Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor delta signaling is critical to pregnancy success.

Successful pregnancy depends on well coordinated developmental events involving both maternal and embryonic components. Although a host of signaling pathways participate in implantation, decidualization, and placentation, whether there is a common molecular link that coordinates these processes remains unknown. By exploiting genetic, molecular, pharmacological, and physiological approaches, we show here that the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) delta plays a central role at various stages of pregnancy, whereas maternal PPARdelta is critical to implantation and decidualization, and embryonic PPARdelta is vital for placentation. Using trophoblast stem cells, we further elucidate that a reciprocal relationship between PPARdelta-AKT and leukemia inhibitory factor-STAT3 signaling pathways serves as a cell lineage sensor to direct trophoblast cell fates during placentation. This novel finding of stage-specific integration of maternal and embryonic PPARdelta signaling provides evidence that PPARdelta is a molecular link that coordinates implantation, decidualization, and placentation crucial to pregnancy success. This study is clinically relevant because deferral of on time implantation leads to spontaneous pregnancy loss, and defective trophoblast invasion is one cause of preeclampsia in humans.

Valproic acid monotherapy in pregnancy and major congenital malformations.

BACKGROUND: The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited. METHODS: We first combined data from eight published cohort studies (1565 pregnancies in which the women were exposed to valproic acid, among which 118 major malformations were observed) and identified 14 malformations that were significantly more common among the offspring of women who had received valproic acid during the first trimester. We then assessed the associations between use of valproic acid during the first trimester and these 14 malformations by performing a case-control study with the use of the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, which is derived from population-based congenital-anomaly registries. Registrations (i.e., pregnancy outcomes with malformations included in EUROCAT) with any of these 14 malformations were compared with two control groups, one consisting of infants with malformations not previously linked to valproic acid use (control group 1), and one consisting of infants with chromosomal abnormalities (control group 2). The data set included 98,075 live births, stillbirths, or terminations with malformations among 3.8 million births in 14 European countries from 1995 through 2005. RESULTS: Exposure to valproic acid monotherapy was recorded for a total of 180 registrations, with 122 registrations in the case group, 45 in control group 1, and 13 in control group 2. As compared with no use of an antiepileptic drug during the first trimester (control group 1), use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration; the adjusted odds ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2 (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2 (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8). Results for exposure to valproic acid were similar to results for exposure to other antiepileptic drugs. CONCLUSIONS: The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.

Prepregnancy body mass index and resting metabolic rate during pregnancy.

AIM: The resting metabolic rate (RMR) varies among pregnant women. The factors responsible for this variability are unknown. This study aimed to assess the influence of the prepregnancy body mass index (BMI) on the RMR during late pregnancy. METHODS: RMR, height, weight, and total (TEE) and activity (AEE) energy expenditures were measured in 46 healthy women aged 31 ± 5 years (mean ± SD) with low (<19.8), normal (19.8-26.0), and high (>26.0) prepregnancy BMI at 38.2 ± 1.5 weeks of gestation (t(gest)) and 40 ± 7 weeks postpartum (t(post)) (n = 27). RESULTS: The mean t(gest) RMR for the low-, normal-, and high-BMI groups was 1,373, 1,807, and 2,191 kcal/day, respectively (p = 0.001). The overall mean t(gest) RMR was 316 ± 183 kcal/day (21%), higher than the overall mean t(post) value and this difference was correlated with gestational weight gain (r = 0.78, p < 0.001). The scaled metabolic rate by allometry (RMR/kilograms⁰·⁷³) was similar in the low-, normal-, and high-BMI groups, respectively (p = 0.45). Changes in t(gest) TEE closely paralleled changes in t(gest) RMR (r = 0.84, p < 0.001). AEE was similar among the BMI groups. CONCLUSION: The RMR is significantly increased in the third trimester of pregnancy. The absolute gestational RMR is higher in women with high prepregnancy BMI due to increased body weight. The scaled metabolic rate (RMR/kilograms⁰·⁷³) is similar among the BMI groups of pregnant women.

The Alcohol Use Disorders Identification Test (AUDIT) as a screening tool for excessive drinking in primary care: reliability and validity of a French version.

