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Mark Miller

Publications and source records attributed to Mark Miller.

At least 19 recordsLinked to original sources
PubMed2024

Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts.

BACKGROUND: Incorporating genomic data into risk prediction has become an increasingly useful approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. METHODS: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. RESULTS: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p-0.003), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. CONCLUSION: Results, especially those from the eMRS, reinforce earlier findings that methylation and trauma are interconnected and can be leveraged to increase the correct classification of those with vs. without PTSD. Moreover, our models can potentially be a valuable tool in predicting the future risk of developing PTSD. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting the condition and, relatedly, improve their performance in independent cohorts.

DNA methylation↗
PubMed2007

Treating late-life depression with interpersonal psychotherapy in the primary care sector.

BACKGROUND: Interpersonal psychotherapy (IPT) is an empirically-validated intervention for treating late-life depression. OBJECTIVE: To determine the manner in which IPT is utilized by primary care physicians in relation to antidepressant medications. METHODS: The authors reviewed treatment logs prepared by care managers during the first 12 months of a patient's participation in the PROSPECT clinical trial to determine initial and longitudinal treatment patterns utilized by physicians, and clinical outcomes associated with initial treatment assignment. RESULTS: Primary care physicians in practices randomized to PROSPECT's intervention arm initially prescribed an antidepressant medication for 58% of eligible patients and referred only 11% of them to IPT. Over time, however, 27% of patients participated in IPT as monotherapy or augmentation therapy. Initial treatment assignment was not associated with depressive status at 4 and 12 months nor with suicidal ideation at 4, 8, and 12 months. CONCLUSION: IPT is an effective treatment for late-life depression whose greater use by primary care physicians should be encouraged.

Aged↗
PubMed2006

Cutting edge: TREM-2 attenuates macrophage activation.

The triggering receptor expressed on myeloid cells 2 (TREM-2) delivers intracellular signals through the adaptor DAP12 to regulate myeloid cell function both within and outside the immune system. The role of TREM-2 in immunity has been obscured by the failure to detect expression of the TREM-2 protein in vivo. In this study, we show that TREM-2 is expressed on macrophages infiltrating the tissues from the circulation and that alternative activation with IL-4 can induce TREM-2. TREM-2 expression is abrogated by macrophage maturation with LPS of IFN-gamma. Using TREM-2(-/-) mice, we find that TREM-2 functions to inhibit cytokine production by macrophages in response to the TLR ligands LPS, zymosan, and CpG. Furthermore, we find that TREM-2 completely accounts for the increased cytokine production previously reported by DAP12(-/-) macrophages. Taken together, these data show that TREM-2 is expressed on newly differentiated and alternatively activated macrophages and functions to restrain macrophage activation.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules.

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in cftr, a gene encoding a PKA-regulated Cl(-) channel. The most common mutation results in a deletion of phenylalanine at position 508 (DeltaF508-CFTR) that impairs protein folding, trafficking, and channel gating in epithelial cells. In the airway, these defects alter salt and fluid transport, leading to chronic infection, inflammation, and loss of lung function. There are no drugs that specifically target mutant CFTR, and optimal treatment of CF may require repair of both the folding and gating defects. Here, we describe two classes of novel, potent small molecules identified from screening compound libraries that restore the function of DeltaF508-CFTR in both recombinant cells and cultures of human bronchial epithelia isolated from CF patients. The first class partially corrects the trafficking defect by facilitating exit from the endoplasmic reticulum and restores DeltaF508-CFTR-mediated Cl(-) transport to more than 10% of that observed in non-CF human bronchial epithelial cultures, a level expected to result in a clinical benefit in CF patients. The second class of compounds potentiates cAMP-mediated gating of DeltaF508-CFTR and achieves single-channel activity similar to wild-type CFTR. The CFTR-activating effects of the two mechanisms are additive and support the rationale of a drug discovery strategy based on rescue of the basic genetic defect responsible for CF.

3T3 Cells↗
PubMed2006

Effects of phosphatidylserine on exercise capacity during cycling in active males.

