There is also a series of neurological or psychiatric disorders i

There is also a series of neurological or psychiatric disorders in which biological clocks are dysfunctional. Table III. Chronobiology and the frontier of disorders. Diagnosing chronobiological changes From a clinical point of view, there are several uncertainties when diagnosing changes in chronobiology. First, a defect

in the biological clock might not manifest Survivin inhibitor supplier itself by recurring Inhibitors,research,lifescience,medical clinical manifestations that have irregular cycles. Second, a disorder that does not a priori imply biological clock dysfunctions might nevertheless manifest itself in regular cycles. This is the case of many disorders that show premenstrual exacerbations. Third, and more importantly, most psychiatric disorders seem to have composite mechanisms, and chronobiological mechanisms might be associated with other pathophysiological changes. Fourth, a precise and repeated measurement of symptoms is needed Inhibitors,research,lifescience,medical in order to evaluate a periodic exacerbation of a syndrome.

Free-running circadian rhythms The term “free-running” refers to situations where the circadian rhythm differs from 24 hours and is not entrained to astronomical time. The most frequent cases of free-running in everyday conditions have been described in blind people.80 Free-running in healthy subjects A small number of physically and mentally healthy Inhibitors,research,lifescience,medical subjects have been described who had a free-running circadian Inhibitors,research,lifescience,medical rhythm. Wirz-Justice81 described the 9-month sleep log of a healthy student who occasionally had very long rest-activity cycles, with no deleterious consequences. Yet, persons with a non-24-hour sleep-wake syndrome can present clinical manifestations when they attempt, as most

do, to force their activity/rest Inhibitors,research,lifescience,medical cycle to the astronomical 24hour cycle, as was illustrated in the case of a 43-year-old man who complained of recurring days, every 4 weeks, of disabling fatigue and sleep difficulties. He was instructed to live with no time constraints (albeit with the knowledge of time and under the influence of light) for 8 weeks and his circadian rhythm took on a period of 25.8 hours, with the disappearance of the episodes of fatigue.82 Free-running, personality, and psychiatric disorders In a study in 110 subjects isolated from time cues during a month, about 1 in 5 subjects showed the phenomenon of Internal desynchronization, where the period of the temperature Edoxaban rhythm deviates from that of rest-activity, for example a rest-activity period of 19 hours and a temperature period of 24.4 hours In 1 subject, or of respectively 33.2 and 24.9 In another. When It occurred, this desynchronization generally persisted for several days. Subjects with such desynchronization had higher scores of neurotlclsm (P<0.001) and of bodily preoccupations (P<0.05).83 Overall, free-running seems to occur more frequently in neurological or psychiatric patients.

26 With regard to transgenic rats, the observation that gene tran

26 With regard to transgenic rats, the observation that gene transfers were performed after development only had transient consequences on 5-HTT and 5-HT reuptake underlines the limits of that particular model.33 Finally, autoradiographic experiments conducted with the rat sublines differing for platelet 5-HTT protein expression and function suggest that these two sublines may not differ with regard Inhibitors,research,lifescience,medical to central 5-HTT protein expression.34 Detection of strain differences in 5-HTT: behavioral response Taking into account these observations, we performed two scries of experiments.

The first series of experiments took advantage of the finding that WKY do not respond acutely to the tricyclics imipramine Inhibitors,research,lifescience,medical and desipramine when examined in the forced swimming test. Thus, one hypothesis

could be that 5-HTT and/or NA transporters are hyposensitive to the 5-HT reuptake (imipramine) and NA reuptake (imipramine and desipramine) inhibitory properties of these antidepressants. Accordingly, we used in vitro, in vivo, and ex vivo methods to examine the 5-HTT in WKY, SHR, and LEW35 Acute administration of the SSRI citalopram (1-10 mg/kg, IP 1 h before an elevated plus-maze test) to SHR, LEW, and WKY promoted anxiety and/or hypoactivity in SHR Inhibitors,research,lifescience,medical and LEW, but not in WKY. This initially reinforced the hypothesis that WKY 5-HTTs are hyposensitive to drugs endowed with 5-HT reuptake properties.

