Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation

In an attempt to decrease the relapse rate after bone marrow transplantation (BMT) for advanced acute leukemia, we initiated studies using 131I-labeled anti-CD45 antibody (BC8) to deliver radiation specifically to hematopoietic tissues, followed by a standard transplant preparative regimen. Biodistribution studies were performed in 23 patients using 0.5 mg/kg trace 131I-labeled BC8 antibody. The BC8 antibody was cleared rapidly from plasma with an initial disappearance half-time of 1.5 +/- 0.2 hours, presumably reflecting rapid antigen- specific binding. The mean radiation absorbed doses (cGy/mCi131I administered) were as follows: marrow, 7.1 +/- 0.8; spleen, 10.8 +/- 1.4; liver, 2.7 +/- 0.2; lungs, 2.1 +/- 0.1; kidneys, 0.7 +/- 0.1; and total body, 0.4 +/- 0.03. Patients with acute myelogenous leukemia (AML) in relapse had a higher marrow dose (11.4 cGy/mCi) than those in remission (5.2 cGy/mCi; P = .001) because of higher uptake and longer retention of radionuclide in marrow. Twenty patients were treated with a dose of 131I estimated to deliver 3.5 Gy (level 1) to 7 Gy (level 3) to liver, with marrow doses of 4 to 30 Gy and spleen doses of 7 to 60 Gy, followed by 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI). Nine of 13 patients with AML or refractory anemia with excess blasts (RAEB) and two of seven with acute lymphocytic leukemia (ALL) are alive disease-free at 8 to 41 months (median, 17 months) after BMT. Toxicity has not been measurably greater than that of CY/TBI alone, and the maximum tolerated dose has not been reached. This study demonstrates that with the use of 131I-BC8 substantially greater doses of radiation can be delivered to hematopoietic tissues as compared with liver, lung, or kidney, which may improve the efficacy of marrow transplantation.     

Immune responses to major histocompatibility complex homozygous lymphoid cells in murine F1 hybrid recipients: implications for transfusion-associated graft-versus-host disease

Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.     

Wireless capsule endoscopy in the investigation of patients with chronic renal failure and obscure gastrointestinal bleeding （preliminary data）

AIM: To investigate the role of wireless capsule endoscopy (WCE) in detection of small bowel (SB) pathology in patients with chronic renal failure (CRF) and obscure bleeding. METHODS: Consecutive CRF patients with obscure bleeding were prospectively studied. Patients with normal renal function and obscure bleeding, investigated during the same period with WCE, were used for the interpretation of results. RESULTS: Seventeen CRF patients (11 overt, 6 occult bleeding) and 51 patients (33 overt, 18 occult bleeding) with normal renal function were enrolled in this study. Positive SB findings were detected in 70.6% of CRF patients and in 41.2% of non-CRF patients (P < 0.05). SB angiodysplasia was identified in 47% of CRF patients and in 17.6% of non-CRF patients. Univariate logistic regression revealed CRF as a significant predictive factor for angiodysplasia (P < 0.05). Therapeutic measures were undertaken in 66% of the patients with the positive findings. CONCLUSION: According to our preliminary results, SB angiodysplasia was found in an increased prevalence among CRF patients with obscure bleeding. WCE is useful in diagnosis of gastrointestinal pathologies and in planning appropriate therapeutic intervention and, therefore, should be included in the work-up of this group of patients.     

A comparative study of feature extraction and blind source separation of independent component analysis (ICA) on childhood brain tumour 1H magnetic resonance spectra

Independent component analysis (ICA) has the potential of determining automatically the metabolite signals which make up MR spectra. However, the realiability with which this is accomplished and the optimal approach for investigating in vivo MRS have not been determined. Furthermore, the properties of ICA in brain tumour MRS with respect to dataset size and data quality have not been systematically explored. The two common techniques for applying ICA, blind source separation (BSS) and feature extraction (FE) were examined in this study using simulated data and the findings confirmed on patient data. Short echo time (TE 30 ms), low and high field (1.5 and 3 T) in vivo brain tumour MR spectra of childhood astrocytoma, ependymoma and medulloblastoma were generated by using a quantum mechanical simulator with ten metabolite and lipid components. Patient data (TE 30 ms, 1.5 T) were acquired from children with brain tumours. ICA of simulated data shows that individual metabolite components can be extracted from a set of MRS data. The BSS method generates independent components with a closer correlation to the original metabolite and lipid components than the FE method when the number of spectra in the dataset is small. The experiments also show that stable results are achieved with 300 MRS at an SNR equal to 10. The FE method is relatively insensitive to different ranges of full width at half maximum (FWHM) (from 0 to 3 Hz), whereas the BSS method degrades on increasing the range of FWHM. The peak frequency variations do not affect the results within the range of ±0.08 ppm for the FE method, and ±0.05 ppm for the BSS method. When the methods were applied to the patient dataset, results consistent with the synthesized experiments were obtained. Copyright © 2009 John Wiley & Sons, Ltd.     

Ras p21 expression in brain tumors: elevated expression in malignant astrocytomas and glioblastomas multiforme.

We have employed an immunohistochemical analysis to study the ras p21 oncoprotein in a total of 41 brain tumors and 1 reactive gliosis. The tumors included 33 astrocytomas, 1 oligodendroglioma, 2 ependymomas, 1 neurilemmoma, 1 malignant meningioma, 1 neuroblastoma and 2 medulloblastomas. Our results indicate that elevated ras p21 expression is a common feature in a range of brain tumors. In particular, elevated ras p21 expression has been found in 18 out of 24 high grade astrocytomas (malignant astrocytomas and glioblastomas multiforme) compared to 3 out of 9 low grade (well differentiated astrocytomas) (P less than 0.05). These results suggest that ras p21 expression may be an important molecular marker of the malignant astrocytomas and glioblastomas multiforme.     

A clinically integrated curriculum in Evidence-based Medicine for just-in-time learning through on-the-job training: The EU-EBM project

Background

Little research has been conducted to investigate role stress experienced by faculty members in medical schools in developing countries. This becomes even more important when the process of reform in medical education has already taken place, such as the case of Iran. The objectives of this study were to investigate and assess the level and source of role-related stress as well as dimensions of conflict among the faculty members of Iranian medical schools. Variables like the length of academic work, academic rank, employment position, and the departments of affiliation were also taken into consideration in order to determine potentially related factors.

Methods

A survey was conducted at three different ranks of public medical schools. The validated Organizational Role Stress Scale was used to investigate the level of role stress and dimensions of role conflict among medical faculty members. The response rate was 66.5%.

Results

The findings show that role stress was experienced in high level among almost all faculty members. All three studied medical schools with different ranks are threatened with relatively the same levels of role stress. Specific differences were found among faculty members from different disciplines, and academic ranks. Also having permanent position and the length of services had significant correlation with the level of role stress. The major role- related stress and forms of conflict among faculty members were role overload, role expectation conflict, inter-role distance, resource inadequacy, role stagnation, and role isolation.

Conclusion

The most role-related stressors and forms of conflict among faculty members include too many tasks and everyday work load; conflicting demands from colleagues and superiors; incompatible demands from their different personal and organizational roles; inadequate resources for appropriate performance; insufficient competency to meet the demands of their role; inadequate autonomy to make decision on different tasks; and a feeling of underutilization. The findings of this study can assist administrators and policy makers to provide an attractive working climate in order to decrease side effects and consequences of role stress and to increase productivity of faculty members. Furthermore, understanding this situation can help to develop coping strategies in order to reduce role-related stress.