BAG1 over-expression in brain protects against stroke

The co-chaperone BAG1 binds and regulates 70 kDa heat shock proteins (Hsp70/Hsc70) and exhibits cytoprotective activity in cell culture models. Recently, we observed that BAG1 expression is induced during neuronal differentiation in the developing brain. However, the in vivo effects of BAG1 during development and after maturation of the central nervous system have never been examined. We generated transgenic mice over-expressing BAG1 in neurons. While brain development was essentially normal, cultured cortical neurons from transgenic animals exhibited resistance to glutamate-induced, apoptotic neuronal death. Moreover, in an in vivo stroke model involving transient middle cerebral artery occlusion, BAG1 transgenic mice demonstrated decreased mortality and substantially reduced infarct volumes compared to wild-type littermates. Interestingly, brain tissue from BAG1 transgenic mice contained higher levels of neuroprotective Hsp70/Hsc70 protein but not mRNA, suggesting a potential mechanism whereby BAG1 exerts its anti-apoptotic effects. In summary, BAG1 displays potent neuroprotective activity in vivo against stroke, and therefore represents an interesting target for developing new therapeutic strategies including gene therapy and small-molecule drugs for reducing brain injury during cerebral ischemia and neurodegenerative diseases.     

Determination of left ventricular mass in dogs with rapid-acquisition cardiac computed tomographic scanning

The development of left ventricular hypertrophy in patients with heart disease often has far-reaching clinical implications with respect to overall morbidity and mortality. Approaches used to assess left ventricular mass include electrocardiography, echocardiography, contrast ventriculography, single photon-emission tomography, and conventional computed tomography. However, all of these modalities suffer from some major draw back that precludes widespread application to all patients. In this study we assessed the accuracy of determinations of left ventricular mass in 22 dogs by rapid-acquisition (50 msec) computed axial tomography (RACAT), an ultrafast computed tomographic (CT) instrument. Electrocardiographically triggered, end-diastolic, short-axis cardiac scans were obtained from apex to base during administration of intravenous iodinated contrast. Myocardial edges were determined for each tomographic scan by two methods: the regional half-contour method (the CT density half way between that of the left ventricular myocardium and adjacent ventricular cavities or lung) and "interactive plateau thresholding" of the cardiac borders. Left ventricular mass by RACAT was calculated as the sum of the mass of each individual scan from apex to base (modified Simpson's rule). Postmortem left ventricular mass ranged from 58 to 160 g. The correlation between true left ventricular mass and tomographically determined mass was excellent (r = .99), with the slope and y intercept not statistically different from 1 and 0, respectively. The standard error of the estimate was 4.1 g. Interobserver and intraobserver variability for determining left ventricular mass demonstrated excellent agreement (r = .99 and r = .99, respectively). We conclude that quantitative assessment of left ventricular mass can be accurately and reproducibly performed in dogs by rapid acquisition CT scanning. It is likely that this technique will be readily transferable to the clinical settings and prove to be an important method for quantifying left ventricular mass in patients.     

Aromatase inhibitor development for treatment of breast cancer

Summary Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue.To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hrurine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples. These data suggest that CGS 20267 can be expected to bring improved response rates in the treatment of metastatic hormone-dependent breast cancer without substantial side effects.Presented by R.J. Santen at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, November 4, 1993; Mini-symposium on New Agents in Breast Cancer (supported by an educational grant from Rhône-Poulenc Rorer).     

温血心停跳液与冷晶体心停跳液对狗心率变异性的影响

为探讨体外循环（ＣＰＢ）导致心脏植物神经系统（ＣＡＳ）损伤的机理,了解温血心停跳液能否防止ＣＰＢ后心率变异性（ＨＲＶ）的降低,采用对照方法观察了温血心停跳液与冷晶体心停跳液对狗ＨＲＶ的影响。结果显示：ＣＰＢ后温血心停跳液组（ＷＢ组）和冷晶体心停跳液组（ＣＣ组）的全频谱（ＴＰ）、低频（ＬＦ）和高频（ＨＦ）均较术前明显降低（Ｐ＜０．０５）,而且ＣＣ组比ＷＢ组降低更明显（Ｐ＜０．０５）,但ＬＦ／ＨＦ在组内及组间均无明显变化（Ｐ＞０．０５）。ＣＰＢ后２４小时平均心率（ＭＨＲ）明显增加（Ｐ＜０．０５）,且ＣＣ组高于ＷＢ组（Ｐ＜０．０５）。本研究表明：采用温血心停跳液或冷晶体心停跳液的ＣＰＢ不会干扰ＣＡＳ平衡,但均能使ＨＲＶ降低,温血心停跳液不能防止ＨＲＶ损害。     

Validity of clinical criteria for the diagnosis of dementia with Lewy bodies

OBJECTIVE: To assess the clinical validity of clinical diagnostic criteria for dementia with Lewy bodies (DLB). METHODS: We assessed the sensitivity, specificity, and positive and negative predictive values of the clinical criteria of the Consortium on dementia with Lewy Bodies (CDLB) in 18 patients with autopsy-proven DLB and in 76 patients with dementia not associated with Lewy bodies, using postmortem diagnosis as a gold standard. RESULTS: CDLB criteria had either high sensitivity or high specificity, but no set of criteria simultaneously provided both high sensitivity and high specificity. Clinical criteria had higher predictive validity in patients with pure DLB than in patients with DLB and AD. Seventy-eight percent of patients with pure DLB had two or more major criteria, compared with 44% of patients with DLB and AD (p<0.02). If the nine patients with DLB and AD were excluded from the DLB group, the CDLB criteria for probable DLB had sensitivity of 78% and specificity of 85%. CDLB criteria for probable DLB (two or more major criteria) distinguished DLB from AD with a sensitivity of 78% and a specificity of 64%. CONCLUSIONS: The proposed CDLB criteria have high negative predictive value and thus do well at excluding patients with DLB. Positive predictive value of 75% can be achieved by a combination of any three major or minor criteria, providing the analysis is confined to patients with mild to moderate dementia. Criteria were most accurate if confined to patients with pure DLB who had mild to moderate dementia.     

