Beta2-microglobulin amyloidosis in hemodialysis and peritoneal dialysis patients

Beta(2)-microglobulin (beta(2)-M) amyloidosis is an important cause of morbidity in patients on dialysis. In this cross-sectional study, we evaluated supraspinatus tendon thickness (as a measure of shoulder involvement from beta(2)-M amyloidosis) in patients who are on hemodialysis (HD) compared with those on continuous ambulatory peritoneal dialysis (CAPD). In 27 patients on HD who were treated with high-flux dialyzers, 31 patients on CAPD, and 31 healthy volunteers, we performed bilateral shoulder magnetic resonance imaging and measured the supraspinatus tendon thickness using electronic calipers. There were no statistically significant differences in age or dialysis duration between the HD and CAPD patients. Each patient was asked about the presence or absence of shoulder pain. The supraspinatus tendon thickness in HD patients (mean thickness 6.6 +/- 1.3 mm, range 3.20-8.80 mm, N = 53) and CAPD patients (6.8 +/- 0.9 mm, range 4.9-8.8 mm, N = 61) was not significantly different (P = 0.289); however, the mean thickness in either group was higher than in the healthy controls (5.5 +/- 0.6 mm, range 4.3-6.8 mm, N = 61) (HD patients vs. controls: P = 0.000; CAPD patients vs. controls: P = 0.000). Patients with shoulder pain had higher mean supraspinatus tendon thickness measurements than patients without shoulder pain (P = 0.042). The thickness of supraspinatus tendons is not significantly different between patients on CAPD and HD. An association exists between shoulder pain and mean supraspinatus tendon thickness. This hidden complication of ESRD should be further studied in larger populations of dialysis patients.     

Posttransplant T-cell lymphoproliferative disorders--an aggressive, late complication of solid-organ transplantation

T-cell non-Hodgkin's lymphomas are an uncommon occurrence after solid- organ transplantation. We describe a morphologically and immunophenotypically distinct group of T-cell lymphoproliferative disorders that occurred late in the course of six patients with solid- organ transplants. The patients ranged in age from 31 to 56 years (median, 43). Three were male; all were splenectomized. The interval from transplant to the diagnosis of lymphoma ranged from 4 to 26 years (median, 15). Symptoms at presentation were related to sites of involvement. Pulmonary, marrow, and CNS involvement were present in five, four, and one case, respectively. No patient had lymphadenopathy. Five patients had an elevated lactate dehydrogenase level (range, 226 to 4,880 IU/L; median, 1,220 IU/L). Five of six patients had a leukoerythroblastic reaction. All cases had large-cell histology and frequently contained cytoplasmic granules. Those cases tested expressed CD2, CD3, and CD8 and were negative for B-cell antigens. T-cell receptor beta- and gamma-chain genes were clonally rearranged in three of three and one of three cases, respectively. All T-cell posttransplant lymphoproliferative disorders (T-PTLDs) studied were negative for Epstein-Barr virus (EBV), human T-cell leukemia/lymphoma virus type 1 (HTLV-1), human T-cell leukemia/lymphoma virus type 2 (HTLV-2), and human herpes virus type 8 (HHV-8) genomes. Treatment with acyclovir (three patients) or chemotherapy (three patients) resulted in two responses. All patients had an aggressive course, with a median survival duration of 5 weeks. In conclusion, a clinically aggressive T- PTLD may be a late complication of solid-organ transplantation and does not appear to be related to EBV, HTLV-1, HTLV-2, or HHV-8 infection.     

