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This study describes young adult female (YA-F) cancer survivors' uncertainty management strategies related to fertility/family building. Cross-sectional data were analyzed ( n = 98). Participants reported higher rates of seeking information to reduce fertility-related uncertainty (M = 5.48, ±1.03), than avoiding information (M = 4.77, ±1.29). Controlling for relevant covariates (i.e., reproductive distress, household income, and health literacy), greater avoidance was related to higher reproductive distress (β = 0.293, p = 0.011) and lower household income (β = -0.281, p = 0.047). Evidence suggests that some survivors may avoid fertility-related information to manage uncertainty and distress, which may impact family-building success. Fertility avoidance may be an important target of intervention.

Performing nanoscale scanning electron paramagnetic resonance (EPR) requires three essential ingredients: First, a static magnetic field together with field gradients to Zeeman split the electronic energy levels with spatial resolution; second, a radio frequency (rf) magnetic field capable of inducing spin transitions; finally, a sensitive detection method to quantify the energy absorbed by spins. This is usually achieved by combining externally applied magnetic fields with inductive coils or cavities, fluorescent defects, or scanning probes. Here, we theoretically propose the realization of an EPR scanning sensor merging all three characteristics into a single device: the vortex core stabilized in ferromagnetic thin-film discs. On one hand, the vortex ground state generates a significant static magnetic field and field gradients. On the other hand, the precessional motion of the vortex core around its equilibrium position produces a circularly polarized oscillating magnetic field, which is enough to produce spin transitions. Finally, the spin-magnon coupling broadens the vortex gyrotropic frequency, suggesting a direct measure of the presence of unpaired electrons. Moreover, the vortex core can be displaced by simply using external magnetic fields of a few mT, enabling EPR scanning microscopy with large spatial resolution. Our numerical simulations show that, by using low damping magnets, it is theoretically possible to detect single spins located on the disc's surface. Vortex nanocavities could also attain strong coupling to individual spin molecular qubits with potential applications to mediate qubit-qubit interactions or to implement qubit readout protocols.

A core feature of Autistic Spectrum Condition (ASC) is the presence of difficulties in social interactions. This can be explained by an atypical attentional processing of social information: individuals with ASC may show problems with orienting attention to socially relevant stimuli and/or inhibiting their attentional responses to irrelevant ones. To shed light on this issue, we examined attentional orienting and inhibitory control to emotional stimuli (angry, happy, and neutral faces). An antisaccade task (with both prosaccade and antisacade blocks) was applied to a final sample of 29 children with ASC and 27 children with typical development (TD). Whereas children with ASC committed more antisaccade errors when seeing angry faces than happy or neutral ones, TD children committed more antisaccade errors when encountering happy faces than neutral faces. Furthermore, latencies in the prosaccade and antisaccade blocks were longer in children with ASC and they were associated with the severity of ASC symptoms. Thus, children with ASC showed an impaired inhibitory control when angry faces were presented. This bias to negative high-arousal information is congruent with affective information-processing theories on ASC, suggesting that threatening stimuli induce an overwhelming response in ASC. Therapeutic strategies where train the shift attention to emotional stimuli (i.e. faces) may improve ASC symptomatology and their socials functioning., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Many adolescent and young adult female (AYA-F) cancer survivors face decisions about family building using reproductive medicine or adoption to achieve parenthood. This study evaluated associations among reproductive distress, avoidance, and family-building decision making and identified sociodemographic and clinical characteristics related to high distress and avoidance., Methods: A cross-sectional survey assessed AYA-F survivors' oncofertility experiences. Measures included an investigator-designed Unmet Information Needs scale, Reproductive Concerns After Cancer Scale, Impact of Events Scale-Avoidance subscale, Decision Self-Efficacy scale, and Decision Conflict Scale. Two linear regression models evaluated correlates of decision self-efficacy and decisional conflict about family building after cancer. Bivariate analyses evaluated correlates of avoidance using Pearson's correlation, t-test, and ANOVA., Results: AYA-Fs (N = 111) averaged 31-years-old (SD = 5.49) and 3 years post-treatment (range: 1-23 years); 90% were nulliparous. Most common diagnoses were leukemia (24%) and breast cancer (22%). Average decisional conflict was 52.12 (SD = 23.87, range: 0-100); 74% of the sample reported DCS scores within the clinically significant range. Higher levels of reproductive distress (B = -0.23, p = 0.04) and avoidance (B = -0.24, p = 0.02) related to lower decision self-efficacy. Younger age (B = -0.18, p = 0.03), greater unmet information needs (B = 0.33, p < 0.001), and higher levels of reproductive distress (B = 0.34, p = 0.001) related to worse decisional conflict. Predictors of distress and avoidance were identified., Conclusions: After cancer treatment, high fertility distress and avoidant coping were associated with poorer quality decision making about family building after cancer. Fertility counseling post-treatment should support self-efficacy and constructive coping skills to counteract high distress, maladaptive coping, and facilitate values-based decision making., (© 2023 John Wiley & Sons Ltd.)

3D Printed Injection Moulds (3DIM), commonly used for low volume production and prototyping purposes, are known to fail abruptly and have a comparatively shorter life than conventional moulds. Investigating the underlying critical factors affecting failure may help in reducing the risk of abrupt failures and possibly prolong the 3DIM tool life. A hypothesis that the cooling time of the Injection Moulding (IM) process is a critical factor for 3DIM tool failure has been proposed. The failure hypothesis has been validated by theoretical calculations, FEA simulations and experimental investigations. Experiments were performed using two different materials for the 3DIM tool (Visijet M3-X and Digital ABS) and an engineering thermoplastic (Lexan 943-A) as the moulding material. Results showed that cooling time was a critical factor on tool life and managing the thermal loading on a 3DIM tool could lead to increased tool life. The paper identifies cooling time as the critical factor affecting 3DIM tool life and presents a cooling regime that could possibly lead to prolonged tool life.

