Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

[Hepatolienal candidosis as a rare differential diagnosis of disseminated small parenchym lesions]. / Hepatolienale Candidose als seltene Differenzialdiagnose disseminierter kleinherdiger Parenchymveränderungen.

HISTORY: We report about a 17-year-old patient with the secondary malignancy of acute myeloid leukemia (AML). He developed fever of unclear origin during the hematopoietic stem cell transplantation.History We report about a 17-year-old patient with the secondary malignancy of acute myeloid leukemia (AML). He developed fever of unclear origin during the hematopoietic stem cell transplantation. EXAMINATIONS: In the focus search, the routine sonography of the abdomen showed disseminated hypoechoic small- parenchymal lesions of the liver. In the complementary MRI, disseminated small lesions of the liver parenchyma and the spleen were demarked after contrast agent administration. DIAGNOSIS: Imaging revealed suspicion of hepatolienal candiasis.Diagnosis Imaging revealed suspicion of hepatolienal candiasis. THERAPY: Empirical therapy with amphotericin B was used. A sonographic punch biopsy of the liver was performed. The pathological examination showed oval particles in the PAS staining in the sense of an opportunistic mycosis of the Candida infection type. CONCLUSION: The case shows that in immunosuppressed patients, candidiasis must always be considered as a differential diagnosis with simultaneous parenchymal changes in the liver and/or spleen. In addition, in the screening situation, a suitable linear transducer should be used when asking about fungal lesions in the liver and spleen. Alternatively, if suspected hepato-lienal candidiasis could be diagnosed by a contrast-enhanced MRI of the upper abdomen/abdomen.

Extreme mobility enhancement of two-dimensional electron gases at oxide interfaces by charge-transfer-induced modulation doping.

Two-dimensional electron gases (2DEGs) formed at the interface of insulating complex oxides promise the development of all-oxide electronic devices. These 2DEGs involve many-body interactions that give rise to a variety of physical phenomena such as superconductivity, magnetism, tunable metal-insulator transitions and phase separation. Increasing the mobility of the 2DEG, however, remains a major challenge. Here, we show that the electron mobility is enhanced by more than two orders of magnitude by inserting a single-unit-cell insulating layer of polar La(1-x)Sr(x)MnO3 (x = 0, 1/8, and 1/3) at the interface between disordered LaAlO3 and crystalline SrTiO3 produced at room temperature. Resonant X-ray spectroscopy and transmission electron microscopy show that the manganite layer undergoes unambiguous electronic reconstruction, leading to modulation doping of such atomically engineered complex oxide heterointerfaces. At low temperatures, the modulation-doped 2DEG exhibits Shubnikov-de Haas oscillations and fingerprints of the quantum Hall effect, demonstrating unprecedented high mobility and low electron density.

Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later.

BACKGROUND: The CD3 co-receptor complex is essential for signal transduction after specific binding of the T-cell receptor (TCR). CD3E encodes the CD3ε chain, one of the protein components (γ-, δ-, ε- and ζ-chain) of the CD3 co-receptor. As previously reported in one family CD3ε deficiency causes SCID. PATIENT: We report on a patient with SCID due to CD3ε deficiency treated by HLA-haploidentical stem cell transplantation (SCT) (donor: mother) 15 years ago which resulted in development of normal T- and B-cell immunity. Despite conditioning donor cell engraftment was confined to T cells, while all other blood cell lineages remained of patient origin (split chimerism). In spite of normal functions, T-cell numbers never reached normal levels and naïve CD45+RA+ T-cells remained low. At 6 years after SCT the patient developed signs of humoral immunodeficiency, requiring regular substitution of IgG. RESULTS: In a retrospective genetic work up 11 years after SCT, a homozygous splice site mutation in CD3E was identified resulting in the loss of CD3ε protein. The loss of B-cell function as observed in the patient was reflected by a lack of switched memory B cells. To rule out a primary role of CD3ε in B-cell function we studied expression of CD3E in B-cells which was found not to be expressed. DISCUSSION: The clinical presentation of a secondary loss of specific humoral immunity in this constellation of split chimerism after allogeneic haploidentical SCT is unusual and unexpected in a patient with a primary T-cell defect. A most likely explanation is the gradual loss of T-helper-cell function.

