Classification of antipsychotic drugs by gene expression in the frontal cortex of mice.

Antipsychotic drugs are classified as typical and atypical based on extrapyramidal effects. However, since the frontal cortex is one of the most important regions for antipsychotic actions, this study attempted to classify antipsychotic drugs based on gene expression in the frontal cortex. Chlorpromazine and thioridazine were selected as typical antipsychotics, and olanzapine and quetiapine as atypical antipsychotics. Since these drugs have similar chemical structures, the effect of the basic structure on gene expression can be eliminated. Cluster analysis of microarray experiments separated 4-drug-administered mice into chlorpromazine-quetiapine and thioridazine-olanzapine groups. This classification scheme is different from that which is based on criteria currently used to group the typical and atypical drugs and suggests that antipsychotic drugs can be further separated into multiple groups.     

Osteoclastogenesis inhibitory factor exhibits hypocalcemic effects in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy

Osteoclastogenesis inhibitory factor (OCIF) is a novel secreted protein that inhibits osteoclastogenesis both in vitro and in vivo. In this study, we examined the effects of OCIF on serum calcium (Ca) concentrations in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy. In normal mice, a single intraperitoneal injection of OCIF reduced serum Ca levels in a dose-dependent manner. Significant decrease in serum Ca (by 1.6 ± 0.3 mg/dL, n = 5) was observed 2 h after the injection of OCIF at 20 mg/kg and the hypocalcemic effect continued for up to 12 h. Serum phosphate (Pi) concentrations also decreased in response to OCIF. Urinary excretion of Ca, Pi, and creatinine did not change significantly after injection of OCIF or vehicle. In hypercalcemic, tumor-bearing nude mice, a single intraperitoneal injection of OCIF at 20 mg/kg resulted in a dramatic decrease in serum Ca (maximal decrease 2.8 ± 0.37 mg/dL, n = 11), which continued for up to 24 h. The results suggest that OCIF decreased serum Ca through its inhibitory effect on bone resorption. Furthermore, it is suggested that OCIF has therapeutic potential for the treatment of hypercalcemic conditions such as malignancy-associated hypercalcemia.     

Effects of a new analog of thyrotropin-releasing hormone, N alpha-[(S)-4-oxo-2-azetidinyl) carbonyl]-L-histidyl-L-prolinamide dehydrate (YM-14673) on spinal reflex potentials and flexor reflexes in spinalized rats

Experiments were performed on spinalized rats, transected at the Cl level. The intravenous administration of TRH and its analog YM-14673 (N alpha-[(S)-4-oxo-2-azetidinyl) carbonyl]-L-histidyl-L-prolinamide dehydrate) produced marked increases in the amplitude of mono- and polysynaptic reflex potentials and those of the withdrawal flexor reflexes. The effects of YM-14673 were stronger and longer-lasting than those of TRH. The stimulant action of TRH and YM-14673 on the flexor reflexes was not antagonized by prazosin, chlorpromazine, haloperidol or cyproheptadine, suggesting no involvement of the release of catecholamines or serotonin in the stimulant effects of TRH and its analog. Therefore, YM-14673 may be beneficial for the treatment of several spinal motor neuron diseases.     

The evaluation of cystoscopy in the screening of asymptomatic microhematuria

As a prospective study on asymptomatic microhematuria, complete urological examinations including cystoscopy, IVP, ultrasound and urinary cytology were performed on 422 patients over 40 years old between January 1987 and December 1988 (group A). The results of group A was compared with that of retrospective study on 266 patients, who had incomplete urological examination between January 1984 and December 1985 (group B). Cystoscopy was performed on 321 patients (87.2%) in group A and on 108 patients (40.6%) in group B. Bladder tumor was found in 10 cases (2.4%) in group A, including 7 cases of male patients (5.7%), but in only 1 case (0.4%) in group B. Since the negative rate of abnormal urinary cytology was 50% and that of abnormal IVP was 90% in 10 cases of bladder tumor in group A, cystoscopy was considered to be an essential examination for the screening of patients with asymptomatic microhematuria over 40 years old patients.     

Severe hypoglycaemia in a person with insulin autoimmune syndrome accompanied by insulin receptor anomaly type B.

