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Within Deleuzian studies, the concept of heterogenesis has received little comment. No doubt, because it has been more worked by Félix Guattari than by Deleuze himself. It finds its full use in schizoanalysis, a theory where desire is no longer conceived as a lack or as a theater, but as a machine to produce, and where the unconscious is no longer the psychoanalytic unconscious circumscribed in a psychic space “familialized”, but a machinic unconscious which proceeds from interactive processes of a series of machines, or according to the Guattarian vocabulary, from a series of “collective assemblages of enunciation”. As we will see here, it is in the topological sharing of the quadrialtere of assemblages that the heterogenesis between “existential territories” and “universe constellations” is born.

Interview with Jacquese Donguy, a French poet, performer, translator and literary critic, professor at the University of Paris, on experimental poetry in the digital world.

Abstract Tracheotomy is widely used in intensive care units, albeit with great disparities between medical teams in terms of frequency and modality. Indications and techniques are, however, associated with variable levels of evidence based on inhomogeneous or even contradictory literature. Our aim was to conduct a systematic analysis of the published data in order to provide guidelines. We present herein recommendations for the use of tracheotomy in adult critically ill patients developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. These guidelines were conducted by a group of experts from the French Intensive Care Society (Société de Réanimation de Langue Française) and the French Society of Anesthesia and Intensive Care Medicine (Société Francaise d’Anesthésie Réanimation) with the participation of the French Emergency Medicine Association (Société Française de Médecine d’Urgence), the French Society of Otorhinolaryngology. Sixteen experts and two coordinators agreed to consider questions concerning tracheotomy and its practical implementation. Five topics were defined: indications and contraindications for tracheotomy in intensive care, tracheotomy techniques in intensive care, modalities of tracheotomy in intensive care, management of patients undergoing tracheotomy in intensive care, and decannulation in intensive care. The summary made by the experts and the application of GRADE methodology led to the drawing up of 8 formal guidelines, 10 recommendations, and 3 treatment protocols. Among the 8 formal guidelines, 2 have a high level of proof (Grade 1+/−) and 6 a low level of proof (Grade 2+/−). For the 10 recommendations, GRADE methodology was not applicable and instead 10 expert opinions were produced.

Tetanus is a neurologic disorder caused by tetanospasmin, a protein toxin elaborated by Clostridium tetani. Cephalic tetanus is a localized form of the disease causing trismus and dysfunction of cranial nerves. We report the case of a man who presented with facial trauma, complete ophthalmoplegia, exophthalmos, areactive mydriasis, and periorbital hematoma. An orbital CT revealed air bubbles in the right orbital apex. The patient was given a tetanus toxoid booster and antibiotherapy. After extraction of a wooden foreign body, the patient developed right facial nerve palsy, disorders of swallowing, contralateral III cranial nerve palsy, and trismus. Only one case of cephalic tetanus from penetrating orbital wound has been reported in literature 20 years ago. When a patient presents with an orbital wound with ophthalmoplegia and signs of anaerobic infection, cephalic tetanus should be ruled out.

It is unclear how the risk of post-COVID symptoms evolved during the pandemic, especially before the spread of Severe Acute Respiratory Syndrome Coronavirus 2 variants and the availability of vaccines. We used modified Poisson regressions to compare the risk of six-month post-COVID symptoms and their associated risk factors according to the period of first acute COVID: during the French first (March-May 2020) or second (September-November 2020) wave. Nonresponse weights and multiple imputation were used to handle missing data. Among participants aged 15 years or older in a national population-based cohort, the risk of post-COVID symptoms was 14.6% (95% confidence interval [CI], 13.9%-15.3%) in March-May 2020, vs 7.0% (95% CI, 6.3%-7.7%) in September-November 2020 (adjusted relative risk [RR], 1.36; 95% CI, 1.20-1.55). For both periods, the risk was higher in the presence of baseline physical condition(s), and it increased with the number of acute symptoms. During the first wave, the risk was also higher for women, in the presence of baseline mental condition(s), and it varied with educational level. In France in 2020, the risk of six-month post-COVID symptoms was higher during the first than the second wave. This difference was observed before the spread of variants and the availability of vaccines., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

