Application of the MIC breakpoints based on pharmacokinetics and pharmacodynamics parameter in the clinical laboratory

The effectiveness of time-dependent antibiotics such as beta-lactams is related to the time above the MIC (TAM, %). We constructed a program to calculate the TAMs of beta-lactams using the pharmacokinetic parameters of the Japanese dosing regimen of a phase I study of the Japanese Society for Antimicrobial Chemotherapy (JSAC), and compared them with the MIC breakpoints published by the National Committee for Clinical Laboratory Standards (NCCLS) and JSAC. If the effective TAM was assumed to be more than 40% of the dosing interval, the pharmacokinetic/pharmacodynamic (PK/PD) breakpoints calculated by our program were in agreement with the JSAC breakpoints for pneumonia within 1 dilution MIC. When comparing with the NCCLS breakpoints for Enterobacteriaceae or Staphylococcus, the PK/PD breakpoints dosing three times per day of ampicillin (1 g, intravenous dose; i.v.), piperacillin (2 g, i.v.), cefotaxime (1 g, i.v.) and cefmetazole (1 g, i.v.) were calculated to be less than 2-fold dilution MIC, and those of amoxicillin (0.25 g, oral dose; p.o.) and cefaclor (0.5 g, p.o.) were calculated to be less than 3- to 4-fold dilution of MIC. Our program could calculate TAMs and PK/PD breakpoints by inputting the two factors of MIC and dosing interval. If this information is routinely reported to physicians from clinical laboratories, an appropriate dosing schedule could be proposed for various infectious cases.     

Effects of sesamin on aortic oxidative stress and endothelial dysfunction in deoxycorticosterone acetate-salt hypertensive rats

In the present study, we evaluated the relationship between the antihypertensive effect of sesamin, a lignan from sesame oil, and its antioxidative activity in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. After a 5-week treatment period, systolic blood pressure was significantly elevated in normal diet-fed DOCA-salt animals compared with cases in sham-operated animals. Sesamin feeding, tempol (a superoxide dismutase mimetic) treatment or antihypertensive drugs combination (triple therapy; reserpine, hydralazine, hydrochlorothiazide) significantly suppressed the development of DOCA-salt-induced hypertension. Compared with sham-operated rats, the normal diet-fed DOCA-salt rats revealed marked increases in aortic superoxide (O(2)(-)) production. These increases in O(2)(-) production were significantly suppressed by sesamin feeding or tempol treatment, but not by triple therapy. Acetylcholine (Ach)-induced endothelium-dependent relaxation was markedly decreased in normal diet-fed DOCA-salt rats, compared with cases in sham-operated rats. Sesamin feeding and triple therapy significantly improved the DOCA-salt-induced impairment of endothelium-dependent relaxation. However, tempol treatment had no effect on the impaired vasodilator responses induced by DOCA-salt treatment. In DOCA-salt rats with or without sesamin feeding, systolic blood pressure significantly correlated with both aortic O(2)(-) production and endothelium-dependent vascular relaxation. These findings suggest that sesamin feeding inhibits the enhancement of aortic O(2)(-) production in DOCA-salt hypertensive rats, and this effect may contribute to the antihypertensive effect of sesamin. Sesamin feeding-induced improvement of endothelial dysfunction seems to result from the above antioxidative and antihypertensive effects.     

Effects of nefiracetam on cerebral adenylyl cyclase activity in rats with microsphere embolism-induced memory dysfunction

The effects of nefiracetam on the cerebral adenylyl cyclase (AC) activity of animals with microsphere embolism-induced memory dysfunction were examined. Sustained cerebral ischemia in the right cerebral hemisphere was induced by an injection of microspheres into the right internal carotid artery of rats. To examine learning and memory function, the water maze test was performed from day 7 to day 10 after the operation. The escape latency of the microsphere-embolized (ME) rat in the water maze task was longer than that of the sham-operated (Sham) rat, suggesting that spatial memory dysfunction occurred in the ME rat. Gsalpha and Gi(1/2)alpha protein levels in the cerebral cortex, striatum and hippocampus of the ME rat, when determined on day 11, were similar to those of the Sham rats. The basal AC activity in the striatum, but not in the other two regions, of the ME rat decreased. The AC activity in the presence of 10 microM colforsin daropate (Col), a direct stimulator of AC, was increased by approximately 20-fold in sham animals and 7- to 10-fold in the ME rat. Treatment of the ME rat with 10 mg/kg/d nefiracetam p.o. from day 1 to day 10 after the operation shortened the escape latency, restored the basal AC activity in the striatum, and reversed the Col-induced increases in AC in these three regions without any changes in the cerebral Gsalpha and Gi(1/2)alpha protein levels. These results suggest that nefiracetam-mediated activation of AC activity may contribute to the improvement of memory and learning function in sustained cerebral ischemia.     