AIMS: A rare case of the insulin autoimmune syndrome (IAS) accompanied by insulin receptor anomaly is reported. METHODS: Antibodies to insulin and insulin receptor were determined in the patient with severe hypoglycaemia before and after the treatment with prednisolone. RESULTS: Titers of antibody to insulin and insulin receptors were 73.0% and 41.5%, respectively. Drug-induced lymphocyte stimulation tests were all negative for the suspicious drugs. Her HLA-DR was DRB1*0403/04051. Following steroid therapy, the formation of antibodies was suppressed and alleviated her symptoms. Scatchard analysis yielded findings specific to polyclonal antibodies. CONCLUSIONS: The changes in autoantibodies resulted in alleviation of the hypoglycemic symptoms as a result of steroid therapy.     

Initial steroid bolus injection promotes vigorous CD8+ alloreactive responses toward early graft acceptance immediately after liver transplantation in humans.

We have found that steroid bolus withdrawal prior to graft reperfusion increased the incidence of acute cellular rejection (ACR). This study aims to clarify how initial steroid bolus (ISB) injection at reperfusion influences the kinetics of CD8(+) alloreactive immune responses immediately after living donor liver transplantation (LDLT). A total of 49 hepatitis C virus (HCV)-infected recipients were classified into 3 groups according to hierarchical clustering by preoperative CD8(+)CD45 isoforms. The naive T cell proportion was considerably higher in Group I than in Groups II and III, whereas Group II recipients had the highest effector memory (EM) T cells and Group III the highest effector T cells. The frequency of ACR was significantly higher in recipients without ISB than in those with ISB. In particular, the ACR rates were the highest in Group II without ISB. Following ISB, the proportion of effector T cells was promptly upregulated within 6 hours after graft reperfusion, simultaneously with the upregulation of CD27(-)CD28(-) subsets, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha and perforin expression, which significantly correlated with increasing interleukin (IL)-12 receptor beta 1 cells. These were then downregulated to below preoperative levels by tacrolimus (Tac) administered at 24 hours. These changes did not occur in the absence of ISB. In Group II without ISB, the downregulation of IL-12Rbeta1(+) cells was the greatest, consistent with the highest rates of ACR and mortality (60%). In conclusion, ISB must be done in place, especially in Group II with preexisting high EM T cells, to enable the development of early allograft acceptance.     

Iron deficiency down-regulates the Akt/TSC1-TSC2/mammalian Target of Rapamycin signaling pathway in rats and in COS-1 cells

Iron deficiency (ID) is one of the most commonly known forms of nutritional deficiencies. Low body iron is thought to induce neurologic defects but may also play a protective role against cancer development by cell growth arrest. Thus, ID may affect cellular pathways controlling cell growth and proliferation, the mechanism of which is still not fully understood. The serine/threonine protein kinase Akt and its downstream target, the mammalian Target of Rapamycin (mTOR), is known to play a crucial role in the regulation of cell growth and survival. Therefore, we hypothesized that Akt/mTOR pathway could be influenced by ID. Three-week-old male Wistar-strain rats were divided into 3 groups and the 2 groups had free access to a control diet (C group) or an iron-deficient diet (D group). The third group (PF group) were pair-fed the control diet to the mean intake of the D group. After 4 weeks, rats were killed and their brains were sampled. In separate experiments, COS-1 cells were cultured with or without the iron chelator deferoxamine. Western blots of brain samples and COS-1 lysates were used to analyze the expression and phosphorylation state of Akt, TSC2, mTOR, and S6 kinase proteins implicated in the Akt/mTOR pathway. Using 2 different ID models, we show for the first time that iron deficiency depresses Akt activity in rats and in COS-1 cells, leading to a decrease in mTOR activity.     

Human Tumor–infiltrating Lymphocytes Transfected with Tumor Necrosis Factor Gene Could Augment Cytotoxicity to Autologous Tumor Cells

Human tumor–infiltrating lymphocytes (TILs) derived from pleural or ascitic fluid were incubated with recombinant interleukin 2 and transfected with human tumor necrosis factor (TNF) a gene by the lipofection procedure. The resulting TILs secreted significant amounts of TNF in the culture supernatant and exhibited cytotoxicity against established cell lines, such as K562 and Daudi, and autologous tumor cells. The TNF gene–transfected TILs exhibited an augmented killing of autologous tumor cells.