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PubMed2004

Treatment of Parkinson's disease with pergolide and relation to restrictive valvular heart disease.

BACKGROUND: Restrictive valvular heart disease has been reported in patients with Parkinson's disease treated with pergolide. However, few data are available on frequency, severity, dose dependency, and reversibility of pergolide-induced disease, nor on the pulmonary pressures of these patients. We aimed to clarify these characteristics in a large group of patients. METHODS: 78 patients with Parkinson's disease treated with pergolide and 18 never treated with an ergot-derived dopamine agonist (controls) were evaluated by echocardiography. A valvular scoring system was used, ranging from 1 (proven ergot-like restrictive valvular heart disease) to 4 (no disease). For the mitral valve, tenting areas and tenting distances were measured. Systolic pulmonary artery pressures were derived from the tricuspid regurgitant jet. FINDINGS: Restrictive valvular heart disease of any type was present in 26 (33%) patients in the pergolide group and none in controls (p=0.0025). Important disease (score 1 or 2) was present in 15 (19%) patients in the pergolide group and none in controls (p=0.066). Mean tenting distances and tenting areas of the mitral valve were 1.08 cm (range 0.55-2.66) and 2.39 cm2 (0.88-4.59) in the restrictive mitral valve group versus 0.63 cm (0.22-1.20) and 1.39 cm2 (0.39-3.23) in the non-restrictive group (p=0.003 and p<0.0001, respectively). Significant correlation was noted between cumulative doses of pergolide and tenting areas of the mitral valves (r=0.412, p=0.017). Mean systolic pulmonary artery pressures were 39.3 mm Hg (range 25-71) in the high-dose group versus 38.5 mm Hg (20-65) in the low-dose group (p=0.76) and 31 mm Hg (25-40) in controls (p=0.02 vs all patients given pergolide). In six patients, pergolide treatment was stopped because of restrictive valvular heart disease, in two of whom regression of disease was shown. INTERPRETATION: Restrictive valvular heart disease is not a rare finding in patients treated with pergolide. Clinicians should consider changing to a non-ergot drug if this disease is diagnosed.

Aged↗

PubMed2000

Effects of qualitative and quantitative food restriction treatments on feeding motivational state and general activity level of growing broiler breeders.

Growing broiler breeder chickens are fed restricted rations to limit body weight at sexual maturity. This experiment tested a proposal (Brouns, F., Edwards, S.A., English, P.R., 1994. Effect of dietary fibre and feeding system on activity and oral behaviour of group housed gilts. Appl. Anim. Behav. Sci. 39, 215-223.) that feeding motivation is reduced by using qualitative rather than quantitative food restriction, and it examined relationships among suppression of growth rate, feeding motivational state and general activity level. From 2 to 15 weeks of age, female broiler breeders were reared in six groups of 20, each with a different feeding treatment. The six treatments were: high and low levels of diet dilution (600-700 g/kg and 300-350 g/kg oat feed, ad libitum), appetite suppression (50-60 g/kg and 25-30 g/kg calcium propionate, ad libitum) and quantitative restriction (recommended daily ration and twice that amount). Birds were conditioned to an operant (PR1 schedule) feeding procedure with their respective treatment diets from 3 to 7 weeks, and this was used to measure feeding motivation in 12-min tests at three times of day (1000, 1300 and 1600 h) at 8, 10, 12 and 14 weeks. Proportions of time spent sitting were measured as an index of general inactivity in systematic observations at 9, 11, 13 and 15 weeks. Although the diet dilution and appetite suppression (qualitative) treatments did not limit growth rates as intended, they and the quantitative treatments produced a range of mean body weights to compare with feeding motivation whenever birds were tested. With body weight as a covariate, there were significant effects on numbers of operant responses in 12 min (the measure of feeding motivation) of weight, age, time of day and treatmentxtime interaction, but not treatment. Feeding motivation was positively correlated with suppression of growth rate, regardless of how that suppression was achieved. However, the experimental procedure required all test birds to be without food from 0900 or 0915 h, and motivation was lowest in the earliest (1000 h) test with qualitative but not quantitative treatments. Hence, there was some evidence that feeding motivation may be partially suppressed with qualitative food restriction; distinction can be made between short-term and longer-term feeding motivation. General activity level (inversely reflected by time spent sitting) was closely correlated positively with both suppression of growth rate and feeding motivation. As a fundamental relationship between feeding motivation and reduction of growth rate was not altered by using qualitative rather than quantitative food restriction, these results support an earlier conclusion (Savory, C.J., Hocking, P.M., Mann, J.S., Maxwell, M.H., 1996. Is broiler breeder welfare improved by using qualitative rather than quantitative food restriction to limit growth rate? Anim. Welfare 5, 105-127.) that broiler breeder welfare is not improved with qualitative restriction methods.

