Prevalence and drug use correlates of inadvertent fentanyl exposure among individuals misusing drugs in seven U.S. states.

Fentanyl has emerged as the leading cause of fatal drug overdoses in the U.S. Individuals misusing drugs may not always be aware of exposure to fentanyl.To determine the prevalence of fentanyl use and extent of awareness of fentanyl exposure among a national sample of treatment-seeking individuals with opioid use disorder (n = 1098).Participants provided oral fluid and urine specimens, which were tested for drugs by liquid chromatography/tandem mass spectrometry. Participants also provided self-reports of fentanyl use.49.5% tested positive for fentanyl in oral fluid, urine, or both. Of those testing positive for fentanyl, 29.8% were unaware that they had been exposed to fentanyl. Participants testing positive for opioids methadone, and specifically 6-monoacetylmorphine (6-MAM), a unique metabolite of heroin, were significantly more likely to be unaware of fentanyl exposure than participants testing negative for these substances, with a similar trend for oxycodone and tramadol.These findings may be due to fentanyl's effect being difficult to distinguish from that of other opioids, whereas when other types of drugs are adulterated with fentanyl, the differences in effects are likely to be readily discernable. These results support the importance of expanded drug-checking services.

The enduring impact of neurulation stage alcohol exposure: A combined behavioral and structural neuroimaging study in adult male and female C57BL/6J mice.

Prenatal alcohol exposure (PAE) can cause behavioral and brain alterations over the lifespan. In animal models, these effects can occur following PAE confined to critical developmental periods, equivalent to the third and fourth weeks of human gestation, before pregnancy is usually recognized. The current study focuses on PAE during early neurulation and examines the behavioral and brain structural consequences that appear in adulthood. On gestational day 8 C57BL/6J dams received two alcohol (2.8g/kg, i.p), or vehicle, administrations, four hours apart. Male and female offspring were reared to adulthood and examined for performance on the elevated plus maze, rotarod, open field, Morris water maze, acoustic startle, social preference (i.e. three-chambered social approach test), and the hot plate. A subset of these mice was later evaluated using magnetic resonance imaging to detect changes in regional brain volumes and shapes. In males, PAE increased exploratory behaviors on the elevated plus maze and in the open field; these changes were associated with increased fractional anisotropy in the anterior commissure. In females, PAE reduced social preference and the startle response, and decreased cerebral cortex and brain stem volumes. Vehicle-treated females had larger pituitaries than did vehicle-treated males, but PAE attenuated this sex difference. In males, pituitary size correlated with open field activity, while in females, pituitary size correlated with social activity. These findings indicate that early neurulation PAE causes sex specific behavioral and brain changes in adulthood. Changes in the pituitary suggest that this structure is especially vulnerable to neurulation stage PAE.

Human SLFN5 is a transcriptional co-repressor of STAT1-mediated interferon responses and promotes the malignant phenotype in glioblastoma.

We provide evidence that the IFN-regulated member of the Schlafen (SLFN) family of proteins, SLFN5, promotes the malignant phenotype in glioblastoma multiforme (GBM). Our studies indicate that SLFN5 expression promotes motility and invasiveness of GBM cells, and that high levels of SLFN5 expression correlate with high-grade gliomas and shorter overall survival in patients suffering from GBM. In efforts to uncover the mechanism by which SLFN5 promotes GBM tumorigenesis, we found that this protein is a transcriptional co-repressor of STAT1. Type-I IFN treatment triggers the interaction of STAT1 with SLFN5, and the resulting complex negatively controls STAT1-mediated gene transcription via interferon stimulated response elements. Thus, SLFN5 is both an IFN-stimulated response gene and a repressor of IFN-gene transcription, suggesting the existence of a negative-feedback regulatory loop that may account for suppression of antitumor immune responses in glioblastoma.

Acute alcohol exposure during neurulation: Behavioral and brain structural consequences in adolescent C57BL/6J mice.

