Inhibition of RhoA reduces propofol-mediated growth cone collapse, axonal transport impairment, loss of synaptic connectivity, and behavioural deficits.

BACKGROUND: Exposure of the developing brain to propofol results in cognitive deficits. Recent data suggest that inhibition of neuronal apoptosis does not prevent cognitive defects, suggesting mechanisms other than neuronal apoptosis play a role in anaesthetic neurotoxicity. Proper neuronal growth during development is dependent upon growth cone morphology and axonal transport. Propofol modulates actin dynamics in developing neurones, causes RhoA-dependent depolymerisation of actin, and reduces dendritic spines and synapses. We hypothesised that RhoA inhibition prevents synaptic loss and subsequent cognitive deficits. The present study tested whether RhoA inhibition with the botulinum toxin C3 (TAT-C3) prevents propofol-induced synapse and neurite loss, and preserves cognitive function. METHODS: RhoA activation, growth cone morphology, and axonal transport were measured in neonatal rat neurones (5-7 days in vitro) exposed to propofol. Synapse counts (electron microscopy), dendritic arborisation (Golgi-Cox), and network connectivity were measured in mice (age 28 days) previously exposed to propofol at postnatal day 5-7. Memory was assessed in adult mice (age 3 months) previously exposed to propofol at postnatal day 5-7. RESULTS: Propofol increased RhoA activation, collapsed growth cones, and impaired retrograde axonal transport of quantum dot-labelled brain-derived neurotrophic factor, all of which were prevented with TAT-C3. Adult mice previously treated with propofol had decreased numbers of total hippocampal synapses and presynaptic vesicles, reduced hippocampal dendritic arborisation, and infrapyramidal mossy fibres. These mice also exhibited decreased hippocampal-dependent contextual fear memory recall. All anatomical and behavioural changes were prevented with TAT-C3 pre-treatment. CONCLUSION: Inhibition of RhoA prevents propofol-mediated hippocampal neurotoxicity and associated cognitive deficits.

Effects of deep sedation under mechanical ventilation on cognitive outcome in patients undergoing surgery for oral and maxillofacial cancer and microvascular reconstruction.

OBJECTIVE: Cognitive impairment after intensive care unit (ICU) admission is becoming increasingly recognized. High-dose deep sedation has been suggested to play an important role in the development of cognitive impairment. However, the impact of heavy sedation as a single cause in the development of cognitive impairment in ICU patients remains unclear. In this study we investigated whether a three-day deep sedation protocol could reduce cognitive function in mechanically ventilated non-critical patients. DESIGN: A prospective observational study was carried out. PATIENTS: A total of 17 surgical patients were studied. INTERVENTION: None. VARIABLES OF INTEREST: Cognitive function before and after ICU admission. RESULTS: Thirty-one patients requiring three days of sedation after microvascular reconstruction were initially enrolled in the study. Sedation in the ICU was maintained with propofol and dexmedetomidine combined with fentanyl. Cognitive function was assessed using a battery of 6 neuropsychological tests two days before surgery and three weeks after surgery. Finally, a total of 17 patients were included in the analysis. Cognitive impairment (defined as a decline of >20% from the pre-admission cognitive evaluation scores in at least two of 6 tests) was observed in 5 of the 17 patients (29%). However, there were no significant differences between the pre- and post-admission cognitive evaluations in 6 tests. CONCLUSIONS: Middle-term cognitive function can be impaired in some patients subjected to deep sedation during several days following maxillary-mandibular oral surgery with microvascular reconstruction.

Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders.

CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.

[Fundamental and clinical studies on T-1982 (cefbuperazone) in the field of obstetrics and gynecology].

T-1982 (cefbuperazone), a new cephamycin antibiotic, was fundamentally and clinically studied in the field of obstetrics and gynecology. The following results were obtained. The concentrations of T-1982 in arterial and venous blood and genitalia following intravenous injection were measured. The results demonstrated favourable transfer of the drug into various internal genital organs. T-1982 was administered to 12 patients. The efficacy rate was 75.0%, that is to say, good in 9 cases. No side effects were noted in any cases. It is, therefore, presumed that T-1982 is a useful drug for the infectious diseases in the field of obstetrics and gynecology although the number of subjects was not so large in this study.

[Clinical trial of cancer therapy by radiation combined with hyperthermia].

A clinical trial of radiation therapy combined with hyperthermia for various superficial tumors was performed. For the local hyperthermia, heating modalities with microwave, radiofrequency and ultrasound can be used. Some are still insufficient for clinical application in terms of tumor size and site; there fore, for ther studies through a phase II study are necessary to determine a future direction of hyperthermia in clinical case.

[Heat therapy].

Applications of hyperthermia in cancer therapy is now widely studied. Appropriate apparatus for the tumors with various size and positions should be developed. We are developing a system with 2450 MHz microwave and constructed several applicators for the surface tumors and intracavitary tumors. Those were already used in human tumors. Capacitive heating with RF were used for the combined therapy with radiation in Kyoto University. More than 50% of the treated cases were responded well resulting complete regression of tumors. Experimental system of heating with magnetic induction is now studied.

Radiation effects on the fine blood vessels in abdominal organs of mice.

The capillary networks of normal and irradiated abdominal organs of mouse were investigated by a resin cast technique. The structure of the capillary system had characteristic appearances. Radiation effects on the fine vascular structures were demonstrated from one appearances. Radiation effects on the fine vascular structures were demonstrated from one to 30 days after a single dose of 5 to 30 Gy whole body irradiation. Prominent morphologic abnormalities of the shape and distribution of the capillaries were identified, especially in the small intestine.

Vascular structure of experimental tumours. Appearances in scanning electron microscope.

The vascular structure of experimental tumours was investigated by a resin cast technique. Six characteristic types of capillaries were found: club-like, wave-like, tortuous,sinusoid-like, disorderly running and tapering. The vascular structure was correlated to the tumour growth.

Effect of irradiation and chemotherapeutic agents on the capillaries of Ehrlich ascites carcinoma of mice.

The effect of irradiation and chemotherapeutic agents on the capillaries of experimental solid tumours was analysed by the resin cast method. The most evident change of the 5 vascular layers was rarefaction of the newly produced extruding capillaries on the surface of the tumour mass, which was related to the tumour growth.

[Effect of porcine calcitonin on pain caused by cancer-induced bone destruction].

The analgesic effect of porcine calcitonin (PCT) was studied in 32 patients with cancer-induced bone destruction. Twenty patients (62.5%) showed some response among them 10 of 13 patients who had suffered from uncontrollable pain despite other treatment methods such as radiotherapy, and or the administration of other analgesics. The effect was observed about 10 days after the administration of the drug. Combined therapy with PCT and other modalities such as radiotherapy, chemotherapy and hormone therapy had a marked effect in controlling the pain.