Epileptic Targets and Drugs: A Mini-Review.

BACKGROUND: Epilepsy is a neurological disease affected by an imbalance of inhibitory and excitatory signaling in the brain. INTRODUCTION: In this disease, the targets are active in pathophysiology and thus can be used as a focus for pharmacological treatment. METHODS: Several studies demonstrated the antiepileptic effect of drugs acting on the following targets: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, voltage-gated calcium channel (Cav), Gamma aminobutyric acid transporter type 1 (GAT1), voltage-gated sodium channels (Nav), voltage-gated potassium channel of the Q subfamily (KCNQ) and Gamma aminobutyric acid type A (GABAA) receiver. RESULTS: These studies highlight the importance of molecular docking. CONCLUSION: Quantitative Structure-Activity Relationship (QSAR) and computer aided drug design (CADD) in predicting of possible pharmacological activities of these targets.

Are Psychiatry Programs Providing Adequate Parental Leave to Their Residents?

OBJECTIVE: During residency training, parental leave is frequently briefer than may be optimal for the well-being of the family. The Accreditation Council for Graduate Medical Education (ACGME) requires residency programs to have a parental leave policy without providing specific guidelines on its makeup, resulting in varying policies and confusion among residents planning parental leave. This study identifies differences in parental leave policies in psychiatry residencies and discusses if these policies are adequate. METHODS: A 45-question, anonymous survey was emailed to general psychiatry and fellowship program directors in the USA. RESULTS: Out of 520 program directors contacted, 186 completed the survey (35.7% response rate). Among the respondents, 94.1% had policies for maternity leave, 79.8% had policies for paternity leave, and 67.2% had policies for non-childbearing parental leave (e.g., adoption). Variations were reported in implementation, coverage, and accommodations. Most respondents (57.1%) believed that residents would benefit from more parental leave. Some (11.5%) believed that parenthood negatively affected residents' overall performance, especially regarding patient care and clinical skills; 36.5% endorsed that parenthood negatively affected overall residents' well-being; and 7.5% felt negatively when an applicant was pregnant or was planning to become pregnant during residency. Lastly, 32.9% were not confident regarding ACGME, American Board of Psychiatry and Neurology, federal, and hospital policies. CONCLUSIONS: Parental leave policies are not universal in US psychiatry residency and fellowship programs. Some program directors feel that parenthood adversely affects residents' clinical performance as well as well-being. If true, reformation of parental leave policies may be a remedy.

Patient Characteristics and Emergency Treatment Orders in Three Florida Inpatient Psychiatric Units.

Background: Florida law defines emergency treatment orders (ETOs) as an immediate administration of psychotropic medications to a person to expeditiously treat symptoms that may present an immediate danger to the safety of the person or others.1 There is currently little information on who receives ETOs. In this study, we aim to explore correlations between patients' demographics and administering ETOs in order to understand this cohort, which could allow for improved services and alternative interventions. Methods: This retrospective study examined data from 1,460 adult patients who were admitted to an acute inpatient psychiatric unit from January 2015 to December 2017 and who received at least one ETO during their hospital admission. Results: Results revealed that younger patients (18-25 years) were at increased risk of receiving more than one ETO (p=0.039) than patients who were 26 and older. Patients with an elevated body mass index (BMI) (25 kg/m2 or more) also had a significantly increased likelihood of being administered more ETOs (≥4 ETOs) than patients with a lower BMI (defined as less than 25 kg/m2 [p=0.037]). Moreover, patients with a length of stay (LOS) of more than 14 days were more likely to receive more ETOs compared to patients with LOS less than or equal to 14 days (p<0.001). Lastly, patients with a neurocognitive disorder and/or within the schizophrenia spectrum or other psychotic disorders were more likely to receive ETOs (p<0.001) than patients with other diagnoses. Conclusion: There are some correlations in administering ETOs in that younger patients with an elevated BMI, longer LOS and certain diagnoses receive more ETOs. The reason for these findings is not clear. Therefore, prospective studies should be conducted in order to analyze these correlations.

Influence of iron-deficient diets during gestation and lactation on cerebral fatty acids and eicosanoids in guinea pig offspring-Comparison of studies with different sources of dietary lipids.