Prenatal alcohol exposure (PAE) can induce physical malformations and behavioral abnormalities that depend in part on thedevelopmental timing of alcohol exposure. The current studies employed a mouse FASD model to characterize the long-term behavioral and brain structural consequences of a binge-like alcohol exposure during neurulation; a first-trimester stage when women are typically unaware that they are pregnant. Time-mated C57BL/6J female mice were administered two alcohol doses (2.8g/kg, four hours apart) or vehicle starting at gestational day 8.0. Male and female adolescent offspring (postnatal day 28-45) were then examined for motor activity (open field and elevated plus maze), coordination (rotarod), spatial learning and memory (Morris water maze), sensory motor gating (acoustic startle and prepulse inhibition), sociability (three-chambered social test), and nociceptive responses (hot plate). Regional brain volumes and shapes were determined using magnetic resonance imaging. In males, PAE increased activity on the elevated plus maze and reduced social novelty preference, while in females PAE increased exploratory behavior in the open field and transiently impaired rotarod performance. In both males and females, PAE modestly impaired Morris water maze performance and decreased the latency to respond on the hot plate. There were no brain volume differences; however, significant shape differences were found in the cerebellum, hypothalamus, striatum, and corpus callosum. These results demonstrate that alcohol exposure during neurulation can have functional consequences into adolescence, even in the absence of significant brain regional volumetric changes. However, PAE-induced regional shape changes provide evidence for persistent brain alterations and suggest alternative clinical diagnostic markers.

LAPCs contribute to the pathogenesis of allergen-induced allergic airway inflammation in mice.

BACKGROUND: The inflammatory immune response associated with allergic airway inflammation in asthma involves T helper type 2 (Th2) immunity. Given the data that a newly described late activator antigen-presenting cell (LAPC) population promotes Th2 immunity in viral infections, we undertook studies to investigate whether LAPCs have a pathogenic role in allergic airway inflammation. METHODS: We employed acute ovalbumin (OVA) and house dust mite (HDM) sensitization and challenge models to establish allergic airway inflammation in mice, followed by the analysis of lungs and draining lymph node (DLN) cell infiltrates, immunoglobulin E (IgE) production, and airway hyper-responsiveness (AHR). We tested whether adoptive transfer of LAPCs isolated from mice with established allergic airway inflammation augments the development of sensitization in naïve mice. RESULTS: We provide evidence that in both OVA and HDM mouse models of allergic inflammation, LAPCs accumulate in the lungs and draining lymph nodes (DLNs), concomitant with the onset of lung pathology, allergen-specific IgE production, eosinophilia, and Th2 cytokine production. Adoptive transfer experiments using OVA-activated LAPCs reveal exacerbation of disease pathology with an increase in lung inflammatory cells, eosinophilia, circulating IgE, Th2 cytokine production, and a worsening of AHR. OVA-activated LAPCs preferentially increased GATA-3 induction in naïve CD4(+) T cells. CONCLUSIONS: Together, these data suggest an important role for LAPCs in polarizing the Th2 response in mouse models of allergic airway inflammation.

Beta interferon regulation of glucose metabolism is PI3K/Akt dependent and important for antiviral activity against coxsackievirus B3.

UNLABELLED: An effective type I interferon (IFN)-mediated immune response requires the rapid expression of antiviral proteins that are necessary to inhibit viral replication and virus spread. We provide evidence that IFN-ß regulates metabolic events important for the induction of a rapid antiviral response: IFN-ß decreases the phosphorylation of AMP-activated protein kinase (AMPK), coincident with an increase in intracellular ATP. Our studies reveal a biphasic IFN-ß-inducible uptake of glucose by cells, mediated by phosphatidylinositol 3-kinase (PI3K)/Akt, and IFN-ß-inducible regulation of GLUT4 translocation to the cell surface. Additionally, we provide evidence that IFN-ß-regulated glycolytic metabolism is important for the acute induction of an antiviral response during infection with coxsackievirus B3 (CVB3). Last, we demonstrate that the antidiabetic drug metformin enhances the antiviral potency of IFN-ß against CVB3 both in vitro and in vivo. Taken together, these findings highlight an important role for IFN-ß in modulating glucose metabolism during a virus infection and suggest that the use of metformin in combination with IFN-ß during acute virus infection may result in enhanced antiviral responses. IMPORTANCE: Type I interferons (IFN) are critical effectors of an antiviral response. These studies describe for the first time a role for IFN-ß in regulating metabolism--glucose uptake and ATP production--to meet the energy requirements of a robust cellular antiviral response. Our data suggest that IFN-ß regulates glucose metabolism mediated by signaling effectors similarly to activation by insulin. Interference with IFN-ß-inducible glucose metabolism diminishes the antiviral response, whereas treatment with metformin, a drug that increases insulin sensitivity, enhances the antiviral potency of IFN-ß.

