The protective role of phosphodiesterase inhibitors in preventing colorectal cancer and advanced colorectal polyps: a systematic review and meta-analysis.

AIM: Inflammatory cells within the tumour microenvironment are the driving forces behind colorectal cancer (CRC) tumourigenesis. Understanding the different pathways involved in CRC carcinogenesis paves the way for effective repurposing of drugs for cancer prevention. Emerging data from preclinical and clinical studies suggest that, due to their antiproliferative and anti-inflammatory properties, phosphodiesterase-5 inhibitors (PDE5i) might have an anticancer effect. The aim of this study was to clarify through systematic review and meta-analysis of published peer-reviewed studies whether an association exists between PDE5i use and CRC risk. METHOD: This study was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Prospective registration was performed on PROSPERO (CRD42022372925). A systematic review was performed for studies reporting CRC and advanced colorectal polyp incidence in PDE5i 'ever-users' and PDE5i 'never-users'. Meta-analysis was performed using RevMan version 5. RESULTS: Four observational cohort studies and two case-control studies, comprising 995 242 patients were included in the final analysis, of whom 347 126 were PDE5i ever-users. Patients who were PDE5i ever-users had a significantly lower incidence of CRC or advanced colorectal polyps than never-users (OR 0.88, CI 0.79-0.98, p = 0.02). To examine the primary preventative role of PDE5i, subgroup analysis of four studies including patients without a previous history of CRC found that use of PDE5i was associated with a lower incidence of CRC (OR 0.85, CI 0.75-0.95, p = 0.005, I2 = 64%). There was no significant temporal relationship found between PDE5i use and CRC risk as both current users and previous users had a significantly lower incidence of CRC than never-users. CONCLUSION: Our study found a significant anticancer effect of PDE5i, as shown by a reduced risk of CRC in the context of both primary and secondary CRC prevention.

Prophylactic negative wound therapy in laparotomy wounds (PROPEL trial): randomized controlled trial.

BACKGROUND: Superficial surgical site infections are a common post-operative complication. They also place a considerable financial burden on healthcare. The use of prophylactic negative pressure wound therapy has been advocated to reduce wound infection rates. However, there is debate around its routine use. The purpose of this trial is to determine if prophylactic negative pressure wound therapy reduces post-operative wound complications in patients undergoing laparotomy. METHODS/DESIGN: This multi-centre randomised controlled trial will compare standard surgical dressings (control) to two competing negative pressure wound therapy dressings (Prevena™ and PICO™). All patients will be over 18 years, who are undergoing an emergency or elective laparotomy. It is intended to enrol a total of 271 patients for the trial. DISCUSSION: The PROPEL trial is a multi-centre randomised controlled trial of patients undergoing laparotomy. The comparison of standard treatment to two commercially available NPWT will help provide consensus on the routine management of laparotomy wounds. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov (NCT number NCT03871023).

An evaluation of the quality and content of web-based stoma information.

AIM: Although the internet is commonly the first port of call for medical information, it provides unregulated data of variable quality. We aimed to evaluate commonly accessed web-based information on intestinal stomas using validated and novel scoring systems. METHOD: The keywords 'stoma', 'colostomy', 'ileostomy' and 'bowel bag' were entered into the most commonly used internet search engines (Google, Bing and Yahoo). The first ten websites from each search were analysed using the validated Journal of the American Medical Association (JAMA) benchmark criteria and DISCERN scoring systems. A novel stoma-specific score was devised and applied. RESULTS: Forty-three unique websites were identified. The majority (49%) were from nonprofit or governmental agencies and 9% were from commercial entities. The mean total DISCERN score for all websites was 42.4 ± 10.2 (maximum possible score = 75). The mean JAMA and stoma-specific scores were 2.1 ± 1.0 (maximum possible score = 4) and 12.9 ± 6.1 (maximum possible score = 27). The lowest JAMA scores were in the category of attribution, with 70% of websites lacking references for the information provided. A total of 88% displayed disclosure/paid advertiser information. Surgery was described in 67%. An image or diagram was provided in 58% and in 72% a stoma therapist/nurse was mentioned. Information on when to seek medical help was provided in 51%. CONCLUSION: Web-based information on stomas is of variable content and quality. Authorship and information sources are often unclear. Only half provided information on when to seek medical help for complications including high output and dehydration. These findings should be highlighted to patients who utilize the internet to obtain information on stomas.

