Large deletions of the MECP2 gene detected by gene dosage analysis in patients with Rett syndrome

The original article to which this Erratum refers was published in Human Mutation 23:234–244 Human Mutation(2004) 23(3) 234–244     

Selective recognition of malaria antigens by human serum antibodies is not genetically determined but demonstrates some features of clonal imprinting

Malaria infection induces the production of serum antibodiesto a variety of malaria antigens but the prevalence of antibodiesto any particular antigen ins typically mucb less than 100%.It has been assumed that non-responsiveness to defined antigensin malaria immune subjects is due to HLA mediated restricutionof the Immune response. In this study we have investigated therole of HLA and non-HLA genes in the antibody response to twomerozoite surface antigens (MSP1 and MSP2) and a sexual stageantigen (Pfs260/230) opf P{lasmodium falcpartum, and concludethat host genotype is not a major determinant of responsiveness.Although antibody levels vary in accordance with seasonal variationsin malaria transmission in semi-immune children, antibiody levelsremain stable in clncall immine adults.     

Voluntary Heart Rate Control During Static Muscular Effort

To test the hypothesis that voluntary heart rate (HR) control is possible with simultaneous muscular effort, 8 male subjects were trained in feedback assisted bidirectional HR control, and also practiced hand grip exercises requiring different levels of effort for 3 consecutive daily sessions. In a fourth session subjects were required to increase and decrease HR while simultaneously performing muscle contractions of 0%, 10%, 30% and 50% of maximum voluntary contractions. Substantial and reliable variations in HR were produced by instructions and by muscular effort during the first 3 sessions; and in the fourth session bidirectional HR control continued even with the relatively elevated baselines induced by muscular effort. Concomitant chin EMG levels did not vary with degree of muscular effort nor with instructions to increase or decrease HR, but increased over the course of any type of trial. Discussion suggests the use of artificially elevated baselines as a strategy for studying HR deceleration and concludes that the present study provides strong evidence of subjects' abilities to voluntarily control HR during muscular effort. This conclusion lends support to the notion that biofeedback therapies may be of clinical utility in real life by modulating the eliciting effects of stressors.     

Cloning and analysis of the murine Fanconi anemia group C cDNA

Fanconi anemia (FA) is one of a group of disorders characterizedat the cellular level by a combination of hypersensitivity toDNA-damaging agents, chromosomal instability, and defectiveDNA repair. Clinical features of FA include pancytopenia, oftenaccompanied by specific congenital malformations, and a predispositionto leukemia. Since the hematological manifestations are thecritical defect in terms of prognosis, FA is a candidate diseasefor gene replacement therapy, and the development of a mousemodel system is essential for the initial stages of this work.Previously, we have cloned the gene defective in FA group Cby complementation of the intrinsic sensitivity of FA cellsto DNA cross-linking agents. We have now cloned the murine homologueof the human FACC cDNA. The mouse cDNA (Facc) shares 79% aminoacid sequence similarity with the human gene product. The expressionof the mouse cDNA in human FA(C) cells restores the cellulardrug sensitivity to normal levels. Thus, the function of theprotein has been conserved despite the significant sequencedivergence. PCR analysis of mouse tissue RNA reveals that thegene is expressed in all adult tissues, while in situ RNA hybridizationexperiments show tissue specific expression at late stages offetal development. Cross-hybridizing sequences exist in DNAfrom other mammals, chicken and Drosophila. These results supportthe hypothesis that the FACC gene product has a role in a basicaspect of cellular protection against DNA damaging agents andthat this function has been conserved during evolution.     

Prevention for preschoolers at high risk for conduct problems: immediate outcomes on parenting practices and child social competence.

This study investigated the immediate impact of an 8-month center- and home-based prevention program for preschoolers at high risk for conduct problems. We report immediate program effects on observed and self-rated parenting practices and observed child behavior with peers. Ninety-nine preschool-age siblings of adjudicated youths and their families were randomly assigned to an enhanced version of the Incredible Years Series (Webster-Stratton, 1989; n = 50) or to a no-intervention control condition (n = 49). In an intent-to-treat design, the intervention yielded significant effects on negative parenting, parental stimulation for learning, and child social competence with peers. Improvements in negative parenting, stimulation for learning, and child social competence support the potential of the intervention to prevent later conduct problems in high-risk children.     