Journal Article↗

PubMedDate not supplied

Effects of moderate caloric restriction on cortical microvascular density and local cerebral blood flow in aged rats.

The present study was designed to assess the impact of moderate caloric restriction (60% of ad libitum fed animals) on cerebral vascular density and local cerebral blood flow. Vascular density was assessed in male Brown-Norway rats from 7-35 months of age using a cranial window technique. Arteriolar density, arteriole-arteriole anastomoses, and venular density decreased with age and these effects were attenuated by moderate caloric restriction. Analysis of local cerebral blood using [14C]iodoantipyrine indicated that basal blood flow decreased with age in CA1, CA3 and dentate gyrus of hippocampus; similar trends were evident in cingulate, retrosplenal, and motor cortex. Basal blood flow was increased in all brain regions of moderate caloric restricted old animals (compared to old ad libitum fed animals) and no differences were observed between ad libitum fed young and caloric restricted older animals. In response to a CO2 challenge to maximally dilate vessels, blood flow increased in young and old ad libitum fed animals, but a similar increase was not observed in caloric restricted old animals. We conclude that a decrease in cerebral vasculature is an important contributing factor in the reduction in blood flow with age. Nevertheless, vessels from young and old animals have the capacity to dilate in response to a CO2 challenge and, after CO2, no differences are observed between the two age-groups. These results are consistent with the hypothesis that aged animals fail to adequately regulate local cerebral blood flow in response to physiological stimuli. Moderate caloric restriction increases microvascular density and cerebral blood flow in aged animals but tissues exhibit little or no increase in blood flow in response to CO2 challenge. The cause of this deficient response may indicate that vessels are maximally dilated in aged calorically restricted animals or that they fail to exhibit normal regulatory control.

Aging↗

PubMed2001

Ectopic expression of serotonin-positive neurons in the hypothalamus associated with a significant serotonin decrease in the midbrain of food restricted rats.

The effects of food restriction on the serotonergic system were investigated immunohistochemically in both the midbrain and hypothalamic regions of rats. Rats were fed on a restricted feeding schedule consisting of half of the ad libitum quantity for 1, 2, 4 and 6 weeks and a free feeding schedule for 1 week. The optical density of serotonin-positive neurons in the raphe nuclei of the midbrain was found to be significantly lower in the 1 week-food restricted group than in the ad libitum fed control. In the hypothalamus, serotonin-positive neurons were observed in the 1 and 2 week food restricted groups but not in the 4 and 6 week-food restricted groups. This finding was confirmed by immunohistochemistry with tryptophan hydroxylase, a serotonin synthesizing enzyme. In this study, we provide morphological evidence that food restriction has a significant effect on the serotonergic system of the midbrain and hypothalamic regions and suggest some possibilities for the ectopic expression of serotonin-positive neurons after food restriction.

Animals↗

PubMed2000

Reduced number of neurons in the hippocampus and the cerebellum in the postnatal guinea-pig following intrauterine growth-restriction.

