Sunscreens: are they beneficial for health? An overview of endocrine disrupting properties of UV-filters.

Today, topical application of sunscreens, containing ultraviolet-filters (UV-filters), is preferred protection against adverse effects of ultraviolet radiation. Evidently, use of sunscreens is effective in prevention of sunburns in various models. However, evidence for their protective effects against melanoma skin cancer is less conclusive. Three important observations prompted us to review the animal data and human studies on possible side effects of selected chemical UV-filters in cosmetics. (1) the utilization of sunscreens with UV-filters is increasing worldwide; (2) the incidence of the malignant disorder for which sunscreens should protect, malignant melanoma, is rapidly increasing and (3) an increasing number of experimental studies indicating that several UV-filters might have endocrine disruptive effects. The selected UV-filters we review in this article are benzophenone-3 (BP-3), 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), Homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate (OD-PABA) and 4-aminobenzoic acid (PABA). The potential adverse effects induced by UV-filters in experimental animals include reproductive/developmental toxicity and disturbance of hypothalamic-pituitary-thyroid axis (HPT). Few human studies have investigated potential side effects of UV-filters, although human exposure is high as UV-filters in sunscreens are rapidly absorbed from the skin. One of the UV-filters, BP-3, has been found in 96% of urine samples in the US and several UV-filters in 85% of Swiss breast milk samples. It seems pertinent to evaluate whether exposure to UV-filters contribute to possible adverse effects on the developing organs of foetuses and children.

Mixtures of endocrine disrupting contaminants modelled on human high end exposures: an exploratory study in rats.

By diminishing the action of androgens during gestation, certain chemicals can induce irreversible demasculinization and malformations of sex organs in the male rat after gestational exposure. Studies with mixtures of such anti-androgens have shown that substantial combined effects occur even though each individual chemical is present at low, ineffective doses, but the effects of mixtures modelled based on human intakes have not previously been investigated. To address this issue for the first time, we selected 13 chemicals for a developmental mixture toxicity study in rats where data about in vivo endocrine disrupting effects and information about human exposures was available, including phthalates, pesticides, UV-filters, bisphenol A, parabens and the drug paracetamol. The mixture ratio was chosen to reflect high end human intakes. To make decisions about the dose levels for studies in the rat, we employed the point of departure index (PODI) approach, which sums up ratios between estimated exposure levels and no-observed-adverse-effect-level (NOAEL) values of individual substances. For high end human exposures to the 13 selected chemicals, we calculated a PODI of 0.016. As only a PODI exceeding 1 is expected to lead to effects in the rat, a total dose more than 62 times higher than human exposures should lead to responses. Considering the high uncertainty of this estimate, experience on lowest-observed-adverse-effect-level (LOAEL)/NOAEL ratios and statistical power of rat studies, we expected that combined doses 150 times higher than high end human intake estimates should give no, or only borderline effects, whereas doses 450 times higher should produce significant responses. Experiments indeed showed clear developmental toxicity of the 450-fold dose in terms of increased nipple retention (NR) and reduced ventral prostate weight. The 150-fold dose group exhibited significantly increased NR. These observations suggest that highly exposed population groups, especially women of reproductive age, may not be protected sufficiently against the combined effects of chemicals that affect the hormonal milieu required for normal male sexual differentiation.

Effect of the herbicide pendimethalin on rat uterine weight and gene expression and in silico receptor binding analysis.

The endocrine disrupting potential of the herbicide pendimethalin was investigated in vivo on the uterotrophic response and on the expression of estrogen-regulated genes examined by quantitative real-time RT PCR. Receptor binding characteristics of pendimethalin were analyzed by an in silico method. Pendimethalin (150, 225, 300 and 600 mg/kg/day) was administered by oral gavage to immature female rats for 3 days, with ethinylestradiol (0.001 mg/kg/day) as positive control. Pendimethalin caused a small but significant increase in absolute uterine weight at and above 300 mg/kg/day and in relative uterine weight at 600 mg/kg/day. Estrogen receptor (ER)-alpha mRNA levels were not affected, whereas ER-beta mRNA was up-regulated at the highest dose. Progesterone receptor mRNA level was not significantly changed, while insulin-like growth factor-I mRNA was reduced, significantly at 225 mg/kg/day to 65% of control. Androgen receptor (AR) mRNA showed a marked down-regulation at doses of 225 mg/kg/day and above. The expression pattern differed from that of ethinylestradiol. In silico analysis revealed potential binding of pendimethalin to ER-beta and AR, but virtually no binding to ER-alpha. These data demonstrate that pendimethalin exhibits estrogenic activity also in vivo. However, its uterotrophic effect, which is an ER-alpha-mediated response, is very small, and it appears that in vivo actions should rather be sought in ER-beta-regulated functions.

