Are periodontitis and psoriasis associated? A pre-clinical murine model.

AIM: To investigate the bidirectional influence between periodontitis and psoriasis, using the respective experimental models of ligature- and imiquimod-induced diseases on murine models. MATERIALS AND METHODS: Thirty-two C57/BL6J mice were randomly allocated to four experimental groups: control (P- Pso-), ligature-induced periodontitis (P+ Pso-), imiquimod-induced psoriasis (P- Pso+) and periodontitis and psoriasis (P+ Pso+). Samples (maxilla, dorsal skin and blood) were harvested immediately after death. Measures of periodontitis (distance between the cemento-enamel junction and alveolar bone crest [CEJ-ABC] and the number of osteoclasts) and psoriasis (epidermal thickness and infiltrate cell [/0.03mm2]) severity as well as systemic inflammation (IL-6, IL-17A, TNF-α) were collected. RESULTS: The P+ Pso+ group exhibited the most severe experimental periodontitis and psoriasis, with the highest values of CEJ-ABC, number of osteoclasts, epidermal thickness and infiltrate cells in the dorsal skin, as well as the highest blood cytokine concentration. The P+ Pso- group presented with higher cell infiltrate (/0.03mm2) compared to the control group (p <.05), while the P- Pso+ group showed substantially higher alveolar bone loss (CEJ-ABC) than the control group (p <.05). CONCLUSIONS: Experimental periodontitis may initiate and maintain psoriasiform skin inflammation and, vice versa, experimental psoriasis may contribute to the onset of periodontitis. In a combined model of the diseases, we propose a bidirectional association between periodontitis and psoriasis via systemic inflammation.

Indications for staging laparoscopy in pancreatic cancer.

BACKGROUND: To identify indications for staging laparoscopy (SL) in patients with resectable pancreatic cancer, and suggest a pre-operative algorithm for staging these patients. METHODS: Relevant articles were reviewed from the published literature using the Medline database. The search was performed using the keywords 'pancreatic cancer', 'resectability', 'staging', 'laparoscopy', and 'Whipple's procedure'. RESULTS: Twenty four studies were identified which fulfilled the inclusion criteria. Of the published data, the most reliable surrogate markers for selecting patients for SL to predict unresectability in patients with CT defined resectable pancreatic cancer were CA 19.9 and tumour size. Although there are studies suggesting a role for tumour location, CEA levels, and clinical findings such as weight loss and jaundice, there is currently not enough evidence for these variables to predict resectability. Based on the current data, patients with a CT suggestive of resectable disease and (1) CA 19.9 ≥150 U/mL; or (2) tumour size >3 cm should be considered for SL. CONCLUSION: The role of laparoscopy in the staging of pancreatic cancer patients remains controversial. Potential predictors of unresectability to select patients for SL include CA 19.9 levels and tumour size.

Critical review of the prognostic significance of pathological variables in patients undergoing resection for colorectal liver metastases.

OBJECTIVE: The aim of this study was to identify prognostic factors, particularly pathological variables, that influence disease-free and overall survival following resection for colorectal liver metastases (CRLM). METHODS: Patients undergoing CRLM resection from January 2005 to December 2011 were included. Data analysed included information on demographics, laboratory results, operative findings, histopathological features and survival. RESULTS: A total of 259 patients were included. Of these, 138 (53.3%) patients developed recurrent disease, of which 95 died. The median length of follow-up in the remaining patients was 28 months (range: 12-96 months). There were significant associations between recurrence and higher tumour number (P = 0.002), presence of perineural invasion (P = 0.009) and positive margin (R1) resection (P = 0.002). Multivariate analysis showed all three prognostic factors to be independent predictors of disease-free survival. Significantly poorer overall survival after hepatic resection for CRLM was observed in patients undergoing hemi-hepatectomy or more radical resection (P = 0.021), patients with a higher number of tumours (P = 0.024) and patients with perineural invasion (P < 0.001). Multivariate analysis showed perineural invasion to be the only independent predictor of overall survival. CONCLUSIONS: The presence of perineural invasion, multiple tumours and an R1 margin were associated with recurrent disease. Perineural invasion was also an independent prognostic factor with respect to overall survival.

Stage IV colorectal cancer: outcomes following the liver-first approach.

