Comparative efficacy of antitumor necrosis factor agents and tacrolimus in naïve steroid-refractory ulcerative colitis patients.

While retrospective studies have compared the efficacy of anti-tumour necrosis factor (TNF) agents and tacrolimus (TAC) in ulcerative colitis (UC), information regarding first-time use of these agents is limited. The aim of our study was to investigate the short- and long-term efficacy of anti-TNF agents [adalimumab (ADA) and infliximab (IFX)] and TAC in anti-TNF agent- and TAC-naïve steroid-refractory UC patients. We evaluated 150 steroid-refractory UC patients receiving anti-TNF agents (IFX: n = 30, ADA: n = 41) or TAC (n = 79) at eight institutions in Japan. Clinical response rates at 8 weeks were 73.2% and 75.9% while remission rates were 30.1% and 25.3% in the anti-TNF and TAC groups, respectively. Logistic regression analysis showed the male sex and higher C-reactive protein to be independent factors for response to anti-TNF agents and TAC, respectively. Use of TAC was an independent factor for relapse. No differences in response to the treatment or relapse were observed between IFX and ADA. In conclusion, TAC and anti-TNF agents promoted similar short-term effects, but anti-TNF agents ensured better long-term outcomes at first-time treatment of steroid-refractory UC patients.

Gastric mucormycosis complicated by a gastropleural fistula: A case report and review of the literature.

RATIONALE: Mucormycosis is a rare opportunistic fungal infection with poor prognosis. The incidence of mucormycosis has been increasing, and it is a threat to immunocompromised hosts. We present a case of gastric mucormycosis complicated by a gastropleural fistula during immunosuppressive treatment for adult-onset Still disease (AOSD). PATIENT CONCERNS: An 82-year-old woman diagnosed with AOSD who developed gastric ulcers during the administration of an immunosuppressive therapy with corticosteroids, cyclosporine, and tocilizumab complained of melena and epigastralgia. Esophagogastroduodenoscopy showed multiple ulcers covered with grayish or greenish exudates. DIAGNOSES: The patient diagnosed with mucormycosis based on culture and biopsy of the ulcers, which showed nonseptate hyphae branching at wide angles. Mucor indicus was identified using polymerase chain reaction. INTERVENTIONS AND OUTCOMES: Although liposomal amphotericin B was administered, gastric mucormycosis was found to be complicated by a gastropleural fistula. The patient died because of pneumonia due to cytomegalovirus infection, and autopsy revealed the presence of Mucorales around the fistula connecting the stomach and diaphragm. LESSONS: Gastric mucormycosis is refractory to treatment and fatal. Surgical resection, if possible, along with antifungal drugs can result in better outcomes.

Clinical efficacy of adalimumab in Crohn's disease: a real practice observational study in Japan.

BACKGROUND: There are few reports of the efficacy of adalimumab (ADA) for clinical remission and preventing postoperative recurrence in Crohn's disease (CD) in Asian real practice settings. We conducted a Japanese multicenter retrospective observational study. METHODS: We evaluated patients with CD who were treated with ADA at 11 medical institutions in Japan to investigate the clinical efficacy of remission up to 52 weeks and the associated factors to achieve remission with a CD Activity Index (CDAI) < 150. The effects of preventing postoperative recurrence were also evaluated. RESULTS: In 62 patients, the remission rates were 33.9, 74.2, 75.8, 77.4, and 66.1 % at 0, 4, 12, 26, and 52 weeks, respectively. Although 10 patients discontinued treatment due to primary nonresponse, secondary nonresponse, or adverse events, the ongoing treatment rate at 52 weeks was 83.9 %. Comparison of remission and non-remission on univariate analysis identified colonic type and baseline CDAI value as significant associated factors (P < 0.05). In 16 patients who received ADA to prevent postoperative recurrence, the clinical remission maintenance rate was 93.8 % and the mucosal healing rate was 64.3 % during a mean postoperative follow-up period of 32.3 months. CONCLUSIONS: ADA effectively induced remission and prevented postoperative recurrence in patients with CD in a real practice setting.

[Landiolol infusion attenuates increase in heart rate, but does not prevent increase in blood pressure in response to emergence from anesthesia and tracheal extubation].