SeXX matters in immunity.

The significant contributions of sex to an immune response, specifically in the context of the sex bias observed in susceptibility to infectious and autoimmune diseases and their pathogenesis, have until recently, largely been ignored and understudied. This review highlights recent findings related to sex-specific factors that provide new insights into how sex determines the transcriptome, the microbiome, and the consequent immune cell functional profile to define an immune response. Unquestionably, accumulating data confirm that sex matters and must be a consideration when decisions around therapeutic intervention strategies are developed.

Infralimbic and dorsal raphé microinjection of the 5-HT(1B) receptor agonist CP-93,129: attenuation of aggressive behavior in CFW male mice.

RATIONALE: Aggressive behavior and impaired impulse control have been associated with dysregulations in the serotonergic system and with impaired functioning of the prefrontal cortex. 5-HT(1B) receptors have been shown to specifically modulate several types of offensive aggression. OBJECTIVE: This study aims to characterize the relative importance of two populations of 5-HT(1B) receptors in the dorsal raphé nucleus (DRN) and infralimbic cortex (ILC) in the modulation of aggressive behavior. METHODS: Male CFW mice were conditioned on a fixed-ratio 5 schedule of reinforcement to self-administer a 6% (w/v) alcohol solution. Mice repeatedly engaged in 5-min aggressive confrontations until aggressive behavior stabilized. Next, a cannula was implanted into either the DRN or the ILC. After recovery, mice were tested for aggression after self-administration of either 1.0 g/kg alcohol or water prior to a microinjection of the 5-HT(1B) agonist, CP-93,129 (0-1.0 µg/infusion). RESULTS: In both the DRN and ILC, CP-93,129 reduced aggressive behaviors after both water and alcohol self-administration. Intra-raphé CP-93,129 dose-dependently reduced both aggressive and locomotor behaviors. However, the anti-aggressive effects of intra-cortical CP-93,129 were behaviorally specific. CONCLUSIONS: These findings highlight the importance of the serotonergic system in the modulation of aggression and suggest that the behaviorally specific effects of 5-HT(1B) receptor agonists are regionally selective. 5-HT(1B) receptors in a medial subregion of the prefrontal cortex, the ILC, appear to be critically involved in the attenuation of species-typical levels of aggression.

Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism.

RATIONALE: The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists. OBJECTIVE: This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method. METHODS: Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline. RESULTS: Morphine dose-dependently decreased θ(0) (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ(0) or MAX. CONCLUSIONS: The decrease in θ(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids.

Using real-time alerts for clinical trials: Identifying potential study subjects.

BACKGROUND: Clinical trials are widely accepted as a necessary step in evaluating the safety and efficacy of new pharmaceutical products. In order for a sufficiently powered study, a clinical trial depends on the effective and unbiased recruitment of eligible patients. Trials involving seasonal diseases like influenza pose additional challenges. OBJECTIVE: This is a feasibility study of a mobile real-time alerting system to systematically identify potential study subjects for a randomized controlled trial evaluating the safety and efficacy of early intervention with interferon alfacon-1 for patients hospitalized for influenza virus infection. METHODS: The alerting system was setup in a 471-bed acute care teaching hospital, enabled with computerized physician order entry (CPOE) and a rules-based alerting system. Patients were identified from the entire hospital using two alerts types: pharmacy prescription records for antiviral drugs, and positive influenza laboratory results. Email alerts were generated and sent to BlackBerry(®) devices carried by the study personnel for a 6 month period. The alerts were archived automatically on a secure server and were exported for analysis in Microsoft Access. RESULTS: Over a period of 21 weeks, 779 total alerts were received. The study team was alerted to 241 patients, of whom 85 were potential study subjects. The alert system identified all but one of the patients independently identified by infection control. CONCLUSIONS: Real-time identification of potential study subjects is possible with the integration of computerized physician order entry and BlackBerry(®) technology. It is a viable method for the systematic identification of patients throughout a hospital, particularly for trials investigating time-sensitive disease progression.

