A unique phenotype of acquired Glanzmann thrombasthenia due to non-function-blocking anti-αIIbß3 autoantibodies.

Essentials Acquired Glanzmann thrombasthenia (aGT) is generally caused by function-blocking antibodies (Abs). We demonstrated a unique aGT case due to marked reduction of αIIbß3 with anti-αIIbß3 Abs. The anti-αIIbß3 Abs of the patient did not inhibit platelet function but reduced surface αIIbß3. Internalization of αIIbß3 induced by the Abs binding may be responsible for the phenotype. SUMMARY: Background Acquired Glanzmann thrombasthenia (aGT) is a bleeding disorder generally caused by function-blocking anti-αIIbß3 autoantibodies. Aim We characterize an unusual case of aGT caused by marked reduction of surface αIIbß3 with non-function-blocking anti-αIIbß3 antibodies (Abs). Methods A 72-year-old male suffering from immune thrombocytopenia since his 50s showed exacerbation of bleeding symptom despite mild thrombocytopenia. Platelet aggregation was absent with all agonists but ristocetin. Analysis of αIIbß3 expression and genetic analysis were performed. We also analyzed effects of anti-αIIbß3 Abs of the patient on platelet function and αIIbß3 expression. Results Surface αIIbß3 expression was markedly reduced to around 5% of normal, whereas his platelets contained αIIbß3 to the amount of 40-50% of normal. A substantial amount of fibrinogen was also detected in his platelets. There were no abnormalities in ITGA2B and ITGB3 cDNA. These results indicated that reduced surface αIIbß3 expression caused a GT phenotype, and active internalization of αIIbß3 was suggested. Anti-αIIbß3 IgG Abs were detected in platelet eluate and plasma. These Abs did not inhibit PAC-1 binding, indicating that the Abs were non-function-blocking. Surface αIIbß3 expression of a megakaryocytic cell line and cultured megakaryocytes tended to be impaired by incubation with the patient's Abs. After 2 years of aGT diagnosis, his bleeding symptom improved and surface αIIbß3 expression was recovered to 20% of normal with reduction of anti-αIIbß3 Abs. Conclusion We demonstrated a unique aGT phenotype due to marked reduction of surface αIIbß3. Internalization induced by anti-αIIbß3 Abs may be responsible in part for the phenotype.

Visualization of intracerebral arteries by synchrotron radiation microangiography.

BACKGROUND AND PURPOSE: Small cerebral vessels are a major site for vascular pathology leading to cerebral infarction and hemorrhage. However, such small cerebral vessels are difficult to visualize by using conventional methods. The goal of our study was the development of methodology allowing visualization of small cerebral arteries in rodents, suitable for experimental models. MATERIALS AND METHODS: Using barium sulfate as a contrast material, we obtained microangiographic images of physiologic and pathologic changes consequent to cerebral infarction in mouse brain by monochromatic synchrotron radiation (SR). To achieve high-resolution and high-contrast images, we used a new x-ray camera with a pixel size of 4.5 microm, and we set the energy level at 37.5 keV, just above the K absorption of barium. RESULTS: Small intracerebral arteries ( approximately 30 microm in diameter) were clearly visualized, as well as the cortical branches (50-70 microm in diameter) at the brain surface. The limit of detection appeared to be vessels approximately 10 microm in diameter. Compared with the noninfarcted side, the number of intracerebral arteries was dramatically decreased in the middle cerebral artery area affected by stroke. CONCLUSIONS: These results indicate the potential of SR for evaluating pathologic changes in small cerebral arteries and for monitoring the impact of pro- and antiangiogenic therapeutic strategies.

Changes in efferent pulmonary sympathetic nerve activity during systemic hypoxia in anesthetized cats.