BACKGROUND: Tracheal extubation and emergence procedures induce abrupt changes in hemodynamics and humoral responses. The purpose of this study was to examine the effects of different doses of landiolol on hemodynamics during emergence from anesthesia. METHODS: All patients undergoing general anesthesia were enrolled in this study. Immediately after the end of the surgery, all anesthetics were discontinued. Thereafter, during emergence from anesthesia, all patients were ventilated with 100% oxygen and landiolol infusion was started in all but the control group patients. In the normal dose group, landiolol infusion was started at a rate of 0.125 mg x kg(-1) x min(-1) for 1 min, decreasing it to 0.04 mg x kg(-1) x min(-1) until the time of extubation. In the low dose group, landiolol infusion was given at a rate of 0.06 mg x kg(-1) x min(-1) for 1 min and then continuously infused at the rate of 0.02 mg x kg(-1) x min(-1) until extubation. RESULTS: Systolic and diastolic pressure increased during the emergence period in all 3 groups, there being no significant differences in systolic and diastolic pressure between the 3 groups during the observation period. Heart rate increased during the emergence period in the control group. In contrast, heart rate in both normal and low dose groups did not increase during the observation period. CONCLUSIONS: Landiolol could prevent the increase in heart rate but not blood pressure during emergence from anesthesia. Effects on the changes in heart rate between 0.125 and 0.06 landiolol groups were not significantly different.

Dominant-negative effects of the N-terminal half of prion protein on neurotoxicity of prion protein-like protein/doppel in mice.

Prion protein-like protein/doppel is neurotoxic, causing ataxia and Purkinje cell degeneration in mice, whereas prion protein antagonizes doppel-induced neurodegeneration. Doppel is homologous to the C-terminal half of prion protein but lacks the amino acid sequences corresponding to the N-terminal half of prion protein. We show here that transgenic mice expressing a fusion protein consisting of the N-terminal half, corresponding to residues 1-124, of prion protein and doppel in neurons failed to develop any neurological signs for up to 730 days in a background devoid of prion protein. In addition, the fusion protein prolonged the onset of ataxia in mice expressing exogenous doppel. These results suggested that the N-terminal part of prion protein has a neuroprotective potential acting both cis and trans on doppel. We also show that prion protein lacking the pre-octapeptide repeat (Delta25-50) or octapeptide repeat (Delta51-90) region alone could not impair the antagonistic function against doppel.

Newly established in vitro system with fluorescent proteins shows that abnormal expression of downstream prion protein-like protein in mice is probably due to functional disconnection between splicing and 3' formation of prion protein pre-mRNA.

We and others previously showed that, in some lines of prion protein (PrP)-knockout mice, the downstream PrP-like protein (PrPLP/Dpl) was abnormally expressed in brains partly due to impaired cleavage/polyadenylation of the residual PrP promoter-driven pre-mRNA despite the presence of a poly(A) signal. In this study, we newly established an in vitro transient transfection system in which abnormal expression of PrPLP/Dpl can be visualized by expression of the green fluorescence protein, EGFP, in cultured cells. No EGFP was detected in cells transfected by a vector carrying a PrP genomic fragment including the region targeted in the knockout mice intact upstream of the PrPLP/Dpl gene. In contrast, deletion of the targeted region from the vector caused expression of EGFP. By employing this system with other vectors carrying various deletions or point mutations in the targeted region, we identified that disruption of the splicing elements in the PrP terminal intron caused the expression of EGFP. Recent lines of evidence indicate that terminal intron splicing and cleavage/polyadenylation of pre-mRNA are functionally linked to each other. Taken together, our newly established system shows that the abnormal expression of PrPLP/Dpl in PrP-knockout mice caused by the impaired cleavage/polyadenylation of the PrP promoter-driven pre-mRNA is due to the functional dissociation between the pre-mRNA machineries, in particular those of cleavage/polyadenylation and splicing. Our newly established in vitro system, in which the functional dissociation between the pre-mRNA machineries can be visualized by EGFP green fluorescence, may be useful for studies of the functional connection of pre-mRNA machineries.

Immunization with recombinant bovine but not mouse prion protein delays the onset of disease in mice inoculated with a mouse-adapted prion.

Host tolerance to endogenous prion protein (PrP) has hampered the development of prion vaccines as PrP is a major component of prions. Indeed, we show that immunization of mice with mouse recombinant PrP elicited no prophylactic effect against a mouse-adapted prion. However, interestingly, mice immunized with recombinant bovine PrP developed the disease significantly later than non-immunized mice after inoculation of a mouse prion. Sheep recombinant PrP exhibited variable prophylactic effects. Mouse recombinant PrP stimulated only very weak antibody responses. In contrast, bovine recombinant PrP was higher immunogenic and produced variable amounts of anti-mouse PrP autoantibodies. Sheep recombinant PrP was also immunogenic but produced more variable amounts of anti-PrP autoantibodies. These results might open a new way for development of prion vaccines.

