Rise in plasma leptin levels after stimulation of hypothalamic cholinoceptive neurons by neostigmine in rats.

To investigate the role of hypothalamic cholinergic neurons in the regulation of plasma leptin levels, we injected neostigmine, a cholinesterase inhibitor, or vehicle alone into the third cerebral ventricle in free moving male Wistar rats and then measured plasma leptin levels. The administration of neostigmine (5 x 10(-9) or 5 x 10(-8) mol) increased plasma leptin levels 3-6 h after stimulation in a dose-dependent manner, while intravenous injection of neostigmine (5 x 10(-8) mol) had no effect. Atropine (5 x 10(-8) mol) concomitantly injected with neostigmine (5 x 10(-8) mol) prevented neostigmine-induced increase in plasma leptin. The expression of leptin messenger ribonucleic acid (mRNA) in epididymal white adipose tissue was significantly increased at 4 and 6 h after neostigmine injection compared with that before the injection. Plasma levels of corticosterone were significantly increased at 30 min after stimulation with neostigmine and this increase was sustained for 6 h after stimulation. Furthermore, bilateral adrenalectomized rats showed no increase in plasma leptin levels after stimulation. In conclusion, stimulation of hypothalamic cholinoceptive neurons increased plasma leptin levels in rats by increasing leptin production in adipocytes. This increase may be due to an increase in glucocorticoids from the adrenal glands. These results suggest that plasma leptin levels can be regulated by hypothalamic cholinoceptive neurons.

Noninvolvement of hypertriglyceridemia and hyperleptinemia in blood pressure increases induced by dietary lard in rats.

We investigated whether hypertriglyceridemia and hyperleptinemia are involved in the development of increases in blood pressure induced by dietary lard. Rats received either chow alone or chow in which 50% of the energy content was from substituted lard. Each group was divided into two groups according to whether the diet included bezafibrate or not. In another series of experiments, rats were fed either chow alone or chow in which 50% of the energy content was from substituted lard, safflower oil, or sucrose. Systolic blood pressure (SBP) was measured every week during each 7-week feeding period. A steady-state plasma glucose method was used to determine insulin sensitivity after lard substitution with or without bezafibrate. After the 7-week feeding period, the plasma levels of glucose, immunoreactive insulin, triglyceride and leptin were measured. In rats fed with a high lard diet, SBP, plasma levels of immunoreactive insulin, triglyceride, leptin and steady-state plasma glucose concentrations significantly increased, compared with levels of these substances in controls. Bezafibrate treatment completely reversed these effects. In rats fed with a high safflower oil or a high sucrose diet, no significant change was seen in SBP and plasma immunoreactive insulin levels. However, the plasma triglyceride levels were increased by dietary lard or sucrose. Moreover, the plasma leptin level was also increased by dietary lard and safflower oil. Neither dietary hypertriglyceridemia nor hyperleptinemia were involved in the development of increases in blood pressure induced by dietary lard.

Dietary fat-induced increase in blood pressure and insulin resistance in rats.

OBJECTIVES: To determine whether the dietary-fat-induced increase in blood pressure is caused by excess energy intake or the fat composition of the diet, what type of fat increases the blood pressure, and whether insulin resistance is involved in the dietary-fat-induced increase in blood pressure. METHODS: In a series of experiments, rats received: chow alone or chow supplemented with lard or sucrose to provide 33% of a total energy content increased by 50%; chow alone or chow in which 50% of the energy content was from substituted lard, safflower oil or medium-chain triglyceride oil; or chow alone or chow in which 50% of the energy content was from substituted lard, with or without troglitazone. Systolic blood pressure (SBP) was measured every week during each 8-week feeding period. A steady-state serum glucose method was used to determine the insulin sensitivity after the lard substitution with or without troglitazone. RESULTS: Both the lard and sucrose enrichment increased SBP and body weight compared with controls. Lard substitution significantly increased SBP and immunoreactive insulin, although body weight did not differ from control. Neither a diet substituted with safflower oil nor one substituted with medium-chain triglyceride oil influenced SBP. Troglitazone completely inhibited the increase in SBP and immunoreactive insulin induced by the lard. The steady-state serum glucose concentration was significantly greater after the lard substitution than after isoenergetic chow; this effect also was reversed by troglitazone. CONCLUSION: Chronic feeding with lard increased SBP in rats, independently of excess energy intake. Of the fats tested, lard exerted an intrinsic pressor effect. Troglitazone reversed the lard-induced increase in SBP.

