Showing papers by "Paul J. Orchard published in 2012"
TL;DR: A relatively simple and sensitive method to measure levels of dermatan and heparan sulfate derived disaccharides in dried blood spots (DBS) with HPLC-MS/MS is described, and it is demonstrated that this reliably separates MPS I, II and MPS III newborns from controls and heterozygotes.
93 citations
Hannover Medical School1, University of Minnesota2, Ludwig Maximilian University of Munich3, University of North Carolina at Chapel Hill4, Utrecht University5, University of California, San Francisco6, Great Ormond Street Hospital7, University of Oslo8, Children's National Medical Center9, Charité10, Tokai University11, Duke University12, University Hospital of North Norway13, Ruhr University Bochum14
TL;DR: HSCT is a feasible therapeutic option that may promote mental development in alpha-mannosidosis and hearing ability improved in some, but not in all patients, and the extent of the patients’ developmental delay varied over a wide range.
Abstract: Alpha-mannosidosis is a rare lysosomal storage disease. Hematopoietic SCT (HSCT) is usually recommended as a therapeutic option though reports are anecdotal to date. This retrospective multi institutional analysis describes 17 patients that were diagnosed at a median of 2.5 (1.1–23) years and underwent HSCT at a median of 3.6 (1.3–23.1) years. In all, 15 patients are alive (88%) after a median follow-up of 5.5 (2.1–12.6) years. Two patients died within the first 5 months after HSCT. Of the survivors, two developed severe acute GvHD (>=grade II) and six developed chronic GvHD. Three patients required re-transplantation because of graft failure. All 15 showed stable engraftment. The extent of the patients’ developmental delay before HSCT varied over a wide range. After HSCT, patients made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all patients. We conclude that HSCT is a feasible therapeutic option that may promote mental development in alpha-mannosidosis.
54 citations
TL;DR: Despite clinically equivalent IQ and memory, children with MPS IH had poorer attention span than those with attenuated Mps I as well as decreased fractional anisotropy of the corpus callosum.
40 citations
TL;DR: This is the largest report of CSF cytokine levels in cALD to date, and identification of these key cytokines will provide further insight into disease progression and perhaps lead to improved targeted therapies.
Abstract: Background
X-linked adrenoleukodystrophy (ALD) is a metabolic, peroxisomal disease that results from a mutation in the ABCD1 gene. The most severe course of ALD progression is the cerebral inflammatory and demyelinating form of the disease, cALD. To date there is very little information on the cytokine mediators in the cerebral spinal fluid (CSF) of these boys.
Methodology/Principal Findings
Measurement of 23 different cytokines was performed on CSF and serum of boys with cerebral ALD and patients without ALD. Significant elevations in CSF IL-8 (29.3±2.2 vs 12.8±1.1 pg/ml, p = 0.0001), IL-1ra (166±30 vs 8.6±6.5 pg/ml, p = 0.005), MCP-1 (610±47 vs 328±34 pg/ml, p = 0.002), and MIP-1b (14.2±1.3 vs 2.0±1.4 pg/ml, p<0.0001) were found in boys with cALD versus the control group. The only serum cytokine showing an elevation in the ALD group was SDF-1 (2124±155 vs 1175±125 pg/ml, p = 0.0001). The CSF cytokines of IL-8 and MCP-1b correlated with the Loes MRI severity score (p = 0.04 and p = 0.008 respectively), as well as the serum SDF-1 level (p = 0.002). Finally, CSF total protein was also significantly elevated in boys with cALD and correlated with both IL-8, MCP-1b (p = 0.0001 for both), as well as Loes MRI severity score (p = 0.0007).
Conclusions/Significance
IL-8, IL-1ra, MCP-1, MIP-1b and CSF total protein were significantly elevated in patients with cALD; IL-8, MCP-1b, and CSF total protein levels correlated with disease severity determined by MRI. This is the largest report of CSF cytokine levels in cALD to date, and identification of these key cytokines will provide further insight into disease progression and perhaps lead to improved targeted therapies.
35 citations
Center for International Blood and Marrow Transplant Research1, University of Minnesota2, University of California, San Francisco3, Cincinnati Children's Hospital Medical Center4, Boston Children's Hospital5, National Marrow Donor Program6, Federal University of Paraná7, Ohio State University8, Duke University9, Children's Hospital of Philadelphia10, Children's Hospital Los Angeles11, Karolinska Institutet12, University of Pittsburgh13, Great Ormond Street Hospital14, Fred Hutchinson Cancer Research Center15
TL;DR: The finding of higher mortality rates in patients with SCID, non-SCID PIDD, and IEM who survived for at least 2 years after transplantation with normal T cell function or >95% donor chimerism confirms the need for long-term surveillance.
