Post-traumatic stress disorder in parturients delivering by caesarean section and the implication of anaesthesia: a prospective cohort study.

BACKGROUND: Post-traumatic stress disorder (PTSD) occurs in 1-7% of women following childbirth. While having a caesarean section (C-section) is known to be a significant risk factor for postpartum PTSD, it is currently unknown whether coexisting anaesthesia-related factors are also associated to the disorder. The aim of this study was to assess anaesthesia-linked factors in the development of acute postpartum PTSD. METHODS: We performed a prospective cohort study on women having a C-section in a tertiary hospital in Switzerland. Patients were followed up six weeks postpartum. Patient and procedure characteristics, past morbidity or traumatic events, psychosocial status and stressful perinatal events were measured. Outcome was divided into two categories: full PTSD disease and PTSD profile. This was based on the number of DSM-IV criteria of the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) present. The PTSD Checklist Scale and the Clinician Administered PTSD Scale were used for measurement. RESULTS: Of the 280 patients included, 217 (77.5%) answered the questionnaires and 175 (62.5%) answered to an additional phone interview. Twenty (9.2%) had a PTSD profile and six (2.7%) a PTSD. When a full predictive model of risk factors for PTSD profile was built using logistic regression, maternal prepartum and intrapartum complications, anaesthetic complications and dissociative experiences during C-section were found to be the significant predictors for PTSD profile. CONCLUSION: This is the first study to show in parturients having a C-section that an anaesthesia complication is an independent risk factor for postpartum PTSD and PTSD profile development, in addition to known perinatal and maternal risk factors.

Cerclage sling technique using temporalis muscle fascia to manage paralytic lagophthalmos: A preliminary study.

PURPOSE: Despite various existing surgical techniques, treatment of facial nerve palsy remains difficult. The purpose of this report is to present the cerclage sling technique using temporalis fascia to manage paralytic lagophthalmos. METHODS: A series of six patients underwent a cerclage sling technique using temporalis muscle fascia to treat paralytic lagophthalmos. The technique is presented in detail. Symptoms, palpebral fissures, and lagophthalmos were assessed pre- and postoperatively. Data were submitted for statistical analysis. RESULTS: After surgery, all patients achieved a reduction in clinical symptoms. The upper eyelids had lowered, and the inferior eyelids had elevated, reducing ocular exposure even if mild residual lagophthalmos was present. CONCLUSION: Cerclage using the temporalis muscle fascia sling technique is a safe and effective procedure to treat facial nerve paralytic lagophthalmos. A reduction in ocular exposure and lagophthalmos provides improvement in clinical symptoms and eyelid function.

Effects of the neonatal intensive care environment on circadian health and development of preterm infants.

The circadian system in mammals ensures adaptation to the light-dark cycle on Earth and imposes 24-h rhythmicity on metabolic, physiological and behavioral processes. The central circadian pacemaker is located in the brain and is entrained by environmental signals called Zeitgebers. From here, neural, humoral and systemic signals drive rhythms in peripheral clocks in nearly every mammalian tissue. During pregnancy, disruption of the complex interplay between the mother's rhythmic signals and the fetal developing circadian system can lead to long-term health consequences in the offspring. When an infant is born very preterm, it loses the temporal signals received from the mother prematurely and becomes totally dependent on 24/7 care in the Neonatal Intensive Care Unit (NICU), where day/night rhythmicity is usually blurred. In this literature review, we provide an overview of the fetal and neonatal development of the circadian system, and short-term consequences of disruption of this process as occurs in the NICU environment. Moreover, we provide a theoretical and molecular framework of how this disruption could lead to later-life disease. Finally, we discuss studies that aim to improve health outcomes after preterm birth by studying the effects of enhancing rhythmicity in light and noise exposure.

DNA repair in mammalian cells: Direct DNA damage reversal: elegant solutions for nasty problems.

The genomic integrity of all living organisms is constantly jeopardized by physical [e.g. ultraviolet (UV) light, ionizing radiation] and chemical (e.g. environmental pollutants, endogenously produced reactive metabolites) agents that damage the DNA. To overcome the deleterious effects of DNA lesions, nature evolved a number of complex multi-protein repair processes with broad, partially overlapping substrate specificity. In marked contrast, cells may use very simple repair systems, referred to as direct DNA damage reversal, that rely on a single protein, remove lesions in a basically error-free manner, show high substrate specificity, and do not involve incision of the sugar-phosphate backbone or base excision. This concise review deals with two types of direct DNA damage reversal: (i) the repair of alkylating damage by alkyltransferases and dioxygenases, and (ii) the repair of UV-induced damage by spore photoproduct lyases and photolyases. (Part of a Multi-author Review).

