A double three-step theory of brain metastasis in mice: the role of the pia mater and matrix metalloproteinases.

The brain is frequently affected by the spread of lung cancer, and haematogenous metastasis is a common route to brain metastasis. We therefore developed an isogenic brain metastasis model of lung cancer to use the Lewis lung carcinoma cell line and analysed dynamics of neoplastic cells after extravasation. Histological analysis revealed two characteristic patterns: metastatic foci exhibiting an angiocentric pattern were designated 'perivascular proliferations'; neoplastic cells infiltrating the brain parenchyma were designated 'invasive proliferations'. Electron microscopic observation of perivascular proliferations showed that neoplastic cells were confined to the perivascular space. In invasive proliferations, however, fragments of collagen fibre were observed in the gaps between neoplastic cells, indicating that the neoplastic cells had disintegrated the pia-glial membrane. We analysed the expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 by using both immunohistochemical analysis and real-time polymerase chain reaction analysis. MMP-2 expression was significantly higher in invasive proliferations. MMP-9 expression was significantly higher in day 7, but there was no significant difference in day 11. The pia-glial membrane and perivascular space are the barriers that neoplastic cells must overcome to infiltrate the brain. In conclusion, our findings suggest that brain metastasis requires two distinct processes.

Endovascular trapping for a giant aneurysm of the cervical internal carotid artery: a case report.

SUMMARY: We describe a case of giant cervical internal carotid aneurysm successfully treated by endovascular trapping. A 57-year-old woman with a history of maxillary contusion seven years before presented with pharyngeal discomfort during swallowing. MRI revealed a 4 cm mass in the right parapharyngeal space. A common carotid angiogram revealed a giant aneurysm with a wide neck originating from the cervical internal carotid artery; kinking of the internal carotid artery was noted at a point distal to the carotid bifurcation. Analysis of cerebral blood flow by SPECT during a balloon occlusion test showed no hypoperfusion areas, and the patient underwent endovascular trapping. There were no neurological or other complications after the procedure. A follow-up MRI revealed complete thrombosis of the aneurysm. Our results show that endovascular trapping for pseudoaneurysm of the cervical internal carotid artery can be a reliable and effective treatment in patients who tolerate a balloon occlusion test.

Rupture of a large vertebral artery aneurysm following proximal occlusion.

SUMMARY: Proximal occlusion of the vertebral artery is regarded as a safe and effective method of treating aneurysms of the vertebral artery or the vertebrobasilar junction unsuitable for treatment by neck clipping. Complications known to develop after this procedure include ischemic lesions of the perforators and other areas. There are only a limited number of reports on early rupture of aneurysm following proximal occlusion of the vertebral artery for the treatment of unruptured aneurysm. We recently encountered a case of large aneurysm of the vertebral artery identified after detection of brainstem compression. This patient underwent proximal occlusion of the vertebral artery with a coil and developed a fatal rupture of the aneurysm ten days after proximal occlusion. The patient was a 72-year-old woman who had complained of dysphagia and unsteadiness for several years. An approximately 20 mm diameter aneurysm was detected in her left vertebral artery. She underwent endovascular treatment, that is, her left vertebral artery was occluded with coils at a point proximal to the aneurysm. Her initial post-procedure course was uneventful. However, she suddenly developed right-side hemiparesis nine days after procedure. At that time, CT scan suggested sudden thrombosis of the aneurysm. Right vertebral angiography revealed a small part of the aneurysm. She was treated conservatively. Ten days after the procedure, she suffered massive subarachnoid haemorrhage. Both the present case and past reports suggest that proximal occlusion of the vertebral artery is effective in treating relatively large aneurysms unsuitable for treatment by neck clipping or trapping. However, when the bifurcation of the posterior inferior cerebellar artery (PICA) is distal to the occluded point in cases where the PICA bifurcates from the aneurysm or the neck region, blood supply to the aneurysm may persist because anterograde blood flow to the PICA may be preserved. Therefore, clinicians must consider the possibility of aneurysm rupture after proximal occlusion in the following cases: 1) when the aneurysm is large or giant, but non-thrombosed; 2) when thrombosis occurs soon after the procedure; 3) when postoperative angiography shows partial filling of the aneurysm with contrast agent through the contralateral vertebral artery of basilar artery or the cervical muscle branches.