Correlation of drug-perturbed marrow cell growth kinetics and intracellular 1-B-D-arabinofuranosylcytosine metabolism with clinical response in adult acute myelogenous leukemia

To define the relationship between leukemic cell growth, intracellular metabolism of 1-B-D-arabinofuranosylcytosine (ara-C), and the clinical response to timed sequential induction therapy with ara-C in adult acute myelogenous leukemia (AML), growth kinetic and biochemical pharmacologic determinants were examined in AML bone marrow populations. Leukemic blasts from 45 previously untreated patients obtained prior to therapy were cultured in vitro in autologous pretreatment serum (APS) and in serum containing drug-induced humoral stimulatory activity (HSA). Cell populations cultured in HSA demonstrated both increased proliferation, as measured by both [3H]dThd incorporation into DNA and [3H]dThd leukemic blast labeling index, and greater [3H] ara-C leukemic blast labeling index relative to cells maintained in APS. HSA-cultured marrow cells from the 31 patients who achieved complete remission with ara-C-containing therapy demonstrated enhanced intracellular formation of ara-C 5'-triphosphate over three hours and retention of this active form during one subsequent hour in drug-free medium relative to cells maintained in APS. In contrast, cells from the 14 nonresponsive patients demonstrated no such HSA- induced increases in intracellular ara-C metabolism. These studies of human AML marrow cells identify behavior patterns of ara-C activation and net metabolism in the kinetically perturbed, proliferative state that may discriminate clinical sensitivity from clinical resistance to ara-C-based timed sequential therapy. Sensitive AML populations behave similarly to normal hematopoietic cohorts, with direct linkage of HSA- perturbed growth and pharmacologic parameters, while refractory cells demonstrate uncoupling of these determinants in the growth-stimulated state. These in vitro measurements may further serve as a template for prediction of clinical outcome to timed sequential therapy with ara-C, where both pharmacologic and cytokinetic determinants of response are intrinsic to the success of the designed drug scheduling.     

Utilization of a colony assay to assess the variables influencing elimination of leukemic cells from human bone marrow with monoclonal antibodies and complement

We have previously used a chromium-release assay to demonstrate that the cocktail of monoclonal antibodies BA-1, BA-2, BA-3, and complement can effectively lyse human leukemic cells in the presence of excess bone marrow. Using a leukemic cell colony assay, we have reinvestigated the variables influencing lysis of human leukemic cells (KM-3, HPB- NULL, NALM-6) in bone marrow using BA-1, BA-2, BA-3, and complement. Specific variables addressed included the concentration of excess bone marrow cells, the number of treatments, the presence or absence of DNase during the treatment, the combination of antibodies, and the sensitivity of different leukemic cell lines to lysis. Using the colony assay, the BA-1,2,3 cocktail was shown to be more effective than any single antibody or combination of two antibodies. We also determined that the concentration of excess bone marrow cells and number of treatments had a direct bearing on leukemic cell lysis. Although two cycles of treatment were significantly superior to one cycle, three cycles were not significantly superior to two cycles. Inclusion of DNase (10 micrograms/mL) was a critical adjunct that eliminated clumping and facilitated plating cells in the colony assay. Finally, we could show that striking differences existed in the sensitivity of the leukemic cell lines to lysis with the BA-1,2,3 cocktail and complement. NALM-6 cells were the most sensitive (approximately four logs of kill), and KM-3 cells were the most resistant (less than two logs of kill). Our results strongly support the utility of sensitive leukemic cell colony assays in the analysis of marrow treatment variables in autologous bone marrow transplantation.     

Morphological integration of the human brain across adolescence and adulthood

Brain structural covariance norms capture the coordination of neurodevelopmental programs between different brain regions. We develop and apply anatomical imbalance mapping (AIM), a method to measure and model individual deviations from these norms, to provide a lifespan map of morphological integration in the human cortex. In cross-sectional and longitudinal data, analysis of whole-brain average anatomical imbalance reveals a reproducible tightening of structural covariance by age 25 y, which loosens after the seventh decade of life. Anatomical imbalance change in development and in aging is greatest in the association cortex and least in the sensorimotor cortex. Finally, we show that interindividual variation in whole-brain average anatomical imbalance is positively correlated with a marker of human prenatal stress (birthweight disparity between monozygotic twins) and negatively correlated with general cognitive ability. This work provides methods and empirical insights to advance our understanding of coordinated anatomical organization of the human brain and its interindividual variation.

