Comparison of stress distribution in partially and completely edentulous mandibles around splinted and non-splinted implant prostheses: A finite element study.

BACKGROUND: In some treatments using multiple dental implants, the implants are inserted in the bone with splinted or non-splinted implant prostheses. There are some reports about the influence of the splinted and non-splinted implants on stress distribution in the bone using the finite element method (FEM), and there is a controversy in the literature regarding whether the splinted or non-splinted implants prostheses reduce the stress generated on the implant-surrounding bone more efficiently. Additionally, the simple shape of the jaw bones with limited bone area was used for FEM analysis in many studies at the expense of accurate analysis. OBJECTIVE: The aim of this study was to evaluate the difference in stress distribution in the bone between the splinted and non-splinted implants, and between completely and partially edentulous mandibles. METHODS: The implants were inserted in the first premolar, second premolar, and first molar regions of the partial and complete mandibles, and the splinted and non-splinted crowns were attached to the implants. Vertical load (100 N) or oblique load (70 N, 30° from its long axis towards the lingual) was applied on the first premolar. RESULTS: When vertical load was applied to the partially edentulous mandible model, the stress was concentrated intensively on the cortical bone around the first premolar regardless of whether splinted or non-splinted implants were used. On the other hand, the vertical load applied to the completely edentulous mandible model caused the stress to be concentrated intensively on the cortical bone around the first premolar with non-splinted implants. With respect to the oblique load, the stress was concentrated intensively on the cortical bone around the first premolar only with the non-splinted implants, in both the partial and complete mandibles. CONCLUSION: This study shows the different stress distributions of the cortical bone around the implants between the partial and complete mandible. This indicates that the complete mandible should be used for the analysis of bone stress distribution around the implants using FEM.

Appropriate management of high-flow priapism based on color Doppler ultrasonography findings in pediatric patients: four case reports and a review of the literature.

INTRODUCTION: High-flow priapism in children is a very rare condition, and there is no clear consensus on its management. High-flow priapism is associated with increased cavernosal blood flow and broadly divided into two groups based on the presence or absence of arteriocavernous fistula in the corpora cavernosa. OBJECTIVE: This study aimed to determine the appropriate management of high-flow priapism based on the existence of arteriocavernous fistula using penile color Doppler ultrasonography (CDU) findings in the pediatric population. STUDY DESIGN: The cases of four boys aged between 6 and 11 years with high-flow priapism treated between 2009 and 2017 are reported. Two boys had prior perineal trauma, one boy had blunt penile glans trauma, and one had no obvious cause for the condition. All boys initially underwent penile CDU and were treated conservatively or via selective arterial embolization depending upon the presence or absence of an arteriocavernous fistula. RESULTS: Penile CDU revealed an arteriocavernous fistula inside the corpus cavernosum penis in two of four boys and increased blood flow inside the corpus spongiosum in the remaining boys. The former two boys underwent selective arterial embolization and one boy underwent repeated embolization because of remaining arteriocavernous fistula feeding from the contralateral cavernosal artery, whereas the boys with no arteriocavernous fistula on CDU were managed conservatively. All boys were successfully treated within 1 month, and they had normal morning erection and no evidence of recurrent priapism at the follow-up. DISCUSSION: Unlike low-flow priapism, high-flow priapism is not a medical emergency. Therefore, conservative therapy is an appropriate initial treatment, although selective arterial embolization can be effective for high-flow priapism with arteriocavernous fistula, with a success rate of 97% and no reported complications to date. Penile CDU is an imaging technique that can detect focal areas of turbulent flow with sensitivity close to 100%. This study has several limitations including a small number of cases, limited follow-up duration, and possibility of spontaneous arteriocavernous fistula closure in cases treated by arterial embolization. CONCLUSION: Penile CDU could be a reliable tool to diagnose high-flow priapism and detect the presence or absence of arteriocavernous fistula. Although conservative therapy remains the first choice, selective arterial embolization may be an early treatment option when CDU reveals an arteriocavernous fistula.

Calcineurin inhibitors exacerbate coronary arteritis via the MyD88 signalling pathway in a murine model of Kawasaki disease.