Self-expanding metal stent insertion by colorectal surgeons in the management of obstructing colorectal cancers: a 6-year experience.

BACKGROUND: Placement of a self-expanding metal stent (SEMS) in patients presenting with colorectal cancer as an acute large bowel obstruction may obviate emergency surgery, potentially effectively palliating incurable cancers and acting as a bridge to surgery in patients with operable tumours. We present our experience with stenting for malignant acute large bowel obstruction over a 6-year period (2006-2011). METHODS: A prospectively compiled colorectal cancer database was reviewed to identify all patients presenting to our unit with malignant acute large bowel obstruction who had stenting carried out to achieve colonic decompression. All 44 procedures were performed by colorectal surgeons using a combined endoscopic and fluoroscopic technique. RESULTS: Overall, successful decompression was achieved in 42 patients by SEMS insertion (95.5%). Technical and clinical success was achieved in all 30 patients undergoing stenting as a palliative measure (100%). There was no clinical perforation in any of the 44 patients. CONCLUSIONS: SEMSs insertion is a safe and effective technique for colonic decompression in the setting of acute malignant large bowel obstruction as either a palliative measure or as a bridge to subsequent resection.

Case Report: Thrombotic-Thrombocytopenic Purpura Following Ipilimumab and Nivolumab Combination Immunotherapy for Metastatic Melanoma.

A man in his early 50s presented with small bowel obstruction, requiring emergency laparoscopic small bowel resection for the metastatic melanoma of the jejunum with no identifiable primary lesion. One week after his first treatment with ipilimumab and nivolumab, he presented with diffuse abdominal pain, constipation, and fatigue. A computerized tomography scan did not identify a cause for his symptoms. This was rapidly followed by thrombocytopenia on day 11 and then anemia. He commenced intravenous corticosteroids for a suspected diagnosis of immune-related thrombocytopenia. On day 15, a generalized onset motor seizure occurred, and despite plasmapheresis later that day, the patient died from fatal immune-related thrombotic thrombocytopenic purpura (TTP). This was confirmed with suppressed ADAMTS13 (<5%) testing on day 14. Immune-related TTP is a rare and, in this case, fatal immune- related adverse event. Further studies are required to identify additional immunosuppressive management for immune-related TTP.

Characterization of a phosphatidylinositol-specific phosphoinositide 3-kinase from mammalian cells.

BACKGROUND: As phosphoinositides can serve as signalling molecules within cells, the enzymes responsible for their synthesis and cleavage are likely to be involved in the transduction of signals from the cell surface through the cytoplasm. The precise role of the phosphoinositide 3-kinase that has been cloned from mammalian cells is not known, but it has been implicated in receptor-stimulated mitogenesis, glucose uptake and membrane ruffling. The enzyme can use phosphatidylinositol (PtdIns), PtdIns 4-phosphate and PtdIns (4,5)-bisphosphate as substrates in vitro, but it seems to phosphorylate PtdIns (4,5)-bisphosphate preferentially in vivo. The VPS34 gene product of yeast, by contrast, is a phosphoinositide 3-kinase homologue implicated in vacuolar protein sorting that apparently utilizes only PtdIns as a substrate. The significance of this difference in lipid-substrate preference and its relationship to the functions of the two phosphoinositide kinases is unknown. RESULTS: We have characterized a distinct PtdIns-specific phosphoinositide 3-kinase activity in mammalian cells. Unlike the previously identified, broad-specificity mammalian phosphoinositide kinase, this enzyme is resistant to the drug wortmannin and uses only PtdIns as a substrate in vitro; it therefore has the capacity to generate PtdIns 3-phosphate specifically. The newly characterized enzyme, which was purified by chromatography from cytosol, has biochemical and pharmacological characteristics distinct from those of the broad-specificity enzyme. CONCLUSIONS: The enzyme we have characterized may serve to generate PtdIns 3-phosphate for fundamentally different roles in the cell from those of PtdIns (3,4)-bisphosphate and/or PtdIns (3,4,5)-trisphosphate. Furthermore, the functions of the VSP34 gene product, which may not be relevant to the broad-specificity mammalian phosphoinositide 3-kinase, may be related to those of the enzyme we describe.

