Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A.

BACKGROUND: Major depressive disorder (MDD) shows increased coronary artery disease (CAD) risk of unknown mechanism(s). MDD is more common in women than men; CAD diagnosis can be difficult in women. Elevations of the inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA) predict increased CAD risk in populations; few data on these markers exist in MDD, particularly in remitted patients. METHODS: We measured fasting am serum CRP (high sensitivity, CRP(hs)) and SAA in 18 unmedicated, remitted women with MDD (mean age 41 +/- (SD)12, body mass index (BMI) 25.2 +/- 4.1 kg/m(2)) and 18 BMI-matched healthy control subjects (age 36 +/- 10, BMI 25.3 +/- 3.8 kg/m(2)) on 2 separate occasions, > or = 6 days apart. RESULTS: Repeat SAA and CRP(hs) measurements strongly correlated across study days (SAA: r = .83, p < .001; CRP(hs): r = .94, p < .001). Both SAA (5.30 +/- 3.39 vs. 2.84 +/- 1.87 mg/L, p < .005) and CRP(hs) (3.23 +/- 3.17 vs. 1.12 +/- 1.45 mg/L; p < .01) were significantly elevated in MDD women versus controls. CONCLUSIONS: Elevated SAA and CRP(hs) in remitted, unmedicated women with MDD indicate a pro-inflammatory state unrelated to current depressive symptoms or pharmacotherapy. These findings suggest that inflammatory mechanisms may in part underlie findings of increased CAD risk in MDD.     

Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial.

BACKGROUND: We tested whether transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression. METHODS: In a double-blind, multisite study, 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted five times per week with TMS at 10 pulses/sec, 120% of motor threshold, 3000 pulses/session, for 4-6 weeks. Primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD. RESULTS: Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all three scales at weeks 4 and 6. Remission rates were approximately twofold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well tolerated with a low dropout rate for adverse events (4.5%) that were generally mild and limited to transient scalp discomfort or pain. CONCLUSIONS: Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder.     

Partial replication of a DRD4 association in ADHD individuals using a statistically derived quantitative trait for ADHD in a family-based association test.

BACKGROUND: Previous research found an association between single nucleotide polymorphisms (SNPs) in the promoter region of DRD4 and statistically derived phenotypes generated from attention-deficit/hyperactivity disorder (ADHD) symptoms. We sought to replicate this finding by using the same methodology in an independent sample of ADHD individuals. METHODS: Four SNPs were genotyped in and around DRD4 in 2631 individuals in 642 families. We developed a quantitative phenotype at each SNP by weighting nine inattentive and nine hyperactive-impulsive symptoms. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, the screening procedure implemented in PBAT was used to select and test the five SNPs/genetic model combinations with the greatest power to detect an association for DRD4. RESULTS: One of the four SNPs was associated with the quantitative phenotypes generated from the ADHD symptoms (corrected p-values = .02). A rank ordering of the correlation between each of the ADHD symptoms and the quantitative phenotype suggested that hyperactive-impulsive symptoms were more strongly correlated with the phenotype; however, including inattentive symptoms was necessary to achieve a significant result. CONCLUSIONS: This study partially replicated a previous finding by identifying an association between rs7124601 and a quantitative trait generated from ADHD symptoms. The rs7124601 is in linkage disequilibrium (LD) with the SNPs identified previously. In contrast to the previous study, this finding suggests that both hyperactive-impulsive and inattentive symptoms are important in the association.     

Cardiac operations in patients with hematologic malignancies.

OBJECTIVES: Patients with hematologic malignancies are frequently in need of major cardiac operations. Previous reports suggest an increased risk for perioperative complications in these immunodeficient patients. METHODS: Patients diagnosed with any type of hematologic malignancy who underwent open-heart surgery at our institution between 7/1996 and 6/2002 were identified. Their hospital charts were reviewed; demographics, perioperative data and outcomes were recorded. RESULTS: There were 24 patients (20 men, 4 women); mean age was 68+/-13 years (range 31-84 years). Ten patients had chronic lymphocytic leukemia, seven non-Hodgkin lymphomas, three multiple myeloma and one Hodgkin's disease, chronic myelocytic leukemia, hairy cell leukemia and cutaneous T-cell lymphoma each. The mean pre-operative duration of the hematologic disease was 6.6 years. Twenty-two patients underwent coronary artery bypass grafting (with valve replacement in three patients) and two patients had isolated valve replacement. There was one in-hospital death (4.1%). Twelve patients (50%) had a minor or major complication. Seven reoperations were required-five during the same admission (one for mediastinal bleeding, one for an expanding femoral pseudoaneurysm, one for acute cholecystitis and two for IACD/pacer insertion) and two within 30 days (one for deep sternal wound infection and one for leg wound infection). Mean post-operative stay was 8.2+/-5.8 days and mean ICU stay was 1.6+/-1.1 days. There were three late deaths-two were due to progression of the hematologic disease. The 3-year actuarial survival was 83%. CONCLUSIONS: Cardiac operations can be performed with acceptable mortality but significant morbidity rates in patients with hematologic malignancies. Bleeding and infectious complications are most frequently seen and usually lead to reoperations. These findings warrant caution during patient selection.     

Avoidance of Nitrous Oxide for Patients Undergoing Major Surgery: A Randomized Controlled Trial

Background: Nitrous oxide is widely used in anesthesia, often administered at an inspired concentration around 70%. Although nitrous oxide interferes with vitamin B12, folate metabolism, and deoxyribonucleic acid synthesis and prevents the use of high inspired oxygen concentrations, the consequences of these effects are unclear.

