Into the danger zone: How the within-host distribution of parasites controls virulence.

Despite the importance of virulence in epidemiological theory, the relative contributions of host and parasite to virulence outcomes remain poorly understood. Here, we use reciprocal cross experiments to disentangle the influence of host and parasite on core virulence components-infection and pathology-and understand dramatic differences in parasite-induced malformations in California amphibians. Surveys across 319 populations revealed that amphibians' malformation risk was 2.7× greater in low-elevation ponds, even while controlling for trematode infection load. Factorial experiments revealed that parasites from low-elevation sites induced higher per-parasite pathology (reduced host survival and growth), whereas there were no effects of host source on resistance or tolerance. Parasite populations also exhibited marked differences in within-host distribution: ~90% of low-elevation cysts aggregated around the hind limbs, relative to <60% from high-elevation. This offers a novel, mechanistic basis for regional variation in parasite-induced malformations while promoting a framework for partitioning host and parasite contributions to virulence.

Hypertensive crisis: diagnosis, presentation, and treatment.

PURPOSE OF REVIEW: Hypertensive crisis (HTN-C) is a condition of increasing prevalence. It carries significant morbidity and mortality, and prompt recognition and treatment are crucial. There is a paucity of controlled trials, so a working knowledge of the most recent literature in the area of HTN-C is helpful. RECENT FINDINGS: Novel serological markers, including serum corin, have been found to aid in the early identification of end-organ damage from severely elevated blood pressure (BP). In the area of BP following thrombolysis for ischemic stroke, lower target BP (130-140 mmHg) is associated with some improved outcomes. Two large trials of lower BP following mechanical thrombectomy in stroke have failed to show improved outcomes; however, observed data show benefits at lower than currently recommended levels. Clevidipine, a calcium channel blocker marketed for unique use in HTN-C, was found to be noninferior to the generic less expensive nicardipine. Oral nifedipine was found to be the most effective agent for sustained BP reduction in preeclampsia. SUMMARY: HTN-C remains an area with few prospective randomized trials, but there is active research on identifying lower goals for specific clinical scenarios. Ideal therapeutic agents should be tailored for specific end-organ damage.

Imaging of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

PURPOSE OF REVIEW: The current article reviews obstructive forms of hypertrophic cardiomyopathy and associated morphologic cardiac abnormalities. It focuses on echocardiographic imaging of the left ventricular (LV) outflow tract obstruction, its evaluation, prognostication, and differentiation from other conditions mimicking obstructive hypertrophic cardiomyopathy. RECENT FINDINGS: Symptomatic patients with LV outflow tract (LVOT) gradients at least 50 mmHg on maximally tolerated medical therapy are candidates for advanced therapies. Resting echocardiography may only identify 30% of patients with obstructive physiology. Provocative maneuvers are essential for symptomatic patients with hypertrophic cardiomyopathy (HCM). Exercise echocardiography is recommended if they fail to provoke a gradient. Although dynamic LV tract obstruction is seen with obstructive HCM, it is not specific to this condition and exists in other physiologic and pathophysiologic states. Careful clinical evaluation and imaging techniques aid in the differentiation of HCM from these conditions. SUMMARY: Imaging plays an integral role in the diagnosis, prognosis, and risk stratification of HCM patients. Newer imaging technologies, including 3D transthoracic echocardiography, 3D transesophageal, speckle-derived 2D strain, and cardiac MRI, allow for a better hemodynamic understanding of systolic anterior motion and LV tract obstruction. Evolving techniques, that is, artificial intelligence, will undoubtedly further increase diagnostic capabilities. Newer medical therapies are available with the hope that this will lead to better patient management.

Secondary hypertension: evaluation and management.

