Addressing Within-Role Conflicts of Interest in Surgery

In this paper we argue that surgeons face a particular kind of within-role conflict of interests, related to innovation. Within-role conflicts occur when the conflicting interests are both legitimate goals of professional activity. Innovation is an integral part of surgical practice but can create within-role conflicts of interest when innovation compromises patient care in various ways, such as by extending indications for innovative procedures or by failures of informed consent. The standard remedies for conflicts of interest are transparency and recusal, which are unlikely to address this conflict, in part because of unconscious bias. Alternative systemic measures may be more effective, but these require changes in the culture of surgery and accurate identification of surgical innovation.     

Human fibronectin is synthesized as a pre-propolypeptide

Fibronectins (FNs) are extracellular glycoproteins consisting of dimers or multimers of similar but not identical subunits. The subunit differences result from variations in internal primary sequence due to alternative splicing in at least 2 regions of the pre-mRNA. The complete amino acid sequence of mature human cellular FN has been reported recently from cDNA cloning and sequencing. The same approach has now enabled us to deduce, for the first time, that FN has a 26 amino acid signal peptide and that it undergoes proteolytic processing at its N-terminus to eliminate a 5 amino acid pro-sequence (Ser-Lys-Ser-Lys-Arg). The signal sequence matches the consensus format, while this pro-sequence is a distinctive, very hydrophilic and basic peptide.     

Managing Conflicts of Interest in the UK National Institute for Health and Care Excellence (NICE) Clinical Guidelines Programme: Qualitative Study

Background

There is international concern that conflicts of interest (COI) may bias clinical guideline development and render it untrustworthy. Guideline COI policies exist with the aim of reducing this bias but it is not known how such policies are interpreted and used by guideline producing organisations. This study sought to determine how conflicts of interest (COIs) are disclosed and managed by a national clinical guideline developer (NICE: the UK National Institute for Health and Care Excellence).

Methods

Qualitative study using semi-structured telephone interviews with 14 key informants: 8 senior staff of NICE’s guideline development centres and 6 chairs of guideline development groups (GDGs). We conducted a thematic analysis.

Results

Participants regard the NICE COI policy as comprehensive leading to transparent and independent guidance. The application of the NICE COI policy is, however, not straightforward and clarity could be improved. Disclosure of COI relies on self reporting and guideline developers have to take “on trust” the information they receive, certain types of COI (non-financial) are difficult to categorise and manage and disclosed COI can impact on the ability to recruit clinical experts to GDGs. Participants considered it both disruptive and stressful to exclude members from GDG meetings when required by the COI policy. Nonetheless the impact of this disruption can be minimised with good group chairing skills.

Conclusions

We consider that the successful implementation of a COI policy in clinical guideline development requires clear policies and procedures, appropriate training of GDG chairs and an evaluation of how the policy is used in practice.     

Disclosure of Financial Conflicts of Interests in Interventions to Improve Child Psychosocial Health: A Cross-Sectional Study

Academic journals increasingly request a full disclosure of financial conflict of interest (CoI). The Committee for Publication Ethics provides editors with guidance about the course of action in the case of suspected non-disclosure. No prior study has examined the extent to which journal articles on psychosocial interventions disclose CoI, and how journal editors process requests to examine suspected undisclosed CoI. Four internationally disseminated psychosocial interventions were examined. 136 articles related to an intervention, co-authored by intervention developers and published in health sciences journals were retrieved as requiring a CoI statement. Two editors refused consent to be included in the study. COI disclosures and editor responses were coded for 134 articles. Overall, 92/134 (71%) of all articles were found to have absent, incomplete or partly misleading CoI disclosures. Disclosure rates for the four programs varied significantly between 11% and 73%. Journal editors were contacted about 92 published articles with no CoI disclosure or a disclosure that was considered problematic. In 65/92 (71%) of all cases the editors published an ‘erratum’ or ‘corrigendum’. In 16 of these cases the journal had mishandled a submitted disclosure. The most frequent reason for non-publication of an erratum was that the journal had no disclosure policy at the time of the publication (16 cases). Consumers of research on psychosocial interventions published in peer-reviewed journals cannot currently assume that CoI disclosures are adequate and complete. More efforts are needed to achieve transparency.     

