Temporal profile of experimental ischemic edema after threshold amount of insult to induce infarction--ultrastructure, gravimetry and Evans' blue extravasation.

When a threshold amount of temporary ischemic insult to induce focal infarction was given to the unilateral cerebral hemisphere of gerbils, a small focal infarct surrounded by a wide penumbra developed in the rostral portion of the cerebral cortex. During the first 5 hours following recirculation, whole astrocytic cell bodies and processes in the ischemic hemisphere were swollen, with an increase in the number of glycogen granules and in number and size of mitochondria. This swelling was an active reaction of astrocytes for neuronal protection, scavenging potassium, glutamate, and other neuronal metabolic products, and for generating fuels for neurons (cyto-reactive edema). This reactive astrocytic swelling continued in the penumbra, but some dead neurons were found disseminated among the surviving neurons. Whereas, at 12 approximately 48 hours, focal infarction developed in which all cell membranes lost their Gibbs-Donnan's equilibrium due to energetic failure of their membranous Na+/K+ ATPase. This is the cytotoxic edema (cyto-necrotic edema). In the infarct focus, when pericapillary astrocytic end-feet were damaged, the capillary BBB was broken; and thus vasogenic edema was superimposed on the cytotoxic edema.

Regional differences in the rate of energy impairment after threshold level ischemia for induction of cerebral infarction in gerbils.

The development of infarction and/or selective neuronal death in the brain after transient cerebral ischemia depends on the severity of the ischemic episode. After transient cerebral ischemia of the threshold level for the induction of infarction, both changes evolve slowly in various postischemic regions. We examined the relationship of disturbances of energy metabolism to infarction and selective neuronal death in various regions of the postischemic brain subjected to two 10-min occlusions of the unilateral common carotid artery. Our results indicated that in various cerebral regions that developed infarction, the tissue ATP content, in parallel with the succinic dehydrogenase activity, fell to their lowest levels at different times over a 4-day period after circulation had been restored (earliest to latest: dorsolateral thalamus > dorsolateral caudate > chiasmal level cortex > hippocampal CA3 sector > hippocampal CA sector). In the cortex at the infundibular level, disseminated selective neuronal death developed over a 7-day period following restoration of circulation; it was accompanied by only a slight alteration in energy metabolism. The present results indicate that regional differences existed in the rate of energy impairment and evolving infarction in the postischemic gerbil brain. Energy impairment, in association with mitochondrial enzymatic dysfunction, seems to be indispensable for the delayed manifestation of cerebral infarction but not for disseminated selective neuronal death.

[A case report of chronic myelocytic leukemia with multiple brain metastases, which responded to the gamma-knife therapy].

We report a 78-year-old woman who had multiple leukemic cell tumors in the brain in the course of chronic myelocytic leukemia (CML). As far as we could survey, such brain tumors were extremely rare. She had been followed because of chronic phase of CML until October, 1998, when she noticed muscle weakness in her left upper and lower extremity. A head MRI revealed multiple masses in the brain, a biopsy of which revealed a tumor of CML cells. Although 40 Gy gamma-knife therapy had reduced the size and numbers of brain tumors, we found recurrence of left hemiparesis and tumors three months after the gamma-knife therapy. Whole brain irradiation therapy (total 30 Gy) was somewhat effective to the tumor and hemiparesis transiently subsided. Thereafter her general condition worsened again, and she died in June, 1999, eight months after the diagnosis of the brain tumors of leukemic cells. We had not seen any other clinical evidence of generalized blastic crisis in this patient. In our case, MRI of the brain showed two patterns of metastases, tumor forming and cortical invasive type. We thought that these two patterns of brain involvement might show different responses to the radiation therapy, and it was characteristic in this patient.

Combined therapy utilizing a novel Na+/H+ exchange inhibitor (SM-20220) and THAM for ischemic brain edema.

