Attitudes toward Regulations of Reproductive Care in the European Union: A Comparison between Travellers for Cross-Border Reproductive Care and Citizens of the Local Country.

This paper compares two populations with respect to attitudes toward the regulation of reproductive care by the European Union. The two populations are 252 individuals who crossed a national border to receive treatment at an independent clinic in Spain and 45 Spanish citizens who received treatment in their home country. Online surveys were sent to former patients (from many different countries) of a private Spanish clinic. By comparing those who engaged in cross-border reproductive care (CBRC) with those who did not, we examined attitudes toward whether or not the EU should extend to all clients in all countries the type of services the clinic provided. These services included access to anonymous donors and conception via egg or embryo donation. We found that those who travelled abroad were less in favor of EU expanding regulation for the type of services they received than were those in Spain. This study is unusual in focusing on political attitudes rather than the nature of the experience and consequences of cross-border reproductive care. We suggest that individuals who engage in CBRC might be reluctant to see the EU extend reproductive care broadly because debates within both the EU and their home countries could result in the elimination of options that are now available through travel. We suggest that individuals from countries that are popular destinations for CBRC like Spain might want to extend EU reproductive care more broadly so as to reduce the pressure on the medical services in their own country. We suggest directions for further research.

Acceptance and Disclosure: Comparing genetic symmetry and genetic asymmetry in heterosexual couples between egg recipients and embryo recipients.

This paper explores the attitudes and experiences of 203 women in heterosexual couples who conceived via donated eggs (145) or donated embryos (58) in the last 5 years. Online surveys were sent to former patients (from many different countries) of a private Spanish clinic. By comparing the women in heterosexual couples who relied on donated eggs with those who relied on donated embryos, we examined the meaning of the absence of a genetic tie to a child in the two different situations - that of "genetic symmetry" where neither parent has a genetic tie to that of "genetic asymmetry" where only the mother does not have a genetic tie. No existing study has yet shown whether women who rely on donated eggs and women who rely on donated embryos have similar or different attitudes towards issues surrounding the experience of non-genetic motherhood. Three issues are discussed: (1) attitudes toward the importance of genetic ties and genetic information from the donor before and after the birth of their children, (2) patterns of disclosure, and (3) the relationship between attitudes toward genetic information and disclosure decisions. This study showed that although the two groups of women have many of the same attitudes, including attitudes toward the importance of genes as determinants of outcomes for the child, egg recipients are more likely than embryo recipients to agree that the genetic origins are important to them and that their children have a right to know genetic information. We also found that those who conceived with donated eggs more frequently disclose the nature of their conception to their child than do those who conceived with donated embryos.

Sperm donors describe the experience of contact with their donor-conceived offspring.

This study explores the attitudes and experiences of 57 sperm donors who responded to a survey posted online in the United States and indicated that they had had contact with their donor-conceived offspring or the parents of their donor-conceived offspring. On average, 18 years had elapsed since the respondents donated sperm. In the interim between donating and having contact with offspring, most had become curious about their offspring. Most made contact through a bank or online registry. Most respondents had communicated with at least one offspring at least once and most had exchanged photos with offspring. Approximately two-thirds had met in person once; the same proportion had communicated over email or text. Other forms of communication were less common. Almost half of the respondents now considered their donor-conceived offspring to be like a family member. At the same time, donors are respectful of the integrity of the family in which their offspring were raised. Donors with contact are open to having their partners and children know their donor-conceived offspring. Although contact is generally positive, donors report that establishing boundaries and defining the relationship can be very difficult. Some donors also urge those who are thinking of donating to consider the consequences and some suggest avoiding anonymity. There were no significant differences in attitudes and experiences between those who donated anonymously and those who had been identity-release for their offspring when they turned 18.

Modulation by nutrients and drugs of liver acyl-CoAs analyzed by mass spectrometry.