Calcineurin inhibitors (CNIs) have been used off-label for the treatment of refractory Kawasaki disease (KD). However, it remains unknown whether CNIs show protective effects against the development of coronary artery lesions in KD patients. To investigate the effects of CNIs on coronary arteries and the mechanisms of their actions on coronary arteritis in a mouse model of KD, we performed experiments with FK565, a ligand of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in wild-type, severe combined immunodeficiency (SCID), caspase-associated recruitment domain 9 (CARD9)-/- and myeloid differentiation primary response gene 88 (MyD88)-/- mice. We also performed in-vitro studies with vascular and monocytic cells and vascular tissues. A histopathological analysis showed that both cyclosporin A and tacrolimus exacerbated the NOD1-mediated coronary arteritis in a dose-dependent manner. Cyclosporin A induced the exacerbation of coronary arteritis in mice only in high doses, while tacrolimus exacerbated it within the therapeutic range in humans. Similar effects were obtained in SCID and CARD9-/- mice but not in MyD88-/- mice. CNIs enhanced the expression of adhesion molecules by endothelial cells and the cytokine secretion by monocytic cells in our KD model. These data indicated that both vascular and monocytic cells were involved in the exacerbation of coronary arteritis. Activation of MyD88-dependent inflammatory signals in both vascular cells and macrophages appears to contribute to their adverse effects. Particular attention should be paid to the development of coronary artery lesions when using CNIs to treat refractory KD.

Mid-trimester residual cervical length and the risk of preterm birth in pregnancies after abdominal radical trachelectomy: a retrospective analysis.

OBJECTIVE: To investigate the association between mid-trimester residual cervical length (CL) and the risk of preterm birth in pregnancies after abdominal radical trachelectomy (RT). DESIGN: Retrospective cohort study. SETTING: University hospital. POPULATION: A total of 33 deliveries after 22 weeks' gestation in 30 women who underwent abdominal RT including prophylactic cervical cerclage and perinatal care between January 2002 and May 2016. METHODS: The association between mid-trimester residual CL (the distance between the cerclage and the external cervical os) and gestational age at delivery was investigated. Receiver-operating characteristics (ROC) curve analysis was performed to estimate the optimal cut-off values of the mid-trimester residual CL for the prediction of preterm birth. MAIN OUTCOME MEASURES: Preterm birth before 34 weeks' gestation. RESULTS: Mid-trimester residual CL showed a significant correlation with gestational age at delivery (r = 0.36, P < 0.05). There was a significant difference in residual CL between women who did and those who did not give birth before 34 weeks (P < 0.05). Mid-trimester residual CL < 13 mm was a good predictor of birth before 34 weeks, with a sensitivity of 67%, specificity of 75%, positive predictive value of 55% and negative predictive value of 86% (area under ROC curve, 0.75). CONCLUSIONS: Mid-trimester residual CL is significantly correlated with gestational age at delivery. Residual CL assessment could be used to reassure physicians and women that there is only a small chance of preterm birth in pregnancies after abdominal RT. TWEETABLE ABSTRACT: Mid-trimester residual cervical length is a good predictor of preterm birth after radical trachelectomy.

Kawasaki disease: a matter of innate immunity.

Kawasaki disease (KD) is an acute systemic vasculitis of childhood that does not have a known cause or aetiology. The epidemiological features (existence of epidemics, community outbreaks and seasonality), unique age distribution and clinical symptoms and signs of KD suggest that the disease is caused by one or more infectious environmental triggers. However, KD is not transmitted person-to-person and does not occur in clusters within households, schools or nurseries. KD is a self-limited illness that is not associated with the production of autoantibodies or the deposition of immune complexes, and it rarely recurs. Regarding the underlying pathophysiology of KD, innate immune activity (the inflammasome) is believed to play a role in the development of KD vasculitis, based on the results of studies with animal models and the clinical and laboratory findings of KD patients. Animal studies have demonstrated that innate immune pathogen-associated molecular patterns (PAMPs) can cause vasculitis independently of acquired immunity and have provided valuable insights regarding the underlying mechanisms of this phenomenon. To validate this concept, we recently searched for KD-specific PAMPs and identified such molecules with high specificity and sensitivity. These molecules have structures similar to those of microbe-associated molecular patterns (MAMPs), as shown by liquid chromatography-tandem mass spectrometry. We propose herein that KD is an innate immune disorder resulting from the exposure of a genetically predisposed individual to microbe-derived innate immune stimulants and that it is not a typical infectious disease.

Neutrophil interactions with epithelial-expressed ICAM-1 enhances intestinal mucosal wound healing.

