Intrathecal Dexamethasone in Febrile Infection-Related Epilepsy Syndrome: A Case Report.

Objectives: Febrile infection-related epilepsy syndrome (FIRES) is characterized by explosive onset refractory status epilepticus (RSE) in healthy individuals that is refractory to antiseizure medication (ASM), continuous anesthetic infusions (CIs), and immunomodulators. Recently, a case series of patients receiving intrathecal dexamethasone (IT-DEX) was reported with improved RSE control. Methods: We present a child with FIRES with favorable outcome after receiving concomitant anakinra and IT-DaEX. A 9-year-old male patient presented with encephalopathy following a febrile illness. He developed seizures evolving to RSE refractory to multiple ASM, 3 CIs, steroids, IVIG, plasmapheresis, ketogenic diet (KD), and anakinra. After continued seizures and inability to wean off CI, IT-DEX was initiated. Results: He received 6 doses of IT-DEX with resolution of RSE, rapid wean off CI, and improved inflammatory markers. At discharge, he was ambulating with assistance, speaking 2 languages, and ingesting food orally. Discussion: FIRES is a neurologically devastating syndrome with high mortality and morbidity. Proposed guidelines and various treatment strategies are becoming available in the literature. Although treatment with KD, anakinra, and tocilizumab has been successful in previous FIRES cases, our results suggest that the addition of IT-DEX may allow for faster weaning off CI and better cognitive outcomes when initiated early in the course.

A randomized, double-blind, placebo- and positive-controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects.

Durlobactam (formerly ETX2514) is a diazabicyclooctane ß-lactamase inhibitor that inhibits class A, C, and D ß-lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem- and colistin-resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo- and active-controlled, single-infusion, three-way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3-h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3-h i.v. infusion of placebo, and a single 3-h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open-label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post-start of infusion. For the primary ECG end point, placebo-corrected change-from-baseline corrected QT Fridericia's formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration-QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

Self-Report Measures of Anhedonia and Approach Motivation Weakly Correspond to Anhedonia and Depression Assessed via Clinical Interviews.

Self-report scales are popular tools for measuring anhedonic experiences and motivational deficits, but how well do they reflect clinically significant anhedonia? Seventy-eight adults participated in face-to-face structured diagnostic interviews: 22 showed clinically significant anhedonia, and 18 met criteria for depression. Analyses of effect sizes comparing the anhedonia and depression groups to their respective controls found large effects, as expected, for measures of depressive symptoms, but surprisingly weak effect sizes (all less than d=.50) for measures of general, social, or physical anhedonia, behavioral activation, and anticipatory and consummatory pleasure. Measures of Neuroticism and Extraversion distinguished the anhedonic and depressed groups from the controls at least as well as measures of anhedonia and motivation. Taken together, the findings suggest that caution is necessary when extending self-report findings to populations with clinically significant symptoms.

Inverse changes in raphe and cortical 5-HT1B receptor availability after acute tryptophan depletion in healthy human subjects.

Serotonergic neurotransmission plays a key role in the pathophysiology and treatment of various neuropsychiatric diseases. The purpose of this study was to investigate changes in serotonergic neurotransmission after acute tryptophan depletion (ATD) using positron emission tomography (PET) with [11 C]P943, a 5-HT1B receptor radioligand previously shown to be sensitive to changes in 5-HT. Five healthy subjects were scanned on a high resolution PET scanner twice on the same day, before and approximately 5 hours after ingesting capsules containing an amino acid mixture that lacks tryptophan. For each scan, emission data were acquired for 120 min after intravenous bolus injection of [11 C]P943. Binding potential (BPND ) values were estimated from parametric images using the second version of the multilinear reference tissue model (MRTM2, t* = 20 min) with cerebellar grey matter used as a reference region. The change in [11 C]P943 binding (ΔBPND , %) was calculated as (BPND,post  - BPND,pre )/(BPND,pre ) × 100, and correlation analysis was performed to measure linear associations of ΔBPND between raphe and other regions of interest (ROIs). ΔBPND ranged from -6% to 45% in the raphe, with positive values indicating reduced competition from 5-HT. In cortical regions, ΔBPND ranged from -28% to 7%. While these changes did not reach significance, there were significant negative correlations of ΔBPND of the raphe with those of cerebral cortical regions and the thalamus (e.g., r = -.96, p = .011 for average cortex). These findings support the hypothesis that raphe serotonin is a critical modulator of cortical serotonin release via projecting neurons in healthy human subjects.

