It is widely believed that a subset of single nucleotide polymorphisms (SNPs) is able to capture the majority of the information for genotype-phenotype association studies that is contained in the complete compliment of genetic variations. The question remains, how does one select that particular subset of SNPs in order to maximize the power of detecting a significant association? In this study, we have used a simulation approach to compare three competing methods of site selection: random selection, selection based on pair-wise linkage disequilibrium, and selection based on maximizing haplotype diversity. The results indicate that site selection based on maximizing haplotype diversity is preferred over random selection and selection based on pair-wise linkage disequilibrium. The results also indicate that it is more prudent to increase the sample size to improve a study's power than to continuously increase the number of SNPs. These results have direct implications for designing gene-based and genome-wide association studies.

The placement of silk ligatures around the necks of teeth and into the gingival sulcus causes a rapid, acute inflammatory response leading to vigorous osteoclastic resorption of alveolar crestal bone. Associated with the large numbers of osteoclasts are mononuclear cells, predominantly fibroblast-like cells and macrophages. Some fibroblast-like cells contain intracellular collagen fibrils. It is suggested that in periodontal disease these mononuclear cells may compliment the action of osteoclasts by ingesting and degrading matrix molecules mobilized from bone but not ingested or degraded by osteoclasts.

Behavioural economic models of substance choice describe the relationship between changes in unit price and consumption. As the majority of UK non-dependent substance misusers are polysubstance misusers, we investigated the influence of price upon hypothetical purchases of alcohol, amphetamine, cocaine and ecstasy. Forty-three current polysubstance misusers (25 males, 18 females; mean age 21.3 +/- 2.8) were recruited into the study. As the price of alcohol rose, demand was inelastic. Amphetamine was a substitute for alcohol, cocaine was a compliment drug and ecstasy was independent. Demand for amphetamine was elastic as its price rose, but only alcohol was identified as a substitute drug and other drug purchases were independent of amphetamine price. As the price of cocaine increased, demand was elastic. Alcohol and ecstasy were substitute drugs but amphetamine purchase was independent, indicating asymmetrical substitution of alcohol and cocaine. Finally, demand for ecstasy was also elastic, but only cocaine substituted as ecstasy price rose. These results extend previous findings in substance dependent populations using behavioural economic models and support the opinion that purchasing substances is a complex process, involving both socio-economic and psychopharmacological factors. Whilst subjects expressed a preference for ecstasy, these behavioural findings indicated that alcohol was their drug of choice when economic considerations were brought into play. Self-reported drug preference, although facilitating between subjects experimental design, may therefore not accurately represent real world polysubstance misuse.

BACKGROUND

Physical activity (PA) is an important component in the management of Rheumatoid Arthritis (RA). To date the correlates of PA have not been thoroughly investigated in the RA population. The aim of this systematic review was to determine the correlates of PA in the adult RA population.

METHODS

A search of Medline, EMBASE, AMED, CINAHL plus, Pubmed, Web of Science, and the Cochrane Library was conducted. A manual search of reference lists was conducted to compliment the electronic search. Ten studies fulfilled the inclusion criteria and were assessed for methodological quality.

RESULTS

Results determined correlates in 4 categories: sociodemographic, physical, psychological and social variables. The variables varied greatly and were inconsistently studied. Changes were noted from a previous review in 2005 in relation to the association between certain variables and PA, including age, gender, disease duration, pain, exercise beliefs and social support.

CONCLUSIONS

Positive associations with PA were found for motivation, self-efficacy, health perception, and previous PA levels. Negative associations were found for fatigue, a coerced regulation style and certain physiological variables. In addition differences between correlates of PA in the adult RA population and other chronic disease and healthy adult populations have been demonstrated.