Experimental lead arthropathy: an animal model

BACKGROUND: We previously demonstrated short-term effects of intra-articular lead on joint structures in an animal model. We now present histopathologic findings in animals studied over a more extended period. METHODS: Twelve female New Zealand White rabbits had identical lead or stainless steel pellets, or a sham arthrotomy (without implant) inserted in both front knees. The rabbits were killed 4 at a time at 6, 10, and 14 weeks after implantation, and the knee joint structures were evaluated histologically for changes in the synovium, articular cartilage, and meniscus. RESULTS: Histology of the tibial articular surface, femoral articular surface, medial meniscus, lateral meniscus, and synovium showed greater signs of degeneration in the knees with lead implants than controls at all time periods. CONCLUSION: Intrasynovial lead, which does not undergo fibrous encapsulation, has been linked to lead intoxication. Clinical and experimental reports support removal of lead bodies from articular areas in an attempt reduce or slow the degeneration of affected joints. Nonmechanical effects of lead on intraarticular structures may lead to degenerative changes     

Disseminated soft tissue infection and sepsis with Stenotrophomonas maltophilia in a bone marrow transplant patient

A 32-year-old female presented with aplastic anemia and subsequently underwent a one-antigen mismatched bone marrow transplant from her brother. She failed to engraft and a second graft was attempted. Protracted neutropenia of three months' duration despite the use of broad spectrum antibiotics occurred. Stenotrophomonas (Xanthomonas) maltophilia metastatic cellulitis developed that did not respond to appropriate antibiotics.     

The relative frequency of "dementia of unknown etiology" increases with age and is nearly 50% in nonagenarians

CONTEXT: With the recent change in pathological criteria for Alzheimer disease (AD), a group of patients has emerged who do not meet pathological criteria for any well-characterized degenerative dementias. Whether these unclassified patients have vascular dementia or some other form of dementia is not known. OBJECTIVE: To determine the clinical characteristics, pathological substrate, and relative frequency of dementia not caused by well-characterized degenerative dementias. DESIGN/SETTING: Clinicopathological study of a prospectively observed sample of elderly nondemented and demented subjects recruited from our urban community. METHODS: In our series of 128 subjects with prospective neuropsychological evaluations as well as neuropathology, we identified 35 clinically nondemented subjects and 20 demented patients who did not meet pathological criteria for well-characterized degenerative dementias such as AD or dementia with Lewy bodies. The 20 demented patients were grouped together under the term dementia of unknown etiology (DUE). We compared clinical, genetic, neuropsychological, pathological, and neurochemical characteristics of the nondemented group, patients with DUE, and 28 patients with AD and no other pathological abnormality. RESULTS: Mean age at death for patients with DUE was 89.1 +/- 5.8 years compared with 79.9 +/- 11.4 years for AD (P<.001). Patients with AD and DUE did not differ in sex, risk factors, apolipoprotein E genotype, neuropsychological features, or neurological features. Hippocampal sclerosis (in 11 patients with dementia and no controls) and leukoencephalopathy (in 7 patients with dementia and 1 control) were associated with cognitive impairment; other vascular markers were not. Dementia of unknown etiology accounted for 5% of all cases of dementia among patients dying in their 70s, 21% for patients dying in their 80s, and 48% for patients dying in their 90s. CONCLUSIONS: A significant percentage of demented patients older than 80 years do not meet pathological criteria for AD or dementia with Lewy bodies. Hippocampal sclerosis and leukoencephalopathy are common in these patients but rare in clinically nondemented subjects.     

Refining the Amsterdam Criteria and Bethesda Guidelines: testing algorithms for the prediction of mismatch repair mutation status in the familial cancer clinic.

PURPOSE: Hereditary nonpolyposis colon cancer (HNPCC) is a Mendelian dominant syndrome of bowel, endometrial, and other cancers and results from germline mutations in mismatch repair (MMR) genes. HNPCC is now best diagnosed on molecular grounds using MMR mutation screening, aided by microsatellite instability (MSI) and immunohistochemistry in tumors. Selection of families for molecular investigation of HNPCC is usually based on suboptimal methods (Amsterdam Criteria or Bethesda Guidelines), but these can be improved using additional clinical data (mean ages of affected persons and presence of endometrial cancer) in a quantitative model. METHODS: We have verified the performance of the Wijnen model and have shown that it remains valid when HNPCC is diagnosed using mutation screening, MSI, and immunohistochemistry. We have also set up and verified our own models (Amsterdam-plus and Alternative), which perform at least as well as the Wijnen model. RESULTS: The Amsterdam-plus model improves on the Amsterdam Criteria by using five extra variables (numbers of colorectal and endometrial cancers in the family, number of patients with five or more adenomas, number with more than one primary cancer of the colorectum or endometrium, and mean age of presentation) and performs better than the Wijnen model. The Alternative model avoids the need to evaluate the Amsterdam Criteria and performs nearly as well as the other models. CONCLUSION: We believe that a quantitative model, such as the Amsterdam-plus model, should be the first choice for selecting families or patients for evaluation of HNPCC using molecular tests. We present an algorithm for this process.