Risk prediction of very early recurrence, death and progression after acute ischaemic stroke.

BACKGROUND AND PURPOSE: Early recurrent strokes lead to extended hospitalization and high number of complications. We investigated three stroke scores, the Essen Stroke Risk Score (ESRS), the ABCD(2) and the Recurrence Risk Estimator at 90 days (RRE-90) for their prognostic value to predict early recurrent stroke, death and progressive stroke. METHODS: Clinical and radiological data from 1727 consecutive patients with ischaemic stroke, being admitted to the stroke unit, were evaluated retrospectively. Predictive value of stroke scores was tested for early recurrence within 7 days, death and progressive stroke expressed as observational risk and area under the receiver operator curve (AUROC). RESULTS: Early recurrent stroke occurred in 56 patients (3.2%), 40 patients (2.3%) died within the first 7 days and 125 patients (7.2%) had a progressive stroke. ESRS was not predictive for early recurrence, death or progressive stroke. ABCD(2) score was predictive for death (P<0.01; χ(2); AUROC, 0.65; 0.58-0.72), and progressive stroke (P<0.001; χ(2); AUROC, 0.70; 0.66-0.74). RRE-90 predicted early recurrent stroke (P<0.001; χ(2); AUROC, 0.65; 0.58-0.73), early death (P<0.001; χ(2); AUROC, 0.72; 0.66-0.78) and progressive stroke (P<0.001; χ(2); AUROC, 0.66; 0.61-0.71). CONCLUSIONS: RRE-90 bears high potential to not only predict early recurrence but also death and progression after ischaemic stroke. ABCD(2) appears to be useful to predict risk of death and progression. These findings have relevant clinical implications for early triage of patients being admitted to stroke units.

Copper-64-diacetyl-bis(N4-methylthiosemicarbazone): An agent for radiotherapy.

Systemic administration of hypoxia-selective (64)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) has increased significantly the survival time of hamsters bearing human GW39 colon cancer tumors. Radiotherapy experiments were performed in animals bearing either 7-day-old (0.5-1.0 g) or 15-day-old (1.5-2.0 g) tumors. Studies compared animals treated with a single dose of 0, 4, 6, 7, 8, or 10 mCi of (64)Cu-ATSM (1 Ci = 37 GBq) with or without the vasodilator hydralazine. A multiple dose regimen of 3 x 4 mCi at 72-h intervals was studied also. Single doses of >6 mCi of (64)Cu-ATSM and the dose-fractionation protocol significantly increased the survival time of the hamsters compared with controls. The highest dose, 10 mCi of (64)Cu-ATSM, increased survival to 135 days in 50% of animals bearing 7-day-old tumors, 6-fold longer than control animals' survival (20 days), with only transient leucopenia and thrombocytopenia but no overt toxicity. Human absorbed doses were calculated from hamster biodistribution; the dose-critical organs were the lower large intestine (1.43 +/- 0.19 rad/mCi) and upper large intestine (1.20 +/- 0.38 rad/mCi). High-resolution MRI and positron-emission tomography using a therapeutic administration of 10 mCi were used to monitor tumor volume and morphology and to assess tumor dosimetry accurately, giving a tumor dose of 81 +/- 7.5 rad/mCi. (64)Cu-ATSM has increased the survival time of tumor-bearing animals significantly with no acute toxicity and thus is a promising agent for radiotherapy.

Conjugation of monoclonal antibodies with TETA using activated esters: biological comparison of 64Cu-TETA-1A3 with 64Cu-BAT-2IT-1A3.

A simple method for conjugation of monoclonal antibodies (mAbs) with the chelating agent 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), has been developed using commercially available reagents. This method involved activation of a single carboxyl group of TETA with N-hydroxysulfosuccinimide and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide. The resulting activated ester of TETA was reacted with the anti-colorectal carcinoma mAb 1A3 at molar ratios ranging from 10:1 to 100:1 to give immunoconjugates modified with an average of 0.4 to 2.0 functional chelators per antibody molecule. The TETA-1A3 conjugate was labeled with 64Cu at specific activities as high as 15.4 microCi/microgram, and the radiolabeled mAb exhibited high in vitro serum stability and minimal loss of immunoreactivity. The biodistribution of 64Cu-labeled TETA-1A3 in hamsters bearing GW39 human colon carcinoma xenografts was compared to that of 64Cu-BAT-2IT-1A3 (BAT = 6-(p-bromoacetamidobenzyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8,11- tetraacetic acid; 2IT = 2-iminothiolane). Both conjugates showed high tumor uptake (6.60-9.05% injected dose/gram) from 24 to 48 h post-injection and generally similar blood clearance and non-target organ uptakes. Human absorbed dose estimates derived from the hamster biodistribution data showed the critical organs for both conjugates to be the large intestine and the red marrow. Our results suggest that the in vitro and in vivo performance characteristics of 64Cu-TETA-1A3 compare favorably with those of 64Cu-BAT-2IT-1A3 and that further evaluation of the diagnostic and therapeutic efficacy of 64Cu-TETA-1A3 is warranted.

Maximum tolerated dose and large tumor radioimmunotherapy studies of 64Cu-labeled monoclonal antibody 1A3 in a colon cancer model.

