Disseminated Hormographiella aspergillata infection with involvement of the lung, brain, and small intestine following allogeneic hematopoietic stem cell transplantation: case report and literature review.

Disseminated infection by Hormographiella aspergillata is extremely rare and small intestine involvement has not been reported previously. A 51-year-old man with myelodysplastic syndrome developed pneumonia after cord blood cell transplantation. Fungal growth from the biopsied lung was identified as H. aspergillata by morphology and the gene analysis. Although antifungal agents including voriconazole and liposomal amphotericin B were administered, he died of disseminated H. aspergillata infection. We review the literature and discuss the treatment and prognosis.

Olanzapine increases hepatic glucose production through the activation of hypothalamic adenosine 5'-monophosphate-activated protein kinase.

AIMS: To investigate the mechanism of the metabolic disturbance induced by the atypical antipsychotic olanzapine, we examined whether adenosine 5'-monophosphate-activated protein kinase (AMPK) in the hypothalamus and hepatic glucose production are involved in the effect of olanzapine. METHODS: Male 6-week-old ICR mice were used. Blood glucose levels were determined by the glucose oxidase method. The mRNA levels of gluconeogenic or glycolytic enzymes were measured by reverse transcription polymerase chain reaction (RT-PCR). AMPK expression was measured by Western blotting. RESULTS: Systemic injection of olanzapine increased blood glucose levels in both unfasted and fasted mice. However, the increase in fasted mice was less than that in unfasted mice. Central administration of olanzapine also increased the blood glucose levels in unfasted mice, but not in fasted mice. In a pyruvate tolerance test, olanzapine significantly increased blood glucose levels. In addition, olanzapine increased the mRNA levels of glucose-6-phosphatase (G6Pase), a gluconeogenic enzyme, in the liver. Furthermore, olanzapine increased phosphorylated AMPK in the hypothalamus of unfasted mice, and olanzapine-induced hyperglycaemia was inhibited by the AMPK inhibitor compound C. Central administration of the AMPK activator AICAR significantly increased G6Pase mRNA levels in the liver and blood glucose levels. Moreover, both olanzapine- and AICAR-induced hyperglycaemia were attenuated by the ß-adrenergic receptor antagonist propranolol, suggesting that olanzapine and AICAR induce hepatic glucose production through the sympathetic nervous system. CONCLUSIONS: Our results indicate that olanzapine activates AMPK in the hypothalamus, which increases hepatic glucose production via the sympathetic nervous system.

Reduced hyperalgesia induced by nerve injury, but not by inflammation in mice lacking protein kinase C gamma isoform.

Protein kinase C is one of protein kinases which might be involved in the nerve injury- or inflammation-induced hyperalgesia. The present study was designed to investigate the hyperalgesia with thermal paw-withdrawal test induced by sciatic nerve ligation or by intraplantar injection of a complete Freund's adjuvant solution in protein kinase C gamma knockout and its wild-type mice. Either sciatic nerve ligation or intraplantar injection of a complete Freund's adjuvant caused a marked decrease of the paw-withdrawal latency only on the ipsilateral, but not on the contralateral side of the paw in wild-type mice. This ipsilateral hyperalgesia induced by sciatic nerve ligation was significantly attenuated in protein kinase C gamma knockout mice. On the other hand, the ipsilateral hyperalgesia induced by complete Freund's adjuvant remained about the same in protein kinase C gamma knockout mice as in wild-type mice. The results indicate that protein kinase C gamma is involved in the development of the thermal hyperalgesia induced by nerve ligation, but not by complete Freund's adjuvant-induced inflammation.

Involvement of spinal protein kinase C in thermal hyperalgesia evoked by partial sciatic nerve ligation, but not by inflammation in the mouse.

Activation of several protein kinases contributes to the development of hyperalgesia evoked by injuries. The present study was designed to investigate the role of protein kinase C in the spinal cord in thermal hyperalgesia evoked by sciatic nerve ligation or by intraplantar injection of complete Freund's adjuvant. The paw withdrawal latency on the ipsilateral side, but not on the contralateral side, was markedly decreased after sciatic nerve ligation. Intraplantar injection of complete Freund's adjuvant also caused markedly decreases of the paw withdrawal latency. Intrathecal pretreatment with protein kinase C inhibitor calphostin C (100 and 250 ng) attenuated the decrease of the paw withdrawal latency evoked by sciatic nerve ligation. In contrast, the decrease of the paw withdrawal latency evoked by inflammation was only slightly attenuated by intrathecal pretreatment with calphostin C. The results indicate that protein kinase C in the spinal cord is involved in the development of the thermal hyperalgesia evoked by nerve ligation and is much less involved in the thermal hyperalgesia by complete Freund's adjuvant's-induced inflammation.

Novel responses of ZRF, a variant of human MTF-1, to in vivo treatment with heavy metals.

