Cytomegalovirus infection in patients with malignant lymphomas who have not received hematopoietic stem cell transplantation.

BACKGROUND: Life-threatening cytomegalovirus infection (CMVI) has been reported even in patients with malignant lymphoma (ML) who have not received hematopoietic stem cell transplantation (w/o HSCT) but had been treated with chemotherapy or radiotherapy. However, the CMVI incidence and risk factors (RFs) in patients with ML w/o HSCT have not been fully elucidated. This study aimed to evaluate the clinical aspects, including incidence and RFs, of CMVI in patients with ML w/o HSCT. METHODS: We retrospectively reviewed all patients with ML who received chemotherapy or radiotherapy in our department from 2005 to 2013. The overall survival (OS), incidence and RFs of CMVI, and other characteristics of patients with CMVI were analyzed. RESULTS: Overall, 236 patients with ML w/o HSCT were evaluated. Of these, 5.5% (13/236) developed CMVI; 54% (7/13) received steroid pretreatment before primary therapy (PT) for ML; and 62% (8/13) received > 2 therapeutic regimens for ML. The OS curve of patients with CMVI was significantly worse than that of patients without CMVI (p < 0.0001, log-rank test). A univariate analysis identified B symptoms (p = 0.00321), serum albumin < 3.5 g/dL (p = 0.0007837), C-reactive protein level > the upper limit of normal (p = 0.0006962), steroid pretreatment before PT for ML (p = 0.0004262), > 2 therapeutic regimens for ML (p = 0.0000818), T cell lymphoma (p = 0.006406), and non-complete remission (p = 0.02311) as RFs for CMVI. A multivariate analysis identified steroid pretreatment before PT for ML [odds ratio (OR): 4.71 (95% confidence interval [CI]: 1.06-21.0); p = 0.0419] and > 2 therapeutic regimens for ML [OR: 9.25 (95% CI: 2.33-36.8); p = 0.00159] as independent RFs for CMVI in patients with ML w/o HSCT. CONCLUSIONS: Attention should be paid to CMVI development in patients with ML w/o HSCT pretreated with steroids or who had multiple therapeutic regimens.

Centrally administered butyrate improves gut barrier function, visceral sensation and septic lethality in rats.

Short chain fatty acids readily crosses the gut-blood and blood-brain barrier and acts centrally to influence neuronal signaling. We hypothesized that butyrate, a short-chain fatty acid produced by bacterial fermentation, in the central nervous system may play a role in the regulation of intestinal functions. Colonic permeability and visceral sensation was evaluated in rats. Septic lethality was evaluated in a sepsis model induced by subcutaneous administration of both lipopolysaccharide and colchicine. Intracisternal butyrate dose-dependently improved colonic hyperpermeability and visceral nociception. In contrast, subcutaneous injection of butyrate failed to change it. Intracisternal orexin 1 receptor antagonist or surgical vagotomy blocked the central butyrate-induced improvement of colonic hyperpermeability. The improvement of intestinal hyperpermeability by central butyrate or intracisternal orexin-A was blocked by cannabinoid 1 or 2 receptor antagonist. Intracisternal butyrate significantly improved survival period in septic rats. These results suggest that butyrate acts in the central nervous system to improve gut permeability and visceral nociception through cannabinoid signaling. Endogenous orexin in the brain may mediate the reduction of intestinal hyperpermeability by central butyrate through the vagus nerve. We would suggest that improvement of leaky gut by central butyrate may induce visceral antinociception and protection from septic lethality.

[A retrospective analysis of risk factors for severity of nosocomial COVID-19 in patients with hematological malignancy].

