Outcomes of unrelated umbilical cord blood transplantation for X-linked adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a defect in the metabolism of long chain fatty acids leading to demyelination, neurodegeneration, and death. The disease typically presents in young boys and adolescent boys. Allogeneic bone marrow transplantation has been used to halt progression of the disease. However, many patients lack suitable HLA- matched related donors and must rely on unmatched donors for a source of stem cells. The purpose of this study was to evaluate outcomes of unrelated donor umbilical cord blood transplantation after chemotherapy-based myeloablative conditioning and retrospectively determine if baseline studies correlate and help predict outcome. Between November 22, 1996, and November 3, 2005, 12 boys with X-linked ALD who lacked HL- matched related donors were referred to Duke University Medical Center for transplantation. These children were conditioned with myeloablative therapy including busulfan, cyclophosphamide, and antithymocyte globulin before receiving umbilical cord-blood transplants from unrelated donors. Baseline studies of neurophysiologic, neuroimaging, and neurodevelopmental status were performed and patients were subsequently evaluated for survival, engraftment, graft-versus-host disease, and neurodevelopmental outcomes. A substudy evaluated whether baseline neuroimaging and neurophysiologic studies correlated with cognitive and motor function and if these studies were predictive of posttransplantation outcomes. The umbilical cord blood grafts had normal levels of very long chain fatty acids. They delivered a median of 6.98 x 10(7) nucleated cells per kilogram of recipient body weight and were discordant for up to 4 of 6 HLA markers. Neutrophil engraftment occurred at a median of 22.9 days after transplantation. Three patients had grade II-IV acute graft-versus-host disease; 2 had extensive chronic graft-versus-host disease. Cumulative incidence of overall survival of the group at 6 months is 66.7% (95% confidence interval 39.9-93.3%). Median follow-up was 3.3 years (range 12 days to 6.3 years). As previously reported with bone marrow transplantation, symptomatic patients faired poorly with lower survival and rapid deterioration of neurologic function. This study included 3 patients transplanted at a very young age (2.6-3.5 years) before the onset of clinical symptoms who continue to develop at a normal rate for 3-5 years posttransplant. Although baseline Loes scores correlated with cognitive and motor outcome, neurophysiologic studies failed to show statistically significant differences. Transplantation of boys with X-linked ALD using partial HLA-matched umbilical cord blood yields similar results to those previously reported after bone marrow transplantation. Superior outcomes were seen in neurologically asymptomatic boys less than 3.5 years of age at the time of transplantation. Baseline Loes scores were a strong predictor of cognitive and motor outcome.     

Factors associated with external ventricular drain placement accuracy: data from an electronic health record repository

Background

We evaluated external ventricular drain placement for factors associated with placement accuracy. Data were acquired using an electronic health record data requisition tool.

Method

Medical records of all patients who underwent ventriculostomy from 2003 to 2010 were identified and evaluated. Patient demographics, diagnosis, type of guidance and number of catheter passes were searched for and recorded. Post-procedural hemorrhage and/or infection were identified. A grading scale was used to classify accuracy of catheter placements. A multiple logistic regression model was developed to assess features associated with accurate catheter placement.

Results

One hundred nine patients who underwent 111 ventriculostomies from 2003 to 2010 were identified. Patient diagnoses were classified into vascular (63 %), tumor (21 %), trauma (14 %), and cyst (2 %). Procedures were performed freehand in 90 (81 %), with the Ghajar guide in 17 (15 %), and with image guidance in 4 (4 %) patients. Eighty-eight (79 %) catheters were placed in the correct location. Trauma patients were more likely to have catheters misplaced (p?=?0.007) whereas patients in other diagnostic categories were not significantly associated with misplaced catheters. Post-procedural hemorrhage was noted in 2 (1.8 %) patients on post-procedural imaging studies. Five (4.5 %) definite and 6 (5.4 %) suspected infections were identified.

Conclusions

External ventricular drain placement can be performed accurately in most patients. Patients with trauma are more likely to have catheters misplaced. Further development is required to identify and evaluate procedure outcomes using an electronic health record repository.     

Understanding the interaction of Lipoarabinomannan with membrane mimetic architectures

Lipoarabinomannan (LAM) is a critical virulence factor in the pathogenesis of Mycobacterium tuberculosis, the causative agent of tuberculosis. LAM is secreted in urine and serum from infected patients and is being studied as a potential diagnostic indicator for the disease. Herein, we present a novel ultra-sensitive and specific detection strategy for monomeric LAM based on its amphiphilic nature and consequent interaction with supported lipid bilayers. Our strategy involves the capture of LAM on waveguides functionalized with membrane mimetic architectures, followed by detection with a fluorescently labeled polyclonal antibody. This approach offers ultra-sensitive detection of lipoarabinomannan (10?fM, within 15?min) and may be extended to other amphiphilic markers. We also show that chemical deacylation of LAM completely abrogates its association with the supported lipid bilayers. The loss of signal using the waveguide assay for deacylated LAM, as well as atomic force microscopy (AFM) images that show no change in height upon addition of deacylated LAM support this hypothesis. Mass spectrometry of chemically deacylated LAM indicates the presence of LAM-specific carbohydrate chains, which maintain antigenicity in immunoassays. Further, we have developed the first three-dimensional structural model of mannose-capped LAM that provides insights into the orientation of LAM on supported lipid bilayers.     

