CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is an acute neurological disorder with high mortality and no effective treatment. In addition to the initial bleeding event, rebleeding and hematoma expansion are associated with poor outcome in these patients. We studied the effectiveness of the new antifibrinolytic agent CM352, a short-half-life matrix metalloproteinase inhibitor, for achieving early hemostasis and improving functional recovery in a rat model of collagenase-induced ICH. METHODS AND RESULTS: ICH was induced by striatal injection of collagenase, and 1 hour later, rats received an intravenous injection of saline (n=6) or CM352 (1 mg/kg, n=6). Hematoma (basal and after 3 and 24 hours) and lesion (14 days) volumes were quantified on T2-weighted (T2) magnetic resonance images. Neurological and functional recovery was evaluated by using Bederson score and a cylinder test (basal, 24 hours, and 14 days). Early treatment (1 hour) with CM352 was efficient reducing hematoma expansion at 3 hours (P<0.01) and, more markedly, at 24 hours (P<0.01). Decreased bleeding after antifibrinolytic treatment was accompanied by reduced interleukin-6 levels at 3 hours (P<0.05) and smaller lesion volume at 14 days (P<0.01). CM352 drastically reduced sensorimotor impairment (cylinder test) after ICH in rats at 24 hours (P<0.01) and 14 days (P<0.01). Similarly, it also attenuated neurological deficit (Bederson scale) at 24 hours (P<0.01) and 14 days (P<0.01). Interestingly, late (3 hours) CM352 administration also resulted in reduced lesion size and better functional outcome. CONCLUSIONS: CM352, a new antifibrinolytic agent and matrix metalloproteinase inhibitor, effectively prevented hematoma growth and reduced lesion size in ICH in association with improved functional and neurological recovery.

Early stage minimally invasive procedures reduce perihematomal MMP-9 and blood-brain barrier disruption in a rabbit model of intracerebral hemorrhage.

INTRODUCTION: The effects of performing a minimally invasive procedure at different stages after intracerebral hemorrhage (ICH) on perifocal MMP-9 expression and blood-brain barrier (BBB) permeability were evaluated. METHODS: Thirty-six rabbits were randomly distributed into a normal control group (NC group, six rabbits), a model control group (MC group, six rabbits), and a minimally invasive group (MI group, 24 rabbits). A model of ICH was established in the MC and MI groups. In the MI group, the intracerebral hematoma was evacuated by stereotactic minimally invasive procedures over 6 hours (six rabbits), 12 hours (six rabbits), 18 hours (six rabbits), and 24 hours (six rabbits), following successful induction of ICH. All animals were sacrificed within 48 hours after the hematoma was surgically evacuated. A neurological deficit score was determined, and the perihematomal MMP-9 level and the BBB permeability were measured. RESULTS: The neurological deficit score, the perihematomal MMP-9 level, and the BBB permeability of the MI group were decreased significantly compared with the MC group. Performing the MI procedure 6-12 hours after ICH showed the most significant decrease in MMP-9, BBB permeability, and neurological deficit score. CONCLUSION: The optimal time window of performing MI procedures for the intracerebral hematoma evacuation might be within 6-12 hours after hemorrhage.

Management of subcapsular hematoma of the graft after living donor liver transplantation.

Subcapsular hematoma of the graft is a serious complication of liver transplantation (LT), and there has been no discussion in the literature about optimal management except in sporadic case reports. The aim of this work is to review our experience of subcapsular hematoma in living donor liver transplantation (LDLT) and to introduce our management strategy. Among the 818 cases of adult-to-adult LDLT between February 1997 and November 2005, there have been 4 cases of subcapsular hematoma. Two of these developed after percutaneous liver biopsy and the other 2 developed after percutaneous transhepatic biliary drainage (PTBD). Two developed immediately after the procedure, whereas the other 2 developed 8 and 12 days after the procedure, respectively, due to rupture of a pseudoaneurysm. Our management strategy was as follows; after performing dynamic computed tomography for initial diagnosis, these 3 steps were taken: 1) hepatic arteriography and selective embolization of bleeding focus; 2) pigtail catheter drainage (PCD) of subcapsular hematoma; and 3) hepatic vein stenting if there was a sign of outflow disturbance due to compression by a large hematoma. All 4 of our patients recovered from the insult of subcapsular hematoma. In conclusion, our results indicate that patients who develop subcapsular hematoma after LDLT can be treated nonsurgically.

[Cerebrospinal fluid (CSF) cytochemistry of acute cerebrovascular diseases with clear CSF: observation of nonspecific esterase activity of mononuclear phagocytes].

CSF nonspecific esterase (ANAE) activities of mononuclear phagocytes of 35 patients with intracerebral hematoma (ICH) with clear CSF and 25 with cerebral thrombosis and 17 normals were observed. The ANAE activities of ICH were much higher than those of thrombosis significantly (P less than 0.01). Furthermore, the distributions of ANAE activities of all cases suggested that there were few overlaps between both diseases. The CSF cytochemical detection was obviously superior to routine CSF cytological examination in differentiating strokes with clear CSF. The authors concluded that these results provided a simple inexpensive and relatively accurate method to differentiate hemorrhagic from ischemic cerebrovascular diseases in case of without CT.