The regular performance of Pap tests for cervical cancer screening reduces this disease's incidence and mortality. Income inequalities have been reported for this screening, partly because in some countries women must advance or even pay out-of-pocket costs. Because immigrant status is also associated with low Pap test uptake, we aimed to analyze the combined impact of immigrant status and low income on cervical cancer underscreening. This study, based on the French CONSTANCES cohort, uses data from the cohort questionnaires and linked health insurance fund data about Pap test reimbursement. To measure income inequalities in screening, we calculated a Slope Index of Inequality (SII) by linear regression, taking into account the migration status of participants. The majority of the 70,614 women included in the analysis were not immigrants (80.2%), while 12.9% were second-generation immigrants, and 6.9% first-generation immigrants. The proportion of underscreening increased with immigrant status, from 19.5% among nonimmigrants to 23.6% among the second generation, and 26.5% among the first ( P  < 0.01). The proportion of underscreening also increased as income level decreased. The income gradient rose significantly from 14% among nonimmigrants to 21% in second-generation immigrants and 19% in the first generation ( P  < 0.01). Among first-generation migrants, the shorter the duration of residence, the higher the SII. Women who are first- or second-generation immigrants are simultaneously underscreened and subject to a more unfavorable economic gradient than native French women born to native French parents. The accumulation of several negative factors could be particularly unfavorable to screening uptake., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Objective: To assess whether lack of trust in the government and scientists reinforces social and racial inequalities in vaccination practices., Design: A follow-up of the EpiCov random population-based cohort survey., Setting: In July 2021, in France., Participants: Eighty-thousand nine hundred and seventy-one participants aged 18 years and more., Main Outcome Measures: Adjusted odds ratios of COVID-19 vaccination status (received at least one dose/ intends to get vaccinated/ does not know whether to get vaccinated/refuses vaccination) were assessed using multinomial regressions to test associations with social and trust factors and to study how these two factors interacted with each other., Results: In all, 72.2% were vaccinated at the time of the survey. The population of unvaccinated people was younger, less educated, had lower incomes, and more often belonged to racially minoritized groups, as compared to vaccinated people. Lack of trust in the government and scientists to curb the spread of the epidemic were the factors most associated with refusing to be vaccinated: OR = 8.86 (7.13 to 11.00) for the government and OR = 9.07 (7.71 to 10.07) for scientists, compared to vaccinated people. Lack of trust was more prevalent among the poorest which consequently reinforced social inequalities in vaccination. The poorest 10% who did not trust the government reached an OR of 16.2 (11.9 to 22.0) for refusing to be vaccinated compared to the richest 10% who did., Conclusion: There is a need to develop depoliticised outreach programmes targeted at the most socially disadvantaged groups, and to design vaccination strategies conceived with people from different social and racial backgrounds to enable them to make fully informed choices., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bajos, Spire, Silberzan, Sireyjol, Jusot, Meyer, Franck, Warszawski and the EpiCov study group.)

Background: We aimed to study whether social patterns of exposure to SARS-CoV-2 infection changed in France throughout the year 2020, in light to the easing of social contact restrictions., Methods: A population-based cohort of individuals aged 15 years or over was randomly selected from the national tax register to collect socio-economic data, migration history, and living conditions in May and November 2020. Home self-sampling on dried blood was proposed to a 10% random subsample in May and to all in November. A positive anti-SARS-CoV-2 ELISA IgG result against the virus spike protein (ELISA-S) was the primary outcome. The design, including sampling and post-stratification weights, was taken into account in univariate and multivariate analyses., Results: Of the 134,391 participants in May, 107,759 completed the second questionnaire in November, and respectively 12,114 and 63,524 were tested. The national ELISA-S seroprevalence was 4.5% [95%CI: 4.0%-5.1%] in May and 6.2% [5.9%-6.6%] in November. It increased markedly in 18-24-year-old population from 4.8% to 10.0%, and among second-generation immigrants from outside Europe from 5.9% to 14.4%. This group remained strongly associated with seropositivity in November, after controlling for any contextual or individual variables, with an adjusted OR of 2.1 [1.7-2.7], compared to the majority population. In both periods, seroprevalence remained higher in healthcare professions than in other occupations., Conclusion: The risk of Covid-19 infection increased among young people and second-generation migrants between the first and second epidemic waves, in a context of less strict social restrictions, which seems to have reinforced territorialized socialization among peers., Competing Interests: The authors have declared that no competing interests exist

Objective: Although social inequalities in COVID-19 mortality by race, gender and socioeconomic status are well documented, less is known about social disparities in infection rates and their shift over time. We aim to study the evolution of social disparities in infection at the early stage of the epidemic in France with regard to the policies implemented., Design: Random population-based prospective cohort., Setting: From May to June 2020 in France., Participants: Adults included in the Epidémiologie et Conditions de Vie cohort (n=77 588)., Main Outcome Measures: Self-reported anosmia and/or ageusia in three categories: no symptom, during the first epidemic peak (in March 2020) or thereafter (during lockdown)., Results: In all, 2052 participants (1.53%) reported anosmia/ageusia. The social distribution of exposure factors (density of place of residence, overcrowded housing and working outside the home) was described. Multinomial regressions were used to identify changes in social variables (gender, class and race) associated with symptoms of anosmia/ageusia. Women were more likely to report symptoms during the peak and after. Racialised minorities accumulated more exposure risk factors than the mainstream population and were at higher risk of anosmia/ageusia during the peak and after. By contrast, senior executive professionals were the least exposed to the virus with the lower rate of working outside the home during lockdown. They were more affected than lower social classes at the peak of the epidemic, but this effect disappeared after the peak., Conclusion: The shift in the social profile of the epidemic was related to a shift in exposure factors under the implementation of a stringent stay-at-home order. Our study shows the importance to consider in a dynamic way the gender, socioeconomic and race direct and indirect effects of the COVID-19 pandemic, notably to implement policies that do not widen health inequalities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Self-reported data are prone to item non-response and misreporting. We investigated to what extent the use of self-reported data for participation in breast (BCS) and cervical cancer screening (CCS) impacted socioeconomic inequalities in cancer screening participation., Methods: We used data from a large population-based survey including information on cancer screening from self-reported questionnaire and administrative records (n = 14 122 for BCS, n = 27 120 CCS). For educational level, occupation class and household income per capita, we assessed the accuracy of self-reporting using sensitivity, specificity and both positive and negative predictive value. In addition, we estimated to what extent the use of self-reported data modified the magnitude of socioeconomic differences in BCS and CCS participation with age-adjusted non-screening rate difference, odds ratios and relative indices of inequality., Results: Although women with a high socioeconomic position were more prone to report a date for BCS and CCS in questionnaires, they were also more prone to over-declare their participation in CCS if they had not undergone a screening test within the recommended time frame. The use of self-reported cancer screening data, when compared with administrative records, did not impact the magnitude of social differences in BCS participation but led to an overestimation of the social differences in CCS participation. This was due to misreporting rather than to item non-response., Conclusions: Women's socioeconomic position is associated with missingness and the accuracy of self-reported BCS and CCS participation. Social inequalities in cancer screening participation based on self-reports are likely to be overestimated for CCS., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