PURPOSE: The purpose of the study was to investigate the effects of 750 mg of soybean-derived phosphatidylserine, administered daily for 10 d, on exercise capacity, oxygen uptake kinetic response, neuroendocrine function, and feeling states during exhaustive intermittent exercise. METHODS: Following preliminary testing, fourteen active males completed a staged intermittent exercise protocol on two further occasions (T1 and T2) separated by 16 +/- 1 d. The protocol consisted of three 10-min stages of cycling at 45, 55, and 65% VO2max, followed by a final bout at 85% VO2max that was continued until exhaustion. Approximately 5 d after T1 the subjects were assigned, in a double-blind manner, to either phosphatidylserine (PS) or placebo (P). Breath-by-breath respiratory data and heart rate were continually recorded throughout the exercise protocol, and blood samples were obtained at rest, during the rest periods within the protocol (Post-55, Post-65), at the end of exercise (Post-85), 20 min after the completion of exercise (postexercise), and the day following exercise (Post-24 h). RESULTS: The main finding of this study was that supplementation had a significant effect on exercise time to exhaustion at 85% VO2max (P = 0.005). The exercise time to exhaustion in PS increased following supplementation (7:51 +/- 1:36 to 9:51 +/- 1:42 min:s, P = 0.001), whereas P remained unchanged (8:09 +/- 0:54 to 8:02 +/- 0:54 min:s, P = 0.670). Supplementation did not significantly affect oxygen kinetic mean response times (MRT(on) and MRT(off)), serum cortisol concentrations, substrate oxidation, and feeling states during the trial. CONCLUSION: This is the first study to report improved exercise capacity following phosphatidylserine supplementation. These findings suggest that phosphatidylserine might possess potential ergogenic properties.

Adult↗
PubMed2005

In situ characterization of CD4+ T cell behavior in mucosal and systemic lymphoid tissues during the induction of oral priming and tolerance.

The behavior of antigen-specific CD4+ T lymphocytes during initial exposure to antigen probably influences their decision to become primed or tolerized, but this has not been examined directly in vivo. We have therefore tracked such cells in real time, in situ during the induction of oral priming versus oral tolerance. There were marked contrasts with respect to rate and type of movement and clustering between naive T cells and those exposed to antigen in immunogenic or tolerogenic forms. However, the major difference when comparing tolerized and primed T cells was that the latter formed larger and longer-lived clusters within mucosal and peripheral lymph nodes. This is the first comparison of the behavior of antigen-specific CD4+ T cells in situ in mucosal and systemic lymphoid tissues during the induction of priming versus tolerance in a physiologically relevant model in vivo.

Administration, Oral↗
PubMed2005

Preparedness of hospitals to respond to a radiological terrorism event as assessed by a full-scale exercise.

Hospitals and healthcare workers face the challenge of being prepared to manage victims of acts of terrorism that involve chemical, biological, and radiological agents that they do not commonly encounter. One example that is often cited as a potential terrorism scenario is the use of a conventional explosive that is mixed with radioactive material. On November 10, 2004, we conducted a regional multihospital full-scale exercise involving 11 hospitals and 358 victim-observers to evaluate hospital preparedness for such an event. Our results demonstrate that hospitals are not adequately prepared to manage mass casualties with associated radiological contamination.

Disaster Planning↗
PubMed2005

Body pain and treatment response in late-life depression.

OBJECTIVE: The authors investigated the influence of body pain on 1) time to treatment response and 2) suicidal ideation, in late-life depression. They hypothesized that higher levels of body pain would predict a longer time to and lower likelihood of response, and increased levels of suicidal ideation. METHODS: Subjects (N=187) were older adult outpatients (age > or =69 years), with current episodes of major depression, who were openly treated with paroxetine up to 40 mg daily and weekly interpersonal psychotherapy. Response was defined as 3 consecutive weeks of Hamilton Rating Scale for Depression at < or =10. Body pain was measured with the Bodily Pain Index of the SF-36 quality-of-life assessment. Authors used survival-analysis models on the responder sample to test the effect of body pain on response, after controlling for severity of depression. RESULTS: Overall response rate was 75.4%. Nonresponders reported more severe pain at baseline. After covarying for severity of baseline depression, no effect was found for physical pain on time-to-response or degree of suicidality. Bodily pain remained stable during acute treatment for responders, independent of depression response to combination psychotherapy and antidepressant treatment. CONCLUSIONS: Older adult patients with higher levels of physical pain can still respond to antidepressant treatment; however, reported bodily pain may be associated with a more difficult-to-treat depression.

Activities of Daily Living↗
PubMed2005

Papulonecrotic tuberculid: a rare form of cutaneous tuberculosis.

We describe a case of papulonecrotic tuberculid, a rare form of cutaneous tuberculosis, in a 25-year-old Philippino woman who had immigrated to Canada 8 years previously. The patient presented with a 3-week history of tender left cervical adenopathy; 1 week later, she developed multiple ulcerated erythematous nodules and emboluslike lesions scattered over her fingers. Results of a biopsy performed on the lymph node revealed granulomatous lymphadenitis, and Mycobacterium tuberculosis grew from the lymph node. Histopathologic analysis of an ulcerative finger lesion demonstrated nonnecrotizing granulomas with dense lymphocytic inflammation of the superficial dermis; however, results of acid-fast staining, mycobacterial culture, and polymerase chain reaction for M tuberculosis complex were all negative. Different conditions can mimic papulonecrotic tuberculid. Therefore, the diagnosis can be difficult unless M tuberculosis is isolated from a site other than the skin, because stain and culture results from skin biopsy specimens are typically negative and the polymerase chain reaction is positive in only 50% of cases. We review the epidemiology, clinicopathologic features, and differential diagnosis of papulonecrotic tuberculid. Awareness of this entity is important to distinguish it from other conditions and to institute appropriate therapy in a timely fashion.