Intrauterine growth restriction is a risk factor for neurological and behavioural deficits in children although the precise underlying biological correlate for this is unclear. The present study shows that animals with intrauterine growth restriction, induced by a period of reduced placental blood flow during the second half of pregnancy, demonstrate reduced numbers of neurons in the hippocampus and the cerebellum in conjunction with retarded dendritic and axonal growth within these structures. Intrauterine growth restriction was induced at 30 days gestational age by unilateral uterine artery ligation in pregnant guinea-pigs. At one week of age, the total number of CA1 pyramidal neurons in the hippocampus and the Purkinje neurons in the cerebellum were determined using the combined fractionator/optical disector technique. The Cavalieri Principle was used to determine the volume of specific regions within the hippocampus and cerebellum. The body weight of animals that were classified as intrauterine growth-restricted was reduced by 42% (n=8) compared with control animals (n=8, P<0.001), while there was a smaller effect on brain weight (16% reduction, P<0.01). Estimates of the total number of neurons showed a reduction in CA1 pyramidal neurons in growth-restricted animals (4.19+/-0.43x10(5)) compared with control (5.20+/-0.44x10(5), P<0.01), and the volume of the stratum oriens layer above the CA1 region, which contains the apical dendrites of the CA1 pyramidal neurons, was reduced by 21% (P<0.01) in growth-restricted animals. In the cerebellum there was a reduction in the number of Purkinje neurons in growth-restricted animals (3.97+/-0.50x10(5)) compared with control (5.13+/-0.52x10(5), P<0.01), and in the volume of the molecular layer (17%, P<0.05), the internal granular layer (22%, P<0.01) and in the volume of the cerebellar white matter (23%, P<0.01). These results show that a period of placental insufficiency during the second half of pregnancy can effect brain development in a way which could lead to neurological and behavioural deficits in the postnatal animal.

Animals↗

PubMed1997

Effect of feed restriction and season on LH and prolactin secretion, adrenal response, insulin and FFA in group housed pregnant gilts.

A trial was designed to determine the effect of season and feed restriction on LH and prolactin secretion, adrenal response, insulin and FFA in the early pregnant gilt. Groups of cross bred gilts (n = 24) were mated and allocated to two feeding levels; a non-restricted group received close to ad libitum feeding of 3.6 kg whereas, the restricted group received 1.8 kg as recommended by the NRC. The trial was carried out in winter-spring and repeated in summer-autumn to investigate the effects of season. The feeding regimen were fed to the group housed animals for the first two weeks of pregnancy. A 12 h period of blood sampling every 15 min thereafter revealed higher amplitude LH pulses with larger area under the curve in winter compared with summer (1.17 +/- 0.03 vs. 0.69 +/- 0.03 ng ml(-1) and 65.09 +/- 1.46 vs. 33.60 +/- 1.25, P < 0.05). Overall, feed restriction reduced LH pulse frequency (2.5 +/- 0.1 and 1.6 +/- 0.1 pulses/12 h for high and low feeding levels, P < 0.05), but the difference was large in winter and no difference was detected in summer. An ACTH challenge test carried out the day after the frequent sampling revealed greater response to the ACTH challenge in winter in comparison with summer. Plasma prolactin values were generally very low and ranged from 1 to 4.5 ng/ml with highest values detected in the feed restricted group in summer. Plasma FFA and insulin concentrations showed greater pre- versus post-prandial variation in the feed restricted groups. It was concluded, that feed restriction and season affected LH secretion and those effects appeared to be related to the metabolic changes in the early pregnant group housed gilt.

Adrenal Glands↗

PubMed1997

Prognostic implications of restrictive left ventricular filling in acute myocardial infarction: a serial Doppler echocardiographic study.