PURPOSE OF REVIEW: Hypertension (HTN) that can be attributed to a particular source is known as secondary HTN (SH). Often, SH is difficult to control and thus referred to as resistant HTN, although the two terms are not mutually exclusive. RECENT FINDINGS: A common theme across several contributors to SH are coactivation of the sympathetic drive and hormonal changes, independent of hormonal axis activation. The key to effective management of SH is early recognition and treatment to avoid catastrophic cardiovascular disease effects and mortality. SUMMARY: This review article provides a contemporary summary of the conditions associated with SH and briefly reviews diagnostics and management.

Timescale reverses the relationship between host density and infection risk.

Host density shapes infection risk through two opposing phenomena. First, when infective stages are subdivided among multiple hosts, greater host densities decrease infection risk through 'safety in numbers'. Hosts, however, represent resources for parasites, and greater host availability also fuels parasite reproduction. Hence, host density increases infection risk through 'density-dependent transmission'. Theory proposes that these phenomena are not disparate outcomes but occur over different timescales. That is, higher host densities may reduce short-term infection risk, but because they support parasite reproduction, may increase long-term risk. We tested this theory in a zooplankton-disease system with laboratory experiments and field observations. Supporting theory, we found that negative density-risk relationships (safety in numbers) sometimes emerged over short timescales, but these relationships reversed to 'density-dependent transmission' within two generations. By allowing parasite numerical responses to play out, time can shift the consequences of host density, from reduced immediate risk to amplified future risk.

It's a worm-eat-worm world: Consumption of parasite free-living stages protects hosts and benefits predators.

Predation on parasites is a common interaction with multiple, concurrent outcomes. Free-living stages of parasites can comprise a large portion of some predators' diets and may be important resources for population growth. Predation can also reduce the density of infectious agents in an ecosystem, with resultant decreases in infection rates. While predator-parasite interactions likely vary with parasite transmission strategy, few studies have examined how variation in transmission mode influences contact rates with predators and the associated changes in consumption risk. To understand how transmission mode mediates predator-parasite interactions, we examined associations between an oligochaete predator Chaetogaster limnaei that lives commensally on freshwater snails and nine trematode taxa that infect snails. Chaetogaster is hypothesized to consume active (i.e. mobile), free-living stages of trematodes that infect snails (miracidia), but not the passive infectious stages (eggs); it could thus differentially affect transmission and infection prevalence of parasites, including those with medical or veterinary importance. Alternatively, when infection does occur, Chaetogaster can consume and respond numerically to free-living trematode stages released from infected snails (cercariae). These two processes lead to contrasting predictions about whether Chaetogaster and trematode infection of snails correlate negatively ('protective predation') or positively ('predator augmentation'). Here, we tested how parasite transmission mode affected Chaetogaster-trematode relationships using data from 20,759 snails collected across 4 years from natural ponds in California. Based on generalized linear mixed modelling, snails with more Chaetogaster were less likely to be infected by trematodes that rely on active transmission. Conversely, infections by trematodes with passive infectious stages were positively associated with per-snail Chaetogaster abundance. Our results suggest that trematode transmission mode mediates the net outcome of predation on parasites. For trematodes with active infectious stages, predatory Chaetogaster limited the risk of snail infection and its subsequent pathology (i.e. castration). For taxa with passive infectious stages, no such protective effect was observed. Rather, infected snails were associated with higher Chaetogaster abundance, likely owing to the resource subsidy provided by cercariae. These findings highlight the ecological and epidemiological importance of predation on free-living stages while underscoring the influence of parasite life history in shaping such interactions.

Host Controls of Within-Host Disease Dynamics: Insight from an Invertebrate System.

