Sepsis-induced modulation of long-term potentiation induced by theta burst stimulation in the rat hippocampus.

We investigated the influences of sepsis on central synaptic plasticity in vitro. Cecal ligation and puncture (CLP) was performed by creating rat sepsis models, which were divided into early and late sepsis groups (8 and 16 h after CLP, respectively). In the CA1 of the rat hippocampal slices, orthodromically elicited population spikes (PSs) and field excitatory postsynaptic potentials (fEPSPs) were simultaneously recorded, and their long-term potentiation (LTP) was induced by theta burst stimulation (TBS). TBS induced LTPs of PSs and fEPSPs in all groups. In the sham and early sepsis groups, there was no significant difference in LTPs between PSs and fEPSPs. However, in the late sepsis group, the LTP of PSs was greater than that of fEPSPs (p < 0.05) and was greater than the LTPs of PSs in the sham and early sepsis groups (p < 0.05). Superoxide dismutase, administered immediately before CLP, inhibited the enhancement of LTP in PS, as observed in the late sepsis group. The initial rapid potentiation component of LTP in fEPSPs was suppressed or reduced in all groups that underwent CLP. The results indicate that CLP-induced sepsis modulates hippocampal synaptic plasticity, depressing excitatory synaptic transmissions and facilitating somatic excitability, which is induced by septic oxygen superoxide.

The lesion site of organophosphorus-induced central apnea and the effects of antidotes.

Organophosphorus poisoning kills individuals by causing central apnea; however, the underlying cause of death remains unclear. Following findings that the pre-Bötzinger complex impairment alone does not account for central apnea, we analyzed the effect of paraoxon on the brainstem-spinal cord preparation, spanning the lower medulla oblongata to phrenic nucleus. Respiratory bursts were recorded by connecting electrodes to the ventral 4th cervical nerve root of excised brainstem-spinal cord preparations obtained from 6-day-old Sprague-Dawley rats. We observed changes in respiratory bursts when paraoxon, neostigmine, atropine, and 2-pyridine aldoxime methiodide were administered via bath application. The percentage of burst extinction in the paraoxon-poisoning group was 50% compared with 0% and 18.2% in the atropine and 2-pyridine aldoxime methiodide treatment groups, respectively. Both treatments notably mitigated the paraoxon-induced reduction in respiratory bursts. In the neostigmine group, similar to paraoxon, bursts stopped in 66.7% of cases but were fully reversed by atropine. This indicates that the primary cause of central apnea is muscarinic receptor-mediated in response to acetylcholine excess. Paraoxon-induced central apnea is hypothesized to result from neural abnormalities within the inferior medulla oblongata to the phrenic nucleus, excluding pre-Bötzinger complex. These antidotes antagonize central apnea, suggesting that they may be beneficial therapeutic agents.

Dexmedetomidine improves excessive extracellular glutamate-induced synaptic depression (BRAINRES-D-21-00941).

We investigated the effects of dexmedetomidine, a selective α2-adrenergic agonist and a sedative, on excessive glutamate-induced depressions of central excitatory synaptic transmissions in vitro. From the CA1 in rat hippocampal slices, orthodromically elicited population spikes (PSs) and field excitatory postsynaptic potentials (fEPSPs) at 0.1 Hz were simultaneously recorded. ANOVA was used for statistics, and p < 0.05 was accepted as significant. Glutamate (10 mM for 10 min) completely depressed PSs and fEPSPs, which were partially recovered by the following washout for 40 min (57.4 ± 10.2% and 59.9 ± 9.8% of the control, respectively, p < 0.01, n = 6). The recoveries in PSs and fEPSPs were improved by pre-treatment and simultaneous treatment with dexmedetomidine (p < 0.01, n = 6) but were not altered by post-treatment. Dexmedetomidine alone did not alter PSs and fEPSPs. Simultaneous treatment with isoproterenol or dobutamine exacerbated the recoveries in PSs and fEPSPs (p < 0.01, n = 6), but simultaneous treatment with salbutamol, propranolol, phenylephrine or phentramine did not influence the recoveries. Simultaneous treatment with AP5 improved the recoveries in PSs and fEPSPs that were depressed by glutamate alone and by glutamate with dexmedetomidine, isoproterenol or dobutamine (p < 0.01, n = 6). Excessive glutamate depresses glutamatergic excitatory synaptic transmissions by mainly mediating NMDA receptors, and the depressed transmissions are improved by α2-adrenoceptor stimulation but are exacerbated by ß1-adrenoceptor stimulation. Dexmedetomidine has a protective effect on neuronal dysfunctions induced by excessive glutamate, which is one of the main mechanisms of the secondary damage in the central nervous system.