OBJECTIVES: This study was designed to evaluate the relative prognostic significance of restrictive left ventricular (LV) filling after acute myocardial infarction. BACKGROUND: Data regarding the contribution of diastolic dysfunction to prognosis after myocardial infarction are limited, and the additional value over the assessment of systolic dysfunction is not known. METHODS: Serial Doppler echocardiography was performed in 95 patients on days 1, 3 and 7 and 3 months after acute myocardial infarction. Patients were classified into two groups: a restrictive group (n = 12) with a peak velocity of early diastolic filling wave (E)/peak velocity of late filling wave (A) ratio > or = 2 or between 1 and 2 and a deceleration time (DT) < or = 140 ms during at least one echocardiographic study; and a nonrestrictive group (n = 83) with an E/A ratio < or = 1 or between 1 and 2 and a DT > 140 ms at all examinations. RESULTS: Cardiac death occurred in 10 patients during a mean follow-up interval of 32 +/- 17 months. The survival rate at 1 year was 100% in the nonrestrictive group and only 50% in the restrictive group. After 1 year there was a continuing divergence of mortality, resulting in a 3-year survival rate of 100% and 22%, respectively. Univariate Cox analysis revealed that restrictive LV filling, wall motion score index, ejection fraction and end-systolic and end-diastolic volume indexes, as well as peak creatine kinase, peak MB fraction and heart failure during the hospital course were significant predictors of cardiac death, although restrictive filling was the single best predictor (p < 0.0001). Multivariate analysis showed that restrictive filling adds prognostic information to clinical and echocardiographic variables of systolic dysfunction. CONCLUSIONS: Restrictive LV filling after acute myocardial infarction is the single best predictor of cardiac death and adds significantly to clinical and echocardiographic markers of systolic dysfunction.

Case-Control Studies↗

PubMed2003

Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors.

Many mammalian species express restriction factors that confer host resistance to retroviral infection. Here we show that HIV-1 sensitivity to restriction factors is modulated by cyclophilin A (CypA), a host cell protein that binds the HIV-1 capsid protein (CA). In certain nonhuman primate cells, the CA-CypA interaction is essential for restriction: HIV-1 infectivity is increased >100-fold by cyclosporin A (CsA), a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CypA binding. Conversely, disruption of CA-CypA interaction in human cells reveals that CypA protects HIV-1 from the Ref-1 restriction factor. These findings suggest that HIV-1 has co-opted a host cell protein to counteract restriction factors expressed by human cells and that this adaptation can confer sensitivity to restriction in unnatural hosts. Manipulation of HIV-1 CA recognition by restriction factors promises to advance animal models and new therapeutic strategies for HIV-1 and AIDS.

Amino Acid Sequence↗

PubMed2002

Intrauterine growth restriction reduces nephron number and renal excretory function in newborn piglets.

To examine the effects of intrauterine growth restriction on nephron number, renal circulation, and renal excretory functions in newborns, studies were conducted on 1-day-old anaesthetized piglets, divided into normal weight (n = 6) and intrauterine growth restricted (n = 6) piglets. Renal blood flow was measured by coloured microspheres, glomerular filtration rate was measured by inulin clearance, and osmotic clearance and fractional sodium excretion were calculated. In addition, an estimation of the nephron number was performed by counting representative glomerular numbers in microscopic sections. Newborn intrauterine growth restricted piglets exhibited a reduced glomerular filtration rate and osmotic clearance (P < 0.05), whereas renal blood flow and the filtration fraction as well as fractional sodium excretion were similar in normal weight and intrauterine growth restricted piglets. The nephron number was markedly reduced in intrauterine growth restricted piglets even if the nephron number was related to body weight (P < 0.01). There was a positive correlation between nephron number and glomerular filtration rate (r = 0.69, P < 0.05). Reduced glomerular filtration rate of newborn intrauterine growth restricted piglets is associated with a reduced nephron number. Thus, at birth, compensatory response of renal function due to nephron deficit does not exist in intrauterine growth restricted piglets.

Animals↗

PubMed1999

Short-term leptin infusion does not affect circulating levels of LH, testosterone or cortisol in food-restricted pubertal male rhesus macaques.