BACKGROUND: Excessive drinking is a major problem in Western countries. AUDIT (Alcohol Use Disorders Identification Test) is a 10-item questionnaire developed as a transcultural screening tool to detect excessive alcohol consumption and dependence in primary health care settings. OBJECTIVES: The aim of the study is to validate a French version of the Alcohol Use Disorders Identification Test (AUDIT). METHODS: We conducted a validation cross-sectional study in three French-speaking areas (Paris, Geneva and Lausanne). We examined psychometric properties of AUDIT as its internal consistency, and its capacity to correctly diagnose alcohol abuse or dependence as defined by DSM-IV and to detect hazardous drinking (defined as alcohol intake >30 g pure ethanol per day for men and >20 g of pure ethanol per day for women). We calculated sensitivity, specificity, positive and negative predictive values and Receiver Operator Characteristic curves. Finally, we compared the ability of AUDIT to accurately detect "alcohol abuse/dependence" with that of CAGE and MAST. RESULTS: 1207 patients presenting to outpatient clinics (Switzerland, n = 580) or general practitioners' (France, n = 627) successively completed CAGE, MAST and AUDIT self-administered questionnaires, and were independently interviewed by a trained addiction specialist. AUDIT showed a good capacity to discriminate dependent patients (with AUDIT > or =13 for males, sensitivity 70.1%, specificity 95.2%, PPV 85.7%, NPV 94.7% and for females sensitivity 94.7%, specificity 98.2%, PPV 100%, NPV 99.8%); and hazardous drinkers (with AUDIT > or =7, for males sensitivity 83.5%, specificity 79.9%, PPV 55.0%, NPV 82.7% and with AUDIT > or =6 for females, sensitivity 81.2%, specificity 93.7%, PPV 64.0%, NPV 72.0%). AUDIT gives better results than MAST and CAGE for detecting "Alcohol abuse/dependence" as showed on the comparative ROC curves. CONCLUSIONS: The AUDIT questionnaire remains a good screening instrument for French-speaking primary care.

Associations between mood, anxiety or substance use disorders and inflammatory markers after adjustment for multiple covariates in a population-based study.

Inflammation is one possible mechanism underlying the associations between mental disorders and cardiovascular diseases (CVD). However, studies on mental disorders and inflammation have yielded inconsistent results and the majority did not adjust for potential confounding factors. We examined the associations of several pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and high sensitive C-reactive protein (hsCRP) with lifetime and current mood, anxiety and substance use disorders (SUD), while adjusting for multiple covariates. The sample included 3719 subjects, randomly selected from the general population, who underwent thorough somatic and psychiatric evaluations. Psychiatric diagnoses were made with a semi-structured interview. Major depressive disorder was subtyped into "atypical", "melancholic", "combined atypical-melancholic" and "unspecified". Associations between inflammatory markers and psychiatric diagnoses were assessed using multiple linear and logistic regression models. Lifetime bipolar disorders and atypical depression were associated with increased levels of hsCRP, but not after multivariate adjustment. After multivariate adjustment, SUD remained associated with increased hsCRP levels in men (β = 0.13 (95% CI: 0.03,0.23)) but not in women. After multivariate adjustment, lifetime combined and unspecified depression were associated with decreased levels of IL-6 (β = -0.27 (-0.51,-0.02); β = -0.19 (-0.34,-0.05), respectively) and TNF-α (β = -0.16 (-0.30,-0.01); β = -0.10 (-0.19,-0.02), respectively), whereas current combined and unspecified depression were associated with decreased levels of hsCRP (β = -0.20 (-0.39,-0.02); β = -0.12 (-0.24,-0.01), respectively). Our data suggest that the significant associations between increased hsCRP levels and mood disorders are mainly attributable to the effects of comorbid disorders, medication as well as behavioral and physical CVRFs.

Multiplex targeted high-throughput sequencing for Mendelian cardiac disorders.

Mendelian cardiomyopathies and arrhythmias are characterized by an important genetic heterogeneity, rendering Sanger sequencing very laborious and expensive. As a proof of concept, we explored multiplex targeted high-throughput sequencing (HTS) as a fast and cost-efficient diagnostic method for individuals suffering from Mendelian cardiac disorders. We designed a DNA capture assay including all exons from 130 genes involved in cardiovascular Mendelian disorders and analysed simultaneously four samples by multiplexing. Two patients had familial hypertrophic cardiomyopathy (HCM) and two patients suffered from long QT syndrome (LQTS). In patient 1 with HCM, we identified two known pathogenic missense variants in the two most frequently mutated sarcomeric genes MYH7 and MYBPC. In patient 2 with HCM, a known acceptor splice site variant in MYBPC3 was found. In patient 3 with LQTS, two missense variants in the genes SCN5A and KCNQ were identified. Finally, in patient 4 with LQTS a known missense variant was found in MYBPC3, which is usually mutated in patients with cardiomyopathy. Our results showed that multiplex targeted HTS works as an efficient and cost-effective tool for molecular diagnosis of heterogeneous disorders in clinical practice and offers new insights in the pathogenesis of these complex diseases.

