Antibiotic Maximalism: Legislative Assaults on the Evidence-Based Treatment of Lyme Disease

Antibiotics, and the deadly pathogens that have evolved to resist them, are one of the major public health concerns of our time. The introduction of penicillin in the early 1940s signaled a new era—not only for the treatment of devastating infections, but also for the out-witting of antibiotics by fast-evolving bacteria. If the middle of the twentieth century saw the era of antibiotic innovation, the past several years might be labeled the era of antibiotic resistance, when untreatable infections have become a modern scourge. Methicillin-resistant Staphylococcus aureus (MRSA) is the most notorious antibiotic resistant “superbug”; this antibiotic-resistent pathogen has emerged as an endemic problem in hospital and long-term care settings. In 2011, bills were introduced in both houses of Congress to encourage the development of new antibiotics to replace those that have become ineffective. Yet, unless or until a truly “miracle” antibiotic (i.e., one which may not be resisted by bacteria) is someday developed, the only solution to antibiotic resistance is to reduce the use of antibiotics. Surprisingly, amidst public-health efforts to prevent antibiotic-resistant pathogens by reining in excessive antibiotic use, several states have passed laws that legitimize intensive antibiotic regimens even when those regimens contradict the best available medical evidence. Although this unprecedented legislative activity has occurred in the context of a controversial medical diagnosis, chronic Lyme disease, the legal and political repercussions threaten the established role of state medical licensing boards in promoting evidence-based standardization of medical practice. The most intrusive of these statutes prevents state licensing boards from disciplining physicians who prescribe regimens of long-term antibiotic therapy that are specifically proscribed by mainstream clinical practice guidelines (CPGs) on Lyme disease treatment. Such laws promote the view of non-standard practitioners who favor the intensive, maximalist use of antibiotics for a condition that mainstream physicians dispute even exists. In an attempt to protect unnecessary antibiotic regimens, recent legislation legitimizes a treatment paradigm that poses an undue risk of harm to individual patients and to the public health. By enacting laws that protect and legitimize repudiated treatments, state legislatures have responded to a movement of non-standard “Lyme literate medical doctors” (LLMDs)—a movement that has been described as an “antiscience” and “parallel universe of pseudoscientific practitioners” by mainstream practitioners. In addition, by interfering with the legal authority of state medical boards to enforce evidence-based standards on antibiotic use, states have also sided with a fringe movement of physicians who oppose the “encroachment” of third-parties, including the government, upon the physician-patient relationship. These advocates decry the influence of evidence-based clinical guidelines and state medical licensing boards on the medical practice. Removing the power of state regulators to discipline physicians for dangerous, non-standard Lyme disease treatment is perceived as an opening salvo in the attack on the legitimacy of state medical oversight

Effect of Tidal Cycling Rate on the Distribution and Abundance of Nitrogen-Oxidizing Bacteria in a Bench-Scale Fill-and-Drain Bioreactor

Most domestic wastewater can be effectively treated for secondary uses by engineered biological systems. These systems rely on microbial activity to reduce nitrogen (N) content of the reclaimed water. Such systems often employ a tidal-flow process to minimize space requirements for the coupling of aerobic and anaerobic metabolic processes. In this study, laboratory-scale tidal-flow treatment systems were studied to determine how the frequency and duration of tidal cycling may impact reactor performance. Fluorescent in situ hybridization and epifluorescence microscopy were used to enumerate the key functional groups of bacteria responsible for nitrification and anaerobic ammonium oxidation (anammox), and N-removal efficiency was calculated via a mass-balance approach. When water was cycled (i.e., reactors were filled and drained) at high frequencies (16–24 cycles day−1), nitrate accumulated in the columns—presumably due to inadequate periods of anoxia that limited denitrification. At lower frequencies, such as 4 cycles day−1, nearly complete N removal was achieved (80–90%). These fill-and-drain systems enriched heavily for nitrifiers, with relatively few anammox-capable organisms. The microbial community produced was robust, surviving well through short (up to 3 h) anaerobic periods and frequent system-wide perturbation