Enhanced mucosal immunogenicity of prion protein following fusion with B subunit of Escherichia coli heat-labile enterotoxin.

Mucosal vaccine against prion protein (PrP), a major component of prions, is urgently awaited since the oral transmission of prions from cattle to humans is highly suspected. In the present study, we produced recombinant bovine and mouse PrPs fused with or without the B subunit of Escherichia coli heat-labile enterotoxin (LTB) and intranasally immunized mice with these fused proteins. Fusion with LTB markedly enhanced the mucosal immunogenicity of bovine PrP, producing a marked increase in specific IgG and IgA titer in serum. Mouse PrP also showed slightly increased immunogenicity following fusion with LTB. These results demonstrate that LTB-fused PrPs might be potential candidates for protective mucosal prion vaccines.

Biological and biochemical characteristics of prion strains conserved in persistently infected cell cultures.

Abnormal prion protein (PrP(Sc)) plays a central role in the transmission of prion diseases, but the molecular basis of prion strains with distinct biological characteristics remains to be elucidated. We analyzed the characteristics of prion disease by using mice inoculated with the Chandler and Fukuoka-1 strains propagated in a cultured mouse neuronal cell line, GT1-7, which is highly permissive to replication of the infectious agents. Strain-specific biological characteristics, including clinical manifestations, incubation period as related to the infectious unit, and pathological profiles, remained unchanged after passages in the cell cultures. We noted some differences in the biochemical aspects of PrP(Sc) between brain tissues and GT1-7 cells which were unlikely to affect the strain phenotypes. On the other hand, the proteinase K-resistant PrP core fragments derived from Fukuoka-1-infected tissues and cells were slightly larger than those from Chandler-infected versions. Moreover, Fukuoka-1 infection, but not Chandler infection, gave an extra fragment with a low molecular weight, approximately 13 kDa, in both brain tissues and GT1-7 cells. This cell culture model persistently infected with different strains will provide a new insight into the understanding of the molecular basis of prion diversity.

Volatile anesthetics inhibit calcitonin gene-related peptide receptor-mediated responses in pithed rats and human neuroblastoma cells.

Calcitonin gene-related peptide (CGRP) has a potent vasodilatory effect that is mediated by specific receptors predominantly coupled to the activation of adenylate cyclase. The effects of volatile anesthetics on CGRP-induced vasodilation are unclear. We studied the effects of sevoflurane and isoflurane on CGRP-induced vasodilation in pithed rats and CGRP receptor-mediated responses in SK-N-MC cells, which are used as a model system to study the CGRP receptor and its downstream pathways. Male Wistar rats were pithed by inserting a stainless steel rod into the spinal cord. Mean arterial pressure (MAP) and cardiac output were maintained at approximately 100 mmHg and 50 ml.min(-1), respectively, with continuous infusion of noradrenaline. After 30 min of inhalation of anesthetics, CGRP (0.1, 0.3, 1.0, and 3.0 microg/kg) was administered intravenously. In SK-N-MC cells, CGRP-, forskolin-, or cholera toxin-induced cAMP production was measured with or without anesthetics using radioimmunoassays. CGRP receptor binding density and affinity for the agonist were determined with (2-[125I]iodohystidyl10) CGRP with or without the anesthetics. Sevoflurane (4%) and isoflurane (2%) significantly inhibited the decrease in MAP and systemic vascular resistance. Furthermore, both anesthetics significantly inhibited CGRP- but not forskolin-induced cAMP production. Sevoflurane (4%) and isoflurane (4%) significantly inhibited cholera toxin-induced cAMP production. Both anesthetics did not affect ligand binding. These data suggest that sevoflurane and isoflurane inhibit CGRP-induced vasodilation at the site between the CGRP receptor and adenylate cyclase activation. The inhibitory site of volatile anesthetics on the CGRP receptor-mediated response involves Gs protein.

Intraoperative massive pulmonary tumor embolism from clear cell sarcoma in the retroperitoneum: successful treatment using cardiopulmonary bypass.