OBJECTIVES: Although the adipocyte protein leptin has been implicated in the control of reproductive function in rodents, its role in primate reproductive physiology is poorly understood. Because primates in puberty show nighttime LH secretion and there is considerable evidence that the fertile state requires adequate nutrition, we reasoned that animals on the verge of reproductive competence would respond to leptin infusions by secreting LH. Food restriction reduces circulating leptin levels and slows or stops the GnRH pulse generator. Therefore, we examined the endocrine effects of leptin infusions in food-restricted male pubertal primates during the night when they normally secrete LH. In addition, we investigated the effect of leptin on in vitro testosterone production by Leydig cells. SUBJECTS: Four pubertal male rhesus macaques (Macaca mulatta), 4-5.5 kg in weight (2.5-4-year-old) were examined in this study. Leydig cells from adult male rats were to investigate in vitro effects of leptin. DESIGN: To document that animals had entered puberty, blood samples were collected from each of the four animals at 15-minute intervals for 15 h both during the day and at night. Since at this age animals secrete LH mainly at night, blood samples were collected at 15-minute intervals from each of the four animals on two separate occasions for 15 h between 1500 and 0600h. During the experiment, animals were feeding from 0800 to 0830h, cages were completely cleaned of food at 0900h and the afternoon meal was not given to individual animals on the day they were studied. One of the studies served as the control (food restricted group) and during the other, 2 mg (n = 4) or 0.3 mg (n = 3) of recombinant human leptin was administered intravenously during 2000-0100h (food restricted plus leptin group). Blood samples (1 ml) were collected through the indwelling catheter and immediately transferred from the plastic syringe into chilled glass tubes containing 10 microl 14% EDTA. The samples were centrifuged at 5-h intervals and the plasma withdrawn and stored frozen at - 20 degrees C in polypropylene vials until assays were performed. MEASUREMENTS: Bioactive LH was determined and testosterone, cortisol and leptin were measured by radioimmunoassay. RESULTS: During daytime experiments in these animals, LH pulses were sometimes observed late in the day and generally continued for 12-15 h. Food-restricted pubertal males showed delayed or absent LH pulses. Short-term leptin administration to food-restricted male rhesus macaques had no effect on LH, testosterone, or cortisol levels either during or after the infusion. Leptin also had no direct effect on basal or LH-stimulated testosterone production in Leydig cells. CONCLUSIONS: Our data support the notion that leptin is not the missing signal for the acute suppression of reproductive hormones secretion in food-restricted primates.

Animals↗

PubMed1999

Reduction of luteinzing hormone secretion induced by long-term feed restriction in male rats is associated with increased expression of GABA-synthesizing enzymes without alterations of GnRH gene expression.

In rats, fasting or restriction of feed intake impairs the activity of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator which results in reduced luteinizing hormone (LH) secretion. It is still unknown which neurotransmitters are involved in this phenomenon. However, it is known that increased GABA concentrations in the hypothalamus reduce GnRH biosynthesis and release. Therefore, we examined whether 17 days of feed restriction in male rats affected the hypothalamic gene expression of GnRH and the GABA-synthesizing enzymes glutaminase (GLS) and glutamic acid decarboxylase-which exists in two forms, GAD67 and GAD65-in the mammalian brain. Furthermore, the expression of the GnRH receptor (GnRH-R) and the GABA transporter 1 (GAT-1) were investigated. Feed restriction resulted in a 75% reduction in body weight (b.w.) compared to rats fed ad libitum. Serum concentrations of LH and testosterone in the feed restricted group were significantly reduced to approximately 15% of that of rats fed ad libitum, while the FSH concentration remained unchanged. In the mediobasal hypothalamus (MBH) where GnRH is released into the portal vessels, mRNA levels of GAD67 and GLS were increased twofold compared to rats fed ad libitum while no changes were observed in the preoptic area of the hypothalamus (POA) where GnRH is biosynthesised. Neither the expression of preoptic GnRH mRNA nor the expression of GAD65 and of GnRH-R mRNA in both hypothalamic structures was affected by feed restriction. In the anterior pituitary, a significant reduction of the expression of GnRH-R, LH-beta and the alpha subunit was observed in the feed restricted rats, whereas FSH-beta mRNA levels remained constant. Thus, feed restriction selectively increased the expression of GABA-synthesizing enzymes in the MBH but did not modify GnRH expression in the POA. However, the reduced expression of the LH-beta- and alpha-subunit and of the GnRH-R in the anterior pituitary indicates that pulsatile GnRH release may have been attenuated or even abolished. We suggest, that enhanced expression of GABA-synthesizing enzymes reflects increased GABAergic neurotransmission and thereby reducing GnRH release from the MBH.

Animals↗

PubMed2003

Food restriction during lactation results in prolonged hyposensitivity to the positive-feedback effects of oestradiol.