Delta(9)-tetrahydrocannabinol inhibits 17beta-estradiol-induced proliferation and fails to activate androgen and estrogen receptors in MCF7 human breast cancer cells.

BACKGROUND: Delta(9)-tetrahydrocannabinol (THC) exerts palliative effects in cancer patients, but produces adverse effects on the endocrine and reproductive systems. Experimental evidence concerning such effects is controversial. Whether THC exhibits estrogenic or androgenic activity in vitro was investigated. MATERIALS AND METHODS: Estrogenic effects of THC were analyzed in vitro by measuring the proliferation of estrogen-sensitive MCF7 cells. Androgenic activity was investigated by the A-Screen assay that measures androgen-dependent inhibition of proliferation of the androgen receptor (AR)-positive human mammary carcinoma cell line, MCF7-AR1. RESULTS: In contrast to 17beta-estradiol, included as positive control with an EC50 value (concentration required for 50% of maximal 17beta-estradiol-induced proliferation) of 1.00 x 10(-12) M, THC failed to induce cell proliferation in the MCF7 cell line at concentrations between 10(-13) and 10(-4) M. THC inhibited 17beta-estradiol-induced proliferation in wild-type MCF7 and MCF7-AR1 cells, with an IC50 value of 2.6 x 10(-5) M and 9 x 10(-6) M, respectively. CONCLUSION: THC failed to act as an estrogen, but antagonized 17beta-estradiol-induced proliferation. This effect was independent of the AR expression level.

Effects of the Tibetan herbal preparation PADMA 28 on blood lipids and lipid oxidisability in subjects with mild hypercholesterolaemia.

BACKGROUND: Previous studies showed an anti-atherosclerotic effect of PADMA 28, an herbal formula based on Tibetan medicine. As the mechanisms of action are not fully understood, we investigated whether PADMA 28 may lower blood lipids and lipid oxidisability, and affect early endothelial dysfunction. PATIENTS AND METHODS: Sixty otherwise healthy subjects with total cholesterol > or = 5.2 mmol/l and < 8.0 mmol/l were randomly assigned to placebo or PADMA 28, 3 x 2 capsules daily, for 4 weeks (double-blind). Blood lipids (total, LDL-, and HDL-cholesterol, triglycerides, Apo-lipoprotein A1 and B) and ex vivo lipid oxidisability were measured before and after treatment. In a subset of 24 subjects, endothelial function was assessed using venous occlusion plethysmography with intraarterial infusion of acetylcholine. Isolated LDL and plasma both untreated and pre-treated with PADMA 28 extract were oxidised by the radical generator AAPH. Conjugated diene formation was measured at 245 nm. RESULTS: Blood lipids did not change during the study in both groups. In contrast to previous reports in mild hypercholesterolaemia, no endothelial dysfunction was seen and, consequently, was not influenced by therapy. Ex vivo blood lipid oxidisability was significantly reduced with PADMA 28 (area undercurve: 5.29 +/- 1.62 to 4.99 +/- 1.46, p = 0.01), and remained unchanged in the placebo group (5.33 +/- 1.88 to 5.18 +/- 1.78, p > 0. 1). This effect persisted one week after cessation of medication. In vitro experiments confirmed the prevention of lipid peroxidation in the presence of PADMA 28 extracts. Persistent protection was also seen for LDL isolated from PADMA 28-pretreated blood after being subjected to rigorous purification. CONCLUSIONS: This study suggests that the inhibition of blood lipid oxidisability by PADMA 28 may play a role in its anti-atherosclerotic effect.

In vitro and in vivo estrogenicity of UV screens.