Inhibitors,research,lifescience,medical However, the pretreatment with citalopram increased central 5-HT levels and/or decreased 5-HIAA levels in all strains. Hippocampal, but not midbrain or striatal, [3H]citalopram binding at 5-HTTs was lower in WKY than in SHR, whereas the [3H]5-HT reuptake kinetics and the potencies of citalopram (1-1000 nM) needed to inhibit [3H]5-HT reuptake into hippocampal and striatal Inhibitors,research,lifescience,medical synaptosomes did not differ between strains. This was confirmed in vivo by means of microdialysis in the hippocampus of freely moving rats. Thus, although LEW displayed a three- to fourfold higher baseline level of extracellular 5-HT in the hippocampus, compared with SHR and WKY, local perfusion with 1 μM citalopram promoted relative increases first in extracellular 5-HT levels over baseline that were similar in all strains. Acute IP administration of 3.3 mg/kg citalopram (1 h beforehand) decreased [3H]5-HT reuptake into hippocampal synaptosomes to a similar extent in SHR and WKY, check details thereby indicating that the systemic administration of the SSRI has strain-independent effects at hippocampal 5-HT nerve terminals. This study thus failed to detect strain differences in the 5-HTT or in its sensitivity to an SSRI, further indicating that genetic differences in the behavioral responses to SSRIs may involve 5-HTT-independent mechanisms.

88-91 Although human studies are missing, subthalamic nucleus DBS

88-91 Although human studies are missing, subthalamic nucleus DBS in animals has demonstrated significant neuroprotective and neuroplastic properties. Thus, the initiation of DBS earlier in the course of PD has been suggested.92 This is assumed to provide added neuroprotective benefits in addition to symptomatic relief. Currently, several studies are under way exploring the neuroprotective Inhibitors,research,lifescience,medical potential of early DBS in PD (ClinicalTrials.gov identifier: NCT00282152, NCT01274832, NCT00354133). Results from these studies will be important for the discussion of an early intervention in other diseases, for example in depression. Overall, deep brain

stimulation has contributed to a novel view of depression — away from a synaptocentric view to a conceptualization of dysfunctional brain networks for the processing of emotions.93 It has become evident that several neuropsychiatric disorders might be associated with network dysfunctions.94 Initial

studies have demonstrated a positive effect Inhibitors,research,lifescience,medical of DBS on neuroplasticity and neuroprotection. Future studies are required to explore long-term effects of DBS on neuroneogenesis and neuroprotection. Aging and dementia AD is the most common neurodegenerative disease featuring progressive impairments in memory, cognition, Inhibitors,research,lifescience,medical and behaviour, and half of the cases of dementia are caused by AD. The neurodegenerative hallmarks of AD include the accumulation amyloid-β, the deposition of amyloid plaques and the formation of neurofibrillary tangles.95 Similar to the monoamine theory on depression, the cholinergic hypothesis of dementia was proposed in 1982 by Bartus et al who believed that Inhibitors,research,lifescience,medical functional disturbances in cholinergic activity occurred in the brains of healthy older adults and demented patients.96,97

This hypothesis has been supported by positive effects of cholinesterase inhibitors on cognition in patients suffering from AD.98 Although much clinical development research Inhibitors,research,lifescience,medical on cholinergic agents has followed, the clinical effects are limited99 and no therapeutic strategy for AD has demonstrated Resveratrol long-term efficacy to date.100 Thus, new concepts and therapeutic approaches are required. The role of inflammation (eg, cytokines) and SB216763 telomerase activity, which leads to neuronal degeneration94,98 have also been suggested in the neurogenesis theory of depression. These factors lead to a dysregulation of brain networks.99 It is unclear whether amyloid-β itself by its ability to alter synaptic (glutamatergic) transmission and to impair the induction of long-term potentiation.99 A disruption of the connectivity of memory networks have been observable in early AD and asymptomatic individuals with high amyloid burden.100 Novel concepts of aging and dementia as a dysfunction of neuronal networks led to the application of deep brain stimulation in patients suffering from AD.

While most studies in the past focused on technical aspects of CP

While most studies in the past focused on technical aspects of CPR, recently the importance of non-technical factors such as teamwork, communication and leadership have been recognized [3-8]. Several studies have demonstrated that CPR causes significant mental stress in rescuers [9-15], and

health care workers often feel unprepared to manage stress and conflicts in a cardiac arrest situation [16-18]. This is important because the stress Inhibitors,research,lifescience,medical experienced in an emergency situation may impair performance. In line with that, we recently found that feeling stressed and overwhelmed while delivering CPR was associated with worse CPR performance [14]. Hence, stress reducing measures may improve performance in critical situations. To reduce stress, the focus on attentional processes may be a promising venue. Stress can have two opposite effects on attention. First, stress narrows attention Inhibitors,research,lifescience,medical [19].