Subthalamic nucleus stimulation for gait disturbance in Parkinson's disease.

OBJECTIVE: A preliminary study of subthalamic nucleus (STN) stimulation was performed to determine its applicability for the treatment of gait and postural disturbances in Parkinson's disease. METHODS: Five Parkinson's disease patients with freezing gait and postural instability were selected for this study. Their ages ranged from 60 to 73 years (mean+/-standard deviation, 65.6+/-4.8 years). Semi-microelectrode recording was used to identify the STN and to place a chronic electrical stimulation electrode within the right STN in all patients. The Unified Parkinson's Disease Rating Scale and the modified Hoehn and Yahr Staging Scale were used to assess patients in on- and off-drug conditions before surgery and 3 months after surgery. RESULTS: The scores on the Hoehn and Yahr Staging Scale and the total Unified Parkinson's Disease Rating Scale for akinesia (P < 0.05), gait (P < 0.05), and gait and posture (P < 0.01) in off-drug on-stimulation conditions significantly improved over the preoperative and postoperative off-drug off-stimulation conditions (analysis of variance [ANOVA], P < 0.01). Improvement over the preoperative scores was 24% on the Hoehn and Yahr Staging Scale, 43.6% on the total Unified Parkinson's Disease Rating Scale, 33.4% for akinesia, 36.6% for gait, and 38.7% for gait and posture. However, stimulation in the on-drug phase did not show a significant difference compared with pre- and postoperative conditions (ANOVA, P > 0.05). Comparisons between preoperative on-drug and postoperative off-drug on-stimulation conditions revealed that there were no significant differences in the scores, except for gait (ANOVA, P < 0.05). The scores on subscales for falling, freezing, walking, and gait in off-drug on-stimulation conditions were significantly improved over the scores for preoperative and postoperative off-stimulation (ANOVA, P < 0.05), but the score for postural stability remained unchanged. CONCLUSION: Our findings showed that STN stimulation effectively alleviates freezing gait and improves walking to its status during the preoperative on-drug phase and can be applied for treatment of Parkinson's disease patients with these symptoms.

[Gelastic seizures treated by partial resection of a hypothalamic hamartoma].

A 13-year-old girl developed atonic seizure at 2 years of age. At the age of 10 years, gelastic seizures were noted. Magnetic resonance imaging (MRI) revealed a hypothalamic mass protruding down into the basal cistern and up into the third ventricle. An interictal electroencephalogram (EEG) showed paroxysmal spike and wave complex discharges. Since the seizures failed to respond to medical therapy, it was decided to try to control them by removing the mass. The operation was carried out through an interhemispheric trans-lamina terminalis approach. The lesion was so similar to normal brain tissue that the resection had to be limited enough to avoid complications. Histological examination of the mass showed a hamartoma. Postoperative MRI showed residual mass, but no seizure has been noted since the operation. The EEG recorded one year after the operation showed no spike and wave complex discharge, although she was still on anticonvulsant drugs. The authors propose that surgical therapy should be considered as a treatment for intractable gelastic epilepsy with hypothalamic hamartoma and that the first operation should be conservative enough to avoid complications, because it can bring about good results even if it is only a partial resection.

Neural activity of the subthalamic nucleus in Parkinson's disease patients.

