Mark D. Williams

Starvation-induced expression of SspA and SspB: the effects of a null mutation in sspA on Escherichia coli protein synthesis and survival during growth and prolonged starvation

Maxicell labelling and two‐dimensional gel electro‐phoresis (2‐D PAGE) have identified the proteins encoded by sspA and sspB (SspA, SspB) as proteins D27.1 and A25.8, respectively, in the Escherichia coli gene‐protein database. SspA expression increases with decreasing growth rate and is induced by glucose, nitrogen, phosphate or amino acid starvation. The promoter, Pssp, is similar to gearbox promoters. Inactivation of SspA (sspA::neo) blocks sspB expression. [35S]‐methionine‐labelled proteins synthesized during growth and during stationary phase are different in δsspA strains compared to sspA strains. This difference is enhanced during extended stationary phase (24–72 h). Long‐term (10 d) viability of arginine‐starved isogenic strains shows that sspA cultures remain viable significantly longer than δsspA mutants. 2‐D PAGE of proteins expressed during exponential growth shows that expression of at least 11 proteins is altered in δsspA strains. A functional relA gene is required for sspA to affect protein synthesis.

Statins use and risk of depression: A systematic review and meta-analysis

IMPORTANCE Statin use has been associated with depression; however studies of the association between statin use and depression have yielded mixed results. OBJECTIVE To determine whether statin use is associated with depression and to evaluate the evidence supporting this association. DATA SOURCES Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, EMBASE, PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched through December 28, 2012. STUDY SELECTION We included studies that evaluated exposure to statins, reported the development of depression, and relative risks or odds ratios (ORs) or provided data for their estimation. Two reviewers screened 981 abstracts independently using a standardized form, reviewed full text of 59 selected articles, and included 7 studies in this metaanalysis. DATA EXTRACTION AND SYNTHESIS Study design, statin exposure, development of depression, and study quality were extracted by 2 independent reviewers. A pooled OR with 95% confidence interval (CI) was estimated using the random-effects model and heterogeneity was assessed using Cochrans Q test and the I(2) statistic. RESULTS Seven observational studies (4 cohort, 2 nested case-control, and 1 cross-sectional) from 5 countries enrolling 9187 patients were included. Statin users were 32% less likely to develop depression than nonusers (adjusted OR, 0.68; 95% CI, 0.52-0.89). Modest heterogeneity was observed between the studies (I(2)=55%, P=0.01), which could be accounted for by one study, exclusion of which removed the heterogeneity (P=0.40, I(2)=2%) and further strengthened the antidepressant effect of statin (adjusted OR, 0.63; 95% CI, 0.43-0.93). Heterogeneity could not be explained by study design or study population. The quality of supporting evidence was fair. CONCLUSIONS AND RELEVANCE This systematic review and meta-analysis suggests that statin use is associated with lower risk for depression. However, higher-quality studies are needed to confirm the magnitude of this association.

Differences in demographic composition and in work, social, and functional limitations among the populations with unipolar depression and bipolar disorder: results from a nationally representative sample