Food restriction prolongs lactational infertility in rats. Here, we investigated whether an attenuated response to the positive-feedback effects of oestrogen on luteinizing hormone release contributed to this effect. The ability of oestrogen to induce surges in luteinizing hormone in ad libitum fed and food-restricted dams at different times of lactation was compared. The results showed that, on day 20 postpartum, ad libitum fed dams showed luteinizing hormone surges after oestrogen treatment, but food-restricted dams did not. Ovariectomy or RU486 treatment restored the ability of oestrogen to induce luteinizing hormone surges in food-restricted dams, and chronic progesterone exposure reduced oestrogen-induced surges of luteinizing hormone in ad libitum fed ovariectomized dams. Food restriction also resulted in a reduced ability of oestrogen to induce progesterone receptor immunoreactivity, but did not reduce the number of oestrogen receptors (ERalpha) in the anteroventralperiventricular area. As with the surge in luteinizing hormone, the effects of food restriction on oestrogen induction of progesterone receptors were mediated by progesterone. Together, these results suggest that the ability of food restriction to extend the length of lactational diestrus is mediated, in part, by a decrease in sensitivity to the positive-feedback effects of oestrogen. This results from high circulating concentrations of progesterone which apparently reduce the ability of oestrogen to induce progesterone receptor expression.

Animals↗

PubMed1998

Control of expression of LlaI restriction in Lactococcus lactis.

The plasmid encoded LlaI R/M system from Lactococcus lactis ssp. lactis consists of a bidomain methylase, with close evolutionary ties to type IIS methylases, and a trisubunit restriction complex. Both the methylase and restriction subunits are encoded on a polycistronic 6.9 kb operon. In this study, the 5' end of the llal 6.9 kb transcript was determined by primer extension analysis to be 254 bp upstream from the first R/M gene on the operon, llalM. Deletion of this promoter region abolished LlaI restriction in L. lactis. Analysis of the intervening sequence revealed a 72-amino-acid open reading frame, designated llalC, with a conserved ribosome binding site and helix-turn-helix domain. Overexpression of llalC in Escherichia coli with a T7 expression vector produced the predicted protein of 8.2 kDa. Mutation and in trans complementation analyses indicated that C-LlaI positively enhanced LlaI restriction activity in vivo. Northern analysis and transcriptional fusions of the llal promoter to a lacZ reporter gene indicated that C x LlaI did not enhance transcription of the llal operon. Databank searches with the deduced protein sequence for llalC revealed significant homologies to the E. coli Rop regulatory and mRNA stabilizer protein. Investigation of the effect of C x LlaI on enhancement of LlaI restriction in L. lactis revealed that growth at elevated temperatures (40 degrees C) completely abolished any enhancement of restriction activity. These data provide molecular evidence for a mechanism on how the expression of a restriction system in a prokaryote can be drastically reduced during elevated growth temperatures, by a small regulatory protein.

Amino Acid Sequence↗

PubMed1997

Zinc deficiency and energy restriction modify immune responses in mice during both primary and challenge infection with Heligmosomoides polygyrus (Nematoda).

This study characterized the consequences of zinc-sufficient (Zn+, 60 mg zinc/kg diet, ad libitum), zinc-deficient (Zn-075 mg zinc/kg diet, ad libitum) and energy-restricted (ER, 60 mg zinc/kg diet which was restricted to match food intake of Zn- mice) diets on the in vivo and in vitro immune response of BALB/c mice during both primary and challenge infection with Heligmosomoides polygyrus. In Zn+ mice, both primary and challenge infection with H. polygyrus induced not only a strong Th2 response (IgE, IgG1, eosinophilia, IL-4, IL-5, IL-10), but also elements of a TH1 response (IgG3, IFN-gamma). Zinc deficiency significantly depressed Th2-dependent antibody production during both primary and challenge infection, and reduced mitogen and antigen-induced T cell proliferation during the challenge infection. Th2 cytokine production was reduced by zinc deficiency (IL-4), energy restriction (IL-5) and by zinc deficiency possibly in combination with energy restriction (IL-10) during the primary infection whereas TH1 cytokine production (IFN-gamma) was depressed during the challenge infection by zinc deficiency, possibly together with energy restriction. Both zinc deficiency and energy restriction reduced eosinophilia with the more profound effect being exerted by zinc deficiency. Thus, both zinc deficiency and its concurrent energy restriction modify immune responses in the mice during primary and challenge infection with H. polygyrus.