The regular performance of Pap tests reduces the mortality of cervical cancer. Obesity is associated with low Pap test rates. We analyze the combined role of obesity and low income. We calculated a Slope Index of Inequality. Among the 28,905 women included, 23.1% were underscreened. The rate of underscreening increased with BMI. The income gradient increased significantly from 0.17 among normal-weight women to 0.19 in overweight and 0.23 in obese women (p = 0.047). Women who are obese are subject to a double penalty in cervical cancer screening: they are underscreened and subject to a more unfavorable economic gradient than normalweight women., (Copyright © 2021 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Background: Significant differences in COVID-19 incidence by gender, class and race/ethnicity are recorded in many countries in the world. Lockdown measures, shown to be effective in reducing the number of new cases, may not have been effective in the same way for all, failing to protect the most vulnerable populations. This survey aims to assess social inequalities in the trends in COVID-19 infections following lockdown., Methods: A cross-sectional survey conducted among the general population in France in April 2020, during COVID-19 lockdown. Ten thousand one hundred one participants aged 18-64, from a national cohort who lived in the three metropolitan French regions most affected by the first wave of COVID-19. The main outcome was occurrence of possible COVID-19 symptoms, defined as the occurrence of sudden onset of cough, fever, dyspnea, ageusia and/or anosmia, that lasted more than 3 days in the 15 days before the survey. We used multinomial regression models to identify social and health factors related to possible COVID-19 before and during the lockdown., Results: In all, 1304 (13.0%; 95% CI: 12.0-14.0%) reported cases of possible COVID-19. The effect of lockdown on the occurrence of possible COVID-19 was different across social hierarchies. The most privileged class individuals saw a significant decline in possible COVID-19 infections between the period prior to lockdown and during the lockdown (from 8.8 to 4.3%, P = 0.0001) while the decline was less pronounced among working class individuals (6.9% before lockdown and 5.5% during lockdown, P = 0.03). This differential effect of lockdown remained significant after adjusting for other factors including history of chronic disease. The odds of being infected during lockdown as opposed to the prior period increased by 57% among working class individuals (OR = 1.57; 95% CI: 1.00-2.48). The same was true for those engaged in in-person professional activities during lockdown (OR = 1.53; 95% CI: 1.03-2.29)., Conclusions: Lockdown was associated with social inequalities in the decline in COVID-19 infections, calling for the adoption of preventive policies to account for living and working conditions. Such adoptions are critical to reduce social inequalities related to COVID-19, as working-class individuals also have the highest COVID-19 related mortality, due to higher prevalence of comorbidities.

Objectives: To investigate the relationship between patterns of gynaecological check-up and body mass index while accounting for various determinants of health care use., Methods: Sequence analysis and clustering were used to highlight patterns of gynaecological check-up, which included the regularity of breast and cervical cancer screening and visits to the gynaecologist over four years, among 6182 women aged 54-65 included in the CONSTANCES cohort between 2013 and 2015 in France. Multinomial logistic regressions were used to study the association between these patterns and women's body mass index., Results: We identified four patterns of gynaecological check-up, from (A) no or inappropriate check-up (20%) to (D) almost one visit to the gynaecologist every year, overscreening for cervical cancer and frequent use of opportunistic breast cancer screening (12%). From patterns A to D, the proportion of obese women decreased and that of women with normal body mass index increased. Obese and overweight women underwent more breast than cervical cancer screening and were less often overscreened than normal weight women. These differences were only partly explained by the lower socioeconomic situation of overweight and obese women. Beyond the financial barrier, the screening modality and the type of exam may play a role. Among women who were screened for cervical cancer, obese and overweight women were less often screened by a gynaecologist., Conclusion: Further efforts should be made to enhance the take-up of screening among obese women who are deterred by the healthcare system.