33 citations
TL;DR: It is demonstrated that NAC liberates endogenous, protein-bound Cys in human plasma at clinically relevant NAC concentrations, which increases un bound Cys available for GSH biosynthesis.
31 citations
TL;DR: MMPs were found to be elevated in the CSF of boys with cALD and may mechanistically contribute to the breakdown of the blood-brain-barrier and appear to directly correlate to radiographic and clinical neurologic severity.
Abstract: Background
X-linked adrenoleukodystrophy results from mutations in the ABCD1 gene disrupting the metabolism of very-long-chain fatty acids. The most serious form of ALD, cerebral adrenoleukodystrophy (cALD), causes neuroinflammation and demyelination. Neuroimaging in cALD shows inflammatory changes and indicates blood-brain-barrier (BBB) disruption. We hypothesize that disruption may occur through the degradation of the extracellular matrix defining the BBB by matrix metalloproteinases (MMPs). MMPs have not been evaluated in the setting of cALD.
30 citations
TL;DR: No evidence for the reversal of adrenal failure after hematopoietic cell transplantation in X-linked adrenoleukodystrophy is found.
Abstract: No evidence for the reversal of adrenal failure after hematopoietic cell transplantation in X-linked adrenoleukodystrophy
20 citations
TL;DR: In alloHCT recipients with renal dysfunction or severe hepatic injury, dose reductions may be necessary to prevent toxicity and ensure optimal immunosuppression.
Abstract: Mycophenolate mofetil (MMF) is an immunosuppressant routinely used in allogeneic hematopoietic cell transplantation (alloHCT) to promote stem cell engraftment and prevent acute graft vs host disease. Administered as a prodrug, MMF is converted by esterases to the active moiety, mycophenolic acid (MPA). The impact of clinical covariates on unbound MPA exposure was investigated with a population pharmacokinetic approach. Pharmacokinetic data were obtained from routine area under the curve (AUC) monitoring of unbound MPA drug levels in 36 pediatric (n = 31) and young adult (n = 5) patients undergoing alloHCT for a variety of malignant and nonmalignant disorders. Unbound MPA pharmacokinetics were well described by a 2-compartment model with linear elimination and first-order absorption. The important clinical covariates affecting unbound MPA pharmacokinetics were weight, estimated creatinine clearance, and total bilirubin. Unbound MPA clearance was reduced, and exposure (AUC(0-8)) increased in individuals with decreased renal function. In individuals with severe hepatic dysfunction (total bilirubin >10 mg/dL) unbound MPA clearance was approximately 3-fold lower compared with patients with normal to mild hepatic impairment. In alloHCT recipients with renal dysfunction or severe hepatic injury, dose reductions may be necessary to prevent toxicity and ensure optimal immunosuppression.
18 citations
01 Jan 2012
1 citations
01 Jan 2012
TL;DR: It is suggested that haploidentical NK cells can persist and expand as well as allogeneic NK cell infusions, which were tested in patients with poor prognosis AML.
Abstract: We previously demonstrated that autologous NK cell therapy after hematopoietic cell transplantion (HCT) is safe but does not provide an anti-tumor effect We hypothesize that this is due to a lack of NK cell inhibitory receptor mismatching with autologous tumor cells which may be overcome by allogeneic NK cell infusions Here, we test haploidentical, related donor NK cell infusions in a non-transplant setting to determine safety and in vivo NK cell expansion Two lower intensity outpatient immune suppressive regimens were tested: 1) low-dose cyclophophamide and methylprednisolone and 2) fludarabine A higher intensity inpatient regimen of high-dose cyclophosphamide and fludarabine (Hi-Cy/Flu) was tested in patients with poor prognosis AML All patients received subcutaneous IL-2 after infusions Patients who received lower intensity regimens showed transient persistence but no in vivo expansion of donor cells In contrast, infusions after the more intense Hi-Cy/Flu resulted in a marked rise in endogenous IL-15, expansion of donor NK cells and induction of complete hematologic remission in five of nineteen poor prognosis AML patients These findings suggest that haploidentical NK cells can persist and expand