Previous studies showed that mild iron deficiency anaemia (IDA) induced by feeding an iron deficient (ID) diet to female guinea pigs during gestation and lactation to alters the auditory functions of the offspring when corn oil is the only source of dietary lipids. Conversely, feeding an ID diet with a dietary fatty acid composition similar to that of typical human western diets induced minor impairments. Since tissue fatty acid metabolism is affected by dietary iron, the current study measured the impacts of these ID diets (ID-corn and ID-west) compared to the corresponding iron-sufficient control diets (IS-corn and IS-west) on encephalum fatty acid metabolism in the offspring at post-natal day 24. IDA induced by the ID-corn diet resulted in significant increases in encephalum n-6 PUFA content, but IDA induced by the ID-west diet had little impact on fatty acid profiles compared to the IS-west group. Brain COX II protein expression and FADS2 mRNA expression were statistically unaffected in both experiments, but encephalum PGE2 concentrations were significantly reduced in ID-west pups. These results suggest IDA studies during prenatal development should consider dietary lipid compositions.

Active Essential Oils and Their Components in Use against Neglected Diseases and Arboviruses.

The term neglected diseases refers to a group of infections caused by various classes of pathogens, including protozoa, viruses, bacteria, and helminths, most often affecting impoverished populations without adequate sanitation living in close contact with infectious vectors and domestic animals. The fact that these diseases were historically not considered priorities for pharmaceutical companies made the available treatments options obsolete, precarious, outdated, and in some cases nonexistent. The use of plants for medicinal, religious, and cosmetic purposes has a history dating back to the emergence of humanity. One of the principal fractions of chemical substances found in plants are essential oils (EOs). EOs consist of a mixture of volatile and hydrophobic secondary metabolites with marked odors, composed primarily of terpenes and phenylpropanoids. They have great commercial value and were widely used in traditional medicine, by phytotherapy practitioners, and in public health services for the treatment of several conditions, including neglected diseases. In addition to the recognized cytoprotective and antioxidative activities of many of these compounds, larvicidal, insecticidal, and antiparasitic activities have been associated with the induction of oxidative stress in parasites, increasing levels of nitric oxide in the infected host, reducing parasite resistance to reactive oxygen species, and increasing lipid peroxidation, ultimately leading to serious damage to cell membranes. The hydrophobicity of these compounds also allows them to cross the membranes of parasites as well as the blood-brain barrier, collaborating in combat at the second stage of several of these infections. Based on these considerations, the aim of this review was to present an update of the potential of EOs, their fractions, and their chemical constituents, against some neglected diseases, including American and African trypanosomiasis, leishmaniasis, and arboviruses, specially dengue.

Impact of maternal iron deficiency on the auditory functions in the young and adult guinea pig.

OBJECTIVES: The aim of this study was to evaluate the hearing function in the guinea pig offspring at post-natal day (PNd) 24 and PNd84 born from dams suffering from iron deficiency during pregnancy and lactation by using the auditory brainstem response (ABR). METHOD: Female guinea pigs (n = 24 per dietary group) were fed an iron sufficient (IS) diet (114 mg/kg) or an iron deficient (ID) diet (11.7 mg/kg) during the gestation and lactation periods. Pups in both groups were weaned at PNd9 and given the IS diet. The hematocrit level was measured at every trimester of pregnancy and at the day of sacrifice in dams and at PNd24 and PNd84 in pups. The animal body weight was measured on every second day until the day of sacrifice. The ABR was used in pups to measure the hearing threshold using a broad range of stimulus intensities and latency at 100 and 80 dB in response to 2, 4, 8, 16, and 32 kHz tone pips at PNd24 and 84. RESULTS AND DISCUSSION: No significant difference between dietary groups was measured in hearing threshold and absolute latencies in pups at PNd24 and PNd84. Although the ID offspring (n = 16) did not differ in brainstem transmission times (BTTs) at 80 dB compare to the IS siblings (n = 25) at PNd24, they showed significant delayed inter-peak latency (IPL) I-IV at 100 dB suggesting a delayed BTT. At PNd84, the latency of all peaks including IPL I-IV at 80 and 100 dB significantly decreased and was also similar in pups from both dietary groups suggesting a better brain maturation. This is the first study investigating the long-term impact of maternal iron deficiency on the auditory functions in the guinea pig offspring during early development to adulthood.

Increase serum cortisol in young guinea pig offspring in response to maternal iron deficiency.