Background: The combined association between primary care utilization and health status with breast cancer screening (BCS) and cervical cancer screening (CCS) remains unclear. Our aim was to identify women's profiles based on their health status and primary care utilization and study their associated adherence to BCS and CCS recommendations., Methods: Using data from the cohort of people visiting health screening centers (CONSTANCES) in France (2012-2015), we first identified women's profiles based on their health status (self-perceived health, physical, and mental health) and primary care utilization (visit to the General Practitioner [GP], uptake of blood tests) using a multiple correspondence analysis and a hierarchical cluster analysis. We then investigated the association of these profiles to BCS and CCS using logistic regression models adjusted for age, smoking status, sociodemographic and socioeconomic characteristics, and the regularity of gynecologist consultation., Results: We identified five distinct profiles of women with contrasted participation in BCS ( n  = 14,122) and CCS ( n  = 27,120). In multivariate analyses, cancer screening participation increased from women with very good health and poor primary care utilization, to those with poor health and frequent visits to the GP, and those with very good health and average primary care utilization. The most favorable profiles regarding cancer screening rates were women with average-to-poor health and regular visits to the GP and uptake of blood tests., Conclusions: Our results suggest that policies aiming at increasing cancer screening participation should simultaneously account for women's use of primary care and health and consider more specific subgroups than what is usually done. Further research should investigate factors motivating cancer screening practice, such as women's beliefs regarding cancer screening and women's psychological characteristics., Competing Interests: No competing financial interests exist., (© Thi-Van-Trinh Tran et al., 2020; Published by Mary Ann Liebert, Inc.)

Purpose: Despite their higher risk for and mortality from cervical cancer, evidence indicates low rates of cervical cancer screening (CCS) among women with obesity. The literature on the specific factors related to CCS nonadherence in this population is limited., Methods: We examined the data on 2,934 women with obesity included in the CONSTANCES survey from 2012 to 2015. Using the Andersen's behavioral model, we studied the relationships between the socioeconomic, sociodemographic, health, health personal behaviors, and healthcare use-related factors with CCS nonadherence. The analysis was performed using structural equation models., Results: Regular follow-up by a gynecologist, good quality of primary care follow-up, and comorbidities were negatively associated with CCS nonadherence. Limited literacy, older age, being single, living without children, and financial strain were positively associated with CCS nonadherence. Our results do not point to competitive care, since women with comorbidities had better CCS behaviors, which were explained by a good quality of primary care follow-up., Conclusion: Our study identified the factors that explain CCS nonadherence among women with obesity and clarified the effects of health status and healthcare use on screening. Further efforts should be undertaken to reduce the obstacles to CCS by improving care among women with obesity.

Background: Immigrant women often have lower cervical cancer screening (CCS) rates, tend to have a higher body mass index (BMI) and may be more vulnerable to BMI-related stigmatization. Our aim was to assess the role of BMI in differences in CCS rates by migration history., Methods: Analyses were based on the 2012-2015 inclusion data (n = 27,226) for the population-based CONSTANCES cohort, including detailed, self-reported information on demographics and socioeconomic characteristics, migration history, health behaviours, health, and health care use. Measured BMI (underweight (<18.5), normal-weight (18.5-25), overweight (25-30), obese (>30)) was collected. Poisson regression models with robust variance were conducted to assess the contribution of BMI to differences in CCS rates by migration history, and analyses stratified by BMI were done. Multiple imputations were performed., Results: The CCS rates ranged from 87% among French-born women with two French parents to 86% among French-born women with at least one parent of foreign origin, 82% among naturalized immigrants and 74% among non-naturalized immigrants. After adjusting for covariates, non-naturalized immigrants showed an 11% (95% CI: 8%-14%) lower CCS rate than French-born women with two French parents. Adjusting for BMI did not change the estimates. When stratifying by BMI category, non-naturalized immigrants showed an 11% (7%-14%) lower CCS rate then French-born with two French parents when normal weight, a 9% (2%-16%) lower CCS rate when overweight, and an 18% (5%-30%) lower CCS rate when obese., Conclusion: Migration history and BMI jointly impact CCS rates. They were lower among all non-naturalized immigrants, particularly those who were obese., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed at investigating the associations between occupational prestige trajectories and lung and head and neck (HN) cancer risk and to assess to what extent smoking, alcohol drinking, and occupational exposures contribute to these associations., Methods: Using data from the ICARE case-control study (controls (2676 men/715 women), lung cancers (2019 men/558 women), HN cancers (1793 men/305 women), we defined occupational prestige trajectories using group-based modeling of longitudinal data. We conducted logistic regression models., Results: Among men, a gradient was observed from the downward "low to very low" trajectory to the stable very high trajectory. The associations were reduced when adjusting for tobacco and alcohol consumption and occupational exposures. Among women, when compared to the stable high trajectory, there was an increased cancer risk in all trajectories. The associations remained globally unchanged or even increased after adjustment for tobacco and alcohol consumption and did not change when adjusting for occupational exposures. The ORs were smaller for lung than for HN cancers in men., Conclusions: Occupational prestige trajectory is strongly associated with lung and HN cancer risk in men and women.