Objectives: Ambulance officers administering methoxyflurane as an inhalational analgesic may be exposed to trace vapor. Fluoride is a methoxyflurane metabolite, and has been associated with acute renal failure in anesthesia patients and skeletal fluorosis with chronic elevated serum levels from other sources. However, there has been no direct measurement of serum fluoride in occupationally exposed ambulance officers. Thus, this study directly measures serum fluoride over a prolonged period in order to determine renal toxic and skeletal fluorosis risk to ambulance officers who are administering methoxyflurane., Material and Methods: Serum inorganic fluoride concentrations were measured in a prospective observational study of 12 emergency medical technicians (EMTs). The study took 7 serum fluoride measurements over 24 months. A meta-analysis of healthy adult serum fluoride ranges was also conducted., Results: The typical healthy adult serum fluoride range was determined to be 0.21-2.11 μmol/l (p < 0.001). The EMTs' baseline median (IQR) serum fluoride concentrations were 0.4 μmol/l (0.2; 1.0) with maximum 1.6 μmol/l. The EMTs' overall median serum fluoride was 0.4 μmol/l (0.2; 1.3) with maximum 4.0 μmol/l, usually within healthy reference ranges. All results were ≤10% of the suggested single-dose renal toxic threshold. One result was above a threshold for skeletal fluorosis. The highest measured serum fluoride was 24% of the lowest level associated with radiologic evidence of fluorosis. There was no evidence overall of increasing serum fluoride levels., Conclusions: There was no evidence that EMTs' exposure to methoxyflurane resulted in sustained increased serum fluoride. These results imply EMTs' occupational safety from acute renal toxicity when activated carbon filtration is used on patient exhalation. However, 1 serum fluoride result above a skeletal fluorosis threshold suggests that the risk of mild skeletal fluorosis cannot be excluded. Int J Occup Med Environ Health. 2021;34(6):767-77., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

Objective: Nitrous oxide (Entonox ® ) and methoxyflurane (Penthrox ® ) are inhaled analgesics administered in paramedicine. Occupational exposure to nitrous oxide has been associated with negative health effects, and may inhibit professional capability. The effect of occupational exposure to methoxyflurane has not yet been clearly determined. This study identifies the frequency and duration of ambulance officer (AO) occupational exposure to nitrous oxide and methoxyflurane to provide a foundation for future assessments of occupational toxicity risk., Methods: A retrospective database review of Patient Report Forms (PRFs) in 11 months between February 2016 and February 2018 was conducted. Nitrous oxide was available for the first 5 months studied, followed by 6 months methoxyflurane availability. AO-specific measures of attendance, rate of inhaled analgesic use, and duration of analgesic use were determined. Subgroup analysis by AO qualification and rostered work hours was undertaken., Results: A total of 46,759 PRFs were examined, identifying 1,033 cases of nitrous oxide administration and 1456 cases of methoxyflurane was administration. There was a significant increase in the proportion of cases where inhaled analgesia was administered following the replacement of nitrous oxide with methoxyflurane. Relative risk of exposure to methoxyflurane compared with nitrous oxide was 1.22, while median duration of each exposure remained unchanged (32 vs. 33 min)., Conclusions: Methoxyflurane via the Penthrox ® inhaler was more likely to be administered than nitrous oxide. Most AOs are infrequently exposed to inhaled analgesics and are exposed for durations slightly greater than previously reported. Relative risk of exposure was greatest for lower-qualified AOs. Peak number of exposures and duration values suggest a subset of AOs with higher occupational health risk., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background-The visual inspection of aircraft parts such as engine blades is crucial to ensure safe aircraft operation. There is a need to understand the reliability of such inspections and the factors that affect the results. In this study, the factor 'cleanliness' was analysed among other factors. Method-Fifty industry practitioners of three expertise levels inspected 24 images of parts with a variety of defects in clean and dirty conditions, resulting in a total of N = 1200 observations. The data were analysed statistically to evaluate the relationships between cleanliness and inspection performance. Eye tracking was applied to understand the search strategies of different levels of expertise for various part conditions. Results-The results show an inspection accuracy of 86.8% and 66.8% for clean and dirty blades, respectively. The statistical analysis showed that cleanliness and defect type influenced the inspection accuracy, while expertise was surprisingly not a significant factor. In contrast, inspection time was affected by expertise along with other factors, including cleanliness, defect type and visual acuity. Eye tracking revealed that inspectors (experts) apply a more structured and systematic search with less fixations and revisits compared to other groups. Conclusions-Cleaning prior to inspection leads to better results. Eye tracking revealed that inspectors used an underlying search strategy characterised by edge detection and differentiation between surface deposits and other types of damage, which contributed to better performance.

In the non-AIDS group, several underlying conditions and immune defects could lead to different PCP presentations. This study compared PCP presentation and outcome according to the underlying disease. A secondary analysis of a previously published prospective observational study including 544 PCP patients was done. Only non-AIDS patients were included. Underlying disease was defined as chronic lymphocytic leukemia (CLL), organ transplantation, solid cancer, allogeneic hematopoietic stem cell transplant (AHSCT), other hematological diseases, and immunosuppressive treatment. Clinical characteristics and outcomes were compared between groups. Multiple correspondent analyses compared clinical characteristics at diagnosis. Day 30 mortality was analyzed. Three hundred and twenty-one patients were included in the study. The underlying diseases were hematological malignancy (n = 75), AHSCT (n = 14), CLL (n = 19), solid organ transplant (n = 94), solid tumor (n = 39), and immunosuppressive treatment (n = 57). Compared with other underlying diseases, PCP related to CLL was closer to PCP related to AIDS presentation (long duration of symptoms before diagnosis, high level of dyspnea, and low oxygen saturation at diagnosis). Day 30 mortality was associated with underlying disease, oxygen flow, and shock at ICU admission. PCP presentations may vary according to the underlying reason for immunosuppression. Response to treatment and adjuvant steroid therapy should be analyzed regarding this result.

Background: Polymer-based 3D Printed Injection Mould (3DIM) inserts are used as a cost-effective method for low volume injection moulding (50-500 parts). However, abrupt failure leading to a short tool life is a common shortcoming of 3DIM. Need: The underlying causes of raised feature failures on 3DIM are not well known. Failure is commonly attributed to bending or shearing of raised features on the tool. Understanding the causes may help in delaying the failure and increasing tool life., Approach: Tool failure was analysed from a first-principles perspective, using pressure and temperature fields as determined by mould flow simulation. Experimental results were also obtained for two types of tool material (Visijet M3-X and Digital ABS) with polycarbonate (Lexan 943A) as the part material., Findings: Results find against the idea that pin failure in 3DIM tools is caused by bending and shear failures induced by injection pressures. We also conclude that failure of raised features is not necessarily an abrupt failure as mentioned in the literature. Originality: The generally accepted explanation for the failure of raised features in 3DIM tooling is that injection pressures cause bending and shear failure. This paper disconfirms this notion on theoretical and experimental grounds.

