Centre d'Épidémiologie sur les Causes Médicales de Décès

BACKGROUND: Spatial health inequalities have often been analysed in terms of deprivation. The aim of this study was to create an ecological deprivation index and evaluate its association with mortality over the entire mainland France territory. More specifically, the variations with the degree of urbanicity, spatial scale, age, gender and cause of death, which influence the association between mortality and deprivation, have been described. METHODS: The deprivation index, 'FDep99', was developed at the 'commune'(smallest administrative unit in France) level as the first component of a principal component analysis of four socioeconomic variables. Proxies of the Carstairs and Townsend indices were calculated for comparison. The spatial association between FDep99 and mortality was studied using five different spatial scales, and by degree of urbanicity (five urban unit categories), age, gender and cause of death, over the period 1997-2001. 'Avoidable' causes of death were also considered for subjects aged less than 65 years. They were defined as causes related to risk behaviour and primary prevention (alcohol, smoking, accidents). RESULTS: The association between the FDep99 index and mortality was positive and quasi-log-linear, for all geographic scales. The standardized mortality ratio (SMR) was 24% higher for the communes of the most deprived quintile than for those of the least deprived quintile. The between-urban unit category and between-région heterogeneities of the log-linear associations were not statistically significant. The association was positive for all the categories studied and was significantly greater for subjects aged less than 65 years, for men, and for 'avoidable' mortality. The amplitude and regularity of the associations between mortality and the Townsend and Carstairs indices were lower. CONCLUSION: The deprivation index proposed reflects a major part of spatial socioeconomic heterogeneity, in a homogeneous manner over the whole country. The index may be routinely used by healthcare authorities to observe, analyse, and manage spatial health inequalities.

BACKGROUND: This study describes a nationwide survey that estimates the number and characteristics of anesthesia-related deaths for the year 1999. METHODS: Death certificates from the French national mortality database were selected from the International Classification of Diseases, Ninth Revision codes using a variable sampling fraction. Medical certifiers were sent a questionnaire (response rate, 97%), and the anesthesiologist in charge was offered a peer review (acceptance rate, 97%). Files were reviewed to determine the mechanism of each perioperative death and its relation to anesthesia. Mortality rates were calculated using the number of anesthetic procedures estimated from a national 1996 survey and compared with a previous (1978-1982) nationwide study. RESULTS: Among the 4,200 certificates analyzed, 256 led to a detailed evaluation. The death rates totally or partially related to anesthesia for 1999 were 0.69 in 100,000 (95% confidence interval, 0.22-1.2 in 100,000) and 4.7 in 100,000 (3.1-6.3 in 100,000), respectively. The death rate increased from 0.4 to 55 in 100,000 for American Society of Anesthesiologists physical status I and IV patients, respectively. Rates increased with increasing age. Although concerns regarding aspiration of gastric contents remain, intraoperative hypotension and anemia associated with postoperative ischemic complications were the associated factors most often encountered. Deviations from standard practice and organizational failure were often found to be associated with death. CONCLUSION: In comparison with data from a previous nationwide study (1978-1982), the anesthesia-related mortality rate in France seems to be reduced 10-fold in 1999. Much remains to be done to improve compliance of physicians to standard practice and to improve the anesthetic system process.

A RIA procedure for measuring progesterone (PROG), 5 alpha-pregnane-3,20-dione (5 alpha-DH PROG), and 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-TH PROG) has been developed and validated by GLC/mass spectrometry. Measurements were made in intact and adrenalectomized (ADX) male rats, in cyclic, pregnant, spayed, and spayed-ADX females, and in both males and spayed females injected with PROG. The predominant contribution of the ovary to the concentrations of 3 alpha,5 alpha-TH PROG in plasma and brain, was indicated by its larger levels in females, in particular during pregnancy, and by its presence in ovarian tissue and disappearance after ovariectomy. An additional adrenal origin in both males and females was shown. Neither PROG nor 5 alpha-DH PROG disappeared from brain, contrary to plasma, after combined adrenalectomy and gonadectomy, thus suggesting that PROG might be synthetized de novo in brain. However, the concentrations of 3 alpha,5 alpha-TH PROG in plasma and brain of female rats were positively correlated with the concentrations of PROG in plasma, indicating that plasma PROG was the major precursor of 3 alpha,5 alpha-TH PROG. The direct formation of 3 alpha,5 alpha-TH PROG from PROG in brain was strongly suggested by the increased 3 alpha,5 alpha-TH PROG/PROG ratios in brain vs. plasma, when measured in control females, and after injection of PROG to both males and OVX females. It was previously reported that 3 alpha,5 alpha-TH PROG is a sedative/anxiolytic steroid, as a result of its binding to gamma-aminobutyric acid (GABA)A receptors and allosteric potentiation of GABAcergic neurotransmission. Its concentrations in brain reach indeed the neuroactive range in cyclic and pregnant females, and are compatible with a physiological role of this neurosteroid.

