Loss of Cholinergic Muscarinic Receptors in the Frontal Cortex of Alcohol Abusers

Alcohol abuse causes impairment of cognitive function ranging from mild forms to end-stage dementia. Alcohol-related dementia accounts for nearly 20% of all admissions to state mental hospitals and may result from head trauma, thiamine deficiency, Alzheimer's, and other brain diseases that can be diagnosed conclusively only at autopsy. However, we postulate that after all these conditions have been excluded, an "alcohol encephalopathy" remains. This is characterized by impaired synaptic function, which underlies the continuum of impaired intellectual function. We found in 79 histologically normal brains of a nondemented general hospital population a 40% decrease in the density of cholinergic muscarinic receptors in the frontal cortex of alcoholics when compared with matched controls of the same age. Only alcohol abuse and not aging, postmortem changes, medications, clinical (including liver) diseases, or differences in causes of death could account for this loss.     

Myeloablative intensified conditioning regimen with in vivo T-cell depletion (ATG) followed by allografting in patients with advanced multiple myeloma. A phase I/II study of the German Study-group Multiple Myeloma (DSMM)

We investigated toxicity and efficacy of in vivo T-cell depletion with anti-thymocyte globulin (ATG) as part of an intensified myeloablative conditioning regimen followed by allogeneic stem cell transplantation in patients with advanced multiple myeloma. The conditioning regimen consisted of modified total body irradiation, busulfan and cyclophosphamide (n=15) or in the case of prior dose-limiting radiotherapy of busulfan and cyclophosphamide (n=3). The median age was 44 years (range, 29-53) and the median time from diagnosis to transplant was 12 months (range, 6-144). Grade II-IV acute graft-versus-host disease (GvHD) occurred in six patients (35%). Severe grade III/IV GvHD developed in one patient (6%). Three patients died of therapy-related causes (17%). A complete remission (CR) with negative immunofixation after allogeneic transplantation was seen in eight of the evaluable patients (53%). After a median follow-up of 41 months (range, 8-84), the estimated overall survival at 6 years for all patients is 77% (CI 95%: 58-96%). The estimated progression-free survival at 6 years for all patients is 31% (CI 95%: 2-59%) and 46% (CI 95%: 9-83%) for patients with CR. In vivo T-cell depletion with ATG resulted in a low rate of severe GvHD with low treatment-related mortality, and a substantial number of long-term survivors.     

Gender differences in the treatment of cerebrovascular disease

OBJECTIVE: Previous studies have shown that women receive fewer invasive procedures for the treatment of coronary artery disease than men, but gender differences in cerebrovascular disease have not been well studied. Our objective was to explore differences in the treatment of stroke between men and women. DESIGN: Secondary database analyses. STUDY PARTICIPANTS: We examined the use of carotid endarterectomy in a nationally representative sample of Medicare enrollees aged 65 to 84, hospitalized for a principal diagnosis of stroke in 1992, the "all strokes group". We also studied a subgroup of patients, the "carotid disease subgroup", admitted with a principal diagnosis of precerebral arterial occlusion and stenosis or transient cerebral ischemia. MEASUREMENTS: We determined rates of carotid endarterectomy for the all strokes group within gender and age groups and calculated corresponding female-to-male relative risks (RR) and 95% confidence intervals (CI). We also performed similar analyses for the carotid disease subgroup. We then used logistic regression to estimate the relative risk of use of carotid endarterectomy for women, controlling for age and comorbidity. RESULTS: The all-strokes group consisted of 3,356 women and 2,927 men, of whom 1,009 women and 990 men were in the carotid disease subgroup. The overall age-adjusted female-to-male relative risk of undergoing carotid endarterectomy for those aged 65 to 84 was 0.69 (95% CI, 0.64-0.74) in the all strokes group and 0.77 (95% CI, 0.72-0.82) in the carotid disease subgroup. In both analyses, the RR became more pronounced with increasing age. In the all strokes group, for example, the RR was 0.80 (0.70-0.92) for those aged 65 to 69 and 0.39 (0.32-0.48) for those aged 80 to 84. The RR for the all strokes group remained similar in magnitude even after controlling for comorbidity (RR, 0.63 and 95% CI, 0.59-0.70). CONCLUSION: We conclude that women hospitalized for strokes undergo fewer carotid endarterectomies than men. Further studies are needed to examine the reasons for and implications of this gender difference.     

Simultaneous voxel‐wise analysis of brain and spinal cord morphometry and microstructure within the SPM framework

To validate a simultaneous analysis tool for the brain and cervical cord embedded in the statistical parametric mapping (SPM) framework, we compared trauma‐induced macro‐ and microstructural changes in spinal cord injury (SCI) patients to controls. The findings were compared with results obtained from existing processing tools that assess the brain and spinal cord separately. A probabilistic brain‐spinal cord template (BSC) was generated using a generative semi‐supervised modelling approach. The template was incorporated into the pre‐processing pipeline of voxel‐based morphometry and voxel‐based quantification analyses in SPM. This approach was validated on T1‐weighted scans and multiparameter maps, by assessing trauma‐induced changes in SCI patients relative to controls and comparing the findings with the outcome from existing analytical tools. Consistency of the MRI measures was assessed using intraclass correlation coefficients (ICC). The SPM approach using the BSC template revealed trauma‐induced changes across the sensorimotor system in the cord and brain in SCI patients. These changes were confirmed with established approaches covering brain or cord, separately. The ICC in the brain was high within regions of interest, such as the sensorimotor cortices, corticospinal tracts and thalamus. The simultaneous voxel‐wise analysis of brain and cervical spinal cord was performed in a unique SPM‐based framework incorporating pre‐processing and statistical analysis in the same environment. Validation based on a SCI cohort demonstrated that the new processing approach based on the brain and cord is comparable to available processing tools, while offering the advantage of performing the analysis simultaneously across the neuraxis.     