BACKGROUND: With the global spread of coronavirus disease 2019 (COVID-19), patients with cancer may be at a higher risk of suffering from COVID-19. Although patients with hematological malignancy (HM) are reported to have a higher risk of severe COVID-19 compared with those with solid cancer, the effects of treatment for HM on COVID-19 severity have not been fully elucidated. METHODS: We retrospectively analyzed the risk factors, including number and timing of chemotherapeutic regimens for HM, for COVID-19 severity in 17 patients with HM, who had developed nosocomial COVID-19 in our department, by dividing them into two groups; a severe group (N=7) and a non-severe group (N=10). RESULTS: The overall mortality rate was 47%, and mortality in the severe group was significantly higher than that in the non-severe group (odds ratio [OR], 18.44; 95% confidence interval [CI], 1.27-1223.17, P=0.02). Univariate analysis identified two or more chemotherapeutic regimens for HM (OR, 17.34; 95%CI, 1.15-1165.33, P=0.03) and a low hemoglobin level (P=0.02) as significant risk factors for COVID-19 severity. However, a history of chemotherapy for HM within 3 months prior to the onset of COVID-19 was not a significant risk factor (P=0.54). CONCLUSION: A history of multiple chemotherapeutic regimens in patients with HM may be a risk factor for COVID-19 severity, and physicians should be aware of this.

Brain histamine improves colonic hyperpermeability through the basal forebrain cholinergic neurons, adenosine A2B receptors and vagus nerve in rats.

Intestinal barrier dysfunction, leaky gut, is implicated in various diseases, including irritable bowel syndrome (IBS) and neurodegenerative conditions like Alzheimer's disease. Our recent investigation revealed that basal forebrain cholinergic neurons (BFCNs), critical for cognitive function, receive signals from butyrate and orexin, playing a role in regulating intestinal barrier function through adenosine A2B signaling and the vagus. This study explores the involvement and function of brain histamine, linked to BFCNs, in the regulation of intestinal barrier function. Colonic permeability, assessed by quantifying absorbed Evans blue in rat colonic tissue, showed that histamine did not affect increased colonic permeability induced by LPS when administered subcutaneously. However, intracisternal histamine administration improved colonic hyperpermeability. Elevating endogenous histamine levels in the brain with SKF91488, a histamine N-methyltransferase inhibitor, also improved colonic hyperpermeability. This effect was abolished by intracisternal chlorpheniramine, an histamine H1 receptor antagonist, not ranitidine, an H2 receptor antagonist. The SKF91488-induced improvement in colonic hyperpermeability was blocked by vagotomy, intracisternal pirenzepine (suppressing BFCNs activity), or alloxazine (an adenosine A2B receptor antagonist). Additionally, intracisternal chlorpheniramine injection eliminated butyrate-induced improvement in colonic hyperpermeability. These findings suggest that brain histamine, acting via the histamine H1 receptor, regulates intestinal barrier function involving BFCNs, adenosine A2B signaling, and the vagus. Brain histamine appears to centrally regulate intestinal barrier function influenced by butyrate, differentiating its actions from peripheral histamine in conditions like IBS, where mast cell-derived histamine induces leaky gut. Brain histamine emerges as a potential pharmacological target for diseases associated with leaky gut, such as dementia and IBS.

Ghrelin prevents lethality in a rat endotoxemic model through central effects on the vagal pathway and adenosine A2B signaling : Brain ghrelin and anti-septic action.

Accumulating evidence suggest that ghrelin plays a role as an antiseptic peptide. The present study aimed to clarify whether the brain may be implicated ghrelin's antiseptic action. We examined the effect of brain ghrelin on survival in a novel endotoxemic model achieved by treating rats with lipopolysaccharide (LPS) and colchicine. The observation of survival stopped three days after chemicals' injection or at death. Intracisternal ghrelin dose-dependently reduced lethality in the endotoxemic model; meanwhile, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin injection affected the mortality rate. The brain ghrelin-induced lethality reduction was significantly blocked by surgical vagotomy. Moreover, intracisternal injection of a ghrelin receptor antagonist blocked the improved survival achieved by intracisternal ghrelin injection or intravenous 2-deoxy-d-glucose administration. Intracisternal injection of an adenosine A2B receptor agonist reduced the lethality and the ghrelin-induced improvement of survival was blocked by adenosine A2B receptor antagonist. I addition, intracisternal ghrelin significantly blocked the colonic hyperpermeability produced by LPS and colchicine. These results suggest that ghrelin acts centrally to reduce endotoxemic lethality. Accordingly, activation of the vagal pathway and adenosine A2B receptors in the brain may be implicated in the ghrelin-induced increased survival. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the decreased septic lethality caused by brain ghrelin.