Successful diagnosis and treatment of pulmonary aspergillosis-related malignant catatonia using propofol and quetiapine: A case report.

INTRODUCTION: Malignant catatonia (MC) is a movement disorder syndrome characterized by immobility, rigidity, and consciousness disorders that develops in association with mental and physical diseases. It is often fatal due to hyperthermia, rhabdomyolysis, and acute kidney injury. Its clinical symptoms are similar to those of another disorder, neuroleptic malignant syndrome (NMS), and it is often difficult to distinguish between the 2 disorders. PATIENT CONCERNS: An Asian woman in her 60s with history of schizophrenia. She was admitted to our hospital because of symptoms such as fever, unconsciousness, and muscle rigidity. Blood tests showed kidney injury and high creatinine kinase levels. DIAGNOSES: At the time of admission, she had been diagnosed with NMS complicated by pulmonary aspergillosis and was undergoing treatment although there was no improvement. INTERVENTIONS: Subsequently, the administration of propofol, a gamma-aminobutyric acid A agonist, markedly improved the symptoms, and the diagnosis was corrected to MC. At the beginning of her hospitalization, she received dantrolene, bromocriptine, amantadine, and L-3,4-dihydroxyphenylalanine as treatment for NMS, but her symptoms did not improve. With propofol, which is used for sedation, her catatonic symptoms improved markedly. Quetiapine administration further improved the symptoms, and it eventually resolved completely. OUTCOMES: The patient's MC was in remission. Prolonged intensive care management resulted in a decline in activities of daily living, and she required rehabilitation at another hospital. CONCLUSION: This is the first report of MC with suspected involvement of pulmonary aspergillosis. MC differs from NMS, in that it is treated more effectively with gamma-aminobutyric acid A agonists. Although benzodiazepines are the first choice for the diagnosis and treatment of MC, they are ineffective for majority of patients with schizophrenia. However, even in such cases, propofol and quetiapine are effective, and they facilitate diagnosis and treatment.

Pathophysiologic Mechanisms of Hypothermia-Induced Pancreatic Injury in a Rat Model of Body Surface Cooling.

OBJECTIVE: The mechanisms underlying hypothermia-induced pancreatic injury are unclear. Thus, we investigated the pathophysiology of hypothermia-induced pancreatic injury. METHODS: We created a normal circulatory model with body surface cooling in rats. We divided the rats into control (36°C-38°C), mild hypothermia (33°C-35°C), moderate hypothermia (30°C-32°C), and severe hypothermia (27°C-29°C) (n = 5 per group) groups. Then, we induced circulatory failure with a cooling model using high-dose inhalation anesthesia and divided the rats into control (36°C-38°C) and severe hypothermia (27°C-29°C) (n = 5 per group) groups. Serum samples were collected before the introduction of hypothermia. Serum and pancreatic tissue were collected after maintaining the target body temperature for 1 hour. RESULTS: Hematoxylin and eosin staining of the pancreas revealed vacuoles and edema in the hypothermia group. Serum amylase (P = 0.056), lactic acid (P < 0.05), interleukin 1ß (P < 0.05), interleukin 6 (P < 0.05), and tumor necrosis factor α (P = 0.13) levels were suppressed by hypothermia. The circulatory failure model exhibited pancreatic injury. CONCLUSIONS: Hypothermia induced bilateral effects on the pancreas. Morphologically, hypothermia induced pancreatic injury based on characteristic pathology typified by vacuoles. Serologically, hypothermia induced protective effects on the pancreas by suppressing amylase and inflammatory cytokine levels.