[Effect of angiotensin converting enzyme inhibitor lisinopril on sympathetic heart rate response during exercise in the early phase of acute myocardial infarction].

OBJECTIVES: Sympathetic heart rate response decreases in patients with left ventricular dysfunction. Angiotensin converting enzyme (ACE) inhibitors effectively prevent heart failure after myocardial infarction. However, the effect of ACE inhibitors on heart rate response is not well known. The present study investigated the effect of ACE inhibitors on sympathetic heart rate response in the early phase of acute myocardial infarction. METHODS: Sixty-five patients with acute myocardial infarction receiving no beta-blocking agents participated in the study. The subjects consisted of 25 patients (mean age 60.2 +/- 10.7 years) treated with ACE inhibitor lisinopril from the initial stage and 40 control subjects (mean age 57.7 +/- 7.6 years). Cardiopulmonary exercise testing with a treadmill was performed using the ramp protocol in the first month and the third month after the onset of the disease. Heart rate (HR) was measured in the resting state (rest) and immediately after peak exercise (peak). At the same time, blood samples were obtained to investigate the changes in the plasma level of norepinephrine (NE). The degree of sympathetic heart rate response was evaluated as follows: (peak HR - rest HR)/¿(peak NE - rest NE)/rest NE¿ x 100. RESULTS: There were no significant differences between the 2 groups in the first month in anaerobic threshold, peak oxygen uptake and plasma brain natriuretic peptide concentration. Though the change of heart rate was not significant, the change in the plasma level of norepinephrine was significantly lower in the lisinopril group (9.3 +/- 4.4 vs 5.7 +/- 2.8, p < 0.01). In the first month, the heart rate response in the control group was markedly lower than that in the lisinopril group (8.7 +/- 3.5 vs 15.2 +/- 8.5 beats/min/%, p < 0.01). In the third month, the significant difference between the 2 groups disappeared (10.7 +/- 7.9 vs 14.0 +/- 9.7 beats/min/%, NS) due to the increase of the value in the control subjects. CONCLUSIONS: From these results, we conclude that ACE inhibitors are effective to improve sympathetic heart rate response during exercise in the early phase of myocardial infarction.

Physiological role of endothelin-1 in nonworking muscles during exercise in healthy subjects.

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelial cells. However, the role of ET-1 in exercise-induced physiological responses is still to be investigated. The purpose of the present study was to investigate in healthy volunteers whether the ET-1 plasma concentration in nonworking muscles is changed by exercise and to investigate the physiological role of ET-1 during exercise. Bicycle ergometer cardiopulmonary exercise tests were performed in 36 healthy men (mean age, 22.5 years). Blood samples for measuring ET-1 were drawn from the cubital vein during rest and immediately after the exercise test. The ET-1 change ratio was calculated as ET-1 immediately following exercise/ET-1 during the resting state. Cardiac output (CO) was measured during the exercise test by the impedance method. Arterial venous oxygen difference (AVO2D) when CO reached 10L/min or 15L/min was calculated as AVO2D = VO2/CO. Results were as follows: (1) the ET-1 change ratio correlated inversely with exercise time at the anaerobic threshold (r = -0.37, p = 0.03) and peak exercise time (r = -0.35, p = 0.04); (2) the ET-1 change ratio tended toward an inverse correlation with deltaVO2/deltawork rate (r = -0.29, p = 0.09); (3) the ET-1 change ratio correlated positively with AVO2D when CO reached 10L/min (r = 0.42, p = 0.02) and tended toward a positive correlation with AVO2D when CO reached 15 L/min (r = 0.32, p = 0.08). These results indicate that an increase in ET-1 in nonworking muscles may participate in the exercise-induced redistribution of blood flow and in increasing the blood flow to working muscles.

