A case of selective mutism in an 8-year-old girl with thalassaemia major after bone marrow transplantation.

Selective mutism is rare with a prevalence below 1% in the general population, but a higher prevalence in populations at risk (children with speech retardation, migration). Evidence for treatment strategies is hardly available. This case report provides information on the treatment of selective mutism in an 8-year-old girl with preexisting thalassaemia major. As medications she received penicillin prophylaxis (500000 IE/d) and deferasirox (Exjade; 20-25mg/kg/d), an iron chelator. The preexisting somatic disease and treatment complicated the treatment, as there are no data about pharmacological combination therapy. Psychotherapy in day treatment, supported by the use of the SSRI fluoxetine (10 mg), led to a decrease in the selective mutism score from 33 to 12 points, GAF improved by 21 points. Mean levels of fluoxetine plus norfluoxetine were 287.8 ng/ml without significant level fluctuations.

Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation.

Autosomal-recessive hyper-IgE syndrome (AR-HIES) is a combined immunodeficiency recently found to be associated with mutations of DOCK8. Clinically, this disorder is characterized beside recurrent bacterial complications, in particular by an unusual susceptibility to extensive cutaneous viral complications and by a high risk for squamous cell carcinoma. Here, we report on lasting control over the disorder in two patients by hematopoietic cell transplantation (HCT). Both patients were suffering from extensive long-lasting cutaneous viral complications, in particular from disfiguring molluscum contagiosum infections, when treated at the age of 10 and 17 years. Donors were matched unrelated, and conditioning was carried out with a combination of fludarabine, melphalan and BM-targeted radioimmunotherapy. Both patients developed stable, full donor cell chimerism, with the exception of persistent low-IgA serum levels and the exception of normal immune functions. Over the course of several months, cutaneous manifestations of viral disease resolved completely and both patients remain clinically well and free of infectious complications at 4 and 2 years, respectively, after transplantation. This represents the first report indicating HCT to be curative in patients with AR-HIES, which should be considered early before life-threatening complications develop, which include malignancies.

Lithium-induced suicidal erythrocyte death.

Lithium (Li+), an effective drug for treatment of bipolar disorders, is known to alter several Ca²+ transporting systems. Increased cellular Ca²+ has in turn been shown to stimulate eryptosis, the suicidal death of erythrocytes. Eryptosis is characterised by exposure of phosphatidylserine (PS) at the erythrocyte surface and by cell shrinkage. The present experiments explored whether Li+ influences eryptosis. In erythrocytes from healthy volunteers, cytosolic Ca²+ activity (Fluo-3 fluorescence), cell volume (forward scatter) and PS exposure (annexin V binding) were determined by fluorescence-activated cell sorting analysis. Exposure to Li+ (≥ 1 mM) did not significantly modify forward scatter but significantly increased cytosolic Ca²+ activity (within 3 h) and annexin binding (within 48 h). The effect was paralleled by increase of cellular adenosine triphosphate concentration. Glucose depletion (24 h) strongly increased PS exposure, an effect significantly enhanced in the presence of Li+ (≥ 1 mM). In conclusion, Li+ triggers suicidal erythrocyte death, an effect at least partially due to increase of cytosolic Ca²+ activity.

Hematopoietic stem cell transplantation from matched unrelated donors in chronic granulomatous disease.

We report on 12 patients with chronic granulomatous disease transplanted with hematopoietic stem cells from matched unrelated (n = 9) or matched sibling donors (n = 3). The most common infectious complication was pulmonary aspergillosis, which nine patients had previously developed. Only 5 of 12 individuals had normal lung function prior to transplantation. At a mean follow-up of 53 months 9 of the 12 patients are alive including 7 of 9 following matched unrelated donor (MUD) transplantation. One patient died from ARDS, another from systemic BK virus infection, the third from complications of chronic graft-versus-host disease. Seven of nine surviving patients have normal lung function now. HSCT from a MUD is an option worth considering when no matched family donor is available. Restricted lung function prior to HSCT does not appear to be a limiting factor for such treatment.

p53 in recombination and repair.

Convergent studies demonstrated that p53 regulates homologous recombination (HR) independently of its classic tumour-suppressor functions in transcriptionally transactivating cellular target genes that are implicated in growth control and apoptosis. In this review, we summarise the analyses of the involvement of p53 in spontaneous and double-strand break (DSB)-triggered HR and in alternative DSB repair routes. Molecular characterisation indicated that p53 controls the fidelity of Rad51-dependent HR and represses aberrant processing of replication forks after stalling at unrepaired DNA lesions. These findings established a genome stabilising role of p53 in counteracting error-prone DSB repair. However, recent work has also unveiled a stimulatory role for p53 in topoisomerase I-induced recombinative repair events that may have implications for a gain-of-function phenotype of cancer-related p53 mutants. Additional evidence will be discussed which suggests that p53 and/or p53-regulated gene products also contribute to nucleotide excision, base excision, and mismatch repair.