Non-surgical treatment of tetanus infection associated with breast cancer skin ulcer: a case report and literature review.

BACKGROUND: Previous studies have reported poor prognosis in cases of tetanus that develops after bacteria enters via breast cancer-related skin ulcers that are not treated with surgical debridement. Herein, we review the literature concerning this presentation and report the first case of complete remission from tetanus without surgical debridement of the skin ulcer. CASE PRESENTATION: An Asian woman aged over 60 years had a history of skin ulcer caused by breast cancer. She was diagnosed with tetanus due to trismus and opisthotonus. Based on the suspicion that the skin ulcer was the portal of entry for tetanus bacteria, we considered several debridement and thoracic surgical options for tetanus treatment. However, debridement was not performed as the surgery was considered high risk and the patient did not consent to it. The patient received treatment with anti-tetanus globulin and metronidazole; sound insulation and shielding were also performed in a dark room. Subsequently, the patient's symptoms improved, and sound insulation and deep sedation management were completed on 19th day of hospitalization. With no symptom recurrence, the patient was discharged on Day 54. To date, over 3 years after treatment, no evidence of tetanus recurrence has been observed. The case was characterized by a lack of autonomic hyperactivity. The tetanus severity was likely representative of the low amount of toxin that the patient was exposed to. CONCLUSION: This case involved moderate severity tetanus originating from a chronic skin ulcer related to breast cancer. The patient survived without undergoing extensive debridement. No evidence of tetanus relapse was observed during the follow-up period, likely due to vaccination that might have restored the patient's active immunity. Debridement is not always necessary for tetanus complicated by breast cancer skin ulcers. Furthermore, appropriate toxoid vaccination is critical for preventing the onset and recurrence of tetanus in these patients.

Mechanism of central hypopnoea induced by organic phosphorus poisoning.

Whether central apnoea or hypopnoea can be induced by organophosphorus poisoning remains unknown to date. By using the acute brainstem slice method and multi-electrode array system, we established a paraoxon (a typical acetylcholinesterase inhibitor) poisoning model to investigate the time-dependent changes in respiratory burst amplitudes of the pre-Bötzinger complex (respiratory rhythm generator). We then determined whether pralidoxime or atropine, which are antidotes of paraoxon, could counteract the effects of paraoxon. Herein, we showed that paraoxon significantly decreased the respiratory burst amplitude of the pre-Bötzinger complex (p < 0.05). Moreover, pralidoxime and atropine could suppress the decrease in amplitude by paraoxon (p < 0.05). Paraoxon directly impaired the pre-Bötzinger complex, and the findings implied that this impairment caused central apnoea or hypopnoea. Pralidoxime and atropine could therapeutically attenuate the impairment. This study is the first to prove the usefulness of the multi-electrode array method for electrophysiological and toxicological studies in the mammalian brainstem.

Usefulness of venoarterial extracorporeal membranous oxygenation for fatal cibenzoline succinate poisoning.

BACKGROUND: The effect of venoarterial extracorporeal membranous oxygenation (V-A ECMO), plasma exchange (PE), and direct hemoperfusion (DHP) for fatal cibenzoline succinate poisoning is unclear. We report a rare case of severe cibenzoline succinate poisoning along with cardiac arrest, wherein the patient was managed with V-A ECMO, PE, and DHP. We also measured the blood levels of cibenzoline succinate frequently. CASE PRESENTATION: A 51-year-old woman had a refractory cardiac arrest after cibenzoline succinate ingestion. We initiated V-A ECMO, PE, and DHP. Plasma exchange did not improve clinical manifestations. Her clinical condition improved during DHP, but there was no evidence about removal of drugs. On day 3, DHP and ECMO were terminated. On day 9, she was transferred to another hospital without arrhythmia recurrence. CONCLUSION: Venoarterial ECMO is effective in cases of cibenzoline succinate poisoning-related cardiac dysfunction or cardiac arrest. No evidence was obtained for the effects of PE and DHP.