BackgroundExisting literature on mood disorders suggests that the demographic distribution of bipolar disorder may differ from that of unipolar depression, and also that bipolar disorder may be especially disruptive to personal functioning. Yet, few studies have directly compared the populations with unipolar depressive and bipolar disorders, whether in terms of demographic characteristics or personal limitations. Furthermore, studies have generally examined work-related costs, without fully investigating the extensive personal limitations associated with diagnoses of specific mood disorders. The purpose of the present study is to compare, at a national level, the demographic characteristics, work productivity, and personal limitations among individuals diagnosed with bipolar disorder versus those diagnosed with unipolar depressive disorders and no mood disorder.MethodsThe Medical Expenditure Panel Survey 2004-2006, a nationally representative survey of the civilian, non-institutionalized U.S. population, was used to identify individuals diagnosed with bipolar disorder and unipolar depressive disorders based on ICD-9 classifications. Outcomes of interest were indirect costs, including work productivity and personal limitations.ResultsCompared to those with depression and no mood disorder, higher proportions of the population with bipolar disorder were poor, living alone, and not married. Also, the bipolar disorder population had higher rates of unemployment and social, cognitive, work, and household limitations than the depressed population. In multivariate models, patients with bipolar disorder or depression were more likely to be unemployed, miss work, and have social, cognitive, physical, and household limitations than those with no mood disorder. Notably, findings indicated particularly high costs for bipolar disorder, even beyond depression, with especially large differences in odds ratios for non-employment (4.6 for bipolar disorder versus 1.9 for depression, with differences varying by gender), social limitations (5.17 versus 2.85), cognitive limitations (10.78 versus 3.97), and work limitations (6.71 versus 3.19).ConclusionThe bipolar disorder population is distinctly more vulnerable than the population with depressive disorder, with evidence of fewer personal resources, lower work productivity, and greater personal limitations. More systematic analysis of the availability and quality of care for patients with bipolar disorder is encouraged to identify effectively tailored treatment interventions and maximize cost containment.

Role of the Bacillus methanolicus Citrate Synthase II Gene, citY, in Regulating the Secretion of Glutamate in l-Lysine-Secreting Mutants

ABSTRACT The thermotolerant, restrictive methylotroph Bacillus methanolicus MGA3 (ATCC 53907) can secrete 55 g of glutamate per liter (maximum yield, 0.36 g/g) at 50°C with methanol as a carbon source and a source of ammonia in fed-batch bioreactors. A homoserine dehydrogenase mutant, 13A52-8A66, secreting up to 35 g of l-lysine per liter in fed-batch fermentations had minimal 2-oxoglutarate dehydrogenase activity [7.3 nmol min−1 (mg of protein)−1], threefold-increased pyruvate carboxylase activity [535 nmol min−1 (mg of protein)−1], and elevated citrate synthase (CS) activity [292 nmol min−1 (mg of protein)−1] and simultaneously secreted glutamate (20 to 30 g per liter) and l-lysine. The flow of carbon from oxaloacetate is split between transamination to aspartate and formation of citrate. To investigate the regulation of this branch point, the B. methanolicus gene citY encoding a CSII protein with activity at 50°C was cloned from 13A52-8A66 into a CS-deficient Escherichia coli K2-1-4 strain. A citY-deficient B. methanolicus mutant, NCS-L-7, was also isolated from the parent strain of 13A52-8A66 by N-methyl-N′-nitro-N-nitrosoguanidine mutagenesis, followed by selection with monofluoroacetate disks on glutamate plates. Characterization of these strains confirmed that citY in strain 13A52-8A66 was not altered and that B. methanolicus possessed several forms of CS. Analysis of citY cloned from NCS-L-7 showed that the reduced CS activity resulted from a frameshift mutation. The level of glutamate secreted by NCS-L-7 was reduced sevenfold and the ratio of l-lysine to glutamate secreted was increased 4.5-fold compared to the wild type in fed-batch cultures with glutamate feeding. This indicates that glutamate secretion in l-lysine-overproducing mutants can be altered in favor of increased l-lysine secretion by regulating in vivo CS activity.

Null mutation in the stringent starvation protein of Escherichia coli disrupts lytic development of bacteriophage P1