The profile of liver acyl-CoAs induced by dietary fats of variable compositions or by xenobiotic hypolipidemic amphipathic carboxylates was evaluated in vivo using a novel electrospray ionization tandem mass spectrometry methodology of high resolution, sensitivity, and reliability. The composition of liver fatty acyl-CoAs was found to reflect the composition of dietary fat. Treatment with hypolipidemic carboxylates resulted in liver dominant abundance of their respective acyl-CoAs accompanied by an increase in liver fatty acyl-CoAs. Cellular effects exerted by dietary fatty acids and/or xenobiotic carboxylic drugs may be transduced in vivo by their respective acyl-CoAs.

Suppression of hepatocyte nuclear factor-4alpha by acyl-CoA thioesters of hypolipidemic peroxisome proliferators.

Hepatocyte nuclear factor-4alpha (HNF-4alpha) modulates the expression of liver-specific genes that control the production (e.g. apolipoprotein [apo] A-I and apo B) and clearance (e.g. apo C-III) of plasma lipoproteins. We reported that the CoA thioesters of amphipathic carboxylic hypolipidemic drugs (e.g. clofibric acid analogues currently used for treating hyperlipidemia in humans and substituted long-chain dicarboxylic acids) were formed in vivo, bound to HNF-4alpha, inhibited its transcriptional activity, and suppressed the expression of HNF-4alpha-responsive genes. Hypolipidemic PPARalpha (peroxisome proliferator-activated receptor alpha) activators that were not endogenously thioesterified into their respective acyl-CoAs were shown to be effective in rats but not in humans, implying that the hypolipidemic activity transduced by PPARalpha in rats was PPARalpha-independent in humans. The suppressed acyl-CoA synthase of PPARalpha knockout mice left unresolved the contribution made by the acyl-CoA/HNF-4alpha pathway to the hypolipidemic effect of PPARalpha agonists in rodents. Hence, suppression of HNF-4alpha activity by the CoA thioesters of hypolipidemic "peroxisome proliferators" may account for their hypolipidemic activity independently of PPARalpha activation by their respective free carboxylates. The hypolipidemic activity of peroxisome proliferators is mediated in rats and humans by the PPARalpha and HNF-4alpha pathways, respectively.

Analgesic effect of bupivacaine on extraperitoneal laparoscopic hernia repair.

UNLABELLED: Local anesthetics decrease postoperative pain when placed at the surgical site. Patients benefit from laparoscopic extraperitoneal hernia repair because this allows earlier mobilization than the more classical open surgical approach. The purpose of this study was to determine the pain-sparing efficacy of local anesthetics placed in the preperitoneal fascial plane during extraperitoneal laparoscopic inguinal hernia surgery. Forty-two outpatients were included in a double-blind, randomized, placebo-controlled, institutional review board-approved study. At the conclusion of a standardized general anesthetic, 21 patients received 60 mL of 0.125% bupivacaine into the preperitoneal fascial plane before incisional closure, whereas the other 21 patients received 60 mL of the isotonic sodium chloride solution placebo. Postoperative pain was assessed 1, 4, 8, 24, and 72 h postoperatively. In addition, postoperative fentanyl and outpatient acetaminophen 500 mg/hydrocodone 5 mg requirements were recorded. All hernia repairs were performed by the same surgeon. Appropriate statistical analyses were used. There were no significant differences between the bupivacaine and isotonic sodium chloride solution groups with regard to postoperative pain scores, length of postanesthesia care unit stay, or analgesic requirements. Furthermore, neither unilateral versus bilateral repair nor operative time affected the measured parameters. The addition of 60 mL of 0.125% bupivacaine into the preperitoneal fascial plane during extraperitoneal laparoscopic hernia repair did not significantly alter pain scores, supplementary analgesic requirements, or recovery room length of stay. IMPLICATIONS: The placement of 60 mL of 0.125% bupivacaine into the preperitoneal fascial plane during extraperitoneal laparoscopic hernia repair did not significantly alter pain scores, supplementary analgesic requirements, or recovery room length of stay.

Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha.

Dietary fatty acids specifically modulate the onset and progression of various diseases, including cancer, atherogenesis, hyperlipidaemia, insulin resistances and hypertension, as well as blood coagulability and fibrinolytic defects; their effects depend on their chain length and degree of saturation. Hepatocyte nuclear factor-4alpha (HNF-4alpha) is an orphan transcription factor of the superfamily of nuclear receptors and controls the expression of genes that govern the pathogenesis and course of some of these diseases. Here we show that long-chain fatty acids directly modulate the transcriptional activity of HNF-4alpha by binding as their acyl-CoA thioesters to the ligand-binding domain of HNF-4alpha. This binding may shift the oligomeric-dimeric equilibrium of HNF-4alpha or may modulate the affinity of HNF-4alpha for its cognate promoter element, resulting in either activation or inhibition of HNF-4alpha transcriptional activity as a function of chain length and the degree of saturation of the fatty acyl-CoA ligands. In addition to their roles as substrates to yield energy, as an energy store, or as constituents of membrane phospholipids, dietary fatty acids may affect the course of a disease by modulating the expression of HNF-4alpha-controlled genes.

Peroxisome proliferator-activated receptor (PPAR) alpha activation and its consequences in humans.

Amphipathic carboxylates collectively defined as peroxisome proliferators (PP) induce in rodents a pleiotropic effect, mediated by the peroxisome proliferator-activated receptor alpha (PPAR alpha). Treatment with PP results in rodents in hypolipidemia, peroxisome proliferation and liver hypertrophy and hyperplasia leading to non-genotoxic hepatocarcinogenesis. In contrast to rodents, the hypolipidemic effect exerted by PP in humans is not accompanied by peroxisome proliferation nor by induction of peroxisomal beta-oxidation or other activities induced by PP in rodents. Non-responsiveness in humans may be ascribed to a missing liver component in the PPAR alpha transduction pathway specifically involved with transcriptional modulation of chromosomal PPAR alpha responsive genes. Hence, biological effects exerted by PP in the human liver are likely to be mediated by a transduction pathway independent of PPAR alpha.

The "three-in-one block" for treatment of pain in a patient with acute herpes zoster infection.

BACKGROUND AND OBJECTIVES: Herpes zoster infection in elderly patients frequently results in disabling pain, carries a high risk of postherpetic neuralgia (PHN), and can pose a significant therapeutic challenge. METHODS: We describe a successful use of the perivascular technique of lumbar plexus blockade ("three-in-one block") for treatment of pain during acute herpes zoster infection in an 82-year-old severely ill patient in whom other modalities were contraindicated. RESULTS: Three-in-one block using 40 mL of 0.25% bupivacaine with 1:300,000 epinephrine resulted in excellent pain relief that lasted for 2 weeks. CONCLUSIONS: The perivascular technique of lumbar plexus blockade may be a useful alternative to epidural and paravertebral techniques of lumbar blockade in the occasional patient for whom these other approaches are contraindicated.

Thyromimetic mode of action of peroxisome proliferators: activation of 'malic' enzyme gene transcription.

Peroxisome proliferators induce thyroid-hormone-dependent liver activities, e.g. 'malic' enzyme, mitochondrial glycerol-3-phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, S14[Hertz, Aurbach, Hashimoto and Bar-Tana (1991) Biochem. J. 274, 745-751]. Here we report that the thyromimetic effect of peroxisome proliferators with respect to 'malic' enzyme result from transcriptional activation of the 'malic' enzyme gene, mediated by binding of the peroxisome proliferator activated receptor (PPAR alpha)/retinoid X receptor (RXR alpha) heterodimer to a 5'-flanking enhancer of the 'malic' enzyme promoter. The enhancer involved is distinct from the thyroid hormone response element of the 'malic' enzyme promoter and is partly homologous with that which mediates transcriptional activation of peroxisomal acyl-CoA oxidase by peroxisome proliferators. Hence transcriptional activation of thyroid-hormone-dependent liver genes by xenobiotic or endogenous amphipathic carboxylates collectively defined as peroxisome proliferators is mediated by a transduction pathway similar to that involved in transcriptional activation of peroxisomal beta-oxidative genes and distinct from that which mediates thyroid hormone action.

