Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications

Adenosine deaminase (ADA) deficiency is a systemic metabolic disease that causes an autosomal recessive variant of severe combined immunodeficiency (SCID) and less consistently other complications including neurologic abnormalities. Hematopoietic stem cell transplantation (HSCT) is able to correct the immunodeficiency, whereas control of nonimmunologic complications has not been extensively explored. We applied HSCT in 15 ADA-deficient patients consecutively treated at our institutions since 1982 and analyzed long-term outcome. Seven patients received transplants without conditioning from HLA-matched family donors (MFDs); the other 8 patients received conditioning and were given transplants either from HLA-mismatched family donors (MMFDs; n = 6) or from matched unrelated donors (MUDs; n = 2). At a mean follow-up period of 12 years (range, 4-22 years), 12 patients are alive with stable and complete immune reconstitution (7 of 7 after MFD, 4 of 6 after MMFD, and 1 of 2 after MUD transplantation). Six of 12 surviving patients show marked neurologic abnormalities, which include mental retardation, motor dysfunction, and sensorineural hearing deficit. We were unable to identify disease or transplantation-related factors correlating with this divergent neurologic outcome. The high rate of neurologic abnormalities observed in long-term surviving patients with ADA deficiency indicates that HSCT commonly fails to control CNS complications in this metabolic disease

823-2 The ratio of early diastolic mitral flow velocity to early diastolic mitral annular velocity predicts prognosis in patients with chronic congestive heart failure

Arquitectes: Lluís Clotet, Òscar Tusquets Blanca, Carlos DíazProposta d'alçats i seccions del convent dels Àngels.Digitalitzat per Tecnodo

Functional regeneration of glossopharyngeal nerve through micromachined sieve electrode arrays

To assess the potential of micromachined silicon sieve electrodes for long term recording from single afferent sensory fibers, we implanted them between the cut ends of rat glossopharyngeal nerves which innervate taste and somatosensory receptors on the posterior tongue. After the implants had been in place for an average of 101 days nerve regeneration was measured using histological and electrophysiological methods. Axons of the glossopharyngeal nerve regenerated through holes in the sieves and supported the functional regeneration of taste, thermal and mechanoreceptors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29783/1/0000122.pd

Visual-to-auditory sensory substitution alters language asymmetry in both sighted novices and experienced visually impaired users

Visual-to-auditory sensory substitution devices (SSDs) provide improved access to the visual environment for the visually impaired by converting images into auditory information. Research is lacking on the mechanisms involved in processing data that is perceived through one sensory modality, but directly associated with a source in a different sensory modality. This is important because SSDs that use auditory displays could involve binaural presentation requiring both ear canals, or monaural presentation requiring only one – but which ear would be ideal? SSDs may be similar to reading, as an image (printed word) is converted into sound (when read aloud). Reading, and language more generally, are typically lateralised to the left cerebral hemisphere. Yet, unlike symbolic written language, SSDs convert images to sound based on visuospatial properties, with the right cerebral hemisphere potentially having a role in processing such visuospatial data. Here we investigated whether there is a hemispheric bias in the processing of visual-to-auditory sensory substitution information and whether that varies as a function of experience and visual ability. We assessed the lateralization of auditory processing with two tests: a standard dichotic listening test and a novel dichotic listening test created using the auditory information produced by an SSD, The vOICe. Participants were tested either in the lab or online with the same stimuli. We did not find a hemispheric bias in the processing of visual-to-auditory information in visually impaired, experienced vOICe users. Further, we did not find any difference between visually impaired, experienced vOICe users and sighted novices in the hemispheric lateralization of visual-to-auditory information processing. Although standard dichotic listening is lateralised to the left hemisphere, the auditory processing of images in SSDs is bilateral, possibly due to the increased influence of right hemisphere processing. Auditory SSDs might therefore be equally effective with presentation to either ear if a monaural, rather than binaural, presentation were necessary

Lymphoid Enhancer Factor-1 Links Two Hereditary Leukemia Syndromes through Core-binding Factor α Regulation of ELA2

