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.

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.

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.

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.

[Cerebral vasculopathy in pediatric sickle-cell anemia]. / Drépanocytose et atteinte vasculaire cérébrale chez l'enfant.

In children with sickle-cell anemia, cerebral vasculopathy is a frequent and severe complication. It is attributed not only to erythrocyte sickling but also to multiple physiological modifications associated with sickle-cell anemia: platelet and leukocyte activation, endothelial injury and remodeling, coagulation activation, hemolysis and subsequent chronic inflammation, impaired vasomotricity, etc. Intracranial large-vessel remodeling leads to clinical cerebral infarction, whereas microvascular injury and impaired vasoreactivity lead to so-called silent infarcts, which are actually associated with impaired cognitive development. Primary prevention strategies have been developed to screen children for cerebral vasculopathy and to further reduce stroke risk. Annual transcranial Doppler beginning at 2 years of age is recommended, allowing risk stratification. Patients at high risk are enrolled in a monthly transfusion exchange program, which reduces the risk of a first stroke by 90 %. Chronic transfusion therapy has also demonstrated efficacy in preventing a second stroke, as a secondary prevention strategy. Lifelong treatment is recommended, as recurrent stroke has been observed when transfusion is discontinued. The burden of chronic transfusion is heavy for patients. Furthermore, several studies have shown that, despite preventing clinically symptomatic stroke, chronic transfusion therapy may not be effective concerning silent infarct progression. Other therapeutic options are currently being explored to obtain better protection with reduced side effects.

Cerebrovascular complications in children with sickle cell disease.

Cerebrovascular accidents were until recently responsible for much mortality and morbidity in children with sickle cell disease; the likelihood of a child with HbSS having a stroke was 11% before age 20 years, with a peak incidence of ischemic stroke between 2 and 5 years of age, and of hemorrhagic strokes between 20 and 29 years of age. Vessels occlusion is likely initiated by intimal proliferation and amplified by inflammation, excessive adhesion of cells to activated endothelium, hypercoagulable state, and vascular tone dysregulation. Silent infarcts may occur and are associated with decreased cognitive functions. Transcranial Doppler ultrasonography (TCD) was more recently demonstrated able to achieve early detection of the children at high risk for clinical strokes. A randomized study demonstrated that a first stroke may be prevented by monthly transfusion in children with abnormal TCD, leading to a recommendation for annual TCD screening of children aged between 2 and 16 years and monthly transfusion for those with abnormal results. In children who have had a first stroke, the risk of recurrence is more than 50% and is greatly reduced by chronic transfusion, although not completely abolished. Hematopoietic stem cell transplant is indicated in children with cerebral vasculopathy who have an HLA-identical sibling.

[Diagnosis of hypochromic microcytic anemia in children]. / Exploration d'une anémie microcytaire chez l'enfant.

Iron deficiency is the most frequent cause of hypochromic microcytic anemia in children, but other causes, some of them requiring specific management, may be involved. Checking the iron-status is absolutely mandatory. When iron-status parameters are low, inadequate intake, malabsorption, blood loss, and abnormal iron utilization must be tested. In absence of iron deficiency, α- and ß-globin and heme biosynthetic gene status must be checked. Assessing the iron stock level is difficult, because there is an overlap between the values observed in iron-replete and iron-deprived patients, so that at least 2 iron-status parameters must be below normal for diagnosing iron deficiency. Furthermore, inflammation may also mimic some characteristics of iron deficiency. Diagnosing iron deficiency leads to prescribing iron supplementation with follow-up at the end and 3 months after cessation of treatment. When iron stores are not replete at the end of treatment, compliance and dosage must be reevaluated and occult bleeding sought. The latter is also required when the iron store decreases 3 months after cessation of iron replacement.

Processing temporal events simultaneously in healthy human adults and in hemi-neglect patients.

Many theories have been advanced to explain how the brain incorporates time into its computations, in particular for the purpose of estimating the duration of an event. In the present study we examine with a new paradigm the ability to compare the duration of two visual stimuli in the parafoveal visual field, presented either sequentially or overlapping in time. We found that judging the duration of a pair of objects is more difficult when they overlap in time. Furthermore, all healthy participants presented a bias to over-estimate the duration of the second event (a negative time-order-error). We then presented the same task to eight left neglect patients with extinction (N-patients). Relative to the healthy participants, the patients displayed similar loss of sensitivity and increased bias in the time overlap condition. However, N-patients were particularly impaired when the first object was presented in their right visual field and the second one appeared on their left before the first one vanished. Rather than a simple engage/disengage disorder, these results highlight a specific problem with shifting attention to the impaired visual field. We discuss these findings in the light of contemporary models of time estimation.