Activation of phosphoinositide 3-kinase is required for PDGF-stimulated membrane ruffling.

BACKGROUND: There is substantial evidence that phosphoinositide 3-kinase (PI 3-kinase) is a critical component of signalling pathways used by the cell-surface receptors for a variety of mammalian growth factors and other hormones. The physiological product of this enzyme is a highly polar membrane lipid called phosphatidylinositol (3,4,5)-trisphosphate This lipid has been postulated to act as a second-messenger in cells but its putative targets are still unknown. RESULTS: A particular rearrangement of actin filaments, which results in membrane ruffling, is elicited by the activation of PDGF beta-receptors expressed in cultured porcine aortic endothelial cells. We have found that this consequence of PDGF beta-receptor activation is inhibited by three independent manipulations of PI 3-kinase activity: firstly, by the deletion of tyrosine residues in the PDGF beta-receptor to which PI 3-kinase binds; secondly, by the overexpression of a mutant 85 kD PI 3-kinase regulatory subunit to which the catalytic kinase subunit cannot bind; and thirdly, by the addition of the fungal metabolite wortmannin, which is a potent inhibitor of the catalytic activity of PI 3-kinase. CONCLUSIONS: These results argue strongly that phosphatidylinositol (3,4,5)-trisphosphate synthesis is required for growth-factor-stimulated membrane ruffling in porcine aortic endothelial cells, and suggest that synthesis of this lipid may be part of a signalling pathway leading to direct or indirect activation of the small GTP-binding protein Rac.

PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase.

BACKGROUND: Phosphoinositide 3-kinases (PI 3-kinases) are thought to play an important role in coordinating the responses elicited by a variety of growth factors, oncogene products and inflammatory stimuli. These responses include activation of membrane ruffling, chemotaxis, glucose transport, superoxide production, neurite outgrowth and pp70 S6 kinase. Some of these responses are also known to be regulated by Rac, a small GTP-binding protein related to Ras. Neither the transducing elements upstream of Rac, nor those downstream of PI 3-kinase, have been defined. RESULTS: We show here that platelet-derived growth factor (PDGF) can stimulate an increase in the level of GTP-Rac by at least two distinct mechanisms: firstly, by increased guanine nucleotide exchange; and secondly, by inhibition of a Rac GTPase activity. The first of these mechanisms is essential for the activation of Rac, and we show that it is dependent upon PDGR-stimulated synthesis of phosphatidylinositol (3,4,5)-trisphosphate. CONCLUSIONS: These results suggest that Rac activation lies downstream of PI 3-kinase activation on a PDGF-stimulated signalling pathway. Furthermore, as Rac has been implicated in at least two diverse cellular responses that are also though to require activation of PI 3-kinase--a reorganization of the actin cytoskeleton known as membrane ruffling and the neutrophil oxidative burst--these results suggest that Rac may be a major effector protein for the PI 3-kinase signalling pathway in many cell types.

The stress-activated phosphatidylinositol 3-phosphate 5-kinase Fab1p is essential for vacuole function in S. cerevisiae.

