Authors: Joshi AA, Lerman JB, Dey AK, Sajja AP, Belur AD, Elnabawi YA, Rodante JA, Aberra TM, Chung J, Salahuddin T, Natarajan B, Dave J, Goyal A, Groenendyk JW, Rivers JP, Baumer Y, Teague HL, Playford MP, Bluemke DA, Ahlman MA, Chen MY, Gelfand JM, Mehta NN
Journal: JAMA Cardiol. 2018 Sep 12. doi: 10.1001/jamacardio.2018.2769. [Epub ahead of print]
IMPORTANCE: Inflammation is critical to atherosclerosis. Psoriasis, a chronic inflammatory disease associated with early cardiovascular events and increased aortic vascular inflammation (VI), provides a model to study the process of early atherogenesis. Fludeoxyglucose F 18 positron emission tomography/computed tomography (18F-FDG PET/CT) helps quantify aortic VI, and coronary computed tomography angiography provides coronary artery disease (CAD) assessment through evaluation of total plaque burden (TB) and noncalcified coronary plaque burden (NCB), luminal stenosis, and high-risk plaques (HRP). To our knowledge, association between aortic VI and broad CAD indices has not yet been assessed in a chronic inflammatory disease state. Such a study may provide information regarding the utility of aortic VI in capturing early CAD.
OBJECTIVE: To assess the association between aortic VI and CAD indices, including TB, NCB, luminal stenosis, and HRP prevalence, in psoriasis.
DESIGN, SETTING, AND PARTICIPANTS: In a cross-sectional cohort study at the National Institutes of Health, 215 consecutive patients with psoriasis were recruited from surrounding outpatient dermatology practices. All patients underwent 18F-FDG PET/CT for aortic VI assessment, and 190 of 215 patients underwent coronary computed tomography angiography to characterize CAD. The study was conducted between January 1, 2013, and May 31, 2017. Data were analyzed in March 2018.
EXPOSURES: Aortic VI assessed by 18F-FDG PET/CT.
MAIN OUTCOMES AND MEASURES: Primary outcome: TB and NCB. Secondary outcomes: luminal stenosis and HRP.
RESULTS: Among 215 patients with psoriasis (mean [SD] age, 50.4 [12.6] years; 126 men [59%]), patients with increased aortic VI had increased TB (standardized β = 0.48; P < .001), and higher prevalence of luminal stenosis (OR, 3.63; 95% CI, 1.71-7.70; P = .001) and HRP (OR, 3.05; 95% CI, 1.42-6.47; P = .004). The aortic VI and TB association was primarily driven by NCB (β = 0.49; P < .001), whereas the aortic VI and HRP association was driven by low-attenuation plaque (OR, 5.63; 95% CI, 1.96-16.19; P = .001). All associations of aortic VI remained significant after adjustment for cardiovascular risk factors: aortic VI and TB (β = 0.23; P < .001), NCB (β = 0.24; P < .001), luminal stenosis (OR, 3.40; 95% CI, 1.40-8.24; P = .007), and HRP (OR, 2.72; 95% CI, 1.08-6.83; P = .03). No association was found between aortic VI and dense-calcified coronary plaque burden.
CONCLUSIONS AND RELEVANCE: Aortic VI is associated with broad CAD indices, suggesting that aortic VI may be a surrogate for early CAD. Larger prospective studies need to assess these associations longitudinally and examine treatment effects on these outcomes.
Authors: Klubo-Gwiezdzinska J, Lange M, Cochran E, Semple RK, Gewert C, Brown RJ, Gorden P
Journal: Diabetes Care. 2018 Sep 10. pii: dc180884. doi: 10.2337/dc18-0884. [Epub ahead of print]
OBJECTIVE: Type B insulin resistance due to autoantibodies against the insulin receptor is characterized by diabetes refractory to massive doses of insulin, severe hypercatabolism, hyperandrogenism, and a high mortality rate. We analyzed the efficacy of combined immunosuppressive therapy in the management of this extreme form of diabetes.
RESEARCH DESIGN AND METHODS: We performed a prospective cohort study including patients with confirmed insulin receptor autoantibodies, monitored for median 72 months (25th, 75th interquartile range 25, 88), and treated with rituximab, high-dose pulsed steroids, and cyclophosphamide until remission, followed by maintenance therapy with azathioprine. Remission was defined as the amelioration of the hyperglycemia and discontinuation of insulin and/or normalization of hyperandrogenemia.