Pulmonary hypertension (PH) is a relatively misunderstood disease, partly related to the fact that many perceive PH to be a singular diagnosis. An unintended consequence of this is the misapplication of the role of the Doppler-Echocardiographic (DE) examination, as well as an underappreciation for its ability to help discern PH pathophysiology prior to right heart catheterization. Since DE often serves as the "gatekeeper" to invasive right heart catheterization, misinterpretation of the DE can lead to missed or delayed diagnosis with devastating consequences. Too often, the primary or nearly exclusive focus of the DE examination is placed on the pulmonary artery pressure estimation. Two main issues with this approach are that Doppler pressure estimations can be inaccurate and even when accurate, without integration of additional 2-D and Doppler information, the clinician will often still not appreciate the pathophysiology of the PH nor its clinical significance. This review will focus on the 2-D and Doppler features necessary to assess pulmonary vascular disease (PVD), discern the salient differences between PVD and pulmonary venous hypertension (PVH), and how to integrate these key DE parameters such that PH pathophysiology can be determined noninvasively and early in the patient workup. Overreliance on any single DE metric, and especially PA pressure estimation, detracts from the overall diagnostic potential of the DE examination. Integrating the relative balance of right and left heart findings, along with proper Doppler interpretation provides a wealth of clinical and pathophysiologic insight prior to invasive hemodynamic assessment. The end results are heightened awareness and improved identification of which patients should be referred for further invasive testing, as well the use of the DE information to compliment the findings from invasive testing.

BACKGROUND

Evolution involves both deterministic and random processes, both of which are known to contribute to directional evolutionary change. A number of studies have shown that when fitness is treated as a random variable, meaning that each individual has a distribution of possible fitness values, then both the mean and variance of individual fitness distributions contribute to directional evolution. Unfortunately the most general mathematical description of evolution that we have, the Price equation, is derived under the assumption that both fitness and offspring phenotype are fixed values that are known exactly. The Price equation is thus poorly equipped to study an important class of evolutionary processes.

RESULTS

I present a general equation for directional evolutionary change that incorporates both deterministic and stochastic processes and applies to any evolving system. This is essentially a stochastic version of the Price equation, but it is derived independently and contains terms with no analog in Price's formulation. This equation shows that the effects of selection are actually amplified by random variation in fitness. It also generalizes the known tendency of populations to be pulled towards phenotypes with minimum variance in fitness, and shows that this is matched by a tendency to be pulled towards phenotypes with maximum positive asymmetry in fitness. This equation also contains a term, having no analog in the Price equation, that captures cases in which the fitness of parents has a direct effect on the phenotype of their offspring.

CONCLUSIONS

Directional evolution is influenced by the entire distribution of individual fitness, not just the mean and variance. Though all moments of individuals' fitness distributions contribute to evolutionary change, the ways that they do so follow some general rules. These rules are invisible to the Price equation because it describes evolution retrospectively. An equally general prospective evolution equation compliments the Price equation and shows that the influence of stochastic processes on directional evolution is more diverse than has generally been recognized.

The structural carbohydrate polymers glucan and chitin compliment and reinforce each other in a dynamic process to maintain the integrity and physical strength of the fungal cell wall. The assembly of chitin and glucan in the cell wall of the budding yeast Saccharomyces cerevisiae and the polymorphic human pathogen Candida albicans are essential processes that involve a range of fungal-specific enzymes and regulatory networks. The fungal cell wall is, therefore, an attractive target for novel therapies as host cells lack many cell wall-related proteins. The most recent class of antifungal drug approved for clinical use, the echinocandins, targets the synthesis of cell wall β(1-3)glucan. The echinocandins are effective at treating invasive and bloodstream Candida infections and are now widely used in the clinic. However, there have been sporadic reports of breakthrough infections in patients undergoing echinocandin therapy. The acquisition of point mutations in the FKS genes that encode the catalytic β(1-3)glucan synthase subunits, the target of the echinocandins, has emerged as a dominant resistance mechanism. Cells with elevated chitin levels are also less susceptible to echinocandins and in addition, treatment with sub-MIC echinocandin activates cell wall salvage pathways that increase chitin synthesis to compensate for reduced glucan production. The development of drugs targeting the cell wall has already proven to be beneficial in providing an alternative class of drug for use in the clinic. Other cell wall targets such as chitin synthesis still hold great potential for drug development but careful consideration should be given to the capacity of fungi to manipulate their walls in a dynamic response to cell wall perturbations.