Risk factors for acute pancreatitis in patients with accidental hypothermia.

BACKGROUND: Pancreatic damage is commonly observed as a consequence of accidental hypothermia (core body temperature below 35 °C). We aimed to investigate the risk factors for pancreatic damage and the causal relationship in patients with accidental hypothermia. METHODS: This retrospective, single-center, observational case-control study was conducted in the emergency department of a tertiary care medical center. We investigated patients who were admitted for accidental hypothermia over a course of ten years (January 2008 to December 2017). RESULTS: Of the 138 enrolled patients, 70 had elevated serum amylase levels (51%). We observed a correlation between initial core body temperature and serum amylase level (Spearman's rank correlation coefficient -0.302, p < 0.001). Patients who developed acute pancreatitis had a significantly lower initial core body temperature than those who did not develop it (odds ratio = 0.76; 95% confidence interval [CI] = 0.61-0.94; p = 0.011). Receiver operating characteristic analysis showed that a body temperature lower than 28.5 °C at the time of visit was predictive of acute pancreatitis (area under the curve = 0.71, 95% CI = 0.54-0.88, sensitivity = 0.67, specificity = 0.69, p = 0.017). CONCLUSIONS: We concluded that an initial core body temperature lower than 28.5 °C was a risk factor for acute pancreatitis in accidental hypothermia cases. In such situations, careful follow-up is necessary.

Insulin-like growth factor I enhances the expression of aromatase P450 by inhibiting autophagy.

Aromatase, a key enzyme of estrogen biosynthesis, is transcriptionally regulated by many growth factors. IGF-I enhances aromatase activity in a variety of cells, but the mechanism of action has not been determined. We herein report our finding of a novel mechanism of action for IGF-I. IGF-I enhanced the dexamethasone (DEX)-induced aromatase activity by 30% in serum-starved THP-1 cells. The increase was associated with a corresponding increase in the level of aromatase protein but not with any change in the mRNA level. Metabolic labeling experiments revealed that IGF-I inhibited the degradation of aromatase. We identified pepstatin A as the most effective inhibitor of aromatase degradation by in vitro assay. Using a nontoxic concentration of pepstatin A, we examined IGF-I's action on aromatase distribution in microsomes and lysosomes. In the presence of pepstatin A, DEX caused an increase in the amount of aromatase in both microsomes and lysosomes, and IGF-I attenuated the DEX-induced accumulation of aromatase in lysosomes and, conversely, enhanced its accumulation in the microsomes. The addition of serum abolished the IGF-I-induced changes. The transport from microsome to lysosome was fluorescently traced in cells using a recombinant aromatase. IGF-I selectively reduced the aromatase signal in the lysosomes. Finally, we observed that IGF-I enhanced the aromatase activity by 50% as early as 1 h after treatment; furthermore, rapamycin, an enhancer of autophagy, completely negated the effect of IGF-I on the enzyme. These results indicate that IGF-I enhances aromatase by the inhibition of autophagy.

Small primary adenocarcinoma in adenomyosis with nodal metastasis: a case report.

