Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the United States.

BACKGROUND: In 2012, the Food and Drug Administration approved use of bedaquiline fumarate as part of combination therapy for multidrug-resistant tuberculosis (MDR TB). We describe treatment outcomes, safety, and tolerability of bedaquiline in our case series. METHODS: Data on patients started on bedaquiline for MDR TB between September 2012 and August 2016 were collected retrospectively through 4 TB programs using a standardized abstraction tool. Data were analyzed using univariate methods. Adverse events were graded using the Common Terminology Criteria for Adverse Events. RESULTS: Of 14 patients, 7 (50%) had MDR, 4 (29%) had pre-extensively drug-resistant (XDR), and 3 (21%) had XDR TB. All had pulmonary TB, 5 (36%) had pulmonary and extrapulmonary TB, and 9/13 (69%) were smear positive. One patient (7%) had HIV coinfection, 5 (36%) had diabetes mellitus, and 5/14 (36%) had previous treatment TB. All patients were non-US-born and 5/14 (36%) had private insurance. All patients achieved sputum culture conversion within a mean of 71 days (26-116); 5 after starting bedaquiline. Twelve (86%) completed treatment and 1 (7%) moved out of the country. One patient (7%) had QTc prolongation >500 milliseconds and died 20 months after discontinuing bedaquiline of a cause not attributable to the drug. Common adverse events were peripheral neuropathy 7/14 (50%), not customarily associated with bedaquiline use, and QTc prolongation 6/14 (43%). CONCLUSIONS: Of 14 patients, 1 (7%) had an adverse event necessitating bedaquiline discontinuation. Safety, culture conversion, and treatment completion in this series (7%) support use of bedaquiline for the treatment of MDR/XDR TB.

Amplified Sensitivity of Nitrogen-Vacancy Spins in Nanodiamonds Using All-Optical Charge Readout.

Nanodiamonds containing nitrogen-vacancy (NV) centers offer a versatile platform for sensing applications spanning from nanomagnetism to in vivo monitoring of cellular processes. In many cases, however, weak optical signals and poor contrast demand long acquisition times that prevent the measurement of environmental dynamics. Here, we demonstrate the ability to perform fast, high-contrast optical measurements of charge distributions in ensembles of NV centers in nanodiamonds and use the technique to improve the spin-readout signal-to-noise ratio through spin-to-charge conversion. A study of 38 nanodiamonds with sizes ranging between 20 and 70 nm, each hosting a small ensemble of NV centers, uncovers complex, multiple time scale dynamics due to radiative and nonradiative ionization and recombination processes. Nonetheless, the NV-containing nanodiamonds universally exhibit charge-dependent photoluminescence contrasts and the potential for enhanced spin readout using spin-to-charge conversion. We use the technique to speed up a T1 relaxometry measurement by a factor of 5.

HLA typing using genome wide data reveals susceptibility types for infections in a psychiatric disease enriched sample.

BACKGROUND: The infections Toxoplasma gondii (T. gondii), cytomegalovirus, and Herpes Simplex Virus Type 1 (HSV1) are common persistent infections that have been associated with schizophrenia and bipolar disorder. The major histocompatibility complex (MHC, termed HLA in humans) region has been implicated in these infections and these mental illnesses. The interplay of MHC genetics, mental illness, and infection has not been systematically examined in previous research. METHODS: In a cohort of 1636 individuals, we used genome-wide association data to impute 7 HLA types (A, B, C, DRB1, DQA1, DQB1, DPB1), and combined this data with serology data for these infections. We used regression analysis to assess the association between HLA alleles, infections (individually and collectively), and mental disorder status (schizophrenia, bipolar disorder, controls). RESULTS: After Bonferroni correction for multiple comparisons, HLA C∗07:01 was associated with increased HSV1 infection among mentally healthy controls (OR 3.4, p = 0.0007) but not in the schizophrenia or bipolar groups (P > 0.05). For the multiple infection outcome, HLA B∗ 38:01 and HLA C∗12:03 were protective in the healthy controls (OR ≈ 0.4) but did not have a statistically-significant effect in the schizophrenia or bipolar groups. T. gondii had several nominally-significant positive associations, including the haplotypes HLA DRB∗03:01 ∼ HLA DQA∗05:01 ∼ HLA DQB∗02:01 and HLA B∗08:01 ∼ HLA C∗07:01. CONCLUSIONS: We identified HLA types that showed strong and significant associations with neurotropic infections. Since some of these associations depended on mental illness status, the engagement of HLA-related pathways may be altered in schizophrenia due to immunogenetic differences or exposure history.