Many species of receptors form dimers, but how can we use this information to make predictions about signal transduction? This problem is particularly difficult when receptors dimerize with many different species, leading to a combinatoric increase in the possible number of dimer pairs. As an example system, we focus on receptors in the G-protein coupled receptor (GPCR) family. GPCRs have been shown to reversibly form dimers, but this dimerization does not directly affect signal transduction. Here we present a new theoretical framework called a dimerization algebra. This algebra provides a systematic and rational way to represent, manipulate, and in some cases simplify large and often complicated networks of dimerization interactions. To compliment this algebra, Monte Carlo simulations are used to predict dimerization's effect on receptor organization on the membrane, signal transduction, and internalization. These simulation results are directly comparable to various experimental measures such as fluorescence resonance energy transfer (FRET), and as such provide a link between the dimerization algebra and experimental data. As an example, we show how the algebra and computational results can be used to predict the effects of dimerization on the dopamine D2 and somatastatin SSTR1 receptors. When these predictions were compared to experimental findings from the literature, good agreement was found, demonstrating the utility of our approach. Applications of this work to the development of a novel class of dimerization-modulating drugs are also discussed.

BACKGROUND

Platinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies but their acute and motor neurotoxicities are less well characterised. Use was made of nerve conduction studies and needle electromyography (EMG) to assess motor nerve excitability in cancer patients during their first treatment cycle with platinum-based chemotherapy in this study.

METHODS

Twenty-nine adult cancer patients had a neurophysiological assessment either before oxaliplatin plus capecitabine, on days 2 to 4 or 14 to 20 after oxaliplatin plus capecitabine, or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin, undertaken by a neurophysiologist who was blinded to patient and treatment details. Patients completed a symptom questionnaire at the end of the treatment cycle.

RESULTS

Abnormal spontaneous high frequency motor fibre action potentials were detected in 100% of patients (n = 6) and 72% of muscles (n = 22) on days 2 to 4 post-oxaliplatin, and in 25% of patients (n = 8) and 13% of muscles (n = 32) on days 14 to 20 post-oxaliplatin, but in none of the patients (n = 14) or muscles (n = 56) tested prior to oxaliplatin or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin. Repetitive compound motor action potentials were less sensitive and less specific than spontaneous high frequency motor fibre action potentials for detection of acute oxaliplatin-induced motor nerve hyperexcitability but were present in 71% of patients (n = 7) and 32% of muscles (n = 32) on days 2 to 4 after oxaliplatin treatment. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22) and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6).

CONCLUSIONS

Abnormal spontaneous high frequency motor fibre activity is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve hyperexcitability, detectable on EMG on days 2 to 4 post-treatment. Objective EMG assessment of motor nerve excitability could compliment patient-reported symptomatic endpoints of acute oxaliplatin-induced neurotoxicity in future studies.

OBJECTIVE

This manuscript attempts to critically review traditional and currently employed methods of periodontal diagnosis, in the light of current knowledge about individual patients and sites at risk of progressive periodontal attachment loss.

METHODS

Articles published over the last decade from international research journals, have demonstrated that existing methods of periodontal disease diagnosis are seriously deficient with respect to accuracy, their ability to predict ongoing or future disease activity and their ability to determine the current activity status of historically diseased sites.

METHODS

Longitudinal studies have questioned the rationale behind traditional treatment regimes and underlined the importance of site-directed therapy to avoid potentially damaging instrumentation of quiescent or healthy sites. The recent explosion in local, less invasive chemotherapies for periodontal disease management has aimed at addressing the site-specific nature of this group of diseases, but the true benefits of such novel therapies cannot be realised until more accurate and specific diagnostic techniques become available.

CONCLUSIONS

The manuscript concludes that the range of clinical information collected by experienced periodontists using currently available technology is probably sufficient to manage mild-to-moderate chronic adult periodontitis. However, those patients at risk from more aggressive attachment loss, and those individuals that appear refractory to traditional therapies, require the development of more accurate diagnostic tests to compliment the revolution in site-specific therapies. A diagnostic model is presented, which attempts to draw together current and future diagnostic methods for managing the majority of periodontal disease types, and it is suggested that current diagnoses should include some assessment of "risk'.