BACKGROUND: Malignant transformation of adenomyosis is a very rare event. Only about 30 cases of this occurrence have been documented till now. CASE PRESENTATION: The patient was a 57-year-old woman with a slightly enlarged uterus, who underwent total hysterectomy and unilateral adnexectomy. On gross inspection, the uterine wall displayed a single nodule measuring 5 cm and several small gelatinous lesions. Microscopic examination revealed a common leiomyoma and multiple adenomyotic foci. A few of these glands were transformed into a moderately differentiated adenocarcinoma. The endometrium was completely examined and tumor free. The carcinoma was, therefore, considered to be an endometrioid adenocarcinoma arising from adenomyosis. Four months later, an ultrasound scan revealed enlarged pelvic lymph nodes: a cytological diagnosis of metastatic adenocarcinoma was made. Immunohistochemical studies showed an enhanced positivity of the tumor site together with the neighbouring adenomyotic foci for estrogen receptors, aromatase, p53 and COX-2 expression when compared to the distant adenomyotic glands and the endometrium. We therefore postulate that the neoplastic transformation of adenomyosis implies an early carcinogenic event involving p53 and COX-2; further tumor growth is sustained by an autocrine-paracrine loop, based on a modulation of hormone receptors as well as aromatase and COX-2 local expression. CONCLUSION: Adenocarcinoma in adenomyosis may be affected by local hormonal influence and, despite its small size, may metastasize.

Danazol inhibits aromatase activity of endometriosis-derived stromal cells by a competitive mechanism.

OBJECTIVE: To evaluate the inhibitory effect of danazol on estrogen (E) production in endometriosis. DESIGN: Prospective randomized study. SETTING: Academic research unit of the department of obstetrics and gynecology in a university hospital. PATIENT(S): Thirteen patients with endometriosis. INTERVENTION(S): Danazol was added to the culture of endometriosis-derived stromal cells or suspensions of microsomes prepared from chocolate cysts. MAIN OUTCOME MEASURE(S): The aromatase activities as well as mRNA and protein levels of aromatase in endometriosis-derived stromal cells or microsomes of endometriosis were examined. RESULT(S): Danazol treatment with a concentration greater than 10(-6) M significantly suppressed aromatase activity of endometriosis-derived stromal cells under basal and prostaglandin E(2) (PGE(2))-stimulated conditions. Danazol (10(-5) M) did not affect mRNA and protein levels of aromatase. Danazol competitively inhibited aromatase activity (by 1.7 x 10(-6) M of calculated Ki and 2.9 x 10(-5) M of Ki') of endometriosis microsomes. CONCLUSION(S): Danazol competitively inhibited aromatase activity in endometriosis-derived stromal cells without affecting either the mRNA or protein levels of aromatase. These results indicate the efficacy of local application of danazol to endometriotic lesions.

Local application of danazol-loaded hyaluronic acid hydrogel to endometriosis in a rat model.

OBJECTIVE: To evaluate the efficacy of a drug delivery system composed of danazol-loaded hyaluronic acid for local application to endometriosis. DESIGN: Prospective, randomized study. SETTING: Academic research unit of the department of obstetrics and gynecology in a university hospital. PATIENT(S): Adult female Sprague-Dawley rats. INTERVENTION(S): Danazol-loaded hyaluronic acid hydrogel (DZ-HA gel) was injected into the rat endometriosis model. MAIN OUTCOME MEASURE(S): Size and histological changes in experimental endometriosis, the concentration of danazol in the cyst wall and plasma, and estrous cycles were examined. RESULT(S): Histologically, DZ-HA gel-treated cysts displayed marked atrophy of the endometrial epithelium. Increased numbers of apoptotic cells and decreased numbers of proliferative cells were noted with 10 mg/mL DZ-HA gel. Size of treated cysts decreased to approximately 60% at 9 weeks after injection. The estrous cycles were not disturbed during DZ-HA gel treatment. CONCLUSION(S): Local injection of DZ-HA gel achieved endometrial atrophy of an experimental model of endometriosis without disturbing the sexual cycle. These results suggest that local application of DZ using this drug delivery system may prove useful for treating endometriosis.

Aromatase expression in stromal cells of endometrioid endometrial cancer correlates with poor survival.