Interacting molecular loops in the mammalian circadian clock.

We show that, in the mouse, the core mechanism for the master circadian clock consists of interacting positive and negative transcription and translation feedback loops. Analysis of Clock/Clock mutant mice, homozygous Period2(Brdm1) mutants, and Cryptochrome-deficient mice reveals substantially altered Bmal1 rhythms, consistent with a dominant role of PERIOD2 in the positive regulation of the Bmal1 loop. In vitro analysis of CRYPTOCHROME inhibition of CLOCK: BMAL1-mediated transcription shows that the inhibition is through direct protein:protein interactions, independent of the PERIOD and TIMELESS proteins. PERIOD2 is a positive regulator of the Bmal1 loop, and CRYPTOCHROMES are the negative regulators of the Period and Cryptochrome cycles.

Does implicit memory during anaesthesia persist in children?

BACKGROUND: Recent studies suggest that implicit memory (especially perceptual implicit memory) persists during adequate general anaesthesia in adults. Studies in children, however, have failed to demonstrate implicit memory during general anaesthesia, possibly because of differences in methodological design. We therefore designed a prospective study with the aim of evaluating implicit memory in children undergoing general anaesthesia, using a perceptual memory test based on the mere exposure effect, previously tested in a control group. METHODS: Twelve infrequent neutral words were played 12 times in a random sequence via headphones to 36 children aged 8-12 yr during elective or emergency surgery. The children were not premedicated, and general anaesthesia was maintained with isoflurane. The word presentation started immediately after the surgical incision. Within 36 h after the stimulus presentation, the memory was assessed by using a forced-choice preference judgement task. Time constraint and word deterioration with a low-pass filter were used to prevent the subjects from utilizing intentional retrieval. The implicit memory score was obtained by calculating the proportion of target words preferred, which was compared with the chance level (0.5). RESULTS: The percentage of correct responses given by the children was comparable with the chance level. The memory score was mean (sd) 0.48 (0.16) (95% CI 0.43-0.53). CONCLUSIONS: The use of a perceptual implicit memory test based on the mere exposure procedure in children failed to reveal any evidence of implicit memory under general anaesthesia.

Naloxone-responsive acute dystonia and parkinsonism following general anaesthesia.

Various movement disorders such as dystonia may acutely develop during or at emergence from general anaesthesia in patients with or without pre-existing Parkinson disease. These movements are triggered by a variety of drugs including propofol, sevoflurane, anti-emetics, antipsychotics and opioids. The postulated mechanism involves an imbalance between dopaminergic and cholinergic neurotransmitters in the basal ganglia. We report an acute, severe and generalised dystonic reaction in an otherwise healthy woman at emergence from general anaesthesia, dramatically reversed by the administration of naloxone, pointing to a potential role of the fentanyl and morphine that the patient had received. Recent literature on the mechanisms of abnormal movements induced by opioids are discussed. The severity of the reaction with usual doses of opioids, in a patient with no prior history of parkinsonism, led to further investigation that demonstrated the possibility of an enhanced susceptibility to opioids, involving a genetically determined abnormal function of glycoproteine-P and catechol-O-methyltransferase.

Intra-operative awareness in children and post-traumatic stress disorder.