Centrally administered GLP-1 analogue improves intestinal barrier function through the brain orexin and the vagal pathway in rats.

Leaky gut, an altered intestinal barrier function, has been described in many diseases such as irritable bowel syndrome (IBS). We have recently demonstrated that orexin in the brain blocked leaky gut in rats, suggesting that the brain plays a role in regulation of intestinal barrier function. In the present study, we tried to clarify whether GLP-1 acts centrally in the brain to regulate intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of GLP-1 analogue, liraglutide dose-dependently abolished increased colonic permeability in response to lipopolysaccharide. Either atropine or surgical vagotomy blocked the central GLP-1-induced improvement of colonic hyperpermeability. Intracisternal GLP-1 receptor antagonist, exendin (9-39) prevented the central GLP-1-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of orexin receptor antagonist, SB-334867 blocked the GLP-1-induced improvement of intestinal barrier function. On the other hand, subcutaneous liraglutide also improved leaky gut but larger doses of liraglutide were needed to block it. In addition, neither atropine nor vagotomy blocked subcutaneous liraglutide-induced improvement of leaky gut, suggesting that central or peripheral GLP-1 system works separately to improve leaky gut in a vagal-dependent or independent manner, respectively. These results suggest that GLP-1 acts centrally in the brain to reduce colonic hyperpermeability. Brain orexin signaling and the vagal cholinergic pathway play a vital role in the process. We would therefore suggest that activation of central GLP-1 signaling may be useful for leaky gut-related diseases such as IBS.

[Fungal dacryocystitis with cacosmia after penetrating keratoplasty--taxonomy and identification of pathogenic fungi based on DNA sequence analysis].

CASE: A 76-year-old woman with a history of penetrating keratoplasty had cacosmia associated with dacryocystitis. Two species of yeast-like fungi were isolated from the contents of her lacrimal sac. Each cultured fungus had a unique, distinctive odor. Althogh treated with an oral antifungal agent and washing of the nasolacrimal duct, the cacosmia was not improved. The continuous dacryocystitis with cacosmia was treated by dacryocystectomy. Two yeast-like fungi were again isolated from the contents of the lacrimal sac. Pathological examination confirmed a diagnosis of fungal dacryocystitis based on the fungal hyphae observed on the excised lacrimal sac wall. The cacosmia promptly disappeared. The fungi isolated from the contents of lacrimal sac were identified by DNA sequencing as Wickerhamomyces anamalus (Pichia anomala-Candida pelliculosa) and Galactomyces geotrichum (Geotrichum candidum). CONCLUSION: The cause of cacosmia in the present case was fungal dacryocystitis. Antibiotic eye drops and steroid eye drops for the treatment of penetrating keratoplasty can cause atypical fungal presentation in the inconsistently treated lacrimal system and can induce dacryocystitis. Careful usage and consideration is necessary in the long-term use of antibiotics and steroids following corneal transplantation.

Clinical outcomes of coronavirus disease 2019 and seasonal influenza in patients with hematological disorders: a retrospective study.