Diagnostic value of lactate dehydrogenase isoenzymes in cerebrospinal fluid.

To evaluate the diagnostic value of lactate dehydrogenase (LD) isoenzymes in cerebrospinal fluid (CSF), 93 consecutive CSF specimens were analyzed. These specimens were from patients of four categories: tumors, infections, hemorrhages, and others. It was found that the isoenzyme patterns overlapped among different categories, but they differed within each category and were thus helpful in differential diagnosis. For instance, metastatic tumors showed prominent LD-5, whereas a primary brain tumor demonstrated an increase in all fractions. Viral encephalitis revealed an increase in the first three isoenzymes and bacterial meningitis, the last two. In acquired immune deficiency syndrome (AIDS) cases, however, LD isoenzyme changes were demonstrated in CSF when only cryptococcal meningitis and not when encephalitis was present. Both subdural and subarachnoid hemorrhages showed elevation of all fractions in our study. Elevation of the first three fractions was usually due to brain tissue damage or hemorrhage, as proven by our isoenzyme study of hemolysate mixed with CSF. The prominence of the last two fractions was related to anaerobic metabolism in the central nervous system or to granulocytic infiltration. In conclusion, LD isoenzyme analysis in CSF is helpful in differential diagnosis of various CNS disorders, although its sensitivity awaits further improvement.

Hemoglobin-degrading enzymes in experimental subcutaneous hematomas.

The activities of heme oxygenase and biliverdin reductase were determined in subcutaneous (s.c.) hematomas of rats after different periods of vital time. The postmortem stabilities of the heme-degrading enzymes were also studied by keeping the rats with vital hematomas for 1-5 days at temperatures of +4 degrees C and +22 degrees C. A tenfold increase of heme oxygenase activity over the starting level was observed in 2-9-day-old vital hematomas, when the specimens were taken immediately after death. Biliverdin reductase showed only negligible changes. Postmortally, heme oxygenase activity started to decrease in hematomas immediately at +22 degrees C and from day 2 on at +4 degrees C.

The mechanical, enzymatic and morphological changes in acute pulmonary insufficiency following the production of a haematoma in rabbits.

The production of a haematoma in the hindleg of rabbits represents a simplification of post-traumatic models. The lungs, one of the target organs, show similar micromorphological alterations to those described in traumatised human beings. The lungs of rabbits, bearing a hindleg haematoma for 24 hr, showed a significantly increased incidence of micromorphological lung alterations compared to the control group. Moreover, measurement revealed a significantly decreased lung compliance within the haematoma groups. It was demonstrated that whether the haematoma was subcutaneous or intramuscular, similar alterations were seen in lung histology, and in lung compliance values. Studies on the activity of superoxide dismutase in lung tissue homogenates demonstrated a significant decrease in those rabbits having had a haematoma intramuscularly for 24 hr.

[Diagnosis of myocardial infarct by means of a quick determination of the MB fraction of serum creatinephosphokinase]. / Diagnostic de l'infarctus du myocarde par un dosage rapide de la fraction MB de la créatinephosphokinase sérique

A rapid method of determining creatine phosphokinase (CPK) isoenzymes using dithiothreitol, a reducing agent which activates the main fractions of the CPK molecule (MM and MB), was assessed in 68 subjects (34 with myocardial infarction, 18 with skeletal muscle lesions, 16 normal). In acute myocardial infarction, the mean peak of CPK-MB in serum increases to 13.3% of the total CPK (range 8.8% to 21%) from the 18th to the 24th hour after onset of symptoms, whereas in skeletal muscle lesions CPK-MB reaches only 1% of total CPK (range 0% to 2.9%), and in normal subjects CPK-MB is absent. This highly significant difference (p less than 0.001) makes it possible to distinguish accurately between myocardial infarction and skeletal muscle lesions (trauma, hematoma, myositis, hypothyroidism). By its sensitivity (100%) and specificity (97%) this rapid and inexpensive method finds its optimal sphere of application in emergency wards and coronary care units.

Serum enzyme changes after intramuscular bleeding in patients with haemophilia and Christmas disease.

Serum creatine kinase, lactate dehydrogenase, aspartate and alanine transaminases, and aldolase were determined in 41 hospital inpatients with haemophilia or Christmas disease and no significant differences from the normal ranges were found.(3) Levels of these enzymes in a further 10 such patients who had sustained muscle haematomata were determined: in all of these there was a consistent rise in the level of creatine kinase, the peak occurring between 36 and 96 hours. In bleeding disorders a rise in serum creatine kinase levels may be useful as a diagnostic test for intramuscular haemorrhage.