Polyphosphoinositides have many roles in cell signalling and vesicle trafficking [1-3]. Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), a recently discovered PIP2 isomer, is ubiquitous in eukaryotic cells and rapidly accumulates in hyperosmotically stressed yeast. PI(3,5)P2 is synthesised from PI(3)P in both yeast and mammalian cells [4,5]. A search of the Saccharomyces cerevisiae genome database identified FAB1, a gene encoding a PIP kinase homologue and potential PI(3)P 5-kinase. Fab1p shows PI(3)P 5-kinase activity both in vivo and in vitro. A yeast strain in which FAB1 had been deleted was unable to synthesise PI(3,5)P2, either in the presence or absence of osmotic shock. A loss of PI(3,5)P2 was observed also in a temperature-sensitive FAB1 strain at the non-permissive temperature. A recombinant glutathione-S-transferase (GST)-Fab1p fusion protein was shown to have selective PI(3)P 5-kinase activity in vitro. Thus, we have demonstrated that Fab1p is a PI(3)P-specific 5-kinase and represents a third class of PIP kinase activity, which we have termed type III. Deletion of the FAB1 gene produces a loss of vacuolar morphology [6]; it is therefore concluded that PI(3,5)P2, the lipid product of Fab1p, is required for normal vacuolar function.

Characterisation of Exiguobacterium aurantiacum isolates from blood cultures of six patients.

Exiguobacterium spp. are alkaliphilic, halotolerant, non-spore-forming Gram-positive bacilli, hitherto uncharacterized from human infections. Six isolates of Exiguobacterium aurantiacum were obtained from patients with bacteraemia, three of whom had myeloma. All isolates formed orange-yellow pigmented colonies on blood agar, were catalase- and DNase-positive, and grew on nutrient agar at pH 10 and in the presence of NaCl 6% w/v. The six isolates were susceptible to all antimicrobial agents tested and were uniform in their fatty acid and mass spectrum profiles.

Insulin and ATP stimulate actin polymerization in U937 cells by a wortmannin-sensitive mechanism.

ATP and insulin stimulate increases in phosphatidylinositol (3,4,5)-trisphosphate levels in myeloid-derived U937 cells. Quantification of FITC-phalloidin binding by fluorescence-activated cell sorting reveals that both ATP and insulin stimulate actin polymerization with distinctive kinetics in U937 cells. The response to ATP is rapid and dose-dependent with an EC50 of 200 nM, and is abolished by pre-incubation with the Ca2+ chelator BAPTA-AM. At 800 nM concentration, wortmannin, a potent inhibitor of phosphoinositide 3-kinase (PI3K), blocks the late, but not the early phase of actin polymerization stimulated by 100 nM ATP. Responses elicited by 10 micrograms/ml insulin are slower, smaller and more transient than responses to ATP, and are inhibited by preincubation with 100 nM wortmannin. Actin polymerization can also be stimulated by thapsigargin, but not by phorbol ester, providing further evidence for a role for Ca2+ in actin polymerization. These data implicate distinct Ca2+ and PI3K-mediated pathways in the regulation of actin polymerization.

Disseminated Aspergillus terreus infection arising from cutaneous inoculation treated with caspofungin.

A case of disseminated Aspergillus terreus infection in a patient with prolonged neutropenia after stem cell transplant for myeloma is reported. The isolate was resistant to amphotericin B in vitro, and the patient was successfully managed with surgical debridement and the recently licensed antifungal agent caspofungin. There are many challenges associated with treating invasive aspergillosis, particularly that due to A. terreus, and the early use of caspofungin should be considered.

An evaluation of porous alumina ceramic dental implants.

The fabrication, characterization, and clinical results of porous rooted alumina dental implants in animals are presented. Failures of all implants occurred in less than six months and were attributed to the presence of microporosity on the crown and cervical portion of the implant which prevented the establishment of an effective biological seal between the oral cavity and the alveolus.

Treatment of the unstable intertrochanteric fracture. Effect of the placement of the screw, its angle of insertion, and osteotomy.

