Central sites involved in lateral hypothalamus conditioned neural responses to acoustic cues in the rat

1. Unit activity in the lateral hypothalamus (LHA) of the rat was recorded during discrimination learning of cue-tone stimuli (CTS) predicting glucose (CTS1+) or intracranial self-stimulation (ICSS) (CTS2+) as positive reinforcement or electric shock (CTS1-) or tail pinch (CTS2-) as negative reinforcement. The same action, licking, was used as the behavioral response to all stimuli. Procaine hydrochloride, a local anesthetic, was microinjected into the ventral tegmental area (VTA) and the amygdala (AM). LHA neuron responses and licking were analyzed to investigate the afferent input pathway(s) responsible for LHA neural responses to conditioning CTSs in positive reinforcement and to identify the central site involved in CTS learning. Although the animals were restrained, there was no respiratory, cardiac rate, or blood pressure evidence of stress. The headholder was specially designed in our laboratory to avoid pain or discomfort to the animal. The subjects would often, after the first few sessions, voluntarily enter into position in the apparatus, presumably to obtain the reward available during the experiments. 2. In positive reinforcement, a rat was rewarded by 5 microliters of glucose or ICSS when it licked a spout. The rat licked for glucose after CTS1+ or for ICSS after CTS2+. In negative reinforcement, an aversive stimulus, either electric shock or tail pinch, was applied if the rat did not lick the spout. The electric shock and tail pinch were maintained weak enough to produce an avoidance ratio less than 20-30%, averaged in all trials. The rat licked to avoid electric shock after CTS1- or tail pinch after CTS2-. 3. Of 271 LHA neurons analyzed, 202 (74.5%) responded to either or both rewarding and aversive stimuli. The number of neurons that responded to only rewarding stimuli was relatively large (105/271), and the number that responded similarly to both rewarding and aversive stimuli was small (29/271). The effects of both glucose and ICSS, and the effects of both electric shock and tail pinch, were usually similar in neurons analyzed for both rewarding and aversive stimulation. Of 271 neurons, 173 responded differentially to rewarding and aversive stimuli. 4. Neural and behavioral responses were recorded before, during, and after local anesthesia of the VTA in 15 rats and of the AM in 14 rats. Injections of 0.3-0.8 microliters of 5% procaine hydrochloride or 0.9% saline were made at a rate of 0.3 microliters/min through guide cannulae chronically implanted in the VTA and AM, ipsilateral to the recording and ICSS sites in 29 rats that self-stimulated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of amygdalar and lateral hypothalamic neurons to visual information processing of food and nonfood in monkey

Visual information processing was investigated in the inferotemporal cortical (ITCx)-amygdalar (AM)-lateral hypothalamic (LHA) axis which contributes to food-nonfood discrimination. Neuronal activity was recorded from monkey AM and LHA during discrimination of sensory stimuli including sight of food or nonfood. The task had four phases: control, visual, bar press, and ingestion. Of 710 AM neurons tested, 220 (31.0%) responded during visual phase: 48 to only visual stimulation, 13 (1.9%) to visual plus oral sensory stimulation, 142 (20.0%) to multimodal stimulation and 17 (2.4%) to one affectively significant item. Of 669 LHA neurons tested, 106 (15.8%) responded in the visual phase. Of 80 visual-related neurons tested systematically, 33 (41.2%) responded selectively to the sight of any object predicting the availability of reward, and 47 (58.8%) responded nondifferentially to both food and nonfood. Many of AM neuron responses were graded according to the degree of affective significance of sensory stimuli (sensory-affective association), but responses of LHA food responsive neurons did not depend on the kind of reward indicated by the sensory stimuli (stimulus-reinforcement association). Some AM and LHA food responses were modulated by extinction or reversal. Dynamic information processing in ITCx-AM-LHA axis was investigated by reversible deficits of bilateral ITCx or AM by cooling. ITCx cooling suppressed discrimination by vision responding AM neurons (8/17). AM cooling suppressed LHA responses to food (9/22). We suggest deep AM-LHA involvement in food-nonfood discrimination based on AM sensory-affective association and LHA stimulus-reinforcement association.     

