Mast cells in allergy: innate instructors of adaptive responses

The function of mast cells as effector cells in allergy has been extensively studied. However, increasing insight into mast cell physiology has revealed new mast cell functions and has introduced mast cells as key players in the regulation of innate as well as adaptive immunity. For example, mast cells have recently been found to express Toll-like receptors (TLRs), which enable them to participate in the innate immune response against pathogens. Furthermore, mast cells have been reported to interact with B cells, dendritic cells and T cells and thereby modulate the direction of an adaptive immune response. Finally, recent documentation that mast cells express functional MHC class II and costimulatory molecules and release immunologically active exosomes, has raised the possibility that mast cells also engage in (as yet) poorly understood antigen presentation functions. In this review, we explore the hypothesis that mast cells serve as central mediators between innate and adaptive immunity, rather as pure effector cells, during allergic innate responses.     

Plurihormonal pituitary adenoma with concomitant adrenocorticotropic hormone (ACTH) and growth hormone (GH) secretion: a report of two cases and review of the literature

Plurihormonal pituitary adenomas are tumours that show immunoreactivity for more than one hormone that cannot be explained by normal adenohypophysial cytodifferentiation. The most common combinations in these adenomas include growth hormone (GH), prolactin (PRL) and one or more glycoprotein hormone sub-units (β-TSH, β-FSH, β-LH and αSU). The authors report two cases of a plurihormonal pituitary adenoma expressing the rare combination of ACTH and GH. They both underwent successful transphenoidal hypophysectomy (TSH). Long-term post-operative follow-up revealed no evidence of tumour recurrence. Due to the multiple secretions and plurihormonal characteristics clinical diagnosis of composite pituitary adenomas can be difficult. The authors discuss the diagnosis and management of composite pituitary adenomas and review the literature regarding this rare phenomenon.     

Altered body weight associated with substance abuse: a look beyond food intake

Background: Substance abuse can cause a range of harmful secondary health consequences, including body weight changes. These remain poorly understood but can lead to metabolic disorders including obesity and diabetes. Energy balance is a function of the equation: energy balance?=?energy intake – energy expenditure; an imbalance to this equation results in body weight changes. Currently, in the clinical setting, changes to food intake (energy intake) are considered as the primary mediator of body weight changes related to substance abuse, reflected in the current treatment focus on nutritional intervention. The influence of substance abuse on energy expenditure receives less attention. The aim of this think-piece is to consider potential causes of body weight changes during active substance abuse and abstinence, by focussing on the components of the energy balance equation.

Methods: We discuss both human and animal studies on the effects of substance abuse on energy balance, with particular focus on animal models utilising pair-feeding, which enable investigation of energy balance whilst controlling for the effects of altered food intake.

Results: We demonstrate that whilst some drugs of abuse affect food intake, this effect is inconsistent. Furthermore, body weight changes do not match food intake changes.

Conclusion: We provide evidence that drugs of abuse can affect both energy intake and energy expenditure; contributing to the observed body weight changes. This think-piece highlights that treatment strategies for body weight changes related to substance abuse cannot focus solely on nutritional interventions, but should consider the impact of broader disruptions to energy balance.     

A survey of perceptions and practices of complementary alternative medicine among Canadian gastroenterologists

BACKGROUND:

Despite a high prevalence of complementary alternative medicine (CAM) use among inflammatory bowel disease (IBD) patients, there is a dearth of information about the attitudes and perceptions of CAM among the gastroenterologists who treat these patients.

OBJECTIVE:

To characterize the beliefs, perceptions and practices of gastroenterologists toward CAM use in patients with IBD.

METHODS:

A web-based survey was sent to member gastroenterologists of the Canadian Association of Gastroenterology. The survey included multiple-choice and Likert scale questions that queried physician knowledge and perceptions of CAM and their willingness to discuss CAM with patients.