A characteristic feature of gastrointestinal tract inflammatory disorders, such as inflammatory bowel disease, is polymorphonuclear neutrophil (PMN) transepithelial migration (TEM) and accumulation in the gut lumen. PMN accumulation within the intestinal mucosa contributes to tissue injury. Although epithelial infiltration by large numbers of PMNs results in mucosal injury, we found that PMN interactions with luminal epithelial membrane receptors may also play a role in wound healing. Intercellular adhesion molecule-1 (ICAM-1) is a PMN ligand that is upregulated on apical surfaces of intestinal epithelial cells under inflammatory conditions. In our study, increased expression of ICAM-1 resulted in enhanced PMN binding to the apical epithelium, which was associated with reduced PMN apoptosis. Following TEM, PMN adhesion to ICAM-1 resulted in activation of Akt and ß-catenin signaling, increased epithelial-cell proliferation, and wound healing. Such responses were ICAM-1 dependent as engagement of epithelial ICAM-1 by antibody-mediated cross-linking yielded similar results. Furthermore, using an in-vivo biopsy-based, colonic-mucosal-injury model, we demonstrated epithelial ICAM-1 has an important role in activation of epithelial Akt and ß-catenin signaling and wound healing. These findings suggest that post-migrated PMNs within the intestinal lumen can regulate epithelial homeostasis, thereby identifying ICAM-1 as a potential therapeutic target for promoting mucosal wound healing.

Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor.

BACKGROUND: Although T-cell immunity is thought to be involved in the prognosis of epithelial ovarian cancer (EOC) patients, immunosuppressive conditions hamper antitumour immune responses. Thus, their mechanisms and overcoming strategies need to be investigated. METHODS: The role of NF-κB in human EOC cells and macrophages was evaluated by in vitro production of immunosuppressive IL-6 and IL-8 by EOC cells and in vivo analysis of immune responses in nude mice implanted with human EOC cells using an NF-κB inhibitor DHMEQ. RESULTS: In EOC patients, increased plasma IL-6, IL-8, and arginase were observed. The NF-κB inhibitor DHMEQ inhibited the production of IL-6 and IL-8 by EOC cell lines. Immunosuppression of human DCs and macrophages by culture supernatant of EOC cells was reversed with the pretreatment of DHMEQ. Administration of DHMEQ to nude mice implanted with human EOC resulted in the restoration of T-cell stimulatory activity of murine DCs along with the reduction of tumour accumulation and arginase expression of MDSCs. Nuclear factor-κB inhibition in tumour-bearing mice also enhanced antitumour effects of transferred murine naive T cells. CONCLUSIONS: NF-κB is involved in the immunosuppression induced by human EOC, and its inhibitor may restore antitumour immune responses, indicating that NF-κB is an attractive target for EOC treatment.

Allele-specific PCR for a cost-effective & time-efficient diagnostic screening of spinal muscular atrophy.

BACKGROUND & OBJECTIVES: Genetic diagnosis of spinal muscular atrophy (SMA) is complicated by the presence of SMN2 gene as majority of SMA patients show absence or deletion of SMN1 gene. PCR may amplify both the genes non selectively in presence of high amount of DNA. We evaluated whether allele-specific PCR for diagnostic screening of SMA is reliable in the presence of high amount of genomic DNA, which is commonly used when performing diagnostic screening using restriction enzymes. METHODS: A total of 126 blood DNA samples were tested in amounts ranging 80-200 ng, referred for the genetic diagnosis of SMA using both conventional PCR-RFLP and allele-specific PCR. RESULTS: The results from both methods showed agreement. Further, allele-specific PCR was found to be a time-efficient and cost-effective method. INTERPRETATION & CONCLUSIONS: Our study demonstrated the accuracy of our allele-specific PCR and the results were comparable compatible with that of PCR-RFLP, indicating its practical application in SMA diagnostic screening.

Infectivity of HBV DNA positive donations identified in look-back studies in Hyogo-Prefecture, Japan.