Seasonal malaria chemoprevention packaged with malnutrition prevention in northern Nigeria: A pragmatic trial (SMAMP study) with nested case-control.

Integrating seasonal malaria chemoprevention (SMC), recommended by the WHO since 2012 to prevent malaria infection, with nutrition interventions may improve health outcomes and operational efficiencies. This study assessed the effects of co-packaging interventions on distribution coverage, nutrition, and clinical malaria outcomes in northern Nigeria. From August to November 2014, community volunteers delivered sulfadoxine-pyrimethamine and amodiaquine (SP-AQ) door-to-door each month to approximately 7,000 children aged 6-24 months in seven wards of Madobi, Kano State, Nigeria. In three of the wards children additionally received a lipid-based nutrient supplement (LNS-medium quantity), Plumpy Doz. Coverage, adherence, and anthropometric outcomes were assessed through baseline, midline, and endline household surveys. A facility-based case-control study was also conducted to estimate impact on clinical malaria outcomes. Coverage of SP-AQ was similar between arms at 89% (n = 2,409 child-months [88-90%]) in the SP-AQ only arm and 90% (n = 1,947 child-months [88-92%]) in the SP-AQ plus LNS arm (p = 0.52). Coverage of LNS was 83% (n = 2,409 child-months [81-84%]). Whilst there were marked changes in anthropometric status between baseline, midline and endline, these were largely accounted for by socioeconomic status and must be interpreted with care due to possible measurement issues, especially length-based indices. Overall nutritional status of our most robust measure, weight-for-age, does appear to have improved by endline, but was similar in the two study arms, suggesting no additional benefit of the LNS. While the odds of clinical malaria among those who received the intended intervention were lower in each study arm compared to children who did not receive interventions (SP-AQ only OR = 0.23 [0.09-0.6]; SP-AQ plus LNS OR = 0.22 [0.09-0.55]), LNS was not shown to have an additional impact. Coverage of SMC was high regardless of integrating LNS delivery into the SMC campaign. Supplementation with LNS did not appear to impact nutritional outcomes, but appeared to enhance the impact of SP-AQ on clinical odds of malaria. These results indicate that combining nutritional interventions with seasonal malaria chemoprevention in high-risk areas can be done successfully, warranting further exploration with other products or dosing. Trial Registration: ISRCTN 11413895.

Education Milestones for Newly Diagnosed Pediatric, Adolescent, and Young Adult Cancer Patients: A Quality Improvement Initiative.

The diagnosis of cancer in a child, adolescent, or young adult is an emotionally overwhelming time. To improve the quality of education and support provided to patients and caregivers with a new cancer diagnosis, we executed a quality improvement initiative to (a) define key education milestones for the delivery of essential education during the first 2 months following diagnosis and (b) to define role accountability within the multidisciplinary team for delivery of content and execution of tasks. To develop education milestones, we (a) identified educational content from review of the literature, (b) determined the sequence of content delivery through qualitative interviews with patients and caregivers, and (c) developed education milestones by evaluation of existing workflows. To develop task lists, we (a) determined which multidisciplinary team member was best suited to deliver specific content and (b) defined discrete tasks required to execute education milestones. Key content topics and preferred sequence are as follows: Emotional Adjustment to Diagnosis, When and How to Call the Doctor, Medication Management, Practical Needs, Line Care, and Access to Nontherapeutic Clinical Trials. Eight education milestones were defined across the initial 2 months following cancer diagnosis. The education milestones are paired with task lists. The education milestones and task lists guide the execution of complex education across a multidisciplinary service line in an emotionally challenging time. Early information focuses on essential content, role responsibility is clearly defined, and psychosocial support services are purposefully and iteratively integrated into care during the initial weeks following a cancer diagnosis.

Introducing malaria rapid diagnostic tests in private medicine retail outlets: A systematic literature review.