Local electrostatic imaging of striped domain order in LaAlO3/SrTiO3.

The emerging field of complex oxide interfaces is generically built on one of the most celebrated substrates--strontium titanate (SrTiO3). This material hosts a range of phenomena, including ferroelasticity, incipient ferroelectricity, and most puzzlingly, contested giant piezoelectricity. Although these properties may markedly influence the oxide interfaces, especially on microscopic length scales, the lack of local probes capable of studying such buried systems has left their effects largely unexplored. Here we use a scanning charge detector--a nanotube single-electron transistor--to non-invasively image the electrostatic landscape and local mechanical response in the prototypical LaAlO3/SrTiO3 system with unprecedented sensitivity. Our measurements reveal that on microscopic scales SrTiO3 exhibits large anomalous piezoelectricity with curious spatial dependence. Through electrostatic imaging we unravel the microscopic origin for this extrinsic piezoelectricity, demonstrating its direct, quantitative connection to the motion of locally ordered tetragonal domains under applied gate voltage. These domains create striped potential modulations that can markedly influence the two-dimensional electron system at the conducting interface. Our results have broad implications to all complex oxide interfaces built on SrTiO3 and demonstrate the importance of microscopic structure to the physics of electrons at the LaAlO3/SrTiO3 interface.

Realization of pristine and locally tunable one-dimensional electron systems in carbon nanotubes.

The ability to tune local parameters of quantum Hamiltonians has been demonstrated in experimental systems including ultracold atoms, trapped ions, superconducting circuits and photonic crystals. Such systems possess negligible disorder, enabling local tunability. Conversely, in condensed-matter systems, electrons are subject to disorder, which often destroys delicate correlated phases and precludes local tunability. The realization of a disorder-free and locally-tunable condensed-matter system thus remains an outstanding challenge. Here, we demonstrate a new technique for deterministic creation of locally-tunable, ultralow-disorder electron systems in carbon nanotubes suspended over complex electronic circuits. Using transport experiments we show that electrons can be localized at any position along the nanotube and that the confinement potential can be smoothly moved from location to location. The high mirror symmetry of transport characteristics about the nanotube centre establishes the negligible effects of electronic disorder, thus allowing experiments in precision-engineered one-dimensional potentials. We further demonstrate the ability to position multiple nanotubes at chosen separations, generalizing these devices to coupled one-dimensional systems. These capabilities could enable many novel experiments on electronics, mechanics and spins in one dimension.

Long-term follow-up of children conditioned with Treosulfan: German and Austrian experience.

We report the long-term follow-up of children transplanted with Treosulfan (TREO)-based conditioning in Germany and Austria. Nine centres reported a total of 109 transplantations. Patients were stratified according to the paediatric TRM risk score derived from the paediatric BMT registry (PRST) and compared with the historical transplant population of this registry. Underlying diseases were malignancies, immunodeficiencies, and haematologic and metabolic disorders. TREO total dose ranged from 21-42 g/m(2). Additional conditioning drugs included fludarabine, thiotepa, melphalan, CY and/or TBI. EFS at 3 years for non-malignant and malignant diseases was 88% and 49%, respectively. Leukaemia patients in remission had a survival of 51% at 3 years; nonremission patients relapsed and died within 18 months. TRM and OS in the low-risk groups 0 and 1 were similar to PRST controls. TRM in the high-risk groups 2 and 3 was markedly lower (9% vs 28% and 13% vs 53%, respectively) than in the PRST group, but OS was similar. In conclusion, TREO-based conditioning regimens in children resulted in excellent engraftment and long-term survival in nonmalignant disease. In high-risk malignancy, low acute toxicity was followed by low TRM but it did not translate into increased survival.