Adults who experience intra-operative awareness can develop disturbing long-lasting after-effects, such as daytime anxiety, sleep disturbances, nightmares, flashbacks and, in the worst case, a post-traumatic stress disorder (PTSD). It is unknown whether intra-operative awareness has a similar psychological impact in children. We designed the present study in order to evaluate the incidence of psychological symptoms in children who had either confirmed or possible intra-operative awareness. Attempts were made to locate 11 children who had been identified in a previous study, approximately 1 year following their experience. A PTSD questionnaire was administered to the children and their parents in order to detect any long-term or short-term psychological symptoms (the 1-month postoperative data were evaluated retrospectively). Factors believed to be associated with PTSD, such as intra-operative perceptions, the children's temperament and cognitive strategies, and the parents' coping strategies, were also analysed. Seven children were successfully located and interviewed and no short or long-term psychological symptoms were identified. None of them offered negative appraisals of the traumatic event and none had displayed dysfunctional behaviour or cognitive strategies. Thus, none of them had developed a PTSD syndrome. In contrast with what has been reported in adults, these children claimed not to have experienced major pain, terror or helplessness during their surgery. Despite the small sample size, the results of the present study suggest that children suffer less psychological sequelae than adults following intra-operative awareness. This may be due to the fact that the children reported less frightening intra-operative sensations as compared with the adults, and had less understanding of the anaesthesia procedure, and this may have influenced their appraisal of their awareness and protected them from the full impact of this potentially traumatic experience.

Early- and late-onset preeclampsia and the DNA methylation of circadian clock and clock-controlled genes in placental and newborn tissues.

The placenta is important in providing a healthy environment for the fetus and plays a central role in the pathophysiology of preeclampsia (PE). Fetal and placental developments are influenced by epigenetic programming. There is some evidence that PE is controlled to an altered circadian homeostasis. In a nested case-control study embedded in the Rotterdam Periconceptional Cohort, we obtained placental tissue, umbilical cord leukocytes (UCL), and human umbilical venous endothelial cells of 13 early-onset PE, 16 late-onset PE and 83 controls comprising 36 uncomplicated and 47 complicated pregnancies, i.e. 27 fetal growth restricted and 20 spontaneous preterm birth. To investigate the associations between PE and the epigenetics of circadian clock and clock-controlled genes in placental and newborn tissues, genome-wide DNA methylation analysis was performed using the Illumina HumanMethylation450K BeadChip and a candidate-gene approach using ANCOVA was applied on 939 CpGs of 39 circadian clock and clock-controlled genes. DNA methylation significantly differed in early-onset PE compared with spontaneous preterm birth at 6 CpGs in placental tissue (3.73E-5 ≤ p ≤ 0.016) and at 21 CpGs in UCL (1.09E-5≤ p ≤ 0.024). In early-onset PE compared with fetal growth restriction 2 CpGs in placental tissue (p < 0.05) and 8 CpGs in uncomplicated controls (4.78E-5≤ p ≤ 0.049) were significantly different. Moreover, significantly different DNA methylation in early-onset PE compared with uncomplicated controls was shown at 6 CpGs in placental tissue (1.36E-4≤ p ≤ 0.045) and 11 CpGs in uncomplicated controls (2.52E-6≤ p ≤ 0.009). No significant associations were shown with late-onset PE between study groups or tissues. The most differentially methylated CpGs showed hypomethylation in placental tissue and hypermethylation in uncomplicated controls. In conclusion, DNA methylation of circadian clock and clock-controlled genes demonstrated most differences in UCL of early-onset PE compared with spontaneous preterm birth. Implications of the tissue-specific variations in epigenetic programming for circadian performance and long-term health need further investigation.

Base J originally found in kinetoplastida is also a minor constituent of nuclear DNA of Euglena gracilis.

We have analyzed DNA of EUGLENA: gracilis for the presence of the unusual minor base beta-D-glucosyl-hydroxymethyluracil or J, thus far only found in kinetoplastid flagellates and in DIPLONEMA: Using antibodies specific for J and post-labeling of DNA digests followed by two-dimensional thin-layer chromatography of labeled nucleotides, we show that approximately 0.2 mole percent of EUGLENA: DNA consists of J, an amount similar to that found in DNA of Trypanosoma brucei. By staining permeabilized EUGLENA: cells with anti-J antibodies, we show that J is rather uniformly distributed in the EUGLENA: nucleus, and does not co-localize to a substantial extent with (GGGTTA)(n) repeats, the putative telomeric repeats of EUGLENA: Hence, most of J in EUGLENA: appears to be non-telomeric. Our results add to the existing evidence for a close phylogenetic relation between kinetoplastids and euglenids.

Selection for activation of a new variant surface glycoprotein gene expression site in Trypanosoma brucei can result in deletion of the old one.