Long-term follow-up of patients with congenital myasthenic syndrome caused by COLQ mutations.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COlQ) cause recessive forms of synaptic CMS with end plate AChE deficiency. We present data on 15 COLQ -mutant CMS carrying 16 different mutations (9 novel ones identified) followed-up for an average period of 10 ears. The mean age at the first examination was 19 ears old (range from 3 to 48). We report relapses during short or long-term periods characterized by worsening of muscle weakness sometimes associated with respiratory crises. All the relapses ended spontaneously or with 3-4 DAP or ephedrine with no residual impairment. The triggering factors identified were esterase inhibitors, effort, puberty or pregnancy highlighting the importance of hormonal factors. There was no genotype-phenotype correlation. At the end of the follow-up, 80% of patients were ambulant and 87% of patients had no respiratory trouble in spite of severe relapses.

Neurocognitive deficits and personality traits among euthymic patients with mood disorders in late life.

BACKGROUND: Previous studies revealed that acute depressive episodes are associated with both cognitive deficits and modified personality patterns in late life. Whether or not these psychological changes are present after remission remains a matter of debate. To date, no study provided concomitant assessment of cognition and psychological functions in this particular clinical setting. METHOD: Using a cross-sectional design, 58 remitted outpatients (36 with unipolar early-onset depression (EOD) and 22 with bipolar disorder (BD)) were compared to 62 healthy controls. Assessment included detailed neurocognitive measures and evaluation of the five factor personality dimensions (NEO-Personality Inventory). RESULTS: Group comparisons revealed significant slower processing speed, working and episodic memory performances in BD patients. EOD patients showed cognitive abilities comparable to those of elderly controls. In NEO PI assessment, both BD and EOD patients displayed higher Depressiveness facet scores. In addition, the EOD but not BD group had lower Extraversion factor, and Warmth and Positive Emotion facet scores than controls. CONCLUSIONS: After remission from acute affective symptoms, older BD patients show significant impairment in several cognitive functions while neuropsychological performances remained intact in elderly patients with EOD. Supporting a long-lasting psychological vulnerability, EOD patients are more prone to develop emotion-related personality trait changes than BD patients.

Durée et structure du sommeil et risques métaboliques et cardiovasculaires = [Sleep structure and cardiometabolic disorders]

Introduction : Plusieurs études épidémiologiques et de laboratoire basées sur des estimations subjectives de la durée et de la qualité du sommeil suggèrent que celles-ci pourraient être associées à une augmentation du risque de troubles métaboliques ou cardiovasculaires. Objectif : Dans cette étude nous avons examiné les associations entre les caractéristiques du sommeil évaluées objectivement par Polysomnographie (PSG) et le syndrome métabolique ainsi que ses composants (hypertension, diabète, obésité). Matériel et méthodes : Nous avons analysé les données de 2162 sujets de la population générale (dont le 51.2% étaient des femmes, âge moyen : 58.4±11.1 ans, fourchette d'âge: 40.5-84.4) qui ont participé à l'étude Hypnolaus. Tous les sujets ont eu une évaluation clinique et biologique et ils ont bénéficié d'une PSG complète à domicile. Résultats : Les analyses univariées ont montré que les sujets présentant un syndrome métabolique avaient une diminution du temps total de sommeil, du sommeil lent profond, du sommeil paradoxal et de l'efficacité du sommeil, ainsi qu'une augmentation de l'index de microéveils par rapport aux sujets qui n'avaient pas un syndrome métabolique. Nous avons aussi trouvé des différences significatives de la structure du sommeil en fonction de la présence ou de l'absence d'hypertension, de diabètes et de surpoids/obésité. Cependant, ces différences s'atténuent après ajustement pour des facteurs confondants (âge, genre, tabagisme, prise d'alcool, activité physique, médicaments qui affectent le sommeil, dépression, santé globale et indice de masse corporelle). Seules des différences marginales, non statistiquement significatives, persistaient dans le modèle multiajusté et après stratification en fonction de la présence de troubles respiratoires au cours du sommeil. Conclusions: Dans cet échantillon de la population générale nous avons mis en évidence des associations significatives entre la structure du sommeil et le syndrome métabolique ainsi que ses composants. Cependant, ces associations ne sont pas indépendantes des autres facteurs de risque cardiométabolique connus. Nous en concluons que les variations normales de la durée et de la structure du sommeil contribuent peu ou pas au syndrome métabolique et ses troubles associés.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

Déglutition et états de conscience altérée [Swallowing in disorders of consciousness.]

