Treadmill running combined with microdialysis can evaluate motor deficit and improvement following dopaminergic grafts in 6-OHDA lesioned rats

To evaluate the physiological role of striatal dopamine (DA) during exercise and the mechanism of functional recovery mediated by grafted DAergic neurons, the locomotor ability (treadmill running) and DA turnover were investigated using treadmill running combined with in vivo microdialysis in the intact control rats, 6-hydroxydopamine (6-OHDA) lesioned rats (hemi-parkinsonian model rats) and DAergic cell grafted rats. The 3 groups of rats were trained to run on a straight treadmill at a speed of 1,800 cm/min for 20 min every day for 7 consecutive days. If the rats could not follow the speed they got electrostimulation (ES) from the grid behind the treadmill belt. The numbers of ES rats received during treadmill running were counted to quantify the locomotor ability. Control rats could keep up with the treadmill easily (0-1 ES/10 min), whereas lesioned rats could not follow the speed (80-100 ES/10 min). Most of the grafted rats received only a few ES, but a few received over 100 ES/10 min. Extracellular DA and its metabolites, dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA), were measured by in vivo microdialysis and high-performance liquid chromatography (HPLC) during and after treadmill running. In control rats the basal levels of DA, DOPAC and HVA were 2.3 fmol/μl, 1,109.8 fmol/μl and 612.2 fmol/μl, respectively. They increased up to 130%, 140% and 160% by running. In 6-OHDA lesioned rats basal values of DA, DOPAC and HVA were less than 10% of controls. We did not perform microdialysis in these rats since they got too much ES during running. In grafted rats that showed good recovery in locomotor ability, DA returned to almost control level (1.9 fmol/μl), but those of DOPAC (127.8 fmol/μl) and HVA (100.2 fmol/μl) were still low. DA, DOPAC and HVA increased up to 130%, 130% and 150% by running in a similar pattern as in intact rats. These results suggest that grafted neurons can release and metabolize DA in the host striatum both tonically and phasically in relation with internal and external stimuli and also suggest that treadmill running ability is a good indicator of DA turnover in the striatum. Thus, the treadmill running test with microdialysis is useful for quantitative evaluation of motor function in grafted animals.     

An acute fatal occupational cadmium poisoning by inhalation

Summary A 43-year-old male smelter was admitted to a hospital on account of severe dyspnea about 2 days after exposure to brownish-yellow smoke produced by melting of copper scrap. On admission pronounced hypoxemia was revealed, and an oxygen-enriched gas was administered after intubation. Although inspired oxygen concentration was gradually increased, hypoxemia progressed and he died on day 11 in hospital.The principal autopsy finding was chiefly confined to the lungs. Both lungs were heavy (the left weighing 1,470 g; the right 1,710 g) and firm to the touch. Histologically, no normal alveoli were found throughout the entire lung. Some alveolar spaces were occupied by pneumocytes, others by organized exudate with fibrosis. Interstitial fibrosis was present. Patchy areas of inflammatory cell infiltrations as well as intra-alveolar hemorrhages were observed. On the basis of the above findings a diagnosis of diffuse alveolar damage was made.Based on the available evidence (presence of cadmium in the copper scrap, feature of the smoke, clinical signs with latent time, and high cadmium concentration of the lung), the diffuse alveolar damage was considered to have been caused by inhaled cadmium. The pulmonary change of the present case was more advanced in pathologic stage in comparison with those reported in the literature.     

The way for carrying medicine and its containers (V). "Packaging material--paper"

In the Edo era, paper was useful as the most suitable packaging materials for carrying medicines. It was considered that the wrapping paper protected medicines from an imaginary gaseous medium "ki", which meant atmospheric moisture in this case. Also brand name and indications of medicines were printed on the wrapping paper for taking a medicine correctly. In the 18th century, wrapping paper for medicine was produced. It was specially processed for wrapping medicines only, and it was called "yakutaishi" in Japanese.     

Phase II study of (2" R)-4'-O-tetrahydropyranyladriamycin (THP) in patients with advanced or recurrent gastric cancer. Clinical study group of THP for gastric cancer in Japan

A multi-institutional collaborative phase II study of (2"R)-4-O-tetrahydropyranyladriamycin (THP) was performed by intravenous administration to patients with advanced or recurrent gastric cancer. The administration schedules were (1) 40-60 mg/body every 3 or 4 weeks and (2) 20-40 mg/body once a week. Of 58 registered patients, 49 cases were eligible and 37 cases were evaluable for response. The therapeutic results were 1 CR, 4 PR, 14 NC and 18 PD. The response rate of the evaluable cases was 13.5%. The side effects were mainly bone marrow suppression and digestive symptoms. In particular, the frequency of leukopenia was a high 75.5%, while there was a decrease in hemoglobin in 38.8% and anorexia in 30.6%. The frequency and severity of alopecia, which is a known problem with anthracyclines, were slight, and no abnormal electrocardiograms were observed.     

Apparently unprovoked seizures precipitated by prefebrile condition

We investigated the clinical features of the patients whose body temperature exceeded 38 degrees C, in 0.5-6 hours after an afebrile seizure (prefebrile seizure). Patients with meningoencephalitis and epilepsy were excluded from this study. From May 1995 to April 1997, seven cases of prefebrile seizures admitted to PL hospital. Three of the 7 had a status and one had a cluster of seizures. Five patients had had several febrile seizures prior to the onset of prefebrile seizures. One developed epilepsy during the follow-up period. We speculate that prefebrile seizures have several factors of complex febrile seizures and require a careful follow-up.     

Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity.

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) have been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis. We recently showed that certain 'liquid' tumors such as leukemia not only produce VEGF, but also express functional VEGFR, resulting in an autocrine loop for tumor growth and propagation. A chimeric anti-VEGFR2 (or kinase insert domain-containing receptor, KDR) antibody, IMC-1C11, was shown to be able to inhibit VEGF-induced proliferation of human leukemia cells in vitro, and to prolong survival of nonobese diabetic-severe combined immune deficient (NOD-SCID) mice inoculated with human leukemia cells. Here we produced two fully human anti-KDR antibodies (IgG1), IMC-2C6 and IMC-1121, from Fab fragments originally isolated from a large antibody phage display library. These antibodies bind specifically to KDR with high affinities: 50 and 200 pM for IMC-1121 and IMC-2C6, respectively, as compared to 270 pM for IMC-1C11. Like IMC-1C11, both human antibodies block VEGF/KDR interaction with an IC(50) of approximately 1 nM, but IMC-1121 is a more potent inhibitor to VEGF-stimulated proliferation of human endothelial cells. These anti-KDR antibodies strongly inhibited VEGF-induced migration of human leukemia cells in vitro, and when administered in vivo, significantly prolonged survival of NOD-SCID mice inoculated with human leukemia cells. It is noteworthy that the mice treated with antibody of the highest affinity, IMC-1121, survived the longest period of time, followed by mice treated with IMC-2C6 and IMC-1C11. Taken together, our data suggest that anti-KDR antibodies may have broad applications in the treatment of both solid tumors and leukemia. It further underscores the efforts to identify antibodies of high affinity for enhanced antiangiogenic and antitumor activities.