Magnesium dynamics and sympathetic nervous system activity in patients with chronic heart failure.

This study was undertaken in patients with heart failure to investigate the relation between plasma norepinephrine (NE) concentration and Mg dynamics. The study subjects comprised 16 patients with chronic heart failure (mean age 64.9+/-10.0 years). Cardiopulmonary exercise testing was performed on all patients, and anaerobic threshold (AT), peak oxygen uptake (peak VO2) and peak exercise time were measured. Resting and peak values of plasma NE concentration and serum and erythrocyte magnesium concentration were also measured. The results were as follows: the serum Mg concentration was increased significantly immediately after exercise (p<0.01), and the erythrocyte Mg concentration showed a tendency to decrease (p<0.1). The resting plasma NE level was inversely correlated with AT (p<0.05, r=-0.57), peak VO2 (p<0.05, r=-0.55) and peak exercise time (p<0.01, r=-0.62). When the plasma NE concentration at rest was analyzed in 2 groups of patients, ie, those with higher than average and those with lower than average concentrations, the resting erythrocyte Mg concentration was significantly lower in the high-NE group (2.2+/-0.3 mg/dl) than in the low-NE group (2.7+/-0.5 mg/dl) (p<0.05). The data indicate that patients with chronic heart failure associated with high NE levels at rest who showed low exercise tolerance have intracellular hypomagnesemia, which may be caused by Mg migration from intracellular to extracellular spaces.

Specialty-related disparities of readmission in patients with chronic heart failure: the importance of hospital-clinic cooperation.

OBJECT: The purpose of this study was to elucidate differences in readmission rates and late outcome in outpatients with chronic heart failure treated in different clinical settings. PATIENTS AND METHODS: This study included 65 consecutive patients who were admitted to our CCU due to acute heart failure for the first time and discharged from our institution. After their discharge, 31 were cared for by a cardiologist in the outpatient clinic of our institution (group A) and the other 34 were cared for by a general practitioner in a clinic (group B). The various findings during the acute phase and the follow-up period were retrospectively compared between the two groups. In addition, the incidence of unexpected readmission and prolonged outcomes were compared between the two groups. RESULTS: The patients in group B were older than those in group A, but no other differences were noted in patient characteristics. More patients in group A required more than one hospitalization within 6 months from discharge (group A, 35.5%; group B, 8.9%, p<0.01; follow-up period, 17.1+/-5.9 months). There was no difference in the survival rate between the groups. CONCLUSION: We concluded that stabilized outpatients should receive comprehensive care from a general practitioner to avoid the need for readmission after discharge.

Bone mineral density in the distal radius in a healthy Japanese population and in relation to fractures of the distal radius.

Changes in bone mineral density with age were measured in the distal radius of healthy adults using dual energy X-ray absorptiometry. A total of 2789 healthy women (20-95 years old) and 1255 healthy men (20-87 years old), and 72 women (52-94 years old) and 23 men (51-79 years old) with fractures of the distal radius were assessed. Bone mineral density remains relatively stable in men despite aging, and was significantly higher than in women in every decade. In women aged 70 years and more, the bone mineral density was significantly lower in the fracture group than the non-fracture group. In men with fractures of the distal radius, there were no significant differences between bone mineral density and age. In the fracture groups loss of radial inclination after reduction correlated with decreased bone mineral density, but there was no significant regression between bone mineral density and the decrease in radial length or palmar tilt.

Exercise-induced changes in plasma atrial natriuretic peptide and brain natriuretic peptide concentrations in healthy subjects with chronic sleep deprivation.