Introduction: Intramedullary spinal cord gangliogliomas (ISCGGs) account for 35-40% of all intramedullary tumors in children. These tumors have a different algorithm for treatment and prognosis than other medullary tumors, such as astrocytomas and spinal ependymomas. The objective of the study was to review the literature and examine an approach to diagnosing and treating this tumor based on a case report of ISCGG diagnosed at our center., Method: An exhaustive review of cases of ISCGG published via the PubMed-NCBI platform between 1911 and 2018 was performed, and each patient's epidemiological characteristics, tumor location, symptoms, radiological diagnosis and treatment were appended., Results: A total of 167 cases of ISCGG were found, including our own. In our sample, 52% of patients were female and the most commonly affected age group was 0-9 years of age (35% of patients). Motor deficit has been found to be the main symptom in a larger proportion of adults patients versus pediatric patients. On X-ray, this tumor shows greater hyperintensity and contrast uptake than astrocytomas and ependymomas, as well as a higher percentage of intratumoral cysts. The BRAF V600E mutation is less common in spinal as opposed to supratentorial gangliogliomas. Surgery with complete resection is the treatment of choice. Only 19% of the patients in the sample received radiotherapy, and only 9% received chemotherapy as their only line of treatment., Conclusions: ISCGGs are common in the pediatric population and require strong suspicion for proper diagnosis and treatment, as the risk of recurrence of ISCGGs is 3 times greater than that of supratentorial gangliogliomas., (Copyright © 2020 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.)

Successful implementation of Health and Safety (H&S) systems requires an effective mechanism to assess risk. Existing methods focus primarily on measuring the safety aspect; the risk of an accident is determined based on the product of severity of consequence and likelihood of the incident arising. The health component, i.e., chronic harm, is more difficult to assess. Partially, this is due to both consequences and the likelihood of health issues, which may be indeterminate. There is a need to develop a quantitative risk measurement for H&S risk management and with better representation for chronic health issues. The present paper has approached this from a different direction, by adopting a public health perspective of quality of life. We have then changed the risk assessment process to accommodate this. This was then applied to a case study. The case study showed that merely including the chronic harm scales appeared to be sufficient to elicit a more detailed consideration of hazards for chronic harm. This suggests that people are not insensitive to chronic harm hazards, but benefit from having a framework in which to communicate them. A method has been devised to harmonize safety and harm risk assessments. The result was a comprehensive risk assessment method with consideration of safety accidents and chronic health issues. This has the potential to benefit industry by making chronic harm more visible and hence more preventable.

Aim: Historically methoxyflurane was used for anaesthesia. Evidence of nephrotoxicity led to abandonment of this application. Subsequently, methoxyflurane, in lower doses, has re-emerged as an analgesic agent, typically used via the Penthrox inhaler in the ambulance setting. We review the literature to consider patient and occupational risks for methoxyflurane., Method: Articles were located via PubMed, ScienceDirect, Google Scholar, Anesthesiology journal and the Cochrane Library., Results: Early studies investigated pharmacokinetics and considered the resulting effects to pose minimal risk. Pre-clinical rodent studies utilised a species not vulnerable to the nephrotoxic fluoride metabolite of methoxyflurane, so nephrotoxicity was not identified until almost a decade after its introduction, and was initially met with scepticism. Further evidence of nephrotoxicity led to abandonment of methoxyflurane use for anaesthesia. Subsequent research suggested there are additional risks potentially relevant to recurrent patient or occupational exposure. Specifically, greater than expected fluoride production after repeated low-dose exposure, increased fluoride production due to medication-caused hepatic enzyme induction, fluoride deposition in bone potentially acting as a slow-release fluoride compartment, which suggests a risk of skeletal fluorosis, and hepatotoxicity. Gestational risk is unclear., Conclusions: Methoxyflurane poses a potentially substantial health risk in high (anaesthetic) doses, and there are a number of pathways whereby repeated exposure to methoxyflurane in lower doses may pose a risk. Single analgesic doses in modern use generally appear safe for patients. However, the safety of recurrent patient or occupational healthcare-worker exposure has not been confirmed, and merits further investigation., Competing Interests: Ms Allison reports a grant from the NZ National Science Challenge, and a grant from the NZ Tertiary Education Commission, during the conduct of the study, and is a paramedic who utilises methoxyflurane for patient analgesia.

Background: communication is important for project teams. There is a need to better understand how members respond to communication at project meetings, and how this affects the team roles the participants adopt., Methods: observational data were collected from (a) two engineering organisations and (b) five university engineering student teams. A mixed methods approach was used, comprising observations (recorded with the interaction diagram method), questionnaires and interviews., Results: participants adjusted their communication style to the behaviour of other people and to different communication settings. This happened with three different dynamics: micro-level (grounding processes in conversation), mezzo-level (emotional and rational regulation) and macro-level (over a period of time). Originality: a new theory was presented for the process of team behaviour during project meetings; specifically, role adoption and communication behavioural changes. Participants change their team roles within three different dynamics: at the macro-, mezzo- and micro-levels, corresponding to the organisation, project and meeting, respectively. The changing of team roles in project meetings arises from rational and emotional regulation. The findings have the potential to assist managers and supervisors to better understand and manage the team dynamics on their projects.

Team communication plays a vital role in engineering management, however, there is a paucity of work that examines how team roles emerge as a response to the communicative processes between participants. This research explored role adoption using qualitative methods comprising observations, questionnaires and semi-structured interviews. Five student teams doing final year projects at a university in New Zealand were observed during the academic year and then interviewed at the final stage of project completion. A number of team roles in the engineering context were identified for students and their supervisors: Explorer; Initiator; Facilitator; Active and Passive Information Provider; Outsider; Active and Passive Connector; Passive Collector; Arbitrator; Gatekeeper and Representative. Personal factors, such as social sensitivity, were correlated with the choice of team behaviour pattern. In addition, the team roles could be arranged in circular order to create a circumplex, the two axes of which were identified as Personal Agency/Communion and Social engagement/Social disengagement., Competing Interests: The authors declare no conflict of interest.

Therapeutic antibodies have been used for several decades and their associated market (project numbers, approvals…) continues to grow. Remarkably, a new threshold was crossed in the early 2010's to make this decade the decade of immunotherapy. Over the past 10 years, 62 antibodies have been approved, the number of annual transactions between stakeholders has increased to more than 300 (three times more in 2018 than in 2009). The revolution of immunotherapy in cancer treatment and the recent use of antibodies as first-line treatment are the major turning points in oncology. Thus, the last three years alone represent two thirds of the most important deals of the decade involving immunotherapies. Immunotherapy is currently experiencing a golden age that has resulted in many successes, especially in France where biotechnology companies and large pharmaceutical companies have achieved impressive therapeutic and financial results., (© 2019 médecine/sciences – Inserm.)

