Effect of hydroxyurea exposure before puberty on sperm parameters in males with sickle cell disease.

Sperm parameters are known to be impaired in men with sickle cell disease (SCD). Although treatment with hydroxyurea (HU) has an impact on sperm quality, sperm preservation is impossible before puberty. This study's primary objective was to analyze and compare sperm parameters in male patients with SCD exposed (or not) to HU before puberty. Twenty-six sperm samples from 15 patients (median age, 17 years; range, 16-23) treated with HU during childhood were compared with 46 samples from 23 HU-naïve patients (20 years; 16-24). The median age at HU initiation was 6 years (1-14 years), the median duration of HU treatment was 4 years (0.5-10), and the mean dose of HU was 22.4 ± 3.7 mg/kg per day. Although we observed substantial quantitative and qualitative semen abnormalities in all patients, there were no significant differences in semen volume, sperm concentration, total sperm count, or spermatozoa motility, morphology, and vitality between the HU-exposed and HU-naïve groups. At the time of the semen analysis, 100% of the patients in the HU-exposed group and 52% of the patients in the HU-naïve group received transfusion therapy. The specific effect of HU on spermatogenesis in very young infants and the putative value of transfusion for reversing the toxicity of HU warrant further investigation.

Time perception of simultaneous and sequential events in early-onset schizophrenia.

Timing disorders in schizophrenia are a well-known phenomenon. However, no studies have yet assessed the role of temporal distortions in early-onset schizophrenia (EOS), despite evidence that distorted time perception may share genetic risk factors with schizophrenia and may be a useful indicator in identifying individuals at risk for schizophrenia. In the present study, we investigated the ability of 10 patients with EOS (mean age = 21.5 years, SD = 6) matched with 20 healthy control participants (mean age = 25.3 years, SD = 4.6) in order to compare the durations of two visual events, presented either sequentially or overlapping in time, along with neuropsychological assessments of attention, working memory, and executive functions. Each participant had to judge a total of 336 stimuli. We found that temporal overlap had a greater negative effect on ability to judge the duration of a pair of stimuli in EOS patients than in healthy control participants. In addition, EOS patients showed impairments in attention and executive functions. Furthermore, in EOS patients, the scores for executive and attentional functions were significantly correlated with accuracy of temporal estimation in the overlap condition (r = 0.31, p < 0.05 and r = 0.57, p < 0.05, respectively). These preliminary results suggest that impairments in neuropsychological functions participate in the deficit in time estimation observed in patients with EOS. These conclusions highlight the importance of testing time perception in patients with EOS and could contribute to the development of cognitive remediation-based therapy for these patients.

[Time perception and schizophrenia: Phenomenological and neuropsychological approach]. / Perception temporelle et schizophrénie : approche phénoménologique et neuropsychologique.

