Clinical correlations of diffusion and perfusion lesion volumes in acute ischemic stroke

The aim of this study was to describe the clinico-radiological correlations of magnetic resonance (MR) perfusion and diffusion-weighted imaging (DWI) abnormalities in ischemic stroke. Eighteen patients had undergone MR imaging and clinical evaluation within 24 h of symptom onset and at or after 7 days. During the first 24 h the volume of perfusion abnormality (measured on the relative mean transit time map) was larger than the DWI lesion in 12/18 patients. In 6/18 patients the DWI lesion volume was larger. Acutely (<24 h) all lesion volumes showed a significant correlation with acute clinical severity measured by the National Institutes of Health Stroke Scale score. The correlations of the hypoperfusion volume (rho = 0.86, p = 0.0001) and the volume 'tissue at risk' (larger than the DWI and perfusion lesion volumes, rho = 0.86, p = 0. 0001) with acute clinical severity were slightly higher than for the DWI lesion volume (rho = 0.76, p = 0.0001). The difference between the volume of tissue at risk (acutely) and the infarct on follow-up T(2)-weighted imaging correlated significantly with change in clinical severity from acute to chronic time points (rho = 0.72, p = 0.001). Such clinico-radiological relationships may support the use of DWI and perfusion MR in decisions concerning the administration and evaluation of stroke therapies.     

Evaluation of the contribution of platelets to clot strength by thromboelastography in rabbits: the role of tissue factor and cytochalasin D

The contribution of platelets and soluble clotting components to clot strength has been the focus of several clinical studies using thromboelastography; it would, therefore, be beneficial to develop an animal model with which to mechanistically approach hemostatic disorders. Thus, we proposed to determine if the contribution of platelet function (G(P), dyne/cm(2)) and soluble components of the coagulation pathway to total clot strength (G(T)) in rabbits were similar to those in humans. Blood was sampled from the ear arteries of conscious rabbits (n = 12); 350 microL of the blood was placed in a thromboelastograph. Ten microliters of normal saline, cytochalasin D (an inhibitor of microtubule function, 10 microM final concentration), or tissue factor (a potent stimulator of platelet function, 0.00625% final concentration) was added to the blood sample, and thromboelastography performed for 1 h. The G(T) (mean +/- SD) was significantly (P < 0.001) different among samples exposed to normal saline, cytochalasin D, or tissue factor, with G(T) values of 7238 +/- 1432, 937 +/- 372, and 16,556 +/- 3314, respectively. G(P) was responsible for 87% and 94% of G(T) in the absence or presence of tissue factor, respectively. G(P) did not significantly correlate with platelet concentration in the absence or presence of tissue factor. The contribution of G(P) to G(T) is similar to that observed in humans. IMPLICATIONS: Rabbits may serve as a model of hemostasis that closely approximates human situations to mechanistically determine the etiology of coagulopathy. The contribution of platelet function to total clot strength is similar to that observed in humans.     

Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes.

PURPOSE: This article summarizes data submitted to the U.S. Food and Drug Administration for marketing approval of azacitidine as injectable suspension (Vidaza, Pharmion Corporation, Boulder, CO) for treatment of patients with myelodysplastic syndrome. EXPERIMENTAL DESIGN: In one phase 3 controlled trial, 191 study subjects were randomized to treatment with azacitidine or to observation; an additional 120 patients were treated with azacitidine in two phase 2 single arm studies. The primary efficacy end point was the overall response rate, defined as complete or partial normalization of peripheral blood counts and bone marrow blast percentages for at least 4 weeks. RESULTS: In the controlled trial, the overall response rate was 15.7% in the azacitidine treatment group; there were no responders in the observation group (P < 0.0001). Response rates were similar in the two single arm studies. During response patients stopped being red cell or platelet transfusion dependent. Median duration of responses was at least 9 months. An additional 19% of azacitidine-treated patients had less than partial responses, most becoming transfusion independent. The most common adverse events attributed to azacitidine were gastrointestinal, hematologic, local (injection site), and constitutional. There were no azacitidine-related deaths. CONCLUSIONS: On May 19, 2004 the U.S. Food and Drug Administration approved azacitidine as injectable suspension for treatment of patients with the following myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. Full prescribing information is available at http://www.fda.gov/cder/foi/label/2004/050794lbl.pdf. Azacitidine is the first agent approved for treatment of myelodysplastic syndrome.     

Can large B-cell lymphoma mimic cystic lesions of the spleen?

A 58-yr-old male with a history of hepatitis C virus infection, presented with a 2-mo history of intractable left upper abdominal pain. He had fallen from a ladder 2 yr previously, landing on his left side. Abdominal computed tomography identified a large cystic mass in the spleen. The patient was brought to the operating room with a presumptive diagnosis of symptomatic, post-traumatic, false cyst of the spleen. Instead, at surgery, a splenic mass with dense adhesions to the diaphragm and stomach was found. On final histological analysis, it was diagnosed to be a large B-cell lymphoma. Despite its rarity, gastroenterologists and surgeons should be aware of large B-cell lymphoma when encountering cystic lesions of the spleen, because the management of benign cystic disease is usually nonsurgical.     

Effects of hTERT on metal ion-induced genomic instability

There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longer-term genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERT- cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased beta-galactosidase staining and apoptosis. This instability was not present in telomerase-positive hTERT+ cells. In contrast, in hTERT+ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERT- cells. The growth and survival of both metal-exposed hTERT+ and hTERT- cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.     

AMOUNT AND DURATION OF IMMUNITY INDUCED BY INTRADERMAL INOCULATION OF CULTURED VACCINE VIRUS

Continued cultivation of vaccine virus in a medium consisting of minced chick embryo tissue and Tyrode''s solution has resulted in a virus qualitatively changed to such an extent that considerable amounts of it can be injected intradermally into human beings without danger or inconvenience. Individuals who are vaccinated intradermally with the cultured virus should be revaccinated dermally six months to a year later with a potent calf lymph virus in order to obtain a satisfactory immunity to smallpox without being subjected to the dangers and inconvenience associated with primary vaccinations with calf lymph virus.