Benign Tumours of Nasopharynx—Revisited

Benign tumours of nasopharynx are extremely rare; seen predominantly in children and young adults. Patients usually present with seemingly innocuous symptoms and an error in judgement can be catastrophic. This is a retrospective analysis of patients diagnosed to have benign tumours of nasopharynx by histopathological examination in our tertiary care referral centre. The period of study is from September 2009 to August 2010. Eight patients with complete clinical data were identified and included in the study. All the patients were males with a mean age of 21.37 years (range 10–43). Following surgical excision patients were followed up for a mean period of 6.5 months (range 3–14). The Clinical profile, investigation modalities, treatment options are being analysed here.     

Platelet Functions in Cardiopulmonary Bypass Surgery

Background

Haemorrhage after Cardio Pulmonary Bypass (CPB) Surgery is a well recognised complication that leads to significant morbidity and mortality. The incidence varies between 5-25% depending upon the clinical situation. Several factors are implicated as causative but none have been precisely proved.

Methods

Our study was an attempt to evaluate the haemostatic defect with particular reference to platelet function abnormalities during cardio pulmonary bypass surgery, in order to reduce the morbidity and mortality associated with post CPB haemorrhage. Flow cytometric evaluation of different platelet glycoproteins like GPIb/IX, GPIIb/IIIa and GMP-140 was done.

Results

The marker expression showed deregulation during surgery which returned to base after bypass was terminated. In contrast, the cases with bleeding showed significant variation. P-Selectin (GMP 140) expression decreased progressively till 3^rd post-operative day showing lack of activation of platelets in cases of severe bleeding.

Conclusion

Longer duration of CPB initiates plasmin generation through heparin, which raises the PAI-1-tPA complex and thereby down regulating the functions of platelets. This suggests a link between duration of CPB, bleeding, platelet dysfunction and fibrinolysis. Hence serial estimations of the levels of GMP-140 and tPA can predict severe bleeding.Key Words: CardioPulmonary Bypass, Platelet dysfunction, flowcytometry, platelet glycoproteins, haemorrhage     

Intracranial Ewing sarcoma

The occurrence of primary extraosseous Ewing sarcoma (EES) of the central nervous system (CNS) has only rarely been reported in the literature. It is important to distinguish this entity from the more common central primitive neuroectodermal tumor (PNET) of brain, since the management of these tumors is different from that of EES. We present the clinical, radiologic, and pathologic features of two cases of EES occurring in the brain. The diagnosis was further confirmed by detection of a rearrangement of the FLI1 and/or EWS gene loci in tumors from both patients using fluorescent in situ hybridization (FISH). Although rare, the possibility of EES should be considered particularly when tumors that arise near the meningeal surface of the brain and have the pathologic appearance of a PNET. Demonstration of t(11;22)(q24;q12) by molecular analysis essentially confirms the diagnosis and enables the oncologist to choose appropriate therapy.     

Krabbe disease treated with hematopoietic stem cell transplantation: serial assessment of anisotropy measurements--initial experience

PURPOSE: To prospectively compare diffusion-tensor magnetic resonance (MR) imaging anisotropy measurements of white matter (WM) regions in early and late treatment groups of Krabbe disease patients treated with stem cell transplantation. MATERIALS AND METHODS: The study was approved by the Institutional Review Board and was compliant with Health Insurance Portability and Accountability Act; informed consent was obtained from the families of all patients. Patients with early-onset Krabbe disease (four girls and three boys) underwent diffusion-tensor MR imaging before and after stem cell transplantation. Fractional anisotropy (FA) values from serial studies were compared in patients who underwent transplantation at less than 1 month (early group, two girls and one boy) and those who underwent transplantation at 5-8 months (late group, two girls and two boys). FA values were measured in the genu and splenium of the corpus callosum, the frontal WM, and the internal capsule; were compared with those of five age-matched children in the comparison group (normal MR images and no proved neurologic disease); and were expressed as a ratio. Images obtained after transplantation were evaluated at approximately 1 (n = 7), 2 (n = 6), 3 (n = 1), and 4 (n = 1) years. RESULTS: Before transplantation, mean FA ratios in the early group for all four WM regions ranged between 97% and 117%. At 1 year, mean FA ratios at all locations were either 92% or 93%. At 2 years after transplantation, mean FA ratios were between 83% and 92%. In one patient imaged at 3 years, the mean FA ratio was 97%; in another patient imaged at 4 years, the mean FA ratio was 77%. Before transplantation, mean FA ratios in the late group ranged between 55% and 74%. Mean FA ratios were between 37% and 50% at 1 year after transplantation and between 36% and 39% at 2 years. CONCLUSION: All patients had decreases in FA ratios over time. The early group had higher initial FA ratios and lower subsequent decreases, which may indicate amelioration of the dysmyelinating process.     

Resistance of Mycobacterium tuberculosis to the first line anti tubercular drugs--a twenty year review

Tuberculosis and more so the multi drug resistant variety has been thrust into the forefront as a serious and life threatening illness in recent years. The advent of AIDS contributes to this substantially, especially in the developed world where it had become practically non- existent. We reviewed our data over the past 20 years with a view to determine when drug resistance began to manifest in the strains.