OBJECTIVES: Based on clinical, phenomenological and neurobiological observations, psychiatrists often report a deficit in time estimation in patients with schizophrenia. Cognitive models of time estimation in healthy subjects have been proposed and developed for approximately 30 years. The investigation of time perception is pertinent to the understanding of neurobiological and cognitive abnormalities in schizophrenia. Brain lesions and neuroimaging studies have shown that the critical brain structures engaged in time perception include the prefrontal and parietal lobes, thalamus, basal ganglia and cerebellum. These brain areas have been implicated in the physiopathology of schizophrenia in that there is impaired coordination of activity among these regions. Clinical and experimental date strongly suggest that patients with schizophrenia are less accurate in their ability to estimate time than healthy subjects. The specificity of these clinical and behavioral impairments is still in question. The aims of this article are to present an overview of the literature regarding time estimation and schizophrenia, to discuss specific issues related to how perceptual dysfunction in schizophrenia may lead to abnormalities in time perception, and to propose new perspectives towards an integrative approach between phenomenology and neuroscience. METHODS: We present a review of the literature describing the current theory in the field of time perception, which is supported by a connectionist model, postulating that temporal judgment is based upon a pacemaker-counter device that depends mostly upon memory and attentional resources. The pacemaker emits pulses that are accumulated in a counter, and the number of pulses determines the perceived length of an interval. Patients with schizophrenia are known to display attentional and memory dysfunctions. Moreover, dopamine regulation mechanisms are involved in both the temporal perception and schizophrenia. DISCUSSION: It is still unclear if temporal impairments in schizophrenia are related to a specific disturbance in central temporal processes or are due to certain cognitive problems, such as attentional and memory dysfunctions, or biological abnormalities. While psychopathological and phenomenological work strongly suggests that time perception disturbance may be the key or core symptom in schizophrenia, neuroscience studies have failed to do the same. The question of specificity of temporal perception impairments in schizophrenia remains contested. Neuroscience studies suggest that time symptoms in patients with schizophrenia are only secondary to thought disorders and primary cognitive impairments. This debate refers to the etiologic/organic versus psychogenesis/psychological dichotomy and may be over-taken. CONCLUSION: Clinical evidence associated with psychopathological, biological and cognitive theories strongly suggests that patients with schizophrenia have a deficit in time perception. Discrimination and reproduction of durations have been found to be constantly impaired and disorganized. There is still much work to be done to identify the exact sources of variability in temporal judgments in schizophrenia, and the study of developmental course of time perception could be an interesting route. Regardless of the role of temporal deficits in the pathogenesis of schizophrenia (as a general cognitive disorder or a core role), clinical and phenomenological data encourage us to conduct further studies, especially in the field of developmental psychology.

"Where is the sun" for hemi-neglect patients?

Human observers use prior constraints to disambiguate a scene; in particular, light is preferentially seen as coming from above but also slightly from the left. One explanation of this lateral bias could be a cerebral hemispheric difference. The aim of the present study was to determine the preferred light source position for neglect patients. For this purpose, we used the ambiguous shaded "Polo Mint" stimulus, a ring divided into eight equal sectors. All sectors but one were the same shape, convex or concave, as determined by the light source position. Participants had to report the side (left or right) of the odd sector or, in a separate experiment, to report its shape (convex or concave). Eight patients with spatial neglect (left neglect N=7, right neglect N=1) after a right or left temporo-parietal or thalamic lesion and 14 control participants ran the experiment. Left neglect patients showed a significantly different light bias from the bias observed for controls and for the right neglect patient (i.e., a reduction of the left bias or a right bias rather than a left bias). We conclude that some disabilities presented by patients with spatial neglect may be due to difficulties processing information that is not present in the visual field or imagined in the representational scene.

Osteopenia and vitamin D deficiency in children with sickle cell disease.

OBJECTIVES: To assess the prevalence in children with sickle cell disease of low bone mineral density (BMD), a feature found in up to 82% of adults but not well known in children. METHODS: In 53 children (45 SS, 4 SC, 4 Sbeta-thalassemia) with a mean age of 12.8 +/- 2.4 years, we assessed height; weight; sexual maturation; number of hospitalizations, painful crises, and transfusions in the last 3 years; calcium intake; steady-state hemoglobin and leukocyte count; calcaemia, phosphataemia, and calciuria/creatinuria; serum 25-(OH)D and PTH concentrations; and osteocalcin, urinary deoxypyridinoline, and the C-terminal component of pro-collagen type I. BMD was assessed using dual X-ray absorptiometry. RESULTS: Mean lumbar spine Z-score was -1.1 +/- 1.3 (-3.9 to +1.8). The Z score was significantly lower in girls than in boys in the prepubertal subgroup (-1.74 +/- 0.27 vs. -0.53 +/- 0.31) (P = 0.0169), but not in the pubertal group (-1.15 +/- 0.41 vs. -1.33 +/- 0.70). BMD was not associated with any of the disease-severity markers in girls but was unexpectedly associated with fewer vaso-occlusive crises and hospitalizations in boys. BMD did not correlate with hemoglobin or leukocyte counts. Vitamin D deficiency [25-(OH)D < 12 ng/mL] was found in 76% of patients and secondary hyperparathyroidism (PTH > 46 pg/mL) in 38%. BMD was not related to calcium intake, vitamin D status, osteocalcin, or bone resorption markers. CONCLUSION: A slight BMD decrease was found in SCD children, starting before puberty and being more marked in females. The decrease was unrelated to disease severity, vitamin D deficiency, or bone hyperresorption, suggesting abnormal bone formation as the underlying mechanism.

