Real-world Experience of Caplacizumab for Adolescents in the First-line Setting: Case Reports.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy resulting in high mortality. Caplacizumab is approved for treatment of adults with acquired thrombotic thrombocytopenic purpura that has shown faster platelet normalization, clinical improvement, and reduced risk of recurrent/refractory disease. We report 2 cases of adolescents treated off-label with caplacizumab who were able to stop before 30 days from end of plasma exchange after platelets normalized and ADAMTS13 activity recovered to >20% to 30%. Our results show similar efficacy to other reports of patients under 18 receiving caplacizumab in first line, regardless of plasma exchange strategy, and may offer insight into early cessation criteria.

The endoplasmic reticulum acetyltransferases ATase1/NAT8B and ATase2/NAT8 are differentially regulated to adjust engagement of the secretory pathway.

Nε-lysine acetylation of nascent glycoproteins within the endoplasmic reticulum (ER) lumen regulates the efficiency of the secretory pathway. The ER acetylation machinery consists of the membrane transporter, acetyl-CoA transporter 1 (AT-1/SLC33A1), and two acetyltransferases, ATase1/NAT8B and ATase2/NAT8. Dysfunctional ER acetylation is associated with severe neurological diseases with duplication of AT-1/SLC33A1 being associated with autism spectrum disorder, intellectual disability, and dysmorphism. Neuron-specific AT-1 over-expression in the mouse alters neuron morphology and function, causing an autism-like phenotype, indicating that ER acetylation plays a key role in neurophysiology. As such, characterizing the molecular mechanisms that regulate the acetylation machinery could reveal critical information about its biology. By using structure-biochemistry approaches, we discovered that ATase1 and ATase2 share enzymatic properties but differ in that ATase1 is post-translationally regulated via acetylation. Furthermore, gene expression studies revealed that the promoters of AT-1, ATase1, and ATase2 contain functional binding sites for the neuron-related transcription factors cAMP response element-binding protein and the immediate-early genes c-FOS and c-JUN, and that ATase1 and ATase2 exhibit additional modes of transcriptional regulation relevant to aging and Alzheimer's disease. In vivo rodent gene expression experiments revealed that Atase2 is specifically induced following activity-dependent events. Finally, over-expression of either ATase1 or ATase2 was sufficient to increase the engagement of the secretory pathway in PC12 cells. Our results indicate important regulatory roles for ATase1 and ATase2 in neuron function with induction of ATase2 expression potentially serving as a critical event that adjusts the efficiency of the secretory pathway for activity-dependent neuronal functions.

Acceptability of Using a Robotic Nursing Assistant in Health Care Environments: Experimental Pilot Study.

BACKGROUND: According to the US Bureau of Labor Statistics, nurses will be the largest labor pool in the United States by 2022, and more than 1.1 million nursing positions have to be filled by then in order to avoid a nursing shortage. In addition, the incidence rate of musculoskeletal disorders in nurses is above average in comparison with other occupations. Robot-assisted health care has the potential to alleviate the nursing shortage by automating mundane and routine nursing tasks. Furthermore, robots in health care environments may assist with safe patient mobility and handling and may thereby reduce the likelihood of musculoskeletal disorders. OBJECTIVE: This pilot study investigates the perceived ease of use and perceived usefulness (acceptability) of a customized service robot as determined by nursing students (as proxies for nursing staff in health care environments). This service robot, referred to as the Adaptive Robotic Nurse Assistant (ARNA), was developed to enhance the productivity of nurses through cooperation during physical tasks (eg, patient walking, item fetching, object delivery) as well as nonphysical tasks (eg, patient observation and feedback). This pilot study evaluated the acceptability of ARNA to provide ambulatory assistance to patients. METHODS: We conducted a trial with 24 participants to collect data and address the following research question: Is the use of ARNA as an ambulatory assistive device for patients acceptable to nurses? The experiments were conducted in a simulated hospital environment. Nursing students (as proxies for nursing staff) were grouped in dyads, with one participant serving as a nurse and the other acting as a patient. Two questionnaires were developed and administrated to the participants based on the Technology Acceptance Model with respect to the two subscales of perceived usefulness and perceived ease of use metrics. In order to evaluate the internal consistency/reliability of the questionnaires, we calculated Cronbach alpha coefficients. Furthermore, statistical analyses were conducted to evaluate the relation of each variable in the questionnaires with the overall perceived usefulness and perceived ease of use metrics. RESULTS: Both Cronbach alpha values were acceptably high (.93 and .82 for perceived usefulness and perceived ease of use questionnaires, respectively), indicating high internal consistency of the questionnaires. The correlation between the variables and the overall perceived usefulness and perceived ease of use metrics was moderate. The average perceived usefulness and perceived ease of use metrics among the participants were 4.13 and 5.42, respectively, out of possible score of 7, indicating a higher-than-average acceptability of this service robot. CONCLUSIONS: The results served to identify factors that could affect nurses' acceptance of ARNA and aspects needing improvement (eg, flexibility, ease of operation, and autonomy level).