This paper scrutinizes the assertion that knowledge gaps concerning health risks from climate change are unjust, and must be addressed, because they hinder evidence-led interventions to protect vulnerable populations. First, we construct a taxonomy of six inter-related forms of invisibility (social marginalization, forced invisibility by migrants, spatial marginalization, neglected diseases, mental health, uneven climatic monitoring and forecasting) which underlie systematic biases in current understanding of these risks in Latin America, and advocate an approach to climate-health research that draws on intersectionality theory to address these inter-relations. We propose that these invisibilities should be understood as outcomes of structural imbalances in power and resources rather than as haphazard blindspots in scientific and state knowledge. Our thesis, drawing on theories of governmentality, is that context-dependent tensions condition whether or not benefits of making vulnerable populations legible to the state outweigh costs. To be seen is to be politically counted and eligible for rights, yet evidence demonstrates the perils of visibility to disempowered people. For example, flood-relief efforts in remote Amazonia expose marginalized urban river-dwellers to the traumatic prospect of forced relocation and social and economic upheaval. Finally, drawing on research on citizenship in post-colonial settings, we conceptualize climate change as an 'open moment' of political rupture, and propose strategies of social accountability, empowerment and trans-disciplinary research which encourage the marginalized to reach out for greater power. These achievements could reduce drawbacks of state legibility and facilitate socially-just governmental action on climate change adaptation that promotes health for all., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Honeybees have an essential role in ecosystems pollinating wild flowers and cultivated crops, representing an important cultural and economic benefit for humans. Honeybee populations are decreasing over the last decade, due to multifactorial causes. The aim of this field study was to investigate the effects of the presence of the invasive species Vespa velutina, a bee predator, in oxidative stress parameters of honeybee workers. To achieve this objective, positive or negative apiaries for the presence of the V. velutina were selected. Five honeybees from six hives of each apiary were sampled in spring, summer and autumn, analysing a total of 233 samples. Analysis of mRNA expression of oxidative stress-related genes, catalase enzymatic activity and lipid peroxidation were performed. An increase in sod2, tpx3, trxR1, gtpx1, gstS1, coxI, cytC and if2mt genes expression, as well as a raise in catalase activity and lipid peroxidation were observed in V. velutina positive samples. Thus, here we present a new methodology to analyze the impact of the predation pressure of the invasive species V. velutina on honeybees under field conditions. In conclusion, the results obtained in this study indicate the negative impact of the presence of the yellow-legged hornet on honeybees' health and the activation of their antioxidant system to protect them against this biotic stressor. Moreover, the redox status they present could increase the susceptibility of honeybees, essential insects that currently receive many inputs of different stresses, to another stressor., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Recording of team meeting's processes with electronic devices can be problematic because of the invasiveness of the process: issues with privacy; interpretation difficulty with noise or quiet speech; and distortion of participants' behaviour. There is a need for less intrusive methods. We developed the interaction diagram method by extending the directed graph nature of sociograms to capture the time sequence of events, including the identification of the person, communication behaviour, and duration of interactions. The method was tested on engineering team meetings. Data processing by quantitative and qualitative analysis is shown to be feasible. Several team roles were observed in the engineering context: Initiator; Passive collector; Explorer; Information provider; Facilitator; Arbitrator; Representative; Gatekeeper; Connector; and Outsider. The work provides a graphical representation of the record of the interaction flow during meetings. It does this without needing video recording. It is also an efficient method, as it does not require subsequent transcription or coding. It provides a procedure to quickly analyse communication situations, identify group roles, and compare group activity at different meetings.

The storage of temperature-sensitive healthcare products requires control of the cold chain. Healthcare facilities must have the appropriate equipment at their disposal and ensure the traceability and monitoring of temperatures., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The use of drugs among adolescents/youth often results in a high degree of distress for the family members who live with them. This in turn can lead to a deterioration of mental (psychological) health, hindering any attempt to successfully cope with the situation. The goal of our research was to study the effect of the Community Reinforcement and Family Training (CRAFT) program on parents of adolescents/young adult drug users. Study volunteers ( n = 50) were parents from Valencia (Spain) that were divided into two groups. The experimental group ( n = 25) was made up of parents whose sons and daughters exhibited problems with drug use and the constructed noncausal baseline group ( n = 25) was made up of parents whose sons and daughters did not show any substance abuse problems. For both groups, self-esteem (Rosenberg Self-Esteem Scale), depression (BDI-II), anxiety (STAI), and anger (STAXI-II) were evaluated before and after the application of the CRAFT program. Results show a significant improvement in the experimental group's self-esteem, depression, and anger state and a decrease in negative moods. These changes in parents produce a positive effect on their substance-using sons and daughters: of the 25 participants, 15 contacted specialized addiction treatment resources for the first time.

In Chile, while dog rabies has decreased markedly over the last 30 years, bat rabies is still reported frequently. In order to shed new light on the spatiotemporal trends of these reports, we analysed active and passive data from years 1985 and 2012, which included 61 076 samples from 289 counties of Chile. We found that from 1994 to 2012, more than 15 000 bat samples were submitted for diagnostics through passive surveillance, 9·5% of which tested positive for rabies. By contrast, the prevalence of infection was only ~0·4% among the nearly 12 000 bat samples submitted through active surveillance. We found that the prevalence of dog rabies dropped steadily over the same period, with just a single confirmed case since 1998. None of the 928 samples from wild animals, other than bats, were positive for rabies. Although there has been only one confirmed case of human rabies in Chile since 1985, and a single confirmed case in a dog since 1998, bats remain a reservoir for rabies viruses. While active surveillance indicates that rabies prevalence is low in bat colonies, the high proportion of positive bats submitted through passive surveillance is a concern. To prevent human rabies, local public health agencies should increase research on the basic ecology of bats and the role of stray dogs and cats as potential rabies amplifiers.

Pneumocystis jirovecii pneumonia (PCP) in patients without AIDS is increasingly common. We conducted a prospective cohort study of consecutive patients with proven PCP; of 544 patients, 223 (41%) had AIDS (AIDS patients) and 321 (59%) had other immunosuppressive disorders (non-AIDS patients). Fewer AIDS than non-AIDS patients required intensive care or ventilation, and the rate of hospital deaths--17.4% overall--was significantly lower for AIDS versus non-AIDS patients (4% vs. 27%; p<0.0001). Multivariable analysis showed the odds of hospital death increased with older age, receipt of allogeneic bone marrow transplant, immediate use of oxygen, need for mechanical ventilation, and longer time to treatment; HIV-positive status or receipt of a solid organ transplant decreased odds for death. PCP is more often fatal in non-AIDS patients, but time to diagnosis affects survival and is longer for non-AIDS patients. Clinicians must maintain a high index of suspicion for PCP in immunocompromised patients who do not have AIDS.