[Interdisciplinary AWMF guideline for the treatment of primary antibody deficiencies]. / Interdisziplinäre AWMF-Leitlinie zur Therapie primärer Antikörpermangelerkrankungen.

BACKGROUND: Currently, management of antibody deficient patients differs significantly among caregivers. Evidence and consensus based (S3) guidelines for the treatment of primary antibody deficiencies were developed to improve the management of these patients. METHODS: Based on a thorough analysis of current evidence (systematic literature search in PubMed; deadline November 2011) 14 recommendations were finalized during a consensus meeting in Frankfurt in November 2011 using structured consensus methods (nominal group technique). Experts were nominated by their scientific societies/patient initiatives (Tab. 1). RESULTS: The guidelines focus on indication, practical issues and monitoring of immunoglobulin replacement therapy as well as on different routes of administration. Furthermore recommendations regarding supportive measures such as antiinfective therapy, vaccinations and physiotherapy are given. Combining literature evidence and experience of caregivers within this evidence and consensus based guidelines offers the chance to improve the quality of care for anti-body deficient patients.

Hematopoietic stem cell transplantation for severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) is a heterogeneous group of congenital diseases characterized by their presentation with life threatening infections in the first months of life. The clinical presentation and the therapeutic outcome is influenced by multiple factors: the genetic defect, infectious complications, the presence of maternal T cells the development of Omenn syndrome, as well as non-immunological signs and symptoms of the disease. Hematopoietic stem cell transplantation (HSCT) to date is the only established curative option and allows long-term cure of the disease. Therapeutic objectives of HSCT in SCID clearly differ from those in malignant or hematological disease. Disease specific aspects and their influence on the therapeutic strategy in SCID will be discussed in this review.

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.

Patients with early relapse of primary hemophagocytic syndromes or with persistent CNS involvement may benefit from immediate hematopoietic stem cell transplantation.

Primary hemophagocytic syndromes represent a group of rare immunodeficiencies, which are characterized by development of life-threatening systemic inflammatory manifestations, so-called accelerated phases. Immunosuppressive therapies are only temporarily effective to control this complication and the prognosis is dismal unless treated by hematopoietic SCT (HSCT). At present, optimal modalities of this potentially curative approach remain incompletely defined. In this study, we analyzed our experience in 18 patients with primary hemophagocytic syndromes treated since 1984 in our center by HSCT. Ten of these patients had previously developed accelerated phases and were in remission at the time of HSCT, whereas five patients had findings of active disease, with two cases in early phases of recurrences of less than 2 weeks duration and three cases with persistent central nervous system disease, whereas three patients had never experienced accelerated phases. In the group with active disease, four of five patients are long-term survivors and are well, whereas one patient died of CMV pneumonia. This outcome compares favorably with results in patients transplanted in remission, where 6 of 10 are long-term survivors. Our findings indicate that HSCT can have a favorable prognosis even in patients with active disease of primary hemophagocytic syndrome.

Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide.

Malignant infantile osteopetrosis (MIOP) is a rare hereditary disorder of osteoclast function, which can be reversed by hematopoietic stem cell transplantation (SCT). We observed a high incidence of hepatic veno-occlusive disease (VOD) in transplanted patients and explored the prevention of this complication by using defibrotide (DF) as a prophylaxis. Twenty children with MIOP were consecutively transplanted in our center between 1996 and 2005. Eleven of these patients were transplanted between 1996 and 2001 and experienced an overall incidence of VOD of 63.6% (7/11). VOD was severe in three patients and one patient succumbed to VOD-related multi-organ failure. Owing to this very high incidence of VOD, DF prophylaxis was initiated in nine patients consecutively transplanted between 2001 and 2005. In this group, only one patient (11.1%) was diagnosed with moderate VOD. We report here a very high risk in patients with MIOP to develop VOD after transplantation. Prophylactic DF was implemented in our current transplant protocol and reduced the VOD rate significantly in this high-risk population.