BACKGROUND: Many patients with malaria-like symptoms seek treatment in private medicine retail outlets (PMR) that distribute malaria medicines but do not traditionally provide diagnostic services, potentially leading to overtreatment with antimalarial drugs. To achieve universal access to prompt parasite-based diagnosis, many malaria-endemic countries are considering scaling up malaria rapid diagnostic tests (RDTs) in these outlets, an intervention that may require legislative changes and major investments in supporting programs and infrastructures. This review identifies studies that introduced malaria RDTs in PMRs and examines study outcomes and success factors to inform scale up decisions. METHODS: Published and unpublished studies that introduced malaria RDTs in PMRs were systematically identified and reviewed. Literature published before November 2016 was searched in six electronic databases, and unpublished studies were identified through personal contacts and stakeholder meetings. Outcomes were extracted from publications or provided by principal investigators. RESULTS: Six published and six unpublished studies were found. Most studies took place in sub-Saharan Africa and were small-scale pilots of RDT introduction in drug shops or pharmacies. None of the studies assessed large-scale implementation in PMRs. RDT uptake varied widely from 8%-100%. Provision of artemisinin-based combination therapy (ACT) for patients testing positive ranged from 30%-99%, and was more than 85% in five studies. Of those testing negative, provision of antimalarials varied from 2%-83% and was less than 20% in eight studies. Longer provider training, lower RDT retail prices and frequent supervision appeared to have a positive effect on RDT uptake and provider adherence to test results. Performance of RDTs by PMR vendors was generally good, but disposal of medical waste and referral of patients to public facilities were common challenges. CONCLUSIONS: Expanding services of PMRs to include malaria diagnostic services may hold great promise to improve malaria case management and curb overtreatment with antimalarials. However, doing so will require careful planning, investment and additional research to develop and sustain effective training, supervision, waste-management, referral and surveillance programs beyond the public sector.

Expanding access to parasite-based malaria diagnosis through retail drug shops in Tanzania: evidence from a randomized trial and implications for treatment.

BACKGROUND: Tanzania has seen a reduction in the fraction of fevers caused by malaria, likely due in part to scale-up of control measures. While national guidelines require parasite-based diagnosis prior to treatment, it is estimated that more than half of suspected malaria treatment-seeking in Tanzania initiates in the private retail sector, where diagnosis by malaria rapid diagnostic test (RDT) or microscopy is illegal. This pilot study investigated whether the introduction of RDTs into Accredited Drug Dispensing Outlets (ADDOs) under realistic market conditions would improve case management practices. METHODS: Dispensers from ADDOs in two intervention districts in Tanzania were trained to stock and perform RDTs and monitored quarterly. Each district was assigned a different recommended retail price to evaluate the need for a subsidy. Malaria RDT and artemisinin-based combination therapy (ACT) uptake and availability were measured pre-intervention and 1 year post-intervention through structured surveys of ADDO owners and exiting customers in both intervention districts and one contiguous control district. Descriptive analysis and logistic regression were used to compare the three districts and identify predictive variables for testing. RESULTS AND DISCUSSION: A total of 310 dispensers from 262 ADDOs were trained to stock and perform RDTs. RDT availability in intervention ADDOs increased from 1% (n = 172) to 73% (n = 163) during the study; ACT medicines were available in 75% of 260 pre-intervention and 68% of 254 post-intervention ADDOs. Pre-treatment testing performed within the ADDO increased from 0 to 65% of suspected malaria patients who visited a shop (95% CI 60.8-69.6%) with no difference between intervention districts. Overall parasite-based diagnosis increased from 19 to 74% in intervention districts and from 3 to 18% in the control district. Prior knowledge of RDT availability (aOR = 1.9, p = 0.03) and RDT experience (aOR = 1.9, p = 0.01) were predictors for testing. Adherence data indicated that 75% of malaria positives received ACT, while 3% of negatives received ACT. CONCLUSIONS: Trained and supervised ADDO dispensers in rural Tanzania performed and sold RDTs under real market conditions to two-thirds of suspected malaria patients during this one-year pilot. These results support the hypothesis that introducing RDTs into regulated private retail sector settings can improve malaria testing and treatment practices without an RDT subsidy. Trial registration ISRCTN ISRCTN14115509.

Determinants of malaria diagnostic uptake in the retail sector: qualitative analysis from focus groups in Uganda.