AIMS/OBJECTIVES: To clarify transfusion incidence of hepatitis B virus (HBV) infected blood negative for mini pool-nucleic acid amplification testing (MP-NAT). BACKGROUND: Japanese Red Cross (JRC) blood centres screen donated blood to avoid contamination with HBV. However, a low copy number of HBV may be overlooked. METHODS/MATERIALS: In Hyogo-Prefecture, JRC blood centres screened 787 695 donations for HBV from April 2005 to March 2009. Of these, 685 844 were donations from the repeat donors. To detect the donors with HBV, serological tests, MP-NAT and/or individual donation (ID)-NAT were performed. To detect the recipients with transfusion-transmitted HBV infection (TTHBI), serological analysis and/or ID-NAT were performed. RESULTS: In this study, 265 of the 685 844 repeat donations were serologically and/or MP-NAT positive for HBV. Their repository samples from the previous donation were examined in a look-back study; 13 of the 265 repository samples proved ID-NAT positive. Twelve recipients were transfused with HBV-infected blood components derived from 10 of the 13 HBV-infected donors. Only 1 of the 12 recipients was identified as TTHBI case. Seven of the 12 recipients escaped from our follow-up study and 4 recipients were negative for HBV during the observation period. CONCLUSION: On the basis of the look-back study among the repeat donors in Hyogo-Prefecture, Japan, donations with HBV-infected blood negative for MP-NAT occurred with a frequency of 13 in 685 844 donations (∼1/53 000 donations). However, more than half of the recipients transfused with HBV-infected blood negative for MP-NAT could not be followed up. It is necessary to establish a more cautious follow-up system.

Percutaneous transhepatic biliary drainage catheter tract recurrence in cholangiocarcinoma.

BACKGROUND: The aim of the study was to clarify the incidence, risk factors and treatment of percutaneous transhepatic biliary drainage (PTBD) catheter tract recurrence in patients with resected cholangiocarcinoma. METHODS: The medical records of 445 patients with perihilar and distal cholangiocarcinoma who underwent resection following PTBD were reviewed retrospectively. RESULTS: PTBD catheter tract recurrence was detected in 23 patients (5.2 per cent). The mean(s.d.) interval between surgery and onset of the recurrence was 14.4(13.8) months. On multivariable analysis, duration of PTBD (60 days or more), multiple PTBD catheters and macroscopic papillary tumour type were identified as independent risk factors. In four patients with synchronous metastasis, the PTBD sinus tract was resected simultaneously, at the time of initial surgery. Of 19 patients with metachronous metastasis, 15 underwent surgical resection of the metastasis. Survival of the 23 patients with PTBD catheter tract recurrence was poorer than that of the 422 patients without recurrence (median 22.8 versus 27.3 months; P = 0.095). Even after surgical resection of PTBD catheter tract recurrence, survival was poor. CONCLUSION: PTBD catheter tract recurrence is not unusual. The prognosis for these patients is generally poor, even after resection. To prevent this troublesome complication, endoscopic biliary drainage is first recommended when drainage is indicated.

Value of indocyanine green clearance of the future liver remnant in predicting outcome after resection for biliary cancer.

BACKGROUND: It is difficult to predict hepatic functional reserve accurately before major hepatectomy. The aim of this study was to analyse the usefulness of the future liver remnant plasma clearance rate of indocyanine green (ICGK-F, calculated as plasma clearance rate of indocyanine green (ICGK) x proportion of the future liver remnant) in predicting death after major hepatectomy. METHODS: Data on ICGK and ICGK-F were collected prospectively and analysed retrospectively for 274 patients who underwent right hepatectomy, right trisectionectomy or left trisectionectomy for biliary cancer between 1991 and 2008. The mortality rate and incidence of postoperative complications were analysed. Patients were separated into two groups according to year of operation (85 patients operated on between 1991 and 2000; 189 from 2001 to 2008). RESULTS: In multiple logistic regression analyses, an ICGK-F less than 0.05 had the strongest impact on the incidence of postoperative mortality (odds ratio 8.06; P < 0.001). The postoperative mortality rate was significantly lower in the later period (P < 0.001). In patients with an ICGK-F value between 0.040 and 0.049, the mortality rate in the early period was 30 per cent, whereas it was only 8 per cent in the later period. CONCLUSION: An ICGK-F of 0.05 is a useful cut-off value for predicting mortality and morbidity. With careful perioperative patient management in an experienced institution, this cut-off value can be lowered further.

Prevention by lansoprazole, a proton pump inhibitor, of indomethacin -induced small intestinal ulceration in rats through induction of heme oxygenase-1.