Background: Delirium is associated with substantial morbidity and mortality rates in elderly hospitalised patients, and a growing problem due to increase in life expectancy. Implementation of standardised non-pharmacological delirium prevention strategies is challenging and adherence remains low. Pharmacological delirium prevention with haloperidol, currently the drug of choice for delirium, seems promising. However, the generalisability of randomised controlled trial results is questionable since studies have only been performed in selected postoperative hip-surgery and intensive care unit patient populations. We therefore present the design of the multicenter, randomised, double-blind, placebo-controlled clinical trial on early pharmacological intervention to prevent delirium: haloperidol prophylaxis in older emergency department patients (The HARPOON study)., Methods/design: In six Dutch hospitals, at-risk patients aged 70 years or older acutely admitted through the emergency department for general medicine and surgical specialties are randomised (n = 390) for treatment with prophylactic haloperidol 1 mg or placebo twice daily for a maximum of seven consecutive days. Primary outcome measure is the incidence of in-hospital delirium within seven days of start of the study intervention, diagnosed with the Confusion Assessment Method, and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for delirium. Secondary outcome measures include delirium severity and duration assessed with the Delirium Rating Scale Revised 98; number of delirium-free days; adverse events; hospital length-of-stay; all-cause mortality; new institutionalisation; (Instrumental) Activities of Daily Living assessed with the Katz Index of ADL, and Lawton IADL scale; cognitive function assessed with the Six-item Cognitive Impairment Test, and the Dutch short form Informant Questionnaire on Cognitive Decline in the Elderly. Patients will be contacted by telephone three and six months post-discharge to collect data on cognitive- and physical function, home residency, all-cause hospital admissions, and all-cause mortality., Discussion: The HARPOON study will provide relevant information on the efficacy and safety of prophylactic haloperidol treatment for in-hospital delirium and its effects on relevant clinical outcomes in elderly at-risk medical and surgical patients., Trial Registration: EudraCT Number: 201100476215; ClinicalTrials.gov Identifier: NCT01530308; Dutch Clinical Trial Registry: NTR3207.

Introduction: Alcoholism causes psychological, behavioral and cognitive symptoms that need to be addressed together. The neuropsychological alterations among alcohol-dependent people are considered to make the therapeutic work complex and longer. A cognitive rehabilitation program is sometimes difficult to achieve with these patients. Functional results are often difficult to anticipate. However, the consequences of this therapeutic approach are multiple and there are many interactions between psycho-affective, behavioral and cognitive components. A neuropsychological approach can be used like a tool to improve metacognition. A bad contribution to treatment programs is often secondary to the illusion of a satisfying intellectual functioning. Patients' motivation for the therapeutic work is very changeable. A complete consciousness of impairments can help them to stay involved., Case Report: The following case shows the cognitive effects and secondary benefits associated with a neuropsychological work, which was carried out by a chronic ethylic patient with severe physical and cognitive symptoms. The patient aged 50, with a good qualification level (scientific section in the final year of secondary school, with no diploma, then attended a training program to become a croupier) was suffering from chronic alcoholism since his adolescence. He arrived in the closed unit after many hospitalizations in psychiatric and hepato-gastroenterology units. He had been showing mental confusion. He presented a frontal and subcortical profile of alcohol-related dementia according to Oslin's criteria. MRI revealed global cerebral atrophy, more pronounced on the fronto-parietal cortex with cerebellar leukoencephalopathy, but no pontine central myelinolysis. The neurocognitive program had two main lines: reducing attentional, executive and graphical deficits with training exercises (individual and group sessions) and compensating memory, and executive disorders with an external aid. The cognitive program had been assessed by means of repeated psychometric measures, behavior and metacognition estimated by direct clinical observations. The cognitive remediation was carried out during a 10-month hospitalization, and then in an outpatient rehabilitation setting over a 12-month period. The external individual sessions were associated with medical consultations and support for reintegration at home provided by the mobile psychiatric team., Results: The test results showed a significant improvement in attentional processes and executive functions. On graphic level, his writing was recovered after 10 months. Impairment within episodic memory processes-encoding was observed, and prospective memory was reinforced by external aids. At the end of the program, the use of an agenda proved to be effective even if updating was difficult once back home. Although a part of these effects could be expected, their psychological influence on the patient must be underlined: his perception of the alcohol related problem had been modified with more consciousness of the neurobiological consequences and a strong desire of personal implication. He worked a lot on his own (always under supervision) on cognitive exercises and succeeded in remaining abstinent for nearly 2 years. He died of complications of acute hepatitis., Discussion: All the cognitive assessments and rehabilitation results seem to have increased his participation in the global therapeutic care. Therapeutic tools used for cognitive work give a concrete picture of the consequences of alcohol consumption and the necessary time to retrieve brain capacities. Visible improvements in terms of reduction in disability-handicaps encouraged the patient, valued his efforts, and increased his determination to solve his alcohol related problem. Thus, cognitive programs can help to reduce passiveness and develop activeness. This patient regarded therapeutic difficulties as a challenge, not as an obstacle. We can reasonably assume the effect of the cognitive rehabilitation on the Persistence of the Cloninger's biosocial model. This increase in temperament corresponds to a certain form of tenacity, which would facilitate abstinence., (Copyright © 2013. Published by Elsevier Masson SAS.)

Purpose: We examined, retrospectively, the efficacy of voriconazole in Fusarium eye infections., Methods: Voriconazole-treated patients with proven or probable keratitis or endophthalmitis from the voriconazole database (9 patients) and six French ophthalmology departments (15 patients) were included. Sociodemographic features, predisposing factors, history of corneal trauma, associated ocular conditions, other diseases and prior therapies were analysed. Investigator-determined success was defined as infection resolution with medical treatment. Failure was no response or persistent infection and required surgery., Results: Most patients were Caucasian (83 %) and male (71 %). The infection was keratitis (63 %) or endophthalmitis (37 %) and proven in 23 (96 %). Prior therapy included topical and/or systemic amphotericin (46 %), fluconazole (17 %) or others (33 %), often in combination. Causative fungi were Fusarium solani (14, 58 %), Fusarium moniliforme (1), Fusarium oxysporum (1) and Fusarium spp. (8). Voriconazole was administered systemically, topically and/or by intraocular injection, and 16 patients (67 %) received salvage and eight primary therapy. The overall response was 67 % (73 % keratitis and 56 % endophthalmitis) but seven patients required adjunctive surgery. However, response was 63 % for eight primary therapy patients and 69 % for 16 salvage therapy patients. Response by species was Fusarium solani 64 % (9/14) and all others 80 % (8/10). In 13 patients (77 %), voriconazole was used in combination (response 69 vs. 64 % alone) with topical [amphotericin B 10/24 (42 %), caspofungin 5 (21 %), natamycin 1 (4 %)] and systemic agents [caspofungin 3 (13 %), amphotericin 2 (8 %)]., Conclusions: Topical and systemic voriconazole appears to be effective alone or in combination with other agents for treating severe Fusarium keratitis or endophthalmitis.