The African trypanosome Trypanosoma brucei expresses the active variant surface glycoprotein (VSG) gene in a telomeric VSG gene expression site. We have generated trypanosomes with a neomycin resistance gene inserted behind an active VSG gene expression site promoter, and a hygromycin resistance gene behind a silent one. By alternating drug selection, we could select for trypanosomes that had switched between the two marked VSG gene expression sites. Surprisingly, trypanosomes that had activated a new VSG gene expression site had often lost the old one. Using polymerase chain reaction (PCR), we screened large numbers of switched trypanosomes and found that sequences lost invariably included the drug marker near the promoter, as well as the telomeric VSG gene many tens of kilobases away. We postulate that stable activation of a new expression site requires silencing of the old one. If silencing does not occur at a sufficient rate by normal switch-off, stable activation of the new site can only occur if the old site is lost in random deletion events. The fact that we pick up these normally infrequent deletions, indicates that inactivation of the old VSG expression site could be rate limiting during switching in our strain of T. brucei.

Control of VSG gene expression sites in Trypanosoma brucei.

Antigenic variation in African trypanosomes continues to be one of the most elaborate and intriguing strategies ever devised by a protozoan parasite to avoid complete destruction by the immune defense of its mammalian host. Here we review some of the recent advances in our understanding of this strategy, concentrating on (unpublished) work from our laboratory.

A case-control study of risk factors for breast cancer in Brazil, 1978-1987.

BACKGROUND: There are still controversies regarding the role of many risk factors assessed for breast cancer worldwide. In Brazil, it represents a major cause of death among women but yet few analytical studies have been published to date. METHODS: The association of selected factors with breast cancer was assessed in a case-control study of 300 women, aged 25-75 years, treated at the Federal University Hospital, Belo Horizonte, Brazil, from 1978 to 1987. In all, 300 cases with diagnosed breast carcinoma were compared with 600 controls matched on age and date of diagnosis. Socio-economic, demographic and reproductive factors were analysed. RESULTS: Multiple logistic regression analysis showed the following factors to be independently associated with increased risk of breast cancer: a) monthly family income (odds ratio [OR] = 1.69, 95% confidence interval [CI]: 1.18-2.42); b) being a housewife (OR = 2.86, 95% CI: 1.83-4.47; c) parity of less than six deliveries and nulliparous women (OR = 5.06, 95% CI: 3.01-8.52 and OR = 2.42, CI: 1.64-3.59, respectively); d) history of breast cancer among first degree female relatives (OR = 9.35, 95% CI: 3.22-27.14); and e) oral contraceptive use (OR = 1.81, 95% CI: 1.15-2.85). Irregular menstrual cycle (OR = 0.44, 95% CI: 0.25-0.75) was associated with breast cancer as a protective effect. CONCLUSIONS: The study has confirmed most risk/protective factors previously demonstrated elsewhere in the world and provides clear documentation of breast cancer epidemiology in Brazil.

Structure function analysis of mammalian cryptochromes.

Members of the photolyase/cryptochrome family are flavoproteins that share an extraordinary conserved core structure (photolyase homology region, PHR), but the presence of a carboxy-terminal extension is limited to the cryptochromes. Photolyases are DNA-repair enzymes that remove UV-light-induced lesions. Cryptochromes of plants and Drosophila act as circadian photoreceptors, involved in light entrainment of the biological clock. Using knockout mouse models, mammalian cryptochromes (mCRY1 and mCRY2) were identified as essential components of the clock machinery. Within the mammalian transcription-translation feedback loop generating rhythmic gene expression, mCRYs potently inhibit the transcription activity of the CLOCK/BMAL1 heterodimer and protect mPER2 from 26S-protesome-mediated degradation. By analyzing a set of mutant mCRY1 proteins and photolyase/mCRY1 chimeric proteins, we found that the carboxyl terminus has a determinant role in mCRY1 function by harboring distinguished domains involved in nuclear import and interactions with other clock proteins. Moreover, the carboxyl terminus must cross-talk with the PHR to establish full transcription repression capacity in mCRY1. We propose that the presence of the carboxyl terminus in cryptochromes, which varies in sequence composition among mammalian, Drosophila, and plant CRYs, is critical for their different functions and possibly contributed to shape the different architecture and biochemistry of the clock machineries in these organisms.

Intra-operative awareness in children: the value of an interview adapted to their cognitive abilities.