BACKGROUND: The multicenter national Mortalité 2005 survey aimed at describing the distribution of causes of death among HIV-infected adults in France in 2005 and its changes as compared with 2000. METHODS: Physicians involved in the management of HIV infection notified deaths and documented the causes using a standardized questionnaire similar to the previous survey performed in 2000. RESULTS: Overall, 1042 deaths were notified in 2005 (vs 964 in 2000): with median age, 46 years (vs 41 years); men, 76%; and median last CD4 cell count, 161/mm (vs 94). The proportion of underlying causes of death due to AIDS decreased (36% in 2005 vs 47% in 2000), and the proportion of cancer not related to AIDS or hepatitis (17% vs 11%), liver related disease (15% vs 13%: hepatitis C, 11%, and hepatitis B, 2%), cardiovascular disease (8% vs 7%), or suicide (5% vs 4%) increased. Among the 375 AIDS-related deaths, the most frequent event was non-Hodgkin lymphoma (28%). Among cancers not related to AIDS or hepatitis, the most frequent localizations were lung (31%) and digestive tract (14%). Among the 154 liver-related deaths, 24% were due to hepatocarcinoma. CONCLUSIONS: The heterogeneity of causes of death among HIV-infected adults was confirmed and intensified in 2005, with 3 causes following AIDS: cancers and liver-related and cardiovascular diseases.

The current definition of a chronic obstructive pulmonary disease (COPD) exacerbation (ECOPD) is based solely on worsening respiratory symptoms, with severity classified post hoc by the healthcare resource used to treat the event, which may vary among practitioners and healthcare systems. These shortcomings support a need to revise the ECOPD definition and severity classification to one that is useful at time of patient contact. To achieve this, an expert panel used a modified Delphi method of five rounds of questions generated by a thorough review of the literature, supplemented by virtual discussions. For the 80 identified questions, the agreement level was rated using a Likert scale from 0 (strongly disagree) to 9 (strongly agree). Consensus was defined a priori as a median score ≥7 (strong agreement). The proposed definition states: "In a patient with COPD, an exacerbation is an event characterized by dyspnea and/or cough and sputum that worsens over ≤14 days, that may be accompanied by tachypnea and/or tachycardia, often associated with increased local and systemic inflammation caused by airway infection, pollution, or other insult to the airways." Three severity categories (mild, moderate, or severe) were defined using integration of six clinically measurable variables: intensity of dyspnea, oxygen saturation, respiratory rate, heart rate, C-reactive protein, and, if indicated, arterial blood gases. In conclusion, by incorporating measurable clinical and laboratory variables at the time of exacerbation, the Rome proposal for an updated definition of ECOPD could help standardize care and outcomes for clinicians and researchers alike.

In March 2011, the Acromegaly Consensus Group met to revise and update the guidelines on the diagnosis and treatment of acromegaly complications. The meeting was sponsored by the Pituitary Society and the European Neuroendocrinology Association and included experts skilled in the management of acromegaly. Complications considered included cardiovascular, endocrine and metabolic, sleep apnea, bone diseases, and mortality. Outcomes in selected, related clinical conditions were also considered, and included pregnancy, familial acromegaly and invasive macroadenomas. The need for a new disease staging model was considered, and design of such a tool was proposed.

Generalized lymphatic dysplasia (GLD) is a rare form of primary lymphoedema characterized by a uniform, widespread lymphoedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. This may present prenatally as non-immune hydrops. Here we report homozygous and compound heterozygous mutations in PIEZO1, resulting in an autosomal recessive form of GLD with a high incidence of non-immune hydrops fetalis and childhood onset of facial and four limb lymphoedema. Mutations in PIEZO1, which encodes a mechanically activated ion channel, have been reported with autosomal dominant dehydrated hereditary stomatocytosis and non-immune hydrops of unknown aetiology. Besides its role in red blood cells, our findings indicate that PIEZO1 is also involved in the development of lymphatic structures.