Transfusing children with hemoglobinopathies.

Thalassemia and sickle cell disease (SCD) are among the most common inherited diseases worldwide. Red blood cell transfusion is a cornerstone of their treatment, but its indications have significantly changed over the past years. New therapies are emerging in both syndromes: among them, hematopoietic stem cell transplantation is now routinely proposed, and gene therapy has shown promising preliminary results.

[Hydroxyurea treatment in patients affected with sickle cell anemia: efficacy and safety]. / Traitement des patients drépanocytaires par hydroxyurée: efficacité et tolérance.

Hydroxyurea is the unique drug having demonstrated an efficacy in preventing recurrences of painful crises, acute chest syndromes and in reducing transfusional needs in patients severely affected with sickle cell disease. However, there is a wide variation in the clinical response to hydroxyurea in sickle cell patients, with children generally experiencing greater benefits than adults. Short- and middle-term tolerances are good. Our uncertainties about long-term tolerance are mainly that we do not know the consequences of the drug on ulterior fertility in boys treated early and for long periods. Hydroxyurea has just been licensed for sickle cell adults and children in Europe. Its prescription for the moment must be restricted to severely affected patients, enrolled in long-term follow-up protocols.

[Is therapeutic progress in the management of sickle cell disease applicable in sub-Saharan Africa?]. / Les progrès thérapeutiques dans la prise en charge de la drépanocytose sont-ils applicables en Afrique subsaharienne?

The life expectancy of patients with sickle cell disease has improved in the United States and Europe thanks to the use of penicillin prophylaxis, appropriate immunizations, neonatal screening, implementation of a quality transfusional policy, hydroxyurea therapy, detection and treatment of cerebral vasculopathy, recognition of situations that can benefit from allogenic marrow transplantation, and improvements in bone marrow transplantation techniques. The cost of almost all these techniques is far beyond the means of health care systems in Africa where they cannot be used. However at least three, i.e., penicillin, vaccines, and hydroxyurea, could be easily accessible in the framework of defined therapeutic strategies. If daily penicillin and pneumococcal vaccine Pneumo 23 are required, it would likely be necessary to select a conjugated vaccine other than Prevenar that does not provide protection against all strains present in Africa. Neonatal screening is still a rare procedure in sub-Saharan countries. Periodic transfusion is steadily improving but exchange transfusion programs aimed in particular at preventing neurological complications are still unfeasible. Indications for hydroxyurea therapy in Africa are more common due to the lack of access to chronic transfusion and must be based on consensus decision. Use of bone marrow transplantation, i.e., the only currently available curative treatment, is still possible only in northern hemisphere countries where it is still restricted to children with severe forms and an HLA-compatible family donor.

Management of iron overload in hemoglobinopathies.

Hemoglobinopathies, thalassemia and sickle cell disease are among the most frequent monogenic diseases in the world. Transfusion has improved dramatically their prognosis, but provokes iron overload, which induces multiple organ damages. Iron overload is related to accumulation of iron released from hemolysis and transfused red cell, but also, in thalassemic patients, secondary to ineffective erythropoiesis, which increases intestinal iron absorption via decreased hepcidin production. Transfusion-related cardiac iron overload remains a main cause of death in thalassemia in well-resourced countries, and is responsible for severe hepatic damages in sickle cell disease. Regular monitoring by Magnetic Resonance Imaging (MRI) using myocardial T2* (ms) and Liver Iron Content (LIC) (mg of iron/g dry weight) are now standards of care in chronically transfused patients. Serum ferritin level measurements and record of the total number of transfused erythrocyte concentrates are also helpful tools. Three iron chelators are currently available, deferoxamine, which must be injected subcutaneously or intravenously, and two oral chelators, deferiprone and deferasirox. We will review the main characteristics of these drugs and their indications.

[Sickle cell disease in France in 2006: results and challenges]. / La drépanocytose en France en 2006: acquis et défis.