Greenhouse Gas Emissions Over a Tidal Cycle in a Freshwater Wetland

Tidal freshwater wetlands are located at the interface of non-tidal freshwater riverine systems and estuarine tidal systems. These habitats experience freshwater tides, creating unique redoximorphic soil characteristics while simultaneously presenting an opportunity for hydrologic nutrient transport into the system. Because of this periodic flooding and draining, tidal freshwater wetlands are systems of intense biogeochemical transformations, which are microbially mediated. Several microbial transformations (e.g., methanogenesis, incomplete denitrification, and nitrification) result in the production of greenhouse gases (CO2, CH4, and N2O) at globally-significant levels. For example, wetlands are one of the greatest sources of methane on Earth, accounting for 20-33% of the global methane budget (Schlesinger and Bernhardt, 2013). Compared to global methane emission estimates, the global nitrous oxide budget remains largely uncertain (Tian et al. 2015), and the contribution of wetlands is currently unknown (Schlesinger and Bernhardt, 2013). However, given that recent work by Liengaard et al. (2012) estimated that nitrous oxide emissions from the Pantanal wetland system in South America alone represent ~2% of global emissions, it is reasonable to expect wetlands to be major contributors to atmospheric concentrations of this potent greenhouse gas. Despite the growing recognition that wetlands are important sources of greenhouse gases, little research has examined how flux rates vary in response to basic environmental drivers such as tidal cycling Objectives: The main objective of this study is to assess rates of CO2, CH4, and N2O production at high and low tides in a tidal freshwater wetlands. In addition, we sought to determine if pore water ion concentrations and edaphic characteristics fluctuate over a tidal cycle

Small interfering RNA-producing loci in the ancient parasitic eukaryote Trypanosoma brucei

BACKGROUND: At the core of the RNA interference (RNAi) pathway in Trypanosoma brucei is a single Argonaute protein, TbAGO1, with an established role in controlling retroposon and repeat transcripts. Recent evidence from higher eukaryotes suggests that a variety of genomic sequences with the potential to produce double-stranded RNA are sources for small interfering RNAs (siRNAs). RESULTS: To test whether such endogenous siRNAs are present in T. brucei and to probe the individual role of the two Dicer-like enzymes, we affinity purified TbAGO1 from wild-type procyclic trypanosomes, as well as from cells deficient in the cytoplasmic (TbDCL1) or nuclear (TbDCL2) Dicer, and subjected the bound RNAs to Illumina high-throughput sequencing. In wild-type cells the majority of reads originated from two classes of retroposons. We also considerably expanded the repertoire of trypanosome siRNAs to encompass a family of 147-bp satellite-like repeats, many of the regions where RNA polymerase II transcription converges, large inverted repeats and two pseudogenes. Production of these newly described siRNAs is strictly dependent on the nuclear DCL2. Notably, our data indicate that putative centromeric regions, excluding the CIR147 repeats, are not a significant source for endogenous siRNAs. CONCLUSIONS: Our data suggest that endogenous RNAi targets may be as evolutionarily old as the mechanism itself

Water adsorption on vanadium oxide thin films in ambient relative humidity.

In this work, ambient pressure x-ray photoelectron spectroscopy (APXPS) is used to study the initial stages of water adsorption on vanadium oxide surfaces. V 2p, O 1s, C 1s, and valence band XPS spectra were collected as a function of relative humidity in a series of isotherm and isobar experiments. Experiments were carried out on two VO2 thin films on TiO2 (100) substrates, prepared with different surface cleaning procedures. Hydroxyl and molecular water surface species were identified, with up to 0.5 ML hydroxide present at the minimum relative humidity, and a consistent molecular water adsorption onset occurring around 0.01% relative humidity. The work function was found to increase with increasing relative humidity, suggesting that surface water and hydroxyl species are oriented with the hydrogen atoms directed away from the surface. Changes in the valence band were also observed as a function of relative humidity. The results were similar to those observed in APXPS experiments on other transition metal oxide surfaces, suggesting that H2O-OH and H2O-H2O surface complex formation plays an important role in the oxide wetting process and water dissociation. Compared to polycrystalline vanadium metal, these vanadium oxide films generate less hydroxide and appear to be more favorable for molecular water adsorption

hZip2 and hZip3 zinc transporters are down regulated in human prostate adenocarcinomatous glands