Changes in efferent sympathetic nerve activity to the pulmonary vessels during systemic hypoxia have yet to be elucidated. The purpose of this study was to determine the pulmonary sympathetic nerve activity (PSNA) changes in response to acute systemic hypoxia before and after sinoaortic denervation plus vagotomy in anesthetized cats. The denervation was performed to estimate the central nervous system-mediated peripheral chemoreceptor- and baroreceptor-independent PSNA change. PSNA was recorded from the central end of the cut nerve bundle, which was isolated from the lobar artery supplying the diaphragmatic lobe. Renal sympathetic nerve activity (RSNA) and systemic and pulmonary arterial pressures were also measured simultaneously. The animals were submitted to approximately 3-min periods of graded hypoxia (16, 12, 8, 5, and 3% O2 inhalations). PSNA did not change from normoxia down to an arterial O2 partial pressure (PaO2) of approximately 45 Torr (with 12-21% O2 inhalations). Below this level, PSNA began to increase, and markedly so (approximately 2.5-fold) at a PaO2 of approximately 15 Torr (with 3% O2). The hypoxic PSNA increase was significantly larger than that for RSNA, with a PaO2 of less than approximately 30 Torr (with 3-8% O2). Particularly at a PaO2 of approximately 15 Torr, the magnitude of the PSNA increase was two times greater than that for RSNA. After denervation, the hypoxic PSNA increase was significantly attenuated at a PaO2 of approximately 25 to approximately 45 Torr (with 5-12% O2), but the attenuation was very small; therefore most of the PSNA increase persisted. The hypoxic RSNA increase, in contrast, was mostly abolished after denervation. The data indicate that the neural reflex effect of systemic hypoxia on PSNA is significantly greater than that on RSNA and suggest that the hypoxic PSNA increase is mostly mediated by central mechanisms, whereas that for RSNA is chiefly caused by peripheral chemoreceptors.

Effects of baroreceptor reflex on efferent pulmonary sympathetic nerve activity in anesthetized cat.

We analyzed the baroceptor reflex effect on efferent pulmonary sympathetic nerve activity (PSNA) in anesthetized cats. PSNA was recorded from the central end of the cut nerve bundle, which was isolated from the lobar artery supplying the diaphragmatic lobe. Renal sympathetic nerve activity (RSNA) and aortic blood pressure (AP) were also simultaneously measured. There were grouped discharges synchronous with cardiac cycle and its respiratory modulation in PSNA. In a given cardiac cycle, the discharge patterns differed between the pulmonary and renal nerves. Average sympathetic nerve activity and AP obtained from 100 consecutive cardiac cycles showed that the baroreceptor reflex delay time on the pulmonary nerve (266 ms) was longer than that on the renal nerve (195 ms). The data indicate nonuniformity in the cardiac-related PSNA and RSNA. The grouped PSNA disappeared with hexamethonium bromide, indicating that PSNA originates from postganglionic efferent fibers. To examine the baroreflex response of PSNA, AP was increased by 70 mmHg with phenylephrine and decreased by 70 mmHg with nitroprusside. PSNA changed inversely to the changes in mean aortic pressure (MAP). In the delta MAP-delta PSNA curve, delta PSNA reached the maximum level (74%) and the noise level at -56 +/- 4 and 58 +/- 4 mmHg, respectively. The mean slope of the curve was 1.5 +/- 0.1%/mmHg. RSNA also responded inversely to the MAP change.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of anesthesia on cardiac and renal sympathetic nerve activities and plasma catecholamines.

The effects of pentobarbital and chloralose on cardiac sympathetic nerve activity (CSNA), renal sympathetic nerve activity (RSNA), arterial pressure (AP), and heart rate (HR) were examined using conscious cats. Arterial blood was sampled intermittently to measure plasma epinephrine. Pentobarbital (25-30 mg/kg iv) decreased CSNA, RSNA, AP, and HR. The reduction of CSNA (71 +/- 7%) was larger and lasted longer than that of RSNA (33 +/- 12%). Chloralose (40-50 mg/kg iv) decreased CSNA 66 +/- 9% and HR, increased RSNA 127 +/- 122%, and did not affect AP. The baroreflex relationship between AP and CSNA was examined by increasing AP to 145 mmHg and decreasing AP to 55 mmHg. Both pentobarbital and chloralose shifted the AP-CSNA relationship curve downward and blunted the slope of the curve, indicating that both drugs attenuate tonic and baroreflex cardiac sympathetic outflow. Pentobarbital and chloralose reduced plasma epinephrine, suggesting a decrease in adrenal sympathetic nerve activity. It is concluded that pentobarbital or chloralose affects differentially sympathetic outflows to different organs such as the heart, kidney, and adrenal gland.