This paper examines the efficiency of the incongruence length difference test (ILD) proposed by Farris et al. (1994) for assessing the incongruence between sets of characters. DNA sequences were simulated under various evolutionary conditions: (1) following symmetric or asymmetric trees, (2) with various mutation rates, (3) with constant or variable evolutionary rates along the branches, and (4) with different among-site substitution rates. We first compared two sets of sequences generated along the same tree and under the same evolutionary conditions. The probability of a Type-I error (wrongly rejecting the true hypothesis of congruence) was substantially below the standard 5% level of significance given by the ILD test; this finding indicates that the choice of the 5% level is rather conservative in this case. We then compared two data sets, still generated along the same tree, but under different evolutionary conditions (constant vs. variable evolutionary rate, homogeneity vs. heterogeneity rate of substitution). Under these conditions, the probability of rejecting the true hypothesis of congruence was greater than the 5% given by the ILD test and increased with the number of sites and the degree to which the tree was asymmetric. Finally, the comparison of the two data sets, simulated under contrasting tree structures (symmetric vs. asymmetric) but under the same evolutionary conditions, led us to reject the hypothesis of congruence, albeit weakly, particularly when the number of informative sites was low and among-site substitution rate heterogeneous. We conclude that the ILD test has only limited power to detect incongruence caused by differences in the evolutionary conditions or in the tree topology, except when numerous characters are present and the substitution rate is homogeneous from site to site.

BACKGROUND: To identify the growth in the number of anesthetic procedures since 1980 and the changes in the practice of anesthesia, the present survey was designed to collect and analyze the anesthetic activity performed in France in 1996, from a representative sample collected in all French hospitals and clinics. METHODS: This study, initiated by the French Society of Anesthesia and Intensive Care, collected information that included the characteristics of patients (age, sex, American Society of Anesthesiologists status), the techniques of anesthesia, and the nature of the procedure for which anesthesia was required. All French private, public, and military hospitals were asked to participate in the survey. In each hospital in the country, all anesthetic procedures were documented and collected during 3 consecutive days, chosen at random during a 12-month period, to obtain a representative sample of the annual activity. All data were analyzed at the INSERM (National Institute of Health and MEDICAL RESEARCH: At the conclusion of the study, 5% of hospitals were randomly assigned to be audited to check for missing data and errors. The rate of anesthetic activity was calculated as the ratio between the annual number of anesthetic procedures and the number of the general population in the same age group. RESULTS: The participation rate of hospitals was 98%. The analysis of the 62,415 collected questionnaires allowed extrapolation of the anesthetic activity to 7,937,000 anesthetic procedures (95% confidence interval, +/- 387,000) performed in France in 1996. Thus, the annual rate of anesthetic procedures was 13.5 per 100 population, varying between 5.4 per 100 in girls aged 5-14 yr and 30.2 per 100 in men aged 75-84 yr. Surgery was involved in 71% of anesthesia cases. Regional anesthesia alone was performed in 20% of all surgical cases and was combined with general anesthesia in 3% of additional cases. Anesthesia for obstetric procedures represented 9% of all cases. Seventy-six percent of all anesthetic procedures started between 12:00 A.M. and 7:00 A.M. were related to obstetric activities. CONCLUSION: In comparison with a previous study, the present survey shows that the number of anesthetic procedures has increased by 120% since 1980, and the rate of anesthetic procedures increased from 6.6 to 13.5 per 100 population, the major changes being observed in patients aged > or = 75 yr and in those with an American Society of Anesthesiologists physical status of 3. In the same time period, the number of regional anesthetic procedures increased 14-fold. In obstetrics, the practice of epidural analgesia extended from 1.5% to 51% of all deliveries of the country.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