For tasks that are relatively easy, narrowing attention can lead to improved performance by supporting a focus on the task [20]. However, narrowing of attention entails the danger of not noticing potentially Inhibitors,research,lifescience,medical important information, a phenomenon known as “tunnel vision” [21]. Furthermore, it is also related to premature closure, which is characterized by making decisions based on insufficient consideration of information available [22]. The second mechanism refers to an BAY 87-2243 chemical structure impaired ability to suppress irrelevant information, increased distractibility, ultimately leading to misjudgements Inhibitors,research,lifescience,medical of priorities [23-25]. A related mechanism refers to non-systematic scanning of informational cues [22]. However, information that

distracts from task priorities may not only stem from external events but may also be generated internally, for instance Inhibitors,research,lifescience,medical by worrying about one’s own performance (intrusive thoughts) [26]. Such intrusive thoughts may be increased by noticing that one’s performance is not optimal [27], thus possibly leading to a vicious circle. The response to acute stress is highly Adenylyl cyclase dependent on the individual’s perception of demands and resources [10,28], and on stress reactivity [29]. Therefore, stress management training may reduce stress [30]. Indeed, stress management training has had positive effects not only on stress indicators but also on performance [31,32]. However, although such procedures have been implemented in medical settings, they typically have not been evaluated in terms of medical performance [33]. Based on positive results achieved in other performance settings [15,32,34], and based on our recent finding that a brief leadership instruction improves CPR performance [5,35] we hypothesized that a brief task-focusing strategy may reduce stress and improve CPR performance.

These trials

demonstrated tumor specificity and adequate

These trials

demonstrated tumor specificity and adequate agent distribution with adverse effects similarly limited to target tissue damage and minimal to no systemic toxicity. These trials were limited, however, by the specificity of the delivered agents, which targeted only a subpopulation of tumor cells. Prior to our clinical trial, paclitaxel was the only conventional chemotherapeutic agent delivered via CED in a Inhibitors,research,lifescience,medical clinical trial [15]. This was mainly because paclitaxel does not cross the BBB, thus allowing the investigators to demonstrate that DW-MRI could be used to approximate the volume of distribution of CED. The trial resulted in a large incidence (40%) of chemical meningitis, a major drawback to the choice of paclitaxel [15, 16]. Though these studies highlighted initial challenges in the application of CED, they demonstrated the importance of careful and rational selection of agents for use in this method of delivery. 3. Early Experiences: CED of Integrase inhibitor Topotecan Our initial experience with

CED Inhibitors,research,lifescience,medical of antitumor agents utilized the cytotoxic agent topotecan. Topotecan is a camptothecin-class drug and acts as a topoisomerase-I inhibitor. It causes single-strand DNA breaks during DNA replication [17, 18]. This drug was selected after we demonstrated in vitro cytotoxicity Inhibitors,research,lifescience,medical against various malignant glioma cell lines [19]. Due to its activity in cells in the S-phase of division, topotecan is ideal for the treatment of mitotically active glioma cells

in the setting of relatively quiescent brain tissue. Previous experience with topotecan demonstrated poor penetration of the blood-brain barrier and significant dose-limiting toxicities, limiting systemic administration [20–23]. However, these same properties make it an ideal drug for administration Inhibitors,research,lifescience,medical via CED. In addition, an important aspect of the choice of topotecan was its effect on a vital Inhibitors,research,lifescience,medical cellular process, namely, the role of topoisomerase I on DNA processes. This focus on conventional chemotherapeutic agents as opposed to targeted therapies allows for greater coverage of heterogeneous glioma subpopulations. While targeted therapies can be successful in eliminating a specific subpopulation of PDK4 glioma cells that express a certain antigen, this provides a selective advantage for remaining neoplastic cells. Preclinical testing of topotecan that was performed in a model of glioblastoma was developed using a PDGF-B expressing retrovirus injected stereotactically into the adult white matter of rats to infect glial progenitors [19]. This resulted in the consistent development of tumors that closely resembled glioblastoma, with pseudopalisading necrosis, invasion, glomeruloid vascular proliferation, and survival of 14–19 days [24]. Topotecan was delivered using an implantable osmotic pump connected to an intracerebral infusion cannula (Alzet; Cupertino, CA) that was implanted into the tumor.