Malignant neoplasms rarely extend into the inferior vena cava and up to the right side of the heart. Although massive pulmonary tumor embolism occurs relatively rarely, it can be a catastrophic problem. Intraoperative pulmonary tumor embolism and cardiac arrest occurred in a 68-year-old woman while dissecting the inferior vena cava to resect a pararenal tumor extending into the retrohepatic inferior vena cava. Abrupt arterial hypotension, tachycardia, and increased central venous pressure lead to the diagnosis of massive pulmonary tumor embolism. Emergency cardiopulmonary bypass was commenced under profound hypothermia and cardiac arrest. The tumors in the main pulmonary artery were extracted, and fragments of remnant tumor were retrieved by a vascular endoscope, a Fogarty catheter, and milking of the lung. Following embolectomy, the tumor in the retrohepatic to infrarenal inferior vena cava was removed and the primary tumor together with the infrarenal inferior vena cava was resected under hepatic vascular exclusion and partial cardiopulmonary bypass. The inferior vena cava below the renal veins was not reconstructed. The patient recovered with slight retrograde amnesia. A postoperative pulmonary perfusion scintigram showed no defect in the pulmonary circulation. She is well now 8 months after surgery. Safe prevention measures should be accomplished as a part of the perioperative management of patients with inferior vena cava tumor thrombus that may be fragile, and cardiopulmonary bypass should always be stand-by on surgery.

Synthesis and histone deacetylase inhibitory activity of cyclic tetrapeptides containing a retrohydroxamate as zinc ligand.

Cyclic tetrapeptide retrohydroxamic acids were prepared as histone deacetylase (HDAC) inhibitors and evaluated the inhibitory activity and found that they have potential as anticancer drugs.

Increased plasma concentrations of the mature form of adrenomedullin during cardiac surgery and hepatosplanchnic hypoperfusion.

Adrenomedullin is a potent vasodilatory peptide. Plasma adrenomedullin (AM) concentrations increase during and after cardiopulmonary bypass (CPB). However, the cause of this increase and its site of production have not been identified. We investigated the role of the hepatosplanchnic and cerebral circulations in the increase of plasma AM and investigated whether tissue hypoxygenation is a cause of the AM increase seen during CPB. We measured plasma total AM (AM-T) and the biologically active form of AM, mature AM (AM-m), in seven patients undergoing CPB. Both plasma AM-T and AM-m concentrations increased significantly 60 min after weaning from CPB. At this time point, arterial AM-T and AM-m concentrations were 18-fold and 10-fold larger, respectively, than baseline values measured after the induction of anesthesia. The plasma AM-m concentration and the ratio of AM-m/AM-T in blood from the hepatic vein were significantly larger than those from the radial artery or jugular bulb. The AM-m/AM-T ratio decreased during CPB, suggesting that production of the intermediate form of AM, AM-glycine, is more than that of AM-m. The oxygen tension of the hepatic venous blood (PhvO2) was significantly less during CPB. Plasma AM-m concentrations sampled from the hepatic vein showed a significant negative correlation with PhvO2 at 10 min (r = 0.824; P < 0.02) and 60 min (r = 0.828; P < 0.02) after the onset of CPB. These data suggest that the hepatosplanchnic circulation is an important source of AM-m during CPB. Furthermore, hypoxygenation of the hepatosplanchnic region may be an important cause of this AM-m increase.

Anesthetic management for clipping a giant basilar artery aneurysm with moderate hypothermia, extracorporeal circulation assistance, and propofol infusion.

A 65-year-old female patient underwent surgery to clip a giant basilar artery aneurysm with closed-chest extracorporeal circulation using femorofemoral bypass. Moderate hypothermia (27 degrees C-30 degrees C), retention of spontaneous circulation, and propofol infusion (3-5 mg. kg(-1). h(-1)) were used under general anesthesia. Blood outflow via femoral vein was sufficient to maintain cardiopulmonary bypass and to induce hypothermia. Hemodynamics were controlled with dopamine and noradrenaline. In this case, extracorporeal circulation under moderate hypothermia was used to assist rather than substitute for spontaneous circulation, and spontaneous circulation was maintained at all times. We think that this method had advantages over deep hypothermic circulatory arrest with regard to intraoperative risks and postoperative complications.

Preliminary results of a monitoring system to confirm the preservation of cavernous nerves.

BACKGROUND: It is important to preserve the neurovascular bundle (NVB) during nerve-sparing surgery. This article presents the preliminary results of our monitoring system for the postoperative preservation of erectile function. METHODS: In 15 patients undergoing radical prostatectomy and 20 patients undergoing radical cystoprostatectomy, intraoperative electrical stimulation along the NVB was performed to measure changes in intracavernous pressure before and after prostate removal. Seven of the radical prostatectomy patients and eight of the radical cystoprostatectomy patients underwent nerve-sparing surgery. Postoperative erectile function was evaluated in 25 patients not receiving adjuvant hormonal therapy. RESULTS: The NVB was judged to be preserved at least on one side electrophysiologically in 14 of 15 patients. Pathologically, three patients had pT3 cancer. Postoperatively, sufficient erectile function was demonstrated using the International Index of Erectile Function 5 in three patients, nocturnal penile tumescence in three patients, and a questionnaire or an interview in three patients. The other patients were incompletely erectile. None of the 11 patients not receiving adjuvant hormonal therapy, in whom NVB was not preserved, were erectile. CONCLUSION: If the successful criterion of nerve-sparing surgery is defined as a change in intracavernous pressure of 4 cm H2O or more being observed at least unilaterally, and the successful criteria of erectile function preservation includes being sufficiently erectile as revealed by an interview, the sensitivity of our system was 69.2% (9/13) and the specificity was 100% (12/12). Neither adverse reactions to the measurement, nor inadequacy of cancer excision accompanying NVB sparing, were observed. These results suggest that our system can predict postoperative erectile function fairly accurately.