Chaos attractors of ventricular elastance to evaluate cardiac performance

Quantitative evaluation of cardiac function is very important in the clinical application of a ventricular assist device. This article reports a new evaluating method of E max, which is the most reliable parameter to evaluate cardiac function. Fluctuation in the E max time series data was evaluated by the nonlinear mathematical analyzing method including chaos and fractal theory. Experimental goats were anesthetized with halothane inhalation, and left ventricular volume and pressure were measured with other hemodynamic parameters to evaluate E max during various drug administrations. E max was evaluated by two methods. One was the conventional pressure volume loop evaluation and the other was the parameter optimization method without left ventricular volume data. As a result, E max evaluated by the parameter optimization method correlated well with the E max with conventional PV curve. Furthermore, interesting results were obtained. There were rhythmical fluctuations in the E max time series data. By the methodology of Takens, E max time series data was embedded into the phase space and a strange attractor was observed. These results may be important when considering E max evaluation during left ventricular assistance.     

Dynamic and not static change in ventricular repolarization is a substrate of ventricular arrhythmia on chronic ischemic myocardium

OBJECTIVE: The restitution mechanism has been the focus of attention as the possible mechanism behind ventricular fibrillation (VF). However, its contribution in chronic ischemic heart has not been established. METHODS: We investigated chronic ischemic dogs with occlusion of left anterior descending artery. Sixty unipolar electrograms were simultaneously recorded from an entire cardiac surface. Activation-recovery intervals (ARIs) and QRST deflection area (AQRST) were measured during constant atrial pacing. The ischemic dogs were divided into two groups, five dogs in VF(+) group or seven dogs in VF(-) group, according to VF occurrence by programmed electrical stimulation. RESULTS: When investigating ARI dispersions on an epicardium, there was no difference between VF(+) and VF(-) groups. The relationship between ARIs and diastolic intervals was quantified as an electrical restitution curve. The slopes of the ARI restitution curve for the anterior left ventricle in VF(+) dogs were significantly steeper than those of VF(-) dogs. The amplitude of AQRST alternans were significantly greater in VF(+) dogs than VF(-) dogs. CONCLUSIONS: Combined observation of steep restitution slopes and increased electrical alternans supported the restitution mechanism as being involved in the arrhythmia. Dynamic restitution properties and not static single-beat ARI dispersion may play an important role in the VF arrhythmia in the chronic ischemic heart.     

Treatment of ischial pressure sores by means of sclerotherapy using absolute ethanol

The ischial region is a common site of pressure sore. The ischial pressure sore with a large subcutaneous bursa is resistant to conservative treatment and tends to require radical surgical treatment. In this article the authors describe their experience with a simple surgical treatment on 8 ischial pressure sores in 7 patients with subcutaneous bursa by means of sclerotherapy using absolute ethanol. This method involves causing the bursa to become scarred and closing it up by sterilizing, fixing, and denaturing by the pharmacologic effect of absolute ethanol instead of surgical excision of the bursa. This alternative method has a possibility of treating pressure sores as well as other fistulous diseases in various areas.     

Study of multiple cerebral aneurysms comprised of both ruptured and unruptured aneurysm--an analysis of incidence rate with respect to site and size

