Spatial and evolutionary predictability of phytochemical diversity

To cope with environmental challenges, plants produce a wide diversity of phytochemicals, which are also the source of numerous medicines. Despite decades of research in chemical ecology, we still lack an understanding of the organization of plant chemical diversity across species and ecosystems. To address this challenge, we hypothesized that molecular diversity is not only related to species diversity, but also constrained by trophic, climatic, and topographical factors. We screened the metabolome of 416 vascular plant species encompassing the entire alpine elevation range and four alpine bioclimatic regions in order to characterize their phytochemical diversity. We show that by coupling phylogenetic information, topographic, edaphic, and climatic variables, we predict phytochemical diversity, and its inherent composition, of plant communities throughout landscape. Spatial mapping of phytochemical diversity further revealed that plant assemblages found in low to midelevation habitats, with more alkaline soils, possessed greater phytochemical diversity, whereas alpine habitats possessed higher phytochemical endemism. Altogether, we present a general tool that can be used for predicting hotspots of phytochemical diversity in the landscape, independently of plant species taxonomic identity. Such an approach offers promising perspectives in both drug discovery programs and conservation efforts worldwide.

Phytochemical diversity describes the richness and abundance of the specialized metabolites produced by vegetation. It is a key aspect of plant functional diversity and, thus, affects plant fitness (1), ecosystem functioning (2), and services to humankind (3). Despite its relevance, chemical ecologists still struggle to understand both the evolutionary origin of phytochemical diversity and its variation across ecosystems (4). Only a small fraction of the >300,000 currently described phytochemicals (5) has been ascribed to a known ecosystem function or process (6). This is because most identification work has been undertaken on model organisms, such as crop plants (7), and because drug discovery programs have so far been based on prior ethno-medicinal knowledge or random sampling, rather than systematic sampling from the tree of life (8) or guided by ecologically relevant information (9). The ability to better predict the presence and diversity of phytochemicals of interest from phylogenetic information, or from specific environments or habitat types, could uncover the full spectrum and function of phytochemicals in the landscape while also orienting drug discovery research (10). Moreover, documenting landscape variability in phytochemical diversity is particularly important in the context of land use change, which is causing losses of plants that possess a yet-unknown value to medicine and science (11).The plant metabolome includes both primary functions, expected to be conserved across species, and specialized functions, associated to specific lineages or environments (1). Thus, phytochemical variation in the landscape is expected to arise from a combination of evolutionary (12, 13) and ecological (14, 15) constraints. From a macroevolutionary standpoint, some classes of phytochemical compounds are specific to plant clades (e.g., glucosinolates in Brassicaceae, or tropane alkaloids in Solanales; ref. 16). Such lineage-dependent variation is thought to be driven by chemical defense innovations followed by coevolutionary dynamics with herbivores (17, 18). In particular, the escape-and-radiate model (13) predicts that plant lineages diversify by creating novel, more potent, or complex chemical mixtures in response to biotic pressure (19). Therefore, plant lineages that have experienced more evolutionary split events are predicted to have evolved higher levels of phytochemical diversity (13). From an ecological perspective, phytochemical diversity is expected to be the result of plant adaptation to abiotic and biotic conditions, both of which vary along ecological gradients in landscapes (2, 20). For example, habitats that impose constraints on plant growth, such as cold and resource-poor environments, may be expected to drive selection toward potent chemical defense mechanisms that reduce tissue loss (21). At the same time, it is well established that herbivores and pathogens can promote divergent selection between plant congeners, leading to increasing chemical dissimilarity (22). As such, species relatedness alone is a poor predictor of site-level phytochemical diversity.Here, we questioned whether phytochemical diversity can be predicted from the phylogenetic and ecological heterogeneity observed in the landscape. We hypothesized that phytochemical diversity is not only related to local plant species diversity but is also constrained by other ecological factors, especially trophic, climatic, edaphic, and topographic variation. We developed a methodological framework involving: 1) comprehensive sampling of plant species along ecological transects that cover the entire range of regional vegetation ecological boundaries; 2) assessing species-level phytochemical composition and combining it with species distribution models (SDMs) for extrapolating phytochemical diversity across the landscape based on species occurrences; 3) extracting climatic and topographical variables associated with each unique molecule observed across all species to build molecular distribution models (MDMs); and 4) projecting phytochemical diversity and composition across the landscape based on these MDMs (SI Appendix, Fig. S1). Here, we consider phytochemical diversity both as the richness of clustered metabolic features and the presence/absence of the families of compounds they represent. We expected that phytochemical diversity values compiled from the projected MDMs would better explain plot-level phytochemical diversity and composition than phytochemical diversity calculated from plant species composition alone.     

