Extensive meningoencephalitis, retrobulbar neuritis and pulmonary involvement in a patient of neurobrucellosis

We report an unusual case of neurobrucellosis who presented with headache, vision loss, confusional state, retrobulbar neuritis and left hemiparesis. Neuroimaging studies showed features of ischemic infarct and white matter abnormalities. Pulmonary involvement in form of lobar pneumonia of left basal lobe was another unusual manifestation. Diagnosis was based on the rising titers of antibrucella antibody. Patient showed remarkable improvement on triple drug therapy in form of doxycycline, rifampicin and streptomycin.     

Rapid progression to gummatous tertiary syphilis in a patient with HIV

Co-infection with human immunodeficiency virus-1 (HIV) and syphilis is associated with rapid progression to tertiary syphilis. This case report describes the early development of gummatous skin disease and suspected neurosyphilis in a patient with untreated HIV and approaches to treatment.     

Analysis of membrane proteins in metagenomics: Networks of correlated environmental features and protein families

Recent metagenomics studies have begun to sample the genomic diversity among disparate habitats and relate this variation to features of the environment. Membrane proteins are an intuitive, but thus far overlooked, choice in this type of analysis as they directly interact with the environment, receiving signals from the outside and transporting nutrients. Using global ocean sampling (GOS) data, we found nearly ∼900,000 membrane proteins in large-scale metagenomic sequence, approximately a fifth of which are completely novel, suggesting a large space of hitherto unexplored protein diversity. Using GPS coordinates for the GOS sites, we extracted additional environmental features via interpolation from the World Ocean Database, the National Center for Ecological Analysis and Synthesis, and empirical models of dust occurrence. This allowed us to study membrane protein variation in terms of natural features, such as phosphate and nitrate concentrations, and also in terms of human impacts, such as pollution and climate change. We show that there is widespread variation in membrane protein content across marine sites, which is correlated with changes in both oceanographic variables and human factors. Furthermore, using these data, we developed an approach, protein families and environment features network (PEN), to quantify and visualize the correlations. PEN identifies small groups of covarying environmental features and membrane protein families, which we call “bimodules.” Using this approach, we find that the affinity of phosphate transporters is related to the concentration of phosphate and that the occurrence of iron transporters is connected to the amount of shipping, pollution, and iron-containing dust.Integral membrane proteins play a fundamental role in sensing and interacting with the environment, allowing the influx and efflux of ions and molecules and relaying information about environmental conditions to the cell. Thus, the abundance and types of membrane protein families in a microbial community may give information about functional capabilities and nutritional requirements. In marine microorganisms, especially those inhabiting the oligotrophic (nutrient-poor) surface waters of the oceans, membrane protein content might provide insight into types of nutrients and conditions in the waters in which the organisms were isolated. For example, the recent discovery of spectral tuning of the light-driven proton pump proteorhodopsin reveals a relationship between a single amino acid mutation and dominant light wavelengths in the microbe''s surroundings (Rusch et al. 2007).Several recent studies have begun to relate functional attributes of microbial communities, such as central metabolism or broad functional classes (e.g., protein synthesis), to specific habitats (Tringe et al. 2005; Dinsdale et al. 2008) or environmental features (DeLong et al. 2006; Kunin et al. 2008; Gianoulis et al. 2009). In addition, new methods are allowing the integration of quantitative features of the environment alongside microbial function (DeLong et al. 2006; Gianoulis et al. 2009).Given their important role in environmental sensing and transport, membrane proteins may serve as an even more sensitive barometer of environmental conditions than broad functional classes or central metabolism. In addition, integration of many different environmental conditions is needed to develop a comprehensive understanding of the complex interplay between environmental conditions and microbial communities. In particular, new techniques are needed to investigate the relationship between natural processes such as nutrient fluxes and the impact of humans on the environment (anthropogenic effects), such as pollution. Given the nutrient fluctuations and anthropogenic effects observed in the world''s oceans, understanding the relationship between such factors and microbial adaptations is particularly timely. Indeed, Halpern et al. (2008) estimated that 40% of the world''s oceans are substantially affected by human activity by computing indices for pollution, shipping, ultraviolet radiation, and climate change, among others.To gain a better understanding of the relationship between environmental conditions and membrane protein content and abundance, we used 29 samples from the Global Ocean Sampling (GOS) Expedition (Rusch et al. 2007). This survey provided metagenomic sequence and environmental data (chlorophyll, water depth, sample depth, salinity, temperature), as well as GPS coordinates of the sampled sites. We used the GPS coordinates to extract additional environmental features from several disparate sources, providing both natural features, such as nutrient concentrations, and anthropogenic features, such as pollution. Integration of these quantitative measurements allowed us to investigate the relationship between microbial communities, nutrient dynamics, and anthropogenic effects, and in particular the relative importance of the various classes of membrane proteins in microbial adaptations.     