Objective: The differences in clinical outcomes in hospitalized patients with hematological disorders (HD) who developed either coronavirus disease 2019 (COVID-19) or seasonal influenza (SI) are not fully understood. To examine these differences, we retrospectively analyzed the baseline characteristics and clinical outcomes of hospitalized patients with HD admitted from 2016 to 2021. Patients and Methods: Patients with HD who developed COVID-19 (in the past 1 year) (n=21) or SI (in the past 5 years) (n=23) in the Department of Hematology/Oncology, Asahikawa Kosei General Hospital were evaluated. Results: The median ages of the patients with HD with either COVID-19 or SI were 80 and 68 years, respectively (P=0.03). The groups showed no significant differences in sex ratio, body mass index, or Eastern Cooperative Oncology Group performance status. In the COVID-19 and SI groups, the most common primary diseases were diffuse large B-cell lymphoma (43%) and multiple myeloma (39%), respectively. The median numbers of days of oxygen administration (8 vs. 0 days), quarantine (25 vs. 6 days), and hospitalization (72 vs. 21 days) were significantly higher in HD patients with COVID-19 than those in HD patients with SI (all P<0.001). The overall 90-day survival of patients with HD and COVID-19 was significantly shorter than that of patients with HD and SI (P=0.019). Moreover, patients with HD and COVID-19 had a higher risk of in-hospital mortality (43% vs. 9%; odds ratio, 7.50; 95% confidence interval, 1.26-82.4; P=0.01) compared to patients with HD and SI. Conclusion: Patients with HD and COVID-19 required longer periods of in-hospital medical and showed poorer survival than those with SI. During the COVID-19 pandemic, hematologists should closely monitor the condition of patients with COVID-19 to closely monitor their condition to prevent deaths.

Oxytocin acts centrally in the brain to improve leaky gut through the vagus nerve and a cannabinoid signaling in rats.

Brain oxytocin plays a role in gastrointestinal functions. Among them, oxytocin acts centrally to modulate gastrointestinal motility and visceral sensation. Intestinal barrier function, one of important gut functions, is also regulated by the central nervous system. Little is, however, known about a role of central oxytocin in the regulation of intestinal barrier function. The present study was performed to clarify whether brain oxytocin is also involved in regulation of intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of oxytocin dose-dependently abolished increased colonic permeability in response to lipopolysaccharide while intraperitoneal injection of oxytocin at the same dose failed to block it. Either atropine or surgical vagotomy blocked the central oxytocin-induced improvement of colonic hyperpermeability. Cannabinoid 1 receptor antagonist but not adenosine or opioid receptor antagonist prevented the central oxytocin-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of oxytocin receptor antagonist blocked the ghrelin- or orexin-induced improvement of intestinal barrier function. These results suggest that oxytocin acts centrally in the brain to reduce colonic hyperpermeability. The vagal cholinergic pathway or cannabinoid 1 receptor signaling plays a vital role in the process. The oxytocin-induced improvement of colonic hyperpermeability mediates the central ghrelin- or orexin-induced improvement of intestinal barrier function. We would therefore suggest that activation of central oxytocin signaling may be useful for leaky gut-related diseases such as irritable bowel syndrome and autism.

Activation of basal forebrain cholinergic neurons improves colonic hyperpermeability through the vagus nerve and adenosine A2B receptors in rats.

Intestinal barrier dysfunction, a leaky gut, contributes to the pathophysiology of various diseases such as dementia and irritable bowel syndrome (IBS). We recently clarified that orexin, ghrelin, or adenosine A2B signaling in the brain improved leaky gut through the vagus nerve. The present study was performed to clarify whether basal forebrain cholinergic neurons (BFCNs) are implicated in the central regulation of intestinal barrier function. We activated BFCNs using benzyl quinolone carboxylic acid (BQCA), a positive muscarinic M1 allosteric modulator, and evaluated colonic permeability by quantifying the absorbed Evans blue in rat colonic tissue. Intracisternal (not intraperitoneal) injection of BQCA blocked the increased colonic permeability in response to lipopolysaccharide. Vagotomy blocked BQCA-induced improvement of colonic hyperpermeability. Intracisternally administered pirenzepine, a muscarinic M1 selective antagonist, prevented intestinal barrier function improvement by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Adenosine A2B receptor antagonist but not dopamine or opioid receptor antagonist prevented BQCA-induced blockade of colonic hyperpermeability. Additionally, intracisternal injection of pirenzepine blocked orexin- or butyrate-induced intestinal barrier function improvement. These results suggest that BFCNs improve leaky gut through adenosine A2B signaling and the vagal pathway. Furthermore, BFCNs mediate orexin- or butyrate-induced intestinal barrier function improvement. Since BFCNs play a role in cognitive function and a leaky gut is associated with dementia, the present finding may lead us to speculate that BFCNs are involved in the development of dementia by regulating intestinal barrier function.