Background: Chloroquine (CQ) was the main malaria therapy worldwide from the 1940s until the 1990s. Following the emergence of CQ-resistant Plasmodium falciparum, most African countries discontinued the use of CQ, and now promote artemisinin-based combination therapy as the first-line treatment. This change was generally initiated during the last decade in West and Central Africa. The aim of this study is to describe the changes in CQ susceptibility in this African region, using travellers returning from this region as a sentinel system., Methods: The study was conducted by the Malaria National Reference Centre, France. The database collated the pfcrtK76T molecular marker for CQ susceptibility and the in vitro response to CQ of parasites from travellers' isolates returning from Senegal, Mali, Ivory Coast or Cameroon. As a proxy of drug pressure, data regarding CQ intake in febrile children were collated for the study period. Logistic regression models were used to detect trends in the proportions of CQ resistant isolates., Results: A total of 2874 parasite isolates were genotyped between 2000-2011. The prevalence of the pfcrt76T mutant genotype significantly decreased for Senegal (from 78% to 47%), Ivory Coast (from 63% to 37%), Cameroon (from 90% to 59%) and remained stable for Mali. The geometric mean of the 50% inhibitory concentration (IC50) of CQ in vitro susceptibility and the proportion of resistant isolates (defining resistance as an IC50 value > 100 nM) significantly decreased for Senegal (from 86 nM (59%) to 39 nM (25%)), Mali (from 84 nM (50%) to 51 nM (31%)), Ivory Coast (from 75 nM (59%) to 29 nM (16%)) and Cameroon (from 181 nM (75%) to 51 nM (37%)). Both analyses (molecular and in vitro susceptibility) were performed for the 2004-2011 period, after the four countries had officially discontinued CQ and showed an accelerated decline of the resistant isolates for the four countries. Meanwhile, CQ use among children significantly deceased in this region (fixed effects slope = -0.3, p < 10-3)., Conclusions: An increase in CQ susceptibility following official withdrawal of the drug was observed in travellers returning from West and Central African countries. The same trends were observed for molecular and in vitro analysis between 2004-2011 and they correlated to the decrease of the drug pressure.

Introduction: Factor VII activating protease (FSAP) is a plasma protease with FVII and pro-urokinase (pro-uPA) activating properties. A single nucleotide polymorphism (SNP) (Marburg I, MI) in the FSAP gene (HABP-2) leads to a low activity of the MI-FSAP towards pro-uPA, but supposedly not towards FVII and is described as a risk factor for athero-thrombosis and liver fibrosis. Recently we found, however, that FVII is an extremely poor substrate of FSAP and identified tissue factor pathway inhibitor (TFPI) as a novel substrate for FSAP. This prompted us to re-investigate the proteolytic activity profile of FSAP and to re-define its role in haemostasis., Material and Methods: Using purified protein and genotyped plasma samples, we systematically compared the activities of wild type (WT) and MI-FSAP towards natural plasma substrates. The influence of FSAP on coagulation was studied in prothrombin time assays., Results: FSAP from homozygous MI-carriers has a general low proteolytic activity making this variant a natural "knock-down". In human plasma WT-FSAP, but not MI-FSAP, accelerated the extrinsic coagulation by inactivation of TFPI. The diminished ability of MI-FSAP to cleave TFPI is reflected by a positive correlation between the FSAP enzymatic activity and cleaved TFPI in the circulation., Conclusion: Most likely TFPI cleavage by WT-FSAP occurs in vivo and contributes to an elevated level of endogenous FVIIa. This may explain why MI-FSAP is not a clear indicator for deep vein thrombosis in population studies. The loss of the pro-fibrinolytic protective function of FSAP in carriers of the MI-SNP may account for the association of the MI-SNP with atherosclerosis and thromboembolic complications., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

On January 12, 2010, Port-au-Prince, Haiti, was shattered by a violent earthquake that killed or injured thousands of its citizens. Local emergency services became overwhelmed and international assistance was required. French relief teams were deployed to assist local hospitals in caring for the victims. The medical care activity of the team at Diquini Hospital from January 17-26 was analyzed. Priority was given to surgery, leading to the creation of a pre- and post-operative area and a medical care unit. Special attention was required for infection prevention, pain relief, minor surgery, and pre-surgery triage. The continual influx of accompanied victims necessitated the creation of a receiving area. In spite of the assistance from several foreign surgical teams, some patients had to be evacuated to French or American facilities, particularly children, patients with spinal cord injuries, and those needing intensive care. Analysis of the actions undertaken highlights the importance of well-prepared and flexible medical teams and the ability to provide local and regional anesthesia, including the necessary medical supplies and equipment. Medical care activity, especially post-surgical care, was a predominant, ongoing need. The ability to provide medical care required organization and cooperation among local health care providers and other relief workers.

The aim of the study was to show whether there was a connection between drug use and Eating Disorders, as well as to identify the type of drugs most widely used and to ascertain whether they are used to suppress appetite. An "ad hoc" scale was developed using the items of the Eating Disorder Diagnostic Scale, whose aim is to detect cases at risk of certain types of eating disorder, and items for assessing drug use. This scale was applied to samples of teenagers (n=446) aged 13-18 from various secondary schools in the Valencia Region (Comunidad Valenciana) in Spain. An association was found between teenagers that use drugs, and particularly between the variable "use of some kind of drug as an appetite suppressant", and being at risk of having an eating disorder. Tobacco was the drug most commonly used (accounting for 66% of those within the risk threshold of the Eating Disorder Diagnostic Scale). We conclude that those teenagers from the sample who fall within any of the risk thresholds consume more drugs than those who do not fall within the risk threshold of the Eating Disorder Diagnostic Scale. Stimulant-type drugs are those most widely used by these teenagers with the aim of suppressing appetite.

Late-acquired stent malapposition (LASM) is a common finding after sirolimus-eluting stent (SES) implantation and may be the cause for late stent thrombosis. Inflammation may play a pivotal role in LASM just as it plays in stent restenosis. We have therefore investigated seven polymorphisms involved in inflammatory processes, related in previous reports to restenosis, on the risk of LASM in SES patients. Patients with ST-elevation myocardial infarction who underwent SES implantation and had intravascular ultrasonography (IVUS) data available for both immediate post-intervention and 9-month follow-up were included in the present study. In total, 104 patients from the MISSION! Intervention Study were genotyped for the caspase-1 5352 G/A, eotaxin 1382 A/G, CD14 260 A/G, colony stimulating factor 2 1943 C/T, IL10 -1117 C/T, IL10 4251 C/T, and the tumor necrosis factor alpha 1211 C/T polymorphisms. LASM occurred in 26/104 (25%) of patients. We found a significantly higher risk for LASM in patients carrying the caspase-1 (CASP1) 5352 A allele (RR = 2.32; 95% CI 1.22-4.42). In addition, mean neointimal growth was significantly lower in patients carrying this LASM risk allele (1.6 vs. 4.1%, p = 0.014). The other six polymorphisms related to inflammation were not significantly related to the risk of LASM. In conclusion, carriers of the 5352 A allele in the caspase-1 gene are at increased risk of developing LASM after SES implantation. If this is confirmed in larger studies, then screening for this polymorphism in patients undergoing percutaneous coronary interventions could eventually help cardiologists to better select between commercially available stents.