Iron deficiency (ID) has been reported as a risk factor in the pathology of attention-deficit/hyperactivity disorder, although the mechanisms seem unclear. Previous results from our research group showed that guinea pig offspring born from ID dams were significantly more active in the Open Field Test than the controls. This behavior could potentially be associated to stress. We therefore hypothesized that maternal iron deficiency (MID) elevates the offspring serum cortisol, a biomarker of stress, during childhood and possibly at mature age. Twenty-four female guinea pigs were fed an iron-sufficient (IS) diet (114 mg/kg) or ID diet (11.7 mg/kg) during the gestation and lactation. Pups in both groups were weaned at postnatal day (PNd) 9 and given an IS diet. Hematocrit and serum cortisol levels were measured in dams at every trimester of gestation and in pups at PNd24 and 84. We found no impact of MID on dam's cortisol values. However, our findings indicate that MID increased cortisol secretion in the offspring during childhood, cortisol values being significantly elevated in ID than IS pups at PNd24 (P < .05). During adulthood (PNd84), both groups showed comparable cortisol levels. The elevated cortisol secretion observed in the offspring born from ID mothers during childhood may indicate increased stress reactivity which may have contributed to the higher level of activity when tested in a novel open environment. These findings suggest that MID can potentially act as internal stressor affecting the early development conceivably leading to increased stress levels in the children.

[Pharmaceutical record's use in drugs sales service: Analysis of five months of experimentation]. / Utilisation du dossier pharmaceutique en rétrocession : analyse de 5 mois d'expérimentation.

OBJECTIVE: The pharmaceutical record integrated in the health insurance card is now exploitable by hospital pharmacists. The aim of this study is to assess the impact of pharmaceutical record's use in hospital drugs sales service and the relevance of this tool to secure the ambulatory dispensing of drugs. METHOD: All patients admitted in hospital drugs sales service between June and October 2016 were included. With the patient's consent, pharmaceutical record was created and/or consulted and implemented. When it included the city pharmacy's treatment, a pharmaceutical analysis was carried out to research drug interaction with hospital drugs sales service's treatment. If a contraindicated or not recommended association was detected, a pharmaceutical intervention was sent to the general practitioner, by secured mail. Each stage was timed. RESULTS: For the 183 included patients, 40 pharmaceutical records have been created and 74 completed. For the 69 remaining patients, pharmaceutical record could not be used. At the end of these 5 months, 86 pharmaceutical records included city pharmacy's and hospital treatments. The pharmaceutical analysis performed have shown 24 drugs interactions related to hospital treatment; seven inappropriate associations were transmitted to the general practitioner. Five minutes were required for both the use and the analysis of pharmaceutical record. CONCLUSION: Now, the pharmaceutical record is systematically used in the hospital drugs sales service, and its content is systematically analyzed. It represents one of the tool improving communication between town-hospital networks, and helps secure the ambulatory drugs dispensation.

Computational Studies Applied to Flavonoids against Alzheimer's and Parkinson's Diseases.

Neurodegenerative diseases, such as Parkinson's and Alzheimer's, are understood as occurring through genetic, cellular, and multifactor pathophysiological mechanisms. Several natural products such as flavonoids have been reported in the literature for having the capacity to cross the blood-brain barrier and slow the progression of such diseases. The present article reports on in silico enzymatic target studies and natural products as inhibitors for the treatment of Parkinson's and Alzheimer's diseases. In this study we evaluated 39 flavonoids using prediction of molecular properties and in silico docking studies, while comparing against 7 standard reference compounds: 4 for Parkinson's and 3 for Alzheimer's. Osiris analysis revealed that most of the flavonoids presented no toxicity and good absorption parameters. The Parkinson's docking results using selected flavonoids as compared to the standards with four proteins revealed similar binding energies, indicating that the compounds 8-prenylnaringenin, europinidin, epicatechin gallate, homoeriodictyol, capensinidin, and rosinidin are potential leads with the necessary pharmacological and structural properties to be drug candidates. The Alzheimer's docking results suggested that seven of the 39 flavonoids studied, being those with the best molecular docking results, presenting no toxicity risks, and having good absorption rates (8-prenylnaringenin, europinidin, epicatechin gallate, homoeriodictyol, aspalathin, butin, and norartocarpetin) for the targets analyzed, are the flavonoids which possess the most adequate pharmacological profiles.