The effect of lansoprazole, a proton pump inhibitor (PPI), on indomethacin-induced small intestinal ulceration was examined in rats, particularly in relation to heme oxygenase (HO)-1. The animals were administered indomethacin (10 mg/kg, p.o.) and killed 24 h later. Lansoprazole (30-100 mg/kg, p.o.) and omeprazole (30-100 mg/kg, p.o.) were given 30 min before the administration of indomethacin, while tin-protoporphyrin IX (SnPP: 30 mg/kg, i.v.), an inhibitor of HO-1, was injected 10 min before indomethacin or lansoprazole. Indomethacin produced hemorrhagic lesions in the small intestine, accompanied with an increase of mucosal invasion of enterobacteria, inducible nitric oxide synthase (iNOS) expression, and myeloperoxidase (MPO) activity in the mucosa. Pretreatment with lansoprazole dose- dependently reduced the severity of the indomethacin-induced intestinal lesions, with suppression of the increased MPO activity, while omeprazole had no effect. Pretreatment with SnPP significantly exacerbated these intestinal lesions and almost totally abolished the protective effect of lansoprazole. The up-regulation of iNOS mRNA expression following indomethacin was suppressed by lansoprazole in a SnPP-inhibitable manner, although the enhanced enterobacterial invasion remained unaffected. The amount of HO-1 protein in the intestinal mucosa was significantly increased by lansoprazole but not by omeprazole. Prior administration of carbon monoxide (CO)-releasing molecule-2 (CORM-2; 10 mg/kg, i.p.) significantly reduced the severity of these lesions and the enhancement of mucosal iNOS mRNA expression induced in the small intestine by indomethacin. These results suggest that lansoprazole prevents indomethacin-induced small intestinal ulceration, and this effect is associated with inhibition of iNOS expression, through up-regulation of HO-1/CO production in the mucosa.

The concept of perihilar cholangiocarcinoma is valid.

BACKGROUND: The term perihilar cholangiocarcinoma has been used for all tumours involving or requiring resection of the hepatic confluence. However, it does not distinguish between intrahepatic and extrahepatic hilar tumours, and has no clinicopathological basis. This retrospective study examined whether the concept of perihilar cholangiocarcinoma is valid clinically. METHODS: Some 250 patients with perihilar cholangiocarcinoma were divided into extrahepatic (EHC, 167 patients) and intrahepatic (IHC, 83) groups based on tumour location. Clinicopathological data were compared between these groups. RESULTS: Liver, portal vein, venous and lymphatic invasion, and nodal metastasis were more common in IHCs than EHCs, whereas histological grade and incidence of perineural invasion were similar. IHCs were more advanced at the time of surgery; stage III or IV disease was found in 37.7 per cent of EHCs and 59 per cent of IHCs. Survival was marginally better for patients with EHCs than for those with IHCs (29.3 versus 20 per cent at 5 years; P = 0.057), but survival rates were similar for each tumour stage in the American Joint Committee on Cancer classification. CONCLUSION: Combining EHC and IHC under the term perihilar cholangiocarcinoma is valid, as these tumours have comparable biological behaviour, with similar clinical management depending on stage and invasion.

Roles of nitric oxide (NO) and NO synthases in healing of dextran sulfate sodium-induced rat colitis.

We examined the effects of various NO inhibitors on the healing of DSS-induced rat colitis. Experimental colitis was induced by feeding rats for 6 days with 2.5% DSS in drinking water. After DSS treatment, the animals were fed normally and killed various days up to 7 days later. L-NAME (a nonselective NOS inhibitor) or aminoguanidine (a selective iNOS inhibitor) was given p.o. twice daily for 6 days starting from the termination of DSS treatment. The area of lesions, colon length and MPO activity were measured on day 7 after DSS treatment. DSS treatment caused severe lesions in the colon, accompanied by an increase in MPO activity and a decrease in colon length. The lesions healed gradually after discontinuation of DSS treatment, with a histological restoration and subsidence of inflammation. The healing of DSS-induced colonic lesions was significantly impaired by daily administration of L-NAME or aminoguanidine, the effects being all but equivalent between these drugs, and the effect of L-NAME was significantly reverted by the co-administration of L-arginine. The expression of nNOS protein was observed in the colonic mucosa with or without DSS treatment, while those of iNOS and eNOS were markedly upregulated after DSS treatment. Likewise, the expression of VEGF was also up-regulated in the colon following DSS treatment, and this response was suppressed by both L-NAME and aminoguanidine. These results suggest that endogenous NO produced by mainly iNOS and partly eNOS contributes to the healing of DSS-induced colonic lesions, through the upregulation of VEGF expression and enhancement of angiogenesis.