Interferon-beta is a key regulator of proinflammatory events in experimental autoimmune encephalomyelitis.

BACKGROUND: Interferon (IFN)-ß is an effective therapy for relapsing-remitting multiple sclerosis, yet its mechanism of action remains ill-defined. OBJECTIVES: Our objective was to characterize the role of IFN-ß in immune regulation in experimental autoimmune encephalomyelitis (EAE). METHODS: IFN-ß(+/+) and IFN-ß(-/-) mice were immunized with myelin oligodendrocyte glycoprotein peptide in the presence or absence of IFN-ß, to induce EAE. Disease pathogenesis was monitored in the context of incidence, time of onset, clinical score, and immune cell activation in the brains, spleens and lymph nodes of affected mice. RESULTS: Compared with IFN-ß(+/+) mice, IFN-ß(-/-) mice exhibited an earlier onset and a more rapid progression of EAE, increased numbers of CD11b(+) leukocytes infiltrating affected brains and an increased percentage of Th17 cells in the central nervous system and draining lymph nodes. IFN-ß treatment delayed disease onset and reduced disease severity. Ex vivo experiments revealed that the lack of IFN-ß results in enhanced generation of autoreactive T cells, a likely consequence of the absence of IFN-ß-regulated events in both the CD4(+) T cells and antigen-presenting dendritic cells. Gene expression analysis of IFN-ß-treated bone marrow macrophages (CD11b(+)) identified modulation of genes affecting T cell proliferation and Th17 differentiation. CONCLUSIONS: We conclude that IFN-ß acts to suppress the generation of autoimmune-inducing Th17 cells during the development of disease as well as modulating pro-inflammatory mediators.

Tetanus as a cause of rhabdomyolysis and acute renal failure.

Acute renal failure developed in an elderly woman with a rapidly progressive illness characterized by nuchal rigidity, limb spasm, repetitive grunting vocalizations without intelligible speech, and risus sardonicus. Eventually she developed characteristic findings of increased tone in her masseter muscles (trismus) and rigid upper and lower extremities, consistent with generalized tetanus. Increasing serum creatinine was temporally associated with rising creatine phosphokinase (CPK) and striking elevations of plasma myoglobin. The patient had marked lability of blood pressure and pulse. She improved briefly after tetanus toxoid and broad-spectrum antibiotics, but died of heart failure after 9 days of hospitalization. A necrotic pelvic tumor was believed to be the source of infection. Tetanus is a preventable disease, which has not been eradicated, even in Western populations. Full-blown tetanus has a high fatality rate, and should be considered in the differential diagnosis of acute renal failure in the setting of rising CPK and continued release of muscle myoglobin.

Antiviral strategies: the present and beyond.

Historically, vaccine strategies have proven to be most effective at eradicating the targeted virus infections. With the advent of new or re-emerging altered viruses, some of which jump species to infect humans, the threat of viral pandemics exists. The protracted time to develop a vaccine during a pandemic necessitates using antiviral drugs in the intervening months prior to vaccine availability. Antiviral drugs that are pathogen specific, for example Amantidine, Tamiflu and Relenza, targeted against influenza viruses, are associated with the emergence of virus strains that are drug resistant. The use of ribavirin, a more broad spectrum antiviral, in combination therapies directed against influenza and hepatitis C virus, has proven effective, albeit to a modest extent. Attention is focused on the potential use of interferons (IFN)-alpha/beta as broad spectrum antivirals in acute infections, to invoke both direct antiviral effects against viruses and activation of specific immune effector cells.