Ultraviolet (UV) screens are increasingly used as a result of growing concern about UV radiation and skin cancer; they are also added to cosmetics and other products for light stability. Recent data on bioaccumulation in wildlife and humans point to a need for in-depth analyses of systemic toxicology, in particular with respect to reproduction and ontogeny. We examined six frequently used UVA and UVB screens for estrogenicity in vitro and in vivo. In MCF-7 breast cancer cells, five out of six chemicals, that is, benzophenone-3 (Bp-3), homosalate (HMS), 4-methyl-benzylidene camphor (4-MBC), octyl-methoxycinnamate (OMC), and octyl-dimethyl-PABA (OD-PABA), increased cell proliferation with median effective concentrations (EC(50)) values between 1.56 and 3.73 microM, whereas butyl-methoxydibenzoylmethane (B-MDM) was inactive. Further evidence for estrogenic activity was the induction of pS2 protein in MCF-7 cells and the blockade of the proliferative effect of 4-MBC by the estrogen antagonist ICI 182,780. In the uterotrophic assay using immature Long-Evans rats that received the chemicals for 4 days in powdered feed, uterine weight was dose-dependently increased by 4-MBC (ED(50 )309mg/kg/day), OMC (ED(50) 935 mg/kg/day), and weakly by Bp-3 (active at 1,525 mg/kg/day). Three compounds were inactive by the oral route in the doses tested. Dermal application of 4-MBC to immature hairless (hr/hr) rats also increased uterine weight at concentrations of 5 and 7.5% in olive oil. Our findings indicate that UV screens should be tested for endocrine activity, in view of possible long-term effects in humans and wildlife.

Early manifestations of Prader-Willi syndrome: influence of growth hormone.

Pediatricians and neonatologists now understand the clinical picture of Prader-Willi syndrome (PWS) in infants as genetic tools are available to confirm this diagnosis. Hence, an increasing number of very young, still underweight children are being diagnosed with PWS. Some features, such as low prenatal weight and below-average height, subsequent poor growth velocity and increased body fat, possibly in infancy, may be interpreted as a consequence of early growth hormone (GH) deficiency. This raises the question of when is the best time for the initiation of GH treatment. This article presents the results of a study in which ten very young children with PWS (mean age 1.0 year) were treated with exogenous GH. We conclude that GH treatment in young, underweight children, as well as in older children with PWS: (1) normalizes growth and body proportions; (2) probably reduces fat mass and increases muscle mass; (3) may enhance motor development; and (4) is necessary, but obviously not sufficient, to normalize body composition and fat distribution. Whether there is a benefit in treating children with PWS from such an early age requires longer-term studies.

Cardiovascular risk factors improve during 3 years of growth hormone therapy in Prader-Willi syndrome.

UNLABELLED: Cardiovascular risk factors in Prader-Willi syndrome (PWS, OMIM 176270) may be independently caused by overweight or hypothalamic growth hormone (GH) deficiency. The present observational study in 23 children with PWS, aged 0.3-14.6 years, focuses on the specific pattern, age-dependency and interrelation of cardiovascular risk factors, namely percentage fat mass and regional fat distribution, triglycerides (TG), lipoprotein cholesterols (LDL-C, HDL-C), lipoprotein (a) (Lp(a)), apolipoproteins A-I (Apo A-I) and B (Apo B), as well as on the longer-term effects of GH therapy (ca. 0.037 mg/kg per day for 3 years on average). We report that in children above 4 years, percentage body fat was increased in all and waist-to-hip-ratio (WHR) in 35%. Abnormal levels of LDL-C, Apo B, HDL-C and TG were found in 6, 7, 6 and 3 children, respectively. Lp(a) was above 300 mg/l in 5 patients and remained unchanged during GH therapy. However, percentage fat mass dropped to the upper normal range and WHR became normal in all patients receiving GH therapy, as did the ratio of LDL-C to HDL-C, subsequent to decreasing LDL-C and increasing HDL-C. Nevertheless, we could not find any significant correlation between parameters of total fat mass or fat distribution and serum lipid parameters, except for abdominal fat distribution (trunk-/leg-fat ratio) to TG before therapy. CONCLUSION: Several cardiovascular risk factors are already present in prepubertal children with Prader-Willi-syndrome and they are improved by growth hormone treatment, acting both on body composition and lipid metabolism.

Diazepam-binding inhibitor/acyl-CoA-binding protein mRNA and peripheral benzodiazepine receptor mRNA in endocrine and immune tissues after prenatal diazepam exposure of male and female rats.