BACKGROUND: To date, there is limited data on the liver-first approach in the management of colorectal liver metastases (CRLM). The aim of the study was to assess the outcomes of the liver-first approach for patients with synchronous CRLM in two tertiary referral centers. METHODS: Patients with stage IV colorectal cancer selected for the liver-first approach from January 2009 to December 2012 in two tertiary referral centers were included. Data collated included demographics, chemotherapy, operative findings, histo-pathological features, and survival. RESULTS: Thirty-seven patients with synchronous CRLM were considered for the liver-first approach. Twenty-five patients had rectal cancer. All patients underwent induction chemotherapy. Thirty patients underwent hepatic resections with no post-operative deaths. Following liver resection, five patients failed to proceed to colorectal resection and one patient had complete response to chemo-radiotherapy. Of the 25 patients that completed the liver-first approach, 13 patients had recurrent disease, of which 12 patients died. The overall 1- and 3-year survival rates were 65.9% and 30.4%, respectively. CONCLUSION: The liver-first approach is a feasible strategy for patients with synchronous CRLM and may improve survival in selected patients. The selection of patients should be incorporated in a multidisciplinary approach to achieve the best possible outcomes.

In vitro and in vivo characterization of a novel Hedgehog signaling antagonist in human glioblastoma cell lines.

Glioblastoma multiforme (GBM) is composed of heterogeneous and genetically different cells, which are highly invasive and motile. The standard chemotherapeutic agent, temozolomide, affects GBM cell proliferation but is generally unable to prevent tumor recurrence. Hedgehog pathway activation has been reported to be relevant in GBM and different pharmacological pathway modulators have been identified. We report that by growing a commercially available recurrent GBM cell line (DBTRG-05MG) without serum and in the presence of defined growth factors; we obtained a less differentiated cell population, growing in suspension as neurospheres, in which the Hedgehog pathway is activated. Furthermore, the expression profile of Hedgehog pathway components found in DBTRG-05MG neurospheres is similar to primary stem-like cells derived from recurrent GBM patients. We report the effect of our novel specific Smoothened receptor antagonist (SEN450) on neurosphere growing cells and compared its effect to that of well known benchmark compounds. Finally, we showed that SEN450 is both antiproliferative on its own and further reduces tumor volume after temozolomide pretreatment in a mouse xenograft model using DBTRG-05MG neurosphere cells. Altogether our data indicate that the Hedgehog pathway is not irreversibly switched off in adherent cells but can be reactivated when exposed to well-defined culture conditions, thus restoring the condition observed in primary tumor-derived material, and that pharmacological modulation of this pathway can have profound influences on tumor proliferation. Therefore, pharmacological inhibition of the Hedgehog pathway is a potentially useful therapeutic approach in GBM.

The radiological management of pseudoaneurysms complicating pancreatitis.

CONTEXT: Pseudoaneurysms associated with pancreatitis are rare, and bleeding pseudoaneurysms are associated with a high mortality. OBJECTIVE: The aim of this study was to report the outcomes of endovascular and percutaneous therapy in the management of pseudoaneurysms secondary to pancreatitis. PATIENTS: Patients who underwent angiography for pseudoaneurysms associated with pancreatitis from 2005 to 2011 were identified from the angiography database. MAIN OUTCOME MEASURES: Patient demographics, clinical presentation, radiological findings, treatment, and outcomes were retrospectively reviewed. RESULTS: Nineteen pseudoaneurysms associated with pancreatitis in 13 patients were identified. The diagnosis of a pseudoaneurysm was made by computerised tomography angiography in seven patients, followed by portal venous phase contrast enhanced CT (n=4), duplex ultrasound (n=1) and angiography (n=1). At angiography, coil embolisation was attempted in 11 patients with an initial success rate of 82% (n=9). One patient underwent successful embolisation with percutaneous thrombin injection. The recurrence rate following initial successful embolisation was 11% (n=1). There were no episodes of re-bleeding following embolisation but re-bleeding following thrombin injection was observed in one case. The morbidity and mortality rate in the 12 patients that were successfully treated was 25% (n=3) and 8% (n=1), respectively. All 12 patients that were successfully treated demonstrated radiological resolution of their pseudoaneurysms, with a median follow-up of 20 months. CONCLUSION: Endovascular embolisation is a suitable first-line management strategy associated with low recurrence rates. The role of percutaneous thrombin injection is yet to be defined.

Standard versus tubeless percutaneous nephrolithotomy: a systematic review.