INTRODUCTION: Interest in studying swallowing disorders in patients with altered consciousness has increased over the past decade. Swallowing deficit is frequently encountered in severe brain-injured patients. STATE OF ART: Results of studies have highlighted different factors such as the delay between the injury and the treatment and the level of consciousness of these patients, as well as the presence or not of tracheotomy, which will determine the feasibility of resuming oral feeding. Nowadays, very few valid and sensitive scales can be used to assess swallowing deficit in patients with disorders of consciousness. The Facial Oral Tract Therapy (FOTT) scale is an inter-professional multidisciplinary approach offering a structured way to evaluate and treat patients with swallowing disorders. In contrast with other scales, patients do not have to follow verbal instructions for the FOTT. PERSPECTIVES: This paper presents a review of existing literature on the assessment and management of swallowing disorders in patients with altered state of consciousness, and a description of the FOTT method. CONCLUSION: The FOTT seems to be an interesting assessment and rehabilitation tool for patients with disorders of consciousness. However, clinical studies are needed to confirm the validity and sensitivity of this technique.

Personality trait risk factors for attempted suicide among young women with eating disorders.

OBJECTIVE: - Clinical observations and a review of the literature led us to hypothesize that certain personality and character traits could provide improved understanding, and thus improved prevention, of suicidal behaviour among young women with eating disorders. METHOD: - The clinical group consisted of 152 women aged between 18 and 24 years, with DSM-IV anorexia nervosa/restrictive type (AN-R = 66), anorexia nervosa/purging type (AN-P = 37), bulimia nervosa/non-purging type (BN-NP = 9), or bulimia nervosa/purging type (BN-P = 40). The control group consisted of 140 subjects. The assessment measures were the Minnesota Multiphasic Personality Inventory-second version (MMPI-2) scales and subscales, the Beck Depression Inventory (BDI) used to control for current depressive symptoms, plus a specific questionnaire concerning suicide attempts. RESULTS: - Suicide attempts were most frequent in subjects with purging behaviour (30.0% for BN-P and 29.7% for AN-P). Those attempting suicide among subjects with eating disorders were mostly students (67.8%). For women with AN-R the scales for 'Depression' and 'Antisocial practices' represented significant suicidal risk, for women with AN-P the scales for 'Hysteria', 'Psychopathic deviate', 'Shyness/Self-consciousness', 'Antisocial Practices', 'Obsessiveness' and 'Low self-esteem' were risk indicators and for women with BN-P the 'Psychasthenia', 'Anger' and 'Fears' scales were risk indicators. CONCLUSION: - This study provides interesting results concerning the personality traits of young women with both eating disorders and suicidal behaviour. Students and those with purging behaviour are most at risk. Young women should be given more attention with regard to the risk of suicide attempts if they: (a). have AN-R with a tendency to self-punishment and antisocial conduct, (b). have AN-P with multiple physical complaints, are not at ease in social situations and have antisocial behaviour, or (c). if they have BN-P and tend to be easily angered with obsessive behaviour and phobic worries. The MMPI-2 is an interesting assessment method for the study of traits indicating a risk of suicidal behaviour in young subjects, after controlling for current depressive pathology.

Termination of pregnancy among teenagers - why more surgical terminations?