HLA class II DPB1, DQA1, DQB1, and DRB1 genotypic associations with occupational allergic cough to Bunashimeji mushroom

We previously reported that two-third of workers in a Bunashimeji mushroom (Hypsizigus marmoreus) farm complained of respiratory allergic symptoms, but one-third workers did not suffer from such symptoms even when working for a long period. CD4+ T-helper (Th) cells increased, and Th2/Th1 ratio increased in the allergic workers. To address these immunological backgrounds, we have investigated whether there is any relationship between mushroom allergy and human leukocyte antigen (HLA) class II alleles of DPB1, DQA1, DQB1, and DRB1 by using the polymerase chain reaction-restriction fragment length polymorphism (RFLP) and sequencing-based typing methods. We observed that the allele frequencies of DQA1*0103, DQB1*0601, and DRB1*0803 were significantly higher in the workers having no allergic symptoms than allergic workers (DQA1*0103: 57 vs 25%, DQB1*0601: 49 vs 14%, and DRB1*0803: 29 vs 0%). However, this phenomenon was not seen in workers producing another kind of mushroom, Honshimeji (Lyophyllum aggregatum). The HLA-DRB1*0803 allele alone, the DRB1*0803, DQA1*0103, DQB1*0601 haplotype, or both were negatively associated with allergy to Bunashimeji, and these alleles might be involved in the prevention of Bunashimeji mushroom-specific respiratory allergy.     

Expression of interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 in the murine cerebellum and neuropathological effect of leukemia inhibitory factor on cerebellar Purkinje cells

Expression of glycoprotein 130 and the related receptors, including interleukin-6 receptor and leukemia inhibitory factor receptor, was examined in the murine cerebellum at the protein level. Western blot analysis revealed that interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 were expressed in the murine cerebellum. Immunoreactivities for interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 were strongly localized on the cell body of Purkinje cells, indicating that both interleukin-6 and leukemia inhibitory factor could act directly on Purkinje cells in murine adult mice. The expressions of interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 were observed on the cell membranes of Purkinje cells by immunoelectron microscopy. Immunoreactivity for the interleukin-6 receptor was also detected in the cytoplasm of Purkinje cells. Injection of a murine hemopoietic cell line, FDC-P1 cells, transfected with the complementary DNA encoding the leukemia inhibitory factor led to a reduction in calbindin-positive dendrites of the Purkinje cells.

The present results suggest that the leukemia inhibitory factor affects cerebellar functions through Purkinje cells.     

Treatable ischemic neuronal damage in the gerbil hippocampus

The Mongolian gerbil is known to develop delayed neuronal death in the hippocampus following brief forebrain ischemia (Brain Res 239: 57-69). Morphological, biochemical, or electrophysiological studies on this neuronal injury have shown that neurons still retain potential reversibility at the earlier period of alteration. To examine this possibility, immediately following 5 min of ischemia in the gerbil, pentobarbital, diazepam, or nizofenone was injected. Seven days following ischemic insult, animals were perfusion fixed and neuronal density in the hippocampal CA1 subfield was counted. Most of the neurons in the CA1 sector survived ischemic insult when a drug was given, whereas most of them were lost without the treatment. The average neuronal density of treated groups showed a statistically significant (p less than 0.01) persistence compared with that of control group. The effective dosage of the drugs were 20-40 mg/kg in pentobarbital, 10-20 mg/kg in diazepam, and 12.5-25 mg/kg in nizofenone. On the other hand, when pentobarbital was injected 1 hr following ischemia, while neurons still remain intact morphologically, it showed no effect. This result indicates that the neuronal damage of "delayed neuronal death" type is reversible if treatment is instituted at an early period of cell change.     

A comparative, well-controlled study of ceftizoxime suppository against ceftizoxime intravenous injection in infantile acute pneumonia

We have attempted to clinically define the therapeutic usefulness of ceftizoxime suppository (CZX-S) in children with bacterial pneumonia, in a randomized trial. Intravenous injection of ceftizoxime (CZX) was used as the control. The results are summarized below. Subjects were inpatients with bacterial pneumonia, ranging in age from 9 months to 7 years and 10 months. As a rule, the daily dose was either four 250 mg (in potency) suppositories given at 6-hour intervals or 60 mg/kg body weight intravenous CZX (control) given in 4 injections at 6-hour intervals over a period of 7 days. The number of children in the study was 67. These children were divided into 2 dosage groups (suppository, 35; injection, 32) with matching pretreatment background factors. The severity of the target disease in the majority of the children was "moderate". The rate of therapeutic effectiveness was 97.1% for the suppository and 93.8% for the injection, and did not differ significantly between the 2 groups. Rates of efficacy by severity, presence or absence of underlying diseases, daily dose and/or complications were high without exception, and did not differ significantly between the 2 groups. Eradication rates for causative microorganisms, as studied in 16 children of each group, were both 93.8%. The 2 most frequently isolated causative organisms were Haemophilus influenzae and Streptococcus pneumoniae. Side effects were examined for 36 children of each group. The frequency of side effects did not differ significantly between the suppository group (2 with diarrhea and 1 with abdominal pain) and the injection group (1 with urticaria), and 8.3% and 2.8%, respectively. The frequency of abnormal laboratory test findings differed significantly (P less than 0.01) with respect to eosinophilia which occurred in 7 (20.6%) of the injected subjects but was not encountered in the subjects treated with suppositories. Other abnormal laboratory findings included thrombocytosis in 3 (14.3%) of the injection group and increased GOT in 1 (3.2%) of the suppository group. The suppository formulation of CZX appears to be a highly useful substitute for the injectable form, and should find a special use in children whose treatment with injections experiences some difficulty.     