The neural activity pattern of the subthalmic nucleus (STN) was investigated in five patients with Parkinson's disease who were scheduled for electrode implantation for chronic stimulation of the STN. The initial target was placed 8 mm or 10 mm lateral to the midline, 3 mm to 4 mm posterior to the midcommissural point, and 5 mm to 6 mm below the intercommissural (AC-PC) line. The STN was identified by semi-microelectrode recordings with a trajectory moving laterally in 2-mm steps. The amplitudes of multi-unit activities were relatively low at depths from 8 mm to 5 mm above and from 1 mm to 4 mm below the target, while those 4 mm to 0 mm above the target were significantly higher than at the other sites (ANOVA, Fisher's test, p < 0.05), with the highest amplitude at 2 mm above the target (91.0 +/- 23.3 mu v, n = 15). In the mediolateral direction, amplitudes were relatively higher in the lateral portion, and amplitudes at 14 mm lateral to the midline were significantly higher than at the other sites (ANOVA, Fisher's test, p < 0.05). The target for chronic electrical stimulation was determined to be at the midpoint of the hyperactive STN, i.e., 12 mm lateral to the midline in three patients and 13 mm lateral in two patients. Movement-related neural activity was observed at 5 sites, i.e., 3 sites responded to passive movement of the contralateral wrist and 2 sites to passive knee and/or ankle movement. In conclusion, our data show that the lateral part of the STN is hyperactive in PD, and recordings of neural activities contributed greatly to identifying the STN and determining the target for chronic stimulation within it.

Secondary thalamic degeneration after cerebral infarction in the middle cerebral artery distribution: evaluation with MR imaging.

PURPOSE: To evaluate secondary degeneration of the ipsilateral thalamus after cerebral infarction in the middle cerebral artery (MCA) distribution by using magnetic resonance (MR) imaging. MATERIALS AND METHODS: Thirty patients (17 men, 13 women; aged 30-85 years) with embolic cerebral infarction in the MCA distribution underwent serial MR imaging 2 hours to 12 months after a stroke. In 23 of the 30 patients, the authors evaluated cerebral blood flow with single photon emission computed tomography (SPECT). RESULTS: T2-weighted spin-echo images disclosed a hyperintense area in the ipsilateral thalamus in 14 patients (47%) 1-12 months after stroke. The hyperintense area was confined to the dorsomedial or anterior and dorsomedial nuclei of the thalamus in nine of the 14 patients; it extended from the dorsomedial or anterior and dorsomedial nuclei to the ventral lateral nucleus or pulvinar in the remaining five patients. Hypoperfusion of the ipsilateral thalamus was observed in 21 of the 23 patients who underwent SPECT. Twelve of the 21 patients also showed a hyperintense area in the ipsilateral thalamus on the MR images. CONCLUSION: MR imaging is useful in evaluating secondary thalamic degeneration after cerebral infarction. In clinical practice, this secondary degeneration should not be mistaken for other lesions such as further cerebral infarction.

[Two cases of advanced breast cancer effectively treated with chemoendocrine therapy and radiotherapy].

We reported 2 cases of breast cancer with lymph node metastasis treated with CAF (cyclophosphamide, adriamycin, 5-fluorouracil) and medroxyprogesterone acetate (MPA). Case 1 was stage IV [T4b, N3 M1 (lung)] and case 2 was stage IIIa (T1, N2, M0). The two cases responded well to CAF and MPA therapy in local and systemic lesions, and then underwent radiotherapy and lymph node resection without mastectomy. After these treatments, both cases were thought to be disease-free. Major side effects were allopecia, obesity, and leukopenia. These results suggest that combination chemoendotherapy, radiotherapy, and surgery can be utilized for most patients with moderately advanced breast cancer.

Transmission of hepatitis C in an isolated area in Japan: community-acquired infection. The South Kiso Hepatitis Study Group.