AbstractWithin-host processes (representing the entry, establishment, growth, and development of a parasite inside its host) may play a key role in parasite transmission but remain challenging to observe and quantify. We develop a general model for measuring host defenses and within-host disease dynamics. Our stochastic model breaks the infection process down into the stages of parasite exposure, entry, and establishment and provides associated probabilities for a host's ability to resist infections with barriers and clear internal infections. We tested our model on Daphnia dentifera and the parasitic fungus Metschnikowia bicuspidata and found that when faced with identical levels of parasite exposure, Daphnia patent (transmitting) infections depended on the strength of internal clearance. Applying a Gillespie algorithm to the model-estimated probabilities allowed us to visualize within-host dynamics, within which signatures of host defense could be clearly observed. We also found that early within-host stages were the most vulnerable to internal clearance, suggesting that hosts have a limited window during which recovery can occur. Our study demonstrates how pairing longitudinal infection data with a simple model can reveal new insight into within-host dynamics and mechanisms of host defense. Our model and methodological approach may be a powerful tool for exploring these properties in understudied host-parasite interactions.

Context-Dependent Host-Symbiont Interactions: Shifts along the Parasitism-Mutualism Continuum.

AbstractSymbiotic interactions can shift along a mutualism-parasitism continuum. While there are many studies examining dynamics typically considered to be mutualistic that sometimes shift toward parasitism, little is known about conditions underlying shifts from parasitism toward mutualism. In lake populations, we observed that infection by a microsporidian gut symbiont sometimes conferred a reproductive advantage and other times a disadvantage to its Daphnia host. We hypothesized that the microsporidian might benefit its host by reducing infection by more virulent parasites, which attack via the gut. In a laboratory study using field-collected animals, we found that spores of a virulent fungal parasite were much less capable of penetrating the guts of Daphnia harboring the microsporidian gut symbiont. We predicted that this altered gut penetrability could cause differential impacts on host fitness depending on ecological context. Field survey data revealed that microsporidian-infected Daphnia hosts experienced a reproductive advantage when virulent parasites were common while resource scarcity led to a reproductive disadvantage, but only in lakes where virulent parasites were relatively rare. Our findings highlight the importance of considering multiparasite community context and resource availability in host-parasite studies and open the door for future research into conditions driving shifts along parasitism to mutualism gradients.

Cardiovascular effects of preeclampsia.

PURPOSE OF REVIEW: Preeclampsia complicates 3-5% of first and 15% of subsequent pregnancies. This study reviews the evidence of increase cardiovascular risk in these women. RECENT FINDINGS: Women with preeclampsia are at two-fold higher risk for development of coronary artery disease, stroke and death, and four-fold increased risk of heart failure. Preeclampsia developed in early part of pregnancy confers greater risk than later in pregnancy. Common factors that predispose women to preeclampsia also confer high risk for developing cardiovascular disease include obesity, metabolic abnormalities, dyslipidaemia, insulin resistance, heightened inflammatory responses, hypercoagulable states and endothelia dysfunction. SUMMARY: Patients with preeclampsia should be screened at regular intervals by a preventive cardiologist and treated accordingly.

Towards a mechanistic understanding of competence: a missing link in diversity-disease research.

Biodiversity loss may increase the risk of infectious disease in a phenomenon known as the dilution effect. Circumstances that increase the likelihood of disease dilution are: (i) when hosts vary in their competence, and (ii) when communities disassemble predictably, such that the least competent hosts are the most likely to go extinct. Despite the central role of competence in diversity-disease theory, we lack a clear understanding of the factors underlying competence, as well as the drivers and extent of its variation. Our perspective piece encourages a mechanistic understanding of competence and a deeper consideration of its role in diversity-disease relationships. We outline current evidence, emerging questions and future directions regarding the basis of competence, its definition and measurement, the roots of its variation and its role in the community ecology of infectious disease.

Management of resistant hypertension.

PURPOSE OF REVIEW: Resistant hypertension is defined as blood pressure above patient goal despite three different antihypertensive agents at optimal dose including a diuretic. Resistant hypertension is increasingly common issue in clinical practice and it is a major risk factor of cardiovascular disease. RECENT FINDINGS: All patients with resistant hypertension should be evaluated for possible correctable factors associated with pseudoresistance, such as poor adherence, white coat hypertension and suboptimal measurement of blood pressure. In patients with resistant hypertension, thiazide diuretics should be considered as one of the first agents, in addition to mineralocorticoids receptor antagonist. SUMMARY: Resistant hypertension can be associated with secondary cause that is why treatment can be challenging and should always include lifestyle modification and evaluation for possible secondary causes, in addition to adding a fourth agent or considering newer interventional therapies, such as renal denervation or other device-based options.

