Trimethylamine (TMA) N-oxide (TMAO), a gut-microbiota-dependent metabolite, both enhances atherosclerosis in animal models and is associated with cardiovascular risks in clinical studies. Here, we investigate the impact of targeted inhibition of the first step in TMAO generation, commensal microbial TMA production, on diet-induced atherosclerosis. A structural analog of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases, and to both inhibit TMA production from physiologic polymicrobial cultures (e.g., intestinal contents, human feces) and reduce TMAO levels in mice fed a high-choline or L-carnitine diet. DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apolipoprotein e−/− mice without alterations in circulating cholesterol levels. The present studies suggest that targeting gut microbial production of TMA specifically and non-lethal microbial inhibitors in general may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases. •Gut microbial trimethylamine lyases are a therapeutic target for atherosclerosis•3,3-dimethyl-1-butanol inhibits microbial trimethylamine formation•3,3-dimethyl-1-butanol attenuates choline diet-enhanced atherosclerosis•Non-lethal gut microbial enzyme inhibition can impact host cardiometabolic phenotypes Drugging the gut microbiota with a non-lethal inhibitor that blocks production of the metabolite trimethylamine reduces the formation of atherosclerotic lesions and represents the first step toward treatment of cardiometabolic diseases by targeting the microbiome.
Background There is currently no standard therapy for women with metastatic or locally recurrent breast cancer. The microtubule polymerization inhibitor eribulin, approved in March 2011, is the first monochemotherapy with a proven survival benefit and tolerable toxicity in this patient group.
Patients and methods Using a retrospective analysis of 27 mostly heavily pretreated patients in two large German breast cancer centers, the efficacy and tolerability of eribulin in daily practice were compared with the results of the pivotal EMBRACE and 301 studies.
Results Despite the patients being older and having more advanced disease, the retrospective analysis showed a comparable progression-free survival of 3.7 months. When eribulin was used in an early-line treatment, the progression-free survival observed was 7 weeks longer compared with use in a late-line therapy. The differences in tolerability were not significant.
BACKGROUND: Pulmonary nodules (PNs) are a common reason for referral to pulmonologists. Th e majority of data for the evaluation and management of PNs is derived from studies performed in academic medical centers. Little is known about the prevalence and diagnosis of PNs, the use of diagnostic testing, or the management of PNs by community pulmonologists. METHODS: Th is multicenter observational record review evaluated 377 patients aged 40 to 89 years referred to 18 geographically diverse community pulmonary practices for intermediate PNs (8-20 mm). Study measures included the prevalence of malignancy, procedure/test use, and nodule pretest probability of malignancy as calculated by two previously validated models. Th e relationship between calculated pretest probability and management decisions was evaluated. RESULTS: Th e prevalence of malignancy was 25% (n 5 94). Nearly one-half of the patients (46%, n 5 175) had surveillance alone. Biopsy was performed on 125 patients (33.2%). A total of 77 patients (20.4%) underwent surgery, of whom 35% (n 5 27) had benign disease. PET scan was used in 141 patients (37%). Th e false-positive rate for PET scan was 39% (95% CI, 27.1%-52.1%). Pretest probability of malignancy calculations showed that 9.5% (n 5 36) were at a low risk, 79.6% (n 5 300) were at a moderate risk, and 10.8% (n 5 41) were at a high risk of malignancy. Th e rate of surgical resection was similar among the three groups (17%, 21%, 17%, respectively; P 5 .69). CONCLUSIONS: A substantial fraction of intermediate-sized nodules referred to pulmonologists ultimately prove to be lung cancer. Despite advances in imaging and nonsurgical biopsy techniques, invasive sampling of low-risk nodules and surgical resection of benign nodules remain common, suggesting a lack of adherence to guidelines for the management of PNs.
With aging, significant changes in circadian rhythms occur, including a shift in phase toward a “morning” chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann’s area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.
Cho-Yi Chen, Proceedings of the National Academy of Sciences 2015 of the USA ; published ahead of print December 22, 2015, doi:10.1073/pnas.1508249112.