17,18 Fludeoxyglucose (FDG)-positron emission tomography (PET) sc

17,18 Fludeoxyglucose (FDG)-positron emission tomography (PET) scans, where blood flow and glucose utilization over different brain regions can be measured, may also provide useful information as to disease progression over time.19 Further, methods are improving to image amyloid plaques in

living patients using PET ligands that bind Aβ.20 These methods have been used to measure significant changes in amyloid deposition in patients with MCI.21 The most promising of these neuroimaging techniques and biochemical readouts could in time be used together as surrogate markers to provide an accurate assessment of disease state over time within Inhibitors,research,lifescience,medical an individual or across a population. There is a risk, however, of focusing too heavily on surrogate markers. In studies of rosiglitizone for diabetes, negative outcomes on disease appeared despite expected positive effects on the surrogate.22 Cholesterol has long been used as a surrogate for heart disease; however, in clinical Inhibitors,research,lifescience,medical trials of high-density lipoprotein-modifying drugs (such as torceptrabib) for prevention of heart disease, a positive effect on the surrogate was seen even though clinical outcomes were Inhibitors,research,lifescience,medical worsened.23 As in AD, these other chronic degenerative diseases have complex, multifactorial causes that are not necessarily reflected in the surrogate marker. Therefore, while using surrogate markers can be quite a meaningful

method to monitor aspects of disease progression, it is crucial to keep in mind the limitations of this approach. Understanding genetic risk factors for AD is another

method to facilitate early detection of high-risk individuals, while also providing insight into disease mechanisms. The discovery Inhibitors,research,lifescience,medical of genes underlying risk for AD has provided us with many of our most promising drug targets. Individuals with the apolipoprotein E4 allele (ApoE4), for example, have a significantly greater risk Inhibitors,research,lifescience,medical of developing Alzheimer’s disease, and often exhibit an earlier age of onset and a more aggressive form of the disease.24’1 While ApoE4 is a known risk factor for AD, we still do not fully understand its mechanism of function in AD pathogenesis. Identifying genetic subtypes of AD could allow for the buy G007-LK development of more individualized therapies, as well as aid in clinical trial design for novel drug therapies. In fact, in the Phase II trial for Bapineuzumab, a monoclonal Annual Review of Biochemistry antibody to β-amyloid developed by Wyeth and Elan, ApoE4 carriers were separated from noncarriers in the analysis. Only noncarriers demonstrated a significant benefit from the treatment, which would not have been detected had the population been analyzed as a whole.25 It is our hope that in the near future early detection techniques, such as measurements of Aβ load, neuroimaging analysis, and/or genetic testing will function much like cholesterol testing does for heart disease.

Both preclinical studies25 and clinical studies suggest that a mo

Both preclinical studies25 and clinical studies suggest that a more fine-grained multidimensional approach to impulsivity may be warranted and that nonplanning impulsivity may be a key ingredient of BPD. Aggression One of the more common impulsive behaviors evidenced by people with BPD are expressions of anger or reactive aggression. Thus, the kind of anger that is observed in BPD Inhibitors,research,lifescience,medical patients is an impulsive type of aggression, but the aggressive components may be analyzed by somewhat different measures than the impulsive components. For example, psychometric measures designed to measure aggression include the Buss-Perry Aggression Questionnaire (BPAQ),26 as well as measures

of life history of overt aggressive behaviors (life history of aggression [LHA]). Both measures have well-established psychometric properties and heritability has been established in twin studies using the Buss Durkee Hostility Interview (BDHI),27 a precursor of the BPAQ. Preliminary data also suggest that life history of aggression may be heritable. Laboratory Inhibitors,research,lifescience,medical paradigms that assess aggression behaviorally are available, including the Point Subtraction Aggression Paradigm (PSAP).28 In the PSAP, an experimental subject is instructed to accumulate “points” that can be exchanged for money and is told that they are playing in conjunction with a “confederate subject,” while in reality responses are generated by Inhibitors,research,lifescience,medical computer. Aggressive

responses are often retaliatory to provocations from the “confederate” and do not net the subject of the study HCS assay actual “points,” but may be initiated as an aggressive response to the perceived aggression of the confederate. Inhibitors,research,lifescience,medical The PSAP has been externally validated in violent and nonviolent male parolees and responses to this laboratory test have been correlated with other psychometric measures of aggression.29 The heritability of this laboratory measure has not been definitively established, but is being systematically assessed