Intra-operative awareness in paediatric patients has been little studied for many years because of the difficulties in relying on children's testimony. Earlier questionnaires used to detect this complication were not adapted to children's language and memory capacities. By using a qualitative method, a semi-structured in-depth interview adapted to their cognitive abilities, we have now conducted a prospective evaluation of the incidence and risk factors for intra-operative awareness in children undergoing general anaesthesia. Data were obtained from interviews with 410 children (aged 6-16 years) which were conducted within 36 h of general anaesthesia for elective or emergency surgery. One month after surgery, 293 of these patients were interviewed again. Three independent adjudicators classified each potential case of awareness. We considered awareness to include both the 'confirmed awareness' and the 'possible awareness' cases. The accuracy of the children's recall was calculated. The relationship between their awareness and the anaesthesia management was examined. There were five cases of confirmed awareness, and six cases of possible awareness. The incidence of confirmed awareness was 1.2%, but when the possible cases were also considered, the overall incidence of this complication was as high as 2.7% (95% confidence interval, 1.4-5.0%). The only predictive factor identified was the multiple manoeuvres with which the airways were secured (odds ratio, 8.4; 95% confidence interval, 2.4-29.07%). The present study confirms the existence of intra-operative awareness in the paediatric population. The application of a semi-structured in-depth interview adapted to the cognitive capacities of the children appears to enhance the detection of awareness in this population.

Immune adaptive response induced by Bicotylophora trachinoti (Monogenea: Diclidophoridae) infestation in pompano Trachinotus marginatus (Perciformes: Carangidae).

Fish have developed protective strategies against monogeneans through immunological responses. In this study, immune adaptive response to parasites was analysed in the pompano Trachinotus marginatus infested by Bicotylophora trachinoti. Hosts were pre-treated with formalin and after 10 days assigned to one of the following experimental treatments: (1) fish infested with remaining eggs of B. trachinoti; (2) fish infested with remaining eggs of B. trachinoti and experimentally re-infested by exposure to T. marginatus heavily infested with B. trachinoti. Samples were collected at 0, 15, and 30 days. Gills were dissected to check the presence of B. trachinoti. Blood was collected for haematological and biochemical assays. Spleen and head-kidney were dissected for phagocytosis assay. The spleen-somatic index was also calculated. Re-infested fish showed a faster and higher parasite infestation than infested ones. The parasite mean abundance at 15 days was 24.86+/-13.32 and 11.67+/-8.57 for re-infested and infested fish, respectively. In both groups, hosts showed an immune adaptive response to parasite infestation that was marked by an increased number of leukocytes. Also, phagocytosis (%) in spleen and head-kidney cells was stimulated after parasite infestation (92.50+/-3.73 and 66.00+/-9.54, respectively), becoming later depressed (77.39+/-6.69 and 53.23+/-9.14, respectively). These results support the hypothesis that monogenean infestation induces a biphasic response of the non-specific defence mechanisms in the pompano T. marginatus. This response is marked by an initial stimulation followed by a later depression of the non-specific defence mechanisms.

Chronic asthma and rhinitis due to Candida albicans, epidermophyton, and trichophyton.

Asthma and rhinitis due to Candida albicans is well known. Trichophyton and Epidermophyton are not usually considered as causal agents for these diseases. During the years 1982 and 1983 all of the cases of chronic asthma or rhinitis exhibiting a positive immediate skin response (greater than or equal to 10 mm) to one of these three antigens were selected for this study (60 asthma and 75 rhinitis). They all went through nasal and bronchial provocation tests with the specific antigen. Late reactions were also registered. A RAST was performed in some of the patients reacting to Candida albicans. Following inhalation challenge with antigens, an immediate response was obtained in 91 cases (asthma 30, rhinitis 51). A dual response was observed in 17 cases of asthma and in 13 cases of rhinitis. A RAST-Candida albicans was done in 64 cases. Results were positive in 52 patients. In 46 cases there was a correlation between the RAST and the provocation tests. Hyposensitization treatment was given to 92 patients. After 2 years of treatment, a good to excellent response could be observed in almost 60% of the treated cases. A rough estimation of the incidence of immediate bronchial and nasal hypersensitivity among patients with chronic asthma and rhinitis to the three yeasts gives the approximate figure of 8% to 10%.