Animal Nutritional Physiological Phenomena↗

PubMed1998

Restricted surgical management of vulvar intraepithelial neoplasia 3: Focus on exclusion of invasion and on relief of symptoms.

van Beurden M, van der Vange N, ten Kate FJW, de Craen AJM, Schilthuis MS, Lammes FB. Restricted surgical management of vulvar intraepithelial neoplasia 3: Focus on exclusion of invasion and on relief of symptoms. Int J Gynecol Cancer 1998; 8: 73-77. A study was undertaken to determine the effectiveness of extensive and restricted surgery for vulvar intraepithelial neoplasia (VIN) 3. All consecutive patients with VIN 3 admitted to a tertiary referral hospital were included. The main outcome measures were relief and recurrence of symptoms and progression to invasive disease in patients with VIN 3 after extensive or restricted surgery. Of every vulvoscopic visible lesion a biopsy was taken to establish extent and grade of VIN and to rule out invasive carcinoma. Patients with unifocal VIN 3 underwent extensive surgery. Patients with multifocal VIN 3 underwent extensive or restricted surgery or an expectant management was adopted, depending on the existence of symptoms and the presence of invasive vulvar carcinoma. Forty-seven patients were evaluated. Eighty-three percent of patients had a long history of symptoms. Eight patients (17%) had unifocal VIN 3. In 9% of the patients a superficially invasive vulvar carcinoma was found, ie with a depth of invasion of 1 mm or less. Only 20% of the extensively operated patients had free surgical margins. There was recurrence of symptoms in all of the extensively operated patients, in contrast to a 26% persistence or recurrence rate of symptoms in the restrictedly operated patients. In patients with multifocal VIN 3 who underwent restricted surgery, young age of the patient (P = 0.02) and large extension of VIN 3 (P = 0.02) were significant factors in predicting persistence or recurrence of symptoms. Only once was a superficially invasive vulvar carcinoma diagnosed during follow-up, and this was in an extensively operated patient. Vulvoscopically directed biopsies in VIN 3 are a safe method to exclude invasive disease. Restricted surgery is effective in relieving symptoms in multifocal VIN 3.

Journal Article↗

PubMed1996

Release of vasoactive agents during cordocentesis: differences between normally grown and growth-restricted fetuses.

OBJECTIVE: The purpose of this study was to evaluate whether cordocentesis is associated with the release of vasoactive substances and whether there are differences between normally grown and growth-restricted fetuses. STUDY DESIGN: 6-Keto-prostaglandin F1 alpha (the stable metabolite of prostacyclin), endothelin-1, and cyclic guanosine monophosphate were measured in fetal blood at the beginning and closing of cordocentesis in 30 normally grown fetuses and 25 growth-restricted fetuses. This latter group was characterized by abnormal Doppler index values in umbilical artery and middle cerebral artery, suggestive of chronic hypoxemia as the causative factor of the impaired growth. In six growth-restricted fetuses bradycardia occurred at the end of the procedure. Umbilical artery pulsatility index was measured by Doppler ultrasonography immediately before and after the procedure. RESULTS: The median interval between the two blood samples obtained by cordocentesis was 90 seconds (range 60 to 320 seconds). During this interval a significant rise of 6-keto-prostaglandin F1 alpha (p < or = 0.0001) and endothelin-1 (p = 0.03) was evidenced in normally grown fetuses. The increase in 6-keto-prostaglandin F1 alpha was significantly related (r = 0.52, p = 0.002) to the fall of umbilical artery pulsatility index occurring after the procedure. In growth-restricted fetuses cordocentesis induced a marked increase of endothelin-1 (p = 0.0002), which was significantly related to the severity of acidosis (r = 0.52, p = 0.018), whereas no modifications were evidenced for the other agents tested. The increase of endothelin-1 was higher in those growth-restricted fetuses showing bradycardia at the end of the procedure than in growth-restricted fetuses that did not (p = 0.04). The variations of the vasoactive substances assayed were not significantly related to the type of procedure (transamniotic or transplacental), the amount of blood aspirated during the procedure, the interval elapsing between the first and second samples, the gestational age at which the procedure was performed, and the degree of fetal smallness. CONCLUSION: Cordocentesis induces the rapid release of vasoactive substances and the effect differs between normally grown and growth-restricted fetuses. This may explain the different hemodynamic response and the higher rate of complications occurring in the latter group after cordocentesis.