in studies of twins Inhibitors,research,lifescience,medical (Coccaro et al, personal communication). Another laboratory test for evaluating the propensity for aggression in response to provocation is the Taylor Aggression Paradigm,30 in which aggressive responses to mild electric shocks are administered to the subject, ostensibly by a fictitious opponent. Aggressive behavior is evaluated as a function of the shock intensities administered by the subject Nature Reviews Cancer to this fictitious opponent. This paradigm has been used extensively in the evaluation of alcoholinduced aggression31 and has been applied to studies of reactive aggression in BPD (Coccaro et al, personal communication). Aggressive responding in the PSAP paradigm is a stable trait that can distinguish between aggressive and nonaggressive subjects, but, for both of these measures, the precise prevalence in specific personality disorders, such as BPD, and the degree of genetic influence on the PSAP has not been determined.

2003) While the

2003). While the olfactory systems and olfactory learning abilities of several species of slugs and Gamma-secretase activity snails have been extensively studied (Chase 1981, 1985; Chase and Tolloczko 1993; Gelperin 1994; Gervais et al. 1996; Sahley and Crow 1998; Balaban 2002), almost nothing is known about the anatomy and physiology of mucus trail chemosensation. This study identifies connections between Inhibitors,research,lifescience,medical the lip extensions that mediate mucus trail detection and the cerebral ganglia, and demonstrates that mucus stimuli detected by the lip extensions

are processed in the same central ganglia and in the same manner as odor molecules detected by the olfactory system. Our anatomical and tract-tracing experiments show that in the Euglandina, the nerve from the inferior tentacle joins with the nerve from the lip extension, and the combined nerve connects to the procerebral Inhibitors,research,lifescience,medical lobe where neurons from the lip extension synapse in the cell body layer. While a large swelling at the point where the lip extension nerve and oral tentacle nerve comes together suggests a ganglion, it is Inhibitors,research,lifescience,medical unlikely that afferent nerves from the sensory epithelium terminate at this point as nickel-lysine and Lucifer yellow taken up by the distal ends of lip extension nerve are transported past this point to the cerebral ganglion. Our results

suggest that the connectivity and processing of input from the lip extension may have arisen in the Euglandina as an elaboration of the neural processing dedicated to the oral tentacle in other snails and slugs. This hypothesis is supported by our observation Inhibitors,research,lifescience,medical that in Euglandina, the lip extension nerve and oral tentacle nerve join, and the joined nerve Inhibitors,research,lifescience,medical enters the cerebral ganglion in the mid-lateral area where the oral tentacle enters in other land snails. In the Euglandina, backfilling

the lip extension nerve produces extensive labeling of the procerebrum appearing to cover the entire procerebrum, and resembles the results of backfilling of the Cantareus olfactory nerve more than the Cantareus oral tentacle nerve backfilling. Labeling of the Euglandina olfactory nerve produces labeling of the procerebrum that looks substantially the same as the labeling produced by backfilling the lip extension nerve. In addition to the similarity Liothyronine Sodium between the anatomical labeling, the neuronal activity of the Euglandina procerebrum is similar to neuronal activity recorded from the procerebra of other land snails. The activity is characterized by a widespread oscillation in local field potential with a frequency of 0.1–0.3 Hz, and stimulation with odorants changes the frequency and amplitude of the oscillations (Chase 1981; Gelperin and Tank 1990; Kimura et al. 1993; Delaney et al. 1994; Ermentrout et al. 1998).

The clinical research sites were multidisciplinary outpatient cli

The clinical research sites were multidisciplinary outpatient clinics that offer brain health assessment and treatment services (such as EEG testing) for any medical condition. Expert clinicians at each site completed diagnostic interviews and were

blinded to the results of the BRISC and other self-report assessments. Recruitment This retrospective study recruited participants through advertising and self-referral. Inclusion criteria were in regard to the capacity to undergo a computerized test: reading at Year 5 level (equivalent to Year 6 in England and fifth grade in the United States), Inhibitors,research,lifescience,medical normal (or corrected to normal) vision, and ability to use a keyboard. The protocol received unlike independent ethics committee Inhibitors,research,lifescience,medical or institutional review board approval before recruitment of participants. All participants signed and dated an approved informed consent form. Where participants consented, these data have also been made available for open sharing and secondary analysis by the research community (Gordon et al. 2005, 2008). All research is in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Main measures The assessment of behavioral health status At the testing site, participants Inhibitors,research,lifescience,medical first completed a computer battery of detailed