Mechanism of cardiac-related synchronized cardiac sympathetic nerve activity in awake cats.

To examine the mechanism of cardiac-related sympathetic discharge, the periodicity of synchronized cardiac sympathetic nerve activity (CSNA) was measured in awake cats before and after baroceptor denervation using an interval histogram. We found two major periodicities, i.e., Tc = 48-164 ms (20-6 cycles/s) and Tb = 164-512 ms (6-2 cycles/s). In the baroceptor-intact state, the modes of Tc (C) and Tb (B) were 96 ms (10 cycles/s) and 368 ms (2.7 cycles/s), respectively, whereas the cardiac interval (CI) was 366 ms (2.7 cycles/s). Probability of B mode was larger than that of C mode. During tachycardia by atropine, B mode decreased to 304 ms in proportion to CI of 308 ms, whereas C mode remained the same. Probability of B and C modes decreased reflexly by hypertension. Under baroceptor denervation, C mode remained unchanged but its probability increased significantly. A 2-6 cycles/s Tb rhythm could be found, but its probability decreased significantly. Tb periodicity consists of 2Tc, 3Tc, and 4Tc. These results suggest that C mode may reflect a fundamental periodicity of central origin and that B mode reflects a periodicity of cardiac-related synchronized CSNA, which is produced in a probabilistic manner by reflex inhibition of fundamental rhythm due to periodic baroceptor input.

Studies on sustained-release suppositories. I. Effect of alginic acid addition on rectal absorption of bacampicillin in rabbits.

Sustained-release suppositories of bacampicillin (BAPC) were prepared by the use of the adduct which was precipitated from an aqueous solution containing BAPC and alginic acid (Alg). As the suppository base, Witepsol H-15 and macrogol were used. Absorptions of BAPC from the suppositories were prolonged in rabbits, but the bioavailabilities were decreased compared to that after administration of BAPC alone. However, these absorptions were improved enormously by the addition of surface-active agents, that is, an excellent prolonged absorption and high bioavailability were obtained. Interestingly, similar prolonged absorption could be obtained only by mixing Alg with BAPC in a suppository base. Further, this absorption rate was found to be controlled by the amount of Alg addition. The absorption profiles from a suppository containing the mixture differed from that containing the adduct in exhibiting both high plasma level and prolonged absorption. This may be due to simultaneous fast absorption of BAPC itself and formation of the adducts. Thus, it seemed that BAPC preparations containing Alg may be practically useful as a rectal preparation with prolonged action and giving a high plasma level.

Fundamental rhythm of cardiac sympathetic nerve activity in awake cats at rest and during body movement.

Cardiac sympathetic nerve activity (CSNA in imp/s) was measured in the postganglionic fibers of awake cats at rest, during body movement, and with excitement. The CSNA showed synchronized discharges with various periodicities. Rhythms of the synchronized CSNA were analyzed by an interval histogram (IIH). The IIH showed a multimodal distribution. The first model interval (Tc) was in a range of 75 to 125 ms. An 8-12 cycle/s Tc rhythm, i.e., inverse value of Tc, was always observed in the awake cat at rest and during body movements. Probability of the 8-12 cycle/s Tc rhythm was smallest at rest, increased during body movement, and was largest with excitement. These results suggested that the 8-12 cycle/s Tc rhythm, observed in all states in the conscious cat, is a fundamental rhythm of central cardiovasomotor origin. The subsequent model distribution (Tb = 2 x Tc, 3 x Tc, 4 x Tc, or 5 x Tc) ranged from 150 to 700 ms, mostly 200 to 500 ms. A 2-5 cycle/s Tb rhythm, i.e., inverse value of Tb, appeared more frequently at rest than that during body movement or with excitement. A new model concerning a mechanism to cause the 2-5 cycle/s Tb rhythm is suggested.