Rigor and reproducibility in rodent behavioral research.

Behavioral neuroscience research incorporates the identical high level of meticulous methodologies and exacting attention to detail as all other scientific disciplines. To achieve maximal rigor and reproducibility of findings, well-trained investigators employ a variety of established best practices. Here we explicate some of the requirements for rigorous experimental design and accurate data analysis in conducting mouse and rat behavioral tests. Novel object recognition is used as an example of a cognitive assay which has been conducted successfully with a range of methods, all based on common principles of appropriate procedures, controls, and statistics. Directors of Rodent Core facilities within Intellectual and Developmental Disabilities Research Centers contribute key aspects of their own novel object recognition protocols, offering insights into essential similarities and less-critical differences. Literature cited in this review article will lead the interested reader to source papers that provide step-by-step protocols which illustrate optimized methods for many standard rodent behavioral assays. Adhering to best practices in behavioral neuroscience will enhance the value of animal models for the multiple goals of understanding biological mechanisms, evaluating consequences of genetic mutations, and discovering efficacious therapeutics.

An investigation of mental imagery in bipolar disorder: Exploring "the mind's eye".

OBJECTIVES: Mental imagery abnormalities occur across psychopathologies and are hypothesized to drive emotional difficulties in bipolar disorder (BD). A comprehensive assessment of mental imagery in BD is lacking. We aimed to test whether (i) mental imagery abnormalities (abnormalities in cognitive stages and subjective domains) occur in BD relative to non-clinical controls; and (ii) to determine the specificity of any abnormalities in BD relative to depression and anxiety disorders. METHODS: Participants included 54 subjects in the BD group (depressed/euthymic; n=27 in each subgroup), subjects with unipolar depression (n=26), subjects with anxiety disorders (n=25), and non-clinical controls (n=27) matched for age, gender, ethnicity, education, and premorbid IQ. Experimental tasks assessed cognitive (non-emotional) measures of mental imagery (cognitive stages). Questionnaires, experimental tasks, and a phenomenological interview assessed subjective domains including spontaneous imagery use, interpretation bias, and emotional mental imagery. RESULTS: (i) Compared to non-clinical controls, the BD combined group reported a greater impact of intrusive prospective imagery in daily life, more vivid and "real" negative images (prospective imagery task), and higher self-involvement (picture-word task). The BD combined group showed no clear abnormalities in cognitive stages of mental imagery. (ii) When depressed individuals with BD were compared to the depressed or anxious clinical control groups, no significant differences remained-across all groups, imagery differences were associated with affective lability and anxiety. CONCLUSIONS: Compared to non-clinical controls, BD is characterized by abnormalities in aspects of emotional mental imagery within the context of otherwise normal cognitive aspects. When matched for depression and anxiety, these abnormalities are not specific to BD-rather, imagery may reflect a transdiagnostic marker of emotional psychopathology.

Deficient import of acetyl-CoA into the ER lumen causes neurodegeneration and propensity to infections, inflammation, and cancer.

The import of acetyl-CoA into the ER lumen by AT-1/SLC33A1 is essential for the N(ε)-lysine acetylation of ER-resident and ER-transiting proteins. A point-mutation (S113R) in AT-1 has been associated with a familial form of spastic paraplegia. Here, we report that AT-1S113R is unable to form homodimers in the ER membrane and is devoid of acetyl-CoA transport activity. The reduced influx of acetyl-CoA into the ER lumen results in reduced acetylation of ER proteins and an aberrant form of autophagy. Mice homozygous for the mutation display early developmental arrest. In contrast, heterozygous animals develop to full term, but display neurodegeneration and propensity to infections, inflammation, and cancer. The immune and cancer phenotypes are contingent on the presence of pathogens in the colony, whereas the nervous system phenotype is not. In conclusion, our results reveal a previously unknown aspect of acetyl-CoA metabolism that affects the immune and nervous systems and the risk for malignancies.