BACKGROUND/AIMS: The spread of hepatitis C virus (HCV) infection not due to drug needle sharing or transfusion is largely unknown in communities. A search for risk factors for HCV infection in an endemic area might elucidate inapparent modes of transmission. METHODS: We conducted screening for hepatitis virus markers and parenteral exposures to blood among 435 inhabitants in an isolated area known for its endemicity for non-A, non-B hepatitis and in a nonendemic area with 1542 inhabitants. RESULTS: The prevalence of hepatitis B surface antigen was the same in both areas. The prevalence of antibody to HCV verified by the recombinant immunoblot assay was 32.4% in the highly endemic area and 2.3% in the nonendemic area (P < 0.001). Risk factors for HCV infection in the highly endemic area were complex but included folk remedies such as acupuncture and "vacuuming" for congested blood in muscle by the use of a warm glass bottle. CONCLUSIONS: Folk remedies such as acupuncture and cutting of the skin using nonsterilized knives should be considered as possible routes of HCV transmission not associated with blood transfusion or sharing of drug paraphernalia.

[Innovation of undergraduate medical education for future patient oriented medical care].

Recent supersubspecialization of medical sciences and technologies have developed DOS (Doctor/Disease Oriented System) in medical practice, and teaching of medical knowledge (cognitive domain) and techniques (psychomotor domain) have been overemphasized. However, the up-to-date knowledge and skills the students learn will become obsolete by the time they go into clinical practice. DOS has led to recognition of patient's rights and introduction of POS (Patient/Problem Oriented System) for the future medical practice with such concepts as holistic care, primary care, terminal care, truth telling, informed consent, quality of life, and death with dignity. What students must learn is not factual knowledge and techniques, but problem solving skills, habits for continuing self-education, and attitudes for holistic care of patients with proper communication skills. To attain such objectives, problem-based experiential self-learning methods and teaching communication skills through role playing, simulated patients, workshops, nursing practice, and clinical clerkship have been advocated. We introduced such new teaching strategies in our medical school about 10 years ago, and have been impressed by their effectiveness.

Anticoagulant activity of sulfatide and its anti-thrombotic effect in rabbit.

The mechanism of anticoagulant activity of sulfatide (galactosylceramide I3-sulfate), which exists in serum lipoproteins of various mammals except rodents, was investigated, together with the pharmacological effects of the glycolipid on the blood coagulation system in rabbits. The sulfatide was shown to be an effective anticoagulant when it was added in vitro in the form of pure micelle without auxiliary lipids such as phosphatidylcholine and/or cholesterol. The anticoagulant activity of synthetic galactosylceramide I6-sulfate, a positional isomer with respect to the sulfate group, was stronger than that of the sulfatide. The anticoagulant activity was specifically inhibited by anti-sulfatide antibody. The study on the pharmacological effects of sulfatide showed that the fibrin-precipitation time after single injection of the lipid (10 mg/kg body weight) into rabbits increased 2.5-fold compared with the normal level, and the maximum effect was observed 1 h after the injection. The half-life of anticoagulant activity was 5 h. These results suggest that sulfatide may be effective for the prevention of thrombosis. Sulfatide may be safer than other anticoagulant drugs, because it is a natural component of serum lipoproteins. Further, it may well play an essential role as an endogenous anticoagulant in mammals. Unlike heparin, sulfatide failed to inhibit thrombin and coagulation factor Xa activities in the presence of antithrombin III, indicating that the anticoagulant mechanism of sulfatide is independent of antithrombin III. These results indicate that the anticoagulant activity of sulfatide is potent and specific, and the lipid may be available as a useful and safe antithrombotic drug.

Study of neural activities of the primary auditory cortex and middle latency auditory evoked potentials.