Hypomutability at the polyadenine tract in SMN intron 3 shows the invariability of the a-SMN protein structure.

Recently, the axonal-SMN (a-SMN) protein, which is generated by the gene responsible for spinal muscular atrophy (SMA), SMN, has been reported. Surprisingly, the a-SMN transcript includes the entire sequence of SMN intron 3. We had expected a high frequency of insertion/deletion mutations at a polyadenine tract in this intron, since simple repetitive sequence motifs are prone to mutations. Such mutations could change the C-terminal structure of the a-SMN protein. However, our study showed that almost all individuals, including healthy individuals, SMA patients and SMA-like patients, carried only alleles with a normal polyadenine tract. Hypomutability of the polyadenine tract in SMN intron 3 suggests the existence of transcriptional mechanisms preventing alterations to the open reading frame of axonal SMN and not allowing variability in the protein structure of a-SMN.

New classification of cystic duct carcinoma.

BACKGROUND: Farrar's criteria for cystic duct carcinoma (histopathologic diagnosis of a carcinoma strictly limited to the cystic duct) are impractical especially when making a diagnosis of primary cystic duct carcinoma in its advanced stage. Therefore, in our previous study, we proposed a new definition of cystic duct carcinoma: a gallbladder tumor, the center of which is located in the cystic duct. In this study, we further propose a new classification for cystic duct carcinomas diagnosed by our definition. PATIENTS AND METHODS: This study included 44 surgical patients with cystic duct carcinoma diagnosed by our criteria. These patients were further classified into two groups: hepatic hilum type (HH, n = 29), in which the tumor mainly invades the hepatic hilum, and cystic confluence type (CC, n = 15), in which the tumor mainly involves the confluence of the cystic duct. The clinicopathologic features of these two groups were analyzed retrospectively. RESULTS: There was more papillary or well differentiated adenocarcinoma in the CC type lesions than in the HH type. The perineural and vascular invasion were more common in the HH type than in the CC type. The survival rate tends to be higher for patients with the CC type than for those with the HH type (p = 0.064). Moreover, we found a significantly different sex ratio between these two groups (female sex was predominant for the HH type, whereas male sex was predominant for the CC type). CONCLUSION: Our new classification showed two distinct types of advanced cystic duct carcinoma, which may help in understanding the clinical characteristics of the carcinoma originated in the cystic duct.

Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent.

BACKGROUND: Enterobacteria and cytokines both play roles in the pathophysiology of NSAID-induced enteropathy. Toll-like receptor (TLR) 4 recognises lipopolysaccharide (LPS), resulting in activation of an inflammatory cascade via the accessory protein MyD88. AIMS: To investigate role of TLR4 in inflammatory responses in indomethacin-induced enteropathy. METHODS: Indomethacin was administered p.o. to non-fasting rats and mice to induce small intestinal damage. The extent of such damage was evaluated by measuring the injured area stained dark blue with Evans blue. Rats were given antibiotics (ampicillin, aztreonam or vancomycin) p.o., or intraperitoneal LPS (a TLR4 ligand) or neutralising antibodies against neutrophils, tumour necrosis factor (TNF)-alpha, or monocyte chemotactic protein (MCP)-1. Furthermore, the intestinal ulcerogenicity of indomethacin was examined in TLR4-mutant, TLR4(-/-), and MyD88(-/-) mice. RESULTS: Indomethacin induced small intestinal damage with an increase in expression of TNF-alpha and MCP-1 in both rats and mice. Antibodies against neutrophils, TNF-alpha and MCP-1 inhibited the damage by 83%, 67% and 63%, respectively, in rats. Ampicillin and aztreonam also inhibited this damage, and decreased the number of Gram-negative bacteria in the small intestinal contents of the rat. However, vancomycin, which exhibited no activity against Gram-negative bacteria, had no preventive effect against this damage. Administration of LPS 1 h after indomethacin aggravated the damage, whereas LPS pretreatment inhibited it with reduction of expression of TLR4 and cytokines. In TLR4-mutant mice, the damage and cytokine expression were markedly inhibited. TLR4(-/-) and MyD88(-/-) mice were also resistant to the damage. CONCLUSIONS: Indomethacin may injure the small intestine through a TLR4/MyD88-dependent pathway.