The Disclosure of Genetic Information: A Human Research Ethics Perspective

Increasing emphasis on genetic research means that growing numbers of human research projects in Australia will involve complex issues related to genetic privacy, familial information and genetic epidemiology. The Office of Population Health Genomics (Department of Health, Western Australia) hosted an interactive workshop to explore the ethical issues involved in the disclosure of genetic information, where researchers and members of human research ethics committees (HRECs) were asked to consider several case studies from an ethical perspective. Workshop participants used a variety of approaches to examine the complex ethical issues encountered, but did not consistently refer to the values and principles outlined in the National Statement on Ethical Conduct in Human Research (NHMRC 2007) or apply rational ethical approaches. Overall, the data suggested that both researchers and HREC members may benefit from further education and support regarding the application of ethical frameworks to the issues encountered in genetic research.     

Conflicts of Interest in Environmental Management: Estimating the Costs and Benefits of a Tree Invasion

Some alien tree species used in commercial forestry cause major problems as invaders of natural ecosystems. One such case, the black wattle tree, was introduced into South Africa from Australia in the 19th century. It is an important commercial species, as well as an aggressive invader, giving rise to significant environmental impacts and conflicts of interest. This paper provides an analysis of costs and benefits associated with this species in South Africa at a national level. The results suggest that a do nothing scenario (with no attempts being made to control the spread of the species beyond the limits of plantations) is not sustainable, as the benefit–cost ratio is around 0.4. The most attractive control option will be to combine physical clearing and plant-attacking biological control with the continuation of the commercial growing activities. In case this is not practically feasible the next best option is a combination of seed-attacking biological control, physical control and the development of secondary industries based on wood products from clearing programmes. There is, however, a 40% loss of benefits involved with this option when compared with the first best option. The techniques used in this study, and the findings relating to the scenarios that deliver the best returns on investment, should be of broad relevance to the problem of dealing with conflicts of interest relating to invasive alien plants that have commercial value.     

Inadequate Cold Tolerance as a Possible Limitation to American Chestnut Restoration in the Northeastern United States

The American chestnut (Castanea dentata (Marshall) Borkh.), once a major component of eastern forests from Maine to Georgia, was functionally removed from the forest ecosystem by chestnut blight (an exotic fungal disease caused by Cryphonectria parasitica (Murr.) Barr), first identified at the beginning of the twentieth century. Hybrid‐backcross breeding programs that incorporate the blight resistance of Chinese chestnut (Castenea mollissima Blume) and Japanese chestnut (Castenea crenata Sieb. & Zuc.) into American chestnut stock show promise for achieving the blight resistance needed for species restoration. However, it is uncertain if limitations in tissue cold tolerance within current breeding programs might restrict the restoration of the species at the northern limits of American chestnut's historic range. Shoots of American chestnut and hybrid‐backcross chestnut (i.e., backcross chestnut) saplings growing in two plantings in Vermont were tested during November 2006, February 2007, and April 2007 to assess their cold tolerance relative to ambient low temperatures. Shoots of two potential native competitors, northern red oak (Quercus rubra L.) and sugar maple (Acer saccharum L.), were also sampled for comparison. During the winter, American and backcross chestnuts were approximately 5°C less cold tolerant than red oak and sugar maple, with a tendency for American chestnut to be more cold tolerant than the backcross chestnut. Terminal shoots of American and backcross chestnut also showed significantly more freezing damage in the field than nearby red oak and sugar maple shoots, which showed no visible injury.     

Latency of Infection in Unripe Avocados by Colletotrichum gloeosporioides is Not Due to Inadequate Enzyme Potential

Colletotrichum gloeosporioides produced exo-pectin lyase and protease in a) liquid cultures with incorporated washed cell wall material from unripe or ripe avocado and b) autoclaved immature fruit. The activity of exo-pectin lyase and protease produced in liquid cultures incorporating washed cell walls from immature fruits was almost the same as when washed cell walls from ripe fruits were incorporated. Ripe fruit tissue rotted by the fungus contained exo-pectin lyase, endo-polygalacturonase (endo-PG) and protease. The endo-PG was found to be endogenous to avocado fruit, and had a pH optimum of 5.5. The pH optima of exo-pectin lyase and protease were 8.5 and 7.5 respectively in all three enzyme preparations. All these enzyme preparations completely macerated avocado fruit tissue discs in vitro in less than 3 h of incubation but not potato tuber discs. Neither immature nor ripe fruit contained substances, proteinaceous or otherwise, which could inhibit the exo-pectin lyase or protease activity of these preparations. The results indicated that C. gloeosporioides possesses sufficient enzyme potential to invade cell walls of unripe fruit and that the fruit tissue does not have a mechanism to inactivate such enzymes.     