We investigated in the gerbil model whether the therapeutic effect of a novel Na+/H+ exchange inhibitor SM-20220 on ischemic brain edema could be enhanced by improving the decreased intracellular pH with an alkalizing agent, tris (hydroxymethyl) aminomethane (THAM). The left carotid artery of the animals was occluded twice for 10 min at a 5 hr interval. Ischemia-positive animals were selected and classified into the SM-20220- (0.5 mg/kg, i.p.) THAM- (2.0 ml/kg, i.v., 0.3M-THAM), combination of SM-20220 (0.5 mg/kg, i.p.) and THAM (2.0 ml/kg, i.v.), and vehicle- (0.9% saline, i.p.) treatment groups. Each agent was administered at 0, 6, 12 and 36 hr after recirculation following the 2nd episode of ischemia. The brain water, sodium and potassium contents were measured at 12, 24, and 48 hr after recirculation. The water content of the ischemic hemisphere 12 hr after recirculation was significantly lower in the combination-treated group (79.02%; P < 0.05) than in either the SM-20220- (79.28%) or THAM-treated group (79.32%). At 24 hr after recirculation the water content was significantly lower in the combination-treated group (79.83%, P < 0.05) than in the vehicle group (80.95%). At 48 hr after recirculation there were no significant differences in the water content between the vehicle group and any of the other treatment groups. The changes in brain water (delta H2O) and sodium plus potassium (delta Na + delta K) content in the ischemic hemisphere showed a significant correlation in each group. The combined treatment with the novel Na+/H+ exchange inhibitor SM-20220 and THAM is more effective on ischemic brain edema than treatment with a single agent. The results of this study indicate that improvement of intra- and extracellular acidosis by THAM infusion enhanced the activity of the NHE inhibitor SM-20220.

Evolution of energy failure after repeated cerebral ischemia in gerbils.

We have examined the regional differences in the evolution of energy failure in experimental focal cerebral ischemia. In gerbil brain subjected to repeated unilateral common carotid artery occlusion, the tissue ATP content, pH and succinic dehydrogenase activity decreased at different rates after the circulation had been restored in various cerebral regions. Light microscopical infarction became apparent at different rates following the impairment of the energy metabolism in these regions. In brain cortex with selective neuronal necrosis, only minor alterations in energy metabolism were detectable over a 7-day period following the restoration of the circulation. The present data show that the rate of energy failure is significantly different in various cerebral regions after repeated periods of cerebral ischemia in the gerbil. A slowly evolving impairment of the cerebral energy metabolism after circulation of the brain has been restored appears to be indispensable for the delayed formation of infarction after transient cerebral ischemia.

[A case report of dementia with cluttering-like speech disorder and apraxia of gait].

A 57-year-old woman presented with a slowly progressive gait disturbance in 1992 (53 years of age). Over the next year, she gradually began to talk less, but her speech itself became more rapid than before. He speech was frequently too fast even for family members to understand. In 1997, she was admitted to our hospital. On admission, the patient was disoriented but able to follow simple verbal commands, to name things, and to write simple words. Neither apraxia, aphasia, hemispatial neglect, nor a corpus callosum disconnection syndrome was observed. There was no muscle weakness or atrophy. She showed a positive Babinski sign with mild spasticity in the legs and Gegenhalten, but no rigidity. Her speech was monotonous and abnormally fast (cluttering-like speech). Her speech became faster and faster toward the end of sentences, skipping several syllables or even words. She was unable to speak slowly and clearly, even when efforts were made to pace her speech to the speed set by the examiner. She was able to stand only with a wide base of support and body flexion. When standing, she was unable to place one foot directly beside the other; as she tried to have one foot near the other, the former repelled the latter. She had great difficulties in taking her first step forward, and showed rapid freezing of gait even when she managed to succeed in starting. She was able to imitate walking or bicycling with her legs unloaded, indicating that her gait disturbance was a kind of apraxia of gait. Her intelligence was somehow difficult to assess because of her peculiar speech disturbance. However, her family members had noticed her memory disturbance and personality change (offensiveness) since 3 to 4 years before the admission. Moreover, she was defective not only on Hasegawa Damentia Scale-Revised but also on Raven's Colored Progressive Matrices which estimates non-verbal intelligence. It was also noted that she was inattentive and lazy in thinking on questionnaires. Thus we considered that she was at least mildly demented and the type of dementia was of frontal pathology. Laboratory data were all normal except for the head MRI, which demonstrated prominent and thinness of the corpus callosum from the anterior part of the body to splenium without any other brain lesions that could cause the thinness secondarily. Our case resembles two cases reported by Sunohara et al in 1985, together comprising a unique clinical feature. Although Sunohara et al did not refer to the thinness of the corpus callosum in their cases, the clinical profiles in our case and theirs raise the possibility that they form a new disease entity. A further study in a large number of similar cases, including autopsies will provide a conclusion.