Peripheral benzodiazepine (BDZ) receptor (PBR) and diazepam-binding inhibitor/acyl-CoA-binding protein (DBI/ACBP) characterized as a ligand at central BDZ receptors, at PBR with involvement in the regulation of steroidogenesis, and as an intracellular acyl-CoA transporter, are both known to interact with BDZ in adult systems. We investigated their expression after prenatal exposure to BDZ. Diazepam (1.25 mg/kg per day s.c.) was administered to time-pregnant Long Evans rats from gestational day (GD) 14 to 20. Expression of mRNAs encoding for PBR and for DBI/ACBP was studied in the same animals with (33)P-labeled 60 mer oligonucleotides (oligos) by in situ hybridization at GD20, and with (32)P-labeled oligos by Northern blot in steroidogenic and immune organs at postnatal day (PN) 14 and in adult offspring. Prenatal diazepam increased DBI/ACBP mRNA expression in male fetal adrenal and in fetal and PN14 testis. Thymus exhibited increased DBI/ACBP mRNA in male fetuses and in adult female offspring, and reduced organ weight at PN14 in both sexes. In female spleen, an increase in DBI/ACBP mRNA and a decrease in PBR mRNA was seen at PN14. Apart from the finding in spleen, no drug-induced changes in PBR mRNA were observed. The effects of prenatal diazepam were superimposed on treatment-independent sex differences in DBI/ACBP mRNA and PBR mRNA expression. Our data indicate that expression of DBI/ACBP mRNA in steroidogenic and immune organs can be affected by exposure to BDZ during ontogeny, while PBR mRNA expression appears to be less sensitive. They further reveal marked sex differences in the developmental patterns of the two proteins during pre- and postpubertal ontogeny.

CYP 450 enzyme induction by chronic oral musk xylene in adult and developing rats.

Developmental and adult toxicity of musk xylene was studied in Long Evans (LE) rats fed with chow containing musk xylene (MX) in food pellets in concentrations of 1 mg, 10 mg, 33 mg, 100 mg and 1000 mg MX per 1 kg chow corresponding to a daily intake of 0.07-0.08 mg MX/kg up to 70-80 mg MX/kg body weight. Adult male and female rats were MX exposed for a minimum of 10 weeks before mating. Exposure continued throughout pregnancy, birth and lactation. The effects of MX on CYP1A1/1A2 were studied in liver microsomes by EROD (7-ethoxyresorufin-rosomes deethylase) for CYP1A1 and by MROD (methoxyresorufin-o-demethylase) for CYP1A2 activity and by Western blotting. MX induced these enzymes dose dependently in adult and developing rats at PN (postnatal day) 1 and 14. The lowest effective maternal dose was 2-3 mg MX/kg/day. Western blot data of CYP2B and CYP3A indicated the induction of both P450 enzyme proteins in developing rats at PN 14 at the higher dose of 70-80 mg MX/kg/day. In contrast, upon high MX exposure CYP2B but not CYP3A was found to be induced in adult first generation male and female rats, indicating differential sensitivity to MX in development.

Prognostic significance of oxygen uptake kinetics during low level exercise in patients with heart failure.

Oxygen uptake kinetics during low-intensity exercise were investigated in 48 patients with congestive heart failure to assess their prognostic value compared with established predictors of prognosis including neurohumoral stimulation. Mean response time of oxygen uptake during low-intensity exercise, which does not require the patient's maximal effort, appears to be an important predictor of prognosis in these patients.

Andreas Grüntzig's balloon catheter for angioplasty of peripheral arteries (PTA) is 25 years old.

History of Andreas Grüntzig's time spent in Angiology and Radiology of the Zürich University Hospital (1969-1975). First, the pioneer of catheter therapy discovered that the Achilles tendon reflex is significantly prolonged during claudication pain. Furthermore, he participated actively in the clinical evaluation of Doppler ultrasound. After a stay in the Aggertalklinik (Engelskirchen near Köln, Germany), where he learnt Charles Dotter's original procedure with Eberhard Zeitler, he introduced catheter therapy of peripheral arteries in Zürich. In the same period he developed a new, rigid, sausage-shaped balloon catheter (polyvinylchloride), manufactured the device on his kitchen table together with his wife Michaela, Maria and Walter Schlumpf, and used it first on February 12, 1974 in a patient with intermittent claudication due to subtotal stenosis of the superficial femoral artery. The first successful dilatation of an iliac artery stenosis by his double-lumen catheter, which was modified later on into the famous coronary catheter, followed on January 23, 1975. Soon, the innovative catheter became commercially available (Cook and Schneider Companies). Andreas Grüntzig not only excelled in pioneering novel techniques, but also in patient care, in a prospective follow-up study of his own 242 patients lasting 15 years (results summarized in this article), in the teaching of Swiss scholars like Felix Mahler, Ernst Schneider and Bernhard Meier and many more in the world, and in organizing life demonstrations for large numbers of participants. His career in Cardiology, his work in Atlanta Georgia, USA, and his early tragic death in an airplane accident are briefly mentioned.

Ontogeny of diazepam binding inhibitor/acyl-CoA binding protein mRNA and peripheral benzodiazepine receptor mRNA expression in the rat.