Policy design for territorial equity in multi-level and multi-sectoral political systems: Comparing health and education strategies.

The EU has many plans to foster equity and spatial justice. However, each has separate reference points, and it is difficult to find an overall vision. To demonstrate, we analyse two sectoral strategies to identify their implications for spatial justice strategies. Education focuses on early investment and public service reform. Health prioritises intersectoral action to address the 'social determinants' beyond the control of health services. Both warn against equating territorial cohesion or spatial justice with equal access to public services. These findings could inform European Commission strategy, but it tends to respond with renewed rhetoric rather than reconsidering its approach.

La UE tiene muchos planes para fomentar la equidad y la justicia espacial. Sin embargo, cada uno tiene puntos de referencia distintos, y es difícil encontrar una visión global. Para demostrarlo, este estudio analizó dos estrategias sectoriales para identificar sus implicaciones en las estrategias de justicia espacial. La educación se centra en la inversión temprana y la reforma de los servicios públicos. La salud prioriza las acciones intersectoriales para abordar los 'determinantes sociales' más allá del control de los servicios sanitarios. Ambos sectores advierten del peligro de equiparar la cohesión territorial o la justicia espacial con la igualdad de acceso a los servicios públicos. Estos hallazgos podrían informar la estrategia de la Comisión Europea, pero ésta tiende a responder con una retórica renovada en lugar de reconsiderar su enfoque.

The future of public health policymaking after COVID-19: a qualitative systematic review of lessons from Health in All Policies.

Background: 'Health in All Policies' (HiAP) describes the pursuit of health equity. It has five main elements: treat health as a human right; identify evidence of the 'social determinants' of health inequalities, recognise that most powers to affect health are not held by health departments, promote intersectoral policymaking and collaboration inside and outside of government, and generate political will. Studies describe its potential but bemoan a major implementation gap. Some HiAP scholars learn from policymaking research how to understand this gap, but the use of policy theories is patchy. In that context, our guiding research question is: How does HiAP research use policy theory to understand policymaking? It allows us to zoom-out to survey the field and zoom-in to identify: the assumed and actual causes of policy change, and transferable lessons to HiAP scholars and advocates. Methods: Our qualitative systematic review (two phases, 2018 and 2020) identified 4972 HiAP articles. Of these, 113 journal articles (research and commentary) provide a non-trivial reference to policymaking (at least one reference to a policymaking concept). We use the 113 articles to produce a general HiAP narrative and explore how the relatively theory-informed articles enhance it. Results: Most articles focus on policy analysis (identifying policy problems and solutions) rather than policy theory (explaining policymaking dynamics). They report a disappointing gap between HiAP expectations and policy outcomes. Theory-informed articles contribute to a HiAP playbook to close that gap or a programme theory to design and evaluate HiAP in new ways.   Conclusions: Few HiAP articles use policy theories for their intended purpose. Policy theories provide lessons to aid critical reflection on power, political dilemmas, and policymaking context. HiAP scholars seek more instrumental lessons, potentially at the cost of effective advocacy and research.

Peer Review of Paediatric Endocrine Services in the UK: A Template for Quality and Service Improvement.

BACKGROUND: Independent peer review of healthcare services can complement existing internal-, institutional-, and national-level regulatory mechanisms aimed at improving quality of healthcare. However, this has not been reported for paediatric endocrinology services in the UK. We aimed to test feasibility and acceptability through a first cycle of a national peer review of paediatric endocrine services. METHODS: Tertiary centres in paediatric endocrinology across the UK were assessed against 54 quality standards, developed by the British Society for Paediatric Endocrinology and Diabetes (BSPED) in five domains of healthcare by a team comprising paediatric endocrinologists and specialist nurses. The evaluation was supported by a self-assessment. A post-peer-review questionnaire was used as feedback. RESULTS: All 22 centres in the UK underwent independent peer review between 2011 and 2017. Each served a median population of 2.6 million (range 1-8 million) and offered 1,872 (range 779-6,738) outpatient consultations annually. A total of 43 (range 30-49) standards were met in combined evaluation of all centres. Variance of adherence for essential standards ranged from 52 to 97% at individual centres with 90% adherence demonstrated by 32% of centres. Post-review feedback showed 20/22 (95%) validating the utility of the peer review. CONCLUSIONS: The BSPED peer review of all UK centres providing paediatric endocrine services is shown to be feasible and provides a quality benchmark for replication by national services.

