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11.
12.
NA Hanchard DR Murdock PL Magoulas M Bainbridge D Muzny YQ Wu M Wang AL McGuire JR Lupski RA Gibbs CW Brown 《Clinical genetics》2013,83(5):457-461
The advent of whole‐exome next‐generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½‐year old female patient with a 2‐year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work‐up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di‐deoxy sequencing. WES revealed a de novo non‐synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future. 相似文献
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Human spleen cell generation of factors stimulating human pluripotent stem cell, erythroid, and myeloid progenitor cell growth 总被引:2,自引:0,他引:2
Mitogen-stimulated murine spleen cells produce humoral substances capable of supporting murine hematopoiesis and pluripotent stem cell proliferation in vitro. Thus, we evaluated conditioned media generated by human spleen cells (SCM) in the presence or absence of mitogens for factors stimulatory for human pluripotent (CFU-GEMM), erythroid (BFU- E), and myeloid (CFU-GM) precursors. Two and one half percent to 10% SCM stimulated proliferation of all three types of precursor cells from nonadherent buoyant human marrow target cells. Mitogen-stimulated SCM augmented CFU-GM (175% to 225%), whereas CFU-GEMM and BFU-E growth was essentially unchanged. Cell separation procedures used to determine which cells provided these microenvironmental stimuli indicated that nonadherent mononuclear spleen cells provided the bulk of the CSF-GM, whereas adherent cells (95% nonspecific esterase + monocyte- macrophages) and nonadherent cells provided similar proportions of CSF- mix and erythroid burst-promoting activity (BPA). The nonadherent cells generating high levels of CSF-mix, BPA, and CSF-GM were predominantly Leu-1-negative, ie, non-T, cells. In the presence or absence of mitogens, SCM was a more potent source (1.3- to 3.8-fold) than peripheral leukocyte CM of the growth factors for the three progenitor cell types. Specific in situ cytochemical stains for analyzing morphology of myeloid colonies demonstrated that SCM stimulated the proliferation of the same types and proportions of colonies as human placental CM, suggesting that these CMs may contain similar CSF-GMs. These data show the contribution of spleen cell subsets to the generation of hematopoietic growth factors and the responsiveness of these cells to various mitogenic stimuli. 相似文献
15.
Native associations of early hematopoietic stem cells and stromal cells isolated in bone marrow cell aggregates 总被引:4,自引:3,他引:4
In suspensions of murine bone marrow, many stromal cells are tightly entwined with hematopoietic cells. These cellular aggregations appear to exist normally within the marrow. Previous studies showed that lymphocytes and stem cells adhered to stromal cells via vascular cell adhesion molecule 1 (VCAM1). Injection of anti-VCAM1 antibody into mice disrupts the aggregates, showing the importance of VCAM1 in the adhesion between stromal cells and hematopoietic cells in vivo. Early hematopoietic stem cells were shown to be enriched in aggregates by using a limiting-dilution culture assay. Myeloid progenitors responsive to WEHI-3CM in combination with stem cell factor (c-kit ligand) and B220- B-cell progenitors responsive to insulin-like growth factor-1 in combination with interleukin-7 are not enriched. We propose a scheme of stromal cell-hematopoietic cell interactions based on the cell types selectively retained within the aggregates. The existence of these aggregates as native elements of bone marrow organization presents a novel means to study in vivo stem cell-stromal cell interaction. 相似文献
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17.
Baron PL Bianchi R Livraghi S Bussini S Bava L Scarpini E Conti G Scarlato G Tacconi MT Oggioni N Petruccioli Mg Cavaletti G Tredici G. 《Journal of the peripheral nervous system : JPNS》2001,6(1):40-41
Experimental lead intoxication is an important model for the study of cellular and molecular mechanisms of segmental demyelination in peripheral nerve. In this report we have compared pathological changes with the molecular and immunohistochemical expression of the proteins of compact and non-compact myelin in the demyelinating neuropathy induced in Sprague-Dawley rats after chronic administration (3 and 6 months) of lead acetate in drinking water. All the rats underwent the neurophysiological determination of the conduction velocity in the tail nerve at baseline and 3, 4.5 and 6 months after the beginning of the lead acetate administration. At the end of the treatment period the rats were sacrificed and sciatic nerve specimens were obtained. The neurophysiological study demonstrated a significant decrease in the nerve conduction velocity, which was already evident at the first determination (3 months) and persisted along the entire experiment. The neurophysiological results were in agreement with the pathological observations performed in the sciatic nerve, where several large demyelinated fibers were observed in the lead-intoxicated rats. Northern and Western blot analysis demonstrated that steady state mRNA and protein levels for P0, MBP, PMP22 and PLP were not changed comparing treated and control rats. Immunohistochemistry on teased fibers revealed that those proteins were distributed in areas of compact myelin along the internodes. In control fibers, as expected, MAG was found in the periaxonal cytoplasm, at nodes of Ranvier, and in the Schmidt-Lanterman incisures. In lead neuropathy, MAG was still limited to discrete regions, but the intensity of staining was reduced, in accordance with changes of paranodal structures. Immunohistochemical localization of other proteins of non-compacted myelin, including connexin-32, E-cadherin and β-catenin was also examined. Our data further suggest that chronic lead intoxication in the rat produces segmental demyelination due primarily to Schwann cell dysfunction. 相似文献
18.