<p>Abstract</p> <p>Background</p> <p>The normal human prostate glandular epithelium has the unique function of accumulating high levels of zinc. In prostate cancer this capability is lost as an early event in the development of the malignant cells. The mechanism and factors responsible for the ability of the normal epithelial cells to accumulate zinc and the loss of this capability in the malignant cells need to be identified. We previously reported that Zip1 is an important zinc uptake transporter in prostate cells and is down regulated in the malignant cells in situ along with the depletion of zinc levels. In this report we investigated the expression of two other Zip family zinc transporters, Zip2 and Zip3 in malignant versus nonmalignant (normal and BPH) glands. Zip2 and Zip3 relative protein levels were determined by immunohistochemistry analysis of human prostate tissue sections.</p> <p>Results</p> <p>Normal and BPH glandular epithelium consistently exhibited the strong presence of both Zip 2 and Zip3; whereas both transporters consistently were essentially non-detectable in the malignant glands. This represents the first report of the expression of Zip3 in human prostate tissue; and more importantly, reveals that ZiP2 and Zip3 are down regulated in malignant cells in situ as we also had demonstrated for Zip1. Zip2 and Zip3 transporter proteins were localized predominantly at the apical cell membrane, which is in contrast to the Zip1 localization at the basolateral membrane. Zip2 and Zip3 seemingly are associated with the re-uptake of zinc from prostatic fluid.</p> <p>Conclusion</p> <p>These results coupled with previous reports implicate Zip2 and Zip3 along with Zip1 as important zinc uptake transporters involved in the unique ability of prostate cells to accumulate high cellular zinc levels. Zip1 is important for the extraction of zinc from circulation as the primary source of cellular zinc. Zip 2 and Zip3 appear to be important for retention of the zinc in the cellular compartment. The down regulation of all three transporters in the malignant cells is consistent with the loss of zinc accumulation in these cells. Since zinc imposes tumor suppressor effects, the silencing of the gene expression for these transporters is a required event for the manifestation of the malignant activities of the neoplastic cells. This now provides new insights into the genetic/molecular events associated with the development of prostate cancer; and supports our concept of Zip1, and now Zip2 and Zip3, as tumor suppressor genes and zinc as a tumor suppressor agent.</p

The Transcriptome of the Human Pathogen Trypanosoma brucei at Single-Nucleotide Resolution

The genome of Trypanosoma brucei, the causative agent of African trypanosomiasis, was published five years ago, yet identification of all genes and their transcripts remains to be accomplished. Annotation is challenged by the organization of genes transcribed by RNA polymerase II (Pol II) into long unidirectional gene clusters with no knowledge of how transcription is initiated. Here we report a single-nucleotide resolution genomic map of the T. brucei transcriptome, adding 1,114 new transcripts, including 103 non-coding RNAs, confirming and correcting many of the annotated features and revealing an extensive heterogeneity of 5′ and 3′ ends. Some of the new transcripts encode polypeptides that are either conserved in T. cruzi and Leishmania major or were previously detected in mass spectrometry analyses. High-throughput RNA sequencing (RNA-Seq) was sensitive enough to detect transcripts at putative Pol II transcription initiation sites. Our results, as well as recent data from the literature, indicate that transcription initiation is not solely restricted to regions at the beginning of gene clusters, but may occur at internal sites. We also provide evidence that transcription at all putative initiation sites in T. brucei is bidirectional, a recently recognized fundamental property of eukaryotic promoters. Our results have implications for gene expression patterns in other important human pathogens with similar genome organization (Trypanosoma cruzi, Leishmania sp.) and revealed heterogeneity in pre-mRNA processing that could potentially contribute to the survival and success of the parasite population in the insect vector and the mammalian host

Flexible, Print-in-Place 1D-2D Thin-Film Transistors Using Aerosol Jet Printing

In this work, we overcome temperature constraints and demonstrate 1D−2D thin-film transistors (1D−2D TFTs) in a low-temperature (maximum exposure ≤80 °C) full print-in-place process (i.e., no substrate removal from printer throughout the entire process) using an aerosol jet printer. Semiconducting 1D CNT channels are used with a 2D hexagonal boron nitride (h-BN) gate dielectric and traces of silver nanowires as the conductive electrodes, all deposited using the same printer. The aerosol jet-printed 2D h-BN films were realized via proper ink formulation, such as utilizing the binder hydroxypropyl methylcellulose, which suppresses redispersion between adjacent printed layers. In addition to an ON/ OFF current ratio up to 3.5 Å~ 105, channel mobility up to 10.7 cm2·V-1·s-1, and low gate hysteresis, 1D−2D TFTs exhibit extraordinary mechanical stability under bending due to the nanoscale network structure of each layer, with minimal changes in performance after 1000 bending test cycles at 2.1% strain. It is also confirmed that none of the device layers require high-temperature treatment to realize optimal performance. These findings provide an attractive approach toward a cost-effective, direct-write realization of electronics