To describe the initial neuroradiology findings in a cohort of military service members with primarily chronic mild traumatic brain injury (TBI) from blast by using an integrated magnetic resonance (MR) imaging protocol.
Materials and Methods
This study was approved by the Walter Reed National Military Medical Center institutional review board and is compliant with HIPAA guidelines. All participants were military service members or dependents recruited between August 2009 and August 2014. There were 834 participants with a history of TBI and 42 participants in a control group without TBI (not explicitly age- and sex-matched). MR examinations were performed at 3 T primarily with three-dimensional volume imaging at smaller than 1 mm3 voxels for the structural portion of the examination. The structural portion of this examination, including T1-weighted, T2-weighted, before and after contrast agent administrtion T2 fluid attenuation inversion recovery, and susceptibility-weighted images, was evaluated by neuroradiologists by using a modified version of the neuroradiology TBI common data elements (CDEs). Incident odds ratios (ORs) between the TBI participants and a comparison group without TBI were calculated.
The 834 participants were diagnosed with predominantly chronic (mean, 1381 days; median, 888 days after injury) and mild (92% [768 of 834]) TBI. Of these participants, 84.2% (688 of 817) reported one or more blast-related incident and 63.0% (515 of 817) reported loss of consciousness at the time of injury. The presence of white matter T2-weighted hyperintense areas was the most common pathologic finding, observed in 51.8% (432 of 834; OR, 1.75) of TBI participants. Cerebral microhemorrhages were observed in a small percentage of participants (7.2% [60 of 834]; OR, 6.64) and showed increased incidence with TBI severity (P < .001, moderate and severe vs mild). T2-weighted hyperintense areas and microhemorrhages did not collocate by visual inspection. Pituitary abnormalities were identified in a large proportion (29.0% [242 of 834]; OR, 16.8) of TBI participants.
Blast-related injury and loss of consciousness is common in military TBI. Structural MR imaging demonstrates a high incidence of white matter T2-weighted hyperintense areas and pituitary abnormalities, with a low incidence of microhemorrhage in the chronic phase.
Radiology; 278;1 (Ahead of Print), Gerard Riedy, MD, PhD , Justin S. Senseney, MS , Wei Liu, DSc , John Ollinger, PhD , Elyssa Sham, BA , Pavel Krapiva, MD , Jigar B. Patel, MD , Alice Smith, MD , Ping-Hong Yeh, PhD , John Graner, PhD , Dominic Nathan, PhD , Jesus Caban, PhD , Louis M. French, PsyD , Jamie Harper, MPH , Victoria Eskay, BA , John Morissette , Terrence R. Oakes, PhD. DOI: http://dx.doi.org/10.1148/radiol.2015150438
To facilitate MRI-guided catheterization procedures, we present an MRI-compatible remote catheter navigation system that allows remote navigation of steerable catheters with 3 degrees of freedom.
The system consists of a user interface (master), a robot (slave), and an ultrasonic motor control servomechanism. The interventionalist applies conventional motions (axial, radial and plunger manipulations) on an input catheter in the master unit; this user input is measured and used by the servomechanism to control a compact catheter manipulating robot, such that it replicates the interventionalist’s input motion on the patient catheter. The performance of the system was evaluated in terms of MRI compatibility (SNR and artifact), feasibility of remote navigation under real-time MRI guidance, and motion replication accuracy.
Real-time MRI experiments demonstrated that catheter was successfully navigated remotely to desired target references in all 3 degrees of freedom. The system had an absolute value error of <1 mm in axial catheter motion replication over 30 mm of travel and 3∘±2∘ for radial catheter motion replication over 180∘. The worst case SNR drop was observed to be <3 %; the robot did not introduce any artifacts in the MR images.
An MRI-compatible compact remote catheter navigation system has been developed that allows remote navigation of steerable catheters with 3 degrees of freedom. The proposed system allows for safe and accurate remote catheter navigation, within conventional closed-bore scanners, without degrading MR image quality.
M. A. Tavallaei, International Journal of Computer Assisted Radiology and Surgery, pp 1-9, First online:
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