Magnetic resonance angiography findings in the early post-carotid endarterectomy period

This preliminary study was designed to investigate the ability of multiple axial volume three-dimensional fourier transform (3DFT) time-of-flight (TOF) magnetic resonance angiography (MRA) to depict the carotid bifurcation in the early post-carotid endarterectomy period. Five patients underwent intra-operative digital subtraction angiography (DSA) and carotid MRA within 5 days of carotid endarterectomy. An axial volume fast imaging in steady-state precession (FISP) gradient-echo 3DFT TOF carotid MRA technique in this limited series appeared to display accurately the surgically significant abnormalities at the carotid bifurcation after endarterectomy. However, in normal or near-normal intra-operative DSA studies, overestimation of internal carotid artery stenoses was encountered. Postoperative MRA demonstrates potential as a useful non-invasive investigation after carotid endarterectomy but should be interpreted with caution until larger studies become available.     

Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer.

Increased expression of alternatively spliced variants of the CD44 family of cell adhesion molecules has been associated with tumour metastasis. In the present study, expression of alternatively spliced variants of CD44 and their cellular distribution have been investigated in human colonic tumours and in the corresponding normal mucosa, in addition to benign adenomatous polyps. The expression of CD44 alternatively spliced variants has been correlated with tumour progression according to Dukes'' histological stage. CD44 variant expression was determined by immunohistochemisty using monoclonal antibodies directed against specific CD44 variant domains together with RT-PCR analysis of CD44 variant mRNA expression in the same tissue specimens. We demonstrate that as well as being expressed in colonic tumour cells, the full range of CD44 variants, CD44v2-v10, are widely expressed in normal colonic crypt epithelium, predominantly in the crypt base. CD44v6, the epitope which is most commonly associated with tumour progression and metastasis, was not only expressed by many benign colonic tumours, but was expressed as frequently in normal basal crypt epithelium as in malignant colonic tumour cells, and surprisingly, was even absent from some metastatic colorectal tumours. Expression of none of the CD44 variant epitopes was found to be positively correlated with tumour progression or with colorectal tumour metastasis to the liver, results which are inconsistent with a role for CD44 variants as indicators of colonic cancer progression.     

Stereoselective urinary excretion of formoterol and its glucuronide conjugate in human

AIMS: Formoterol is an inhaled beta2-adrenoceptor agonist used as a racemic mixture of the active (R; R)- and inactive (S; S)-enantiomers (rac-formoterol). Glucuronidation is an important route of metabolism in humans which occurs faster for (S; S)-formoterol in human liver microsomes. The aim of this study was to investigate the stereoselectivity of urinary excretion of formoterol and its glucuronide conjugate after oral dosing with rac-formoterol. METHODS: Seven nonsmoking volunteers (six males, one female) were included in the study. After an overnight fast, a single 60 micro g oral dose of rac-formoterol fumarate dihydrate was ingested. Urine samples were collected at 1 h intervals for the first 4 h, and at 6, 8, 12 and 24 h after dosing. Formoterol enantiomers were analysed by chiral h.p.l.c. assay and formoterol glucuronides were determined as formoterol enantiomers after enzymatic cleavage with beta-glucuronidase. RESULTS: The female subject displayed a different pattern of metabolism and statistical analysis was therefore limited to data for the six males. The median (range) of the total urinary excretion of formoterol was 37.8% (20.9-51.2%) of the dose. The medians (ranges) of the amounts of (R; R)- and (S; S)-formoterol and of (R; R)- and (S; S)-formoterol glucuronide excreted were 2.1 (1.0-2.9), 3.5 (2.6-3.8), 21.0 (13.1-31.0) and 10.3 (4.2-14.6)%, respectively, of the dose. Unchanged (S; S)-formoterol excretion was significantly greater than that of unchanged (R; R)-formoterol and (R; R)-formoterol glucuronide excretion was significantly greater than that of (S; S)-formoterol glucuronide. The total RR-formoterol (unchanged drug plus glucuronide) excreted was significantly greater than the total (S; S)-formoterol. CONCLUSIONS: Our study demonstrates that the urinary excretion of formoterol in male humans after oral administration of rac-formoterol is stereoselective with preferential excretion of the active (R; R)-formoterol as unchanged drug and glucuronide. The different pattern of metabolism in the female subject provides impetus for further studies of the effect of gender on the stereoselective metabolism and pharmacokinetics of formoterol.     

Clinical correlates of inpatient suicide

BACKGROUND: Previous suicide assessment research has led to standard predictors of risk. Despite this, there are approximately 30,000 suicides per year in the United States, 5% to 6% of which occur in hospitals. The primary purpose of this study is to improve our ability to assess risk and intervene successfully. METHOD: Charts from 76 patients who committed suicide while in the hospital, or immediately after discharge, were reviewed. The week before suicide was rated for both standard risk predictors and, using items from the Schedule for Affective Disorders and Schizophrenia (SADS), for presence and severity of symptoms found to be correlated with acute risk in recent studies. RESULTS: Regarding standard predictors, only 49% (N = 37) had any prior suicide attempt and 25% (N = 19) were admitted for this reason. Thirty-nine percent (30/76) were admitted for suicidal ideation, but 78% denied suicidal ideation at their last communication about this; 46% (N = 35) showed no evidence of psychosis; of those on precautions (N = 45), 51% (N = 23) were on q 15 minute suicide checks or 1:1 observation; and 28% (N = 21) had a no-suicide contract in effect. On SADS ratings, 79% (N = 60) met criteria for severe or extreme anxiety and/or agitation. CONCLUSION: Standard risk assessments and standard precautions used were of limited value in protecting this group from suicide. Adding severity of anxiety and agitation to our current assessments may help identify patients at acute risk and suggest effective treatment interventions. The importance of a matched comparison group to ascertain if this sample can be blindly discriminated from inpatients who do not commit suicide is clear.     