Introduction: In 2012, a study by K. Chatziioannidou and S-C. Renteria showed that teenagers chose to undergo a surgical termination of pregnancy (TOP) more often than a medical TOP (mifepristone followed by misoprostol) when they decided to terminate a pregnancy. It also showed that the teenagers' choice for a medical versus surgical method is inversely proportional to the adults' choice although the efficiency of the medical method showed even better results for teenagers than for adults. According to the hypothesis made, the reasons for this choice might be influenced by the following facts: (i) the belated call to make an appointment, the medical procedure not being available after 9 weeks of gestation; (ii) the imperative request for confidentiality; (iii) the beliefs and subjective appreciation of the medical staff. Objectives: The aim of this retrospective and qualitative study is to analyse the reasons why, in case of a TOP, teenagers chose the surgical method more often than their adult counterparts. Material: (i) All teenagers who were admitted for an abortive procedure during 2011 in the in- or outpatient ward. (ii) The professional team (midwives and sexual and reproductive counsellors) in charge in the case of a TOP request. Methods: The information about the patient's history and the biopsycho- social data was retrieved from the patient files filled out by midwives and sexual and reproductive health counsellors during the first appointment for a TOP request or during its process. The professionals' appreciation was evaluated by means of a semi-structured questionnaire. Results: Concerning the choice of the method for a pregnancy termination, the results of our research show that: (i) Out of 47 teenagers, 27 chose the surgical method and 17 the medical method. (ii) Three had a second trimester abortion (which includes use of the medical method). (iii) Fifteen teenagers out of the 27 who chose a surgical method consulted between the 9th and 14th weeks of amenorrhoea and therefore did not have any other choice. The reasons for their 'late arrival' will be explained in detail. The 12 teenagers who arrived before the 8th week of amenorrhoea and chose to undertake abortion by suction & curettage under general anaesthesia did it for the following reasons: (i) Four were afraid of bleeding and pain. (ii) Five thought that the organisation of the surgical procedure was easier. (iii) Two did not trust the abortion pill. (iv) One was taken to her mother's gynaecologist where she had a D&C. Confidentiality was requested nine times out of 27 when choosing the surgical method, and six times out of 17 when choosing the medical method. Therefore, although confidentiality concerns a third of the teenagers' pregnancy termination requests, it does not seem to be a significant element for the choice of the method. As for the subjective appreciation of the professionals, the first results of the discussions seem to show that teenagers were reluctant or resistant towards the medical method. Conclusion: This study shows that the reasons why teenagers still prefer the use of the surgical over the medical method compared to adults, seem to include the late request for an appointment, fear of pain and bleeding and organisational issues. Confidentiality does not seem to greatly influence the teenagers' choice. Nonetheless, medical professionals seem to favour the suction curettage procedure performed under anesthesia because they associate young age with vulnerability and psychological frailty and consequently diminished ability to cope with pain and emotional distress during the medical procedures.

Telomere length dynamics in normal individuals and in patients with hematopoietic stem cell-associated disorders.

The telomere length in nucleated peripheral blood (PB) cells indirectly reflects the mitotic history of their precursors: the hematopoietic stem cells (HSCs). The average length of telomeres in PB leukocytes can be measured using fluorescence in situ hybridization and flow cytometry (flow FISH). We previously used flow FISH to characterize the age-related turnover of HSCs in healthy individuals. In this review, we describe results of recent flow FISH studies in patients with selected hematopoietic stem cell-associated disorders: chronic myelogenous leukemia (CML) and several bone marrow failure syndromes. CML is characterized by a marked expansion of myeloid Philadelphia chromosome positive (Ph+) cells. Nevertheless, nonmalignant (Ph-) HSCs typically coexist in the bone marrow of CML patients. We analyzed the telomere length in > 150 peripheral blood leukocytes (PBLs) and bone marrow samples of patients with CML as well as samples of Ph- T-lymphocytes. Compared to normal controls, the overall telomere fluorescence in PBLs of patients with CML was significantly reduced. However, no telomere shortening was observed in Ph- T-lymphocytes. Patients in late chronic phase (CP) had significantly shorter telomeres than those assessed earlier in CP. Our data suggest that progressive telomere shortening is correlated with disease progression in CML. Within the group of patients with bone marrow failure syndromes, we only found significantly shortened telomeres (compared to age-adjusted controls) in granulocytes from patients with aplastic anemia (AA). Strikingly, the telomere length in granulocytes from AA patients who had recovered after immunosuppressive therapy (recAA) did not differ significantly from controls, whereas untreated patients and nonresponders with persistent severe pancytopenia (sAANR) showed marked and significant telomere shortening compared to healthy donors and patients with recAA. Furthermore, an inverse correlation between age-adjusted telomere length and peripheral blood counts was found in support of a model in which the degree of cytopenia and the amount of telomere shortening are correlated. These results support the concept of extensive proliferation of HSCs in subgroups of AA patients and suggest a potential use of telomere-length measurements as a prognostic tool in this group of disorders as well.