Various cytokines produced by bone marrow cells can protect adult cardiomyocytes against apoptosis. Thus, we investigated the feasibility of implanting adult cardiomyocytes in combination with bone marrow cells for myocardial repair. Ventricular cardiomyocytes were isolated from adult rats and cocultured with bone marrow cells. Using a rat model of doxorubicin-induced cardiomyopathy, we injected 6 x 10(5) adult cardiomyocytes, 3 x 10(7) bone marrow cells, or both into damaged hearts, for myocardial repair. Coculture of the cardiomyocytes with the bone marrow cells enhanced the expression of integrin-beta1D and focal adhesion kinase in cardiomyocytes, resulting in increased survival and decreased apoptosis of the cardiomyocytes after 7 days of culture. Compared with the baseline levels, cardiac function was preserved by the implantation of bone marrow cells alone and by the implantation of cardiomyocytes in combination with bone marrow cells, but it was decreased significantly 28 days after the implantation of cardiomyocytes alone. Furthermore, apoptosis of the host cardiomyocytes was decreased significantly after the implantation of bone marrow cells alone, or in combination with cardiomyocytes, compared with that after the implantation of cardiomyocytes alone (p < 0.01). Interestingly, the implantation of adult cardiomyocytes in combination with bone marrow cells resulted in a dramatic increase in the survival of donor cardiomyocytes, and induced the myogenic differentiation of donor bone marrow stem cells. Our findings indicate that cardiomyocytes and bone marrow cells can assist and compliment each other; thus, the implantation of adult cardiomyocytes in combination with bone marrow cells shows promise as a feasible new strategy for myocardial repair.

OBJECTIVE

To identify patient characteristics that are associated with increased ICU length of stay, resource use, and hospital mortality after coronary artery bypass surgery.

METHODS

Prospective, multicenter study.

METHODS

Six tertiary care hospitals.

METHODS

A consecutive sample of 2,435 unselected ICU admissions following coronary artery by-pass surgery.

METHODS

Demographic, operative characteristics and APACHE III score were collected during the first postoperative day; and APACHE III scores and therapeutic interventions during the first three postoperative days. Hospital survival and ICU length of stay were also recorded. Multivariate equations were derived and cross-validated to predict hospital mortality, ICU length of stay, and ICU resource use.

RESULTS

Unadjusted hospital mortality rate was 3.9% (range 1.0% to 6.0%), mean ICU length of stay was 3.7 days (range 3.2 to 4.7 days), and first 3-day ICU resource use (TISS points) was 99 (range 68 to 116). The range of actual to predicted ICU length of stay varied from 0.86 to 1.26; and resource use from 0.71 to 1.16.

CONCLUSIONS

A limited number of operative characteristics, the post-operative acute physiology score (APS) of APACHE III and patient demographic data can predict hospital death rate, ICU length of stay, and resource use immediately following coronary by-pass surgery. These estimates may compliment assessments based on pre-operative risk factors in order to more precisely evaluate and improve the efficacy and efficiency of cardiovascular surgery.

BACKGROUND

The decline in malaria coinciding with the introduction of newer, costly anti-malarials has prompted studies into the overtreatment for malaria mostly in East Africa. The study presented here describes prescribing practices for malaria at health facilities in a West African country.

METHODS

Cross-sectional surveys were carried out in two urban Gambian primary health facilities (PHFs) during and outside the malaria transmission season. Facilities were comparable in terms of the staffing compliment and capability to perform slide microscopy. Patients treated for malaria were enrolled after consultations and blood smears collected and read at a reference laboratory. Slide reading results from the PHFs were compared to the reference readings and the proportion of cases treated but with a negative test result at the reference laboratory was determined.

RESULTS

Slide requests were made for 33.2% (173) of those enrolled, being more frequent in children (0-15 yrs) than adults during the wet season (p = 0.003). In the same period, requests were commoner in under-fives compared to older children (p = 0.022); however, a positive test result was 4.4 times more likely in the latter group (p = 0.010). Parasitaemia was confirmed for only 4.7% (10/215) and 12.5% (37/297) of patients in the dry and wet seasons, respectively. The negative predictive value of a PHF slide remained above 97% in both seasons.