Transcriptional suppression of the transferrin gene by hypolipidemic peroxisome proliferators.

Activation of gene expression by hypolipidemic peroxisome proliferators (e.g. native and substituted long chain fatty acids, aryloxyalkanoic fibrate drugs) is accompanied by transcriptional suppression of liver transferrin gene in treated animals or human hepatoma cell line. Transcriptional suppression of liver transferrin by hypolipidemic peroxisome proliferators results from (a) displacement of hepatic nuclear factor (HNF)-4 from the transferrin promoter by nonproductive binding of the peroxisome proliferator-activated receptor-retinoic acid X receptor heterodimer to the (-76/-52) PRI promoter element of the human transferrin gene and (b) suppression of liver HNF-4 gene expression by hypolipidemic peroxisome proliferators with a concomitant decrease in its availability for binding to the transferrin PRI promoter element. HNF-4 gene suppression and its displacement from the transferrin promoter result in eliminating HNF-4-enhanced transcription of transferrin. Liver transferrin suppression by hypolipidemic peroxisome proliferators may result in reduced iron availability as well as modulation of transferrin-induced differentiation processes. Transcriptional suppression of HNF-4-enhanced liver genes (e.g. apolipoprotein C-III, transferrin) may complement the pleiotropic biological effect exerted by hypolipidemic peroxisome proliferators.

Activation of gene transcription by prostacyclin analogues is mediated by the peroxisome-proliferators-activated receptor (PPAR).

Xenobiotic amphipathic carboxylates, known collectively as hypolipidemic peroxisome proliferators (e.g., aryloxyalkanoic acids), or native long-chain fatty acids induce liver peroxisome proliferation and other biological activities. This broad spectrum of effects results from modulation of transcription of specific genes mediated by binding of peroxisome-proliferators-activated receptors (PPAR) to respective sequence-specific promoter elements (PPRE). The broad specificity and relatively low potency of reported hypolipidemic peroxisome proliferators prompted us to search for specific highly potent peroxisome proliferators. Here we report that stable prostacyclin analogues may act in such a manner. mPPAR alpha-mediated expression of a reporter gene linked to the peroxisomal rat acyl-CoA oxidase promoter was dose-dependently induced by carbaprostacyclin and iloprost. The ED50 for carbaprostacyclin was 25 nM, and carbaprostacyclin was therefore 25-fold and 200-fold more effective than the most potent xenobiotic (5,18,11,14-eicosatetraynoic acid) and native (arachidonic acid) inducers, respectively. Induction was further increased by cotransfecting the cells with mPPAR alpha and an expression vector for retinoic acid-X-receptor. PPAR-mediated activation of gene expression by prostacyclin analogues was specific for PPAR and was not observed using other members of the superfamily. No activation of gene expression was induced by other prostaglandins or leukotrienes at concentrations 100-fold higher than those of the prostacyclin analogues. Induction of gene expression by prostacyclin analogues was inhibited in cells transfected with the long-chain-acyl-CoA synthase, indicating that the acidic form of prostacyclin, rather than the respective CoA derivative or a metabolite derived thereof, serves as the activator of the PPAR/PPRE transduction pathway. Hence, PPAR-mediated modulation of gene transcription by prostacyclins may form the basis for their novel role as regulators of gene expression. Xenobiotic hypolipidemic peroxisome proliferators and native long-chain fatty acids seem to exploit the PPAR/PPRE transduction pathway used by prostacyclin.

Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III.