Sickle cell disease is currently recognized as the most frequent genetic disease screened in the neonatal period in France, and begins to be funded by Public Health Authorities. Despite these issues, SCD is still largely unknown, in particular by general public and practitioners, and education about the disease has to be intensified. Respective roles of proximate and reference centres have to be better defined. Screening of heterozygous patients remains to be organized. Limits of definition of a severe form, and therapeutic options need to be debated.

[Influenza vaccination coverage rate in children with underlying chronic disorders in 7 French pediatric wards]. / Couverture vaccinale vis-à-vis de la grippe chez les enfants de la région parisienne atteints d'une affection de longue durée.

UNLABELLED: In France, annual influenza vaccination is recommended and free of charge for children with chronic disease (chronic lung, heart or kidney disease, diabetes, haemoglobinopathy, immune deficiency). The national goal is to reach 75% influenza vaccination coverage by 2008, but data on coverage in high risk children are limited. OBJECTIVES: To estimate the influenza vaccination coverage in children with an underlying chronic health condition in the Paris region, during in- or out-patient visit at hospital. METHODS: A multicentre cross-sectional descriptive study was carried out over 2 months before the 2004-2005 flu vaccination campaign in 7 French paediatric hospitals (Paris region). Inclusion criteria for this survey were: children aged 6 months to 18 years, with an underlying chronic disease requiring annual influenza vaccination, with a vaccination card available, so as to check their vaccination status. Reasons for non vaccination were recorded. RESULTS: Data from 239 children were analysed. 56% of patients were males (mean age: 8.1 years). Two patients had 2 separate underlying chronic disorders; 69% had a haemoglobinopathy, 16.3% had a chronic respiratory disease, and 7.5% had diabetes. The influenza vaccination rate for 2003-2004 was 43.7% (haemoglobinopathy: 55.5%; chronic respiratory diseases: 12.8%). This rate increased from 20.4% to 43.7% between 1999 and 2003. Less than 16% of parents remembered having received a voucher for free vaccination from the National Health Insurance Agency. CONCLUSION: Efforts are still needed to achieve the 2008 objectives of 75% coverage.

Increased PIVKA-II concentrations in patients with cystic fibrosis.

Serum vitamin K concentrations and prothrombin induced by absence of vitamin K (PIVK-II) concentrations were assayed in 43 patients with cystic fibrosis. Twenty nine showed a normal PIVKA-II and vitamin K concentrations; 14 showed an increased PIVKA-II concentration, in one of whom serum vitamin K was decreased. Although their vitamin K concentrations were normal, some patients with cystic fibrosis still had an increased PIVKA-II. There was a significant correlation between PIVKA-II concentrations and the administration of antibiotics, a factor which has not previously been considered responsible for an increase in PIVKA-II.

Molecular epidemiology of chronic pulmonary colonisation by Pseudomonas aeruginosa in cystic fibrosis.

The epidemiology of pulmonary colonisation by Pseudomonas aeruginosa was studied in 21 patients with cystic fibrosis (CF) by field inversion gel electrophoresis. DraI-DNA restriction patterns were analysed for 187 P. aeruginosa isolates from these patients. The results revealed that the strains present in individual patients varied during the course of chronic colonisation; the emergence of new strains often was associated with periods of antibiotic therapy. Patients often were colonised by more than one strain (two or three strains were present in 54% of the patients) and the strains obtained from unrelated patients were highly heterogeneous, in contrast to those isolated from a pair of twins. These results demonstrate the heterogeneity and variability of P. aeruginosa isolates in the pulmonary flora of chronically infected CF patients.

Implications of prenatal diagnosis of sickle cell disease.

Prenatal diagnosis (PND) of sickle cell disease (SCD) has been feasible since about 15 years. The number of PND performed for SCD has constantly increased during these years, but its availability raises difficult ethical questions for parents and counsellors. Concerning at-risk parents, only 50% (data in the literature) to 70% (personal data) ask for PND. Our study shows that mainly cultural reasons, then religious ones, educational level and the number of children in the family weigh on the parents' decision to request this diagnosis. The counsellors' position is difficult since clinical severity of the disease is highly variable, there is no early prognostic factor, and the median life expectancy of patients in industrialized countries exceeds 40 years. We need to define a counselling which would consider the image of the illness in the populations involved, in order to help parents understand the implications of the choice they are asked to make.