RESULTS:

Fifty-three per cent of respondents considered themselves to be IBD subspecialists. The majority (86%) of gastroenterologists reported that less than one-half of their patient population had mentioned the use of CAM. Only 8% of physicians reported initiating a conversation about CAM in the majority of their patient encounters. Approximately one-half (51%) of respondents were comfortable with discussing CAM with their patients, with lack of knowledge being cited as the most common reason for discomfort with the topic. Most gastroenterologists (79%) reported no formal education in CAM. While there was uncertainty as to whether CAM interfered with conventional medications, most gastroenterologists believed it could be effective as an adjunct treatment.

CONCLUSION:

Our findings demonstrate that gastroenterologists were hesitant to initiate discussions about CAM with patients. Nearly one-half were uncomfortable or only somewhat comfortable with the topic, and most may benefit from CAM educational programs. Interestingly, most respondents appeared to be receptive to CAM as adjunct therapy alongside conventional IBD treatment.     

From the Cover: Erosion of functional independence early in the evolution of a microbial mutualism

Many species have evolved to function as specialized mutualists, often to the detriment of their ability to survive independently. However, there are few, if any, well-controlled observations of the evolutionary processes underlying the genesis of new mutualisms. Here, we show that within the first 1,000 generations of initiating independent syntrophic interactions between a sulfate reducer (Desulfovibrio vulgaris) and a hydrogenotrophic methanogen (Methanococcus maripaludis), D. vulgaris frequently lost the capacity to grow by sulfate respiration, thus losing the primary physiological attribute of the genus. The loss of sulfate respiration was a consequence of mutations in one or more of three key genes in the pathway for sulfate respiration, required for sulfate activation (sat) and sulfate reduction to sulfite (apsA or apsB). Because loss-of-function mutations arose rapidly and independently in replicated experiments, and because these mutations were correlated with enhanced growth rate and productivity, gene loss could be attributed to natural selection, even though these mutations should significantly restrict the independence of the evolved D. vulgaris. Together, these data present an empirical demonstration that specialization for a mutualistic interaction can evolve by natural selection shortly after its origin. They also demonstrate that a sulfate-reducing bacterium can readily evolve to become a specialized syntroph, a situation that may have often occurred in nature.From flowering plants and their pollinators to the microbial endosymbionts of insects, there are many examples in nature of obligate mutualists (1, 2), or species dependent upon a mutually beneficial interaction for their survival or reproduction. How these interactions evolve is a mystery because much theory predicts that cooperative interactions should be unstable (3) and because of the difficulty of inferring evolutionary events that occurred in the distant past (4). Although there are few, if any, empirical observations of evolution toward dependence on mutualism, there are now several examples of mutualisms evolving de novo in the laboratory (5–8). This advancement has provided researchers an experimental framework to study populations and ecological conditions in the early stages of evolution (5–8).Here, we describe our observations of rapid and repeated evolution of increased dependency on a mutualism through natural selection. This interaction is similar to a widespread relationship between prokaryotes that plays a pivotal role in the decomposition of carbon in many oxygen-free environments. In these syntrophic mutualisms, bacteria ferment organic acids, producing hydrogen or formate as by-products, which are then used by hydrogen-consuming species, often methanogenic archaea (9). Removal of hydrogen and formate benefits the bacteria because the free energy (ΔG) available decreases with increasing concentrations of these products (9). A variety of bacterial species have been described that seem to be specialized for fermenting organic acids in syntrophic association with hydrogen-consuming species (10–13). Notably, most clades of characterized syntrophs share a recent common ancestry with sulfate reducers (10, 14). Some retain vestiges of the sulfate-reducing pathway, and several lines of evidence hint at the possibility that specialized syntrophs were once sulfate reducers (11, 14).Sulfate-reducing bacteria gain energy from organic acids, such as lactate, in the absence of oxygen by coupling their oxidation to the reduction of sulfate to sulfide. These bacteria play a critical role in sulfur and carbon cycling, contribute to corrosion in the petroleum industry and wastewater treatment plants, and have been used for bioremediation of toxic heavy metals (15). The ability of sulfate reducers to grow in syntrophic association with methanogens was first demonstrated in laboratory studies (16) and is now generally recognized to be of environmental relevance (17–19). Many sulfate reducers would therefore be better described as facultative syntrophs, well adapted to environments of fluctuating electron acceptor availability (17, 20). Past evolutionary transitions of sulfate-reducing bacteria between obligate and facultative syntrophs is also indicated by comparative analyses indicating horizontal transfer of genes in the pathway of sulfate respiration (21, 22). Thus, the evolutionary adaptive flexibility of sulfate-reducing bacteria suggests that they offer an attractive experimental system to study the evolution of mutualism.To understand how mutualisms, and syntrophic interactions in particular, might evolve from their origin, we paired the sulfate-reducing bacterium, Desulfovibrio vulgaris Hildenborough, with the archaeon, Methanococcus maripaludis S2, and propagated 22 initially isogenic planktonic cocultures for 1,000 generations in medium with lactate but no sulfate or added hydrogen. In this environment, neither species can gain energy from the oxidation of lactate without syntrophic cooperation.Within the first 300 generations of evolution, the cocultures evolved increased stability, higher yields, and higher growth rates, with both species contributing to these changes (6), a trend that continued through 1,000 generations. We describe a common evolutionary outcome of these experiments. Many of the independently evolved D. vulgaris accumulated loss-of-function mutations in genes required for the reduction of sulfate, suggesting strong selection for mutations resulting in loss of the ability to respire sulfate during evolution in syntrophy.     

Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein

Two to three years after infection, a fraction of HIV-1-infected individuals develop serologic activity that neutralizes most viral isolates. Broadly neutralizing antibodies that recognize the HIV-1 envelope protein have been isolated from these patients by single-cell sorting and by neutralization screens. Here, we report a new method for anti-HIV-1 antibody isolation based on capturing single B cells that recognize the HIV-1 envelope protein expressed on the surface of transfected cells. Although far less efficient than soluble protein baits, the cell-based capture method identified antibodies that bind to a new broadly neutralizing epitope in the vicinity of the V3 loop and the CD4-induced site (CD4i). The new epitope is expressed on the cell surface form of the HIV-1 spike, but not on soluble forms of the same envelope protein. Moreover, the new antibodies complement the neutralization spectrum of potent broadly neutralizing anti-CD4 binding site (CD4bs) antibodies obtained from the same individual. Thus, combinations of potent broadly neutralizing antibodies with complementary activity can account for the breadth and potency of naturally arising anti-HIV-1 serologic activity. Therefore, vaccines aimed at eliciting anti-HIV-1 serologic breadth and potency should not be limited to single epitopes.     

Does method of sternal repair influence long-term outcome of postoperative mediastinitis?

Background

Post-sternotomy mediastinitis reduces survival after cardiac surgery, potentially further affected by details of mediastinal vascularized flap reconstruction. The aim of this study was to evaluate survival after different methods for sternal reconstruction in mediastinitis.

Methods

Two hundred twenty-two adult cardiac surgery patients with post-sternotomy mediastinitis were reviewed. After controlling infection, often augmented by negative pressure therapy, muscle flap, omental flap, or secondary closure was performed. Outcomes were reviewed and survival analysis was performed.

Results

Baseline characteristics were similar. In-hospital mortality (15.7%) did not differ between groups. Secondary closure was correlated with negative pressure therapy and reduced length hospital of stay. Recurrent wound complications were more common with muscle flap repair. Survival was unaffected by sternal repair technique. By multivariate analysis, heart failure, sepsis, age, and vascular disease independently predicted mortality, while negative pressure therapy was associated with survival.

Conclusions

Choice of sternal repair was unrelated to survival, but mediastinal treatment with negative pressure therapy promotes favorable early and late outcomes.