Activation of central adenosine A2B receptors mediate brain ghrelin-induced improvement of intestinal barrier function through the vagus nerve in rats.

Leaky gut that is a condition reflecting intestinal barrier dysfunction has been attracting attention for its relations with many diseases such as irritable bowel syndrome or Alzheimer dementia. We have recently demonstrated that ghrelin acts in the brain to improve leaky gut via the vagus nerve. In the present study, we tried to clarify the precise central mechanisms by which ghrelin improves intestinal barrier function through the vagus nerve. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), blocked the intracisternal ghrelin-induced improvement of intestinal hyperpermeability while dopamine, cannabinoid or opioid receptor antagonist failed to prevent it. Since DPCPX can block adenosine A1 and adenosine A2B receptors, we examined which subtype is involved in the mechanism. Intracisternal injection of adenosine A2B agonist but not adenosine A1 agonist improved colonic hyperpermeability, while peripheral injection of adenosine A2B agonist failed to improve it. Intracisternal adenosine A2B agonist-induced improvement of colonic hyperpermeability was blocked by vagotomy. Adenosine A2B specific antagonist, alloxazine blocked the ghrelin- or central vagal stimulation by 2-deoxy-d-glucose-induced improvement of intestinal hyperpermeability. These results suggest that activation of adenosine A2B receptors in the central nervous system is capable of improving intestinal barrier function through the vagal pathway, and the adenosine A2B receptors may mediate the ghrelin-induced improvement of leaky gut in a vagal dependent fashion. These findings may help us understand the pathophysiology in not only gastrointestinal diseases but also non-gastrointestinal diseases associated with the altered intestinal permeability.

Acquired hemophilia A associated with Epstein-Barr-virus-associated T/natural killer-cell lymphoproliferative disease: A case report.

INTRODUCTION: Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII). Hematological malignancies, especially lymphoid malignancies, are known to be underlying causes of AHA; however, thus far, there is no report of AHA associated with Epstein-Barr-virus-associated T/natural killer-cell lymphoproliferative disease (EBV-T/NK-LPD). Here, we present a case of AHA that developed during treatment for EBV-T/NK-LPD. HISTORY: A 69-year-old man visited our hospital because of general fatigue. Blood examination showed pancytopenia, and computed tomography revealed whole-body lymphadenopathy, but there were no findings indicating hematological malignancy from bone marrow aspiration and cervical lymph node biopsy. The level of EBV DNA in peripheral blood was extremely high, and he was diagnosed with EBV-T/NK-LPD. EBV-T/NK-LPD improved with prednisolone (PSL) administration. Seventeen months after starting treatment, the patient complained of back and right leg pain. At that time, he had been treated with low-dose PSL, and EBV-T/NK-LPD was well controlled. Imaging revealed hematoma of the right iliopsoas muscle. Prolonged activated partial thromboplastin time (APTT) was the only abnormal finding in a screening coagulation test. FVIII coagulant activity was below detection limit, and FVIII inhibitor level was increased. From these results, he was diagnosed with AHA.A higher dose of PSL was administered, and, after 1 month of treatment, FVIII activity gradually increased, and FVIII inhibitor level became undetectable. APTT also normalized, and complete remission was achieved and maintained for 13 months with low-dose PSL. During treatment, EBV-T/NK-LPD was well controlled. CONCLUSION: It is speculated that proliferating lymphocytes interfere with normal immune functions and that abnormal autoantibodies are produced from those lymphocytes in patients with LPD. Therefore, we speculate that EBV-infected and proliferating monoclonal NK cells might have modulated the immune system and produced autoantibodies against FVIII, thus causing AHA in this patient with EBV-T/NK-LPD.