Selective effects of Lipiodolized antitumor agents

Lipiodol Ultra-Fluid (Lipiodol) remains selectively in the tumor for an extended time when applied through arteries feeding the tumor. Although lipophilic antitumor drugs are selective when combined with Lipiodol, wide application of common hydrophilic agents is limited, as these compounds are insoluble in oil. We propose "Lipiodolization" of water-soluble agents using as an intermediate Urografin, a water-soluble contrast medium. Thirteen patients with primary hepatocellular carcinoma were treated with this Lipiodol-Urografin system containing antitumor agents. Marked decrease in serum alpha-fetoprotein (AFP) levels, decrease in tumor size in the hepatic imaging, and histologic studies of the resected specimen revealed this mode of therapy to be effective in 10 of 13 patients (77%) with hepatocellular carcinoma. Lipiodolization of antitumor agents is a new approach to selective cancer chemotherapy.     

Cordyceps militaris Fruit Body Extract Decreases Testosterone Catabolism and Testosterone-Stimulated Prostate Hypertrophy

The androgens testosterone and dihydrotestosterone (DHT) are essential for a variety of systemic functions in mature males. Alteration of these hormones results in late-onset hypogonadism (LOH) and benign prostate hyperplasia (BPH). The fruit bodies of fungi of the genus Cordyceps have been regarded as folk medicine or health food with tonic and antifatigue effects. The extract from the fruit body of Cordyceps militaris parasitizing Samia cynthia ricini (CM) was evaluated as a novel-candidate natural product for ameliorating male andropause symptoms. To explore the effects of CM on LOH and BPH, CM was applied to rat models and cultured testicular cells and prostate cells. The concentrations of androgens in the serum and culture media were determined by ELISA. Expression of steroidogenic enzymes and androgen-related genes was evaluated by qPCR, and prostatic cell proliferation was assessed with the cell-viability assay. CM maintained the serum levels of testosterone and DHT, but inhibited testosterone-induced prostate hypertrophy. CM also increased the secretion of testosterone and DHT by primary testicular cells, with no changes in the mRNA expression of steroidogenic enzymes, but decreased the growth of prostatic cell lines. Our data suggest that CM could improve both LOH and BPH in males.     

Analysis of acute-phase toxicities of intensity-modulated proton therapy using a model-based approach in pharyngeal cancer patients

Pharyngeal cancer patients treated with intensity-modulated proton therapy (IMPT) using a model-based approach were retrospectively reviewed, and acute toxicities were analyzed. From June 2016 to March 2019, 15 pharyngeal (7 naso-, 5 oro- and 3 hypo-pharyngeal) cancer patients received IMPT with robust optimization. Simulation plans for IMPT and intensity-modulated X-ray therapy (IMXT) were generated before treatment. We also reviewed 127 pharyngeal cancer patients with IMXT in the same treatment period. In the simulation planning comparison, all of the normal-tissue complication probability values for dysphagia, dysgeusia, tube-feeding dependence and xerostomia were lower for IMPT than for IMXT in the 15 patients. After completing IMPT, 13 patients completed the evaluation, and 12 of these patients had a complete response. The proportions of patients who experienced grade 2 or worse acute toxicities in the IMPT and IMXT cohorts were 21.4 and 56.5% for dysphagia (P < 0.05), 46.7 and 76.3% for dysgeusia (P < 0.05), 73.3 and 62.8% for xerostomia (P = 0.43), 73.3 and 90.6% for mucositis (P = 0.08) and 66.7 and 76.4% for dermatitis (P = 0.42), respectively. Multivariate analysis revealed that IMPT was independently associated with a lower rate of grade 2 or worse dysphagia and dysgeusia. After propensity score matching, 12 pairs of IMPT and IMXT patients were selected. Dysphagia was also statistically lower in IMPT than in IMXT (P < 0.05). IMPT using a model-based approach may have clinical benefits for acute dysphagia.