Recent observations have shown that plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) correlate with cardiac function or prognosis in heart failure patients. However, relatively little is known about changes in their plasma concentration during commonly occurring physiological states such as fatigue. Therefore, this study was designed to examine the physiological changes of plasma ANP and BNP concentrations using a chronic sleep-deprivation model. Bicycle ergometer cardiopulmonary exercise tests were performed in 10 healthy volunteers (mean age: 22.7 years). Blood samples for measuring ANP and BNP were drawn during the resting state and immediately after each exercise test. Cardiac output (CO) was measured during the exercise test by the impedance method. The study conditions were designed as follows: (A) a day following a period of normal sleep (control state) and (B) a day preceded by 1 month during which sleep lasted <60% of normal (chronic sleep-deprived state). Results were as follows. (1) Peak oxygen uptake and peak CO decreased during the sleep-deprived state compared with the control state. (2) There was no difference between peak heart rates measured during exercise under the 2 conditions. (3) Plasma ANP concentration during exercise increased significantly during the control state, whereas only a tendency toward increase was observed during the sleep-deprived state. (4) Plasma BNP concentration during exercise tended to increase in the control state compared with the resting state, whereas there was no difference in plasma BNP between after exercise and resting state in the sleep-deprived state. These results indicate that changes of ANP or BNP induced by exercise tended to be decreased by chronic sleep deprivation.

Prognostic factors for supratentorial low grade astrocytomas in adults.

The principal prognostic factors and effect on survival were retrospectively evaluated in 56 adult patients with supratentorial low grade astrocytomas treated between 1967 and 1993. Fifteen factors were evaluated with uni- and multivariate analysis to investigate their importance in predicting the length of survival. The median patient age at presentation was 42 years and the median survival was 5.0 years. The following characteristics were associated with improved patient survival by univariate analysis (p < 0.01): Age group, preoperative Karnofsky scale, and extent of surgery. Age group and Karnofsky scale were significant by multivariate analysis, but not the extent of surgery. Thus the usefulness of cytoreductive surgery in the management remains unclear, but the extent of surgery is determined by the characteristics of the tumor and the potential of the patient. Since 93% of our patients received postoperative radiotherapy, the effect of adjuvant irradiation could not be determined.

Synthetic collagen fibers coated with a synthetic peptide containing the YIGSR sequence of laminin to promote peripheral nerve regeneration in vivo.

The usefulness of collagen fibers and the YIGSR sequence (Tyr-lle-Gly-Ser-Arg) of laminin for nerve regeneration were examined in vivo. Type I collagen gel (G-group), Type I collagen fibers (F-group), Type I collagen fibers coated with laminin (L-group) or the YIGSR sequence (Y-group) were packed into silicone tubes, 15 mm long, and transplanted to the sciatic nerves of Wistar rats. Empty silicone tubes were used as the control. The animals were sacrificed 8 weeks after transplantation. Bridging of the nerve was confirmed in the F-(7/12), Y-(7/10) and L-group (6/10), but no bridging was observed in any of the animals of the G- and control group. Nerve regeneration among the space of collagen fibers was observed, and it was suggested that fibroblasts infiltrated the gap in the substance of the degenerated collagen fibers were followed by Schwann cells on the basis of immunocytochemistry. The number of myelinated axons per regenerated tissue in the tube (density), and total area of myelinated axons per measured regenerated tissue in the tube (% axon area) in each the L- and Y-group were significantly higher than that in the F-group (P < 0.05). These results suggest the possibility of obtaining adequate nerve regeneration with new artificial materials only.

Embolization of scalp AVF.