questions to provide an independent determination of behavioral health status. This assessment comprised established items to assess current or lifetime psychiatric and neurological conditions (Table 1). Stepwise stratification logic was used to determine “clinical” versus “healthy” behavioral health according to the criteria summarized in Figure Inhibitors,research,lifescience,medical 1. Figure 1 Summary of the criteria for independent classification of “good” versus “poor” brain health status. Table 1 Summary items Inhibitors,research,lifescience,medical used in the independent assessment of clinical versus healthy status The BRISC After the assessment of behavioral

health status, yet in the same testing session, participants completed the 45-question BRISC (Appendix 1) via computer, which took about 10 min to complete. The results provided one score for risk (negativity bias) and Batimastat two scores for coping (emotional resilience and social skills; Rowe et al. 2007; Williams et al. 2008). As indicated in Appendix 1, the 15-question mini version of the BRISC is made up of the five highest-loading BRISC items for each of the core content domains: negativity bias, emotional resilience, and social skills. Responses to each BRISC question were made on a scale of 1–5, with 5 representing higher functioning (less risk, better coping). We summed the responses for negativity bias, for emotional resilience, and for social skills (raw scores are shown in Appendix 2 for the 45-question BRISC and Appendix 3 for the mini-BRISC).

11 The development of AF in the absence of traditional risk facto

11 The development of AF in the absence of traditional risk factors, referred to as lone AF, suggested a potential role for genetics as a mediator of disease. Indeed, a family with lone AF transmitted with an autosomal dominant pattern of inheritance was first documented by Wolff in 1943.12 Epidemiological studies have found that individuals who have a first-degree AZD8055 solubility dmso relative with lone AF carry a 7- to 8-fold increased risk.13 Even more dramatic, the presence of an affected sibling was associated with a 70- and 34-fold increased risk in males and females, respectively.14 Inhibitors,research,lifescience,medical Although more pronounced in the context of

lone AF, the form of the arrhythmia associated with structural Inhibitors,research,lifescience,medical heart disease has also been shown to have a heritable component. A prospective cohort analysis from the Framingham Heart Study involving 2,243 subjects found that parental

AF conferred a 1.85-fold increased risk in offspring.15 A similar study from Iceland involving 5,269 patients corroborated the latter result, identifying a 1.77-fold increased risk of developing AF in first-degree relatives.16 This greater vulnerability is not attenuated by adjustment for traditional risk factors linked to the arrhythmia, suggesting that the heightened risk is secondary to an underlying genetic etiology.17 Collectively, these findings provide convincing epidemiological evidence Inhibitors,research,lifescience,medical to suggest that genetics play Inhibitors,research,lifescience,medical a critical role in the development of both

lone and structural AF. Mechanistic Subtype of AF 1: Gain-of-Function Potassium Channels and Enhanced Atrial Action Potential Repolarization The first causative gene responsible for familial AF was found in 2003. The culprit locus on this occasion was mapped to the short arm of chromosome 11 (11p15.5) in a four-generation Chinese family with an autosomal dominant pattern of inheritance for lone AF.18 Chromosome 11p15.5 was noted to contain the KCNQ1 gene, which encodes the poreforming α subunit of the slow component Inhibitors,research,lifescience,medical of the delayed rectifier potassium current (IKs). Loss-of-function mutations within KCNQ1 had previously been recognized as the cause for long QT syndrome type 1, a cardiac channelopathy associated with malignant ventricular arrhythmias and sudden cardiac death.19 Given its biological plausibility based on its established link with a cardiac arrhythmic http://www.selleckchem.com/products/yo-01027.html disorder, KCNQ1 was considered an ideal candidate gene. Sequencing of KCNQ1 identified a Ser140Gly mutation that segregated with AF cases within the family. Following identification of the putative culprit mutation, in vitro functional studies using COS-7 cells found that coexpression of mutant Ser140Gly KCNQ1 with KCNE1, the β subunit of IKs, resulted in markedly increased current density relative to the wild-type gene. These findings suggested that the Ser140Gly mutation resulted in a gain of function leading to increased IKs.