Adult↗
PubMed2004

Epoxide hydrolase-catalyzed enantioselective synthesis of chiral 1,2-diols via desymmetrization of meso-epoxides. lzhao@diversa.com.

The discovery, from nature, of a diverse set of microbial epoxide hydrolases is reported. The utility of a library of epoxide hydrolases in the synthesis of chiral 1,2-diols via desymmetrization of a wide range of meso-epoxides, including cyclic as well as acyclic alkyl- and aryl-substituted substrates, is demonstrated. The chiral (R,R)-diols were furnished with high ee's and yields. The discovery of the first microbial epoxide hydrolases providing access to complementary (S,S)-diols is also described.

Alcohols↗
PubMed2004

The efficacy of electroporated plasmid vaccines correlates with long-term antigen production in vivo.

We sought to determine whether in vivo electroporation might overcome the requirement for strong transcriptional promoters in plasmid vaccines. We tested plasmid vaccines containing viral promoters that exhibited a broad range of transcriptional activities by in vitro assay. In contrast to the in vitro observations, no difference in gene expression was measured in vivo 24h following injection when the plasmids were introduced via electroporation. Despite the similarities in gene expression in vivo, the cellular and humoral responses elicited by these plasmid vaccines were dramatically different and correlated more closely with the promoter activity measured in vitro. When antigen production in vivo was measured over a longer period following injection, significant differences in gene expression became apparent after 2-3 days and the differences in gene expression at day 7 correlated well with plasmid immunogenicity. These studies reconfirm the importance of antigen production for effective plasmid vaccination and demonstrate that the duration of gene expression should also be considered when designing plasmid vaccines.

Animals↗
PubMed2004

Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels.

OBJECTIVE: To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. SETTING: One hundred fifty-seven intensive care units in the United States and Canada. PATIENTS: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. INTERVENTIONS: Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result. MEASUREMENTS AND MAIN RESULTS: In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo. CONCLUSIONS: Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.

APACHE↗
PubMed2004

Molecular and kinetic comparison of the novel extended-spectrum beta-lactamases CTX-M-25 and CTX-M-26.

CTX-M-25 is a novel extended-spectrum beta-lactamase isolated from a single Canadian Escherichia coli isolate. Susceptibility testing demonstrated that this enzyme confers resistance to both cefotaxime and ceftazidime, but the level of resistance was reduced with the addition of beta-lactamase inhibitors. The bla(CTX-M-25) gene was detected on a 111-kb plasmid. It is a member of the CTX-M-8 group and has the closest amino acid identity (99%; three amino acid substitutions) with CTX-M-26. The bla(CTX-M-26) gene was detected on a 100-kb plasmid isolated from a Klebsiella pneumoniae strain from the United Kingdom, and plasmid profiling revealed that it showed some homology to the bla(CTX-M-25)-harboring plasmid. Both CTX-M genes were located downstream of ISEcp1, although the copy upstream of bla(CTX-M-25) was disrupted by IS50-A. Comparative kinetic studies of recombinant CTX-M-25 and CTX-M-26 enzymes showed that CTX-M-25 has a higher level of ceftazidime hydrolysis (kcat values, 33 and 0.005 s(-1) for CTX-M-25 and CTX-M-26, respectively).

Amino Acid Sequence↗
PubMed2004

Exploring nitrilase sequence space for enantioselective catalysis.

Nitrilases are important in the biosphere as participants in synthesis and degradation pathways for naturally occurring, as well as xenobiotically derived, nitriles. Because of their inherent enantioselectivity, nitrilases are also attractive as mild, selective catalysts for setting chiral centers in fine chemical synthesis. Unfortunately, <20 nitrilases have been reported in the scientific and patent literature, and because of stability or specificity shortcomings, their utility has been largely unrealized. In this study, 137 unique nitrilases, discovered from screening of >600 biotope-specific environmental DNA (eDNA) libraries, were characterized. Using culture-independent means, phylogenetically diverse genomes were captured from entire biotopes, and their genes were expressed heterologously in a common cloning host. Nitrilase genes were targeted in a selection-based expression assay of clonal populations numbering 10(6) to 10(10) members per eDNA library. A phylogenetic analysis of the novel sequences discovered revealed the presence of at least five major sequence clades within the nitrilase subfamily. Using three nitrile substrates targeted for their potential in chiral pharmaceutical synthesis, the enzymes were characterized for substrate specificity and stereospecificity. A number of important correlations were found between sequence clades and the selective properties of these nitrilases. These enzymes, discovered using a high-throughput, culture-independent method, provide a catalytic toolbox for enantiospecific synthesis of a variety of carboxylic acid derivatives, as well as an intriguing library for evolutionary and structural analyses.

Aminohydrolases↗