Background: Some contextual factors associated with participation in cervical cancer screening are reported in the literature, but few studies have examined their combined effect. Our objective was to assess the role of contextual characteristics, separately and in combination, in participation in cervical cancer screening in France., Methods: Marginal Poisson regression models - taking into account the correlation between women in a given commune - were conducted using data from the Baromètre Santé 2010 survey. The characteristics of the commune of residence of the women studied were the potential spatial accessibility to general practitioners (GP) and gynecologists, the agglomeration category, and the socioeconomic level., Results: The analyses were performed in 3380 women, 88.2% of whom were up to date with their cervical cancer screening. Once the individual characteristics were taken into account, the screening participation rate was similar in all the communes, with the exception of those with poor access to a gynecologist and good access to a GP, where the rate was 6% lower (95%CI: 0.5-11%) than in the communes with good access to both GP and gynecologist. The same association with accessibility was observed in small agglomerations. Compared to women living in the more advantaged communes, the screening participation rate was 8% (2-12%) lower in those living in the more disadvantaged ones, except when accessibility to both types of physician was high., Discussion: We observed an association between potential spatial accessibility to care in women's residential communities and their cervical cancer screening practices, in particular in small agglomerations, rural communes, and more disadvantaged communes., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Smoking only partly explains the higher lung cancer incidence observed among socially deprived people. Occupational exposures may account for part of these inequalities, but this issue has been little investigated. We investigated the extent to which smoking and occupational exposures to asbestos, silica and diesel motor exhaust mediated the association between education and lung cancer incidence in men. We analyzed data from a large French population-based case-control study (1976 lung cancers, 2648 controls). Detailed information on lifelong tobacco consumption and occupational exposures to various carcinogens was collected. We conducted inverse probability-weighted marginal structural models. A strong association was observed between education and lung cancer. The indirect effect through smoking varied by educational level, with the strongest indirect effect observed for those with the lowest education (OR = 1.34 (1.14-1.57)). The indirect effect through occupational exposures was substantial among men with primary (OR = 1.22 (1.15-1.30) for asbestos and silica) or vocational secondary education (OR = 1.18 (1.12-1.25)). The contribution of smoking to educational differences in lung cancer incidence ranged from 22 % (10-34) for men with primary education to 31 % (-3 to 84) for men with a high school degree. The contribution of occupational exposures to asbestos and silica ranged from 15 % (10-20) for men with a high school degree to 20 % (13-28) for men with vocational secondary education. Our results highlight the urgent need for public health policies that aim at decreasing exposure to carcinogens at work, in addition to tobacco control policies, if we want to reduce socioeconomic inequalities in the cancer field.

Background: Recent randomized trials report that mortality is lower with high-convection-volume hemodiafiltration (HDF) than with hemodialysis (HD)., Study Design: We used data from the French national Renal Epidemiology and Information Network (REIN) registry to investigate trends in HDF use and its relationship with mortality in the total population of incident dialysis patients., Setting & Participants: The study included those who initiated HD therapy from January 1, 2008, through December 31, 2011, and were dialyzed for more than 3 months; follow-up extended to the end of 2012., Factor: HDF use at the patient and facility level., Outcomes: All-cause and cardiovascular mortality, using Cox models to estimate HRs of HDF as time-dependent covariate at the patient level, with age as time scale and fully adjusted for comorbid conditions and laboratory data at baseline, catheter use, and facility type as time-dependent covariates. Analyses completed by Cox models for HRs of the facility-level exposure to HDF updated yearly., Results: Of 28,407 HD patients, 5,526 used HDF for a median of 1.2 (IQR, 0.9-1.9) years; 2,254 of them used HDF exclusively. HRs for all-cause and cardiovascular mortality associated with HDF use were 0.84 (95% CI, 0.77-0.91) and 0.73 (95% CI, 0.61-0.88), respectively. In patients treated exclusively with HDF, these HRs were 0.77 (95% CI, 0.67-0.87) and 0.66 (95% CI, 0.50-0.86). At the facility level, increasing the percentage of patients using HDF from 0% to 100% was associated with HRs for all-cause and cardiovascular mortality of 0.87 (95% CI, 0.77-0.99) and 0.72 (95% CI, 0.54-0.96), respectively., Limitations: Observational study., Conclusions: Whether analyzed as a patient- or facility-level predictor, HDF treatment was associated with better survival., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Acetate-free dialysis (AFD) improves haemodynamic stability during dialysis, compared with standard haemodialysis (HD) with a small amount of acetic acid. Using the national REIN registry, we classified 15 160 incident patients who started HD from 2008 to 2010 into three exposure categories according to the type of dialysate used in their dialysis unit: standard dialysate only (reference), both standard and AFD (mixed unit) or HCl dialysate only (100% HCl unit)., Methods: Cox survival analysis was adjusted for 15 baseline comorbidities, laboratory data and haemodiafiltration (HDF). We took patient clustering within units into account, used age as the time scale and treated patient exposure to AFD and to HDF as time-dependent variables., Results: Median age (interquartile range) was 70.5 years (58.1-78.8). Over a median follow-up of 1.8 years (1.2-2.6), 658 patients were dialysed in a 100% HCl unit, 3021 in a mixed unit and 11 481 were never exposed to AFD. The relation between AFD and mortality was not constant with age (Schoenfeld residuals test P = 0.01 for mixed group and P = 0.03 for 100%HCl group). Patients older than 70 years had a significantly lower mortality risk associated with AFD [hazard ratio (HR) = 0.79, 95% confidence interval (CI) = 0.67 to 0.94 for patients exposed in a 100% HCl unit; HR = 0.83, 95% CI = 0.74 to 0.94 for patients exposed in a mixed unit], but no association was found in younger patients., Conclusions: AFD was associated with improved survival independent of comorbidities and HDF in patients aged 70 years and older but not in patient younger than 70 years., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Anti-peptide antibodies that specifically recognize the alpha1 subunit of class A-D voltage-gated Ca2+ channels and a monoclonal antibody (MANC-1) to the alpha2 subunit of L-type Ca2+ channels were used to investigate the distribution of these Ca2+ channel subtypes in neurons and glia in models of brain injury, including kainic acid-induced epilepsy in the hippocampus, mechanical and thermal lesions in the forebrain, hypomyelination in white matter, and ischemia. Immunostaining of the alpha2 subunit of L-type Ca2+ channels by the MANC-1 antibody was increased in reactive astrocytes in each of these forms of brain injury. The alpha1C subunits of class C L-type Ca2+ channels were upregulated in reactive astrocytes located in the affected regions in each of these models of brain injury, although staining for the alpha1 subunits of class D L-type, class A P/Q-type, and class B N-type Ca2+ channels did not change from patterns normally observed in control animals. In all of these models of brain injury, there was no apparent redistribution or upregulation of the voltage-gated Ca2+ channels in neurons. The upregulation of L-type Ca2+ channels in reactive astrocytes may contribute to the maintenance of ionic homeostasis in injured brain regions, enhance the release of neurotrophic agents to promote neuronal survival and differentiation, and/or enhance signaling in astrocytic networks in response to injury.