Human metallothionein-II is synthesized as a stable membrane-localized fusion protein in Escherichia coli

A synthetic gene encoding human metallothionein-II (HMT) was cloned into the specially constructed high-copy-number expression vector, pUA7, and expressed in Escherichia coli. The plasmid construct includes the promoter/operator and regulatory sequences of the Salmonella typhimurium ara operon and part of the 5'-coding and all of the 3'-noncoding regions of the E. coli lpp. Upon induction with arabinose, the resulting Lpp::HMT fusion protein was produced 75,000-fold over uninduced cells, with a relatively stable mRNA (T1/2 of 8.3 min) and a completely stable protein. In addition, over 95% of the final fusion protein was localized in the outer membrane and was capable of binding heavy metals (especially cadmium) in vitro. Cells producing Lpp::HMT bioaccumulated heavy metals (e.g., cadmium) 66-fold over nonproducing cells.     

Equilibrium Between Dimeric and Monomeric Forms of Human Epidermal Growth Factor is Shifted Towards Dimers in a Solution

The Protein Journal - An interplay between monomeric and dimeric forms of human epidermal growth factor (EGF) affecting its interaction with EGF receptor (EGFR) is poorly understood. While EGF...     

Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer

Prostaglandin endoperoxide H synthases 1 and 2, also known as cyclooxygenases (COXs) 1 and 2, convert arachidonic acid (AA) to prostaglandin endoperoxide H(2). Prostaglandin endoperoxide H synthases are targets of nonspecific nonsteroidal anti-inflammatory drugs and COX-2-specific inhibitors called coxibs. PGHS-2 is a sequence homodimer. Each monomer has a peroxidase and a COX active site. We find that human PGHS-2 functions as a conformational heterodimer having a catalytic monomer (E(cat)) and an allosteric monomer (E(allo)). Heme binds tightly only to the peroxidase site of E(cat), whereas substrates, as well as certain inhibitors (e.g. celecoxib), bind the COX site of E(cat). E(cat) is regulated by E(allo) in a manner dependent on what ligand is bound to E(allo). Substrate and nonsubstrate fatty acids (FAs) and some COX inhibitors (e.g. naproxen) preferentially bind to the COX site of E(allo). AA can bind to E(cat) and E(allo), but the affinity of AA for E(allo) is 25 times that for E(cat). Palmitic acid, an efficacious stimulator of human PGHS-2, binds only E(allo) in palmitic acid/murine PGHS-2 co-crystals. Nonsubstrate FAs can potentiate or attenuate actions of COX inhibitors depending on the FA and whether the inhibitor binds E(cat) or E(allo). Our studies suggest that the concentration and composition of the free FA pool in the environment in which PGHS-2 functions in cells, the FA tone, is a key factor regulating PGHS-2 activity and its responses to COX inhibitors. We suggest that differences in FA tone occurring with different diets will likely affect both base-line prostanoid synthesis and responses to COX inhibitors.     

Mechanical Expansion of Steel Tubing as a Solution to Leaky Wellbores

Wellbore cement, a procedural component of wellbore completion operations, primarily provides zonal isolation and mechanical support of the metal pipe (casing), and protects metal components from corrosive fluids. These are essential for uncompromised wellbore integrity. Cements can undergo multiple forms of failure, such as debonding at the cement/rock and cement/metal interfaces, fracturing, and defects within the cement matrix. Failures and defects within the cement will ultimately lead to fluid migration, resulting in inter-zonal fluid migration and premature well abandonment. Currently, there are over 1.8 million operating wells worldwide and over one third of these wells have leak related problems defined as Sustained Casing Pressure (SCP)¹. The focus of this research was to develop an experimental setup at bench-scale to explore the effect of mechanical manipulation of wellbore casing-cement composite samples as a potential technology for the remediation of gas leaks. The experimental methodology utilized in this study enabled formation of an impermeable seal at the pipe/cement interface in a simulated wellbore system. Successful nitrogen gas flow-through measurements demonstrated that an existing microannulus was sealed at laboratory experimental conditions and fluid flow prevented by mechanical manipulation of the metal/cement composite sample. Furthermore, this methodology can be applied not only for the remediation of leaky wellbores, but also in plugging and abandonment procedures as well as wellbore completions technology, and potentially preventing negative impacts of wellbores on subsurface and surface environments.     