CONCLUSIONS

The study provides evidence for considerable overtreatment for malaria in a West African setting comparable to reports from areas with similar low malaria transmission in East Africa. The data suggest that laboratory facilities may be under-used, and that adherence to negative PHF slide results could significantly reduce the degree of overtreatment. The "peak prevalence" in 5-15 year olds may reflect successful implementation of malaria control interventions in under-fives, but point out the need to extend such interventions to older children.

The majority of orally administered drugs are described to be passively transported across the lipophilic cell membranes [Lennernäs, H. et al. (1994) Intestinal drug absorption during induced net water absorption in human; a mechanistic study using antipyrine, atenolol and enalaprilat. Br. J. Clin. Pharmacol. 37, 589-596; [1] Artursson, P. Application of physicochemical properties of molecules to predict intestinal permeability. Proceedings of the AAPS Workshop on Permeability Definitions and Regulatory Standards, Arlington, VA, 17-19 August 1998] [2]. Parallel artificial membrane permeability assay (PAMPA), as a passive-permeability screen with focus on the simulation of transcellular processes, is an excellent compliment to cellular models in absorption, distribution, metabolism, excretion (ADME) screening of research compounds. Being fast, versatile, and low-cost, PAMPA is a compelling and biologically relevant model of transport. The problem of low solubility of research compounds has been largely eliminated in the PAMPA method. This review will emphasize how high-resolution PAMPA can help in the design of structural features into molecules to improve their absorption-related properties.:

Malignant glioblastomas (GBM) are highly malignant brain tumors that have extensive and aberrant tumor vasculature, including multiple types of vessels. This review focuses on recent discoveries that the angiogenic factor YKL-40 (CHI3L1) acts on glioblastoma-stem like cells (GSCs) to drive the formation of two major forms of tumor vascularization: angiogenesis and vasculogenic mimicry (VM). GSCs possess multipotent cells able to transdifferentiate into vascular pericytes or smooth muscle cells (PC/SMCs) that either coordinate with endothelial cells (ECs) to facilitate angiogenesis or assemble in the absence of ECs to form blood-perfused channels via VM. GBMs express high levels of YKL-40 that drives the divergent signaling cascades to mediate the formation of these distinct microvascular circulations. Although a variety of anti-tumor agents that target angiogenesis have demonstrated transient benefits for patients, they often fail to restrict tumor growth, which underscores the need for additional therapeutic tools. We propose that targeting YKL-40 may compliment conventional anti-angiogenic therapies to provide a substantial clinical benefit to patients with GBM and several other types of solid tumors.

Postprandial lipoproteins are potentially atherogenic. The aim of this study was to elucidate whether acute consumption of red wine (RW) and dealcoholised red wine (DRW) regulates postprandial lipid and lipoprotein metabolism in 17 dyslipidaemic postmenopausal women. A mixed meal accompanied by either water, RW or DRW was consumed on three separate visits, in random order, 2 weeks apart. One fasting and 6 hourly postprandial blood samples were taken for lipid analysis. Results showed no significant quantitative changes in postprandial apolipoprotein (apo) B48 levels following the consumption of DRW or RW compared to water. However, qualitatively, DRW may reduce arterial exposure to apoB48-containing lipoproteins over the 6-h postprandial period measured. DRW consumption did not significantly change postprandial TG or insulin levels. A 35% (p = 0.02) increase in postprandial triglyceride (TG) levels and a 54% (p = 0.02) increase in insulin levels were observed following RW consumption, compared to water. In conclusion, acute DRW consumption had no effect on postprandial lipid and lipoprotein metabolism in dyslipidaemic postmenopausal women. However, the consumption of full-compliment RW exacerbated the postprandial lipaemic and insulin response over the 6-h period. Collectively, our findings suggest that neither polyphenols nor red wine reduce atherosclerotic risk by acutely modulating postprandial lipaemia over a 6-h period.