Clinical and Molecular Features of Renal and Pheochromocytoma/Paraganglioma Tumor Association Syndrome (RAPTAS): Case Series and Literature Review.

Context: The co-occurrence of pheochromocytoma (PC) and renal tumors was linked to the inherited familial cancer syndrome von Hippel-Lindau (VHL) disease more than six decades ago. Subsequently, other shared genetic causes of predisposition to renal tumors and to PC, paraganglioma (PGL), or head and neck paraganglioma (HNPGL) have been described, but case series of non-VHL-related cases of renal tumor and pheochromocytoma/paraganglioma tumor association syndrome (RAPTAS) are rare. Objective: To determine the clinical and molecular features of non-VHL RAPTAS by literature review and characterization of a case series. Design: A review of the literature was performed and a retrospective study of referrals for investigation of genetic causes of RAPTAS. Results: Literature review revealed evidence of an association, in addition to VHL disease, between germline mutations in SDHB, SDHC, SDHD, TMEM127, and MAX genes and RAPTAS [defined here as the co-occurrence of tumors from both classes (PC/PGL/HNPGL and renal tumors) in the same individual or in first-degree relatives]. In both the literature review and our case series of 22 probands with non-VHL RAPTAS, SDHB mutations were the most frequent cause of non-VHL RAPTAS. A genetic cause was identified in 36.3% (8/22) of kindreds. Conclusion: Renal tumors and PC/PGL/HNPGL tumors share common molecular features and their co-occurrence in an individual or family should prompt genetic investigations. We report a case of MAX-associated renal cell carcinoma and confirm the role of TMEM127 mutations with renal cell carcinoma predisposition.

Patient preferences for diabetes treatment attributes and drug classes.

OBJECTIVE: To identify which treatment attributes are most influential in determining patient preferences for diabetes treatments and explore patient preferences for diabetes drug classes. RESEARCH DESIGN AND METHODS: US adults with type 1 or type 2 diabetes completed an online adaptive conjoint analysis survey. The survey examined 14 attributes, including efficacy, regimen, and risk of common side effects and rare but serious adverse events. Respondents selected between hypothetical treatments with different attributes. Sawtooth Software, ordinary least-squares regression, and hierarchical Bayes regression were used to calculate utilities (i.e. preference weights), importance ratings, and shares of preference across 13 diabetes drug classes or combination products. RESULTS: A total of 167 adults (mean age 58 years; 55% female) with type 1 or type 2 diabetes completed the survey. Based on importance ratings, the most influential attributes driving preferences were regimen, risk of diarrhea, weight change, risk of hypoglycemia, and efficacy. Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) were highly preferred in direct comparison to each of the other classes (range: 84.2-99.9%), with the exception of dipeptidyl peptidase-4 inhibitors (DPP-4is); DPP-4is (52.9%) were preferred over SGLT-2is (47.1%). CONCLUSIONS: Although preferences varied across participants, attributes with the greatest likelihood of affecting daily life and routine were generally more influential in determining patient preferences. DPP-4is and SGLT-2is were overwhelmingly preferred over other drug classes, primarily due to favorable regimen and side effect profiles. Understanding patient preferences can help optimize patient-centered treatment and may lead to improved patient satisfaction, adherence, and outcomes. LIMITATIONS: The primary limitations of this study are that a small sample size of type 1 diabetes patients were included, which may reduce the reliability of the preference estimates, and patients were recruited from a patient panel and may not be representative of patients with diabetes in the US.

Dietary LC-PUFA in iron-deficient anaemic pregnant and lactating guinea pigs induce minor defects in the offsprings' auditory brainstem responses.