Adenosine A1 receptor agonist induces visceral antinociception via 5-HT1A, 5-HT2A, dopamine D1 or cannabinoid CB1 receptors, and the opioid system in the central nervous system.

We have recently demonstrated that N(6)-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, acts centrally to induce a visceral antinociception. Since serotonin (5-HT), cannabinoid (CB), dopamine or opioid signaling in the central nervous system is involved in the regulation of visceral sensation, we made a hypothesis that the signaling may play a role in the CPA-induced visceral antinociception. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously administered CPA significantly increased the threshold of colonic distension-induced AWR. Intracisternal injection of either 5-HT1A or 5-HT2A receptor antagonist blocked the CPA-induced visceral antinociception while 5-HT1B antagonist did not block the CPA-induced visceral antinociception. Subcutaneous injection of dopamine D1 receptor antagonist, CB1 receptor antagonist or naloxone significantly blocked the CPA-induced visceral antinociception while neither subcutaneous injection of dopamine D2 receptor antagonist nor CB2 receptor antagonist blocked the CPA-induced anti-pain action. These results suggest that 5-HT1A, 5-HT2A, dopamine D1, CB1 receptors and the opioid system in the CNS may specifically mediate the CPA-induced visceral antinociception. These findings may help in understanding the physiological relevance of central adenosine with special reference to the pathophysiology of altered visceral sensation especially in irritable bowel syndrome.

5-HT2A receptors but not cannabinoid receptors in the central nervous system mediate levodopa-induced visceral antinociception in conscious rats.

We have recently demonstrated that levodopa acts centrally to induce antinociceptive action against colonic distension through dopamine D2 receptors in rats. Since serotonin (5-HT) and cannabinoid are involved in the regulation of visceral sensation, we hypothesized that they may contribute to levodopa-induced visceral antinociception. We evaluated visceral sensation by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously administered levodopa increased the threshold of colonic distension-induced AWR; moreover, an intracisternal injection of methiothepin, an unspecific 5-HT receptor antagonist, blocked the levodopa-induced visceral antinociception. Subsequently, we examined the roles of three 5-HT receptor subtypes: 5-HT1A, 5-HT1B, and 5-HT2A, in levodopa-induced visceral antinociception. Ketanserin is a 5-HT2A receptor antagonist that was intracisternally injected and blocked the levodopa-induced antinociception, but neither WAY100635 (5-HT1A receptor antagonist) nor isomoltane (5-HT1B receptor antagonist) did so. Antagonists AM251 (cannabinoid 1 receptor antagonist) or AM630 (cannabinoid 2 receptor antagonist) did not change the levodopa-induced visceral antinociception, suggesting that cannabinoid signaling may not be implicated in levodopa-induced visceral antinociception. We also examined the relation between dopamine D2 and 5-HT2A receptor signaling in the control of visceral sensation. Ketanserin, but not WAY100635, potently blocked the visceral antinociception by quinpirole, which is a dopamine D2 agonist. These results suggest that 5-HT2A receptors in the central nervous system may play specific roles in levodopa-dopamine D2 receptor-induced antinociceptive action against colonic distension.

Ghrelin acts in the brain to block colonic hyperpermeability in response to lipopolysaccharide through the vagus nerve.