Indirect effects in a planktonic disease system.

Indirect effects, both density- and trait-mediated, have been known to act in tandem with direct effects in the interactions of numerous species. They have been shown to affect populations embedded in competitive and mutualistic networks alike. In this work, we introduce a four-dimensional system of ordinary differential equations and investigate the interplay between direct density-effects and density- and trait-mediated indirect effects that take place in a yeast parasite-zooplankton host-incompetent competitor system embedded in a food web which also includes resources and predators. Among our main findings is the demonstration that indirect effects cause qualitative and quantitative changes almost indistinguishable from direct effects and the corroboration through our analysis of the fact that the effects of direct and indirect mechanisms cannot be disentangled. Our results underpin the conclusions of past studies calling for comprehensive models that incorporate both direct and indirect effects to better describe field data.

Emerging Therapy in Hypertension.

PURPOSE OF THE REVIEW: Pharmacology remains the mainstay of treatment for hypertension across the globe. In what may seem like a well-trodden field, there are actually an exciting array of new pathways for the treatment of hypertension on the horizon. This review seeks to discuss the most recent research in ongoing areas of drug development in the field of hypertension. RECENT FINDINGS: Novel areas of research in the field of hypertension pharmacology include central nervous system regulators, peripheral noradrenergic inhibitors, gastrointestinal sodium modulators, and a counter-regulatory arm of the renin-angiotensin-aldosterone system. This review discusses these pathways in a look into the current status of emerging pharmacological therapies for hypertension.

Future pharmacological therapy in hypertension.

PURPOSE OF REVIEW: Hypertension (HTN) is a widespread and growing disease, with medication intolerance and side-effect present among many. To address these obstacles novel pharmacotherapy is an active area of drug development. This review seeks to explore future drug therapy for HTN in the preclinical and clinical arenas. RECENT FINDINGS: The future of pharmacological therapy in HTN consists of revisiting old pathways to find new targets and exploring wholly new approaches to provide additional avenues of treatment. In this review, we discuss the current status of the most recent drug therapy in HTN. New developments in well trod areas include novel mineralocorticoid antagonists, aldosterone synthase inhibitors, aminopeptidase-A inhibitors, natriuretic peptide receptor agonists, or the counter-regulatory angiotensin converting enzyme 2/angiotensin (Ang) (1-7)/Mas receptor axis. Neprilysin inhibitors popularized for heart failure may also still hold HTN potential. Finally, we examine unique systems in development never before used in HTN such as Na/H exchange inhibitors, vasoactive intestinal peptide agonists, and dopamine beta hydroxylase inhibitors. SUMMARY: A concise review of future directions of HTN pharmacotherapy.

Renal fossa recurrence after nephrectomy for renal cell carcinoma: prognostic features and oncological outcomes.