Morphological and electrophysiological techniques were used to examine granule cells and their mossy fiber axons in nine surgically resected hippocampal specimens from temporal lobe epilepsy (TLE) patients. Timm histochemistry showed mossy fiber sprouting into the inner molecular layer (IML) of the dentate in a subset of tissue samples. In slices from five tissue samples, stimulus-induced bursting activity could be induced with a low concentration (2.5 microM) of bicuculline; bursts were sensitive to the N-methyl-D-aspartate (NMDA) blocker, APV. There was a general correlation between such sprouting and experimentally induced hyperexcitability. Fourteen granule cells from five tissue samples were intracellularly stained [with lucifer yellow (LY) or neurobiotin]. Axons from a subset of these neurons showed axon collaterals reaching into the IML, but this axon projection pattern for single cells was not directly correlated with degree of mossy fiber sprouting shown grossly by Timm staining. Electron microscopic examination of intracellularly stained elements showed mossy fiber axon terminals making asymmetric synaptic contacts (including autapses on the granule cell dendrite) with dendritic shafts and spines in both apical and basal domains. These data are consistent with the hypothesis that mossy fiber sprouting provides a structural basis for recurrent excitation of granule cells, but does not provide direct support of the hypothesis that mossy fiber sprouting causes hyperexcitability. The data suggest that granule cell bursting activity is at least in part a function of compromised synaptic inhibition, since levels of gamma-aminobutyric acid (GABA) blockade that are generally subthreshold for burst induction were epileptogenic in some tissue samples from human epileptic hippocampus.

Amplification of complementary DNA by the polymerase chain reaction and anti-peptide antibodies were used to characterize the expression of two alternatively spliced forms of a metabotropic glutamate receptor (mGluR1 alpha and mGluR1 beta) in the central nervous system of the rat. Polymerase chain reaction analysis showed that mGluR1 alpha was the predominate of the two forms in the cerebellum, diencephalon, mesencephalon, olfactory bulb and brainstem, while mGluR1 beta was the major form present in the hippocampus. Approximately equal amounts of the two receptors were expressed in the cerebral cortex, septum and striatum. Immunochemical analyses of the two receptors were conducted in the rat cerebellum and hippocampus. An mGluR1 alpha-specific antibody labelled a protein with a relative molecular weight of 146,000 on immunoblots of the hippocampus and cerebellum. Immunoblot analysis of the developmental expression of mGluR1 alpha in the hippocampus and cerebellum demonstrated that in both structures, the levels of mGluR1 alpha were at or near their maximum levels in the adult brain. In contrast, two mGluR1 beta-specific antibodies failed to detect mGluR1 beta on immunoblots of brain tissue, thus precluding an immunocytochemical analysis of this receptor. Although low levels of a higher-molecular weight protein, possibly a dimeric form of mGluR1 beta were seen with one of the mGluR1 beta-specific antibodies, we hypothesize that some of the mGluR1 beta present in brain tissue may undergo proteolytic cleavage of the carboxy terminus. Immunocytochemical analysis of mGluR1 alpha showed that very high levels of this receptor were expressed in Purkinje cell bodies and dendrites. In the granule cell layer, some Golgi neurons were immunostained. The granule cells were not labelled. In the hippocampus, mGluR1 alpha immunoreactivity was present in interneurons of the stratum oriens and the dentate hilar region. Double-labelling studies demonstrated that these interneurons were also immunopositive for the neuropeptide somatostatin. The presence of mGluR1 alpha in cells of the hippocampus that are associated with the release of somatostatin, suggest that this receptor could play a role in regulating hippocampal excitability in both normal and epileptic tissues.