Tacrolimus and mycophenolate mofetil after nonmyeloablative matched-sibling donor allogeneic stem-cell transplantations conditioned with fludarabine and low-dose total body irradiation.

We evaluated tacrolimus/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after a nonmyeloablative stem cell transplantation (NST) from a matched sibling donor (MSD). Thirty-two patients (median age, 57 years) with advanced hematologic malignancies, who were poor candidates for a conventional myeloablative transplantation, received fludarabine (30 mg/m(2), day -4 to day -2), total-body irradiation (TBI) (200 cGy, day 0), infusion of donor peripheral blood progenitor cells (day 0), oral tacrolimus 0.06 mg/kg twice daily (from day 3), and oral MMF at 15 mg/kg twice daily (days 0-+27). Tacrolimus was tapered from day +100 to day +180 in those patients with indolent malignancies (n = 25), and from day +35 to day +56 in those with aggressive tumors (n = 7). Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a nonfatal graft rejection. Rates of grades II-IV and III-IV acute GVHD were 15.6% and 3%, respectively. Acute GVHD was diagnosed at median day +78 (range, days +31-+84). Extensive chronic GVHD was observed in 10 of 24 evaluable patients (41.6%) at a median onset of day +198 (range, days +128-+277), either spontaneously (n = 5) or elicited after tumor progression (n = 5). Five patients experienced transplantation-related mortality (TRM) (15.6%) from either acute GVHD-related multiorgan failure (MOF) (n = 3) or infectious complications (n = 2). At median follow-up of 19 months (range, 2-41 months), the overall survival, progression-free survival, and disease-free survival rates are 62.5%, 50%, and 40%, respectively. In conclusion, the use of tacrolimus/MMF after MSD NST is associated with encouraging rates of GVHD control.     

Phosphatidylserine externalization in human sperm induced by calcium ionophore A23187: relationship with apoptosis, membrane scrambling and the acrosome reaction

BACKGROUND: Translocation of phosphatidylserine (PS) from the inner to the outer leaflet of the plasma membrane is a modification of the lipid architecture occurring in sperm. This is one of the earliest signs of apoptosis that can be monitored by the calcium-dependent binding of annexin V. METHODS AND RESULTS: Flow cytometric analysis of annexin V binding was performed. Calcium ionophore A23187 led to a significant increase in the proportion of living sperm with PS exposure: 7.3 3.2% of cells in the untreated ejaculate versus 47.5 5.6% of cells after 1 h of incubation with A23187. Conversely, diminution of mitochondrial membrane potential [DiOC6(3)/propidium iodide (PI) assay], caspase activation [fluorescein isothiocyanate (FITC)-Val-Ala-Asp-fluoromethylketone (VAD-FMK)/PI assay], increased plasma membrane permeability (Yo-Pro-1/PI assay) and increased DNA fragmentation [TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling assay], which are among the main signs of apoptosis, were not observed in sperm, even after 4 h of incubation with A23187. However, A23187 significantly increased the proportion of sperm with plasma membrane scrambling and with a reacted acrosome, as detected with the merocyanine 540 probe (M540) and the monoclonal anti-human CD46-PE antibody respectively. CONCLUSIONS: Our results suggest that PS exposure in human sperm, as induced by A23187, is mainly related to the acrosome reaction rather than to apoptosis.     

Relationship between health beliefs and psychological variables in diabetic patients

The present paper is focused on the relationship between psychological variables and health beliefs in 93 diabetic men. A Diabetes Health Belief Scale was used to assess general health motivation, treatment beneficial, severity, susceptibility, psychological barriers, cues to action, and structural elements. The psychological variables included two measures of locus of control, depression, somatization, interpersonal sensitivity, obsessive—compulsiveness, anxiety, self-esteem, and attitudes toward diabetes, doctor, and medical care. Ten of the 11 psychological variables were correlated with various aspects of health beliefs. This indicates the extent to which the health beliefs are enmeshed with the psychological dynamics of the person. It would seem important to take such a psychological profile into consideration when attempting to understand and even alter the health beliefs.     