OBJECTIVE: This article systematically analyses comparative studies to evaluate the efficacy and safety of tubeless percutaneous nephrolithotomy (PCNL) versus standard PCNL. METHODS: The Medline, EMBASE, PsycINFO, Cochrane and DARE databases were searched from 1997 to February 2011. Comparative studies evaluating outcomes from standard versus tubeless PCNL were included. Primary outcome measures were post-operative pain scoring, analgesic requirements, duration of hospitalisation/convalescence, operation time, major/minor complications and stone-free rates. RESULTS: Twenty-four studies were included (11 randomised control trials and 13 retrospective or prospective studies). Levels of pain recorded, analgesic requirements, duration of inpatient stay and convalescence time were all significantly reduced in the tubeless PCNL group. Cost was reduced in two studies. Morbidity was not significantly different between the groups. There was no significant difference between groups regarding stone-free status. DISCUSSION: This systematic review has demonstrated that tubeless PCNL is a viable alternative to tubed PCNL in uncomplicated cases. Benefits are as described above. There is no evidence suggesting that patient safety is compromised by the absence of post-operative nephrostomy. The tubeless method has been reported in challenging cases such as stag-horn stones, horseshoe or ectopic kidneys. Promising outcomes have been demonstrated in elderly patients and when clinical needs demand a supracostal approach. Multi-centre randomised controlled trials are needed to fully establish the effectiveness of the tubeless method.

Multimodal molecular imaging system for pathway-specific reporter gene expression.

Preclinical imaging modalities represent an essential tool to develop a modern and translational biomedical research. To date, Optical Imaging (OI) and Magnetic Resonance Imaging (MRI) are used principally in separate studies for molecular imaging studies. We decided to combine OI and MRI together through the development of a lentiviral vector to monitor the Wnt pathway response to Lithium Chloride (LiCl) treatment. The construct was stably infected in glioblastoma cells and, after intracranial transplantation in mice, serial MRI and OI imaging sessions were performed to detect human ferritin heavy chain protein (hFTH) and firefly luciferase enzyme (FLuc) respectively. The system allowed also ex vivo analysis using a constitutive fluorescence protein expression. In mice, LiCl administration has shown significantly increment of luminescence signal and a lower signal of T2 values (P<0.05), recorded noninvasively with OI and a 7 Tesla MRI scanner. This study indicates that OI and MRI can be performed in a single in vivo experiment, providing an in vivo proof-of-concept for drug discovery projects in preclinical phase.

Identification and characterization of a small-molecule inhibitor of Wnt signaling in glioblastoma cells.

Glioblastoma multiforme (GBM) is the most common and prognostically unfavorable form of brain tumor. The aggressive and highly invasive phenotype of these tumors makes them among the most anatomically damaging human cancers with a median survival of less than 1 year. Although canonical Wnt pathway activation in cancers has been historically linked to the presence of mutations involving key components of the pathway (APC, ß-catenin, or Axin proteins), an increasing number of studies suggest that elevated Wnt signaling in GBM is initiated by several alternative mechanisms that are involved in different steps of the disease. Therefore, inhibition of Wnt signaling may represent a therapeutically relevant approach for GBM treatment. After the selection of a GBM cell model responsive to Wnt inhibition, we set out to develop a screening approach for the identification of compounds capable of modulating canonical Wnt signaling and associated proliferative responses in GBM cells. Here, we show that the small molecule SEN461 inhibits the canonical Wnt signaling pathway in GBM cells, with relevant effects at both molecular and phenotypic levels in vitro and in vivo. These include SEN461-induced Axin stabilization, increased ß-catenin phosphorylation/degradation, and inhibition of anchorage-independent growth of human GBM cell lines and patient-derived primary tumor cells in vitro. Moreover, in vivo administration of SEN461 antagonized Wnt signaling in Xenopus embryos and reduced tumor growth in a GBM xenograft model. These data represent the first demonstration that small-molecule-mediated inhibition of Wnt signaling may be a potential approach for GBM therapeutics.

The need for early treatment of clubfeet in peripheral hospitals in sub-Saharan Africa: a survey of clubfoot management in Zambia.

In the developing world, neglected clubfoot often results in a permanent and disabling deformity with subsequent social implications. Data from the four organizations that manage clubfoot in Zambia were collected using clinic and operating room registries and analyzed using Fisher exact test. In the central hospitals in the capital city 65% (204/313 feet) of clubfeet were suitable for treatment by the Ponseti method compared with only 23% (38/166 feet) in the peripheral hospitals (P < 0.001, two-tailed Fisher's exact test). In the central hospitals only 14% (42/313 feet) of clubfeet required extensive surgery for neglected clubfeet compared with 29% (49/116 feet) in peripheral hospitals (P < 0.015, two-tailed Fisher's exact test). Patients from outside the capital have a higher percentage of neglected clubfeet that are no longer suitable for conservative management and require extensive, complex and costly surgical treatment. By allowing earlier access to less invasive procedures the burden of disability may be reduced.

Retrospective study of patients with acute pancreatitis: is serum amylase still required?