OBJECTIVES: To describe the clinicopathological features associated with increased risk of renal fossa recurrence (RFR) after radical nephrectomy (RN) and to describe the prognostic features associated with cancer-specific survival (CSS) among patients with RFR treated with primary locally directed therapy, systemically directed therapy or expectant management. PATIENTS AND METHODS: The records of 2 502 patients treated with RN for unilateral, sporadic, localized renal cell carcinoma (RCC) between 1970 and 2006 were reviewed. CSS after RFR was estimated using the Kaplan-Meier method. Associations with the development of RFR and CSS after RFR were evaluated using Cox proportional hazards regression models. RESULTS: A total of 33 (1.3%) patients developed isolated RFR (iRFR) and 30 (1.2%) patients developed RFR in the setting of synchronous metastases after RN (study cohort, N = 63). The median follow-up for the series was 9.0 years after RN and 6.0 years after RFR diagnosis. On multivariable analysis, advanced pathological stage (pT2: hazard ratio [HR] 4.36, P = 0.004; pT3/4: HR 4.39, P = 0.003) and coagulative necrosis (HR 2.71, P = 0.006) were independently associated with increased risk of iRFR. The median time to recurrence was 1.5 years after RN among the 33 patients with iRFR, and 1.4 years among all patients. Overall, the median CSS was 2.5 years after diagnosis of iRFR, 1.3 years after RFR in the setting of synchronous metastases, and 2.2 years overall. After primary locally directed therapy (surgery, ablation or radiation), systemic therapy or expectant management, the 3-year CSS rates among patients with iRFR were 63%, 50% and 13% (P = 0.001) and were 64%, 50% and 28% (P = 0.006) among all patients, respectively. On multivariable analysis, when compared with observation, locally directed therapies were associated with a significantly decreased risk of death from RCC (HR 0.26, P < 0.001). CONCLUSIONS: Renal fossa recurrence is a rare event after RN for RCC and portends a poor prognosis, even in the absence of synchronous metastases. Development of iRFR is associated with advanced stage and aggressive tumour biology. Patients who underwent primary locally directed therapy had superior CSS compared with those treated with expectant management, supporting the use of aggressive local treatment in carefully selected patients with RFR. Future research is needed to determine the optimum role and sequencing of combined therapy in patients with this rare entity.

Decreased Skeletal Muscle Mass is Associated with an Increased Risk of Mortality after Radical Nephrectomy for Localized Renal Cell Cancer.

PURPOSE: We evaluate the association between severe skeletal muscle deficiency or sarcopenia, and disease progression, cancer specific mortality and all cause mortality in patients with localized renal cell carcinoma treated with radical nephrectomy. MATERIALS AND METHODS: The baseline lumbar skeletal muscle index of 387 patients treated with radical nephrectomy for nonmetastatic renal cell carcinoma between 2000 and 2010 was measured on preoperative computerized tomography. Sarcopenia was classified according to gender specific consensus definitions as male-skeletal muscle index less than 55 cm(2)/m(2) and female-skeletal muscle index less than 39 cm(2)/m(2). Progression-free, cancer specific and overall survival was estimated with the Kaplan-Meier method. Associations with progression, cancer specific mortality and all cause mortality were summarized with hazard ratios. RESULTS: Of 387 patients 180 (47%) had sarcopenia. Patients with sarcopenia were older, more likely to be male (77% vs 56%, p <0.001), to have a smoking history (67% vs 55%, p=0.02), and to have nuclear grade 3 or greater disease (67% vs 60%, p=0.05), but were otherwise similar to patients without sarcopenia. Median postoperative followup was 7.2 years. Patients with sarcopenia had inferior 5-year cancer specific survival (79% vs 85%, p=0.05) compared to those without sarcopenia, as well as significantly worse 5-year overall survival (65% vs 74%, p= 0.005). As a continuous variable, increasing skeletal muscle index was linearly associated with a decreased risk of cancer specific mortality and all cause mortality. Moreover, on multivariable analysis sarcopenia was associated with increased cancer specific mortality (HR 1.70, p=0.047) and all cause mortality (HR 1.48, p=0.039). CONCLUSIONS: Sarcopenia is independently associated with cancer specific mortality and all cause mortality after radical nephrectomy for renal cell carcinoma. These findings underscore the importance of assessing skeletal muscle index for risk stratification, patient counseling and treatment planning.

Standardizing the Definition of Biochemical Recurrence after Radical Prostatectomy-What Prostate Specific Antigen Cut Point Best Predicts a Durable Increase and Subsequent Systemic Progression?