Intelligence in offspring born to women exposed to intimate partner violence: a population-based cohort study.

Background: Intimate partner violence (IPV) is a risk factor for developmental problems in offspring. Despite a high prevalence of IPV in the UK and elsewhere, the longer-term outcomes of offspring born to exposed mothers remain under-researched. Methods: Population-based cohort study. We assessed IPV prevalence by type and timing for 3,153 mother-child pairs with complete data within our study population and examined associations between IPV and offspring IQ. We used multiple-imputation to evaluate bias due to our exclusion of observations with missing covariate data. Results: Nearly one in five mothers reported IPV during the study period, with 17.6% reporting emotional violence and 6.8% reporting physical violence. Taking into account potential confounders, the IQ scores of children born to mothers exposed to physical violence remained lower than those of maternally unexposed children (full-scale IQ = -2.8 points [95%CI -4.9 to -0.7], verbal IQ = -2.2 [95%CI -4.4 to -0.1], performance IQ = -2.7 [95%CI  -5.0 to -0.5]) and odds of below-average intelligence (IQ<90) remained increased for full-scale (OR 1.48 [95%CI 1.03 to 2.14] and performance IQ (OR 1.48 [95%CI 1.08 to 2.04]) but not verbal IQ (OR 1.06 [95%CI 0.69 to 1.64]). Most physical violence occurred postnatally, and relative odds were most substantial when mothers were exposed to violence across pre-/perinatal and postnatal study periods (OR performance IQ<90 = 2.97 [95%CI 1.30 to 6.82]). Conclusions: Maternal exposure to physical IPV is associated with lower offspring IQ at age 8. Associations persisted after adjusting for potential confounders and were driven by violence occurring postnatally.

Acceptability and feasibility pilot randomised controlled trial of medical skin camouflage for recovery of women prisoners with self-harm scarring (COVER): the study protocol.

INTRODUCTION: Self-harm in prison is a major public health concern. Less than 5% of UK prisoners are women, but they carry out more than a fifth of prison self-harm. Scars resulting from self-harm can be traumatising and stigmatising, yet there has been little focus on recovery of women prisoners with self-harm scarring. Medical skin camouflage (MSC) clinics treat individuals with disfiguring skin conditions, with evidence of improved well-being, self-esteem and social interactions. Only one community study has piloted the use of MSC for self-harm scarring. METHODS AND ANALYSIS: We describe an acceptability and feasibility pilot randomised controlled trial; the first to examine MSC for women prisoners who self-harm. We aim to randomise 20-25 women prisoners to a 6-week MSC intervention and 20-25 to a waitlist control (to receive the MSC after the study period). We aim to train at least 6-10 long-term prisoners with personal experience of self-harm to deliver the intervention. Before and after intervention, we will pilot collection of women-centred outcomes, including quality of life, well-being and self-esteem. We will pilot collection of self-harm incidents during the intervention, resources used to manage/treat self-harm and follow-up of women at 12 weeks from baseline. Data on recruitment, retention and dropout will be recorded. We aim for the acceptability of the intervention to prison staff and women prisoners to be explored in qualitative interviews and focus groups. ETHICS AND DISSEMINATION: Ethical approval for COVER has been granted by the North East-York Research Ethics Committee (REC) for phases 1 and 2 (reference: 16/NE/0030) and West of Scotland REC 3 for phases 3 and 4 (reference: 16/WS/0155). Informed consent will be the primary consideration; it will be made clear that participation will have no effect on life in prison or eligibility for parole. Due to the nature of the study, disclosures of serious self-harm may need to be reported to prison officials. We aim for findings to be disseminated via events at the study prison, presentations at national/international conferences, journal publications, prison governor meetings and university/National Health Service trust communications. TRIAL REGISTRATION NUMBER: NCT02638974; Pre-results.

Noradrenergic Transmission at Alpha1-Adrenergic Receptors in the Ventral Periaqueductal Gray Modulates Arousal.

