Pharmacological studies of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate. Effects on experimental pancreatitis

The effects of FUT-187 (6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate, CAS 103926-82-5), a novel synthetic protease inhibitor, were examined in experimental rat and canine models of pancreatitis. 1. FUT-187 significantly increased the survival of rats with trypsin- and phospholipase A2-induced pancreatitis in a dose-dependent manner (10-100 mg/kg, p.o.). 2. FUT-187 decreased plasma enzymatic activity reflecting the degree of pancreatitis in rats with ethionine-induced pancreatitis, and showed a tendency to ameliorate histopathological changes in the pancreas (10-100 mg/kg p.o.). 3. FUT-187 (10 mg/kg) produced an obvious improvement of various biochemical parameters of pancreatitis and also reduced histopathological changes in the pancreas in animals with experimental pancreatitis produced by the closed duodenal loop method. In addition, FUT-187 significantly increased the survival of dogs when given by direct administration into the lumen of the closed duodenal loop. The therapeutic effects of FUT-187 in experimental pancreatitis were nearly equal in most instances to those of camostat mesilate. Thus, FUT-187 would appear to be an effective new agent for the treatment of pancreatitis.     

An experimental study on the pathogenesis of congenital hand malformation--with reference to local disturbance in the limb bud and congenital constriction band syndrome

In order to study congenital constriction band syndrome, we performed local cauterization of the lower limb buds of embryos in fertilized white leghorn eggs between hour 0 on day 4 (day 4-0) and day 7-0 of incubation. Constriction bands, acrosyndactyly, and amputation of digits, malformations characteristic of this syndrome, were all induced by intervention after day 5-0, when digital ray formation was first observed, indicating that they all develop after ray formation. Histological examination showed that encapsulation and shedding of the lesion containing hematoma and necrotic tissue at the distal end of a digital ray led to digit amputation. When the cells encapsulating this lesion extend over another digital ray, moreover, the ray tips fuse, while the rest of the two digits involved remain discrete-resulting in acrosyndactyly.     

Glued Carbon Fiber Electrodes for Diaphragm Pacing

Carbon fibers with fibrin glue were used as electrodes for diaphragm pacing. The electrodes were applied to three mongrel dogs and the effectiveness was tested. The carbon leads were glued to phrenic nerves by means of the fibrinogen and thrombin bilaterally. The tidal volumes and threshold current level for stimulation were measured at various time up to 9 weeks after implantation. Effective contraction of diaphragm were observed for 9 weeks. By using this electrode, the exfoliation of the nerve is not necessary, the nerve can be maintained in an intact state, and the risk of the implanting operation can be minimized.     

Serum thymidine kinase,a possible marker for monitoring the effect of bone marrow transplant treatment in early recovery phase

We measured serum thymidine kinase (TK) activity with a radioenzyme assay system employing [I-125]-iododeoxyuridine as the tracer on serial specimens from five bone marrow transplant (BMT) patients before and after transplantation. The serum level of TK activity in the 4 patients with effective BMT treatment ranged from 3.0 to 16.9 U/L (mean, 7.80 U/L) before transplantation and from 27.3 to 236.1 U/L (mean, 82.95 U/L) after the BMT treatment. Mean serum TK activity increased 13.17-fold (range, 1.68 to 29.14-fold). In contrast, the activity in the patient with ineffective BMT treatment was not significantly different during, before, or after BMT treatment. In addition, serum TK activity in BMT patients was well correlated with the change in the number of leukocytes before and after BMT treatment [r = +0.709 (p less than 0.01), y = 0.012 x +0.87]. We conclude that the determination of serum TK activity in BMT patients is very useful in monitoring the course of bone marrow transplantation in the early recovery phase.     

Phenytoin desensitization monitored by antigen specific T cell response using carboxyfluorescein succinimidyl ester dilution assay

We evaluated drug-specific T cell responses in a patient with refractory partial seizures and paroxysmal kinesigenic choreoathetosis successfully treated with clinical desensitization to phenytoin. Drug-induced lymphocyte transformation test before desensitization was negative with a stimulation index of 130%. The frequencies and cytokine-producing phenotypes of phenytoin-specific T cells were examined simultaneously by using a carboxyfluorescein succinimidyl ester (CFSE) dilution assay. Before desensitization, the proportion of CFSElow CD4+ cells in whole CD4+ was 3.09%; 13.6% of CFSElow CD4+ cells were stained with anti-interferon gamma antibody. After desensitization, phenytoin-specific CFSElow CD4+ cells decreased to background level. These results indicate that CFSE dilution assay will be useful for the diagnosis and monitoring of drug hypersensitivity.     