As initial steps toward understanding the regulation and function of the stringent starvation protein (SSP) of Escherichia coli, we have isolated the ssp gene (encoding SSP), defined the operon in which ssp is found, and created insertion-deletion mutations of the ssp gene in recBC, sbc and recD strains by linear DNA transformation. During attempts to move the insertion-deletion structure to other strains by P1 transduction, we found that P1 was unable to form plaques on hosts lacking an intact ssp gene. The delta ssp mutation, however, did not affect transduction of the delta ssp strains and mutant strains were able to support lysogenic P1. When P1 lytic growth was induced, an increase in P1 DNA was detected without lysis or plaque formation. Examination of proteins synthesized in the delta ssp host during induction revealed the absence of P1 late gene products. Also, the apparent continued synthesis of early gene products during late time points was observed in the delta ssp host. The results reported here suggest that the defect in P1 lytic growth brought about by the absence of SSP occurs at the point at which bacteriophage P1 shifts from early to late gene expression. We also report the results of experiments on stable RNA synthesis following amino acid (aa) starvation induced by serine hydroxamate, and experiments on stable RNA synthesis following resupplementation of a limiting aa. These experiments show that SSP is not involved in stable RNA synthesis. Additionally, complementation studies have shown that ssp is identical to the previously described pog gene of E. coli.

Direct Costs of Bipolar Disorder Versus Other Chronic Conditions: An Employer-Based Health Plan Analysis

OBJECTIVE This study was a retrospective data-based analysis of health care utilization and costs for patients diagnosed as having bipolar disorder compared with patients with diagnoses of depression, diabetes, coronary artery disease, or asthma. METHODS Data were from an employer-based health plan. Consistent diagnosis and continuous enrollment from 2004 to 2007 were used to identify the study population (total N = 7,511), including those with bipolar disorder (N = 122), depression (N = 1,290), asthma (N = 2,770), coronary artery disease (N = 1,759), diabetes (N = 1,418), and diabetes with coronary artery disease (N = 455). Resource utilization quantified as cost (total, specialty care, psychiatric outpatient) and number of visits (specialty care and outpatient psychiatric care) was compared across groups. RESULTS Patients with bipolar disorder had higher adjusted mean per member per month (PMPM) costs than any other comparison group except for those with both diabetes and coronary artery disease. The cost was predominantly related to pharmacy costs and both inpatient and outpatient psychiatric care. A subset of 20% of patients with bipolar disorder accounted for 64% of the total costs. This subgroup of patients was more likely to be female, to have frequent hospital stays, and to have a higher number of comorbidities. Depressed patients, in contrast to bipolar disorder patients, had higher adjusted mean PMPM costs in primary care and nonpsychiatric inpatient costs. CONCLUSIONS Health care costs for bipolar disorder exceeded those for several common chronic illnesses. These data provide further evidence for employers, insurers, and providers to seek innovative models to deliver effective and efficient care to individuals with bipolar illness.

A System-Based Approach to Depression Management in Primary Care Using the Patient Health Questionnaire-9

Primary care physicians are more likely to see patients with depression than with any other disorder except hypertension, and its management poses a challenge to busy primary care practices. The Patient Health Questionnaire-9, a simple self-administered tool of proven validity and reliability, is a commonly used screening instrument for depression in primary care practice. This review article provides a system-based approach to depression management using the Patient Health Questionnaire-9 to guide clinicians in the identification and treatment of depression and its follow-up care.

Treatment outcomes of depression: the pharmacogenomic research network antidepressant medication pharmacogenomic study.

Background The effectiveness of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD) is controversial. Aims The clinical outcomes of subjects with nonpsychotic MDD were reported and compared with the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study outcomes to provide guidance on the effectiveness of SSRIs. Methods Subjects were treated with citalopram/escitalopram for up to 8 weeks. Depression was measured using the Quick Inventory of Depressive Symptomatology—Clinician Rated (QIDS-C16) and the 17-item Hamilton Depression Rating Scale. Results The group of subjects with at least 1 follow-up visit had a remission (QIDS-C16 ⩽ 5) rate of 45.8% as well as a response (50% reduction in QIDS-C16) rate of 64.8%, and 79.9% achieved an improvement of 5 points or higher in QIDS-C16 score. The Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study subjects were more likely to achieve a response than STAR*D study subjects. After adjustment for demographic factors, the response rates were not significantly different. When reporting the adverse effect burden, 60.5% of the subjects reported no impairment, 31.7% reported a minimal-to-mild impairment, and 7.8% reported a moderate-to-severe burden at the 4-week visit. Conclusions Patients contemplating initiating an SSRI to treat their MDD can anticipate a high probability of symptom improvement (79.9%) with a low probability that their symptoms will become worse. Patients with lower baseline severity have a higher probability of achieving remission. The Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study replicates many findings of the first phase of the STAR*D study after controlling for the differences between the studies.