BACKGROUND: Dysregulation of arousal is symptomatic of numerous psychiatric disorders. Previous research has shown that the activity of dopamine (DA) neurons in the ventral periaqueductal gray (vPAG) tracks with arousal state, and lesions of vPAGDA cells increase sleep. However, the circuitry controlling these wake-promoting DA neurons is unknown. METHODS: This study combined designer receptors exclusively activated by designer drugs (DREADDs), behavioral pharmacology, electrophysiology, and immunoelectron microscopy in male and female mice to elucidate mechanisms in the vPAG that promote arousal. RESULTS: Activation of locus coeruleus projections to the vPAG or vPAGDA neurons induced by DREADDs promoted arousal. Similarly, agonist stimulation of vPAG alpha1-adrenergic receptors (α1ARs) increased latency to fall asleep, whereas α1AR blockade had the opposite effect. α1AR stimulation drove vPAGDA activity in a glutamate-dependent, action potential-independent manner. Compared with other dopaminergic brain regions, α1ARs were enriched on astrocytes in the vPAG, and mimicking α1AR transmission specifically in vPAG astrocytes via Gq-DREADDS was sufficient to increase arousal. In general, the wake-promoting effects observed were not accompanied by hyperactivity. CONCLUSIONS: These experiments revealed that vPAG α1ARs increase arousal, promote glutamatergic input onto vPAGDA neurons, and are abundantly expressed on astrocytes. Activation of locus coeruleus inputs, vPAG astrocytes, or vPAGDA neurons increase sleep latency but do not produce hyperactivity. Together, these results support an arousal circuit whereby noradrenergic transmission at astrocytic α1ARs activates wake-promoting vPAGDA neurons via glutamate transmission.

Behavioral responses of dopamine beta-hydroxylase knockout mice to modafinil suggest a dual noradrenergic-dopaminergic mechanism of action.

Modafinil is approved for use in the treatment of excessive daytime sleepiness. The precise mechanism of modafinil action has not been elucidated, although both dopamine (DA) and norepinephrine (NE) systems have been implicated. To explore the roles of DA and NE in the mechanism of modafinil-induced arousal, dopamine beta-hydroxylase knockout (Dbh -/-) mice were examined in behavioral paradigms of arousal (photobeam breaks and behavioral scoring of sleep latency). Dbh -/- mice completely lack NE but have hypersensitive DA signaling. It was hypothesized that Dbh -/- mice would be unresponsive to modafinil if the compound acts primarily via NE, but would be hypersensitive to modafinil if it acts primarily via DA. Dbh -/- mice had increased sensitivity to the locomotor-activating and wake-promoting effects of modafinil. Paradoxically, the alpha1-adrenergic receptor antagonist, prazosin, attenuated the effects of modafinil in control mice, but not in Dbh -/- mice. Blockade of DA receptors with flupenthixol decreased modafinil-induced locomotion and wake in both control and Dbh -/- mice. These results suggest that both NE and DA are involved in the behavioral effects of modafinil in control mice, but the requirement for NE can be bypassed by hypersensitive DA signaling.

Antithrombotic activity of TNF-alpha.

Basic and clinical observations suggest that thrombosis and inflammation are closely related. Here we addressed the role played by TNF-alpha in thrombus formation and growth in an in vivo mouse model. Using intravital microscopy, we show that systemic administration of TNF-alpha at doses found in sepsis transiently inhibits thrombus formation and delays arterial occlusion upon vascular injury. These results were reflected in a prolonged bleeding time. Platelets isolated from the TNF-alpha-treated mice showed a marked decrease in fibrinogen binding and P-selectin expression as well as reduced platelet aggregation in response to various agonists. In contrast, in vitro treatment of platelets with TNF-alpha did not affect their function. TNF receptor 1- and 2-deficient mice exhibited normal thrombogenesis in the presence of TNF-alpha. Additionally, the inhibitory effect of TNF-alpha was lost either after treatment with NG-monomethyl-l-arginine, an inhibitor of NO production, or in mice deficient for iNOS. These results indicate that under inflammatory conditions, when leukocytes need free passage to transmigrate into tissues, TNF-alpha decreases platelet activation and inhibits thrombi formation. This effect is not exerted directly on platelets but mediated through the rapid generation of NO in the vessel wall.

Multicentre validation of a microRNA-based assay for diagnosing indeterminate thyroid nodules utilising fine needle aspirate smears.