Assessment of skull base involvement of nasopharyngeal carcinoma by bone SPECT using three detectors system]

SPECT of the skull was performed on twelve patients with histologically proven nasopharyngeal carcinoma using newly developed three detectors SPECT system (Toshiba GCA 9300A) mounted with fan-beam collimators, for the purpose of early detection of skull base involvement of the disease. This SPECT system has extremely improved resolution with FWHM of 8 mm in the center, and it provides clear tomographic images of the skull which has anatomically complex structure. SPECT image was taken 3 hours after injection of 740 MBq (20 mCi) of 99mTc-MDP following whole body skeletal survey. In twelve patients with confirmed nasopharyngeal carcinoma, 8 patients showed positive findings on SPECT. Three of SPECT positive patients also showed destructive findings on CT. Other five positive patients did not show destructive findings on CT at their initial examinations, but in three of them CT findings turned to positive later. SPECT was superior to CT in early detection of skull base involvement. We believe that SPECT of the skull is a diagnostic tool for early detection of skull base involvement of nasopharyngeal carcinoma.     

Effects of lumbar skin warming on gastric motility and blood pressure in humans

We examined the possibility that lumbar skin warming can increase gastrointestinal motility by investigating the electrogastrogram (EGG), blood pressure, and heart rate with psychometric ratings in healthy humans. Scores of mood state profiles showed that lumbar skin warming (42 degrees C, 20 min) decreased tension-anxiety, depression, anger-hostility, fatigue, and confusion of the participants. A multiple bandpass filter analysis of EGGs showed that a postural transition from orthostatic to supine for measurement caused an increase in dominant frequency of 25-29% towards the frequencies of the normal interdigestive migrating motor complex (IMC). The spectral power of the IMC band, 2.55-3.05 cycles/min, was increased by 20 min-warming, reflecting the increase in gastric contractility. No increase in the spectral power was observed in the time-matched control group without skin warming. Therefore, an increase in contractility is a characteristic of lumbar skin warming. The systolic blood pressure increased by 15% during warm stimulation. Interbeat intervals were not influenced by warm stimulation. An analysis of interbeat intervals by a fast Fourier transform method showed that the cardiac sympathetic and parasympathetic nerves did not play a major role in raising the blood pressure. Vasoconstriction of the mesenteric artery was therefore considered to cause a blood pressure increase during warming. It is hypothesized that vasoconstriction of the visceral arteries by lumbar skin warming increases the blood pressure and gastrointestinal contractility.     

Evaluation of the theory of cardiac-output computation from transthoracic impedance plethysmogram

To analyse the limit of the stimation of stroke volume by thoracic impedance plethysmography (SV_z), we considered an elastic tube forced with a trapezoidal flow input as a model of the aorta, and, based on Kubicek's equation, the volume input (SV_a) was related to its impedance change via the model system parameters such as elasticity, fiuid inertia, peripheral resistance, total impedance across the tube and the rise and fall time of the input. SV_z is equal to SV_a only when the inflow is a square wave. The ratio SV_z/SV_a decreases with increasing input rise time, while it increases with increasing fall time, if the maximum flow rate and ejection time of the inflow are held constant. SV_z hardly changes in association with changes in elasticity, fluid inertia, peripheral resistance or total impedance. A part of the results, the relationship between SV_z, transthoracic total impedance and aortic flow waveform, was also demonstrated in dogs.     

Design of a multichannel solid-state recorder and its application to temperature measurement

The development of a multichannel unconstrained memory system for monitoring physiological information is described. The system comprises a portable recorder, worn by the subject, to detect and store data in memory and a readout unit for transferring the data to a microcomputer. Using the microcomputer, the physiological data are displayed, retrieved and analysed. The portable recorder consists of a memory control unit, an instrumentation unit, an LCD timer and batteries. In the memory-control unit the data are transferred to EPROM (erasable programmable read-only memory), which is a nonvolatile memory. This memory, removed from the protable recorder, can be delivered to the laboratory and its contents analysed without interrupting the field experiment. In connection with the instrumentation unit, an 8-channel skin thermometer was designed and tested. It was accurate to within ±0.08°C compared with a standard thermometer.     

Long-term potentiation in the optic tectum of rainbow trout

We examined synaptic plasticity in the optic tectum of rainbow trout by extracellular recordings. We found that the field-excitatory postsynaptic potential in the retinotectal synapses was potentiated by repetitive stimuli of 1.0 Hz for 20 s to the retinotectal afferents. The long-term potentiation (LTP) developed slowly, and was maintained for at least 2 h. Applications of an antagonist for N-methyl-D-aspartic acid (NMDA) receptors or Mg²⁺-free saline showed that activation of NMDA receptors was required to form the LTP beyond the induction period. The present findings indicate that presynaptic stimulation in the retinotectal synapses causes LTP mediated by NMDA receptors in the optic tectum of rainbow trout.