We have investigated the plasma proteome using 2D gel electrophoresis and matrix-assisted laser desorption/ionization tandem time of flight from patients with high altitude pulmonary edema (HAPE). A complete proteomic analysis was performed on 20 patients with HAPE and ten healthy sea level controls. In total, we have identified 25 protein spots in human plasma and found that 14 of them showed altered changes in HAPE patients, which mainly were acute phase proteins (APPs), compliment components, and apolipoproteins among others. Among the APPs, haptoglobin α2 chain, haptoglobin β chain, transthyretin, and plasma retinol binding precursor showed overexpression in HAPE patients as compared to controls. To validate the result of proteomic analysis, two proteins were selected for enzyme-linked immunosorbent assay and Western blotting analysis. Our data conclusively shows that two proteins, haptoglobin and apolipoprotein A-I are upregulated in plasma of HAPE patients. These proteins may provide a fast and effective control of inflammatory damage until the subsequent mechanisms can begin to operate. Taken together, our findings further support the hypothesis that inflammatory response system is linked to the pathophysiology of HAPE.

The main function of the lung is to support gas exchange, and defects in lung development or diseases affecting the structure and function of the lung can have fatal consequences. Most of what we currently understand about human lung development and disease has come from animal models. However, animal models are not always fully able to recapitulate human lung development and disease, highlighting an area where in vitro models of the human lung can compliment animal models to further understanding of critical developmental and pathological mechanisms. This review will discuss current advances in generating in vitro human lung models using primary human tissue, cell lines, and human pluripotent stem cell derived lung tissue, and will discuss crucial next steps in the field.

The brown bullhead Ameiurus nebulosus is a species of the family Ictaluridae commonly used as a sentinel of environmental contamination. While these fish have been utilized for this purpose in areas contaminated with polychlorinated biphenyls (PCBs), few controlled, laboratory-based studies have been designed to document the effects of PCB mixtures in this species. Here, brown bullhead were exposed to the PCB mixture, Aroclor 1248, via intraperitoneal injection and the effects on immune function, plasma hormones and disease resistance were evaluated. Exposure to this mixture led to a decrease in bactericidal activity and circulating antibodies to Edwardsiella ictaluri present from a previous exposure to this pathogen. A subsequent E. ictaluri disease challenge led to significantly higher mortality in A1248 treated fish compared to vehicle-control fish. The mitogenic response to the T-cell mitogen, phytohemaglutinin-P, was increased compared to vehicle-control fish. The steroid hormone, cortisol, and the thyroid hormone, T3, were also significantly lower in A1248 exposed fish. In summary, we have validated a number of functional immune assays for application in brown bullhead immunotoxicity studies. Additionally, we have demonstrated that the PCB mixture (A1248) modulates both immune function and endocrine physiology in brown bullhead. Such data may compliment the interpretation of data yielded from applied field studies conducted in PCB contaminated aquatic ecosystems.

Sixteen patients with various degrees of postburn hypertrophic scars were evaluated by ultrasonography and elastometry. An Aloka Echo Camera (SSD-500) with a 7.5 MHz probe and a Cutometer SEM 575 skin elastometer were used. Serial monthly examinations were performed using both pieces of equipment. In some patients, more than one scar was assessed. The assessments were correlated with clinical grading of the progress of the scars. It was noted that ultrasonography was very sensitive in the localization of scar tissues, distinguishing them from normal skin, assessment of thickness and also delineation of the extent of scar tissues. The subcutaneous part of the scar could be assessed. Cutometer SEM 575 is a new machine that applies a gentle suction to the skin to measure its viscoelasticity. It is sensitive, the inter-observer variation is low, and it could be used for the grading of a scar. These two assessment techniques compliment other methods of scar assessment and will prove useful when assessment of response to treatment is required.

Rectal cancer treatment has evolved during the past 40 years with the use of a standardized surgical technique for tumour resection: total mesorectal excision. A dramatic reduction in local recurrence rates and improved survival outcomes have been achieved as consequences of a better understanding of the surgical oncology of rectal cancer, and the advent of adjuvant and neoadjuvant treatments to compliment surgery have paved the way for a multidisciplinary approach to disease management. Further improvements in imaging techniques and the ability to identify prognostic factors such as tumour regression, extramural venous invasion and threatened margins have introduced the concept of decision-making based on preoperative staging information. Modern treatment strategies are underpinned by accurate high-resolution imaging guiding both neoadjuvant therapy and precision surgery, followed by meticulous pathological scrutiny identifying the important prognostic factors for adjuvant chemotherapy. Included in these strategies are organ-sparing approaches and watch-and-wait strategies in selected patients. These pathways rely on the close working of interlinked disciplines within a multidisciplinary team. Such multidisciplinary forums are becoming standard in the treatment of rectal cancer across the UK, Europe and, more recently, the USA. This Review examines the essential components of modern-day management of rectal cancer through a multidisciplinary team approach, providing information that is essential for any practising colorectal surgeon to guide the best patient care.

