioning (Hempel-test) in a group of children with known perinatal load with background levels of dioxins. Bayley-test (n = 32) at 2 years, and additionally investigated growth, medical history, physical condition, TT4, TT4/TBG, TSH, AST and ALT at the age of 2.5 years did not reveal abnormalities, or differences between the high- and the low-exposure group. Although the Hempel-test was normal in all children (n = 31), we found in 22 out of 29 items less suboptimal scores in the high-exposure group; in five items this difference reached significance (p < 0.05). Total-score and subtotal-score (posture of legs and feet excluded) revealed lower "suboptimality-scores" with a wider range in the high-exposure group in comparison to the low-exposure group (total-score p = 0.008 mean 6.7 SD 3.6 and mean 9.3 SD 1.8 respectively and subtotal-score p = 0.06 mean 4.5 SD 2.9 and mean 6.1 SD 1.6 respectively (Mann-Whitney or Wilcoxon Two-Sample Test). Similar signs of enhanced maturation have been described in the tadpole due to low dosis of TCDD. Reflexes were higher (p = 0.02), with a wider range of findings in the high-exposure group. Our hypothesis is that these findings may be due to thyroxine agonistic action of dioxins, which is in accordance with the earlier described signs of relatively high thyroid function in the first 11 weeks of life in this high-exposure group.

Missing effects of background dioxin exposure on development of breast-fed infants during the first half year of life.

Fetal exposure to higher levels of PCBs can result in low birth weight and neurological disorders of the newborn. In this study the effects of exposure to the highly toxic dioxins and dibenzofurans, structurally related to PCBs, was investigated in a population of 38 healthy infants. The infants were divided into two groups, according to concentrations of dioxins and dibenzofurans in their mothers milk fat. Neonatal body weight, length, Quetelet index and liver size were determined at different time points during the first half year of life. Additionally neurological development was determined. Comparing these items between the high and low exposure groups did not show any statistically significant differences. The results of this study do not reveal any effect of exposure to background levels of dioxins and dibenzofurans, but in utero exposure to these toxic agents may result in symptoms later in life. Therefore follow-up study of this well defined group will be performed.

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin or 2,2',4,4',5,5'-hexachlorobiphenyl on vitamin K-dependent blood coagulation in male and female WAG/Rij-rats.

Newborns are susceptible to hemorrhages (hemorrhagic disease of the newborn or HDN) due to vitamin K deficiency. Induction of cytochrome P450 in the fetal liver by maternal anticonvulsant therapy such as phenobarbital or phenytoin is considered to be a major cause. An observed increase in late hemorrhagic disease (LHD) in breast fed neonates gave rise to the hypothesis that PCBs and dioxins, P450-inducing contaminants present in human milk, might effect vitamin K-dependent blood coagulation. This hypothesis was studied in rats. Administration of a single oral dose of 0.003, 0.03, 0.3, 3 or 30 nmol 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) per kg bodyweight or 0.75, 4, 20, 100 or 500 micromol 2,2',4,4',5,5'-hexachlorobiphenyl/kg bw (HxCB) to female and male rats resulted in dose-related reductions of the vitamin K-dependent coagulation factor VII. The highest factor VII reduction in female rats was 44%, observed after TCDD exposure. The Lowest Observed Adverse Effect Level (LOAEL) of TCDD on female factor VII levels was 0.3 nmol/kg bw (96 ng/kg). There was a significant inverse correlation between Factor VII levels and induction of hepatic ethoxyresorufin O-deethylating (EROD) activity, reflecting CYP1A1, and total P450 content. HxCB had no effect on female coagulation factors. In contrast, in male rats only exposure to HxCB, which induces mainly CYP2B1 and 2B2, decreased both coagulation factors dramatically up to 88%. The LOAEL of HxCB on factor VII in male rats was 100 micromol/kg bw (36 mg/kg). In general, effects on coagulation factors in male rats exceeded those in females. In addition, sex-dependent differences of TCDD and HxCB were observed on the hepatic vitamin K cycle enzyme activities in female and male rats. Vitamin K-dependent (gamma-glutamyl carboxylase activity was mainly induced in female rats; 2.3-fold in the highest dose group of TCDD. In male rats only vitamin K 2,3-epoxide reductase (KO-reductase) activity was induced 1.7-fold by the highest dose of HxCB. KO-reductase activity in female rats was also increased by TCDD, however, less pronounced than the carboxylase activity. Concluding, the hepatic vitamin K cycle still functions and is not blocked by TCDD or HxCB, thus explaining the observed reduction in factor VII. Finally, the possible role of P450 in vitamin K deficiency is discussed. Based on these results it is suggested to investigate the possible role of PCBs and dioxin-like compounds in LHD in more detail.

Prenatal exposure to anticonvulsant drugs and spatial ability in adulthood.

By disturbing steroid hormone balances in the fetus, the anticonvulsant drugs phenobarbital and phenytoin may affect certain aspects of cognitive functioning. In order to test this hypothesis, we studied hormone related cognitive functioning in 72 men and 75 women who had been prenatally exposed to these drugs and equal numbers of matched control subjects. The groups did not differ on word fluency, dichotic listening and a Water Level Test. On Card Rotations, however, anticonvulsant-exposed males and females obtained significantly lower scores than control subjects. These results suggest that in both males and females prenatal exposure to phenobarbital and phenytoin may affect holistic spatial processing.

Studies on long-lasting consequences of prenatal exposure to anticonvulsant drugs.

Based on neonatal examination at birth, it has been estimated that epileptic women have a 2-3 times greater risk of giving birth to an infant with congenital anomalies. But anticonvulsant drugs may also have more subtle influences on the developing foetus which are not visible at birth but only emerge later in life. Evidence for these functional teratogenic influences has been provided by animal research and follow-up studies in young children. This article discusses these findings in human and animal studies. In addition, the outline of a study carried out at the Department of Obstetrics and Neonatology, Academic Medical Centre, Amsterdam, is described. In this study cognitive functioning, fertility and gender role behaviour of young adults, who had been prenatally exposed to barbiturates and/or hydantoins was examined.