AIMS: The distinction between benign and malignant thyroid nodules has important therapeutic implications. Our objective was to develop an assay that could classify indeterminate thyroid nodules as benign or suspicious, using routinely prepared fine needle aspirate (FNA) cytology smears. METHODS: A training set of 375 FNA smears was used to develop the microRNA-based assay, which was validated using a blinded, multicentre, retrospective cohort of 201 smears. Final diagnosis of the validation samples was determined based on corresponding surgical specimens, reviewed by the contributing institute pathologist and two independent pathologists. Validation samples were from adult patients (≥18 years) with nodule size >0.5 cm, and a final diagnosis confirmed by at least one of the two blinded, independent pathologists. The developed assay, RosettaGX Reveal, differentiates benign from malignant thyroid nodules, using quantitative RT-PCR. RESULTS: Test performance on the 189 samples that passed quality control: negative predictive value: 91% (95% CI 84% to 96%); sensitivity: 85% (CI 74% to 93%); specificity: 72% (CI 63% to 79%). Performance for cases in which all three reviewing pathologists were in agreement regarding the final diagnosis (n=150): negative predictive value: 99% (CI 94% to 100%); sensitivity: 98% (CI 87% to 100%); specificity: 78% (CI 69% to 85%). CONCLUSIONS: A novel assay utilising microRNA expression in cytology smears was developed. The assay distinguishes benign from malignant thyroid nodules using a single FNA stained smear, and does not require fresh tissue or special collection and shipment conditions. This assay offers a valuable tool for the preoperative classification of thyroid samples with indeterminate cytology.

The effects of norepinephrine transporter inactivation on locomotor activity in mice.

BACKGROUND: Acute administration of different classes of antidepressants can enhance or reduce spontaneous locomotor activity in a novel environment, but the effects of chronic antidepressant treatment on spontaneous locomotor activity in novel and familiar environments are less well characterized. Because norepinephrine is an important regulator of spontaneous locomotor activity, we speculated that norepinephrine transporter blockade contributes to the effects of some antidepressants on spontaneous locomotor activity. METHODS: Antidepressant drugs (reboxetine, desipramine, imipramine, venlafaxine, bupropion) were administered acutely (intraperitoneal) or chronically (via osmotic minipump) to control and norepinephrine transporter knockout mice, and spontaneous locomotor activity in novel or familiar environments was recorded. RESULTS: Acute treatment with most norepinephrine transporter-blocking antidepressants decreased spontaneous locomotor activity in a novel environment, whereas chronic treatment decreased spontaneous locomotor activity in both novel and familiar environments. The exception was bupropion, a dual norepinephrine transporter/dopamine transporter blocker, which tended to increase spontaneous locomotor activity. Coadministration of reboxetine and the dopamine transporter blocker GBR 12909 also increased spontaneous locomotor activity. Norepinephrine transporter knockout mice had low basal spontaneous locomotor activity, which was increased by bupropion, whereas reboxetine had no effect in norepinephrine transporter knockout mice. CONCLUSIONS: Acute or chronic inactivation of the norepinephrine transporter decreases spontaneous locomotor activity in novel and familiar environments unless coupled with dopamine transporter blockade.

The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice.

Epilepsy and depression are comorbid disorders, but the mechanisms underlying their relationship have not been identified. Traditionally, many antidepressants have been thought to increase seizure incidence, although this remains controversial, and it is unclear which medications should be used to treat individuals suffering from both epilepsy and depression. Since the neurotransmitter norepinephrine (NE) has both antidepressant and anticonvulsant properties, we speculated that NE transporter (NET) inhibitor antidepressants might be therapeutic candidates for comorbid individuals. To test this idea, we assessed the effects of chronic administration (via osmotic minipump) of the selective NET inhibitor reboxetine on flurothyl-induced seizures in mice. We found that reboxetine had both proconvulsant and anticonvulsant properties; it lowered both seizure threshold and maximal seizure severity. NET knockout (NET KO) mice essentially phenocopied the effects of reboxetine on flurothyl-induced seizures, and the trends were extended to pentylenetetrazole and maximal electroshock seizures (MES). Furthermore, reboxetine had no further effect in NET KO mice, demonstrating the specificity of reboxetine for the NET. We next tested the chronic and acute effects of other classes of antidepressants (desipramine, imipramine, sertraline, bupropion, and venlafaxine) on seizure susceptibility. Only venlafaxine was devoid of proconvulsant activity, and retained some anticonvulsant activity. These results suggest that chronic antidepressant drug treatment has both proconvulsant and anticonvulsant effects, and that venlafaxine is a good candidate for the treatment of epilepsy and depression comorbidity.