Research into the pathologic mechanisms of neurodegenerative diseases has revealed that CREB binding protein (CBP) plays an important role in cognitive dysfunction. Loss of one copy of this gene leads to a syndrome with severe cognitive dysfunction. We investigated the association between four common variants in the CBP gene and cognitive function in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Baseline associations between genetic variation and cognitive function were assessed with linear regression. Longitudinal associations were assessed with linear mixed models. All analyses were adjusted for sex, age, education, country, version of test, and pravastatin use. The intron 4CT and intron 3AC polymorphisms in the CBP gene were associated with better cognitive performance at baseline and during follow-up. Furthermore, the haplotype with the variant alleles of these two polymorphisms also showed a protective effect on cognitive function in all cognitive domains (all p<0.03). Genetic variation in the CBP gene is associated with better cognitive performance in an elderly population. Future research is necessary to investigate the effect of these polymorphisms on the expression of CBP levels and how these polymorphisms affect the gene expression mediated by CBP., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Estrogen action is mediated by the two receptor isoforms: estrogen receptor alpha and beta. Both receptors are expressed in human prostate tissue and have different action profiles. ERalpha is positively correlated with the malignancy of prostate cancer, while ERbeta may protect against abnormal prostate cell growth. 17β-Estradiol (E2), at least in part, induces cancerous transformations by causing deleterious mutations through the formation of reactive oxygen species (ROS). The aim was to study the effect of E2 on oxidative stress and the expression of uncoupling proteins (UCPs) and antioxidant enzymes in several prostate cancer cell lines with different ERalpha/ERbeta ratios. The cell prostate lines with a lower ERalpha/ERbeta ratio had lower oxidative stress, which could be partially explained by the increased expression of antioxidant enzymes and UCPs. Moreover, the action of E2 on the expression of antioxidant enzymes and UCPs was dual and dependent on the ERalpha/ERbeta ratio. Treatments with 0.1 nM E2 in cell lines with high ERalpha/ERbeta ratio produced a decrease in antioxidant enzymes and UCPs levels, with an increase in ROS production. These effects disappeared when the treatment was done in the presence of an ERalpha antagonist (MPP). In the cell lines with greatest levels of ERbeta and the lowest ERalpha/ERbeta ratio, E2 treatment caused the up-regulation of antioxidant enzymes and UCPs with a look-up decrease in ROS production. These effects were reversed when the cells were treated with E2 in the presence of an ERbeta antagonist (R,R-THC). On the whole, our results suggest a dual E2 effect; increasing or decreasing oxidative stress in part by modulation of UCPs and antioxidant enzymes according to the abundance ERbeta and ERalpha/ERbeta ratio in prostate cancer cell lines., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Introduction. The FSAP-Marburg I polymorphism (1704G > A), which reduces FSAP activity, is associated with late complications of carotid stenosis in humans. Therefore, this study examines the influence of the Marburg I polymorphism and the closely linked Marburg II polymorphism (1280G > C) on various cardiovascular outcomes in two large independent study populations. Methods. The two Marburg polymorphisms in the HABP2 gene encoding FSAP were genotyped in a large population of elderly patients at risk for vascular disease (the PROSPER-study, n = 5804) and in a study population treated with a percutaneous coronary intervention (the GENDER-study, n = 3104). Results. In the PROSPER study, the Marburg I polymorphism was associated with an increased risk of clinical stroke (HR: 1.60, 95% CI: 1.13-2.28) and all-cause mortality (HR: 1.33, 95% CI: 1.04-1.71). In the GENDER study carriers of this variant seemed at lower risk of developing restenosis (HR: 0.59, 95% CI: 0.34-1.01). The Marburg II polymorphism showed similar but weaker results. Conclusion. The increase in stroke risk in Marburg I carriers could be due to differential effects on smooth muscle cells and on matrix metalloproteinases, thereby influencing plaque stability. The possible protective effect on restenosis could be the result of reduced activation of zymogens, which are involved in hemostasis and matrix remodeling.

Aims: This study was designed to investigate the counterbalancing influence of genetic variation in the promoter of the gene encoding P300/CBP associated factor (PCAF), a lysine acetyltransferase (KAT), on coronary heart disease (CHD) and mortality., Methods and Results: The association of genetic variation in the PCAF-gene with CHD, restenosis and mortality was investigated in three large cohorts. The results were combined to examine overall effects on CHD mortality and on restenosis risk. Compared with the homozygous -2481G allele in the PCAF promoter, a significant reduction in CHD mortality risk with the homozygous -2481C PCAF promoter allele was observed. A combined risk reduction for CHD death for the three studies was 21% (15-26%; p=8.1×10(-4)). In elderly patients (>58 years) the effects were stronger. Furthermore, this PCAF allele was significantly associated with all-cause mortality (p=0.001). Functional analysis showed that nuclear factors interact in vitro with the oligonucleotides encompassing the -2481G/C polymorphism and that this interaction might be influenced by this polymorphism in the PCAF promoter. Moreover, modulation of PCAF gene expression was detectable upon cuff-placement in an animal model of reactive stenosis., Conclusion: We showed in three large prospective studies that the -2481C allele in the PCAF promoter is associated with a significant survival advantage in elderly patients. Our observations promote the concept that epigenetic processes are under genetic control and that, other than environment, variation in genes encoding KATs may also determine susceptibility to CHD outcomes and mortality.