The effects of intraventricular injection of kainic acid on the Na,K-ATPase (Na,K pump) were examined in discrete pyramidal cell regions of rat hippocampus. [3H]Ouabain binding was used to quantitate Na,K-ATPase catalytic subunits and in situ hybridization was used to determine Na,K-ATPase mRNA levels. Large decreases were found in both [3H]ouabain binding and alpha 3 isoform mRNA in hippocampus areas, especially in the CA3 pyramidal cell layer, which sustains heavy cell losses as a result of bilateral, intraventricular injection of kainic acid. Substantial decreases in the high affinity component of ouabain binding and in the alpha 3 isoform mRNA (but not isoforms for other Na,K-ATPase subunits) were also observed in the CA1 region of hippocampus, an area preserved in this model. High affinity [3H]ouabain binding was decreased 25-33% in the stratum pyramidale and stratum radiatum after treatment with kainic acid, and alpha 3 mRNA was decreased by 26-50%. To further characterize the decrease in alpha 3 mRNA, animals were killed at 1, 2, and 3 weeks after injection of kainate and results show a large decrease in alpha 3 mRNA only at 2 weeks recovery time. While the pathology underlying temporal lobe epilepsy is unclear, changes in the Na,K-ATPase may be involved in abnormal firing characteristics of cells in epileptic tissue.

The role of specific neuronal populations in epileptic foci was studied by comparing epileptic and non-epileptic cortex removed from patients with low-grade gliomas. Epileptic and nearby (within 1 to 2 cm) non-epileptic temporal lobe neocortex was identified using electrocorticography. Cortical specimens taken from four patients identified as epileptic and nonepileptic were all void of tumor infiltration. Somatostatin- and gamma-aminobutyric acid (GABAergic)-immunoreactive neurons were identified and counted. Although there was no significant difference in the overall cell count, the authors found a significant decrease in both somatostatin- and GABAergic-immunoreactive neurons (74% and 51%, respectively) in the epileptic cortex compared to that in nonepileptic cortex from the same patient. It is suggested that these findings demonstrate changes in neuronal subpopulations that may account for the onset and propagation of epileptiform activity in patients with low-grade gliomas.

Following kainate (KA)-induced lesions of subfield CA3--a lesion relevant to human temporal lobe epilepsy--remaining pyramidal cells in CA1 display synchronous hyperexcitability associated with a loss of synaptic inhibition. Despite this loss, inhibitory interneurons in CA1 remain viable, and the density and function of GABAergic receptors on the CA1 pyramidal cells are maintained at approximately normal levels. To further evaluate inhibition in this system, the authors examined interactions between pyramidal cells and inhibitory interneurons in paired intracellular recordings. Recordings were carried out in rat hippocampal slices 2-4 weeks following bilateral intraventricular KA injections. The frequency of synaptic interactions between CA1 basket cells and pyramidal cells was lower in hyperexcitable slices than in controls; both synapses in the recurrent inhibitory circuit appeared to be involved. No recurrent excitatory interactions were seen between pyramidal cell pairs in lesioned or normal slices. The weakened interconnections between pyramidal cells and interneurons are consistent with the decreased inhibition previously found in this model. Unexpectedly, strong stimulation, which may directly activate local inhibitory circuitry, was effective in reducing hyperexcitability in KA-lesioned slices. These data suggest that development of recurrent excitatory connections among CA1 hippocampal pyramidal cells contribute little to tissue excitability, and support the hypothesis that a functional uncoupling between inhibitory interneurons and CA1 pyramidal cells is responsible for the seizure-like activity typical of KA-lesioned hippocampus. The data are also consistent with the hypothesis that in the KA model, the structural circuitry needed for inhibition in CA1 is maintained, and can be functionally activated by appropriate stimuli.

In the hippocampi of individuals with temporal lobe epilepsy, cells in CA1, CA3, and the dentate hilus are often gone, but dentate granule cells and CA2 are relatively spared. Several animal models have been developed which mimic portions of this damage. In the present work, combined intraventricular kainate and forebrain ischemia produced a lesion most like that observed clinically; the dentate granule cells and a resistant cluster of pyramidal cells, which received mossy fiber input, were the only principle neurons remaining. This preparation may be valuable both in determining the nature of cells that survive and in understanding the consequences of such damage.

Ischemic damage to the brain, whether induced experimentally or observed clinically, often produces a pattern of delayed selective cell death in subfield CA1 of hippocampus which has been associated with significant neurologic deficits. The present study demonstrates that this selective vulnerability of CA1 neurons to ischemia, with relative preservation of their neighbors, is expressed in organotypic tissue culture and is prevented by the N-methyl-D-aspartate (NMDA) receptor blocker, MK-801. These data provide conclusive evidence that this selective cell death does not have a vascular etiology but is mediated by factors intrinsic to the hippocampal neurons and/or local circuitry. This model system provides an opportunity both to examine mechanisms of ischemic cell death in an avascular environment and to study methods of prevention in the absence of systemic variables.

Experimental hyperthermic seizures in 15-day-old rats resulted in both an alteration in the benzodiazepine (BDZ) binding site in the hippocampal region and morphologic changes in hippocampal neurons. These alterations were not apparent until adulthood. Experimental adult animals also showed a reduced anticonvulsant response to a selective BDZ ligand when challenged with pentylenetetrazol. Developmental hyperthermic seizures may initiate dynamic changes in the hippocampus that contribute to adult functional impairment.