We report scalp arteriovenous fistulas (AVFs) in which we performed embolization and examine the treatment method. The subjects were four cases of scalp AVF treated by embolization. All cases were male and three had a past history of scalp injury. As the feeding artery, we found a single artery in one case and multiple arteries in three cases. In three cases we employed a transarterial approach by cutting down the scalp and embolized the fistula with NBCA (N-butyl-cyanoacrylate). We conducted the embolization procedure as follows in order to securely occlude the fistula; 1) we obtained the precise location of fistula by the superselective angiography; 2) we induced the tip of microcatheter to immediately in front of fistula; 3) when high flow shunt was manifested, we controlled the flow by retaining the balloon catheter in the external carotid artery; 4) and injected NBCA by compressing around the fistula from above the scalp with a cylindrical instrument to prevent the migration of embolic material to the venous side. As a result, all cases were completely cured and there was no major complication except for transient postoperative pain. If the transfemoral approach to fistula is impossible, it is considered effective to cut down near the fistula and embolize the scalp AVF by direct puncture to the feeding artery with NBCA as embolic material.

Intracranial pressure monitoring using a newly developed transducer-tipped ventricular drainage catheter.

A transducer-tipped ventricular drainage catheter (TVDC) was developed to allow continuous measurement of intracranial pressure (i.c.p.) without interrupting cerebrospinal fluid (CSF) drainage. The 8.5 Fr catheter with a double lumen has 16 side holes for CSF drainage and a small silicone strain-gauge transducer on the side of the catheter tip to measure the ICP directly. The transducer is composed of a 2 x 1 mm2 silicone plate. Calibration must be performed before insertion. The calibrated catheter is inserted into the ventricles, usually via the anterior horn of the lateral ventricles to the foramen of Monro. Recalibration is not necessary even if the patient's head is tilted. The TVDC was applied to patients in whom ICP was suspected to be high and in whom the ventricles were large enough for tapping. The ICP wave form and values measured by the TVDC and the manometer method were equivalent. The drift phenomenon did not occur throughout the entire measurement period. The TVDC is very useful for both controlling and monitoring ICP.

Efficacy of oral magnesium administration on decreased exercise tolerance in a state of chronic sleep deprivation.

We have previously reported that chronic sleep deprivation causes a deficiency of intracellular magnesium (Mg) and decreased exercise tolerance. The aim of this study was to clarify whether oral administration of Mg could be effective in restoring the exercise tolerance that is decreased by chronic sleep deprivation. A bicycle ergometer cardiopulmonary exercise test was performed by 16 healthy volunteers (mean age 21.9 years). They were divided into 2 groups: 8 received doses of 100 mg of Mg orally per day for 1 month (Mg group) and the remaining 8 received no Mg and served as the control group. The study conditions were designed as follows: (1) the usual state (good sleep); and (2) the sleep-deprived state (sleeping time up to 60% less than the usual state for 1 month). The ratio of intracellular Mg content of the sleep-deprived state to the usual sleep state was significantly higher in the Mg group (p<0.05) than the untreated control group. There was no difference between the sleep-deprived state and the usual state with regard to anaerobic threshold and peak oxygen uptake in the Mg group, whereas both of these decreased in the sleep-deprived state in the control group. These results indicate that decreased exercise tolerance observed in the sleep-deprived state could be improved by oral Mg administration.

Irrigation system equipped on a high-speed air drill--technical note.

An irrigation system which can easily be applied to the conventional high-speed air drill was developed to allow simultaneous irrigation during micro-drilling. The irrigation system is constructed with a tube of 0.8 mm outer diameter and supporting rings. Irrigation is entirely coordinated with drilling by a single foot switch. The tube of the system ejects normal saline intermittently toward the cutter bar tip. Use of this system in skull base surgery showed that effective irrigation and a clean operative field was achieved even in a narrow space under the operating microscope, saline is ejected exactly on the point of drilling and over-heating does not occur so that heat-related damage to the local nerves and blood vessels is avoided. The system can easily be applied to any type of high-speed air drill by using supporting rings of the correct size. This irrigation system is particularly useful in microneurosurgery using the high-speed air drill.

Morphological Study of Carotid Artery of WHHL Rabbit after Balloon Dilatation.

