Feasibility of source images of computed tomographic angiography to detect the extent of ischemia in hyperacute stroke

BACKGROUND AND PURPOSE: Computed tomographic angiography (CTA) is suggested to be a promising tool for patient selection for thrombolytic therapy of acute stroke. It does not only provide information on intracranial vasculature, but also on the capacity of the collateral circulation and the pattern of poorly perfused brain tissue. The objective of our study was to evaluate whether the presence and size of critically hypoperfused tissue assessed with flow positron emission tomography (PET) as a gold standard can reliably be identified on CTA source images. METHODS: Fifteen potential candidates for early thrombolysis underwent CTA 65-170 min (mean 107 min) after the onset of acute anterior circulation stroke. Regional cerebral perfusion was measured between 27 and 86 min (mean 59 min) later with [(15)O]-H(2)O and PET, and the volume of critically hypoperfused cortical tissue was assessed. CTA source images were evaluated by a neuroradiologist and an experienced stroke neurologist. The patients were classified into three groups according to the presumed size of the perfusion deficit on CTA (large, small, no perfusion deficit). RESULTS: PET revealed the presence of critical cortical hypoperfusion in 10 patients, 5 had no critical cortical hypoperfusion. The neuroradiologist correctly identified the presence of a perfusion deficit in all patients, the neurologist had two false negative and one false positive ratings. Concerning the size of the perfusion deficit, there was considerable inaccuracy in both raters. CONCLUSIONS: The usefulness of CTA source images in yielding information about the perfusion state of stroke patients in clinical routine should not be overestimated.     

In vitro drug resistance profile of Philadelphia positive acute lymphoblastic leukemia is heterogeneous and related to age: a report of the Dutch and German Leukemia Study Groups

BACKGROUND: The t(9;22)(q34;q11) translocation leading to the Philadelphia (Ph) chromosome resulting in BCR-ABL gene fusion is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). PROCEDURE: We studied the relation between t(9;22), determined by karyotype, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), and in vitro drug resistance, measured by the MTT assay, in precursor B-cell ALL at diagnosis. The findings in twenty-one Ph-positive (Ph+) childhood common/precursorB (c/preB) cases were compared with 254 Ph-negative (Ph-) ALL cases. RESULTS: A large range of LC(50) values was found within the Ph+ patients. Moreover, LC(50) values did not differ significantly between Ph+ and Ph- samples for prednisolone, dexamethasone, L-asparaginase, vincristine, anthracyclines, thiopurines, epipodophyllotoxins, and 4H00-ifosfamide, even after matching for important prognostic features (age, white blood cell count (WBC), and immunophenotype). Adult Ph+ (n = 12) ALL was more resistant to prednisolone (> 270-fold, P = 0.030), and displayed an overall tendency to resistance when compared to matched cases of Ph- (n = 15) adult precursor B-cell ALL. Within Ph+ ALL, in vitro prednisolone resistance increased significantly with age (P = 0.006). The expression of lung resistance protein (LRP), but not P-glycoprotein (P-gp) or multidrug resistance protein (MRP), was significantly higher in all Ph+ patients. CONCLUSIONS: Both childhood and adult Ph+ precursor B-cell ALL samples display a heterogeneous in vitro resistance profile, with relatively sensitive and resistant cases. The adult Ph+ samples, however, are generally more resistant compared to matched Ph- controls, reaching significance for prednisolone. The correlation of prednisolone resistance with age within the Ph+ cases might help explain the poorer prognosis of adult Ph+ ALL.     

Flow velocity and pulsatility of the ocular circulation in chronic intracranial hypertension

OBJECTIVES: The aim of this study is to examine the relationship of ocular blood flow velocities and pulsatility to intracranial pressure (ICP). METHODS: We measured arterial and venous flow velocities using color Doppler imaging (CDI) and calculated resistance indices for the central retinal (CRA) and the ophthalmic (OA) arteries from 16 patients (32 eyes) with chronic intracranial hypertension (ICH) and varying degrees of ICP and papilledema. The results were compared with normal data from 16 age-matched, healthy subjects. RESULTS: Arterial flow velocities were significantly decreased for the aggregate subject group compared with controls. A corresponding rise in arterial resistance with increasing ICP in the mild-moderate range was noted. Unexpectedly, with more severe elevations of ICP these trends reversed. CONCLUSIONS: In mild-moderate increased cerebrospinal fluid (CSF) pressure, a reduction of flow velocities may result because of increased vascular resistance. Paradoxically, in more severe chronic ICH, we hypothesize that local autoregulatory vascular changes and/or diversion of cerebral blood flow into the ophthalmic circulation may normalize these parameters. This phenomenon may partially underlie the relative sparing of visual function early in the course of pseudotumor cerebri (PTC), regardless of actual ICP levels.     

Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson's disease

OBJECTIVE: To determine whether the Nurr1 gene, which is critical for the development and maintenance of nigral dopaminergic neurons, is a risk factor associated with PD. BACKGROUND: The Nurrl gene is highly expressed in the dopaminergic neurons in the midbrain. Knockout of the gene results in agenesis of nigral dopaminergic neurons and heterozygous knockout mice increases 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. METHODS: This study included 105 patients with familial PD (fPD) and 120 patients with sporadic PD (sPD) and 221 age-matched healthy control subjects. The polymorphisms and mutations of the Nurr1 gene in patients with PD were initially examined by heteroduplex analysis and sequencing analysis from PCR-amplified Nurr1 gene fragments. A polymorphism in the BseRI restriction site was identified, and a relatively large-scale analysis then was conducted by three independent investigators who were blinded to the clinical status of the subjects. RESULTS: A homozygous 7048G7049 polymorphism was found in intron 6 of the Nurr1 gene, which was significantly higher in fPD (10/105; 9.5%) and in sPD (5/120; 4.2%) compared with healthy control subjects (2/221; 0.9%). The mean age and the SD at onset of these homozygote patients with PD was 52 +/- 15 years for fPD and 46 +/- 7 years for sPD. The clinical features of these homozygote patients with PD did not differ from those of typical PD. CONCLUSIONS: The homozygote polymorphism of 7048G7049 in intron 6 of the Nurr1 gene is associated with typical PD.     

Hepatitis B antigen in screened blood units for transfusion in renal dialysis patients

Blood units for transfusion are screened routinely in Ontario for the presence of hepatitis B antigen (HB-Ag) by counter-immunoelectrophoresis (CIEP). Since the radioimmunoassay (RIA) method is more sensitive for this purpose we used it to test blood units delivered to the hospital's Renal Dialysis Unit in order to determine if HB-Ag-carrying blood donors were being missed by the less sensitive CIEP method.

Out of the 606 blood units tested, eight were found to contain HB-Ag, an incidence of 13 out of 1000 donors. This finding indicates that the counter-immunoelectrophoresis method is insufficiently sensitive as a safe screening method for detection of hepatitis antigen.

     

Occurrence of Reovirus Infection in Ontario

Reovirus Type 2 was isolated from three patients aged 5, 9 and 10 years. The etiological role of Reovirus in one case was confirmed by demonstration of antibodies in convalescent serum and none in acute serum. Symptoms in this case were suggestive of infectious mononucleosis. In the second case, rhinitis and non-purulent otitis were preceded by two waves of fever, abdominal pain and emesis. Acute serum was not available but convalescent serum had a high titre to a Reovirus, thus supporting a Reovirus etiology. Symptoms in the third case were fever, intermittent headache, neck stiffness, abdominal cramps and weakness of a leg. Because of the unavailability of convalescent serum, evidence of a Reovirus etiology was incomplete. No attempt is made to associate Reovirus with a particular clinical picture. Rather, attention is simply drawn to the existence of Reovirus infections in Ontario.     

Prediction of arteriovenous access steal syndrome utilizing digital pressure measurements