[Transfusion in patients with hemoglobinopathies]. / Transfusion des patients atteints d'hémoglobinopathies.

A-Thalassemia involves a production deficiency concerning the synthesis of alpha-globin chains, and beta-thalassemia involves the beta-globin chains. Only a few patients in France are affected by the major form of thalassemia (certain types of homozygotic beta-thalassemia). Also, the systematic screening of 'at-risk' couples and prenatal diagnosis has helped to considerably reduce the incidence of new cases. The decision to perform regular blood transfusions is made when Hb levels fall below values that are compatible with normal activity. Hb levels above 10 g/dL permit normal educational, recreational and professional activity. This level is generally maintained via a 15 mL/kg erythrocyte concentrate supplement every three weeks, or 20 mL/kg every four weeks. However, the appearance of antierythrocytic autoantibodies is possible, and this may also result in an increase in blood transfusion requirements. In intermediate thalassemia patients, residual Hb levels are maintained at between 7 and 10 g/dL, and transfusion of erythrocyte concentrates is only made in the case of aggravation of chronic anemia or when there are signs of intolerance to chronic anemia. In France, there is relatively large population of patients with sickle cell disease. Blood transfusion is a major element in the treatment of these patients. Simple transfusion is performed in cases of a lack of iron or folates, increased hemolysis, splenic sequestration or parvovirus 19 infection. The target hematocrit should mostly remain at the patient's baseline value. Exchange transfusions are not performed on a regular basis, but only in cases of stroke or other severe vaso-occlusive events, or when a patient has to be prepared for surgery. A minority of subjects are involved in chronic blood transfusion, which is used mostly to prevent cerebrovascular accidents but also in cases of cardiac, renal, or respiratory insufficiency. There is an increased prevalence of antierythrocytic alloimmunization in sickle cell patients, most probably because of the discrepancies in red cell antigens between mainly Caucasian blood donors and Afro-Caribbean recipients.

[Autologous transfusion: when best should not be the enemy of good enough...]. / Transfusion autologue: quand le mieux ne doit pas être l'ennemi du bien....

Autologous blood transfusion has been shown to decrease allogeneic transfusion in patients undergoing elective procedures, in adults as well as in children. However, its indication must be carefully discussed for each patient, since, on the one hand, viral risks associated with allogeneic blood are greatly reduced, while on the other hand, adverse events may occur in some patients with poor physical condition. An assessment of the ratio 'benefit-risk' has to be made for each patient.

[Iron chelation in 1998]. / La chélation du fer en 1998.

Chronic transfusion regimens lead inevitably to iron overload, causing progressive organ dysfunctions and limiting life expectancy, so that iron chelation is needed in multiple-transfused patients to reduce iron accumulation and toxicity. Desferal is still the most used and the most efficacious chelator. It must be, however, administered through subcutaneous infusion over 8-12 hours. Difficulties with compliance have prompted an ongoing search for alternatives, and in particular for molecules active after oral administration. The only drug available today is L1. This drug is less active than Desferal, and is responsible for rare agranulocytosis. Its indications are still to be discussed.

[Post-transfusion viral infections in patients with hemoglobinopathies]. / Infections virales post-transfusionnelles chez les patients atteints de maladies de l'hémoglobine.

Thalassemic patients are among the most transfused patients, and therefore the most exposed to transfusion-transmitted infections. Prevalence of anti-HIV antibodies before systematic blood donations screening has been evaluated at 1.56% in a European study. Since implementation of this screening, seroconversion to HIV has been drastically reduced. A prevalence around 40% of patients with anti-hepatitis C antibodies has been found in another European study, using second generation tests. Another conclusion of this last study was that the vaccinal coverage against hepatitis B was insufficient. Sickle cell patients receive variable transfusional supplies. When they are transfused monthly, they have the same transfusional risk as thalassemic patients. As some patients may need to be transfused in Africa, where the transfusional risk is important, most medical teams prefer to transfuse sickle cell patients before any travel to Africa.