Human intestinal parasitism,potable water availability and methods of sewage disposal among nomadic Fulanis in Kuraje rural settlement of Zamfara state

ObjectiveTo ascertain the level of intestinal parasites vis-à-vis the quality of housing and water supply, and sanitary conditions among the people of Kuraje village in Zamfara state.MethodsThe study was cross sectional in nature. Individual households were selected using systematic random sampling methods and pre-tested questionnaires were administered to all the members of each household. Stool samples were collected and processed using standard laboratory procedures. Housing conditions, sources of water and sanitary conditions of the households were also inspected. Results were analysed using Epi Info 2006 model.ResultsThe prevalence of intestinal parasites was 67.0% (347/519). 72.3% (251/347), 17.0% (59/347), and 10.7% (37/347) had one, two and three or more parasites, respectively. The associated factors with intestinal parasites were poor housing and sanitary conditions, lack of potable water and illiteracy. The commonest parasites encountered were hookworm (22.0%), Ascaris lumbricoides (18.5%), and Strongyloides stercoralis (15.6%) while the least common was Enterobius vermicularis (1.6%). Others were Giardia lamblia (5.7%), Hymenolepsis nana (5.0%), Trichuris trichiura (8.8%), Entamoeba histolytica (14.4%) and Schistosoma mansoni (8.4%).ConclusionsThe infection rate of intestinal parasites in Kuraje village is high. More efforts should be intensified towards improvement in sanitary and housing standards, supply of potable water and institution of a more comprehensive literacy programme for the people of the community.     

Left Ventricular Systolic Dysfunction and Cardiovascular Outcomes in Tetralogy of Fallot: Systematic Review and Meta-analysis

BackgroundAlthough there are robust data about the pathophysiology and prognostic implications of left ventricular (LV) systolic dysfunction in patients with acquired heart disease, similar prognostic data about LV systolic dysfunction are sparse in the tetralogy of Fallot (TOF) population. The purpose of this study was to perform a meta-analysis of all studies that assessed the relationship between LV ejection fraction (LVEF) and cardiovascular adverse events (CAEs) defined as death, aborted sudden death, or sustained ventricular tachycardia.MethodsWe used random-effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsOf the 1,809 citations, 7 studies with 2,854 patients (age 28 ± 4 years) were included. During 5.6 ± 3.4 years' follow-up, there were 82 deaths, 17 aborted sudden cardiac deaths, and 56 sustained ventricular tachycardia events. Overall, CAEs occurred in 5.1% (144 patients). As a continuous variable, LVEF was a predictor of CAE (HR 1.29, 95% CI, 1.09-1.53, P = 0.001) per 5% decrease in LVEF. Similarly, LVEF < 40% was also a predictor of CAE (HR 3.22, 95% CI, 2.16-4.80, P < 0.001).ConclusionsLV systolic dysfunction was an independent predictor of CAE, and we observed a 30% increase in the risk of CAE for every 5% decrease in LVEF, and a 3-fold increase in the risk of CAE in patients with LVEF <40% compared with other patients. These findings underscore the importance of incorporating LV systolic function in clinical risk stratification of patients with TOF and the need to explore new treatment options to address this problem.     

Outcomes of first-line endoscopic management for patients with sigmoid volvulus

Background

Sigmoid volvulus is a common cause of colonic obstruction in old and frail patients. Its standard management includes the endoscopic detorsion of the colonic loop, followed by an elective sigmoidectomy to prevent recurrence. However, these patients are often poor candidates for surgery.