PURPOSE AND EXPERIMENTAL DESIGN: To assess the prognostic significance of intratumoral aromatase in endometrioid endometrial cancer, sections from 55 patients with endometrial cancer were evaluated for expression of aromatase using immunohistochemistry, and the correlation between aromatase expression and clinicopathologic parameters were analyzed. RESULTS: Immunohistochemical staining for aromatase was positive for 32 (58%), 20 (36%), and 19 (34%) patients in cancer epithelial cells, stromal cells, and myometrial cells around the flank invasion, respectively. In situ hybridization also detected aromatase mRNA in all three types of cells. RT-PCR analysis revealed that aromatase mRNA was 2.5 +/- 1.0 amol/mug total RNA (mean +/- SE; n = 7) in tumor tissue. Western blot analysis detected the expected aromatase protein size of 58 kDa in cancer tissues more abundantly than in cancer-free endometrium (n = 3). The immunoreactivity in stromal cells correlated positively with advanced surgical stage and poor survival. Survival analysis revealed that the immunoreactivity of stromal cells was a significant prognostic factor, independent of histologic grade, muscular invasion, and lymph node metastasis, but dependent on surgical stage. By contrast, the immunoreactivity of aromatase both in cancer epithelial cells and myometrial cells did not correlate with prognosis. CONCLUSIONS: To the best of our knowledge, this is the first evidence associating intratumoral aromatase expression in stromal cells and poor survival in endometrioid endometrial cancer. This positive linkage indicates that local expression of aromatase plays a role in tumor progression through the formation of in situ estrogens. In situ expression of aromatase may offer a potential target for management of endometrial cancers.

Increased expression of type I 17beta-hydroxysteroid dehydrogenase enhances in situ production of estradiol in uterine leiomyoma.

Expression of 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) was compared between leiomyoma and myometrium. Cytosolic fractions from leiomyoma homogenate displayed 5-fold higher activity (estrone to estradiol), compared with surrounding myometrium (n = 6, P < 0.05), whereas microsomal fractions showed no difference. Oxidative activity (estradiol to estrone) did not differ between leiomyoma and myometrium. Levels of mRNA for 17beta-HSDs were then measured using real-time PCR techniques. Among the eight different types of 17beta-HSDs (types 1-5, 7, 8, and 10), type 1 was the only enzyme displaying differential expression between leiomyoma and myometrium. Mean concentration of type 1 17beta-HSD mRNA was 4-fold higher in leiomyoma than in surrounding myometrium (n = 20, P < 0.05). Type 1 transcript levels correlated significantly with reductive activity in individual samples (n = 6, P < 0.05). Northern blot analysis of leiomyoma and myometrium tissues detected 2.3- and 1.0-kb transcripts of type 1 enzyme, whereas the major 1.3-kb transcript for 17beta-HSD in placenta-derived JEG-3 cells was not detected. None of the factors increasing mRNA levels for type 1 enzyme in placenta increased mRNA levels in leiomyoma. These results indicate that leiomyoma tissues overexpress type 1 17beta-HSD, resulting in high conversion of estrone to estradiol. In situ expression of type 1 17beta-HSD may play a role in self-supported growth of leiomyoma cells.

Lactobacillus kitasatonis sp. nov., from chicken intestine.

Four strains isolated from chicken small intestine and strains JCM 1038 and JCM 1039 (designated as Lactobacillus acidophilus) were characterized by phenotypic and molecular taxonomic methods. They were Gram-positive, catalase-negative, facultatively anaerobic rods that did not produce gas from glucose. These strains had similar phenotypic characteristics and exhibited intergroup DNA relatedness values of >77 %, indicating that they comprised a single species. The 16S rRNA gene sequence of a representative strain, JCM 1039(T) (designated as type strain in this study), was determined and aligned with those of other Lactobacillus species. JCM 1039(T) was placed in the Lactobacillus delbrueckii cluster of the genus Lactobacillus on the basis of phylogenetic analysis and formed an independent cluster that was distinct from its closest neighbours, Lactobacillus amylovorus, Lactobacillus crispatus, Lactobacillus gallinarum, L. acidophilus and Lactobacillus helveticus. Results of DNA-DNA hybridization experiments and whole-cell protein profiles clearly indicated that these strains represent a novel Lactobacillus species, for which the name Lactobacillus kitasatonis sp. nov. is proposed; the type strain of this species is JCM 1039(T).