Thrombopoietin stimulates megakaryocytopoiesis, myelopoiesis, and expansion of CD34+ progenitor cells from single CD34+Thy-1+Lin- primitive progenitor cells

Thrombopoietin (TPO) or MpI ligand is known to stimulate megakaryocyte (MK) proliferation and differentiation. To identify the earliest human hematopoietic cells on which TPO acts, we cultured single CD34+Thy- 1+Lin- adult bone marrow cells in the presence of TPO alone, with TPO and interleukin-3 (IL-3), or with TPO and c-kit ligand (KL) in the presence of a murine stromal cell line (Sys1). Two distinct growth morphologies were observed: expansion of up to 200 blast cells with subsequent differentiation to large refractile CD41b+ MKs within 3 weeks or expansion to 200-10,000 blast cells, up to 25% of which expressed CD34. The latter blast cell expansions occurred over a 3- to 6-week period without obvious MK differentiation. Morphological staining, analysis of surface marker expression, and colony formation analysis revealed that these populations consisted predominantly of cells committed to the myelomonocytic lineage. The addition of IL-3 to TPO-containing cultures increased the extent of proliferation of single cells, whereas addition of KL increased the percentage of CD34+ cells among the expanding cell populations. Production of multiple colony- forming unit-MK from single CD34+Thy-1+Lin- cells in the presence of TPO was also demonstrated. In limiting dilution assays of CD34+Lin- cells, TPO was found to increase the size and frequency of cobblestone areas at 4 weeks in stromal cultures in the presence of leukemia inhibitory factor and IL-6. In stroma-free cultures, TPO activated a quiescent CD34+Lin-Rhodamine 123lo subset of primitive hematopoietic progenitor cells into cycle, without loss of CD34 expression. These data demonstrate that TPO acts directly on and supports division of cells more primitive than those committed to the MK lineage.     

Inflammatory bowel disease in rats： Bacterial and chemical interaction

AIM：To develop a novel model of colitis in rats, using a combination of iodoacetamide and enteropathogenic E. coli（EPEC）, and to elucidate the pathophysiologic processes implicated in the development of ulcerative colitis （UC）.
METHODS： Hale Sprague-Dawley rats （/7 = 158） were inoculated intrarectally on a weekly basis with 4 different combinations： （a） 1% methylcellulose （HC）, （b） 100 μL of 6% iodoacetamide （IA） in 1% HC, （c） 200 p.L containing 4×10^8 colony factor units （CFU） of EPEC, and （d） combined treatment of （IA） followed by bacteria （13） after 2 d. Thirty days post treatment, each of the four groups was divided into two subgroups; the inoculation was stopped for one subgroup and the other subgroup continued with biweekly inoculation until the end of the experiment. Colitis was evaluated by the clinical course of the disease, the macroscopic and microscopic alterations, activity of myeloperoxidase （HPO）, and by TNF-α gene expression. RESULTS： Findings indicative of UC were seen in the combined treatment （IA ＋ B） as well as the IA continued treatment groups： the animals showed slow rate of increase in body weight, diarrhea, bloody stools, high colonic ulcer score, as well as histological alterations characteristic of UC, with an extensive inflammatory reaction. During the course of the experiment, the MPO activity was consistently elevated and the TNF-α gene expression was upregulated compared to the control animals.
CONCLUSION： The experimental ulcerative colitis model used in the present study resembles, to a great extent, the human disease. It is reproducible with characteristics indicative of chronicity.     

Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept

Steroid-resistant acute GVHD (aGVHD) following allogeneic hematopoietic stem cell transplantation (alloHSCT) continues to be associated with a high mortality. We report the results of a phase II study of treatment of steroid-resistant aGVHD with the IL-2 receptor antibody daclizumab combined with the TNF-receptor fusion protein etanercept. Treatment consisted of daclizumab 1 mg/kg given i.v. on days 1, 4, 8, 15, 22 and etanercept 16 mg/m(2) s.c. on days 1, 5, 9, 13, 17. A total of 21 patients (age 15-61 years) with steroid-resistant aGVHD after alloHSCT were included in the study. Donor types were HLA-matched related (n=6), HLA-matched unrelated (n=14), and HLA-mismatched unrelated (n=1). Eight patients achieved complete, and six showed partial remission of aGVHD. Seven patients did not respond. Four of 21 patients are currently alive with a median follow-up of 586 (185-1155) days. Three patients died due to relapsed malignancy. Treatment-related mortality was due to infectious complications (n=11) or organ failure due to aGVHD (n=3). In total, 12 patients developed subsequent chronic GVHD. In conclusion, the data demonstrate an acceptable response rate of the combination of daclizumab and etanercept in the treatment of steroid-resistant aGVHD. Nevertheless, long-term mortality due to infectious complications and chronic GVHD remains high.