RESULTS: All data are given as median (25th, 75th interquartile range). Twenty-two patients aged 42 (25, 57) years, 86.4% women, fulfilled inclusion criteria. At baseline, fasting glucose was 307 (203, 398) mg/dL, HbA1c was 11.8% (9.7, 13.6), total testosterone (women) was 126 (57, 571) ng/dL (normal 8-60), and daily insulin requirement was 1,775 (863, 2,700) units. After 5 (4, 6.3) months, 86.4% (19 of 22) of patients achieved remission, documented by discontinuation of insulin in all patients, normal fasting glucose of 80 (76, 92) mg/dL, HbA1c of 5.5% (5.2, 6), and testosterone (women) of 28 (20, 47) ng/dL. During follow-up of 72 (25, 88) months, 13.6% (3 of 22) of patients developed disease recurrence, occurring 24 (22, 36) months after initial remission, which responded to repeated therapy. None of the patients died.
CONCLUSIONS: Combined immunosuppressive therapy has changed the natural history of this disease, from 54% mortality to a curable form of diabetes and, as such, should be recommended in patients with type B insulin resistance.
Authors: Lynes J, Jackson S, Sanchez V, Dominah G, Wang X, Kuek A, Hayes CP, Benzo S, Scott GC, Chittiboina P, Zaghloul KA, Park DM, Wu J, Hourigan CS, Giles AJ, Wu T, Maric D, Chen J, Quezado M, Heiss JD, Gilbert MR, Nduom EK
Journal: Neurosurgery. 2018 Sep 4. doi: 10.1093/neuros/nyy392. [Epub ahead of print]
BACKGROUND: Glioblastoma is the most common primary malignancy of the brain, with a dismal prognosis. Immunomodulation via checkpoint inhibition has provided encouraging results in non-CNS malignancies, but prediction of responders has proven to be challenging in glioblastoma patients.
OBJECTIVE: To determine the proportion of patients who have a measurable increase of interferon gamma levels in brain tumor tissue after their first dose of nivolumab, and to evaluate the safety of using brain tumor microdialysis to monitor for immune response while evaluating the safety of the combination of anti-programmed death 1 (PD-1) and anti-lymphocyte activation gene 3 (LAG-3) checkpoint inhibition.
METHODS: The study design is a single-center, nonrandomized phase 1 clinical trial. Up to 15 adult patients with recurrent glioblastoma will be enrolled with the goal of 10 patients completing the trial over an anticipated 18 mo. Patients will undergo biopsy; placement of microdialysis catheters and lumbar drains; treatment with anti-PD-1 checkpoint inhibition; comprehensive immune biomarker collection; tumor resection; and then treatment with anti-PD-1 and anti-LAG-3 checkpoint inhibition until progression.
EXPECTED OUTCOMES: We expect interferon gamma levels to increase in the brain as measured via microdialysis in treated patients. Based on published reports, microdialysis in this patient population is expected to be safe, and anti-LAG-3 and anti-PD-1 combined will likely have a similar side effect profile to other checkpoint inhibitor combinations.
DISCUSSION: The failure of recent trials of immune therapies in glioblastoma underscores the need to appropriately measure response in the treated tissue. This trial may provide insight on indicators of which patients will respond to immune therapy.
Authors: Brick K, Thibault-Sennett S, Smagulova F, Lam KG, Pu Y, Pratto F, Camerini-Otero RD, Petukhova GV
Journal: Nature. 2018 Sep 5. doi: 10.1038/s41586-018-0492-5. [Epub ahead of print]
Meiotic recombination differs between males and females; however, when and how these differences are established is unknown. Here we identify extensive sex differences at the initiation of recombination by mapping hotspots of meiotic DNA double-strand breaks in male and female mice. Contrary to past findings in humans, few hotspots are used uniquely in either sex. Instead, grossly different recombination landscapes result from up to fifteen-fold differences in hotspot usage between males and females. Indeed, most recombination occurs at sex-biased hotspots. Sex-biased hotspots seem to be partly determined by chromosome structure, and DNA methylation, which is absent in females at the onset of meiosis, has a substantial role. Sex differences are also evident later in meiosis as the rate at which meiotic breaks are repaired as crossovers differs between males and females in distal regions. The suppression of distal crossovers may help to minimize age-related aneuploidy that arises owing to cohesion loss during dictyate arrest in females.