Across the cortical sheet, communities of brain regions covary in morphological features such as cortical thickness or volume; this phenomenon is referred to as structural covariance (1). Structural covariance can arise from morphological integration, where the anatomy of different brain regions is shaped by shared developmental processes. In particular, if the same developmental program shapes the morphology of different brain regions, we would expect those brain regions to covary across individuals in a population where there is variation in that shared developmental program (2). Consequently, the degree to which a given individual deviates from population-level structural covariation in the brain could provide a powerful indicator of how faithfully that individual has enacted the layered developmental programs (3) that underpin human neuroanatomical variation. However, although the study of individual deviations from anatomical covariance norms has a long and successful history in research on nonhuman animals (3)—particularly in the case of deviations from bilateral symmetry (“fluctuating asymmetry”) (4)—there has been a relative lag in their application to human data. This gap is particularly striking given the increasingly rich and spatiotemporally dense morphometric data sets provided by modern magnetic resonance imaging (MRI) of the living human brain (5). Here, to close this gap, we introduce and apply anatomical imbalance mapping (AIM), a method that provides person-level estimates of both global and interregional deviations from structural covariation norms.We use AIM to characterize spatiotemporal patterning of anatomical imbalance in the human brain within a primary cross-sectional neuroimaging data set of 185 structural MRI scans from healthy youth aged 6 through 25 y and then replicate these developmental findings in an overlapping sample of individuals with longitudinal scans (648 scans from 399 participants). Studying participants in this age range allows us to evaluate time-varying anatomical imbalance and thereby delineate the integration of neurodevelopmental processes that are active in this critical etiological time window for neuropsychiatric disease (6–8). In particular, we seek to assess whether anatomical imbalance is developmentally dynamic (i.e., whether individuals change in their distance from population covariance over time). To further assess the robustness and reproducibility of our findings, we pursue a similar analysis in three independent developmental neuroimaging data sets. Next, to test for dynamism of anatomical imbalance across the human lifespan, we extend AIM to analyze three further data sets, which in combination with our developmental data sets include scans from 21,711 individuals from 6 to 87 y of age. In particular—motivated by the growing consensus that developmental and aging processes act on shared neural substrates (9–11)—we use this expanded lifespan data set to ask whether and how developmental changes in anatomical imbalance are “mirrored” in typical aging. Finally, to address the notion that interindividual variation in anatomical imbalance may serve as a proxy for developmental instability (12), we relate interindividual variation in anatomical imbalance to independent measures of 1) developmental stress, as captured by birthweight disparity between monozygotic twins, and 2) intelligence quotient (IQ), which has previously been associated with fluctuating asymmetry (13).     

Tolerance induction by megadose hematopoietic progenitor cells: expansion of veto cells by short-term culture of purified human CD34(+) cells

Stem cell-dose escalation is one way to overcome immune rejection of incompatible stem cells. However, the number of hematopoietic precursors required for overcoming the immune barrier in recipients pretreated with sublethal regimens cannot be attained with the state-of-the-art technology for stem cell mobilization. This issue was addressed by the observation that cells within the human CD34(+) population are endowed with veto activity. In the current study, we demonstrated that it is possible to harvest about 28- to 80-fold more veto cells on culturing of purified CD34(+) cells for 7 to 12 days with an early-acting cytokine mixture including Flt3-ligand, stem cell factor, and thrombopoietin. Analysis of the expanded cells with fluorescence-activated cell-sorter scanning revealed that the predominant phenotype of CD34(+)CD33(-) cells used at the initiation of the culture was replaced at the end of the culture by cells expressing early myeloid phenotypes such as CD34(+)CD33(+) and CD34(-)CD33(+). These maturation events were associated with a significant gain in veto activity as exemplified by the minimal ratio of veto to effector cells at which significant veto activity was detected. Thus, whereas purified unexpanded CD34(+) cells exhibited veto activity at a veto-to-effector cell ratio of 0.5, the expanded cells attained an equivalent activity at a ratio of 0.125. The availability of novel sources of veto cells such as those in this study might contribute to the realization of immunologic tolerance in "minitransplants," without any risk of graft-versus-host disease.     

