The effect of bethanechol on tracheobronchomalacia in preterm infants with bronchopulmonary dysplasia: a retrospective cohort study.

OBJECTIVE: Bethanechol has demonstrated improvement in trachealis tone in animal models, but no trials have studied efficacy in infants. This study aimed to examine if bethanechol improves a standardized pulmonary severity score (PSS) in infants with severe bronchopulmonary dysplasia with a diagnosis of tracheobronchomalacia (TBM). STUDY DESIGN: This retrospective cohort study evaluated cases treated with bethanechol matched with controls who did not receive bethanechol. TBM was diagnosed by dynamic computography. Daily PSS was recorded for each infant from 40 to 55 weeks post-menstrual age. RESULTS: Cases' mean PSS change was 21% lower than the controls' mean PSS change pre- and post-bethanechol (95% CI -40%, -2%) by paired t-test (p = 0.03). Matched differences (controls' PSS - cases' PSS) demonstrated greater mean PSS difference post-bethanechol compared to pre-bethanechol 0.17, (95% CI 0.05, 0.29) by paired t-test (p = 0.009). CONCLUSION: Infants with TBM treated with bethanechol compared to those not treated had a lower PSS reflecting improved respiratory status.

Acetylcholine receptor agonists effectively attenuated multiple program cell death pathways and improved left ventricular function in trastuzumab-induced cardiotoxicity in rats.

AIMS: Cardiotoxicity is a seriously debilitating complication of trastuzumab (TRZ) therapy in patients with cancer as a consequence of overexpression of the human epidermal growth factor receptor 2. Although most TRZ-induced cardiotoxicity (TIC) cases are reversible, some patients experience chronic cardiac dysfunction, and these irreversible concepts may be associated with cardiomyocyte death. Acetylcholine receptor (AChR) activation has been shown to exert cardioprotection in several heart diseases, but the effects of AChR agonists against TIC have not been investigated. MAIN METHOD: Forty adult male Wistar rats were randomized into 5 groups: (i) CON (0.9 % normal saline), (ii) TRZ (4 mg/kg/day), (iii) TRZ + α7nAChR agonist (PNU-282987: 3 mg/kg/day), (iv) TRZ + mAChR agonists (bethanechol: 12 mg/kg/day), and (v) TRZ + combined treatment (Combined PNU-282987 and bethanechol). KEY FINDINGS: The progression of TIC was driven by mitochondrial dysfunction, autophagic deficiency, and excessive myocyte death including by pyroptosis, ferroptosis, and apoptosis, which were significantly alleviated by α7nAChR and mAChR agonists. Interestingly, necroptosis was not associated with development of TIC. More importantly, the in vitro study validated the cytoprotective effects of AChR activation in TRZ-treated H9c2 cells, while not interfering with the anticancer properties of TRZ. All of these findings indicated that TRZ induced mitochondrial dysfunction, autophagic deficiency, and excessive myocyte death including pyroptosis, ferroptosis, and apoptosis, leading to impaired cardiac function. These pathological alterations were attenuated by α7nAChR and mAChR agonists. SIGNIFICANCE: α7nAChR and mAChR agonists might be used as a future therapeutic target in the mitigation of TIC.

Efficacy of bethanechol chloride in the treatment of radiation-induced xerostomia in patients with head and neck cancer: A systematic review and meta-analysis.

BACKGROUND AND PORPUSE: Salivary glands sustain collateral damage following radiotherapy (RT) to treat cancers of the head and neck, leading to complications, including xerostomia and hyposalivation. This systematic review (SR) with meta-analysis was performed to determine the effectiveness of bethanechol chloride in preventing salivary gland dysfunction in this context. MATERIALS AND METHODS: Medline/Pubmed, Embase, Scopus, LILACS via Portal Regional BVS and Web of Science were searched electronically in accordance with the Cochrane manual and reported PRISMA guidelines. RESULTS: 170 patients from three studies were included. Results from the meta-analysis suggest that bethanechol chloride is associated with increases in: whole stimulating saliva (WSS) after RT (Std. MD 0.66, 95% CI 0.28 to 1.03, P < 0.001); whole resting saliva (WRS) during RT (Std. MD 0.4, 95% CI 0.04 to 0.76, P = 0.03); and WRS after RT (Std. MD 0.45, 95% CI 0.04 to 0.86, P = 0.03). CONCLUSION: The present study suggests that bethanechol chloride therapy may be effective in patients with xerostomia and hyposalivation.