Authors: Zhang DL, Ghosh MC, Ollivierre H, Li Y, Rouault TA
Journal: Blood. 2018 Sep 13. pii: blood-2018-04-842997. doi: 10.1182/blood-2018-04-842997. [Epub ahead of print]
Ferroportin (FPN), the only known vertebrate iron exporter, transports iron from intestinal, splenic, and hepatic cells into the blood to provide iron to other tissues and cells in vivo. Most of the circulating iron is consumed by erythroid cells to synthesize hemoglobin. Here we found that erythroid cells not only consumed large amounts of iron, but also returned significant amounts of iron to the blood. Erythroblast-specific Fpn knockout (Fpn KO) mice developed lower serum iron levels in conjunction with tissue iron overload, and increased FPN expression in spleen and liver without changing hepcidin levels. Our results also showed that Fpn KO mice, which suffer from mild hemolytic anemia, were sensitive to phenylhydrazine-induced oxidative stress, but were able to tolerate iron deficiency upon exposure to a low iron diet and phlebotomy, supporting that the anemia of Fpn KO mice resulted from erythrocytic iron overload and resulting oxidative injury rather than a RBC production defect. Moreover, we found that the mean corpuscular volume (MCV) values of gain-of-function FPN mutation patients were positively associated with serum transferrin saturations, whereas MCVs of loss-of-function FPN mutation patients were not, supporting that erythroblasts donate iron to blood through FPN in response to serum iron levels. Our results indicate that FPN of erythroid cells plays an unexpectedly essential role in maintaining systemic iron homeostasis and protecting RBCs from oxidative stress, providing insight into the pathophysiology of FPN diseases.
Authors: Chen YW, Das M, Oyarzabal EA, Cheng Q, Plummer NW, Smith KG, Jones GK, Malawsky D, Yakel JL, Shih YI, Jensen P
Journal: Mol Psychiatry. 2018 Sep 13. doi: 10.1038/s41380-018-0245-8. [Epub ahead of print]
Noradrenergic signaling plays a well-established role in promoting the stress response. Here we identify a subpopulation of noradrenergic neurons, defined by developmental expression of Hoxb1, that has a unique role in modulating stress-related behavior. Using an intersectional chemogenetic strategy, in combination with behavioral and physiological analyses, we show that activation of Hoxb1-noradrenergic (Hoxb1-NE) neurons decreases anxiety-like behavior and promotes an active coping strategy in response to acute stressors. In addition, we use cerebral blood volume-weighted functional magnetic resonance imaging to show that chemoactivation of Hoxb1-NE neurons results in reduced activity in stress-related brain regions, including the bed nucleus of the stria terminalis, amygdala, and locus coeruleus. Thus, the actions of Hoxb1-NE neurons are distinct from the well-documented functions of the locus coeruleus in promoting the stress response, demonstrating that the noradrenergic system contains multiple functionally distinct subpopulations.
Authors: Gill J, Latour L, Diaz-Arrastia R, Motamedi V, Turtzo C, Shahim P, Mondello S, DeVoto C, Veras E, Hanlon D, Song L, Jeromin A
Journal: Neurology. 2018 Sep 12. pii: 10.1212/WNL.0000000000006321. doi: 10.1212/WNL.0000000000006321. [Epub ahead of print]
OBJECTIVES: To determine whether a panel of blood-based biomarkers can discriminate between patients with suspected mild traumatic brain injury (mTBI) with and without neuroimaging findings (CT and MRI).
METHODS: Study participants presented to the emergency department with suspected mTBI (n = 277) with a CT and MRI scan and healthy controls (n = 49). Plasma concentrations of tau, glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1, and neurofilament light chain (NFL) were measured using the single-molecule array technology.
RESULTS: Concentrations of GFAP, tau, and NFL were higher in patients with mTBI, compared with those of controls (p's < 0.01). GFAP yielded an area under the curve (AUC) of 0.93 (95% confidence interval [CI] 0.90-0.96), confirming its discriminatory power for distinguishing mTBI from controls. Levels of GFAP, tau, and NFL were higher in patients with trauma-related intracranial findings on CT compared with those with normal CT, with the only significant predictor being GFAP (AUC 0.77, 95% CI 0.70-0.84). Among patients with mTBI, tau, NFL, and GFAP differentiated subjects with and without MRI abnormalities with an AUC of 0.83, with GFAP being the strongest predictor. Combining tau, NFL, and GFAP showed a good discriminatory power (AUC 0.80, 95% CI 0.69-0.90) for detecting MRI abnormalities, even in patients with mTBI with a normal CT.
CONCLUSION: Our study confirms GFAP as a promising marker of brain injury in patients with acute mTBI. A combination of various biomarkers linked to different pathophysiologic mechanisms increases diagnostic subgroup accuracy. This multimarker strategy may guide medical decision making, facilitate the use of MRI scanning, and prove valuable in the stratification of patients with brain injuries in future clinical trials.
CLASSIFICATION OF EVIDENCE: Class I evidence that blood concentrations of GFAP, tau, and NFL discriminate patients with mTBI with and without neuroimaging findings.