Heavy metal-dependent transcriptional activation of metallothionein (MT) genes is mediated by multiple enhancer sequences, metal responsive element (MRE), located in the upstream region of the genes. Previously, we have reported purification of a zinc-dependent MRE-binding protein, zinc regulatory factor (ZRF), from HeLa cells, and have pointed to the close relationship between ZRF and mouse MRE-binding transcription factor-1 (MTF-1) according to the analysis of partial amino acid sequences. By means of cDNA cloning and the product analyses, we show that ZRF is a variant of human MTF-1 (hMTF-1), which carries a single amino acid exchange in the zinc finger domain. Accordingly, ZRF is renamed hMTF-1b. Expression of hMTF-1b in HeLa cells is constitutive at both mRNA and protein levels, and is unaffected by treatment with cadmium (Cd). On the other hand, when cells were fractionated into nuclear extract and cytosol, a large part of the hMTF-1b was recovered in the cytosol fraction. A significant increase in the amount of nuclear hMTF-1b occurs when cells are treated with various heavy metals, including Cd, Zn, Cu and Ag, which is associated with concomitant decrease in the amount recovered in the cytosol fraction. Since immunocytochemical analysis revealed that intracellular distribution of hMTF-1b is restricted to the nucleus irrespective of the heavy metal treatment, such an increment in the nuclear extracts apparently results from promotion of nuclear retention of hMTF-1b by the heavy metal treatment. Analysis by native gel electrophoresis shows that the mobility of hMTF-1b significantly changes in association with Cd treatment, raising the possibility that a conformational change of hMTF-1b occurs in response to treatment with heavy metals in vivo.

Modification of the expression of naloxone-precipitated withdrawal signs in morphine-dependent mice by diabetes: possible involvement of protein kinase C.

The involvement of cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC) in the modulation of naloxone-precipitated withdrawal jumping in morphine-dependent mice by diabetes was examined. Naloxone-precipitated withdrawal jumps were significantly less in morphine-dependent diabetic mice than in morphine-dependent non-diabetic mice. I.c.v. pretreatment with either calphostin C, a PKC inhibitor, or KT-5720, a PKA inhibitor, attenuated naloxone-precipitated withdrawal jumps in morphine-dependent non-diabetic mice. However, naloxone-precipitated withdrawal jumps in morphine-dependent diabetic mice were not attenuated by i.c.v. pretreatment with either calphostin C or KT5720. Moreover, i.c.v. pretreatment with phorbol-12,13-dibutyrate (PDBu), a PKC activator, attenuated naloxone-precipitated withdrawal jumps in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice. The noradrenaline (NA) turnover in the frontal cortex in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice, was significantly increased 5 min after administration of naloxone. Naloxone-induced enhancement of NA turnover in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice, was blocked by i.c.v. pretreatment with either calphostin C or KT5720 1 hr before naloxone challenge and blocked by PDBu 1 hr before the last injection of morphine. These results suggest that the co-activation of PKC and PKA is needed to elicit naloxone-precipitated withdrawal jumps and enhancement of turnover rate of NA in the frontal cortex in morphine-dependent non-diabetic mice. Furthermore, the attenuation of naloxone-precipitated withdrawal jumps in morphine-dependent diabetic mice may be due, in part, to the desensitization of mu-opioid receptors by the activation of PKC.

Antinociceptive effects of the ORL1 receptor agonist nociceptin/orphanin FQ in diabetic mice.

The antinociceptive potency of nociceptin/orphanin FQ, an opioid-like orphan receptor agonist, was examined using the tail-flick test and the formalin-induced nociception test in diabetic mice. Nociceptin/orphanin FQ, at doses of 0.1 to 10 nmol, intrathecal (i.t.), produced a marked and dose-dependent inhibition of the tail-flick response in both non-diabetic and diabetic mice. The antinociceptive effect of nociceptin/orphanin FQ in the tail-flick test in diabetic mice was greater than that in non-diabetic mice. The antinociceptive effect of nociceptin/orphanin FQ was not antagonized by pretreatment with either beta-funaltrexamine, a selective mu-opioid receptor antagonist, naltrindole, a selective delta-opioid receptor antagonist, or nor-binaltorphimine, a selective kappa-opioid receptor antagonist. The antinociceptive effects of nociceptin/orphanin FQ in diabetic, but not in non-diabetic mice, were abolished when mice were pretreated with capsaicin i.t. 24 h before testing. In the formalin test, nociceptin/orphanin FQ also produced a marked and dose-dependent antinociceptive effect on the first-phase response, but not the second phase-response, in both diabetic and non-diabetic mice. Furthermore, nociceptin/orphanin FQ significantly and dose-dependently reduced the flinching responses to i.t.-administered substance P in diabetic mice, but not in non-diabetic mice. The results of the present experiments clearly indicate that the antinociceptive potency of nociceptin/orphanin FQ is significantly greater in diabetic mice than in non-diabetic mice. Furthermore, the results of this study suggest that the reduction of substance P-mediated nociceptive transmission in the spinal cord may be responsible for the antinociceptive effect of nociceptin/orphanin FQ.

kappa-Opioid receptor-mediated antinociceptive effects of stereoisomers and derivatives of (+)-matrine in mice.