OBJECTIVES: To assess the role of serum amylase and lipase in the diagnosis of acute pancreatitis. Secondary aims were to perform a cost analysis of these enzyme assays in patients admitted to the surgical admissions unit. DESIGN: Cohort study. SETTING: Secondary care. PARTICIPANTS: Patients admitted with pancreatitis to the acute surgical admissions unit from January to December 2010 were included in the study. METHODS: Data collated included demographics, laboratory results and aetiology. The cost of measuring a single enzyme assay was £0.69 and both assays were £0.99. RESULTS: Of the 151 patients included, 117 patients had acute pancreatitis with gallstones (n=51) as the most common cause. The majority of patients with acute pancreatitis had raised levels of both amylase and lipase. Raised lipase levels only were observed in additional 12% and 23% of patients with gallstone-induced and alcohol-induced pancreatitis, respectively. Overall, raised lipase levels were seen in between 95% and 100% of patients depending on aetiology. Sensitivity and specificity of lipase in the diagnosis of acute pancreatitis was 96.6% and 99.4%, respectively. In contrast, the sensitivity and specificity of amylase in diagnosing acute pancreatitis were 78.6% and 99.1%, respectively. Single lipase assay in all patients presenting with abdominal pain to the surgical admission unit would result in a potential saving of £893.70/year. CONCLUSIONS: Determining serum lipase level alone is sufficient to diagnose acute pancreatitis and substantial savings can be made if measured alone.

A radial glia gene marker, fatty acid binding protein 7 (FABP7), is involved in proliferation and invasion of glioblastoma cells.

Glioblastoma multiforme (GBM) is among the most deadly cancers. A number of studies suggest that a fraction of tumor cells with stem cell features (Glioma Stem-like Cells, GSC) might be responsible for GBM recurrence and aggressiveness. GSC similarly to normal neural stem cells, can form neurospheres (NS) in vitro, and seem to mirror the genetic features of the original tumor better than glioma cells growing adherently in the presence of serum. Using cDNA microarray analysis we identified a number of relevant genes for glioma biology that are differentially expressed in adherent cells and neurospheres derived from the same tumor. Fatty acid-binding protein 7 (FABP7) was identified as one of the most highly expressed genes in NS compared to their adherent counterpart. We found that down-regulation of FABP7 expression in NS by small interfering RNAs significantly reduced cell proliferation and migration. We also evaluated the potential involvement of FABP7 in response to radiotherapy, as this treatment may cause increased tumor infiltration. Migration of irradiated NS was associated to increased expression of FABP7. In agreement with this, in vivo reduced tumorigenicity of GBM cells with down-regulated expression of FABP7 was associated to decreased expression of the migration marker doublecortin. Notably, we observed that PPAR antagonists affect FABP7 expression and decrease the migration capability of NS after irradiation. As a whole, the data emphasize the role of FABP7 expression in GBM migration and provide translational hints on the timing of treatment with anti-FABP7 agents like PPAR antagonists during GBM evolution.

Reactive oxygen species regulate the levels of dual oxidase (Duox1-2) in human neuroblastoma cells.

Dual Oxidases (DUOX) 1 and 2 are efficiently expressed in thyroid, gut, lung and immune system. The function and the regulation of these enzymes in mammals are still largely unknown. We report here that DUOX 1 and 2 are expressed in human neuroblastoma SK-N-BE cells as well as in a human oligodendrocyte cell line (MO3-13) and in rat brain and they are induced by platelet derived growth factor (PDGF). The levels of DUOX 1 and 2 proteins and mRNAs are induced by reactive oxygen species (ROS) produced by the membrane NADPH oxidase. As to the mechanism, we find that PDGF stimulates membrane NADPH oxidase to produce ROS, which stabilize DUOX1 and 2 mRNAs and increases the levels of the proteins. Silencing of gp91(phox) (NOX2), or of the other membrane subunit of NADPH oxidase, p22(phox), blocks PDGF induction of DUOX1 and 2. These data unravel a novel mechanism of regulation of DUOX enzymes by ROS and identify a circuitry linking NADPH oxidase activity to DUOX1 and 2 levels in neuroblastoma cells.

Gangrenous cystitis in a 42-year-old male.

Gangrenous cystitis is now an extremely rare condition since the widespread use of antibiotics. The authors report a case of gangrenous cystitis in a previously fit and normal 42-year-old male who presented in acute urinary retention. He underwent a partial cystectomy during an exploratory laparotomy for clinical deterioration and peritonitis. Diagnosis of this rare disease is challenged by its low incidence and lack of characteristic pathognomic features, resulting in delayed diagnosis and increased morbidity and mortality. The authors review the literature to date on the aetiology, presentation, diagnosis and management of gangrenous cystitis and emphasise the importance of early and aggressive surgical management.