Authors: Sallin MA, Kauffman KD, Riou C, Du Bruyn E, Foreman TW, Sakai S, Hoft SG, Myers TG, Gardina PJ, Sher A, Moore R, Wilder-Kofie T, Moore IN, Sette A, Lindestam Arlehamn CS, Wilkinson RJ, Barber DL
Journal: Nat Microbiol. 2018 Sep 10. doi: 10.1038/s41564-018-0231-6. [Epub ahead of print]
Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and is among the top ten causes of all human deaths worldwide. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFNγ production is the primary mechanism of CD4 T-cell-mediated protection. However, IFNγ responses do not correlate with host protection, and several reports demonstrate that additional anti-tuberculosis CD4 T-cell effector functions remain unaccounted for. Here we show that the tumour-necrosis factor (TNF) superfamily molecule CD153 (encoded by the gene Tnfsf8) is required for control of pulmonary Mtb infection by CD4 T cells. In Mtb-infected mice, CD153 expression is highest on Mtb-specific T helper 1 (TH1) cells in the lung tissue parenchyma, but its induction does not require TH1 cell polarization. CD153-deficient mice develop high pulmonary bacterial loads and succumb early to Mtb infection. Reconstitution of T-cell-deficient hosts with either Tnfsf8-/- or Ifng-/- CD4 T cells alone fails to rescue mice from early mortality, but reconstitution with a mixture of Tnfsf8-/- and Ifng-/- CD4 T cells provides similar protection as wild-type T cells. In Mtb-infected non-human primates, CD153 expression is much higher on Ag-specific CD4 T cells in the airways compared to blood, and the frequency of Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In Mtb-infected humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with controlled latent Mtb infection compared to those with active tuberculosis. In all three species, Mtb-specific CD8 T cells did not upregulate CD153 following peptide stimulation. Thus, CD153 is a major immune mediator of host protection against pulmonary Mtb infection and CD4 T cells are one important source of this molecule.
Authors: Boukhvalova AK, Kowalczyk E, Harris T, Kosa P, Wichman A, Sandford MA, Memon A, Bielekova B
Journal: Front Neurol. 2018 Sep 4;9:740. doi: 10.3389/fneur.2018.00740. eCollection 2018.
Embedded sensors of the smartphones offer opportunities for granular, patient-autonomous measurements of neurological dysfunctions for disease identification, management, and for drug development. We hypothesized that aggregating data from two simple smartphone tests of fine finger movements with differing contribution of specific neurological domains (i.e., strength & cerebellar functions, vision, and reaction time) will allow establishment of secondary outcomes that reflect domain-specific deficit. This hypothesis was tested by assessing correlations of smartphone-derived outcomes with relevant parts of neurological examination in multiple sclerosis (MS) patients. We developed MS test suite on Android platform, consisting of several simple functional tests. This paper compares cross-sectional and longitudinal performance of Finger tapping and Balloon popping tests by 76 MS patients and 19 healthy volunteers (HV). The primary outcomes of smartphone tests, the average number of taps (per two 10-s intervals) and the average number of pops (per two 26-s intervals) differentiated MS from HV with similar power to traditional, investigator-administered test of fine finger movements, 9-hole peg test (9HPT). Additionally, the secondary outcomes identified patients with predominant cerebellar dysfunction, motor fatigue and poor eye-hand coordination and/or reaction time, as evidenced by significant correlations between these derived outcomes and relevant parts of neurological examination. The intra-individual variance in longitudinal sampling was low. In the time necessary for performing 9HPT, smartphone tests provide much richer and reliable measurements of several distinct neurological functions. These data suggest that combing more creatively-construed smartphone apps may one day recreate the entire neurological examination.
Authors: Kamada R, Yang W, Zhang Y, Patel MC, Yang Y, Ouda R, Dey A, Wakabayashi Y, Sakaguchi K, Fujita T, Tamura T, Zhu J, Ozato K
Journal: Proc Natl Acad Sci U S A. 2018 Sep 10. pii: 201720930. doi: 10.1073/pnas.1720930115. [Epub ahead of print]
Epigenetic memory for signal-dependent transcription has remained elusive. So far, the concept of epigenetic memory has been largely limited to cell-autonomous, preprogrammed processes such as development and metabolism. Here we show that IFNβ stimulation creates transcriptional memory in fibroblasts, conferring faster and greater transcription upon restimulation. The memory was inherited through multiple cell divisions and led to improved antiviral protection. Of ∼2,000 IFNβ-stimulated genes (ISGs), about half exhibited memory, which we define as memory ISGs. The rest, designated nonmemory ISGs, did not show memory. Surprisingly, mechanistic analysis showed that IFN memory was not due to enhanced IFN signaling or retention of transcription factors on the ISGs. We demonstrated that this memory was attributed to accelerated recruitment of RNA polymerase II and transcription/chromatin factors, which coincided with acquisition of the histone H3.3 and H3K36me3 chromatin marks on memory ISGs. Similar memory was observed in bone marrow macrophages after IFNγ stimulation, suggesting that IFN stimulation modifies the shape of the innate immune response. Together, external signals can establish epigenetic memory in mammalian cells that imparts lasting adaptive performance upon various somatic cells.