Long-term outcomes of myeloablation and autologous transplantation of relapsed acute myeloid leukemia in second remission: a British Society of Blood and Marrow Transplantation registry study.

Relapsed acute myeloid leukemia (AML) in adults has a poor prognosis if treated with chemotherapy alone. Case series have previously supported the role of myeloablation and autologous transplantation as a potentially curative treatment. This study aimed to use the large numbers and extended follow-up data in the British Society of Blood and Marrow Transplantation (BSBMT) registry database to establish long-term outcomes and relate these to biological and procedural factors. The BSBMT registry database was used to retrospectively identify 152 adult patients (age, 16-69 years) with AML in second remission treated with autologous transplantation in 1982-2003. Cytogenetic data were available for 68% of the patients; of these, at diagnosis, 42% had good risk features, 57% had standard risk features, and 1% had poor risk features. Conditioning regimens varied; autologous rescue was provided with bone marrow (BM) (71%), peripheral blood stem cells (PBSCs) (18%), or both (11%), which were harvested during first complete remission (CR1) and/or second CR (CR2). Median follow-up was 84 months (range, 2-200 months). At 10 years, actuarial overall survival (OS) was 32%, progression-free survival (PFS) was 28%, and relapse rate (RR) was 57%. The 100-day nonrelapse mortality (NRM) was 7%, rising to 11% at 1 year and to 14% at 10 years. OS was significantly related to M3 subtype (5-year OS, 66%; P = .005), patient age at diagnosis (P = .005) and transplantation (P = .026), and length of CR1, with greatest significance if the patient was dichotomized at CR1 duration of < 8 months or > or = 8 months (P = .0001). There was no difference in OS between regimens containing total body irradiation (TBI) and chemotherapy alone (P = .7). In relation to the nature of autologous graft material, there was improved OS (P = .025) and PFS (P = .009) with the use of cells harvested entirely in CR1 compared with cells harvested in CR2 or in both CR1 and CR2. Engraftment times were significantly shortened with the use of PBSCs alone or in combination with BM compared with BM alone (P = .0001), but there was no significant long-term impact on OS, PFS, RR, or NRM. This study provides long-term follow-up data in one of the largest series of patients with standard-risk and good-risk AML in CR2 treated with autologous transplantation and supports earlier observations that long-term survival is achievable in about 1/3 of patients overall and in about 2/3 of patients with M3 with a relatively low NRM. Outcomes are better in patients with CR1 > or = 8 months by use of grafts obtained entirely in CR1 and use of PBSCs. TBI conditioning did not confer an advantage. Randomized studies against unrelated donor transplantation are warranted.     

Ocular autoimmunity: the price of privilege?

Summary:  The eye is the prototypic immune-privileged organ. Its antigens were once believed to be expressed exclusively in the eye, which resides behind an efficient blood–organ barrier, and were believed to be unknown to the immune system. Self-tolerance to ocular components was therefore believed to be based not on immune tolerance but on immune ignorance. It is now known that the relationship between the immune system and the eye is much more complex. On the one hand, immune privilege is now known to involve not only sequestration but also active mechanisms that (i) inhibit innate and adaptive immune processes within the eye and (ii) shape the response that develops systemically to antigens released from the eye. On the other hand, retinal antigens are found in the thymus and have been shown to shape the eye-specific T-cell repertoire. However, thymic elimination of self-reactive T cells is incomplete, and such 'escapee' T cells are tolerized in the periphery as they recirculate through the body by encounter with self-antigen in healthy tissues. Due to the relative inaccessibility of the healthy eye to the immune system, peripheral tolerance mechanisms may not operate efficiently for ocular antigens, leaving a weak link in the homeostasis of tolerance. The case shall be made that although immune privilege protects vision by keeping the immune system at bay, a potential for developing destructive anti-retinal autoimmunity may be the price for the day-to-day protection afforded by immune privilege against inflammatory insults.