Evidence for a neuroanatomical difference within the olivo-cerebellar pathway of adults with dyslexia

Recent behavioural evidence has indicated that cerebellar impairment may be strongly associated with dyslexia. Previous neuroanatomical research has shown the presence of anomalies within the cerebral cortex of brains of dyslexic people. This paper reports equivalent analyses on the cerebella of the same brain specimens. Cross sectional areas and cell packing densities of Purkinje cells in the cerebellar cortex, and cells in the inferior olivary and dentate nuclei of four dyslexic and four control brains were measured using the dissector method. A significant difference in mean cell area in medial posterior cerebellar cortex was identified, with the dyslexic cells having larger mean area. Furthermore, analysis of cell size distributions not only confirmed the significant differences in the posterior lobe, with an increased proportion of large neurons and fewer small neurons for the dyslexics, but also revealed significant differences in the anterior lobe, again with a pattern of more large and fewer small cells. Similar distributional differences were seen in the inferior olive. No differences were found in the flocculonodular lobe or the dentate nucleus. While caution is necessary in generalising from the results given the small number of specimens, together with the age difference, the neuroanatomical data established here provides further converging evidence of cerebellar abnormality in dyslexia.     

Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression

BACKGROUND: Although various strategies have been proposed to treat antidepressant nonresponders, little controlled research has been published that examines prospectively the use of switching to an alternate antidepressant. METHODS: This was a multisite study in which outpatients with chronic major depression (with or without concurrent dysthymia), who failed to respond to 12 weeks of double-blind treatment with either sertraline hydrochloride (n = 117) or imipramine hydrochloride (n = 51), were crossed over or switched to 12 additional weeks of double-blind treatment with the alternate medication. Outcome measures included the 24-item Hamilton Rating Scale for Depression and the Clinical Global Impressions--Severity and Improvement scales. RESULTS: The switch from sertraline to imipramine (mean dosage, 221 mg/d) and from imipramine to sertraline (mean dosage, 163 mg/d) resulted in clinically and statistically significant improvements. The switch to sertraline treatment was associated with fewer adverse effect complaints and significantly less attrition owing to adverse effects. Although sertraline treatment also resulted in significantly higher response rates in the intent-to-treat samples (60% in the sertraline group and 44% in the imipramine group), neither the intent-to-treat remission rates nor the response and remission rates among study completers differed significantly. Moreover, after considering the effect of attrition, there were no significant treatment effects on the more comprehensive generalized estimating equation analyses of the continuous dependent measures. CONCLUSIONS: More than 50% of chronically depressed antidepressant nonresponders benefited from a switch from imipramine to sertraline, or vice versa, despite a high degree of chronicity. As in the initial trial, sertraline was generally better tolerated than imipramine. Switching to a standard antidepressant of a different class is a useful treatment strategy for antidepressant nonresponders and could be considered a standard of comparison for future studies of novel alternate strategies.     

Matrix metalloproteases and their inhibitors are produced by overlapping populations of activated astrocytes

Matrix metalloproteases (MMPs) and tissue inhibitors of metalloproteases (TIMPs) are involved in many cell migration phenomena and produced by many cell types, including neurons and glia. To assess their possible roles in brain injury and regeneration, we investigate their production by glial cells, after brain injury and in tissue culture, and we investigate whether they are capable of digesting known axon-inhibitory proteoglycans. To determine the action of MMPs, we incubated astrocyte conditioned medium with activated MMPs, then did western blots for several chondroitin sulphate proteoglycans. MMP-3 digested all five proteoglycans tested, whereas MMP-2 digested only two and MMP-9 none. To determine whether MMPs or TIMPs are produced by astrocytes in vitro, we tested both primary cultures and astrocyte cell lines by western blotting, and compared them with Schwann cells. All cultures produced at least some MMPs and TIMPs, with no obvious correlation with the ability of axons to grow on those cells. Both MMP-9 and TIMP-3 were regulated by various cytokines. To determine which cells produce MMPs and TIMPs after brain injury, we made lesions of adult rat cortex, and did immunohistochemistry. MMP-2 was seen to be induced in activated astrocytes through the whole thickness of the cortex but not deeper, but MMP-3 was not seen in the injured brain. TIMP-2 and TIMP-3 immunoreactivities were induced in activated astrocytes in deep cortex and the underlying white matter. In situ hybridisation confirmed induction of TIMP-2 in glia as well as neurons, but showed no expression of TIMP-4. These results show that both MMPs and TIMPs are produced by some astrocytes, but TIMP production is particularly strong, especially in deep cortex and white matter which is more inhibitory for axon regeneration. Conversely the MMPs produced may not be adequate to promote migration of cells and axons within the glial scar.     

反应停治疗难治性多发性骨髓瘤25例

1临床资料我院2001-02/2004-01接受2个疗程卡氮芥 环磷酰胺 马法兰 泼尼松 长春新碱或2个疗程长春新碱 阿霉素 地塞米松方案化疗无效或复发的难治性多发性骨髓瘤患者25(男16,女9)例,年龄42～80(中位年龄57.2)岁.单用反应停口服治疗,起始剂量200 mg/d,如无不良反应,每周增加100 mg,根据患者耐受情况,最高剂量为600 mg/d,3 mo为1疗程.服药期间禁止使用糖皮质激素类药物及细胞毒药物.