Yasser Sakr Vivian PL Maia Clesar Santos Julia Stracke Mohamed Zeidan Ole Bayer Konrad Reinhart 《Critical care (London, England)》2014,18(2):R68
Introduction
Plasma selenium (Se) concentrations are reduced in critically ill surgical patients, and lower plasma Se concentrations are associated with worse outcomes. We investigated whether adjuvant Se supplementation in the form of sodium selenite could improve outcomes in surgical patients with sepsis.Methods
In this retrospective study, all adult patients admitted to a 50-bed surgical ICU with severe sepsis between January 2004 and April 2010 were included and analysed according to whether they had received adjuvant Se supplementation, which was given at the discretion of the attending physician. When prescribed, Se was administered in the form of sodium selenite pentahydrate (Na2SeO3∙5H2O), in which 100 μg of Se corresponds to 333 μg of sodium selenite. A bolus of sodium selenite corresponding to 1,000 μg of Se was injected intravenously through a central venous line for 30 minutes, followed by infusion of 1,000 μg/day for 24 hours for 14 days until ICU discharge or death. We performed logistic regression analysis to investigate the impact of adjuvant Se supplementation on hospital mortality.Results
Adjuvant Se was administered to 413 (39.7%) of the 1,047 patients admitted with severe sepsis. Age and sex were similar between patients who received adjuvant Se and those who did not. Compared with patients who did not receive adjuvant Se supplementation, patients who did had higher scores on the Simplified Acute Physiology Score II, a greater prevalence of cancer upon admission to the ICU and were more commonly admitted after abdominal surgery. Compared with patients who did not receive adjuvant Se, patients who did had higher hospital mortality rates (46% versus 39.1%; P = 0.027), and longer median (interquartile range (IQR)) ICU stays (15 days (6 to 24) versus 11 days (4 to 24); P = 0.01) and hospital lengths of stay (33 days (21 to 52) versus 28 days (17 to 46); P = 0.001). In multivariable analysis, adjuvant Se supplementation was not independently associated with favourable outcome (odds ratio = 1.19, 95% confidence interval = 0.86 to 1.65; P = 0.288).Conclusions
In this retrospective analysis of a large cohort of surgical ICU patients with severe sepsis, adjuvant Se supplementation in the form of sodium selenite had no impact on in-hospital death rates after adjustment for confounders. 相似文献19.
Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression 总被引:18,自引:26,他引:18
Sullivan KM; Shulman HM; Storb R; Weiden PL; Witherspoon RP; McDonald GB; Schubert MM; Atkinson K; Thomas ED 《Blood》1981,57(2):267-276
Fifty-two of 175 (30%) survivors of allogeneic marrow transplantation developed chronic graft-versus-hose diseases (GVHD). Five with limited chronic GVHD had an indolent clinical course with involvement of only the skin and liver. Forty-seven with extensive chronic GVHD had an unfavorable multiorgan disorder that resembled several autoimmune diseases. Thirteen patients with extensive disease (group I) were not treated and only 2 survive with Karnofsky scores >- 70%. Mortality resulted from infections and morbidity from sica syndrome, pulmonary and hepatic insufficiency, scleroderma-like skin disease, and contractures. Another 13 (group II) received a median of 8 mo prednisone and/or a brief course of antithymocyte globulin, and 3 survive without disability. The other 21 (group III) were treated with a combination of prednisone (1.0 mg/kg/q.o.d.) and either cyclophosphamide, procarbazine, or azathioprine (all 1.5 mg/kg/day) for a median of 13 mo. Combination therapy was well tolerated with only modest myelotoxicity. Fifteen in group III had a good and 4 a fair response to treatment while 2 with no response died. Azathioprine and prednisone was the most effective regimen. All therapy has been discontinued in 12 group III patients: GVHD returned in 5 (including 2 who died in spite of retreatment) while 7 remain free of GVHD for a median of 11 (range 6-30) mo observation. Only I group III survivor is disabled and 16 of the original 21 are alive 2-4 yr after transplant with Karnofsky scores of 70%-100%. Thus, combination immmunosuppression appears to favorably affect and, in some cases, premanently arrest the adverse natural course of extensive chronic GVHD. 相似文献
20.
Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients 总被引:4,自引:3,他引:4
Storb R; Doney KC; Thomas ED; Appelbaum F; Buckner CD; Clift RA; Deeg HJ; Goodell BW; Hackman R; Hansen JA; Sanders J; Sullivan K; Weiden PL; Witherspoon RP 《Blood》1982,59(2):236-246
Sixty-five multiply transfused patients with severe aplastic anemia were given cyclophosphamide followed by grafts anemia were given cyclophosphamide followed by grafts from HLA-identical siblings. The effect of the administration of viable donor buffy coat cells following the marrow inoculum was evaluated with regard to graft rejection and survival. Results in 43 patients so treated are presented along with those in 22 concurrent patients given marrow alone. Most patients given buffy coat had positive in vitro tests of sensitization indicating a high risk for graft rejection, while all but one of the patients given marrow alone had negative tests. Thirty of the 43 (70%) patients given marrow and buffy coat are alive between 10 and 61 mo (median 36) after grafting; 4 died after graft rejection and 6 with acute or chronic graft-versus-host disease (GVHD). Eleven of the 22 (50%) patients given marrow alone are alive between 29 and 65 mo (median 52); 7 died after graft rejection and 3 with GVHD. The addition of buffy coat cell infusions to the marrow inoculum reduced the risk of rejection and increased survival in the currently reported transfused patients when compared to patients grafted before 1976. However, there was an increased risk of chronic GVHD. Recipients of marrow from female donors survived slightly better (73%) than recipients of male marrow (58%). 相似文献