The hypolipidemic effect exerted by beta,beta'-tetramethyl-hexadecanedioic acid (Medica 16) is accounted for by enhanced catabolism of plasma triglyceride-rich lipoproteins due to a decrease in plasma apolipoprotein C-III (Frenkel, B., Mayorek, N., Hertz, R., and Bar-Tana, J. (1988) J. Biol. Chem. 263, 8491-8497; Frenkel, B., Bishara-Shieban, J., and Bar-Tana, J. (1994) Biochem. J. 298, 409-414). Decrease in apolipoprotein C-III exerted by peroxisome proliferators/hypolipidemic amphipathic carboxylates (e.g. Medica 16, fibrate drugs) is shown here to result from suppression of apolipoprotein C-III gene expression. Transcriptional suppression of apolipoprotein C-III is due to transcriptional suppression of hepatic nuclear factor (HNF)-4 as well as displacement of HNF-4 from the apolipoprotein C-III promoter. HNF-4 displacement exerted by peroxisome proliferators/hypolipidemic amphipathic carboxylates is mediated by the peroxisome proliferators activated receptor (PPAR). Transcriptional suppression of HNF-4-enhanced genes (e.g. apolipoprotein C-III) along with transcriptional activation of peroxisomal and other genes by hypolipidemic drugs may account for their broad spectrum pharmacological effect.

Treatment of vulvar vestibulitis syndrome with electromyographic biofeedback of pelvic floor musculature.

Thirty-three women diagnosed as suffering from vulvar vestibulitis syndrome, marked by a significant history of long-term moderate to severe chronic introital dyspareunia and tenderness of the vulvar vestibule, were selected for treatment. Patients were given a computerized electromyographic evaluation of the pelvic floor muscles and were then provided with portable electromyographic biofeedback instrumentation and instructions on the conduct of daily, at-home, biofeedback-assisted pelvic floor muscle rehabilitation exercises. They received intermittent evaluations of pelvic floor muscles to ensure compliance and monitor their progress and symptom changes. The results show that after an average of 16 weeks of practice, pelvic floor muscle contractions increased 95.4%, resting tension levels decreased 68%, and the instability of the muscle at rest decreased by 62%. Subjective reports of pain decreased an average of 83%. Twenty-eight patients had abstained from intercourse for an average of 13 months. Twenty-two of these 28 patients resumed intercourse by the end of the treatment period. Six month follow-up indicated maintenance of therapeutic benefits.

Rigorous management of insulin-dependent diabetes mellitus during pregnancy.

The effect of rigorous management of insulin-dependent diabetes mellitus (IDDM) during pregnancy on the perinatal outcome was assessed by comparing 78 prepartum gravid patients with IDDM managed prospectively with 78 matched controls. The diabetic women were treated with insulin by either infusion pump or split-dose therapy, with the goal of normalization of the fasting blood sugars and hemoglobin Hb A1c values. Differences in the perinatal outcome were evaluated by either chi-square or analysis of variance. Of the women with IDDM, 14% where White class B, 43% class C, 26% class D, 17% classes R and F. The mean Hb A1c value in the first half of pregnancy was 8.49% +/- 2.30%, and 7.34% +/- 1.79% in the second half. Women with IDDM had higher rates of premature delivery (31% vs. 10%, P = 0.003), pre-eclampsia (15% vs. 5%, P = 0.035), and cesarean section (55% vs. 27%, P = 0.002). Complications of infants born to diabetic mothers included large size for gestational age (41% vs. 16%, P = 0.0002), hypoglycemia (14% vs. 1%, P = 0.0025), hyperbilirubinemia (46% vs. 23%, P = 0.0002), and respiratory distress (12% vs. 1%, P = 0.008). The Apgar scores and mortality were similar. Congenital malformations occurred in 7.7% of infants of diabetic mothers and 1.3% of controls (P = 0.05). The maternal Hb A1c level did not correlate with the infant size for gestation. Although the improved medical management of IDDM has decreased neonatal mortality, significant perinatal complications persist.

Transcriptional activation by amphipathic carboxylic peroxisomal proliferators is induced by the free acid rather than the acyl-CoA derivative.