OBJECTIVES: We previously demonstrated that a mild pre-natal/early post-natal iron-deficient anaemic (IDA) diet devoid of long-chain polyunsaturated fatty acids (LC-PUFA) affected development, neurophysiology, and cerebral lipid biochemistry of the guinea pigs' progeny. Impacts of dietary LC-PUFA on altered cerebral development resulting from pre-natal IDA are unknown. To address this health issue, impacts of mild gestational IDA in the presence of dietary LC-PUFA on the offsprings' neural maturation were studied in guinea pigs using auditory brainstem responses (ABRs) and assessments of brain fatty acids (FAs). METHODS: Female guinea pigs (n = 10/group) were fed an iron sufficient (IS) or IDA diet (146 and 12.7 mg iron/kg, respectively) with physiological amounts of LC-PUFA, during the gestation and lactation periods. From post-natal day (PNd) 9 onwards, the IS + PUFA diet was given to both groups of weaned offspring. Cerebral tissue and offsprings' ABR were collected on PNd24. RESULTS: There was no difference in peripheral and brainstem transmission times (BTTs) between IS + PUFA and IDA + PUFA siblings (n = 10/group); the neural synchrony was also similar in both groups. Despite the absence of differences in auditory thresholds, IDA + PUFA siblings demonstrated a sensorineural hearing loss in the extreme range of frequencies (32, 4, and 2 kHz), as well as modified brain FA profiles compared to the IS + PUFA siblings. DISCUSSION: The present study reveals that siblings born from dams exposed to a moderate IDA diet including balanced physiological LC-PUFA levels during pregnancy and lactation demonstrate minor impairments of ABR compared to the control siblings, particularly on the auditory acuity, but not on neural synchrony, auditory nerve velocity and BTT.

Prenatal Iron Deficiency in Guinea Pigs Increases Locomotor Activity but Does Not Influence Learning and Memory.

The objective of the current study was to determine whether prenatal iron deficiency induced during gestation in guinea pigs affected locomotor activity and learning and memory processes in the progeny. Dams were fed either iron-deficient anemic or iron-sufficient diets throughout gestation and lactation. After weaning, all pups were fed an iron-sufficient diet. On postnatal day 24 and 40, the pups' locomotor activity was observed within an open-field test, and from postnatal day 25 to 40, their learning and memory processes were assessed within a Morris Water Maze. The behavioural and cognitive tests revealed that the iron deficient pup group had increased locomotor activity, but solely on postnatal day 40, and that there were no group differences in the Morris Water Maze. In the general discussion, we propose that prenatal iron deficiency induces an increase in nervousness due to anxiety in the progeny, which, in the current study, resulted in an increase of locomotor activity.

Pseudomonas aeruginosa in CF and non-CF homes is found predominantly in drains.

BACKGROUND: For patients with cystic fibrosis (CF) Pseudomonas aeruginosa infection is a major contributor to progressive lung disease. While colonizing strains are thought to be primarily environmental, which environments are important in lung colonization is unclear. METHODS: We took 11,674 samples from a broad range of sites over 3-8 visits to homes with (7) and without (8) CF patients. RESULTS: Twenty-eight percent of sampled drains yielded P. aeruginosa at least once, and a general mixed linear model estimated that 6.3% of samples from drains yield P. aeruginosa. This is more than eight times the estimated recovery from any other type of household environment. CONCLUSIONS: These findings implicate drains as important potential sources of P. aeruginosa infection. They suggest that maximizing P. aeruginosa control efforts for drains would reduce exposure with minimal extra burden to CF patients and families.

Mild iron deficiency anaemia during pregnancy and lactation in guinea pigs alters amplitudes and auditory nerve velocity, but not brainstem transmission times in the offspring's auditory brainstem response.

OBJECTIVES: It is well known that postnatal/early childhood iron deficiency (ID) anaemia (IDA) adversely affects infants' cognitive development and neurophysiology. However, the effects of IDA during gestation and lactation on the offspring are largely unknown. To address this health issue, the impact of mild IDA during gestation and lactation on the offsprings' neural maturation was studied in the guinea pig, using auditory brainstem responses (ABRs) latencies and amplitudes. METHODS: Female guinea pigs (n = 10/group) were fed an iron sufficient (ISD) or deficient diet (IDD) (144 and 11.7 mg iron/kg) during the gestation and lactation periods. From postnatal day (PNd) 9 onward, the ISD was given to both groups of weaned offspring. The offsprings' ABRs were collected on PNd24 using a broad range of stimulus intensities in response to 2, 4, 8, 16, and 32 kHz tone pips. RESULTS: Although the IDA siblings (n = 8) did not differ in brainstem transmission times (BTTs) compared to the IS siblings (n = 8), they showed significant delayed peak I latency at 100 and 80 dB, respectively. Additionally, significantly higher ABR wave amplitudes were observed in the IDA female offspring between 35 and 50 dB (4 kHz), a phenomenon suggestive of a neural hyperactivity (hyperacusis). DISCUSSION: In support to our previous findings, the present results indicate that a mild IDA during gestation and lactation can have detrimental effects on early development of the offsprings' hearing and nervous systems, particularly on neural synchrony and auditory nerve conduction velocity, but not on BTT.