[Hyperuricemia in sickle cell disease in France]. / Hyperuricémie chez les patients drépanocytaires suivis en France.

PURPOSE: Hyperuricemia has been reported to be a common feature of sickle cell disease occurring between 32 to 41% of the patients, in studies conducted during the 1970's. Since then, this notion has been rarely challenged. The objective of this study was to assess the prevalence of hyperuricemia and gout in adult patients with sickle cell disease in France. METHODS: Between May 2007 and March 2009, serum and urinary urate concentration, creatininemia and hemogram were prospectively assessed in all consecutive sickle cell patients, followed in our sickle cell disease centre. All subjects were in a clinically steady state. Clinical acute gout history was also recorded. RESULTS: Sixty-five patients (mean age 31±10.3 years) were investigated. Mean uric acid serum level was 281.6±74µmol/L. Hyperuricemia was evidenced in six patients only (9.2%) (95% IC: 3.5-19.0). None of the patient had a medical history of acute gout. Patients in the higher serum uric acid tertile concentration had higher serum creatinine level (62.3±17.1µmol/L vs 51.5±12.6µmol/L, P<0.01), lower fractional excretion of urate (4.5% vs 6.8%, P<0.03) and higher reticulocyte count (median 219500/mm(3) vs 144000/mm(3), P=0.08) compared to the other patients. CONCLUSION: Hyperuricemia and gout are not a clinical problem in sickle cell disease in our country. Nevertheless, our findings indicate that kidney function has to be fully explored if serum uric acid level is elevated or significantly deteriorates during follow-up. Serum uric acid level could be an early marker of renal dysfunction in sickle cell disease patients.

The vertical-horizontal illusion in hemi-spatial neglect.

The vertical-horizontal illusion is a robust phenomenon of length mis-estimation between two orthogonal lines. This illusion involves an anisotropy component that makes the vertical line appear longer than the horizontal one and a bisection component that makes the bisected line shorter than the bisecting one. Six patients presenting a moderate left hemi-neglect (N-patients) were compared to four right brain damaged patients without neglect (RH-patients) and with control participants in the perception of various spatial configurations of the vertical-horizontal illusion. Relative to controls, we found that both components of the illusion increased in patients: the anisotropy component rose from 5 to 11% and 10% (for N- and RH-patients, respectively) and the bisection component from 17 to 22% and 20% (for N- and RH-patients, respectively). In addition, we found that an horizontal-'T' figure oriented to the left produced much less bias than the same figure oriented to the right. These results are discussed in light of explanations based on attentional disengagement from an image junction and strength of the representation of objects extending over the neglected side.

"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.

[Blood transfusion assessment to 112 homozygous sickle-cell disease patients in university hospital of Brazzaville]. / Evaluation de la transfusion sanguine chez 112 patients drépanocytaires homozygotes au CHU de Brazzaville.

Homozygous, sickle-cell disease (SCD) is responsible for acute complication, especially anaemic crisis and special situation such as acute chest syndrome, stroke and acute priapism. Pregnancy sickle-cell disease presents high risk for the mother and the fetus. In these indications, blood transfusion is the main therapy aiming to reduce anaemia in order to restore hemoglobin's rate or to increase normal Hb proportion. This study aims to assess the short-term efficiency of the red cell transfusion in SCD homozygous form. One hundred and twelve homozygous sickle-cell patients were enrolled in this prospective study: 59 females and 53 males, median age is 21,8 years (extremes: 2 and 45 years). These patients are mostly with very low income. Two groups of patients are included in this study. In the first group, patients present acute anemia crisis caused by infections disease (malaria, bacterial infections). In the second group (20 cases), SCD patients have particularly situations: pregnancy (10 cases); stroke (six cases); cardiac failure (two cases) and priapism (two cases). Transfusion treatment in first group is simple regimen. Transfusion of EC increased median Hb level at 2,9 g/dl (extremes: 1,1 and 4,7). In the second group of patients, 16 cases were transfused by manual partial exchange (1-3) and four patients received simple regimen of transfusion. Median Hb level was 3,1g/dl (extremes: 2,4-4,9 g/dl). HbS percentage reduction was after PTE between -30 and -66,8% (median: -52,6%). According to our diagnostic possibilities (blood serologic test), we have not found any contamination by HIV, HBV and HCV (virus).