A PCR-SSP method to specifically select HLA-A*0201 individuals for immunotherapeutic studies.

HLA-A*0201 is an important restriction element for peptide presentation to T cells in disease and cancer. Mutation studies and analyses using cytotoxic T lymphocytes have shown the functional relevance of subtype-specific differences in HLA-A2 molecules for peptide binding and T-cell receptor recognition. Therefore, many immunotherapeutic studies need to accurately select HLA-A*0201-positive individuals. We designed an easy, robust approach based on the polymerase chain reaction using sequence-specific primers (PCR-SSP) to specifically distinguish A*0201-positive individuals from other HLA-A2 subtypes described to date. The first step includes reactions that give information whether the sample donor is HLA-A2 and, if so, whether the individual is homozygous or heterozygous for HLA-A2. Further, it is determined whether the sample has an HLA-A*0209 or an HLA-A*0201 sequence at the corresponding position in exon 4. Samples that may contain an HLA-A*0201 allele according to the results of this first step are subtyped in a second step nested PCR. Here the strategy is focussed on the discrimination of HLA-A*0201 from the other subtypes by considering divergent nucleotide positions in two ways. One SSP combination amplifies the HLA-A*0201 sequence while a corresponding SSP combination specifically amplifies the subtype or group of subtypes differing from HLA-A*0201 at this position. Thus, at relevant polymorphic nucleotide positions the HLA-A*0201 sequence is both directly and indirectly confirmed. This strategy strongly enhances the reliability of the subtyping and allows better verification of HLA-A*0201-positive patient selection for clinical studies.

Anisotropy, nonlocality, and space-charge field displacement in (2 + 1)-dimensional self-trapping in biased photorefractive crystals.

The complete basic equations for (2+1) -dimensional self-trapped beam propagation in photorefractive media are numerically solved, with the anisotropic nonlocal response, diffusion, and space-charge-field displacement effects taken into account. Initial Gaussian beams show elliptical beam shapes, self-deflection, and long-lived oscillations after propagation. The critical parameters that determine the possible damping of the transients are discussed.

Kerr-lens mode locking without dispersion compensation.

We propose and theoretically investigate a novel operating regime of femtosecond Kerr-lens mode-locked solidstate lasers that avoids group-velocity dispersion compensation by use of a nonresonant semiconductor plate in the focused resonator section that provides an overall negative nonlinear refractive index per round trip. The saturable loss of the laser resonator with an effective self-defocusing nonlinearity is derived from a generalized ABCD matrix formalism, and the correspondingly calculated steady-state pulse parameters show that a Kerrlens mode-locked laser with an overall negative nonlinear refractive index generates stable femtosecond pulses without any dispersion compensation.

Astigmatism and gain guiding in Kerr-lens mode-locked lasers.

The effects of astigmatism and the radial variation of the gain on Kerr-lens mode-locking (KLM) are studied with the help of an extended ABCD matrix formalism. A dramatic broadening of the allowed cavity parameter region is predicted that permits KLM in almost the whole stability region. The cavity design for KLM with an aperture differs significantly from the design for KLM without an aperture, because of the saturable diffraction loss.

Geometrical threshold zones and Gaussian modes in lasers with radially varying gain.

The effect of a radially varying gain in tightly focused lasers is investigated with a generalized ABCD matrix formalism in a nonparabolic approximation. It is shown that the beam sizes can differ strongly from the theoretical with a constant gain or with radially varying gain in a parabolic approximation. Geometrical threshold zones are defined and studied and, instead of the stability zones, determine the possibility of a laser action for a given cavity design.

Soliton propagation and soliton collision in double-doped fibers with a non-Kerr-like nonlinear refractive-index change.

A physical mechanism for a non-Kerr-like nonlinear refractive-index change in double-doped fibers is proposed, which shows for realistic material parameters a bistable (or two-valued) soliton regime with a large bistability range. The collision of two bistable solitons with a frequency difference in such materials is investigated. Solitons of the lower solution branch retain their shape after the collision. In contrast, two solitons of the upper solution branch with a low-frequency difference fuse to a single high-energy soliton after the collision. The possible applications of this effect for nonlinear photonic switching are discussed.