Right paranephric abscess as a rare late complication of laparoscopic cholecystectomy.

A laparoscopic cholecystectomy on a 63-year-old woman was uneventful. Twenty-one months after the operation she complained of dull right flank pain, loss of appetite, weight loss, and cough. CT of the abdomen showed an 8.5 cm mass adjacent to the posterior aspect of the upper pole of the right kidney. CT also demonstrated a small calcification (5 mm diameter) posterior to the upper pole of the right kidney. The patient underwent exploratory laparotomy 2 months after the presentation with flank pain. Examination of the mass showed a thick abscess wall and 250 mL of pus. The patient's symptoms improved after the abscess was drained.

[An autopsy case of deep cerebral venous thrombosis: serial CT, MRI and pathological findings].

A 17-year-old girl developed vomiting of sudden onset, followed by a state of confusion that progressed rapidly to coma within one day. Laboratory tests indicated iron deficiency anemia and reactive thrombocytosis, but there was no evidence of coagulopathy. There was no history of medication including the contraceptive pill, either. Emergency CT scan without contrast enhancement showed increased density along the course of the vein of Galen and internal cerebral veins. A repeated CT scan without contrast enhancement carried out 24 hours after the onset of the illness confirmed extensive bilateral hypodensity of the thalami, basal ganglia and adjacent white matter. There was also a prominent spontaneous increase in the density of the deep cerebral venous system. MRI was performed 3 days after the onset of the illness, which showed absence of a flow void in the region of the internal cerebral veins and septal veins on T1-weighed images. T2-weighted images showed low intensity in these veins. At autopsy, the bilateral internal cerebral veins were occluded by fresh thrombosis and hemorrhagic infarction was seen in the bilateral thalami.

Topographical analysis of cortical neuronal loss associated with disseminated selective neuronal necrosis and infarction after repeated ischemia.

A study was carried out of the distribution and density of the neurons remaining in the gerbil cerebral cortex following two 10-min periods of ischemia at either 3-, 5- or 48-h intervals. As the interval between the periods of ischemia increased, the ischemic injury was reduced from severe to milder infarction, and further from more to less intense disseminated selective neuronal necrosis. This model is suitable for studying the mechanisms of transition from selective neuronal necrosis to infarction at the threshold level of infarction.

[A case report of tongue cancer presenting with SSD type brain embolism induced by chemotherapy with CBDCA and 5-FU].

We report a case of tongue cancer presenting with SSD type brain embolism induced by chemotherapy with CBDCA and 5-FU (CF Therapy) A 35-year-old woman underwent CF therapy for squamous cell carcinoma of the tongue. Immediately after CF therapy, aphasia and serious exercise paralysis appeared. However, symptoms disappeared 2 days later and no abnormality was found by brain CT. We report that SSD type brain embolism is one of the noteworthy side effects of CF therapy.

Brain edema associated with progressive selective neuronal death or impending infarction in the cerebral cortex.