Steal syndrome is a well-known complication of arteriovenous (AV) access placement. To assess the derangement in hemodynamics of the upper extremity after AV access creation, brachial and digital pressures were performed before and after operation. Thirty-five patients (ages 20-88 years) with end-stage renal disease requiring new upper extremity hemodialysis AV access were prospectively evaluated. Values were obtained preoperatively, on the day of surgery, and 1 month postoperatively. Follow-up at 1 year was obtained on all patients. Of the 35 patients, 19 (54%) were diabetic and 9 (26%) had had a prior AV access. The AV accesses created included the following: autogenous brachial-cephalic (n = 14, 40%), autogenous radialcephalic (n = 10, 29%), brachial-basilic transposition (n = 5, 14%), prosthetic brachial-antecubital forearm loop (n = 3, 9%), autogenous brachial-axillary saphenous vein translocation (n = 2, 6%), and 1 (3%) prosthetic brachial-axillary. After AV access creation the digital brachial index (DBI) dropped in 28 (80%) of the 35 patients. Six patients (17%) developed a symptomatic steal, 3 of which (9%) eventually required revision. In those patients without ischemic steal symptoms (n = 29) the mean DBI decreased from 0.9 to 0.7 (p < 0.01) immediately and decreased no further at 1 month. For those with a symptomatic steal the DBI decreased from 0.8 to 0.4 (p < 0.01) immediately and decreased no further at 1 month. Utilizing a DBI less than 0.6, the sensitivity was 100%, the specificity 76%, the positive predictive value 46%, and the negative predictive value 100%. Hemodynamic steal after AV access creation is very common, with symptomatic steal occurring nearly a fifth of the time. Utilizing digital pressure measurements, a DBI less than 0.6 obtained on the day of surgery can reasonably predict which patients are at risk for the development of a symptomatic steal.     

Clinical research and industrial sponsoring: avenues towards transparency and credibility

Clinical research is intended to serve the patient, in the pursuit of a deepened understanding of physiological interactions and their changes in disease, and of potentially beneficial implications for the patient. The impetus to perform clinical research is shaped by various intentions, such as the desire to provide cure or relief, striving for personal and professional success, public attention, financial considerations, or simply scientific curiosity. A similarly wide range of diverging interests must be assumed to impinge on diagnostic and therapeutic decisions in clinical work. How are we to perform clinical research and therapy with the patients' benefit in mind, in view of such a complex motivational status, and how are we to perceive the peculiar interests of those influencing clinical work, including ourselves? In this review, we attempt to elucidate the complex pathways of interaction between physicians and industrial sponsors. Special attention will be paid to the following topics: the pharmaceutical market, public interests, legal and ethical issues, conflicts of interest, and the potential impact of industry-sponsored drug trials on medical information and subsequent therapeutic decisions. We will conclude with recommendations for an acceptable position in the tension between cooperation and corruptibility, a position that grants priority to the patient's needs rather than third party interests.     

Apoptosis, bcl-2 expression, and proliferation in benign and malignant endometrial epithelium: An approach using multiparameter flow cytometry

OBJECTIVE: Disturbances in the regulation of cell proliferation and differentiation play an important role in the formation of neoplastic lesions. Consequently, abnormalities in apoptosis regulation may contribute to this process. Expression of a neoepitope on cytokeratin 18, unmasked by an early caspase cleavage event and recognized by the novel monoclonal antibody M30, is an indicator of early epithelial cell apoptosis. The purpose of this study was to evaluate the quantitative relation among apoptosis (M30), cell persistence (bcl-2), and proliferation (S-phase fraction; SPF) in malignant and benign endometrium. METHODS: Using multiparameter DNA flow cytometry on 54 formalin-fixed paraffin-embedded samples from benign (proliferative, secretory, inactive, and hyperplastic endometrium) and malignant (grades 1-3 endometrial adenocarcinoma) endometrial tissue, bcl-2 expression and M30 reactivity were assessed together with the SPF in the cytokeratin-positive epithelial cells. RESULTS: Benign cyclic endometrium showed a relatively high bcl-2 expression and low M30 reactivity in the proliferative phase whereas in the secretory phase this relation was inverse. In endometrial hyperplasia the expression of bcl-2 was increased compared to that in secretory and postmenopausal endometrium, but still below the level of proliferative samples. The expression of M30 also increased compared to normal proliferative endometrium but did not reach the level of endometrium in the secretory phase of the menstrual cycle. In cancer the expression of bcl-2 decreased with the progression of differentiation grade. For M30 expression this relation was inverse. Overall there was a significant increase of M30 reactivity in cancerous compared to hyperplasia and normal cyclic endometrium. CONCLUSION: Transition of endometrial epithelium from hyperplasia to cancer seems to involve both increased apoptosis and decreased bcl-2 expression. Flow cytometric evaluation of M30 and bcl-2 expression levels, with the SPF, in currettage specimens from postmenopausal patients complaining of bleeding provides a quantitative assessment of endometrial apoptosis, anti-apoptosis, and proliferation. Further studies are needed to determine the relationship among these three processes as indicators of the biological behavior of gynecological tumors.