Methods: Patients having major surgery expected to last at least 2 h were randomly assigned to nitrous oxide-free (80% oxygen, 20% nitrogen) or nitrous oxide-based (70% N2O, 30% oxygen) anesthesia. Patients and observers were blind to group identity. The primary endpoint was duration of hospital stay. Secondary endpoints included duration of intensive care stay and postoperative complications; the latter included severe nausea and vomiting, and the following major complications: pneumonia, pneumothorax, pulmonary embolism, wound infection, myocardial infarction, venous thromboembolism, stroke, awareness, and death within 30 days of surgery.

Results: Of 3,187 eligible patients, 2,050 consenting patients were recruited. Patients in the nitrous oxide-free group had significantly lower rates of major complications (odds ratio, 0.71; 95% confidence interval, 0.56-0.89; P = 0.003) and severe nausea and vomiting (odds ratio, 0.40; 95% confidence interval, 0.31-0.51; P < 0.001), but median duration of hospital stay did not differ substantially between groups (7.0 vs. 7.1 days; P = 0.06). Among patients admitted to the intensive care unit postoperatively, those in the nitrous oxide-free group were more likely to be discharged from the unit on any given day than those in the nitrous oxide group (hazard ratio, 1.35; 95% confidence interval, 1.05-1.73; P = 0.02).     

Postoperative Cognitive Dysfunction in Patients with Preoperative Cognitive Impairment: Which Domains Are Most Vulnerable?

Background: The authors explored the database of the first International Study of Postoperative Cognitive Dysfunction study to specify the domains of cognitive function that were most vulnerable and to determine the pattern of deterioration in patients with preoperative cognitive impairment.

Methods: One thousand two hundred eighteen patients were included in the first International Study of Postoperative Cognitive Dysfunction, where neuropsychological testing was performed at entry to the study, at 1 week, and at 3 months after surgery. The authors' analyses determined the extent to which seven neuropsychological measures changed after surgery with focus on the relation with preoperative cognitive impairment, defined as a preoperative score 1.5 SD below healthy controls in the memory test.

Results: Preoperative cognitive impairment was found in 74 patients at baseline. At 1 week, cognitive deterioration was seen in all tests, but in particular in the Letter Digit Coding and the time of the Stroop interference test, with 14% and 16% of the total sample (n = 1,016) exceeding 2 SD, respectively. At 3 months, deterioration was more uniform. Significantly fewer in the preoperative cognitive impairment group had deterioration in the memory test, both at 1 week and at 3 months, with no patient displaying a deterioration exceeding 2 SD.     

Independent component analysis and clustering improve signal-to-noise ratio for statistical analysis of event-related potentials

OBJECTIVE: To evaluate the effectiveness of a new method of using Independent Component Analysis (ICA) and k-means clustering to increase the signal-to-noise ratio of Event-Related Potential (ERP) measurements while permitting standard statistical comparisons to be made despite the inter-subject variations characteristic of ICA. METHODS: Per-subject ICA results were used to create a channel pool, with unequal weights, that could be applied consistently across subjects. Signals derived from this and other pooling schemes, and from unpooled electrodes, were subjected to identical statistical analysis of the N170 own-face effect in a Joe/No Joe face recognition paradigm wherein participants monitored for a target face (Joe) presented amongst other unfamiliar faces and their own face. Results between the Joe, unfamiliar face and own face conditions were compared using Cohen's d statistic (square root of signal-to-noise ratio) to measure effect size. RESULTS: When the own-face condition was compared to the Joe and unfamiliar-face conditions, the channel map method increased effect size by a factor ranging from 1.2 to 2.2. These results stand in contrast to previous findings, where conventional pooling schemes failed to reveal an N170 effect to the own-face stimulus (Tanaka JW, Curran T, Porterfield A, Collins D. The activation of pre-existing and acquired face representations: the N250 ERP as an index of face familiarity. J Cogn Neurosci 2006;18:1488-97). Consistent with conventional pooling schemes, the channel map approach showed no reliable differences between the Joe and Unfamiliar face conditions, yielding a decrease in effect size ranging from 0.13 to 0.75. CONCLUSIONS: By increasing the signal-to-noise ratio in the measured waveforms, the channel pool method demonstrated an enhanced sensitivity to the neurophysiological response to own-face relative to other faces. SIGNIFICANCE: By overcoming the characteristic inter-subject variations of ICA, this work allows classic ERP analysis methods to exploit the improved signal-to-noise ratio obtainable with ICA.     

Assigning the source of human campylobacteriosis in New Zealand: A comparative genetic and epidemiological approach

Integrated surveillance of infectious multi-source diseases using a combination of epidemiology, ecology, genetics and evolution can provide a valuable risk-based approach for the control of important human pathogens. This includes a better understanding of transmission routes and the impact of human activities on the emergence of zoonoses. Until recently New Zealand had extraordinarily high and increasing rates of notified human campylobacteriosis, and our limited understanding of the source of these infections was hindering efforts to control this disease. Genetic and epidemiological modeling of a 3-year dataset comprising multilocus sequence typed isolates from human clinical cases, coupled with concurrent data on food and environmental sources, enabled us to estimate the relative importance of different sources of human disease. Our studies provided evidence that poultry was the leading cause of human campylobacteriosis in New Zealand, causing an estimated 58–76% of cases with widely varying contributions by individual poultry suppliers. These findings influenced national policy and, after the implementation of poultry industry-specific interventions, a dramatic decline in human notified cases was observed in 2008. The comparative-modeling and molecular sentinel surveillance approach proposed in this study provides new opportunities for the management of zoonotic diseases.