BACKGROUND: In Uganda, as in most other malaria-endemic countries, presumptive treatment for malaria based on symptoms without a diagnostic blood test is still very common. While diagnostic testing in public sector facilities is increasing, many people in Uganda who suspect malaria visit private sector outlets to purchase medications. Increasing the availability and uptake of rapid diagnostic tests (RDTs) for malaria in private outlets could help increase diagnostic testing for malaria but raises questions about the patient demand for and valuation of testing that are less critical for public sector introduction. METHODS: In preparation for a behaviour change campaign to encourage and sustain the demand for RDTs in drug shops, eight focus group discussions with a total of 84 community members were conducted in six districts across Uganda's Eastern Region in November-December 2011. Focus groups explored incentives and barriers to seeking diagnosis for malaria, how people react to test results and why, and what can be done to increase the willingness to pay for RDTs. RESULTS: Overall, participants were very familiar with malaria diagnostic testing and understood its importance, yet when faced with limited financial resources, patients preferred to spend their money on medication and sought testing only when presumptive treatment proved ineffective. While side effects did seem to be a concern, participants did not mention other potential costs of taking unnecessary or ineffective medications, such as money wasted on excess drugs or delays in resolution of symptoms. Very few individuals were familiar with RDTs. CONCLUSION: In order to boost demand, these results suggest that private sector RDTs will have to be made convenient and affordable and that targeted behaviour change campaigns should strive to increase the perceived value of diagnosis.

Test-retest reliability of the novel 5-HT1B receptor PET radioligand [11C]P943.

PURPOSE: [(11)C]P943 is a novel, highly selective 5-HT1B PET radioligand. The aim of this study was to determine the test-retest reliability of [(11)C]P943 using two different modeling methods and to perform a power analysis with each quantification technique. METHODS: Seven healthy volunteers underwent two PET scans on the same day. Regions of interest (ROIs) were the amygdala, hippocampus, pallidum, putamen, insula, frontal, anterior cingulate, parietal, temporal and occipital cortices, and cerebellum. Two multilinear radioligand quantification techniques were used to estimate binding potential: MA1, using arterial input function data, and the second version of the multilinear reference tissue model analysis (MRTM2), using the cerebellum as the reference region. Between-scan percent variability and intraclass correlation coefficients (ICC) were used to assess test-retest reliability. We also performed power analyses to determine the method that would allow the least number of subjects using within-subject or between-subject study designs. A voxel-wise ICC analysis for MRTM2 BPND was performed for the whole brain and all the ROIs studied. RESULTS: Mean percent variability between two scans across regions ranged between 0.4 % and 12.4 % for MA1 BPND, 0.5 % and 11.5 % for MA1 BPP, 16.7 % and 28.3 % for MA1 BPF, and between 0.2 % and 5.4 % for MRTM2 BPND. The power analyses showed a greater number of subjects were required using MA1 BPF compared with other outcome measures for both within-subject and between-subject study designs. ICC values were the highest using MRTM2 BPND and the lowest with MA1 BPF in ten ROIs. Small regions and regions with low binding had lower ICC values than large regions and regions with high binding. CONCLUSION: Reliable measures of 5-HT1B receptor binding can be obtained using the novel PET radioligand [(11)C]P943. Quantification of 5-HT1B receptor binding with MRTM2 BPND and with MA1 BPP provided the least variability and optimal power for within-subject and between-subject designs.

An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of (11)C-LY2459989.