CONTEXT: Little is known about the long-term health of subjects treated with GH in childhood, and Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) is a study addressing this question. OBJECTIVE: The objective of the study was to evaluate the long-term mortality of patients treated with recombinant GH in childhood in France. DESIGN: This was a population-based cohort study. SETTING: The setting of the study was a French population-based register. PARTICIPANTS: A total of 6928 children with idiopathic isolated GH deficiency (n = 5162), neurosecretory dysfunction (n = 534), idiopathic short stature (n = 871), or born short for gestational age (n = 335) who started treatment between 1985 and 1996 participated in the study. Follow-up data on vital status were available in September 2009 for 94.7% of the patients. MAIN OUTCOME MEASURES: All-cause and cause-specific mortality was measured in the study. RESULTS: All-cause mortality was increased in treated subjects [standardized mortality ratio (SMR) 1.33, 95% confidence interval (CI) 1.08-1.64]. In a multivariate analysis adjusted for height, the use of GH doses greater than 50 μg/kg · d was associated with mortality rates using external and internal references (SMR 2.94, 95% CI 1.22-7.07, hazard ratio 2.79, 95% CI 1.14-6.82). All type cancer-related mortality was not increased. Bone tumor-related mortality was increased (SMR 5.00, 95% CI 1.01-14.63). An increase in mortality due to diseases of the circulatory system (SMR 3.07, 95% CI 1.40-5.83) or subarachnoid or intracerebral hemorrhage (SMR 6.66, 95% CI 1.79-17.05) was observed. CONCLUSIONS: Mortality rates were increased in this population of adults treated as children with recombinant GH, particularly in those who had received the highest doses. Specific effects were detected in terms of death due to bone tumors or cerebral hemorrhage but not for all cancers. These results highlight the need for additional studies of long-term mortality and morbidity after GH treatment in childhood.

BACKGROUND: The relative index of inequality and the slope index of inequality are the two major indices used in epidemiologic studies for the measurement of socioeconomic inequalities in health. Yet the current definitions of these indices are not adapted to their main purpose, which is to provide summary measures of the linear association between socioeconomic status and health in a way that enables valid between-population comparisons. The lack of appropriate definitions has dissuaded the application of suitable regression methods for estimating the slope index of inequality. METHODS: We suggest formally defining the relative and slope indices of inequality as so-called least false parameters, or more precisely, as the parameters that provide the best approximation of the relation between socioeconomic status and the health outcome by log-linear and linear models, respectively. From this standpoint, we establish a structured regression framework for inference on these indices. Guidelines for implementation of the methods, including R and SAS codes, are provided. RESULTS: The new definitions yield appropriate summary measures of the linear association across the entire socioeconomic scale, suitable for comparative studies in epidemiology. Our regression-based approach for estimation of the slope index of inequality contributes to an advancement of the current methodology, which mainly consists of a heuristic formula relying on restrictive assumptions. A study of the educational inequalities in all-cause and cause-specific mortality in France is used for illustration. CONCLUSION: The proposed definitions and methods should guide the use and estimation of these indices in future studies.

The plasma membrane remodeling, including the early transverse redistribution of phosphatidylserine, is a general feature occurring in cells in which a death program has been induced. In most cases, studies of this kind have focused mainly on cells. In this study, we report a clear correlation between the degree of apoptosis induced by a variety of agents in several types of cultured cells and the amount of shed membrane microparticles captured in the corresponding supernatants by insolubilized annexin V, a protein showing a strong affinity for phosphatidylserine. Such particles carry membrane antigens specific of the cells they stem from, and through which capture is also feasible. Homologous circulating microparticles were captured in peripheral blood from individuals with HIV-1 infection. A substantial proportion bore CD4 antigen. In some cases, CD4+ particles could be detected even in the absence of circulating CD4+ T cells, testifying to the presence of such resident cells in lymphoid tissues. These results suggest that shed membrane particles are one of the hallmarks of programmed cell death, of particular interest when the corresponding cells are hardly accessible.

OBJECTIVE: The Mortalité 2010 survey aimed at describing the causes of death among HIV-infected patients in France in 2010 and their evolution since 2000. DESIGN AND METHODS: A national sample of clinical sites, providing HIV care and treatment, notified and documented deaths using a standardized questionnaire. RESULTS: The 90 participating wards notified 728 deaths. Median age at death was 50 years (interquartile range 45-58) and 75% were men. The main underlying causes of death were AIDS-related (25% in 2010 vs. 36% in 2005 and 47% in 2000), non-AIDS non-viral hepatitis-related malignancy (22 vs. 17 and 11%), liver-related (11 vs. 15 and 13%), cardiovascular diseases (10 vs. 8 and 7%) and non-AIDS-related infections (9 vs. 4 and 7%). Malignancies (AIDS and non-AIDS-related) accounted for a third of all causes of death. AIDS accounted for 33% of all causes of death among patients mono-infected with HIV vs. only 13% among those co-infected with hepatitis B virus or hepatitis C virus. CONCLUSION: In 2010, 25% of the causes of death among HIV-infected patients remained AIDS-related. Improved screening and earlier HIV treatment should lead to a smaller proportion of deaths due to AIDS. The majority of patients died of various causes, whereas their HIV infection was well controlled under treatment. Improving case management of HIV-infected patients should include a multidisciplinary approach (prevention, screening, treatment), especially in oncology. Smoking cessation should be a priority goal.