The Diazepam Binding Inhibitor/Acyl-CoA Binding Protein (DBI/ACBP) has been implicated in different functions, as acyl-CoA transporter and as an endogenous ligand at the GABA(A) receptor and the peripheral benzodiazepine receptor (PBR). The latter is thought to be involved in control of steroidogenesis. We studied the ontogeny of DBI/ACBP and PBR mRNA expression in embryos and offspring of time-pregnant Long Evans rats by in-situ hybridization with 33P-endlabelled oligonucleotides. Both mRNAs were present in embryo and placenta at gestational day (G)11, the earliest stage studied. DBI/ACBP mRNA was strongly expressed from embryonic through mid-foetal stages in central nervous system (maximum in neuroepithelium), cranial and sympathetic ganglia, anterior pituitary, adrenal cortex, thyroid, thymus, liver and (late foetal) brown adipose tissue, moderately in testis, heart, lung and kidney. In brain, a late foetal decrease of DBI/ACBP mRNA was followed by an increase at postnatal day 6. Peripheral benzodiazepine receptor mRNA expression started very low and increased to moderate levels in adrenal cortex and medulla, testis, thyroid, brown adipose tissue, liver, heart, lung, salivary gland at mid- to late-foetal stages. Data suggest a significant role of DBI/ACBP at early developmental stages. Both proteins may be involved in the control of foetal steroidogenesis. However, differences in developmental patterns indicate that additional functions may be equally important during ontogeny, such as the involvement in lipid metabolism in the case of DBI/ACBP.

Oxygen uptake kinetics during low level exercise in patients with heart failure: relation to neurohormones, peak oxygen consumption, and clinical findings.

OBJECTIVE: To investigate whether oxygen uptake (VO2) kinetics during low intensity exercise are related to clinical signs, symptoms, and neurohumoral activation independently of peak oxygen consumption in chronic heart failure. DESIGN: Comparison of VO2 kinetics with peak VO2, neurohormones, and clinical signs of chronic heart failure. SETTING: Tertiary care centre. PATIENTS: 48 patients with mild to moderate chronic heart failure. INTERVENTIONS: Treadmill exercise testing with "breath by breath" gas exchange monitoring. Measurement of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and noradrenaline. Assessment of clinical findings by questionnaire. MAIN OUTCOME MEASURES: O2 kinetics were defined as O2 deficit (time [rest to steady state] x DeltaVO2 -sigmaVO2 [rest to steady state]; normalised to body weight) and mean response time of oxygen consumption (MRT; O2 deficit/DeltaVO2). RESULTS: VO2 kinetics were weakly to moderately correlated to the peak VO2 (O2 deficit, r = -0.37, p < 0.05; MRT, r = -0.49, p < 0.001). Natriuretic peptides were more closely correlated with MRT (ANF, r = 0.58; BNP, r = 0.53, p < 0.001) than with O2 deficit (ANF, r = 0.48, p = 0.001; BNP, r = 0.37, p < 0.01) or peak VO2 (ANF, r = -0.40; BNP, r = -0.31, p < 0.05). Noradrenaline was correlated with MRT (r = 0. 33, p < 0.05) and O2 deficit (r = 0.39, p < 0.01) but not with peak VO2 (r = -0.20, NS). Symptoms of chronic heart failure were correlated with all indices of oxygen consumption (MRT, r = 0.47, p < 0.01; O2 deficit, r = 0.39, p < 0.01; peak VO2, r = -0.48, p < 0. 01). Multivariate analysis showed that the correlation of VO2 kinetics with neurohormones and symptoms of chronic heart failure was independent of peak VO2 and other variables. CONCLUSIONS: Oxygen kinetics during low intensity exercise may provide additional information over peak VO2 in patients with chronic heart failure, given the better correlation with neurohormones which represent an index of homeostasis of the cardiovascular system.

CYP 450 enzyme induction by chronic oral musk xylene in adult and developing rats.