Brain ghrelin plays a role in gastrointestinal functions. Among them, ghrelin acts centrally to stimulate gastrointestinal motility and induce visceral antinociception. Intestinal barrier function, one of important gastrointestinal functions, is also controlled by the central nervous system. Little is, however, known about a role of central ghrelin in regulation of intestinal permeability. The present study was performed to clarify whether brain ghrelin is also involved in regulation of intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of ghrelin dose-dependently abolished increased colonic permeability in response to LPS while intraperitoneal injection of ghrelin at the same dose or intracisternal injection of des-acyl-ghrelin failed to block it. Carbachol potently attenuated LPS-induced intestinal hyperpermeability, and atropine or bilateral subdiaphragmatic vagotomy prevented the improvement of intestinal hyperpermeability by central ghrelin. Intracisternal (D-Lys3)-GHRP-6, a selective ghrelin receptor antagonist, significantly blocked improvement of intestinal barrier function by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Intracisternal injection of orexin 1 receptor antagonist, SB-334867 blocked intracisternal ghrelin-induced improvement of colonic hyperpermeability. These results suggest that exogenously administered or endogenously released ghrelin acts centrally to improve a disturbed intestinal barrier function through orexinergic signaling and the vagal cholinergic pathway. Central ghrelin may be involved in the pathophysiology and be a novel therapeutic option in not only gastrointestinal diseases such as irritable bowel syndrome but also non-gastrointestinal diseases associated with the altered intestinal permeability.

Brain orexin improves intestinal barrier function via the vagal cholinergic pathway.

Orexins are neuropeptides that are implicated in a number of functions. With regard to the gastrointestinal functions, orexin acts centrally to regulate gastric secretion, gastrointestinal motility and visceral sensation. Little is however known about a role of central orexin in the control of intestinal barrier function. The present study was performed to clarify whether brain orexin plays a role in the control of intestinal permeability. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternally administered orexin-A but not orexin-B dose-dependently blocked the increased intestinal permeability by lipopolysaccharide (LPS) or corticotropin-releasing factor while intraperitoneally injected orexin-A failed to block it. Atropine or vagotomy abolished the action by central orexin-A. Intravenous injection of 2-deoxy-D-glucose (2-DG), a central vagal stimulant, significantly blocked the LPS-induced increase in intestinal permeability and atropine prevented the action of 2-DG. Intracisternal injection of SB-334687, a selective orexin 1 receptor antagonist, significantly blocked the action of 2-DG-induced improvement of intestinal hyperpermeability. These results suggest that exogenously administered or endogenously released orexin acts centrally to improve the intestinal hyperpermeability by LPS via the vagal cholinergic pathway. The findings also suggest for the first time that the brain could control intestinal permeability. The neuronal rapid protective advantage to the host by improving the intestinal barrier function by the neuropeptide may help us understand the brain-gut interaction in stress sensitive gastrointestinal disorders like irritable bowel syndrome associated with the altered intestinal permeability.

Centrally administered orexin prevents lipopolysaccharide and colchicine induced lethality via the vagal cholinergic pathway in a sepsis model in rats.

Orexins are neuropeptides implicated in several physiological functions. Accumulating findings suggest a relationship between orexin and sepsis. A recent study demonstrated that orexin acts centrally to improve conditions in sepsis. The present study aims to clarify the precise mechanisms by which central orexin could induce a protective action against septic conditions. We established a new septic model by treating rats with lipopolysaccharide (LPS) and colchicine and used this to examine the effect of brain orexin on survival. Observation of survival was stopped three days after the chemicals injection or at death. We established a lethal model (rats died within 24 h) by injecting subcutaneously a combination of 1 mg/kg LPS and 1 mg/kg colchicine. A Toll-like receptor 4 (TLR4) inhibitor completely blocked lethality, suggesting a vital role of LPS-TLR4 signaling in the process. Intracisternal orexin-A dose-dependently reduced lethality in the sepsis model while neither intracisternal orexin-B nor intraperitoneal orexin-A changed the mortality rate. Vagal stimulation with carbachol or 2-deoxy-D-glucose improved survival and atropine potently blocked the protection by carbachol or 2-deoxy-D-glucose. The orexin-A-induced reduction of lethality was significantly blocked by atropine or surgical vagotomy. Intracisternal injection of an OX1 receptor antagonist blocked the improvement of survival by intracisternal injection of orexin-A, carbachol, or 2-deoxy-D-glucose. These results suggest that orexin acts centrally to reduce the lethality in our septic model treated (LPS and colchicine). Activation of the vagal cholinergic pathway may mediate the action of orexin, and the OX1 receptor in the brain might play a role in the process. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the mechanisms of septic lethality reduction by brain orexin.