We created unstable intertrochanteric fractures with a large posteromedial defect in eighteen pairs of fresh-frozen femora from cadavera, and used the femora to evaluate the stability of six combinations of treatment with sliding compression screws and sideplates. The variables that were tested were high (150-degree) angle plates compared with low (130-degree) angle plates, the position of the lag-screw in the femoral head and neck (in the center of the head as seen on both anteroposterior and lateral roentgenograms compared with posteroinferiorly), and whether or not medial cortical contact had been re-established with a limited osteotomy of the greater trochanter. The femora were loaded to the point of failure. The mode of failure, maximum load to failure, and bending rigidity of each method of fixation were measured. Of the six types of treatment, the use of a 150-degree-angle plate, position of the lag-screw in the center of the head as seen on both anteroposterior and lateral roentgenograms, and osteotomy of the greater trochanter resulted in the highest mean load to failure and the greatest rigidity. Over-all, re-establishment of medial cortical contact by means of an osteotomy of the greater trochanter significantly improved the mean load to failure and the rigidity of the fixation. The higher-angle plate, although more difficult to insert, increased the mean load to failure but had no effect on rigidity. The position of the lag-screw (in the center of the head as seen on both anteroposterior and lateral roentgenograms or posteroinferiorly) had no bearing on the mean load to failure, but it significantly affected the mode of failure.

Fitness consequences of egg-size variation in the lesser snow goose.

We investigated the relationship between eggsize variation and (a) egg hatching success, (b) chick survival to fledging and recruitment, and (c) adult female survival, over 12 years in the lesser snow goose (Anser caerulescens caerulescens). By comparing the means and variances of egg size for successful and unsuccessful eggs, our aim was to assess the relative fitness of eggs of different sizes and to determine the type of selection operating on egg size in this species. As both egg size and reproductive success vary with age in the lesser snow goose we controlled for the effects of female age. Egg-size variation is very marked in this population, varying by up to 52% for eggs hatching successfully. However, there was no relationship between egg size and post-hatching survival of goslings to fledging or recruitment, either within or between broods, pooling across years. Egg size varied significantly between successful and unsuccessful clutches in only 2 of 33 individual year comparisons. First-laid eggs surviving to onset of incubation, and eggs hatching successfully, were on average larger than unsuccessful eggs, but this was probably due to the confounding effects of female age-specific and sequence-specific egg survival. Variance of egg size differed significantly between successful and unsuccessful eggs in only 3 of 24, and 0 of 21, individual year comparisons for pre- and post-hatching survival respectively. We therefore found little evidence for a relationship between egg-size variation and offspring fitness, or for strong directional, normalising or diversifying selection operating on egg size, in the lesser snow goose. In addition, there was only weak support for the hypothesis that egg-size variation is maintained by temporal variation in selection pressure (sensu Ankney and Bisset 1973). It is likely that egg-size variation represents the pleiotropic expression of alleles affecting more general physiological or metabolic processes. While this does not rule out the existence of alleles with more direct effects on egg size we suggest that their contribution to heritable egg size is small.

Environmental change and the cost of philopatry: an example in the lesser snow goose.

The consequences of philopatric and dispersal behaviours under changing environmental conditions were examined using data from the colony of Lesser Snow Geese (Anser caerulescens caerulescens) breeding at La Pérouse Bay, Manitoba, Canada. In response to increased population size and decreased food abundance over time, increasing numbers of family groups have been dispersing from the traditional feeding areas. Goslings from dispersed broods were significantly heavier (7.3%), and had longer culmens (3.1%), head lengths (2.6%) and marginally longer tarsi (1.9%) on average than goslings that remained within La Pérouse Bay itself. These differences were consistent in each of 5 years. There was no evidence that the larger size of dispersed goslings was due to either a tendency for larger adults to disperse to alternative sites, or increased mortality of smaller goslings among dispersed broods. The most likely cause for the larger size of goslings from dispersed broods was the significantly greater per capita availability of the preferred salt-marsh forage species at non-traditional brood-rearing areas. The larger goslings in non-traditional feeding areas showed significantly higher firstyear survival, suggesting that the use of deteriorating traditional feeding areas may currently be maladaptive in this population.