6-Ketoprostaglandin F1 alpha↗

PubMed2002

Investigation of intraplacental villous arteries by Doppler flow imaging in growth-restricted fetuses.

OBJECTIVE: The purposes of our study were to assess the ability of color and power Doppler sonography to depict the blood flow in the intraplacental villous arteries and to evaluate whether the blood flow of intraplacental villous arteries in a normal pregnancy is different from that in a pregnancy that is associated with intrauterine growth restriction. STUDY DESIGN: Eighty-five women with uncomplicated pregnancy and 16 women with intrauterine growth-restricted fetuses between 27 and 38 weeks of gestation were examined by color and power Doppler imaging. The blood flow of intraplacental villous arteries was analyzed comparatively. The pulsatility index and peak systolic velocity were measured. RESULTS: A unit of 1 intraplacental villous artery-1 and its branches were seen as 1 cotyledon by color and power Doppler imaging. The cotyledon was easily identified and counted. Each cotyledon contained only 1 intraplacental villous artery-1. This method can visualize the intraplacental villous artery-1 to intraplacental villous artery-4 in normal pregnancies. The terminal villous arteries beyond intraplacental villous artery-4 were not imaged. The number of detectable intraplacental villous artery-1 in 1 placenta in intrauterine growth restriction was significantly lower than that in normal pregnancy. The number of detectable branches in intrauterine growth restriction was also significantly lower than in normal pregnancy. No intraplacental villous artery-4 blood flow was found in women with intrauterine growth restriction. In examined arteries, pulsatility index decreased and peak systolic velocity increased significantly with advancing gestational age (P <.02). At any given gestational age, pulsatility index and peak systolic velocity in the peripheral arteries were significantly lower than those in the upstream arteries in normal pregnancy (P <.001). The pulsatility index value of each intraplacental villous artery was also lower than that of the umbilical artery in the women with intrauterine growth restriction (P <.05). There were no differences in pulsatility index in each artery between the groups, although there were a few high pulsatility index values in intrauterine growth restriction. CONCLUSION: Color Doppler and power flow sonography are valuable tools for the detection of the blood flow of intraplacental villous arteries. The decrease in the number of detectable intraplacental villous artery-1 and branches was associated with intrauterine growth retardation.

Adult↗

PubMed2003

Cell-free fetal DNA in the plasma of pregnant women with severe fetal growth restriction.

OBJECTIVE: Although there have been reports of increased fetal nucleated erythrocytes in the blood of pregnant women who are carrying growth-restricted fetuses, there have been no reports of quantification of fetal DNA concentration in the plasma of women with fetal growth restriction. We quantified fetal DNA concentration in the plasma of pregnant women with preeclampsia and/or fetal growth restriction. STUDY DESIGN: We examined maternal plasma from 9 pregnant women with fetal growth restriction and 9 with preeclampsia and from 20 women who were gestational age-matched normal control subjects. All women carried a male fetus. DNA was extracted from 1.5-mL plasma samples, and the DYS14 and beta-globin gene were analyzed by real-time quantitative polymerase chain reaction. RESULTS: The concentration of fetal DNA was significantly higher in subjects with preeclampsia than in fetal growth restriction subjects and normal control subjects. Fetal DNA concentrations in fetal growth restriction subjects were similar to those of normal control subjects. The concentration of total DNA (beta-globin) was significantly higher in subjects with preeclampsia when compared with healthy control subjects. CONCLUSION: We demonstrated that there was no increase in fetal DNA in the plasma of pregnant women with fetal growth restriction and that most fetal DNA in maternal plasma originates from trophoblasts.

Beta-Globulins↗