PURPOSE: Multiple definitions of biochemical recurrence for prostate cancer exist after radical prostatectomy, and variation continues in prostate cancer outcome reporting and secondary treatment initiation. We reviewed long-term prostatectomy outcomes to assess the most appropriate prostate specific antigen cut point that predicts future disease progression. MATERIALS AND METHODS: We identified 13,512 patients with cT1-2N0M0 prostate cancer who underwent radical prostatectomy between 1987 and 2010. Single prostate specific antigen cut points of 0.2, 0.3, 0.4 and 0.5 ng/ml or greater, as well as confirmatory prostate specific antigen value definitions of 0.2 ng/ml or greater followed by prostate specific antigen greater than 0.2 ng/ml and 0.4 ng/ml or greater followed by prostate specific antigen greater than 0.4 ng/ml were tested. Continued prostate specific antigen increase after a designated cut point definition was estimated using cumulative incidence. The strength of association between biochemical recurrence definitions and subsequent systemic progression were analyzed using Cox proportional hazard models and the O'Quigley event based R(2) test. RESULTS: At a median postoperative followup of 9.1 years (IQR 4.9-14.3) a detectable prostate specific antigen developed in 5,041 patients and systemic progression developed in 512. After reaching the prostate specific antigen cut point of 0.2, 0.3 and 0.4 ng/ml, the percentage of patients experiencing a continued prostate specific antigen increase over 5 years was 61%, 67% and 74%, respectively, plateauing at 0.4 ng/ml. The strongest association between biochemical recurrence and systemic progression occurred using a single prostate specific antigen cut point of 0.4 ng/ml or greater (HR 36, R(2) 0.92). CONCLUSIONS: A prostate specific antigen cut point of 0.4 ng/ml or greater reflects the threshold at which a prostate specific antigen increase becomes durable and shows the strongest correlation with subsequent systemic progression. Consideration should be given to using a prostate specific antigen of 0.4 ng/ml or greater as the standard biochemical recurrence definition after radical prostatectomy.

Diverging effects of host density and richness across biological scales drive diversity-disease outcomes.

Understanding how biodiversity affects pathogen transmission remains an unresolved question due to the challenges in testing potential mechanisms in natural systems and how these mechanisms vary across biological scales. By quantifying transmission of an entire guild of parasites (larval trematodes) within 902 amphibian host communities, we show that the community-level drivers of infection depend critically on biological scale. At the individual host scale, increases in host richness led to fewer parasites per host for all parasite taxa, with no effect of host or predator densities. At the host community scale, however, the inhibitory effects of richness were counteracted by associated increases in total host density, leading to no overall change in parasite densities. Mechanistically, we find that while average host competence declined with increasing host richness, total community competence remained stable due to additive assembly patterns. These results help reconcile disease-diversity debates by empirically disentangling the roles of alternative ecological drivers of parasite transmission and how such effects depend on biological scale.

Differential gene expression in response to fungal pathogen exposure in the aquatic invertebrate, Daphnia dentifera.

While vertebrate immune systems are appreciated for their complexity and adaptability, invertebrate immunity is often considered to be less complex. However, immune responses in many invertebrates likely involve sophisticated processes. Interactions between the crustacean host Daphnia dentifera and its fungal pathogen Metschnikowia bicuspidata provide an excellent model for exploring the mechanisms underlying crustacean immunity. To explore the genomic basis of immunity in Daphnia, we used RNA-sequencing technology to quantify differential gene expression between individuals of a single host genotype exposed or unexposed to M. bicuspidata over 24 h. Transcriptomic analyses showed that the number of differentially expressed genes between the control (unexposed) and experimental (exposed) groups increased over time. Gene ontology enrichment analysis revealed that differentially expressed genes were enriched for immune-related molecules and processes, such as cuticle development, prostaglandin, and defense response processes. Our findings provide a suite of immunologically relevant genes and suggest the presence of a rapidly upregulated immune response involving the cuticle in Daphnia. Studies involving gene expression responses to pathogen exposure shine a light on the processes occurring during the course of infection. By leveraging knowledge on the genetic basis for immunity, immune mechanisms can be more thoroughly understood to refine our understanding of disease spread within invertebrate populations.