Effects of baroceptor reflex on cardiac and renal sympathetic nerve activity before and after atropinization in awake cats at rest.

The effects of baroceptor reflex on mean cardiac (MCSNA) and renal sympathetic nerve activity (MRNA) were analyzed before and after atropinized (0.1 mg/kg, i.v.) states in conscious cats at rest. Resting values of MCSNA, MRNA, mean aortic pressure (MAP), and heart rate (HR) were 85 +/- 6 imps/s, 76 +/- 11 imps/s, 100 +/- 4 mmHg, and 164 +/- 10 beats/min, respectively. Both MCSNA and MRNA changed almost inversely to changes in the absolute MAP in the range of 90-140 mmHg. Within this pressure range the gain of baroceptor-sympathetic system to the heart and kidney was 2.31 and 1.84, respectively. MCSNA as well as MRNA was reduced to the noise level at the MAP of 142 and 150 mmHg, respectively. With atropine, MCSNA and MRNA were inhibited centrally whereas HR increased to 192 beats/min. The increase in MAP caused by norepinephrine (2.1 micrograms/kg, i.v.) was enhanced to 75 +/- 7 mmHg by atropine from 31 +/- 4 mmHg in control. The piecewise linear MAP-MCSNA and MAP-MRNA relationships changed to a remarkable clockwise hysteresis loop. During the rising MAP period, the gain of the baroceptor-sympathetic system decreased to 0.91 and 0.97 in MCSNA and MRNA, respectively. During the returning MAP period, a delayed activation in MCSNA and MRNA occurred centrally. We conclude that the baroceptor reflex effect on MCSNA is larger than those on MRNA, and that the baroceptor control of MCSNA and MRNA is modified centrally by atropine in the awake cat at rest.

Central and baroreflex control of sympathetic nerve activity to the heart and kidney in a daily life of the cat.

We measured simultaneously and continuously the sympathetic nerve activity to the heart (CSNA) and kidney (RNA) together with heart rate (HR) and arterial blood pressure (AP) in conscious cats. The time course and magnitude of their responses to behavioral stimuli and norepinephrine iv administration were analyzed quantitatively. The increases in CSNA and RNA occurred almost simultaneously with the onset of standing, walking or eating behavior. The abrupt increases in CSNA and RNA were not preceded by a decrease in AP so it was unlikely to have been a reflex initiated by baroceptors. Rather, the increases in CSNA and RNA were followed by increases in HR and AP. The lag time ranged from 2 to 10 sec. Relative response magnitude of CSNA differed significantly from that of RNA. Thus, when AP increased spontaneously by behavioral stimuli, there was always preceding nonuniform increases in CSNA and RNA. On the other hand, when AP was elevated by norepinephrine iv administration, CSNA and RNA were inhibited proportionally to a rise in AP due to baroreflexes. At rest, the baroreflex effect on CSNA was greater than that on RNA. Cardiac-related discharges of CSNA and RNA, which were induced reflexly by baroceptor input, occurred dominantly at rest. However, with excitement or at the onset of body movements, they were diminished significantly. Our results suggested that AP adjustment associated with various behavior was made directly by a nonuniform central activation of the sympathetic nerve activity to the heart and blood vessels and partly by a central modulation of the baroceptor input.

Cardiac sympathetic nerve activity and heart rate during coronary occlusion in awake cats.