Two hereditary human leukemia syndromes are severe congenital neutropenia (SCN), caused by mutations in the gene ELA2, encoding the protease neutrophil elastase, and familial platelet disorder with acute myelogenous leukemia (AML), caused by mutations in the gene AML1, encoding the transcription factor core-binding factor α (CBFα). In mice, CBFα regulates the expression of ELA2, suggesting a common link for both diseases. However, gene-targeted mouse models have failed to reproduce either human disease, thus prohibiting further in vivo studies in mice. Here we investigate CBFα regulation of the human ELA2 promoter, taking advantage of bone marrow obtained from patients with either illness. In particular, we have identified novel ELA2 promoter substitutions (-199 C to A) within a potential motif for lymphoid enhancer factor-1 (LEF-1), a transcriptional mediator of Wnt/β-catenin signaling, in SCN patients. The LEF-1 motif lies adjacent to a potential CBFα binding site that is in a different position in human compared with mouse ELA2. We find that LEF-1 and CBFα co-activate ELA2 expression. In vitro, the high mobility group domain of LEF-1 interacts with the runt DNA binding and proline-, serine-, threonine-rich activation domains of CBFα. ELA2 transcript levels are up-regulated in bone marrow of an SCN patient with the -199 C to A substitution. Conversely, a mutation of the CBFα activation domain, found in a patient with familial platelet disorder with AML, fails to stimulate the ELA2 promoter in vitro, and bone marrow correspondingly demonstrates reduced ELA2 transcript. Observations in these complementary patients indicate that LEF-1 cooperates with CBFα to activate ELA2 in vivo and also suggest the possibility that up-regulating promoter mutations can contribute to SCN. Two hereditary AML predisposition syndromes may therefore intersect via LEF-1, potentially linking them to more generalized cancer mechanisms

Intra-operative real time intracranial subarachnoid haemorrhage during glial tumour resection: A case report

Glial tumours associated with subarachnoid haemorrhage are very rare. A 64-year-old woman admitted with a history of 3 weeks seizures and a left sided hemiparesis and dysphasia. The magnetic resonance disclosed heterogeneously enhancing a right temporal mass. During surgery, suddenly an abrupt and extensive swelling had occurred both in tumour and the brain tissue. The surgery was completed with a gross total tumour resection together with a partial temporal lobectomy. Postoperative computerized tomography demonstrated a massive subarachnoid hemorrhage (SAH). A cerebral Magnetic Resonance (MR) angiography showed neither an aneurysm nor arteriovenous malformation. Coincidence of an intracerebral tumour and subarachnoid haemorrhage would be devastating

Transumbilical Totally Laparoscopic Single-Port Nissen Fundoplication: A New Method of Liver Retraction: The Istanbul Technique

Mustafa Kemal Ataturk, founder of the Turkish Republic, had guarded many German scientists of a Jewish descent before the Second World War. Dr. Rudolf Nissen was one of the outstanding surgeons who had served in the Turkish university hospitals. He had created an antireflux procedure which is named after his own name while he was working in our clinic, the CerrahpaAYa Hospital. From a laparoscopic approach, the Nissen fundoplication was the gold standard intervention for the surgical treatment of gastroesophageal reflux disease (GERD). Currently, video laparoscopic surgery is evolving quickly with the guidance of new technology. Single-port (SP) laparoscopic transumbilical surgery is one of the newest branches of advanced laparoscopy

Association between the magnitude of intravenous busulfan exposure and development of hepatic veno-occlusive disease in children and young adults undergoing myeloablative allogeneic hematopoietic cell transplantation

BACKGROUND Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight in the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. OBJECTIVE The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen prior to allogeneic HCT. STUDY DESIGN In this observational study we included all patients who received an allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using non-linear mixed effect modelling and expressed as the maximal concentration (Cmax; day 1 and day 1-4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. RESULTS A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier, therefore, we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg*h/L) was associated with increased VOD/SOS risk (12.6% vs. 4.7%; odds ratio (OR) = 2.95, 95% CI 1.13-7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg*h/L) did not further increase the risk of VOD/SOS (15.4% vs. 15.2%; OR = 1.03, 95% CI 0.61-1.75). CONCLUSION The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk

Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders

Graft failure requires urgent salvage HSCT, but there is no universally accepted approach for this situation. We investigated T-cell replete haploidentical HSCT with post-transplantation cyclophosphamide following serotherapy-based, radiation-free, reduced intensity conditioning in children with non-malignant disorders who had rejected their primary graft. Twelve patients with primary or secondary graft failure received T-cell replete bone marrow grafts from haploidentical donors and post-transplantation cyclophosphamide. The recommended conditioning regimen comprised rituximab 375 mg/m2, alemtuzumab 0.4 mg/kg, fludarabine 150 mg/m2, treosulfan 20–24 g/m2 and cyclophosphamide 29 mg/kg. After a median follow-up of 26 months (7–95), eleven of twelve patients (92%) are alive and well with complete donor chimerism in ten. Neutrophil and platelet engraftment were observed in all patients after a median of 18 days (15–61) and 39 days (15–191), respectively. Acute GVHD grade I was observed in 1/12 patients (8%) and mild chronic GVHD in 1/12 patients (8%). Viral reactivations and disease were frequent complications at 75% and 42%, respectively, but no death from infectious causes occurred. In summary, this retrospective analysis demonstrates that a post-transplantation cyclophosphamide-based HLA-haploidentical salvage HSCT after irradiation-free conditioning results in excellent engraftment and overall survival in children with non-malignant diseases