Translating comparative effectiveness of depression medications into practice by comparing the depression medication choice decision aid to usual care: study protocol for a randomized controlled trial

BackgroundComparative effectiveness research (CER) documents important differences in antidepressants in terms of efficacy, safety, cost, and burden to the patient. Decision aids can adapt this evidence to help patients participate in making informed choices. In turn, antidepressant therapy will more likely reflect patients’ values and context, leading to improved adherence and mood outcomes.Methods/DesignThe objective of this study is to develop the Depression Medication Choice decision aid for use during primary care encounters, and to test its efficacy by conducting a clustered practical randomized trial comparing the decision aid to usual depression care in primary care practices.We will use a novel practice-based, patient-centered approach based on participatory action research that involves a multidisciplinary team of designers, investigators, clinicians, patient representatives, and other stakeholders for the development of the decision aid. We will then conduct a clustered practical randomized trial enrolling clinicians and their patients (n = 300) with moderate to severe depression from rural, suburban and inner city primary care practices (n = 10). The intervention will consist of the use of the depression medication choice decision aid during the clinical encounter. This trial will generate preliminary evidence of the relative impact of the decision aid on patient involvement in decision making, decision making quality, patient knowledge, and 6-month measures of medication adherence and mental health compared to usual depression care.DiscussionUpon completion of the proposed research, we will have developed and evaluated the efficacy of the decision aid depression medication choice as a novel translational tool for CER in depression treatment, engaged patients with depression in their care, and refined the process by which we conduct practice-based trials with limited research footprint.Trial registrationClinical Trials.gov: NCT01502891

Supervised, vigorous intensity exercise intervention for depressed female smokers: A pilot study

Introduction: Few studies have evaluated exercise interventions for smokers with depression or other psychiatric comorbidities. This pilot study evaluated the potential role of supervised vigorous exercise as a smoking cessation intervention for depressed females. Methods: Thirty adult women with moderate–severe depressive symptoms were enrolled and randomly assigned to 12 weeks of thrice weekly, in person sessions of vigorous intensity supervised exercise at a YMCA setting (EX; n = 15) or health education (HE; n = 15). All participants received behavioral smoking cessation counseling and nicotine patch therapy. Assessments were done in person at baseline, at the end of 12 weeks of treatment, and at 6 months post-target quit date. Primary end points were exercise adherence (proportion of 36 sessions attended) and biochemically confirmed 7-day point prevalence abstinence at Week 12. Biomarkers of inflammation were explored for differences between treatment groups and between women who smoked and those abstinent at Week 12. Results: Treatment adherence was high for both groups (72% for EX and 66% for HE; p = .55). The Week 12 smoking abstinence rate was higher for EX than HE (11/15 [73%] vs. 5/15 [33%]; p = .028), but no significant differences emerged at 6-month follow-up. Interleukin-6 levels increased more for those smoking than women abstinent at Week 12 (p = .040). Conclusions: Vigorous intensity supervised exercise is feasible and enhances short-term smoking cessation among depressed female smokers. Innovative and cost-effective strategies to bolster long-term exercise adherence and smoking cessation need evaluation in this population. Inflammatory biomarkers could be examined in future research as mediators of treatment efficacy. Implications: This preliminary study found that vigorous intensity supervised exercise is feasible and enhances short-term smoking cessation among depressed female smokers. This research addressed an important gap in the field. Despite decades of research examining exercise interventions for smoking cessation, few studies were done among depressed smokers or those with comorbid psychiatric disorders. A novel finding was increases in levels of a pro-inflammatory biomarker observed among women who smoked at the end of the intervention compared to those who did not.