Human lysosomal acid phosphatase is transported as a transmembrane protein to lysosomes in transfected baby hamster kidney cells.

BHK cells transfected with human lysosomal acid phosphatase (LAP) cDNA (CT29) expressed 70-fold higher enzyme activities of acid phosphatase than non-transfected BHK cells. The CT29-LAP was synthesized in BHK cells as a heterogeneously glycosylated precursor that was tightly membrane associated. Transfer to the trans-Golgi was associated with a small increase in size (approximately 7 kd) and partial processing of the oligosaccharides to complex type structures. CT29-LAP was transferred into lysosomes as shown by subcellular fractionation, immunofluorescence and immunoelectron microscopy. Lack of mannose-6-phosphate residues suggested that transport does not involve mannose-6-phosphate receptors. Part of the membrane-associated CT29-LAP was processed to a soluble form. The mechanism that converts CT29-LAP into a soluble form was sensitive to NH4Cl, and reduced the size of the polypeptide by 7 kd. In vitro translation of CT29-derived cRNA in the presence of microsomal membranes yielded a CT29-LAP precursor that is protected from proteinase K except for a small peptide of approximately 2 kd. In combination with the sequence data available for LAP, these observations suggest that CT29-LAP is synthesized and transported to lysosomes as a transmembrane protein. In the lysosomes, CT29-LAP is released from the membrane by proteolytic cleavage, which removes a C-terminal peptide including the transmembrane domain and the cytosolic tail of 18 amino acids.     

Human mannose 6-phosphate-uncovering enzyme is synthesized as a proenzyme that is activated by the endoprotease furin

N-Acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase, also known as "uncovering" enzyme (UCE), is localized in the trans-Golgi network, where it removes a covering N-acetylglucosamine from the mannose 6-phosphate recognition marker on lysosomal acid hydrolases. Here we show that UCE is synthesized as an inactive proenzyme that is activated by the endoprotease furin, which cleaves an RARLPR/D sequence to release a 24-amino acid propiece. As furin is localized in the trans-Golgi network, newly synthesized UCE is inactive until it reaches this terminal Golgi compartment. LoVo cells (derived from a human colon adenocarcinoma) lack furin activity and have extremely low UCE activity. Addition of furin to LoVo cell extracts restores UCE activity to normal levels, demonstrating that the UCE proenzyme is stable in this cell type. LoVo cells secrete acid hydrolases with phosphomannose diesters as a consequence of the deficient UCE activity. This demonstrates for the first time that UCE is the only enzyme in these cells capable of efficiently uncovering phosphomannose diesters. UCE also hydrolyzes UDP-GlcNAc, a sugar donor for Golgi N-acetylglucosaminyltransferases. The fact that UCE is not activated until it reaches the trans-Golgi network may ensure that the pool of UDP-GlcNAc in the Golgi stack is not depleted, thereby maintaining proper oligosaccharide assembly.     

Inadequate root uptake may represent a major component limiting rice to use urea as sole nitrogen source for growth

Background and aims

Urea represents over 50 % of nitrogen fertilizers applied worldwide to crop production, however one-third of nitrogen fertilized could be recovered by crops. Previous studies have provided useful knowledge of urea-related plant nitrogen-nutrition, whereas information about crop growth-response to urea without its external degradation seems limiting. We thus assess the ability of rice seedlings to use urea at a physiological level.

Methods

Rice growth on urea versus other nitrogen regimes was tested under aseptic conditions. Activity of urease and GS was analyzed; urea, ammonium, total nitrogen and expression of a nitrogen limitation-responsive gene OsDUR3 were examined.

Results

Growth phenotyping revealed urea-dose-dependent growth improvement but significant growth reduction associated with nitrogen-deficiency of plants compared to those on other nitrogen-sources, indicating a physiological impediment of effective urea utilization by rice. Enzymatic assay showed that activities of urease and GS were well expressed in plants supplied with urea. Low concentrations of urea and ammonium were detected in rice (particularly in roots) on 1 mM urea or other nitrogen-forms, and a less nitrogen-content was determined in urea-fed plants. Additionally, the strongest OsDUR3-expression occurred in seedlings on no-nitrogen or 1 mM urea.

Conclusions

We suggest that insufficient urea-absorption but not assimilation represents likely a factor contraining rice to use urea as sole nitrogen-source.