Therapeutic keratoplasty for corneal perforation: clinical results and complications.

PURPOSE: To report the clinical results, postoperative progress, and complications after therapeutic keratoplasty for corneal perforation. METHODS: Twenty consecutive eyes (20 patients) that underwent therapeutic keratoplasty between December 2003 and May 2006 were included. The eyes were evaluated retrospectively for the cause of the corneal perforation, the type of surgical technique and intraoperative complications, anatomic cure rates, graft clarity, visual prognosis, and postoperative complications. RESULTS: The causes of corneal perforation were herpetic keratitis (n = 5), bacterial ulcer (n = 1), fungal ulcer (n = 1), neurotrophic ulcer (n = 3), rheumatoid arthritis (n = 2), Mooren ulcer (n = 2), Terrien marginal corneal degeneration (n = 1), keratoconus (n = 1), and Wegener granulomatosis (n = 1). In 3 cases, the etiology was unknown. Six cases had a previous history of corneal transplantation. Anatomic cures were obtained in 16 (80%) of 20 eyes after the first transplantation procedure. Visual acuity (VA) equal to or better than the preoperative level was achieved in 17 (85%) of 20 eyes. The graft transparency rate was 67% in 15 eyes that underwent central penetrating keratoplasty with fresh donor tissue. Major postoperative complications included cataract (n = 6), glaucoma (n = 4), and recurrent disease (n = 3). CONCLUSIONS: Keratoplasty is valuable for maintaining the ocular integrity and VA. In cases with severe preoperative inflammation of the anterior segment, it is difficult to achieve transparency after the first graft.

Changes in Subfoveal Choroidal Thickness During Pregnancy and After Delivery.

BACKGROUND AND OBJECTIVE: This study was performed to investigate longitudinal changes in the subfoveal choroidal thickness (SFCT) during pregnancy and after delivery. PATIENTS AND METHODS: The SFCT was measured in the first and third trimesters, shortly after delivery, and 1 month after delivery in 25 eyes of 25 women. Enhanced depth imaging optical coherence tomography was used for measurement. RESULTS: The mean SFCT was 347 µm ± 86 µm, 329 µm ± 81 µm, 333 µm ± 81 µm, and 330 µm ± 87 µm in the first and third trimesters, shortly after delivery, and 1 month after delivery, respectively. The SFCT in the first trimester was significantly greater than that in the third trimester, shortly after delivery, and 1 month after delivery. CONCLUSIONS: This study indicates that the SFCT is greater in the first trimester and decreases in the third trimester of pregnancy. The SFCT does not subsequently change until 1 month after delivery. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:816-821.].

Choroidal thickness in pregnant women measured by enhanced depth imaging optical coherence tomography.

PURPOSE: To measure choroidal thickness in healthy pregnant women using enhanced depth imaging optical coherence tomography (EDI-OCT) and compare the measurements with those of healthy non-pregnant women. METHODS: Choroidal thickness was measured at the fovea and at 3 mm superior, inferior, temporal, and nasal to the fovea using EDI-OCT in both healthy pregnant and non-pregnant women. RESULTS: The mean choroidal thickness in pregnant women was 275 ± 84 µm at the subfoveal and 307 ± 89, 277 ± 89, 274 ± 74, and 159 ± 60 µm at 3 mm superior, inferior, temporal, and nasal to the fovea, respectively. In comparison, the mean choroidal thickness in non-pregnant women was 273 ± 92 µm at the subfoveal and 301 ± 73, 290 ± 76, 293 ± 77, and 149 ± 55 µm at 3 mm superior, inferior, temporal, and nasal to the fovea, respectively. No significant statistical differences were found for choroidal thickness between the pregnant and non-pregnant women at any of the measurement points. CONCLUSIONS: The results of this study demonstrate that the choroidal thickness was not significantly different between healthy pregnant and non-pregnant women.