Responses in efferent cardiac sympathetic nerve activity (CSNA) and heart rate (HR) to a 100-s anterior descending coronary artery occlusion were measured in cats under awake, atropinized, anesthetized, or anesthetized and atropinized states. In the conscious state, at 20 and 90 s of occlusion, CSNA increased by 23% and then decreased by 7%, respectively, whereas HR decreased by 5 and 17%, respectively. With atropinization and/or anesthesia, the initial increase in CSNA was inhibited and the later decrease in CSNA was enhanced, whereas the bradycardia was diminished. HR changed in proportion to CSNA responses with high correlations, i.e., r = +0.89, +0.90, +0.96, and +0.91 for the four states, respectively. In the conscious state, the CSNA-HR relation line shifted toward bradycardia, but this shift was blocked by atropinization and anesthesia. This finding suggested that, in the conscious state, cardiac vagal nerve activity (CVNA) increased immediately and did not decrease during occlusion. At the early stage of occlusion, HR response (bradycardia or tachycardia) was determined by the relative contribution of enhanced CSNA and CVNA. At the later stage of occlusion, bradycardia was induced by a combination of decreased CSNA and enhanced CVNA. In anesthesia and/or atropinization it was induced mainly by the decreased CSNA.

Twenty-four-hour pattern of ventricular excitation rhythm in resting normal human subjects.

Using a biotelemetry system, the electrocardiogram (ECG) was continuously measured over 24 hr in a given environmental condition in 8 normal human subjects. The frequency of ventricular excitation rhythm (VER) was obtained from inverse of R-R interval of ECG. This study was undertaken to be informed of the variation of VER over 24 hr in resting normal subjects with different ages. The averaged frequency of VER per day (VERd) and its relative coefficient of variation (CV) ranged from 1.44 to 1.01 Hz (mean: 1.24 Hz) and 26 to 10% (mean: 20%) with age of 10 to 73 years (mean: 42 years). VERd and CV showed a tendency to decrease with age. The VERd histogram showed not a normal distribution but a multimodal distribution. Two or three large positive deviations, denoted as L, N, and H modal components, from the normal distribution curve were detected. The mode of L and H modal components was 1.01 and 1.37 Hz, respectively. The frequency distribution of L and H modal components changed with relation to a circadian rhythm and sleep-wakefulness cycles. An hourly histogram of ventricular excitation rhythm (VERh) frequently showed an unimodal distribution and the relative coefficient of variation of VERh ranged from 7.9 to 13.3% which was smaller than that of CV. The mode of VERh histogram changed in association with the circadian rhythm, the sleep-wakefulness cycles and a fluctuation period of 2 to 3 hr.

Dissociation of end ejection from end systole of ventricle.

Previous experiments showed the cases in which end ejection of the ventricle did not always coincide with end systole as identified by the time for Emax corresponding to the maximally contracted pressure-volume relationship line of the ventricle. The purpose of the present study is to obtain a better insight into the ventricular afterloading conditions that enable end ejection to coincide with end systole of the ventricle by a simulation method. The left ventricle was simulated by a time-varying elastance, E(t), and the afterload by a constant pressure connected to the ventricle via a valve with resistance R and inertance L in series. A sinusoidal wave starting from 0 at onset of systole, reaching Emax at end systole, and returning to 0 at end diastole in each cycle was assigned for E(t). Parameters of the system elements were changed individually. Ventricular pressure, volume and flow were computed by solving the system of ordinary differential equations with a time-varying parameter, E(t). Results indicate that end ejection coincides with end systole only when R and L values fall on a specific curve in an R-L domain for a given set of the other system parameters, and otherwise the 2 ends variably dissociate from each other. Consequently, end ejection should not blindly be used as a substitute for end systole when Emax and end-systolic pressure-volume relations are to be assessed.

Epilepsy in the adolescence.

The impact of recurrent seizures during childhood has a different influence upon the brain condition and mental activity of young epileptics at certain ages. Epilepsy has specific clinical features and characteristic EEG abnormalities, which occur at the developmental stage. Adolescence causes more extra burden to epileptic patients, particularly in the development of mental and/or emotional levels. In this paper, the authors report on two types of age-related phenomena--one benign in nature, and the other malignant. That is, RD (= rolandic discharge) is shown as a benign EEG feature with which sylvian seizure of Lombroso is associated. As a malignant example, psychopathic personality which appeared after the disappearance of epileptic fits, around puberty, was described. We epileptologists are convinced that children with epilepsy, particularly in puberty, have a considerable psychiatric or psychological problem, and must be treated with effective medicines, including medical service and social care.