Does availability of informal care within the household impact hospitalisation?

This study assesses the effect of having informal support available at home on inpatient care use in Switzerland. The main contributions are to consider the availability of care regardless of its source, measured by multiple-adult living arrangements, and to examine this effect by type of inpatient care and source of potential support. A two-part model with region and time fixed effects is estimated to determine the impact of informal care availability on the likelihood of hospitalisation and length of stay, conditional on hospitalisation. The analysis is conducted on a sample of individuals aged 18+ from four waves of the Swiss Household Panel survey (2004-2007). Overall, availability of informal care has no impact on the likelihood of hospitalisation but does significantly reduce length of stay by 1.9 days. Available support has no effect on the shortest stays (up to 10 days), but has a significant impact on acute care stays up to 30 days and longer stays. Additionally, the effect does not significantly vary whether the source of informal support is a spouse only, a spouse and other adults, or other adults only. These results indicate that social changes leading to an expansion in the proportion of one-person households may increase future inpatient care use.

[Postoperative pain trajectories to identify risk of chronic postsurgical pain in living donors for liver transplantation]. / Identification du risque de douleur chronique après hépatectomie pour don de foie par les trajectoires de douleur.

OBJECTIVES: To assess pain trajectories in predicting risk of chronic postoperative pain (CPP) after liver resection for living donor transplantation. STUDY DESIGN: Retrospective analysis of patients undergoing liver resection for living donor transplantation during 3years. PATIENTS AND METHODS: After recording perioperative data, patients presenting CPP at 3months were separated from patients without postsurgical pain problem in order to build a pain trajectory for liver donor patients without CPP. Postoperative course of liver donors with CPP was then compared to that standard pain trajectory. RESULTS: Sixty-five patients (30 females, 35 males) were included. Epidural analgesia was used in 66%; others received autocontrolled analgesia by morphine. Severe acute pain was expressed by 11% and 37% at rest and movement respectively on the first day. Chronic pain involved six patients without any link with gender or type of analgesia. Analysis of pain trajectories shown that these patients presented either higher initial pain at day 1 or positive slopes with worsening of pain. CONCLUSION: Acute postoperative pain is a risk factor of developing CPP. Identification of those people by pain trajectories can be useful to treat them early.

Impaired propulsive motility in the distal but not proximal colon of BK channel ß1-subunit knockout mice.

BACKGROUND: Large-conductance Ca(2+) -activated K(+) (BK) channels regulate smooth muscle tone. The BK channel ß1-subunit increases Ca(2+) sensitivity of the α-subunit in smooth muscle. We studied ß1-subunit knockout (KO) mice to determine if gastrointestinal (GI) motility was altered. METHODS: Colonic and intestinal longitudinal muscle reactivity to bethanechol and colonic migrating motor complexes (CMMCs) were measured in vitro. Gastric emptying and small intestinal transit were measured in vivo. Colonic motility was assessed in vivo by measuring fecal output and glass bead expulsion time. Myoelectric activity of distal colon smooth muscle was measured in vitro using intracellular microelectrodes. KEY RESULTS: Bethanechol-induced contractions were larger in the distal colon of ß1-subunit KO compared to wild type (WT) mice; there were no differences in bethanechol reactivity in the duodenum, ileum, or proximal colon of WT vsß1-subunit KO mice. There were more retrogradely propagated CMMCs in the distal colon of ß1-subunit KO compared to WT mice. Gastrointestinal transit was unaffected by ß1-subunit KO. Fecal output was decreased and glass bead expulsion times were increased in ß1-subunit KO mice. Membrane potential of distal colon smooth muscle cells from ß1-subunit KO mice was depolarized with higher action potential frequency compared to WT mice. Paxilline (BK channel blocker) depolarized smooth muscle cells and increased action potential frequency in WT distal colon. CONCLUSIONS & INFERENCES: BK channels play a prominent role in smooth muscle function only in the distal colon of mice. Defects in smooth muscle BK channel function disrupt colonic motility causing constipation.