The antinociceptive effects of seven matrine-type lupin alkaloids were examined using the acetic acid-induced abdominal contraction test (the writhing test) and the tail-flick test in mice. (+)-Allomatrine, the C-6 epimer of (+)-matrine, produced the antinociceptive effect at 1/3 potency of (+)-matrine or pentazocine. It was demonstrated that the antinociceptive effects of (+)-allomatrine were mediated through the activation of kappa-opioid receptors, while the antinociceptive effect of (+)-matrine was mediated by both mu- and kappa-opioid receptors. (-)-Sophoridine, the C-6 epimer of (+)-matrine, (+)-sophoranol, (-)-14 beta-hydroxymatrine and (+)-matrine N-oxide, which possess a hydrophilic group, and (-)-sophocarpine and (-)-sophoramine having a double bond(s) did not show significant antinociceptive activity.

Possible involvement of protein kinase C in the attenuation of [D-Ala2, NMePhe4, Gly-ol5]enkephalin-induced antinociception in diabetic mice.

The effects of pretreatment with a highly selective protein kinase C inhibitor, calphostin C, on the antinociception induced by the intracerebroventricular (i.c.v.) administration of the mu-opioid receptor agonist [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAMGO) were studied in diabetic and non-diabetic mice. The antinociceptive potency of i.c.v. DAMGO in diabetic mice was lower than that in non-diabetic mice. I.c.v. pretreatment with phorbol 12,13-dibutyrate (50 pmol), a protein kinase C activator, for 60 min attenuated the antinociception induced by i.c.v. DAMGO in non-diabetic mice, but not in diabetic mice. I.c.v. pretreatment with calphostin C (3 pmol) for 60, 120 and 240 min, but not 10 min, increased the antinociceptive effect of DAMGO (10 ng) in diabetic mice, but not in non-diabetic mice. The dose-response curve for DAMGO-induced antinociception in diabetic mice, but not in non-diabetic mice, was shifted to the left by i.c.v. pretreatment with calphostin C (3 pmol) for 60 min. In non-diabetic mice, i.c.v. pretreatment with a high dose of calphostin C (10 pmol) for 60 and 120 min potentiated DAMGO-induced antinociception. These results indicate that protein kinase C may be involved in DAMGO-induced antinociception in mice. Furthermore, these results suggest that the attenuation of DAMGO-induced antinociception in diabetic mice may be due in part to increased protein kinase C activity.

Effects of bilateral transvenous diaphragm pacing on hemodynamic function in patients after cardiac operations. Experimental and clinical study.

The effects of bilateral transvenous diaphragm pacing and intermittent positive-pressure ventilation on hemodynamic function were compared by animal experiment in 18 dogs and by clinical study in 14 patients during the postoperative period after cardiac operations. Aortic, pulmonary arterial, right atrial, and left atrial pressures (transmural) and aortic flow were increased by diaphragm pacing in the canine experiment. In dogs with induced tricuspid insufficiency, aortic pressure, right and left atrial pressures, and aortic blood flow increased, similar to the results obtained in the clinical study. Diaphragm pacing produced a sufficient tidal volume (7.2 to 12 ml/kg) for maintenance of normal blood gas levels in the patients, all of whom recovered spontaneous breathing without any weaning problems after 2 to 6 hours of diaphragm pacing. The catheter electrode used for stimulation was placed 30 mm away from the sinus node to avoid arrhythmias. Respiratory control by diaphragm pacing is hemodynamically superior to that by intermittent positive-pressure ventilation, and its efficacy is expected, especially in critical cases or in diseases or conditions in which the decrease in the load of the right heart affects the hemodynamic status of the patient.

Change of biological activities of (1----3)-beta-D-glucan from Grifola frondosa upon molecular weight reduction by heat treatment.

Changes of biological activities manifested by (1----6)-branched (1----3)-beta-D-glucans of various molecular weights obtained by heat treatment of the corresponding intact beta-glucan at 150 degrees C (HD-LE) were examined. The activities assessed in this study were as follows: an antitumor activity, activation of alternative complement pathway, glucose consumption by macrophages, macrophage-mediated lysosomal enzyme activity in culture supernatant and cell lysate, interleukin-1 (IL-1) activity, and adjuvant activity. HD-LE could be classified into three groups: 1) HD-LE 0 h (MW 800000) which activated all of the biological activities tested, 2) HD-LE 0.5 and 3 h (MW 250000 and 21000) which lacked or exhibited low levels of activities such as activation of alternative complement pathway and lysosomal enzyme secretion, 3) HD-LE 6 h (MW 6400) which only activated glucose consumption and synthesis of lysosomal enzyme. These results suggest that an antitumor glucan is not always a multiple enhancer of host defense mechanisms and that a large molecular weight is required to augment multiple immunological activities.