This study examined the temporal profile of brain edema in the cerebral cortex associated with selective neuronal death or focal infarction after repeated ischemia at an intensity of ischemic insult just under and above the threshold level to induce infarction. The left carotid artery of adult gerbils was twice occluded for 10 min each time with a 5-hr interval between the blockages. In this model, focal infarction developed in coronal sections examined at the chiasmatic level (face A), whereas only selective neuronal death without infarction was found in the coronal section observed at the infundibular level (face B). In each animal, Evans blue (2%) was intravenously injected 1 hr prior to sacrifice as an indicator of blood-brain barrier (BBB) disruption. Brain edema was assessed by gravimetry in samples taken from both faces at 15 min, 5 hr, 12 hr, 24 hr, and 48 hr after the 2nd 10-min ischemia. Evans blue extravasated only in face A, corresponding to focal infarction at 24 and 48 hr after the 2nd 10-min ischemia. The specific gravities of the ischemic cortex of both faces decreased significantly from control at 15 min (P < 0.05) and had recovered by 5 hr after ischemia. By 12 hr, the specific gravities of both faces had again decreased significantly from the control values (P < 0.05), but did not differ significantly from each other. At 24 and 48 hr, the specific gravities of both faces were significantly lower than the control values (P < 0.01), and the specific gravity of face A was markedly lower than that of face B (P < 0.01). We concluded that in face B, where only selective neuronal death without infarction occurred only cytotoxic edema develops, whereas in face A, where infarction progresses, vasogenic edema develops in addition to cytotoxic edema.

Ultrastructure of astrocytes associated with selective neuronal death of cerebral cortex after repeated ischemia.

Astrocytic swelling after ischemic insult has been considered a sign of parturbed cell viability. Investigations using cultured astrocytes and C6 glioma cells have revealed that viable astrocytes swell, spatially buffering various metabolites which are increased by the metabolic turmoil following ischemic insults. In the present study, we have studied the temporal profile of ultrastructural changes of astrocytes in the cerebral cortex associated with progressive selective neuronal, death where infarction is not induced. We occluded the left carotid artery of the Mongolian gerbil twice for 10 minutes at a 5 hr interval. In this model, following reperfusion, selective neuronal death progresses in the coronal section cut at the infundibular level. The whole brains of the sham operated control and postischemic animals were fixed by transcardiac perfusion of glutaraldehyde fixatives, at 15 min, 5 and 12 hr after the 2nd 10 min ischemia. Ultrathin sections including the 3rd and 5th cortical layers were prepared from the cut surface at the level of infundibulum. Mild swelling of astrocytic processes and perivascular end-feet was observed in the 15 min group. Glycogen granules were not prominent. In the 5 hr group, we found a few necrotic neurons disseminated in the cortex. All astrocytic cell processes were swollen with increased number of glycogen granules, especially marked in the perivascular end-feet. In the 12 hr group, necrotic neurons increased in number, astrocytic swelling was more extensive, and glycogen granules were evident in astrocytes. No cellular destruction was observed. We conclude: 1. Swelling progresses in astrocytes which however still remain viable and this process is associated with selective progression of neuronal death. 2. Glycogen granules increase in the swollen yet viable astrocytic cell processes.

Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant, neurodegenerative disorder that affects the cerebellum and other areas of the central nervous system. We have devised a novel strategy, the direct identification of repeat expansion and cloning technique (DIRECT), which allows selective detection of expanded CAG repeats and cloning of the genes involved. By applying DIRECT, we identified an expanded CAG repeat of the gene for SCA2. CAG repeats of normal alleles range in size from 15 to 24 repeat units, while those of SCA2 chromosomes are expanded to 35 to 59 repeat units. The SCA2 cDNA is predicted to code for 1,313 amino acids-with the CAG repeats coding for a polyglutamine tract. DIRECT is a robust strategy for identification of pathologically expanded trinucleotide repeats and will dramatically accelerate the search for causative genes of neuropsychiatric diseases caused by trinucleotide repeat expansions.

Long-term high-colloid oncotic therapy for ischemic brain edema in gerbils.