Several primary and secondary reactions were observed in rat hippocampus at various times following low doses of intraventricular kainic acid. The well documented fulminating lesion of subfield CA3a was evident, however, with the parameters of the present study, the acute neuronal death was restricted to areas which have been shown by others to have an exceptionally dense mossy fiber input. Neurons in subfields CA3c and CA4 also die, however, this was apparent only after a survival time of 2 weeks; prior to this, these cells went through a period of chromatolysis and dendritic swelling. In remaining subfields, principally 'CA2' and CA1, a third type of change was observed at longer intervals of 1 month. This was characterized by neuronal shrinkage and chromophilia and eventual cell loss. The present study provides additional observations on the actions of kainic acid in the hippocampus and may be relevant to the dynamic pathology of temporal lobe epilepsy.

The Genetically Epilepsy-Prone Rat (GEPR) is a widely studied model of epileptiform disorders. While there is considerable evidence that neurotransmitter abnormalities contribute to the unusual sensitivity of these animals to seizures, the possibility that seizure susceptibility may reflect developmental changes in the central nervous system has not been fully addressed. In the present study, 91 GEPR-9 pups were tested for incidence, latency and severity of an audiogenically induced seizure at 6, 9, 12, 15, 18, 21, 24, 27, 28, 29, or 30 days postpartum (1 test per pup) and retested at 60 days. Seizure incidence, latency, and severity were significantly greater on Days 27, 28, 29, and 30 than on all previous days. The first observation of running fits occurred in Day 18 pups and the first evidence of seizures occurred in Day 21 pups. When retested at Day 60, seizure incidence and severity were significantly greater than on initial tests while latency declined. The results suggest that seizure susceptibility in the GEPR-9 occurs as the result of developmental events in the CNS occurring on or shortly after Day 18 postpartum.

Kainic acid lesions of hippocampal subfields CA3-CA4 produced dramatic synchronous afterdischarge activity in subfield CA1 when studied 2-4 weeks post-lesion in the in vitro slice preparation. This epileptiform discharge was correlated with a loss of intrinsic firing-induced afterhyperpolarizations and synaptic IPSPs. Two to 4 months post-lesion, intrinsic afterpotentials and synaptic inhibition appeared normal in most cells studied.

Progesterone induced high levels of female lordotic behavior in 10 of 17 intact, estrogen-primed male rats when it was applied directly to the medial preoptic-anterior hypothalamic area. All 17 males previously had shown lordosis when the serotonergic antagonist methysergide was applied to the same central sites. Few males responded to systemic progesterone and none to intracralial cholesterol. Intradiencephalic Metycaine, a local anesthetic, induced lordosis in eight male that previously had responded to central progesterone. These data indicate that estrogen and progesterone act synergistically to induce lordosis in male rats when progesterone is administered directly to sensitive brain sites.

Benzodiazepine (BZ) binding is being studied in the spinal trigeminal nucleus of the cat 3 and 11 days following unilateral retrogasserian rhizotomy using in vitro autoradiography and computer-assisted densitometry. At 3 days following rhizotomy there is an increase in number and decrease in affinity of flunitrazepam binding sites in the superficial laminae of subnucleus caudalis of the spinal trigeminal complex. By 11 days, affinity remains below control values and binding site number shows an insignificant but detectable increase. There is no change in binding site characteristics in deeper laminae at either survival time. The results are discussed in relation to the physiological hyperactivity and synaptic changes which occur following such lesions and to other conditions of deafferentation.

Intraventricular injection of kainic acid produced a characteristic necrosis in the hippocampal CA3 region of adult rabbits. Neurons in immature rabbit hippocampus were relatively insensitive to the intraventricular neurotoxin, even though these injections caused seizures. In contrast, the immature hippocampus was highly sensitive to kainate delivered systemically. Systemic kainate preferentially killed neurons in the CA1 region, not the CA3 region, of immature animals. Kainate injections also caused cellular damage in brain regions other than hippocampus. In immature rabbits, the pattern of extra-hippocampal damage was similar regardless of the route of kainate delivery. This pattern of extra-hippocampal damage was distinctly different than that seen in adults following intraventricular kainate. These data suggest that kainate-induced damage in the CA3 and CA1 regions of the hippocampus are mediated by different mechanisms. Furthermore, the dissimilar patterns of extra-hippocampal damage in immature and adult rabbits suggest that mature and immature animals have differential sensitivity to kainate, different types of kainate binding sites, and/or different distributions of kainate receptors.

Development of clonic-tonic flurothyl-induced seizures was examined in both normal and genetically epilepsy-prone rats (GEPRs). At each age, from 10 to 30 days, clonus occurred at significantly shorter latencies in GEPRs than in normal rats. The latency to onset of clonic seizures did not change with age, however, in either GEPRs or normal rats. A different pattern of response was observed in the progression to tonic seizures. As normal animals matured, the latency to tonic seizures became longer and, by day 30, the duration of flurothyl exposure necessary to induce tonus was almost 70% greater in normal rats than in the GEPRs. In contrast, in GEPRs, tonic extension occurred immediately following the onset of clonus throughout development. A subset of GEPRs failed to have audiogenic seizures in a 40-day posttest. These animals had a flurothyl response identical to their audiogenic-susceptible litter mates. These data suggest that (a) a protective mechanism which develops against tonic seizures in normal rats fails to mature in the GEPR, and (b) seizure inducing gene-linked neural abnormalities occur in the GEPR independent of pathologies underlying audiogenic seizures.