Preprocedural Considerations in Gastrointestinal Endoscopy

The current practice of open-access endoscopy allows primary care and other non-gastroenterology physicians to directly refer patients for routine gastrointestinal endoscopic procedures. Open-access endoscopy is considered to be more cost-effective and time efficient than the traditional practice of referring patients for preprocedural consultation with a gastrointestinal endoscopist. Several studies have evaluated the performance of endoscopic procedures in an open-access environment and the utility of structured referral mechanisms to ensure safe and appropriately indicated procedures. This review focuses on 4 common preprocedural issues in gastrointestinal endoscopy encountered by primary care physicians: management of anticoagulation and antiplatelet therapy, indication for prophylactic antibiotic drug therapy, need for anesthesia-assisted sedation, and management of poor bowel preparation. We summarize the current guidelines that address these 4 common preprocedural issues to facilitate safe and clinically appropriate procedures in open-access endoscopy.     

Pituitary carcinomas and aggressive pituitary tumours: merits and pitfalls of temozolomide treatment

Pituitary carcinomas are rare, accounting for about 0·2% of all pituitary tumours. They represent a challenge to clinical practice in both diagnosis and treatment. They may present initially as typical pituitary adenomas, with a delayed appearance of aggressive signs, or as aggressive tumours from the outset. Predicting the pituitary tumour behaviour remains difficult: increased mitotic, Ki‐67 and P53 indices might be associated with tumour aggression. The treatment of pituitary carcinomas and aggressive pituitary tumours includes surgery, adjuvant medical treatment, external beam radiotherapy and chemotherapy. Until recently, the treatment of pituitary carcinomas was mainly palliative and did not seem to increase overall survival. Recent case reports have detailed the successful use of temozolomide, an orally administered alkylating agent used to treat malignant gliomas, in the management of pituitary carcinomas and aggressive pituitary tumours. The outcome of treatment might depend on the expression of O ⁶ ‐methylguanine‐DNA methyltransferase (MGMT), a DNA repair enzyme that potentially interferes with drug efficacy. This review describes the clinical presentation and response to temozolomide in 44 patients with pituitary carcinomas or aggressive pituitary tumours reported in the literature. The results suggest that temozolomide should be considered a drug of major importance in the therapeutic algorithm of aggressive pituitary tumours and pituitary carcinomas. Because of the inconsistency of published data, MGMT expression should probably not be taken as a reason to deny these patients the potential benefit of temozolomide treatment, taking into account the paucity of other available treatments.     

How does antifungal pharmacology differ for mucormycosis versus aspergillosis?

Over the last decade, advances in diagnostic systems and the introduction of new antifungal agents have significantly improved outcomes in immunocompromised patients who develop invasive aspergillosis. However, mortality rates remain relatively unchanged for less common, but highly aggressive, mold infections such as mucormycosis. Recent genome sequencing of Rhizopus oryzae revealed evidence of a whole-genome duplication event during the evolution of this pathogen. Consequently, R. oryzae has a 2- to 10-fold enrichment in gene families associated with ergosterol and cell wall biosynthesis, cell growth, iron uptake, and known fungal virulence factors compared with sequenced Aspergillus fumigatus strains. This genetic plasticity may explain the remarkable capability of this pathogen for rapid growth in hostile environments, such as the inflammatory milieu, as well as its relative resistance to multiple antifungal classes. Herein, we examine how pharmacological aspects of treating mucormycosis may differ from those of the more commonly encountered invasive aspergillosis.     

Combination therapy for mucormycosis: why, what, and how?

The high mortality rate of mucormycosis with currently available monotherapy, particularly in hematology patients, has stimulated interest in studying novel combinations of antifungal agents to determine whether superior outcomes might be achieved. Combination lipid polyene-echinocandin therapy is the most promising of such regimens based on safety profile, the availability of parenteral formulations of echinocandins, their synergy in murine models of mucormycosis, and observational clinical data that are concordant. Other options include combination lipid polyene plus deferasirox or posaconazole therapy. Definitive, randomized, placebo-controlled phase III clinical trials are needed to determine whether combination therapy with any of these options is superior to monotherapy. Until such studies are conducted, clinicians will continue to be placed in the unacceptable position of not knowing if and when to administer combination therapy. Such a state of confusion may lead to undertreatment if combination therapy is indeed superior but is not used and, conversely, may lead to unacceptable toxicity and cost to patients if combination therapy is not superior but is used. It is critical that sponsors step forward with funding to conduct these clinical trials to determine whether outcomes from these devastating infections can be improved.