The purpose of this study was 2-fold: to determine the maximum tolerated dose (MTD) of 64Cu-bromoacetamidobenzyl- 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (BAT)-2-iminothiolane (2IT)-monoclonal antibody (MAb) 1A3 in hamsters, and second, to determine the therapeutic efficacy of 64Cu-BAT-2IT-MAb 1A3 at various dose levels in hamsters with large (600 mg), 7-day-old GW39 human colorectal carcinoma tumors. In the MTD studies, non-tumor-bearing hamsters were injected with varying amounts of Cu-64-BAT-2IT MAb 1A3 (>10 mCi) normalized to mCi injected/kg of hamster body weight. Results indicated that the MTD was 150 mCi of Cu-64/kg of body weight. Hamsters receiving higher doses (170-190 mCi/kg) lost greater than 20% of their body weight, and all died between 8 and 13 days (n = 3). All hamsters receiving doses < or = 150 mCi/kg (120-150 mCi; n = 13) survived to the experimental end point (6 weeks) with an overall gain in weight. WBC and platelet counts were depressed in all animals 7 days after treatment but returned to normal values in the survivors by 2 weeks. For larger tumor therapy studies, 40% (8 of 20) of hamsters receiving a single dose of 7.0 mCi and 62.5% (5 of 8) of hamsters receiving 15 mCi of Cu-64-BAT-2IT-MAb 1A3 remained tumor free 4 months after treatment. In dose fractionation studies, hamsters received two 3.5 mCi doses separated by 24 or 48 h with 44% (4 of 9) and 25% (2 of 8) survival, respectively. In every large tumor experimental group, 100% of animals experienced tumor growth inhibition compared to saline control animals. Together, the MTD and the large tumor therapy studies confirm that 64Cu-labeled agents are excellent candidates for radioimmunotherapy trials.

Sex differentials in old-age mortality.

"This article examines levels and trends of sex differentials in life expectancy at older ages for 29 developed countries. Significant sex differentials in life expectancy among the elderly have been found--but no common trend among countries.... The article concludes that it is necessary to draw more attention to old-age mortality, and to sex differentials in particular, since the size and relative weight of the elderly segment of the population continues to grow. Also, it seems to be necessary to include specific goals for old-age mortality in national health strategies aimed at reducing overall mortality and narrowing inequalities between social groups."

HLA extended haplotypes in steroid-sensitive nephrotic syndrome of childhood.

Idiopathic nephrotic syndrome has been postulated to have an immunopathogenic basis. To determine whether steroid-sensitive nephrotic syndrome is associated with greater than expected frequencies of specific extended haplotypes of the major histocompatibility complex, we studied genetic markers (Class I, II, III HLA alleles and glyoxalase I) in 173 subjects in 42 families of patients with nephrotic syndrome of childhood. The single allele, DQW2, was found in 72% of steroid sensitive patients compared with only 35% of the controls (P = 0.003). In half of 32 steroid sensitive, but not 10 steroid resistant, patients, one or both of two specific extended haplotypes (alleles that segregate together) were identified. The first, [HLA-A1, B8, DR3, DRW52, SCO1], occurred in 11 of 64 haplotypes, or 17%, compared to 5% of controls (P = 0.017). The other, [HLA-B44, DR7, DRW53, FC31], occurred in 10 of 64 haplotypes, 16% compared to 3.8% of controls (P = 0.014). Five patients had both haplotypes. Patients with these specific extended haplotypes had a greater frequency of relapses than did those with other haplotypes. These data provide additional support for the hypothesis that steroid-sensitive nephrotic syndrome has an immunogenetic basis.

CT contrast enhancement on brain scans and blood-CSF barrier disturbances in cerebral ischemic infarction.

CT contrast enhancement of the ischemic infarction, blood-CSF barrier function for albumin, and severity of neurological symptoms were evaluated at predefined intervals in 41 patients with supratentorial ischemic infarctions. Contrast enhancement was most frequently observed in the 2nd and 3rd week after the stroke. This late CT enhancement was not related to infarction size and severity of blood-CSF barrier disturbance. The rare appearance of CT enhancement in the 1st week was usually associated with extensive infarctions and accompanied by blood-CSF barrier disturbances. These barrier disturbances, which occurred with higher frequency and greater severity in extensive infarctions (peak 3rd day), generally persisted for several weeks. We suggest that contrast enhancement in the 1st week after an ischemic stroke is due to diapedesis from necrotic capillaries; the more frequently observed late enhancement might be the result of a blood-brain barrier disturbance which in turn is hypothetically attributed to increased pinocytotic activity of regenerated endothelial cells.

Molecular heterogeneity of creatine kinase isoenzymes.

Cytoplasmic creatine kinase (ATP:creatine N-phosphotransferase, EC 2.7.3.2) is a dimeric enzyme exhibiting three isoenzymes (MM, MB and BB). The two subunits have been reported to have identical molecular weights (Mr) of 41 000. We have demonstrated that the M subunits from human, canine, rabbit, mouse and bovine tissue have similar apparent Mr values of 43 000 as determined by SDS-polyacrylamide gel electrophoresis. In contrast, the Mr of the B subunits was different from that of the M subunit and varied with each species (human Mr 44 500; canine Mr 46 000; rabbit Mr 44 000 and mouse Mr 49 000). Cyanogen bromide cleavage showed all M subunits to have identical fragments, while B subunits exhibited cleavage products with patterns unique for each species. Despite the differences in Mr and cyanogen bromide fragment patterns, all B subunits were capable of producing enzymatically active hybrid (MB) molecules in combination with M subunits from any species tested. Mitochondrial creatine kinase subunits exhibited identical molecular weights and were similar to the M subunits and failed to combine with either the cytosolic M or B subunits. Thus, B subunits appear less conserved during evolution compared to M subunits, but have retained the amino acid sequences essential for subunit interaction and enzymatic activity.