The effects of volatile anesthetics on nonadrenergic, noncholinergic depressor responses in rats.

UNLABELLED: The effects of volatile anesthetics on nonadrenergic, noncholinergic (NANC) transmission mediated by calcitonin gene-related peptide (CGRP) are unclear. We studied the effects of isoflurane, halothane, and sevoflurane on NANC depressor responses to electrical spinal cord stimulation in pithed rats whose mean arterial blood pressure was maintained near 120 mm Hg by continuous infusion of methoxamine. Autonomic outflow was blocked by hexamethonium. After 30 min of inhalation of different concentrations of anesthetics, spinal cord stimulation at the lower thoracic level (10 V at 4 Hz; duration, 1 ms) was applied for 30 s to induce a NANC depressor response. Isoflurane at 2% and halothane at 1.5% attenuated NANC depressor responses significantly, whereas isoflurane at 1%, halothane at 0.75%, and sevoflurane at 2% or 4% did not. Volatile anesthetics did not attenuate the release of CGRP after spinal cord stimulation, whereas isoflurane at 2% and halothane at 1.5% significantly inhibited depressor responses to exogenously administered CGRP. Sevoflurane at 4% did not significantly affect CGRP-induced depressor responses. Thus, isoflurane and halothane at large concentrations attenuate NANC depressor responses by attenuating the depressor action of CGRP, not CGRP release. IMPLICATIONS: The anesthetics isoflurane and halothane attenuate nonadrenergic, noncholinergic depressor responses mediated by calcitonin gene-related peptide in the rat without affecting the release of the peptide.

Increasing mean arterial blood pressure has no effect on jugular venous oxygen saturation in insulin-dependent patients during tepid cardiopulmonary bypass.

UNLABELLED: Preexisting diabetes mellitus is one of the major factors related to adverse postoperative neurological disorders after cardiac surgery. In previous reports, we found that diabetic patients more often experienced cerebral desaturation than nondiabetic patients during normothermic cardiopulmonary bypass (CPB). The purpose of this study was to examine the effects of increasing mean arterial blood pressure (MAP) by the administration of phenylephrine on internal jugular venous oxygen hemoglobin saturation (SjvO2) during tepid CPB in diabetic patients. We studied 20 diabetic patients scheduled for elective coronary artery bypass graft surgery and, as a control, 20 age-matched nondiabetic patients. After the induction of anesthesia, a fiberoptic oximetry catheter was inserted into the right jugular bulb to monitor SjvO2. After measuring the baseline partial pressure of the arterial and jugular venous blood gases and cardiovascular hemodynamic values, MAP was increased by the repeated administration of a 10-microg bolus of phenylephrine until it reached 100% of baseline values. There was a significant difference in SjvO2 value between the Diabetic and CONTROL GROUPs after the administration of phenylephrine (Diabetic group, 56% +/- 6%; CONTROL GROUP: 60% +/- 4%) (P < 0.05). There was a significant difference in the arterial-jugular oxygen content difference value between the Diabetic and CONTROL GROUPs after the administration of phenylephrine (diabetic group, 4.9% +/- 0.6%; CONTROL GROUP, 4.5% +/- 0.4%) (P < 0.05). We subdivided the Diabetic group into three groups (Diet Therapy group [n = 4], Glibenclamide group [n = 10], and Insulin-Dependent group [n = 6]). There was a significant difference in the mean slopes of SjvO2 versus cerebral perfusion pressure for increasing cerebral perfusion pressure between the Insulin-Dependent group and the other groups (Dunnett test: P = 0.04). Increasing MAP had no effects on the SjvO2 value in insulin-dependent patients during tepid CPB. IMPLICATIONS: We examined the effects of increasing mean arterial blood pressure (MAP) by the administration of phenylephrine on internal jugular venous oxygen saturation (SjvO2) during tepid cardiopulmonary bypass in diabetic patients and found that increasing MAP had no effect on the SjvO2 value in insulin-dependent patients.