BACKGROUND AND PURPOSE: We evaluated the effects of long-term administration of high-colloid oncotic pressure on ischemic brain edema in Mongolian gerbils. METHODS: Animals that exhibited stroke after 35 minutes of unilateral forebrain ischemia were used. The gerbils were divided into albumin- (1 g/kg body wt, 25% albumin; n = 30) and saline-injected (4 mL/kg; n = 30) groups. Both agents were administered intravenously every 12 hours starting immediately after the recirculation. Plasma colloid oncotic pressure, serum sodium and potassium concentrations, and brain water, sodium, and potassium content were measured 24, 48, and 72 hours after recirculation. RESULTS: Plasma colloid oncotic pressure at 24, 48, and 72 hours after recirculation was significantly higher in the albumin- (26.1 +/- 2.3 mm Hg) than in the saline-treated group (18.5 +/- 1.9 mm Hg; P < .01), and brain water content of the ischemic hemisphere was significantly lower in the albumin group (79.5%, 80.2%, and 80.5%, respectively) than in the saline group (80.9%, 81.6%, and 82.1%, respectively; P < .05) at all three time points. Brain sodium content at 24 hours was significantly lower in the albumin than in the saline group (P < .05), while brain potassium content at 24 and 48 hours was significantly higher in the albumin than in the saline group (P < .05). The changes in brain water and sodium plus potassium content, which were calculated from differences between the ischemic and nonischemic hemispheres, showed a significant correlation in both groups (P < .01), but there was no significant difference between the linear regression lines for both groups. CONCLUSIONS: Long-term high-colloid oncotic pressure was effective in treating ischemic brain edema, probably acting by diminishing the bulk flow through the disrupted blood-brain barrier and ameliorating the vasogenic edema.

Transition from ischemic neuronal necrosis to infarction in repeated ischemia.

To study morphological changes in the cortex that follow repeated ischemia, one, two, and three 7-min unilateral occlusions of the carotid artery at 6-h intervals, and three, four, and five 7-min similar occlusions at 12-h intervals were produced in gerbils. Animals with one and two 7-min occlusions at 6-h intervals showed selective neuronal necrosis in the cortex; those with three 7-min occlusions at 6-h intervals showed focal infarction in the third layer of the cortex. Animals with three 7-min occlusions at 12-h intervals showed selective neuronal necrosis; those with four 7-min occlusions at 12-h intervals showed focal infarction in the third layer. In animals with five 7-min occlusions at 12 h intervals, infarction affecting all layers of the cortex was seen. Results of the present study indicate that cortical infarction occurred when a brief ischemic insult that does not cause any visible morphological damage in cortical neurons was inflicted repeatedly, and that development of infarction in the cortex following repeated episodes of ischemia depended on both the number of insults and the time intervals between them. This finding suggests that there is a threshold of infarction in repeated ischemia. In our model, various stages of ischemic brain injury could be achieved more easily than in transient ischemia by altering the number of insults or the intervals between them. This model is suitable for studying the pathophysiology on transition from ischemic neuronal necrosis to infarction.

Changes in cranial and rectal temperature, blood pressure and arterial blood gas during and after unilateral and bilateral forebrain ischemia in Mongolian gerbils.

Transient forebrain ischemia was produced by occluding the common carotid arteries, either unilaterally or bilaterally, in Mongolian gerbils under halothane anesthesia. After 20-min ischemia, the cranial temperature measured in the temporal muscle decreased compared to the preischemic level, the decrease being larger after the bilateral than after the unilateral occlusion. After recirculation, cranial temperature recovered promptly to the preischemic level in the unilateral group, while it was elevated to above the preischemic level in the bilateral group. The rectal temperature also decreased with a similar time course. During 30-min ischemia, the blood pressure of both groups increased to above the preischemic level, the increase being larger in the bilateral group than in the unilateral group. After recirculation, blood pressure of the unilateral group recovered promptly to the preischemic level, while that of the bilateral group decreased to below the preischemic level. When forebrain ischemia was produced immediately after cessation of halothane inhalation, blood pH, PaO2 or PaCO2 did not change significantly from the control level. However, these values showed larger variation in the bilateral group than in the unilateral group. Unilateral occlusion in preselected gerbils provided a good model of transient brain ischemia, giving rise to uniform experimental results.