In vivo fate and distribution of poly-gamma-D-glutamic acid, the capsular antigen from Bacillus anthracis.

Bacillus anthracis is surrounded by an antiphagocytic capsule composed of poly-gamma-d-glutamic acid (gammaDPGA). Bacterial and fungal capsular polysaccharides are shed into body fluids in large amounts during infection. The goal of our study was to examine the in vivo fate and distribution of the gammaDPGA capsular polypeptide. Mice were injected via the intravenous route with various amounts of purified gammaDPGA. Blood, urine, and various organs were harvested at different times after treatment. Sites of gammaDPGA accumulation were determined by immunoassay using monoclonal antibodies specific for gammaDPGA. The results showed that the liver and spleen were the primary sites for the accumulation of gammaDPGA. As found in previous studies of capsular polysaccharides, the Kupffer cells of the liver and splenic macrophages were sites for the cellular accumulation of gammaDPGA. Unlike capsular polysaccharides, the hepatic sinusoidal endothelial cells were also sites for gammaDPGA accumulation. gammaDPGA was rapidly cleared from serum and was excreted into the urine. gammaDPGA in the urine showed a reduced molecular size relative to native gammaDPGA. The results indicate that in vivo clearance of the polypeptide capsular antigen of B. anthracis shares several features with the clearance of capsular polysaccharides. Key differences between the in vivo behaviors of gammaDPGA and capsular polysaccharides include the accumulation of gammaDPGA in hepatic sinusoidal endothelial cells and a gammaDPGA clearance rate that was more rapid than the clearance reported for capsular polysaccharides.

Upregulation of profilin, cofilin-2 and LIMK2 in cultured pulmonary artery smooth muscle cells and in pulmonary arteries of monocrotaline-treated rats.

Pulmonary hypertension is associated with remodeling of the smooth muscle layer of pulmonary arteries, manifested by reduced smooth muscle cell (SMC) contractility and enhanced motility and growth. These responses are underlied by increased dynamics of the peripheral actin network. Thus, we hypothesized that pulmonary hypertension is associated with upregulation of two proteins that regulate the dynamics of peripheral actin filaments, i.e., profilin and cofilin. We also analyzed the expression of LIMK2, which regulates the actin remodeling capacity of cofilin by phosphorylation. Experimental inflammation was induced by incubation of cultured pulmonary artery SMCs (PASMCs) with inflammatory mediators in vitro, and by subcutaneous administration of monocrotaline to Sprague-Dawley rats in vivo. Expression of messenger RNA (mRNA) was assessed by quantitative RT-PCR, protein levels and phosphorylation were analyzed by immunoblotting. Immune and Masson trichrome stained lung cryosections were analyzed by microscopy. PDGF, IL-1beta, ET-1 and TNFalpha upregulated the profilin, cofilin-2 and LIMK2 mRNA in cultured pulmonary artery SMCs (PASMCs). Along with the development of rat pulmonary artery and right ventricular hypertrophy, monocrotaline treatment also induced the mRNA and protein contents of profilin, cofilin-2 and LIMK2 in PASMCs. The cofilin upregulation was paralleled by a relative decrease of the phospho-cofilin content. The upregulation of profilin, cofilin and LIMK2 in experimental inflammation suggests that by intensifying the remodeling of subcortical actin filaments these proteins may contribute to the enhanced invasiveness and growth of SMCs, and to the development of increased vascular resistance and pulmonary hypertension.