Recovery of normal hematopoietic tissue and tumor following chemotherapeutic injury from cyclophosphamide (CTX): comparative analysis of biochemical and clinical techniques

Simultaneous alterations in the incorporation of 3H-thymidine (3H-TdR) into DNA are induced by CTX in normal host target tissues and L1210 ascites tumor. The timing of suppression and recovery of these nucleoside incorporation alterations was similar at the three CTX doses studied, but some evidence for a dose-response effect was seen as the magnitude of suppression of DNA synthesis increased with increasing dosage. A differential pattern of suppression and recovery of 3H-TdR incorporation in malignant and normal host tissues was observed. The pattern of suppression and recovery of the peripheral white blood count and bone marrow (BM) cellularity, two frequently studied clinical parameters of hematopoietic recovery, were out of phase with the recovery of BM-DNA synthesis and failed to accurately reflect the sensitivity of the BM to subsequent chemotherapeutic injury. In contrast, drug schedules based on the differential recovery patterns of the host tissues and tumor, reflected by their 3H-TdR incorporation into DNA, both reduced toxicity to normal mice and increased the survival of tumor-bearing animals.     

对腹泻病因构成比例变迁及对策的浅议

对腹泻病因构成比例变迁及对策的浅议欧阳钦腹泻是任何人一生中都曾有过的症状，即使在发达国家，成人平均每年发生１～２次，发展中国家其发生率更高；有统计显示全世界每天大约有上亿的人口发生腹泻，足见其十分常见。腹泻症状有轻重缓急之分，轻者不治自愈，重者危及生...     

Predictive value of the velocity of collateral filling in patients with acute ischemic stroke

The velocity of collateral filling can be assessed in dynamic time-resolved computed tomography (CT) angiographies and may predict initial CT perfusion (CTP) and follow-up lesion size. We included all patients with an M1± internal carotid artery (ICA) occlusion and follow-up imaging from an existing cohort of 1791 consecutive patients who underwent multimodal CT for suspected stroke. The velocity of collateral filling was quantified using the delay of time-to-peak (TTP) enhancement of the M2 segment distal to the occlusion. Cerebral blood volume (CBV) and mean transit time (MTT)-CBV mismatch were assessed in initial CTP. Follow-up lesion size was assessed by magnetic resonance imaging (MRI) or non-enhanced CT (NECT). Multivariate analyses were performed to adjust for extent of collateralization and type of treatment. Our study comprised 116 patients. Multivariate analysis showed a short collateral blood flow delay to be an independent predictor of a small CBV lesion (P<0.001) and a large relative mismatch (P<0.001) on initial CTP, of a small follow-up lesion (P<0.001), and of a small difference between initial CBV and follow-up lesion size (P=0.024). Other independent predictors of a small lesion on follow-up were a high morphologic collateral grade (P=0.001), lack of an additional ICA occlusion (P=0.009), and intravenous thrombolysis (P=0.022). Fast filling of collaterals predicts initial CTP and follow-up lesion size and is independent of extent of collateralization.     

Taming the “cobra”: An approach to “Cobra‐Like” formation seen in the occlutech atrial septal defect and patent foramen ovale occluders

Percutaneous closure of secundum atrial septal defect and patent foramen ovale has gained widespread use in recent years. We present a small series of four cases in which a “cobra‐like” formation occurred in an Occlutech Figulla device during the deployment of the left disk, and propose a technique that may resolve this problem. © 2011 Wiley Periodicals, Inc.