[Nitinol stent implantation in benign esophagotracheal fistula]. / Nitinolstentimplantation bei benigner ösophagotrachealer Fistel.

The self-expanding nitinol stent is easy to handle and well tolerated. It offers an improved method in the treatment of perforations of the upper aerodigestive tract. It is easily implantable with rigid and flexible endoscopes. A 45-year-old female patient developed a tracheal necrosis after polytrauma and protracted intubation and ventilation. The permanent cuff pressure caused a 5-cm long fistula located at the posterior trachea 3 cm above the carina. After stabilization of the general condition and spontaneous reduction of the fistula length to 2 cm, we implanted the silicon-covered esophageal stent. Daily bronchoscopic examination was done before and after implantation of the stent. Two days after implantation, we were able to remove the blocked tracheostomy tube. Immediately oral nutrition was possible without complications. Because of its easy and fast application without any complications, the new type of nitinol stent is a promising alternative for ear, nose, and throat patients in bad general condition to provide fast and safe treatment in benign tracheoesophageal fistulas.

Pathway tracing using biotinylated dextran amines.

Biotinylated dextran amines (BDA) are highly sensitive tools for anterograde and retrograde pathway tracing studies of the nervous system. BDA can be reliably delivered into the nervous system by iontophoretic or pressure injection and visualized with an avidin-biotinylated HRP (ABC) procedure, followed by a standard or metal-enhanced diaminobenzidine (DAB) reaction. High molecular weight BDA (10 k) yields sensitive and exquisitely detailed labeling of axons and terminals, while low molecular weight BDA (3 k) yields sensitive and detailed retrograde labeling of neuronal cell bodies. The detail of neuronal cell body labeling can be Golgi-like. BDA tolerates EM fixation and processing well and can, therefore, be readily used in ultrastructural studies. Additionally, BDA can be combined with other anterograde or retrograde tracers (e.g. PHA-L or cholera toxin B fragment) and visualized either by multi-color DAB multiple-labeling - if permanent labels are desired, or by using multiple simultaneous immunofluorescence - if fluorescence viewing is desired. In the same manner, BDA pathway tracing and neurotransmitter immunolabeling can be combined. Note that BDA pathway tracing can also be combined with anterograde or retrograde labeling with fluorescent dextran amines, if one wishes to exclusively use tracers with the favorable transport properties and sensitivities of dextran amines. In this case, the BDA can be visualized together with the fluorescent dextran amines using fluorescence labeling for the BDA, or the fluorescent dextran amines can be visualized together with the BDA by multicolor DAB labeling via immunolabeling of the fluorescent dextran amines using anti-fluorophore antisera. BDA is, thus, a flexible and valuable pathway tracing tool that has gained widespread popularity in recent years.

Lateral subcutaneous brow lift and interbrow muscle resection: clinical experience and anatomic studies.

The authors report consistent improvement in 65 patients with lateral brow ptosis by using a lateral subcutaneous brow lift at the temporal hairline. In 48 of these patients, vertical glabellar wrinkles were improved by the direct excision of procerus, corrugator, and orbicularis muscles through 3-mm medial brow incisions. Anatomic dissections in 10 cadavers and examinations of 50 skulls were used to study the location of the supraorbital and supratrochlear nerves. Dissections revealed that the supratrochlear nerve was never closer than 1.6 cm to the midline at the level of the supraorbital ridge. In no dissection was a supratrochlear foramen noted. Lateral subcutaneous brow lift was consistently successful in elevating the lateral brow. In no patient was nerve damage to the supraorbital nerve noted. In most patients, the temporal hairline was improved by excising a triangle of balding scalp. Through 3-mm medial brow incisions, the interbrow musculature can be excised by using a small rongeur in an area 3.2 cm wide without risk of nerve damage, improving vertical glabellar wrinkles.