UNLABELLED: The κ-opioid receptors (KORs) are implicated in several neuropsychiatric diseases and addictive disorders. PET with radioligands provides a means to image the KOR in vivo and investigate its function in health and disease. The purpose of this study was to develop the selective KOR antagonist (11)C-LY2459989 as a PET radioligand and characterize its imaging performance in nonhuman primates. METHODS: LY2459989 was synthesized and assayed for in vitro binding to opioid receptors. Ex vivo studies in rodents were conducted to assess its potential as a tracer candidate. (11)C-LY2459989 was synthesized by reaction of its iodophenyl precursor with (11)C-cyanide, followed by partial hydrolysis of the resulting (11)C-cyanophenyl intermediate. Imaging experiments with (11)C-LY2459989 were performed in rhesus monkeys with arterial input function measurement. Imaging data were analyzed with kinetic models to derive in vivo binding parameters. RESULTS: LY2459989 is a full antagonist with high binding affinity and selectivity for KOR (0.18, 7.68, and 91.3 nM, respectively, for κ, µ, and δ receptors). Ex vivo studies in rats indicated LY2459989 as an appropriate tracer candidate with high specific binding signals and confirmed its KOR binding selectivity in vivo. (11)C-LY2459989 was synthesized in high radiochemical purity and good specific activity. In rhesus monkeys, (11)C-LY2459989 displayed a fast rate of peripheral metabolism. Similarly, (11)C-LY2459989 displayed fast uptake kinetics in the brain and an uptake pattern consistent with the distribution of KOR in primates. Pretreatment with naloxone (1 mg/kg, intravenously) resulted in a uniform distribution of radioactivity in the brain. Further, specific binding of (11)C-LY2459989 was dose-dependently reduced by the selective KOR antagonist LY2456302 and the unlabeled LY2459989. Regional binding potential values derived from the multilinear analysis-1 (MA1) method, as a measure of in vivo specific binding signal, were 2.18, 1.39, 1.08, 1.04, 1.03, 0.59, 0.51, and 0.50, respectively, for the globus pallidus, cingulate cortex, insula, caudate, putamen, frontal cortex, temporal cortex, and thalamus. CONCLUSION: The novel PET radioligand (11)C-LY2459989 displayed favorable pharmacokinetic properties, a specific and KOR-selective binding profile, and high specific binding signals in vivo, thus making it a promising PET imaging agent for KOR.

Comparison of insecticidal paint and deltamethrin against Triatoma infestans (Hemiptera: Reduviidae) feeding and mortality in simulated natural conditions.

The vector of Chagas disease, Triatoma infestans, is largely controlled by the household application of pyrethroid insecticides. Because effective, large-scale insecticide application is costly and necessitates numerous trained personnel, alternative control techniques are badly needed. We compared the residual effect of organophosphate-based insecticidal paint (Inesfly 5A IGR™ (I5A)) to standard deltamethrin, and a negative control, against T. infestans in a simulated natural environment. We evaluated mortality, knockdown, and ability to take a blood meal among 5(th) instar nymphs. I5A paint caused significantly greater mortality at time points up to nine months compared to deltamethrin (Fisher's Exact Test, p < 0.01 in all instances). A year following application, mortality among nymphs in the I5A was similar to those in the deltamethrin (χ2 = 0.76, df=1, p < 0.76). At months 0 and 1 after application, fewer nymphs exposed to deltamethrin took a blood meal compared to insects exposed to paint (Fisher's Exact Tests, p < 0.01 and p < 0.01, respectively). Insecticidal paint may provide an easily-applied means of protection against vectors of Chagas disease.

Feasibility of distributing rapid diagnostic tests for malaria in the retail sector: evidence from an implementation study in Uganda.

BACKGROUND: Despite the benefits of malaria diagnosis, most presumed malaria episodes are never tested. A primary reason is the absence of diagnostic tests in retail establishments, where many patients seek care. Malaria rapid diagnostic tests (RDTs) in drug shops hold promise for guiding appropriate treatment. However, retail providers generally lack awareness of RDTs and training to administer them. Further, unsubsidized RDTs may be unaffordable to patients and unattractive to retailers. This paper reports results from an intervention study testing the feasibility of RDT distribution in Ugandan drug shops. METHODS AND FINDINGS: 92 drug shops in 58 villages were offered subsidized RDTs for sale after completing training. Data on RDT purchases, storage, administration and disposal were collected, and samples were sent for quality testing. Household surveys were conducted to capture treatment outcomes. Estimated daily RDT sales varied substantially across shops, from zero to 8.46 RDTs per days. Overall compliance with storage, treatment and disposal guidelines was excellent. All RDTs (100%) collected from shops passed quality testing. The median price charged for RDTs was 1000USH ($0.40), corresponding to a 100% markup, and the same price as blood slides in local health clinics. RDTs affected treatment decisions. RDT-positive patients were 23 percentage points more likely to buy Artemisinin Combination Therapies (ACTs) (p = .005) and 33.1 percentage points more likely to buy other antimalarials (p<.001) than RDT-negative patients, and were 5.6 percentage points more likely to buy ACTs (p = .05) and 31.4 percentage points more likely to buy other antimalarials (p<.001) than those not tested at all. CONCLUSIONS: Despite some heterogeneity, shops demonstrated a desire to stock RDTs and use them to guide treatment recommendations. Most shops stored, administered and disposed of RDTs properly and charged mark-ups similar to those charged on common medicines. Results from this study suggest that distributing RDTs through the retail sector is feasible and can reduce inappropriate treatment for suspected malaria.