Objective: Restenosis after percutaneous coronary intervention (PCI) remains an issue even in the drug-eluting stent era. Genetic polymorphisms may provide insight in the pathogenesis of restenosis and may help in the stratification of patients at risk for restenosis. The aim of this study was to examine whether polymorphisms at the toll-like receptor 4 (TLR4) locus, that are associated with impaired innate immune system and with an increased risk of cardiovascular events, were associated with clinical and/or angiographic restenosis after PCI., Methods: The GENetic Determinants of Restenosis (GENDER) project was a prospective, multicenter study that enrolled 3146 consecutive patients after successful PCI. Frequencies of the TLR4 896A/G (Asp299Gly; rs4986790) and 1196C/T (Thr399Ile; rs4986791) polymorphisms and haplotypes were assessed. Patients were followed up for 1 year and in a subgroup of 406 patients angiographic follow-up was obtained., Results: We included a total of 2682 patients that underwent successful PCI. There was no association between genotypes and the risk of target vessel revascularization at 1-year or late luminal loss at 6-months angiographic follow-up (P=0.53 and 0.44, respectively). Absence of association with target lesion revascularization and late luminal loss was replicated in the GEnetic risk factors for In-Stent Hyperplasia study Amsterdam (GEISHA) cohort study of 674 patients and in a subgroup of 550 patients with angiographic follow-up available (P=0.26, and 0.86, respectively). Moreover, in both the studies, no significant differences between haplotypes A/C and G/T were observed for target vessel revascularization at late luminal loss., Conclusion: Although inflammation has been implicated in the pathophysiology of restenosis, the 896A/G and 1196C/T polymorphisms or haplotypes based on these polymorphisms at the TLR4 locus are not associated with an increased risk of target vessel revascularization or angiographic restenosis after PCI. These polymorphisms are not useful for pre-PCI identification of patients at risk for restenosis.

The importance of intracellular calcium ([Ca(2+)]i) regulation in the glomerular filtration barrier (GFB) has recently been highlighted by mutations in the cation channel TRPC6, resulting in a renal-specific phenotype. We examined the effects of FFA, a tool that can activate TRPC6, on [Ca(2+)]i in human conditionally immortalised glomerular endothelial cells (ciGEnC) and human podocytes (ciPod) that form the GFB. Changes in [Ca(2+)]i stimulated by FFA were measured in Fura 2-AM loaded cells. In GEnC, cell activation by FFA was dependent on external Ca(2+), yet in ciPod it was not. Depletion of internal Ca(2+) stores with thapsigargin did not affect cell activation by FFA in ciGEnC, but inhibited it in ciPod in a nephrin-dependent manner, demonstrated using nephrin deficient (ND) ciPod in conjunction with nephrin rescue experiments. FFA induced [Ca(2+)]i store release in ciPod, but not in ciGEnC or ND ciPod. In parallel, there were differences in the localisation of overexpressed TRPC6 between ciGEnC and ciPod. Furthermore, co-transfection of nephrin with TRPC6 in HEK293 cells reduced the FFA-induced increase in [Ca(2+)]i and nephrin clustering altered TRPC6 distribution. In conclusion, cell activation by FFA in podocytes stimulates the opening of a Ca(2+) channel, probably TRPC6, in a nephrin-dependent manner with a different activation profile to GEnC., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objective: Restenosis is the main drawback of percutaneous coronary intervention (PCI). Inherited factors may explain part of the risk of restenosis. Recently, the vitamin D receptor (VDR) has been shown to be involved not only in bone metabolism but also in modulating immune responses and cell proliferation. Since the inflammatory response is implicated in restenosis, VDR-gene variants could therefore contribute to the risk of restenosis., Methods/results: Systematic genotyping for 15 haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene was performed with the high throughput TaqMan allelic discrimination assays in the Genetic Determinants of Restenosis (GENDER) population. A haplotype-based survival analysis revealed an association of haplotypes in blocks 2, 3 and 4 of the VDR-gene with the risk of clinical restenosis (p-values 0.01, 0.04 and 0.02 respectively). After adjustment for clinical risk factors for restenosis, the individual effect of the block 2 AA haplotype (p = 0.011) persisted., Conclusions: The present study indicates that VDR plays a role in restenosis after PCI. Therefore, VDR genotype may be used as risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice.

Percutaneous coronary intervention (PCI) has become an effective therapy to treat coronary artery diseases. However, one of the major drawbacks of PCI is the occurrence of restenosis in 8 to 40% of all treated patients. The GENetic Determinants of Restenosis (GENDER) project was designed to study the association between genetic polymorphisims and clinical restenosis. The discovery of genetic variants associated to the occurrence of restenosis after PCI may provide a more tailored therapy and may serve as rationale for new antirestenotic therapies. So far, several candidate gene approaches had already been performed in the GENDER samples but a Genome Wide Association Scan (GWAS) was still lacking. Here, we present preliminary results from the GWAS we are currently carrying out in the GENDER population. (Neth Heart J 2009;17:262-4.).

PAI-1 expression is regulated by a 4G/5G promoter polymorphism. The 4G allele is associated with greater circadian variation of PAI-1 levels. We hypothesized that the 24 h variation of cardiac risk is more pronounced among persons with the 4G4G genotype than among ones with 4G5G and 5G5G genotypes. We assessed the time of onset of symptoms in 623 consecutive patients with acute myocardial infarction (AMI) enrolled in the MISSION! Study between February 1, 2004, and October 29, 2006. All of the patients were genotyped for the PAI-1 4G/5G polymorphism. We quantified the amplitude of the 24 h variation of AMI with a generalized linear model with Poisson distribution. A morning peak, between 06:00-11:59 h (n = 197; 32% of all cases), in the onset of symptoms of AMI was observed. The group composed of patients with the 4G4G genotype did not have a more pronounced morning peak than the groups composed of other genotypes; the 24 h variation was 38% (95% confidence interval 12-70%) in the group of 4G4G patients and 34% (14-58%) and 56% (20-100%) in the 4G5G and 5G5G groups of patients, respectively. Our findings show that 24 h variation of cardiac risk is not more pronounced among the 4G4G genotype of PAI-1.

Significant progress has been made in the clinical management of a variety of cardiovascular diseases. Nevertheless, the therapeutic efficacy of the current treatment modalities for atherosclerosis and restenosis is not fully sufficient in a large proportion of patients. One of the major contributing factors is the clinical and biological heterogeneity of these still life-threatening diseases, which involve processes that we do not fully understand at the moment. Over the past decades, it has become increasingly clear that part of the gene-environmental interactions relevant for complex diseases is regulated by epigenetic mechanisms such as histone acetylation and DNA methylation. Epigenetic processes modulate gene expression patterns without modifying the actual DNA sequence and have profound effects on the cellular repertoire of expressed genes. They contribute to the expression of genes that play a key role in extracellular matrix formation, inflammation, and proliferation, processes involved in cardiovascular pathologies such as atherosclerosis and restenosis. Therefore, in this review, we argue that epigenetic regulators involved in histone acetylating and deacetylating activities contribute to the pathogenesis of atherosclerosis and restenosis. Furthermore, as alterations in chromatin structure are reversible, these epigenetic modifications are amendable to pharmacological intervention, which may prove to be an effective treatment modality for the management of cardiovascular diseases.