Quantifying environmental adaptation of metabolic pathways in metagenomics

Recently, approaches have been developed to sample the genetic content of heterogeneous environments (metagenomics). However, by what means these sequences link distinct environmental conditions with specific biological processes is not well understood. Thus, a major challenge is how the usage of particular pathways and subnetworks reflects the adaptation of microbial communities across environments and habitats—i.e., how network dynamics relates to environmental features. Previous research has treated environments as discrete, somewhat simplified classes (e.g., terrestrial vs. marine), and searched for obvious metabolic differences among them (i.e., treating the analysis as a typical classification problem). However, environmental differences result from combinations of many factors, which often vary only slightly. Therefore, we introduce an approach that employs correlation and regression to relate multiple, continuously varying factors defining an environment to the extent of particular microbial pathways present in a geographic site. Moreover, rather than looking only at individual correlations (one-to-one), we adapted canonical correlation analysis and related techniques to define an ensemble of weighted pathways that maximally covaries with a combination of environmental variables (many-to-many), which we term a metabolic footprint. Applied to available aquatic datasets, we identified footprints predictive of their environment that can potentially be used as biosensors. For example, we show a strong multivariate correlation between the energy-conversion strategies of a community and multiple environmental gradients (e.g., temperature). Moreover, we identified covariation in amino acid transport and cofactor synthesis, suggesting that limiting amounts of cofactor can (partially) explain increased import of amino acids in nutrient-limited conditions.     

Palliative Care in Lung Cancer: When to Start

Purpose of Review

Despite recent advances in the care of patients with advanced non-small cell lung cancer (NSCLC), significant morbidity and mortality remains. Symptoms caused by the cancer and its treatments can be profoundly debilitating. Palliative care aims to reduce this burden. In this review, we discuss the definition, purpose, benefits, and optimal timing of palliative care in advanced NSCLC.

Recent Findings

Several studies evaluating the value of early palliative care for patients with advanced NSCLC and other advanced malignancies have identified benefits for patients, caregivers, and health systems.

Summary

For patients with advanced NSCLC, introduction of palliative care early in the disease course improves quality of life and even overall survival. Early institution of palliative care should become standard of care for patients with advanced NSCLC.

     

Cancer Clonal Theory,Immune Escape,and Their Evolving Roles in Cancer Multi-Agent Therapeutics

Purpose of Review

The knowledge base of malignant cell growth and resulting targets is rapidly increasing every day. Clonal theory is essential to understand the changes required for a cell to become malignant. These changes are then clues to therapeutic intervention strategies. Immune system optimization is a critical piece to find, recognize, and eliminate all cancer cells from the host. Only by administering (1) multiple therapies that counteract the cancer cell’s mutational and externally induced survival traits and (2) by augmenting the immune system to combat immune suppression processes and by enhancing specific tumor trait recognition can cancer begin to be treated with a truly targeted focus.

Recent findings

Since the sequencing of the human genome during the 1990s, steady progress in understanding genetic alterations and gene product functions are being unraveled. In cancer, this is proceeding very fast and demonstrates that genetic mutations occur very rapidly to allow for selection of survival traits within various cancer clones. Hundreds of mutations have been identified in single individual cancers, but spread across many clones in the patient’s body. Precision oncology will require accurate measurement of these cancer survival-benefiting mutations to develop strategies for effective therapy. Inhibiting these cellular mechanisms is a first step, but these malignant cells need to be eliminated by the host’s mechanisms, which we are learning to direct more specifically.

Summary

Cancer is one of the most complicated cellular aberrations humans have encountered. Rapidly developing significant survival traits require prompt, repeated, and total body measurements of these attributes to effectively develop multi-agent treatment of the individual’s malignancy. Focused drug development to inhibit these beneficial mutations is critical to slowing cancer cell growth and, perhaps, triggering apoptosis. In many cases, activation and targeting of the immune system to kill the remaining malignant cells is essential to a cure.