Most peroxisomal proliferators consist of a carboxylic group attached to a hydrophobic backbone yielding an amphipathic carboxylate molecule. The respective CoA derivatives of peroxisomal proliferators, formed by ATP-dependent CoA thioesterification catalyzed by long-chain-acyl-CoA synthase, have been repeatedly considered as the immediate inducers of peroxisome and other genes. In this study, the putative requirement for prior CoA thioesterification of peroxisomal proliferators was evaluated by analyzing the induced expression of a reporter plasmid promoted by the peroxisomal acyl-CoA-oxidase promoter in cells transiently cotransfected with expression vectors for the peroxisome-proliferator-activated receptor and the long-chain-acyl-CoA synthase. Transcriptional activation of peroxisomal acyl-CoA oxidase by peroxisomal proliferators was inhibited in the presence of transfected functional acyl-CoA synthase. The inhibitory effect was negatively correlated with the capacity of the acyl-CoA synthase to catalyze CoA thioesterification of the respective proliferator. Hence, the immediate inducer is the peroxisomal proliferator free acid rather than the respective CoA derivative or a metabolite derived from the peroxisomal-proliferator-CoA intermediate.

Risk of developing life-threatening ventricular arrhythmia associated with tefenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine.

An observational, historical cohort evaluation was performed to examine the hypothesis that terfenadine (Seldane) exposure increases the risk of developing life-threatening ventricular arrhythmias. The study population consisted of Medicaid recipients from 4 states that were included in the Computerized On-Line Medical Pharmaceutical Analysis and Surveillance System (COMPASS). The drug exposure period was defined prospectively as 30 days in all treatment cohorts. The primary end point was the development of life-threatening ventricular arrhythmias (ventricular tachycardia, fibrillation and flutter, and cardiac arrest and sudden death). The comparison cohorts included terfenadine (n = 181,672), over-the-counter antihistamines (n = 150,689), ibuprofen (n = 181,672) and clemastine (Tavist; n = 83,156). Over the exposure period, a total of 317 life-threatening ventricular arrhythmic events occurred, 244 of which were cardiac arrests. The incidence of total life-threatening ventricular arrhythmic events and cardiac arrests were more frequent in patients receiving over-the-counter antihistamines (relative risk 0.36) than in those receiving terfenadine, a finding that was consistent across all subgroups. There was no increased risk of life-threatening ventricular arrhythmias in the terfenadine cohort as compared with the ibuprofen cohort (relative risk 0.62), and in some analyses, the ibuprofen cohort had a significantly higher arrhythmic event rate. In all comparisons with the clemastine cohort, the terfenadine cohort had a statistically indistinguishable relative risk (1.08). Age, race, sex and cardiovascular risk were all considered in the adjusted relative-risk analyses. No baseline historical characteristic or imbalance of baseline medications explained the differences between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyromimetic effect of peroxisome proliferators.

Xenobiotic amphipathic carboxylates of varying hydrophobic backbones, known collectively as 'peroxisome proliferators' (PP), affect lipoprotein metabolism, calorigenesis, liver redox and phosphate potentials and adipose conversion. Some biological effects exerted by PP are strikingly similar to those exerted by thyroid hormones (TH). Furthermore, similarly to TH, these compounds have been recently found to induce in euthyroid as well as thyroidectomized rats or in rat hepatocytes cultured in TH-free media, liver activities classically considered as TH-dependent, eg malic enzyme (ME) and S14. The thyromimetic effect of PP could be accounted for by transcriptional activation of TH-dependent genes as verified by run-on transcription assays. The thyromimetic effect of PP was found not to be mediated by the TH nuclear receptor. Moreover, in contrast to TH, PP were ineffective as thyromimetic agents in the rat heart or pituitary cells, suggesting a tissue specificity different from that of TH. The overall thyromimetic effect of PP appears to involve transcriptional activation of TH-dependent genes, yet being mediated by a novel transduction pathway.