Developmental and adult toxicity of musk xylene was studied in Long Evans (LE) rats fed with chow containing musk xylene (MX) in food pellets in concentrations of 1 mg, 10 mg, 33 mg, 100 mg and 1000 mg MX per 1 kg chow corresponding to a daily intake of 0.07-0.08 mg MX/kg up to 70-80 mg MX/kg body weight. Adult male and female rats were MX exposed for a minimum of 10 weeks before mating. Exposure continued throughout pregnancy, birth and lactation. The effects of MX on CYP1A1/1A2 were studied in liver microsomes by EROD (7-ethoxyresorufin-o-deethylase) for CYP1A1 and by MROD (methoxyresorufin-o-demethylase) for CYP1A2 activity and by Western blotting. MX induced these enzymes dose dependently in adult and developing rats at PN (postnatal day) 1 and 14. The lowest effective maternal dose was 2-3 mg MX/kg/day. Western blot data of CYP2B and CYP3A indicated the induction of both P450 enzyme proteins in developing rats at PN 14 at the higher dose of 70-80 mg MX/kg/day. In contrast, upon high MX exposure CYP2B but not CYP3A was found to be induced in adult first generation male and female rats, indicating differential sensitivity to MX in development.

[Foot reflex zone massage--general practice and evaluation]. / Fussreflexzonenmassage--Praxis und Evaluation.

Reflexology is a frequently used method of complementary medicine. This review deals with history, theory and practise of this technique. Furthermore, results of the published clinical trials are discussed.

Melanocortin and MCH precursor-derived NEI effects on striatum-midbrain co-cultures.

The possibility of developmental effects of POMC-derived melanocortins and analogs on neurons of fetal rat brain regions exhibiting marked developmental melanocortin receptor expression, was studied in serum-free co-cultures of gestational day 18 striatal and mesencephalic cells, and compared with NEI and NGE. These two peptide fragments of the melanin concentrating hormone precursor, occurring in brain areas devoid of POMC terminals, cross-react with alpha-MSH antibodies; NEI elicits grooming similar to alpha-MSH. Neurofilament protein (NF), growth-associated protein (GAP-43) and synaptophysin of the synaptosomal fraction were determined by ELISA as markers for neuritogenesis, growth cones, and nerve terminal differentiation. Cell survival was analyzed by MTT assay, proportions of major cell types by immunocytochemistry. alpha-Melanocyte-stimulating hormone (alpha-MSH, effective concentration 250-2500 nM), the analog Nle4-, D-Phe7-alpha-MSH (NDP, 3.1-750 nM), and NEI (250 nM) increased NF in 3 day cultures by 11%, 17%, and 22%, respectively, whereas ACTH(1-24) and ACTH(1-39) (25 2500 nM) were ineffective. In 11 day cultures, alpha-MSH (250-750 nM), but not NDP, ACTH(1-24) or ACTH(1-39), increased synaptosomal synaptophysin by 11%. GAP-43 and cell survival remained unaffected. These data indicate that selected melanocortins as well as NEI can influence differentiation of neural processes in brain neurons.

Bioaccumulation of musk xylene (MX) in developing and adult rats of both sexes.

Bioaccumulation of musk xylene (MX) was measured by GC-ECD in adult and developing Long Evans rats. Males and females were fed with MX-containing chow (0.001, 0.01, 0.033, 0.1 g MX/kg food pellets) for 10 weeks before mating. Treatment continued during pregnancy and lactation. Offspring exhibited dose-dependent MX accumulation with 1/2-3/4 of adult female or 3-4 times adult male body fat levels (at 0.1 mg/kg food) at days 1 and 14. Milk levels were comparable to adult female adipose tissue. Data indicate significant transplacental passage and exposure via maternal milk. In rats fed with MX in adulthood, levels were highest in adipose tissue with significant amounts in other organs (ovary, adrenal). Female tissue levels were 3.7-6.8 times higher. This unexplained sex difference was unrelated to lipid content and was absent in offspring.

Relative frequency of functional sympathetic and parasympathetic reinnervation after heart transplantation.

Although there is evidence of partial sympathetic reinnervation late after transplantation, little is known about the relative frequency of sympathetic and, in particular, parasympathetic reinnervation. We examined the heart rate response to various maneuvers (standing up, handgrip exercise, phase 2 of Valsalva maneuver for sympathetic function, carotid sinus massage, phase 4 of Valsalva maneuver, and atropine for parasympathetic function) in 65 patients 3 to 110 months after transplantation and in 16 healthy volunteers and defined reinnervation as either one normal (>50% of control group) and at least one partial (>33% of control group) heart rate response or partial responses in all three tests of the respective part of the autonomic nervous system. Thirty-five (54%) patients had sympathetic reinnervation, but only 16 (25%) had parasympathetic reinnervation (p < 0.001); earliest reinnervation was found 11 months after transplantation, and all but one patient with parasympathetic reinnervation also had sympathetic reinnervation. Signs of sympathetic but not parasympathetic reinnervation were common late (>5 years) after transplantation (74% vs 30%).