SUMMARY: We performed balloon dilatation in the carotid artery of WHHL rabbits and examined subsequent morphological alteration over time. The balloon was inserted as far as the carotid bifurcation and observations were made on the morphological alteration after dilatation in the atherosclerotic intimal thickening from immediately after balloon dilatation over a period of ten months. Immediately after balloon dilatation, endothelial cells came of circularly and stretching, fragmentation off elastic fibers and coming off of smooth muscle cells of the media were confirmed. No change in the degree of thickening after dilatation was seen in the atherosclerotic intimal thickening of the carotid bifurcation. Three weeks later, endothelium covering except some parts, circular neointima and fibrosis of the media were observed; foamy cells had accumulated in the upper layer of the atherosclerotic intimal thickening, and that region was not yet covered with endothelial cells. The progress of fibrous intimal thickening so as to keep the lumen smooth was seen up to six months later, but foamy cells were not found in the neointima.

Changes in regional cortical temperature and cerebral blood flow after cortical spreading depression.

Regional cerebral blood flow (rCBF) measurement by laser Doppler flowmetry and cortical temperature measurement using thermoencephaloscopy (TES) were performed to investigate the relationship between the changes in rCBF and cortical temperature after induced cortical spreading depression (CSD) in rats. TES showed a gradually expanding thermoresponse like an extending circular wave after CSD induced by application of KCl. Similarly, a transient increase in rCBF spread from the site of stimulation with a velocity of propagation of 2.5 mm/min. Simultaneous monitoring of rCBF and cortical temperature showed that the transient increase in rCBF was associated with an initial decrease in cortical temperature, followed by an increase in cortical temperature. We suggest that the cortical temperature is regulated mainly by neurogenic control of the pial microvascular blood supply that is precisely adjusted to the metabolic needs of the cerebral cortex. Non-injured cortex with the fine vascular architecture must be preserved during neurosurgery to allow heat transfer from deep areas of the cortex.

[The effect of hypothermia on CSD propagation in rats].

In the cortical zone surrounding an ischemic or traumatic focus, CSD is a transient phenomenon involving interstitial ions, blood flow and metabolism and is believed to be completely reversible. However, it may extend to secondary brain injuries because CSD releases excitatory amino acids into the extracellular space. In order to prevent secondary brain injuries, it may be effective to block repeated CSD. This study was designed to determine whether hypothermia can block CSD propagation and whether this study is a potentially useful means for preventing secondary brain injuries. Male wistar rats weighing 270 g on average were used for the experiments. The animals were divided into two groups: hypothermic rats (33.5-34 degrees C, rectal temp.) and normothermic rats (37-37.5 degrees C). The changes in rCBF (regional Cerebral Blood Flow) were monitored in order to observe CSD. LDF (Laser Doppler Flowmetry) was used to measure rCBF. The two LDF probes were placed on the parietal cortex (4 mm apart). To elicit CSD, a needle stab injury was made on the cortex or a piece of paper soaked with 10% KCl was applied on the cortex. The velocity of CSD propagation was more prolonged in the hypothermic rats than in the normothermic rats (p < 0.01). There were smaller numbers of repeated CSD in the hypothermic rats than in the normothermic rats. Histological examination of the cerebral cortex revealed shrinkage neurons more distinctly in the normothermic rats than in hypothermic rats. From these results, we can speculate that hypothermic may block CSD propagation and that hypothermic therapy has the potential to prevent secondary brain injuries.

[Antigenicity study of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a novel drug for urinary frequency and incontinence].

An antigenicity study of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Hartley guinea pigs and BALB/cAnN mice. The following results were obtained. No active systemic anaphylaxis reactions were found in guinea pigs immunized by subcutaneous injection of NS-21 alone or in combination with Freund's complete adjuvant (FCA). No 24-hr heterologous passive cutaneous anaphylaxis reactions were elicited in rats by sera from mice immunized by intraperitoneal injection of NS-21 alone or in combination with 3% aluminum hydroxide gel. No passive hemagglutination reactions were elicited by sera from mice immunized by subcutaneous injection of NS-21 in combination with FCA. These results show that NS-21 has no antigenicity under the present experimental conditions.