This study was undertaken to clarify the relationship between the neural activities of the auditory cortex and components of middle latency auditory evoked potentials (ML-AEPs) (NI and PI) in the cat. Extracellular single-unit activities in the auditory cortex AI (AC-AI) were recorded simultaneously with ML-AEPs. In addition, the effects of removal of the AC-AI and AII and the cerebral hemisphere on ML-AEPs were also studied. ML-AEPs of humans consist of Na, Pa, and Nb components with preceding VI and VII, and those of the cat consist of NI, PI and NII with preceding P6 and P7. Among the 21 unit activities obtained from the AC-AI, 14 showed time-locked responses to click stimuli. The positive and negative waves of these unit activities have a phase reversal relation to N7 and P7, respectively. They are not related in latencies to NI and PI. Recording of ML-AEPs from the surface of the AC-AI showed large negative potentials (No), which also had a phase reversal relation to P7. The amplitude of P7 and No decreased after the unilateral and the bilateral removal of the AC-AI and AII. NI and PI decreased in amplitude after the unilateral removal of the cerebral hemisphere and further decreased after the bilateral removal. The above mentioned findings indicate that the neural activities of the primary AC are the ones mostly related to P7 and that NI and PI reflect neural activities of the cerebral hemispheres.

Identification of nociceptive neurons in the medial thalamus: morphological studies of nociceptive neurons with intracellular injection of horseradish peroxidase.

Somatosensory neurons including nociceptive ones in the medial thalamus have been studied extracellularly, and are classified into three types: nociceptive-specific, wide dynamic range, and tap neurons. However, the morphological characteristics of these three neurons have not yet been clarified. We studied the morphological characteristics of the neurons by iontophoretic injection of HRP into single neurons in 32 cats. Nine wide dynamic range neurons and two tap neurons were electrophysiologically identified and successfully stained with HRP in and around the parafascicular and subparafascicular nuclei, and in the mediodorsal nucleus. All nine wide dynamic range neurons had fewer dendrites which formed scanter tufts, whereas the two tap neurons had many more dendrites which formed denser tufts: i.e. wide dynamic range neurons were of the isodendritic type, and the tap neurons were of the allodendritic type, according to Ramón-Moliner's classification. The axons of the two tap neurons ran antero-laterally whereas those of wide dynamic range neurons ran in many directions. These morphological differences suggest that tap neurons may have more specialized and fixed functions than wide dynamic range neurons.

Interstitial laserthermia in neurosurgery.

Deep-seated brain tumor is difficult to treat surgically. Hyperthermia using various energy sources has been tried, but has failed to gain wide use because of equipment problems and poor temperature control. It is possible now to use Nd:YAG laser with a stable low-energy supply as an energy source for laser hyperthermia (laserthermia). Animal study and clinical study were done using SLT CL50, Computer-control Laserthermia System to treat deep-seated brain tumors. Experimental study revealed that laserthermia produced minimal edema, temperature control was satisfactory, and blood-brain barrier opened up for 6 days following laserthermia. Five patients with brain tumors were treated with laserthermia. Follow-up CT scan revealed disappearance of tumor in 4 patients and decrease in volume in 1 patient. Long-term neurological follow up revealed no deterioration. Laserthermia using Nd:YAG laser is safe and easy to use and it is beneficial to treat deep-seated brain tumors.

Verbal versus non-verbal visual evoked potentials: Kanji versus line drawings.

Cortical areas related to perception of verbal and non-verbal stimuli were studied using VEPs. Kanji characters, line drawings (LD), or a blank were displayed. Verbal VEPs were obtained by subtracting the blank-VEPs from the Kanji-VEPs, and non-verbal VEPs by subtracting the blank-VEPs from the LD-VEPs. Both the verbal and non-verbal VEPs showed a negative peak (100-300 msec) focally over bilateral occipital, posterior temporal and parietal areas, and a positive peak diffusely over frontal halves. Differences between the non-verbal from the verbal VEPs showed an initial peak (100-200 msec) focally over bilateral occipital and posterior temporal areas, followed by a peak (200-300 msec) focally over bilateral posterior temporal areas. The frontal areas diffusely showed peaks at 100-200, 200-300 and 300-400 msec. Left-right asymmetries of both the verbal and non-verbal VEPs showed peaks between 100 and 300 msec over posterior temporal, parietal, and occipital areas. Left-right asymmetries of the subtraction to the non-verbal from the verbal VEPs showed a peak (100 msec) over occipital and parietal areas, and a broader peak over posterior temporal area (100-200 msec). Bilateral occipital, posterior temporal, and parietal areas are focally activated by the two perceptions (100-300 msec), while frontal areas are activated diffusely. Further, different processes may be focally involved between the hemispheres over occipital (100-200 msec) and posterior temporal (100-200 and 200-300 msec) regions. Initial left-right asymmetries of the subtracted VEP between the two perception would occur over occipital and parietal areas (100 msec) and last for 200 msec over posterior temporal area.