BACKGROUND: encephalopathy and explored potential prospects of personalised medicine. METHODS: variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

We have summarized data on 233 Alagille syndrome patients reported with mutations in Jagged1 (JAG1). This data has been published by seven different laboratories in Europe, the United States, Australia, and Japan. Mutations have been demonstrated in 60-75% of patients with a clinically confirmed diagnosis of Alagille syndrome. Total gene deletions have been reported in 3-7% of patients, and the remainder have intragenic mutations. Seventy two percent (168/233) of the reported mutations lead to frameshifts that cause a premature termination codon. These mutations will either lead to a prematurely truncated protein, or alternatively, nonsense mediated decay might lead to lack of a product from that allele. Twenty three unique missense mutations were identified (13% of mutations). These were clustered in conserved regions at the 5' end of the gene, or in the EGF repeats. Splicing consensus sequence changes were identified in 15% of patients. A high frequency of de novo mutations (60-70%) has been reported. The spectrum of mutations identified is consistent with haploinsufficiency for JAG1 being a mechanism for Alagille syndrome.

BACKGROUND: Before the introduction of highly active antiretroviral therapy (HAART), malignancies accounted for less than 10% of all deaths among human immunodeficiency virus (HIV)-infected patients. This figure may have increased, and the observed types of malignant disease may have been modified, as a result of decreased occurrence of opportunistic infections, the chronicity of HIV infection, the possible oncogenic role of HIV itself, and the aging of the HIV-infected population. METHODS: All French hospital wards involved in the management of HIV infection were asked to prospectively document the deaths of HIV-infected patients in the year 2000. Underlying causes of death were defined using a standardized questionnaire. RESULTS: Of a total of 964 deaths, 269 (28%) were attributable to malignancies. Acquired immunodeficiency virus (AIDS)-related malignancies were the underlying cause of 149 deaths (15%); among these malignancies were non-Hodgkin lymphoma (n = 105 [11%]), noncerebral lymphoma (n = 78 [median CD4 count, 86 x 10(6) per liter; interquartile range [IQR], 35-231 x 10(6) per liter), and primary cerebral lymphoma (n = 27 [median CD4 count, 20 x 10(6) per liter; IQR, 4-109 x 10(6) per liter). Kaposi sarcoma was associated with 40 deaths (4%), and cervical carcinoma was associated with 5 (0.5%). Non-AIDS-related malignancies were the underlying cause of 120 deaths (13%); these non-AIDS-related malignancies included 103 solid tumors (50 respiratory tumors, 19 hepatocarcinomas, 9 digestive tumors, and 6 anal tumors; median CD4 count, 218 x 10(6) per liter; IQR, 108-380 x 10(6) per liter) and 17 hemopathies (12 Hodgkin lymphomas, 4 myeloid leukemias, and 1 myeloma; median CD4 count, 113 x 10(6) per liter; IQR, 56-286 x 10(6) per liter). Compared with patients who died of other causes, patients who died of solid tumors were more likely to be male, to smoke, to be older, and to have higher CD4 counts. CONCLUSIONS: Malignant disease has been a major cause of death among HIV-infected patients in industrialized nations since the introduction of HAART. Whereas lethal hemopathies and Kaposi sarcoma are associated with advanced immunosuppression, lethal solid tumors can occur in patients with controlled HIV infection.

Congenital imprinting disorders (IDs) are characterised by molecular changes affecting imprinted chromosomal regions and genes, i.e. genes that are expressed in a parent-of-origin specific manner. Recent years have seen a great expansion in the range of alterations in regulation, dosage or DNA sequence shown to disturb imprinted gene expression, and the correspondingly broad range of resultant clinical syndromes. At the same time, however, it has become clear that this diversity of IDs has common underlying principles, not only in shared molecular mechanisms, but also in interrelated clinical impacts upon growth, development and metabolism. Thus, detailed and systematic analysis of IDs can not only identify unifying principles of molecular epigenetics in health and disease, but also support personalisation of diagnosis and management for individual patients and families.

OBJECTIVE: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. METHODS: We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes. RESULTS: We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families. CONCLUSIONS: De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.