The purpose of this investigation was to study the incidence rate of rupture with respect to the site and size of multiple cerebral aneurysms that include both ruptured and unruptured aneurysms. Site and size were investigated in 58 cases of this type of multiple cerebral aneurysm. All cerebral aneurysms were examined with MR angiography, 3D-CT angiography and digital subtraction angiography, as well as seeing measured using 3D-CT or digital subtraction angiography. As regards the site of the 58 ruptured cerebral aneurysms under study, 18 were internal carotid aneurysms (C2 or C3: 4 cases, IC-PC: 12 cases, IC-ancho.: 1 case, IC terminal: 1 case), 25 were anterior communicating aneurysms, 10 were middle cerebral aneurysms, 4 were anterior cerebral aneurysms and 1 case was a VA-PICA aneurysm. The ruptured internal carotid aneurysms were 4.0-21.0 mm in size, the anterior communicating aneurysms were 1.8-13 mm, the middle cerebral aneurysms were 2.0-21.3 mm, the anterior cerebral aneurysms were 3.2-9.1 mm, and the VA-PICA aneurysm was 4.4 mm. The sites of the 89 unruptured cerebral aneurysms break down as follows: 29 were internal carotid aneurysms (C2 or C3: 4 cases, IC-PC: 10 cases, IC-ancho.: 10 cases, IC terminal: 5 cases), 18 were anterior communicating aneurysms, 34 were middle cerebral aneurysms, and there were 5 cases of posterior circulation aneurysm. In size, the unruptured internal carotid aneurysms were 1.0-18.3 mm, the anterior communicating aneurysms were 1.0-6.5 mm, the middle cerebral aneurysms were 1.0-10.3 mm, the anterior cerebral aneurysms were 1.0-3.3 mm, and the posterior circulation aneurysms were 2.2-17.3 mm. Out of 58 ruptured cerebral aneurysms, 44 were of the largest size category, and 53 (91.4%) were in the largest size category and/or anterior communicating aneurysms. The accumulated incidence rate of rupture of anterior communicating aneurysms rose suddenly upon reaching 2 mm in size, and after reaching 3 mm, these aneurysms accounted for a nearly uniform 55%-60% of the incidence rate of rupture. The accumulated incidence rate of rupture of IC-PC aneurysms rose drastically at 4 mm in size with the data describing a parabolic slope when graphed. IC-PC aneurysms represented a uniform 55% of the incidence rate of rupture after reaching 8 mm in size. The accumulated incidence rate of rupture of middle cerebral aneurysms rose in a gently sloping parabola beginning at 4 mm, and stabilized at 20% upon reaching 10 mm. These results suggest that each site is associated with a characteristic size and rate of aneurismal rupture. Special attention should thus be paid to large and anterior communicating aneurysms when operating on multiple cerebral aneurysms.     

Axonogenesis in the medaka embryonic brain

In order to know the general pattern of axonogenesis in vertebrates, we examined axonogenesis in the embryonic brain of a teleost fish, medaka (Oryzias latipes), and the results were compared with previous studies in zebrafish and mouse. The axons and somata were stained immunocytochemically using antibodies to a cell surface marker (HNK-1) and acetylated tubulin and visualized by retrograde and anterograde labeling with a lipophilic dye. The fiber systems developed correlating with the organization of the longitudinal and transverse subdivisions of the embryonic brain. The first axons extended from the synencephalic tegmentum, forming the first fiber tract (fasciculus longitudinalis medialis) in the ventral longitudinal zone of the neural rod, 38 hours after fertilization. In the neural tube, throughout the entire brain two pairs of longitudinal fiber systems, one ventral series and one dorsal or intermediate series, and four pairs of transverse fiber tracts in the rostral brain were formed sequentially during the first 16 hours of axon production. In one of the dorsal longitudinal tracts, its branch retracted and disappeared at later stages. One of the transverse tracts was found to course in the telencephalon and hypothalamus. The overall pattern of the longitudinal fiber systems in medaka brain is similar to that in mouse, but apparently different from that in zebrafish. We propose that a ventral tract reported in zebrafish partially belongs to the dorsal fiber system, and that the longitudinal fiber systems in all vertebrate brains pass through a common layout defined by conserved genetic and developmental programs.     

Transcranial myogenic motor-evoked potentials after transient spinal cord ischemia predicts neurologic outcome in rabbits

OBJECTIVE: Myogenic transcranial motor-evoked potentials (tc-MEPs) were applied to monitor spinal cord ischemia in the repairs of thoracoabdominal aortic aneurysms. We investigated whether tc-MEPs after spinal cord ischemia/reperfusion could be used to predict neurologic outcome in leporine model. METHODS: Tc-MEPs were measured at 30-second intervals before, during, and after spinal cord ischemia (SCI) induced by balloon occlusion of the infrarenal aorta. Twenty rabbits were divided into five groups. Four groups (n = 4 animals in each group) had transient ischemia induced for 10, 15, 20, or 30 minutes. In fifth group, the terminal aorta at the aortic bifurcation was occluded for 30 minutes. All animals were evaluated neurologically 48 hours later, and their spinal cords were removed for histologic examination. RESULTS: The tc-MEPs in each SCI group rapidly disappeared after SCI. After reperfusion, the recovery of tc-MEPs amplitude was inversely correlated to duration of SCI. Tc-MEPs amplitude at one hour after reperfusion was correlated with both neurologic score and number of neuron cells in the spinal cord 48 hours later. Logistic regression analysis demonstrated that the neurologic deficits differed significantly between animals with tc-MEPs amplitude of less than 75% of the baseline and those with an amplitude of more than 75%. CONCLUSIONS: The amplitude of tc-MEPs after ischemia /reperfusion of the spinal cord showed a high correlation with durations of SCI, with neurologic deficits, and with pathologic findings of the spinal cord. Tc-MEPs, therefore, could be used to predict neurologic outcome. In particular, tc-MEPs whose amplitude recovered by less than 75% indicated a risk of paraplegia.