Hyperglycemia induced by hippocampal administration of neostigmine is suppressed by intrahypothalamic atropine.

We investigated the relationship between the hyperglycemia induced by the administration of neostigmine into the hippocampus and the hypothalamus. Prior to the injection of neostigmine (5 x 10(-8) mol) into the hippocampus, 1 microliter each of atropine or hexamethonium (5 x 10(-11)-5 x 10(-8) mol) was injected into the bilateral ventromedial hypothalamus (VMH). Atropine suppressed in a dose-dependent manner the hyperglycemia induced by hippocampal administration of neostigmine, whereas hexamethonium had no significant effect. These observations suggest that the pathway for this experimental hyperglycemia involves, at least in part, the muscarinic cholinergic neurons in the VMH.

Dissociation of hyperthermic and hyperglycemic effects of central prostaglandin F2 alpha.

We previously reported that intraventricular prostaglandins (PGs) produced hyperthermia and hyperglycemia in anesthetized rats. However, the relationship of them is little known. We examined the relationship between hyperthermia and hyperglycemia induced by intraventricular PGF2 alpha using curarized and adrenal demedullated rats. Iv curare completely prevented the PGF2 alpha-induced hyperthermia, but enhanced the hyperglycemic effect of PGF2 alpha. Adrenal demedullation completely prevented the hyperglycemia, but did not affect the hyperthermic effect of PGF2 alpha. To further assess the site of action concerned with PGF2 alpha-induced thermoregulation and glucoregulation in the central nervous system (CNS), we injected saline or PGF2 alpha into the preoptic area of the anterior hypothalamus (POA) in intact rats. After microinjection of PGF2 alpha into the POA, the rectal temperature rose, but the plasma glucose level did not increase significantly, as compared with saline-treated control rats. These results suggest that PGF2 alpha causes the central nervous system to produce hyperthermia via shivering, stimulated the somatic motor system, and to produce hyperglycemia by stimulating central sympathetic outflow to the adrenal medulla, but these operate independently under different neural regulation, and these sensitive sites are organically dissociated in the CNS.

Stereotactic interstitial laser-hyperthermia using Nd-YAG laser.

Laser hyperthermia using Nd-YAG laser was studied experimentally and clinically to treat deep-seated brain tumors. Histological changes, temperature profile, and modification of the blood-brain barrier were studied using cat and rat brains. In a clinical study 5 patients with brain tumors were treated with laser hyperthermia using this computed tomography-stereotactic technique. All tumors of these patients disappeared on computed tomography, and 3 of the 5 patients are still alive without recurrence. It was possible to make optimal lesion and to have accurate peripheral temperature control by using the combination of the Komai stereotactic method and the SLT Nd-YAG laser system. Interstitial laser hyperthermia using this method is easy and safe to use, and it is beneficial to treat deep-seated brain tumors.

CT classification of small thalamic hemorrhages and their clinical implications.

Thirty-seven small thalamic hemorrhages (less than 2 cm) were classified into four types depending on topographic location. Patients with posterolateral lesions had severe sensory and motor disability as well as the worst prognosis. Anterolateral lesions resulted in mild prefrontal signs with milder sensory and motor impairment. Medial hematomas disturbed consciousness in the acute stage, followed by impaired prefrontal signs of long duration. Dorsal hematomas were associated with ipsilateral parieto-occipital signs (aphasia on the left and topographic memory disturbance on the right).