Surgery for hilar cholangiocarcinoma: the Leeds experience.

AIM: To review the experience with hilar cholangiocarcinoma and to determine the results of a radical surgical approach in a UK centre. METHODS: A 10-year review of all patients treated surgically for proximal bile duct carcinoma at a single surgical unit was conducted. Patient demographics, disease details and histopathology reports were reviewed. From January 1993 through December 2003, 106 patients were admitted with the diagnosis of hilar cholangiocarcinoma and 61 patients received surgical exploration. RESULTS: Tumours were staged as follows (UICC 6th edition): stage IB, n=10 IIA, n=9; IIB, n=20; III, n=8; IV, n=14. Out of 61 patients, 44 had a resection (3 bile duct resection alone, 41 liver resection with bile duct resection), 5 were considered unresectable and 12 underwent liver transplantation (LT). The caudate lobe was excised in 34 of the patients and regional lymphadenectomy was systematically carried out. Para-aortic lymphadenectomy was performed in 17 cases. Portal vein resection was needed in 17 and hepatic artery resection was performed in 4 cases. Negative histologic margins (R0) were achieved in 20 patients and microscopic margin involvement (R1) was seen in 16. In the remaining 8 resected patients, localised metastasis were found (peritoneal deposits in 2, liver metastasis in 4 and positive para-aortic lymph nodes in 2); nevertheless the resection was performed and it was considered R2. Overall survival at 3 and 5 years for patients who underwent a resection was 43% and 28% including postoperative deaths. The 1-, 3- and 5-year actuarial survival rates for patients who underwent R0 resection were 78%, 64% and 45% respectively, including the postoperative deaths (n=3). The median survival time was 41.1 months. The 1-, 3- and 5-year actuarial survival rates for R1 resection and R2 were 60%, 26%, 26% and 25% and 0% respectively, while the median survival time for these groups was 15.4 and 6.8 months respectively. The actuarial survival rate at 1, 3 and 5 years for well-differentiated tumours (G1) was 73%, 54% and 40% (median 39.7 months). The figures for G2 were 60%, 48% and 0%. The figures for G3 (poorly differentiated) were 16% and 0% at three years (p=0.03).The overall survival at 3 and 5 years for those patients who had a liver transplant was 41% and 20% including early postoperative mortality. The tumour grading (presence of poorly differentiated tumour) was found to be the only independent factor affecting the survival time producing a hazard ratio of 4.3 (p=0.0034, 95% confidence interval 0.1007-6.342). CONCLUSIONS: Radical surgical resection is the best treatment for hilar cholangiocarcinoma. R0 resection provides acceptable 5-year survival, but R1 resection may also provide acceptable palliation. In our experience TNM stage and tumour grade were the main determinants of long-term survival.

Involvement of prostaglandin E receptor EP3 subtype and prostacyclin IP receptor in decreased acid response in damaged stomach.

We investigated the roles of cyclooxygenase (COX) isozymes and prostaglandin E (PGE) receptor EP1 and EP3 subtypes or prostacyclin IP receptors in the decrease in acid secretion in the damaged mouse stomach. Male C57/BL6 mice, both wild type and animals lacking EP1, EP3, or IP receptors, were used after 18 h of fasting. Under urethane anesthesia, the stomach was mounted on an ex-vivo chamber and perfused with saline, and acid secretion as well as transmucosal potential difference (PD) was measured before and after exposure to 20 mM taurocholate Na (TC) for 20 min. Indomethacin, SC-560 or rofecoxib was given i.d. 30 min before TC. Mucosal exposure to TC in wild-type mice caused a reduction in PD, followed by decrease in acid secretion. Indomethacin attenuated the decrease in acid secretion after exposure to TC in wild-type mice, an effect mimicked by SC-560 but not rofecoxib, yet none of these drugs affected the decrease in PD. An altered acid response after exposure to TC was similarly observed in EP1 (-/-) mice but mitigated in mice lacking either EP3 or IP receptors, although a decrease in PD was observed in all groups. Furthermore, the decreased acid response was also attenuated by prior administration of the EP3- but not EP1- antagonist. Mucosal levels of PGE(2) and 6-keto PGF(1a) increased after exposure to TC in all groups of mice. In conclusion, the decrease in acid secretion in the damaged stomach is mediated by endogenous PGs derived from COX-1, through PGE(2)/EP3 receptors and prostacyclin/IP receptors.