Identification of potential biomarkers and pathogenesis in neutrophil-predominant severe asthma: A comprehensive bioinformatics analysis.

BACKGROUND: Airway neutrophilia has been associated with asthma severity and asthma exacerbations. This study attempted to identify biomarkers, pathogenesis, and therapeutic molecular targets for severe asthma in neutrophils using bioinformatics analysis. METHODS: Fifteen healthy controls and 3 patients with neutrophilic severe asthma were screened from the Gene Expression Omnibus (GEO) database. Based on the analysis of differentially expressed genes (DEGs), functional and pathway enrichment analyses, gene set enrichment analysis, protein-protein interaction network construction, and analysis were performed. Moreover, small-molecule drug candidates have also been identified. RESULTS: Three hundred and three upregulated and 59 downregulated genes were identified. Gene ontology function enrichment analyses were primarily related to inflammatory response, immune response, leukocyte migration, neutrophil chemotaxis, mitogen-activated protein kinase cascade, Jun N-terminal kinase cascade, I-kappaB kinase/nuclear factor-κB, and MyD88-dependent toll-like receptor signaling pathway. Pathway enrichment analyses and gene set enrichment analysis were mainly involved in cytokine-cytokine receptor interaction, the TNF signaling pathway, leukocyte transendothelial migration, and the NOD-like receptor signaling pathway. Furthermore, 1 important module and 10 hub genes (CXCL8, TLR2, CXCL1, ICAM1, CXCR4, FPR2, SELL, PTEN, TREM1, and LEP) were identified in the protein-protein interaction network. Moreover, indoprofen, mimosine, STOCK1N-35874, trapidil, iloprost, aminoglutethimide, ajmaline, levobunolol, ethionamide, cefaclor, dimenhydrinate, and bethanechol are potential drugs for the treatment of neutrophil-predominant severe asthma. CONCLUSION: This study identified potential biomarkers, pathogenesis, and therapeutic molecular targets for neutrophil-predominant severe asthma.

Prevention of salivary gland dysfunction in patients treated with radioiodine for differentiated thyroid cancer: A systematic review of randomized controlled trials.

Introduction: Salivary gland dysfunction (e.g., sialadenitis and xerostomia) is the most common complication of radioactive iodine (RAI) therapy for differentiated thyroid cancer (DTC). Several methods have been used to reduce/prevent this adverse effect. We aimed to systematically review the effectiveness of non-pharmacological and pharmacological interventions in preventing RAI-induced salivary gland dysfunction in patients with DTC. Methods: A systematic review was conducted, according to PRISMA guidelines. The protocol was registered (PROSPERO: CRD42022295229). PubMed, Embase, Scopus, and the Cochrane Library electronic databases were searched from inception to November 2021. Inclusion criteria were randomized controlled trials of DTC patients who were older than 18 years and underwent RAI after thyroidectomy in which at least one studied group received an intervention to prevent salivary gland dysfunction. Results: Twelve studies (a total of 667 participants) were included. Among DTC patients who were treated with RAI, nonpharmacological treatment such as parotid gland massage and aromatherapy ameliorated salivary gland dysfunction. Antioxidants such as vitamin E and selenium demonstrated radioprotective effects on the salivary gland, while other antioxidants did not show radioprotective benefits. Vitamin C showed no significant effects on preventing salivary gland dysfunction. Amifostine had inconsistent outcomes among studies. Among cholinergic agonists, pilocarpine did not demonstrate the radioprotective effect on parotid glands, while bethanechol lowered salivary gland dysfunction. However, the negative results from pilocarpine may be explained by the strong sialorrheic effect of the Cincinnati regimen in both study arms. Conclusion: Among non-pharmacological and pharmacological methods, parotid gland massage, aromatherapy, vitamin E, selenium, amifostine, and bethanechol may have benefits in minimizing RAI-induced salivary gland dysfunction in patients with DTC. The results are limited by a small number of patients and should be confirmed in future larger randomized controlled trials. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=295229, PROSPERO, identifier CRD42022295229.

A systematic review of interventional studies on oral care of palliative patients.