Increased ratio of anti-apoptotic to pro-apoptotic Bcl2 gene-family members in lithium-responders one month after treatment initiation.

BACKGROUND: Lithium is considered by many as the gold standard medication in the management of bipolar disorder (BD). However, the clinical response to lithium is heterogeneous, and the molecular basis for this difference in response is unknown. In the present study, we sought to determine how the peripheral blood gene expression profiles of patients with bipolar disorder (BD) changed over time following intitiation of treatment with lithium, and whether differences in those profiles over time were related to the clinical response. METHODS: Illumina Sentrix Beadchip (Human-6v2) microarrays containing > 48,000 transcript probes were used to measure levels of expression of gene-expression in peripheral blood from 20 depressed subjects with BD prior to and every two weeks during 8 weeks of open-label treatment with lithium.Changes in gene-expression were compared between treatment responders (defined as a decrease in the Hamilton Depression Rating Scale of 50% or more) and non-responders. Pathway analysis was conducted using GeneGO Metacore software. RESULTS: 127 genes showed a differential response in responders vs. non-responders. Pathway analysis showed that regulation of apoptosis was the most significantly affected pathway among these genes. Closer examination of the time-course of changes among BCL2 related genes showed that in lithium-responders, one month after starting treatment with lithium, several anti-apoptotic genes including Bcl2 and insulin receptor substrate 2 (IRS2) were up-regulated, while pro-apoptotic genes, including BCL2-antagonist/killer 1 (BAK1) and BCL2-associated agonist of cell death (BAD), were down-regulated. In contrast, in lithium non-responders, BCL2 and IRS2 were down-regulated, while BAK1 and BAD up-regulated at the one-month time-point. CONCLUSIONS: These results suggest that differential changes in the balance of pro- and anti- apoptotic gene-expression following treatment with lithium may explain some of the heterogeneity in clinical response in BD patients.

Persistent ß2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder.

BACKGROUND: Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the ß2 subunit, may be effective in treating patients with major depressive disorder. Using [123I]5-I-A-85380 single photon emission computed tomography (SPECT), the authors studied the availability of ß2-subunit-containing nAChRs (ß2*-nAChRs) in depressed patients. To understand its molecular basis, the authors also studied ß2*-nAChR binding in postmortem brain samples from depressed subjects. METHOD: The participants were 23 medication-free, nonsmoking subjects with familial, early-onset depression (eight acutely ill and 15 recovered) and 23 age- and gender-matched nonsmoking comparison subjects. Each received one [123I]5-I-A-85380 SPECT scan and an MRI scan. The availability of ß2*-nAChRs was quantified as VT/fP. Postmortem analysis of ß2*-nAChR binding was conducted with [123I]5-I-A-85380 on prefrontal cortex samples from 14 depressed subjects and 14 age-matched comparison subjects. RESULTS: The ß2*-nAChR availability in both the acutely ill and recovered depressed subjects was significantly lower across all brain regions than in the respective comparison subjects, and it was lower in the acutely ill subjects than in those who were recovered. In the depressed patients, ß2*-nAChR availability was significantly correlated with lifetime number of depressive episodes, trauma score, and anxiety score. There were no differences in ß2*-nAChR number between groups in the postmortem study. CONCLUSIONS: Depressed patients have lower ß2*-nAChR availability than do healthy subjects. The difference between ß2*-nAChR availability in vivo and in post-mortem samples may be analogous to data with dopaminergic PET ligands and dopamine receptor availability; lower receptor availability for the SPECT ligand could be caused by greater endogenous acetylcholine.

Prefrontal cortical response to emotional faces in individuals with major depressive disorder in remission.