Repeated unilateral carotid occlusion in Mongolian gerbils: quantitative analysis of cortical neuronal loss.

To develop an experimental model which enables quantitative analysis of chronic neuronal loss in the cerebral cortex, repeated ischemic insult was performed using unilateral carotid artery occlusion in Mongolian gerbils. The effect of the time interval between the repeated ischemic insult on the survival rate of the animals and the amount of cortical neuronal loss were examined. The time course of the cortical neuronal damage in repeated ischemic insult was also studied. We repeated the occlusion four times; i.e., one 10-min and three 7-min occlusions (total 31 min of ischemia). The number of animals surviving for 3 weeks after the last ischemic insult was minimum (15.4%) for animals undergoing occlusions at 1-h intervals and maximum (100%) at 24- and 48-h intervals. The number of ischemic neuronal deaths was also dependent upon the time interval, and it was so pronounced as to allow analysis at intervals of 12 hr or 24 hr in the absence of infarction in the cortex. The number of neuronal deaths could not be determined for animals with occlusion at 1-h intervals due to the production of a large infarction, with which the 3-week survival rate was minimum. The temporal profile of cortical neuronal loss in the repeated ischemic insult at 24-h intervals indicated that the number of cortical neurons significantly decreased until 7 days after the start of the ischemic procedure. This model is useful for clarifying the pathophysiology of chronically developing ischemic neuronal death.

Increase in venous outflow from the corpora cavernosa during mild erection in dogs.

The venous outlet of the corpus cavernosum is generally believed to be obstructed during erection. Some researchers, however, have demonstrated an increased venous outflow during erection. To elucidate this discrepancy, we carried out a pressure-flow study using a perfusion model of the penile deep artery in dogs. Various states of the corpus cavernosum, which were different in cavernous pressure, were induced by a delicate control of electrostimulation to the cavernous nerve. Inflow rate into the corpus cavernosum, inflow resistance and outflow resistance were simultaneously evaluated. The inflow rate in mild erection was higher than in the flaccid state, and the outflow rate was estimated to be also higher than in the flaccid state. A probable reason for the increased outflow rate was that the arterial resistance decreased remarkably, while the venous resistance only slightly increased. In full erection, both the inflow and outflow rates were lower than in the flaccid state because of a great venous resistance. Histological observation of the canine penis indicated that compression of draining veins passing through the tunica albuginea was weak in mild erection, while intense in full erection. It was proposed that in mild erection, the effect of venous occlusion was slight though that of arterial dilation was noticeable, resulting in an increase in the venous outflow.

[A new family of Machado-Joseph disease--an abnormal decrease in signal intensity of the putamen in magnetic resonance imaging].

The propositus (case 1) was a 40 year-old man. He had begun to note unsteady walking at age 26. He was found to have cerebellar ataxia and pyramidal signs in addition to minor features such as progressive external ophthalmoplegia, gaze nystagmus, bulging eyes, intention fasciculation-like movements of facial and lingual muscles, and limb dystonia. These findings were categorized into type II form of the disease. One sister (case 3) aged 37 years, and one brother (case 4) aged 44 years of the propositus had also type II form of the disease. His uncle (case 2) had the same cerebellar and extrapyramidal signs accompanied with peripheral nerve signs such as muscle wasting, weakness, hypo-tonus and decreased deep tendon reflexes, and a diagnosis of type III form of the disease was made. In the T2-weighted magnetic resonance imaging (1.5 T, TR 2000 or 3000 msec, TE 120 msec) of the three patients (case 1, 3 and 4), dorsolateral part of the putamen showed decreased signal intensity. Although hypo-intensity of the putamen is often observed in normal elderly people over 50 years old, it is considered to be abnormal when it exists in relatively young people as in this family members.