Distinctive gene expression signatures in rheumatoid arthritis synovial tissue fibroblast cells: correlates with disease activity.

Gene expression profiling of rheumatoid arthritis (RA) and osteoarthritis (OA) joint tissue samples provides a unique insight into the gene signatures involved in disease development and progression. Fibroblast-like synovial (FLS) cells were obtained from RA, OA and control trauma joint tissues (non-RA, non-OA) and RNA was analyzed by Affymetrix microarray. Thirty-four genes specific to RA and OA FLS cells were identified (P<0.05). HOXD10, HOXD11, HOXD13, CCL8 and LIM homeobox 2 were highly and exclusively expressed in RA and CLU, sarcoglycan-gamma, GPR64, POU3F3, peroxisome proliferative activated receptor-gamma and tripartite motif-containing 2 were expressed only in OA. The data also revealed expression heterogeneity for patients with the same disease. To address disease heterogeneity in RA FLS cells, we examined the effects of clinical disease parameters (Health Assessment Questionnaire (HAQ) score, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF)) and drug therapies (methotrexate/prednisone) on RA FLS cell gene expression. Eight specific and unique correlations were identified: human leukocyte antigen (HLA)-DQA2 with HAQ score; Clec12A with RF; MAB21L2, SIAT7E, HAPLN1 and BAIAP2L1 with CRP level; RGMB and OSAP with ESR. Signature RA FLS cell gene expression profiles may provide insights into disease pathogenesis and have utility in diagnosis, prognosis and drug responsiveness.

Synergy between paclitaxel plus an exogenous methyl donor in the suppression of murine demyelinating diseases.

Progressive demyelination in multiple sclerosis (MS) reflects the negative balance between myelin damage and repair due to physical and molecular barriers, such as astrocytic glial scars, between oligodendrocytes and target neurons. In this paper, we show that combination therapy with paclitaxel (Taxol) plus the universal methyl-donor, vitamin B12CN (B12CN), dramatically limits progressive demyelination, and enhances remyelination in several independent, immune and nonimmune, in vivo and in vitro model systems. Combination therapy significantly reduced clinical signs of EAE in SJL mice, as well as the spontaneously demyelinating ND4 transgenic mouse. Astrocytosis was normalised in parallel to ultrastructural and biochemical evidence of remyelination. The combination therapy suppressed T cell expansion, reduced IFN-gamma, while enhancing IFN-beta and STAT-1 expression, STAT-1 phosphorylation and methylation of STAT-1 and MBP in the brain. Paclitaxel/B12CN has nearly identical effects to the previously described combination of IFN-beta/ B12CN, whose clinical usefulness is transient because of IFN-neutralising antibodies, not observed (or expected) with the present drug combination. This report provides a mechanistic foundation for the development of a new therapeutic strategy in humans with MS.

Interferons and viruses: signaling for supremacy.

Interferon (IFN)-alpha and IFN-beta are critical mediators of host defense against microbial challenges, directly interfering with viral infection and influencing both the innate and adaptive immune responses. IFNs exert their effects in target cells through the activation of a cell-surface receptor, leading to a cascade of signaling events that determine transcriptional and translation regulation. Understanding the circuitry associated with IFN-mediated signal transduction that leads to a specific biological outcome has been a major focus of our laboratory. Through the efforts of graduate students, postdoctoral fellows, a skilled research technologist, and important collaborations with investigators elsewhere, we have provided some insights into the complexity of the IFN system-and the elegance and simplicity of how protein-protein interactions define biological function.

Ocular photodynamic therapy with verteporfin for choroidal neovascularization secondary to ocular histoplasmosis syndrome.