Abnormalities in the response of the orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) to negative emotional stimuli have been reported in acutely depressed patients. However, there is a paucity of studies conducted in unmedicated individuals with major depressive disorder in remission (rMDD) to assess whether these are trait abnormalities. To address this issue, 19 medication-free rMDD individuals and 20 healthy comparison (HC) participants were scanned using functional magnetic resonance imaging while performing an implicit emotion processing task in which they labeled the gender of faces depicting negative (fearful), positive (happy) and neutral facial expressions. The rMDD and HC groups were compared using a region-of-interest approach for two contrasts: fear vs. neutral and happy vs. neutral. Relative to HC, rMDD showed reduced activation in left OFC and DLPFC to fearful (vs. neutral) faces. Right DLPFC activation to fearful (vs. neutral) faces in the rMDD group showed a significant positive correlation with duration of euthymia. The findings support deficits in left OFC and DLPFC responses to negative emotional stimuli during euthymic periods of MDD, which may reflect trait markers of the illness or a 'scar' due to previous depression. Recovery may also be associated with compensatory increases in right DLPFC functioning.

Secondary kill effect of deltamethrin on Triatoma infestans.

Control of the Chagas disease vector, Triatoma infestans, relies on the application of pyrethroid insecticides, especially deltamethrin. We performed laboratory studies to determine whether a T. infestans nymph that comes into contact with a deltamethrin-treated surface horizontally transfers the insecticide to subsequent triatomines. We found that a triatomine that walks on a deltamethrin-treated surface for a short period of time has the ability to transport the insecticide in concentrations sufficient to kill other triatomines with which it comes into contact. The effect was limited to high-density environments, and mortality as a result of secondary exposure was greater among second-instar nymphs compared with fifth-instar nymphs. Our results suggest that deltamethrin could be killing triatomines through both direct and indirect contact, although it remains unclear whether the phenomenon occurs in natural conditions.

Levetiracetam in the management of bipolar depression: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To study the efficacy of adjunctive levetiracetam therapy compared with placebo in the treatment of subjects with depression with bipolar disorder. METHOD: This double-blind, placebo-controlled clinical trial randomly assigned outpatients with bipolar disorder type I and type II who were experiencing a major depressive episode (Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version criteria) to treatment with either placebo or adjunctive levetiracetam (up to 2,500 mg/d flexibly dosed) for 6 weeks. The subjects were recruited from October 2005 to June 2008. The primary efficacy measure was mean change from baseline to week 6 in the Hamilton Depression Rating Scale (21-item). Secondary efficacy assessments included the Montgomery-Åsberg Depression Rating Scale, the Beck Depression Inventory, the Clinical Global Impressions-Bipolar Version scale, the Hamilton Anxiety Rating Scale, and the Young Mania Rating Scale. RESULTS: Of 42 subjects randomly assigned to placebo or drug, 32 received at least 1 postbaseline assessment and thus were included in the analysis. The mean (SD) levetiracetam daily dose at endpoint evaluation was 1,132 (425) mg/d. There was no significant difference in the mean change from baseline to week 6 in the Hamilton Depression Rating Scale scores for levetiracetam compared with placebo. There were no significant differences in any of the secondary outcome measures. CONCLUSIONS: Levetiracetam adjunctive therapy was not superior to placebo in the short-term treatment of subjects with depression with bipolar disorder in the population studied. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00566150.

Increased peripheral blood expression of electron transport chain genes in bipolar depression.

OBJECTIVE: To identify specific genetic pathways showing altered expression in peripheral blood of depressed subjects with bipolar disorder (BPD). METHODS: Illumina Sentrix BeadChip (Human-6v2) microarrays containing >48,000 transcript probes were used to measure levels of gene expression in peripheral blood from 20 depressed subjects with BPD and in 15 healthy control subjects. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to confirm a subset of these differences. RESULTS: A total of 1,180 genes were differentially expressed between subjects with BPD and healthy controls (fold-change >1.3, false discovery rate-corrected p < 0.05, covaried for age and sex). Of these, 559 genes were up-regulated in BPD subjects and 621 were down-regulated. Surprisingly, there was no difference between medicated (n = 11) and unmedicated (n = 9) subjects with BPD for any of these genes. Pathway analysis using GeneGo MetaCore software showed that the most significantly affected pathway was the mitochondrial electron transport chain (ETC). Of the 85 objects (genes or proteins) in this pathway, 22 were up-regulated and 2 down-regulated in subjects with BPD. qRT-PCR confirmed up-regulation of nuclear encoded ETC genes in complexes I, III, IV, and V and, in addition, demonstrated up-regulation of mitochondrially encoded genes in each of these complexes. CONCLUSION: These results suggest that increased expression of multiple components of the mitochondrial ETC may be a primary deficit in bipolar depression, rather than an effect of medication.