The lateral habenula (LHb) plays a role in a wide variety of behaviors ranging from maternal care, to sleep, to various forms of cognition. One prominent theory with ample supporting evidence is that the LHb serves to relay basal ganglia and limbic signals about negative outcomes to midbrain monoaminergic systems. This makes it likely that the LHb is critically involved in behavioral flexibility as all of these systems have been shown to contribute when flexible behavior is required. Behavioral flexibility is commonly examined across species and is impaired in various neuropsychiatric conditions including autism, depression, addiction, and schizophrenia; conditions in which the LHb is thought to play a role. Therefore, a thorough examination of the role of the LHb in behavioral flexibility serves multiple functions including understanding possible connections with neuropsychiatric illnesses and additional insight into its role in cognition in general. Here, we assess the LHb's role in behavioral flexibility through comparisons of the roles its afferent and efferent pathways are known to play. Additionally, we provide new evidence supporting the LHb contributions to behavioral flexibility through organization of specific goal directed actions under cognitively demanding conditions. Specifically, in the first experiment, a majority of neurons recorded from the LHb were found to correlate with velocity on a spatial navigation task and did not change significantly when reward outcomes were manipulated. Additionally, measurements of local field potential (LFP) in the theta band revealed significant changes in power relative to velocity and reward location. In a second set of experiments, inactivation of the LHb with the gamma-aminobutyric acid (GABA) agonists baclofen and muscimol led to an impairment in a spatial/response based repeated probabilistic reversal learning task. Control experiments revealed that this impairment was likely due to the demands of repeated switching behaviors as rats were unimpaired on initial discrimination acquisition or retention of probabilistic learning. Taken together, these novel findings compliment other work discussed supporting a role for the LHb in action selection when cognitive or emotional demands are increased. Finally, we discuss future mechanisms by which a superior understanding of the LHb can be obtained through additional examination of behavioral flexibility tasks.

The discovery of small non-coding RNAs - microRNA (miRNA), short interfering RNA (siRNA) and PIWI-interacting RNA (piRNA) - represents one of the most exciting frontiers in biology specifically on the mechanism of gene regulation. In order to execute their functions, these small RNAs require physical interactions with their protein partners, the Argonaute (AGO) family proteins. Over the years, numerous studies have made tremendous progress on understanding the roles of AGO in gene silencing in various organisms. In this review, we summarize recent progress of AGO-mediated gene silencing and other cellular processes in which AGO proteins have been implicated with a particular focus on progress made in flies, humans and other model organisms as compliment.

We summarize several recent laboratory advances to tackle the problem of tumor-stroma-immune cell microenvironment interaction with the hope of developing and advancing new concepts and therapeutic strategies for prostate cancer therapy by improving bone and soft tissue metastases in prostate cancer patients. Given the emerging enthusiasm for immunotherapy in prostate cancer due to (I) improved understanding of the role of immune cells in the tumor microenvironment, (II) approval by the FDA of an immunotherapeutic drug to treat prostate cancer, and (III) recognition of immunotherapy as a novel approach to treat solid tumors by the Nobel Prize Committee (for discovery of dendritic cells that are used in immunotherapy), the field of tumor immunology is poised for growth in the next decade with the hope of developing new immunomodulatory drugs which will compliment and perhaps eventually replace traditional chemotherapeutic drugs. In this article, we provide a timely review of recent advances in the field of immunotherapy for prostate cancer, lessons learned from successes and failures, the contributory factors in the tumor microenvironment that could be rendered hostile to cancer cells, an exciting area of future research.