PURPOSE: To evaluate the use of ocular photodynamic therapy (OPT) with verteporfin in patients with choroidal neovascularization (CNV) from ocular histoplasmosis syndrome (OHS) and to compare these results with those for a natural history group. METHODS: A retrospective chart review was performed to identify cases of CNV secondary to OHS treated with OPT. Complete data were available for 38 of 41 eligible eyes. Data regarding the following variables were abstracted from the patient charts: demographic characteristics, previous surgery, angiographic features, number and timing of treatments with OPT, follow-up time, and visual acuity. The visual acuity results of eyes receiving photodynamic therapy were compared with those for a natural history cohort. RESULTS: On average, OHS patients who received treatment developed 0.88 line of visual improvement. Visual acuity improved or stayed the same in 69% (22 of 32) of eyes, improved by > or = 2 lines in 44% (14 of 32), and improved by > or = 4 lines in 22% (7 of 32). Patients who received OPT were 2.07 times more likely to have improved or constant vision than were those in the natural history group as described in one retrospective series (odds ratio = 2.07; 95% confidence interval, 0.78-5.56; P = 0.162). Thirty-eight percent (12 of 32) of eyes had undergone submacular surgery for CNV before any OPT. CONCLUSIONS: Ocular photodynamic therapy with verteporfin may be beneficial in patients with CNV secondary to OHS, even in the setting of previous submacular surgery.

Survival from primary breast cancer after routine clinical use of mammography.

Clinical trials indicate that mammography provides a substantial breast cancer survival benefit; however, there is a need to demonstrate that this benefit extends to clinical practice and to determine the extent that current reductions in mortality are attributable to regular screening or adjuvant systemic therapy. Mammography was used routinely at our institution across a broad age range, in an era when most patients received no adjuvant systemic therapy. We examined breast cancer survival for a cohort of 678 stage I-III primary invasive breast cancer patients accrued from 1971 to 1990, and followed to 1996; 18% received adjuvant hormonal therapy and 15% received adjuvant chemotherapy. There were 61 women less than 40 years old; 136, 40-49 years; 341, 50-69 years; 140, > or =70 years. Factors available for multivariate investigations were age (years), tumor size (cm), nodal status (N-, Nx, N+), ER (fmol/mg protein), PgR (fmol/mg protein), adjuvant radiotherapy (no, yes), adjuvant hormonal therapy (no, yes), and adjuvant chemotherapy (no, yes). Forward stepwise multivariate regression with log-normal survival analysis was used to examine the effects of these factors on disease-specific survival. Ten-year survival by tumor size was adjusted for the effects of other significant factors. For women less than 40 years of age, 10-year survival at the T1a, T1b, T1c, and T2 cut-points for tumor size is, respectively, 0.77, 0.74, 0.67, 0.44; for 40-49 years it is 0.92, 0.90, 0.85, 0.62; for 50-69 years it is 0.81, 0.79, 0.75, 0.62; for > or =70 years it is 0.84, 0.81, 0.73, 0.44. With routine use of clinical mammography and up to 26 years of follow-up, we found breast cancer survival to be significantly better (p< or = 0.05) for all women with smaller tumors and that survival indicated a change in natural disease history with early detection. The Canadian National Breast Screening Study (NBSS) controls had significantly smaller tumors (p < 0.001) than our patients, which may indicate access to mammography outside of the NBSS that reduced the apparent survival benefit for clinical trial mammography.

Aggressive behavioral phenotypes in mice.

Aggressive behavior in male and female mice occurs in conflicts with intruding rivals, most often for the purpose of suppressing the reproductive success of the opponent. The behavioral repertoire of fighting is composed of intricately sequenced bursts of species-typical elements, with the resident displaying offensive and the intruder defensive acts and postures. The probability of occurrence as well as the frequency, duration, temporal and sequential patterns of aggressive behavior can be quantified with ethological methods. Classic selection and strain comparisons show the heritability of aggressive behavior, and point to the influence of several genes, including some of them on the Y chromosome. However, genetic effects on aggressive behavior critically depend upon the background strain, maternal environment and the intruder. These factors are equally important in determining changes in aggressive behavior in mice with a specific gene deletion. While changes in aggression characterize mutant mice involving a variety of genes, no pattern has emerged that links particular gene products (i.e. enzyme, peptide, receptor) to either an increase or a decrease in aggressive behavior, but rather emphasizes polygenic influences. A potentially common mechanism may be some components of the serotonin system, since alterations in 5-HT neurotransmission have been found in several of the KO mice that display unusual aggressive behavior.