BACKGROUND: To study and review the effectiveness of oral care interventions for palliative patients for amelioration of clinical conditions affecting oral cavity. METHODS: Following PRISMA standard, a systematic evaluation of articles published between 2000 and 2021 was undertaken utilising five databases on interventions studies. This comprehensive review consists of randomised controlled trials (RCTs) and specific types of non-randomised studies (NRS) examining oral care interventions for palliative patients. Three independent authors screened search records, identified related studies, extracted data and evaluated risk of bias. The key findings of each study were summarised according to the research questions and data that generated during the data extraction procedure. RESULTS: Out of the 67 identified studies, seven were included in this review (five RCTs and two NRSs) involving head-and-neck cancer, oral cancer, oral mucositis, xerostomia and individuals with malignant disease. Interventions studied were: Ziziphus honey, artificial saliva, CAM2028-Benzydamine, morphine mouthwash, ketamine mouthwash, bethanechol tablets and caphosol with regular oral-care. The durations of interventions in the included studies were largely short-term (six weeks or less). Overall, six studies revealed good results in support of the intervention, with magnitudes of effect ranging from 13.2-10,110.0%. However, just four researches found significant changes, with magnitudes of effect ranging from 50.0-10,110.0%. Although two of the trials have not revealed significant changes in the results, investigations have indicated a reduction in oral conditions in the group with interventions. Only one trial has not indicated an improvement in oral conditions in the groups which received the interventions. DISCUSSION: By assessing the efficacy of available oral hygiene interventions for palliative patients, this systematic review can help palliative team finds the viable strategies to apply in controlling oral problems among hospice patients. Even though only four of the seven research found a statistically significant difference, most studies found great effectiveness in favour of intervention.

Dog and human bladders have different neurogenic and nicotinic responses in inner versus outer detrusor muscle layers.

The aim of this study was to investigate layer and species variations in detrusor muscle strip responses to myogenic, neurogenic, and nicotinic, and muscarinic receptor stimulations. Strips from bladders of 9 dogs and 6 human organ transplant donors were dissected from inner and outer longitudinal muscle layers, at least 1 cm above urethral orifices. Strips were mounted in muscle baths and maximal responses to neurogenic stimulation using electrical field stimulation (EFS) and myogenic stimulation using potassium chloride (KCl, 120 mM) determined. After washing and re-equilibration was completed, responses to nicotinic receptor agonist epibatidine (10 µM) were determined followed by responses to EFS and muscarinic receptor agonist bethanechol (30 µM) in continued presence of epibatidine. Thereafter, strips and full-thickness bladder sections from four additional dogs and three human donors were examined for axonal density and intramural ganglia. In dog bladders, contractions to KCl, epibatidine, and bethanechol were 1.5- to 2-fold higher in the inner longitudinal muscle layer, whereas contractions to EFS were 1.5-fold higher in the outer (both pre- and post-epibatidine). Human bladders showed 1.2-fold greater contractions to epibatidine in the inner layer and to EFS in the outer, yet no layer differences to KCl or bethanechol were noted. In both species, axonal density was 2- to 2.5-fold greater in the outer layer. Dogs had more intramural ganglia in the adventitia/serosa layer, compared with more internal layers and to humans. These findings indicate several layer-dependent differences in receptor expression or distribution, and neurogenic responses in dog and human detrusor muscles, and myogenic/muscarinic differences between dog versus humans.

Dualplex lateral flow assay for simultaneous scopolamine and "cannibal drug" detection based on receptor-gated mesoporous nanoparticles.

We report herein the design of a strip-based rapid test utilizing bio-inspired hybrid nanomaterials for the in situ and at site detection of the drug scopolamine (SCP) using a smartphone for readout, allowing SCP identification in diluted saliva down to 40 nM in less than 15 min. For this purpose, we prepared a nanosensor based on mesoporous silica nanoparticles loaded with a fluorescent reporter (rhodamine B) and functionalized with bethanechol, a potent agonist of recombinant human muscarinic acetylcholine receptor M2 (M2-AChR). M2-AChR interaction with the anchored bethanechol derivative leads to capping of the pores. The sensing mechanism relies on binding of SCP to M2-AChR resulting in pore opening and delivery of the entrapped rhodamine B reporter. Moreover, the material was incorporated into strips for lateral-flow assays coupled to smartphone readout, giving fast response time, good selectivity, and exceptional sensitivity. In an attempt to a mobile analytical test system for law enforcement services, we have also developed a dualplex lateral flow assay for SCP and 3,4-methylenedioxypyrovalerone (MDPV) also known as the so-called "cannibal drug".

Liver vitronectin release into the bloodstream increases due to reduced vagal muscarinic signaling after cerebral stroke in female mice.

Vitronectin (VTN) is a glycoprotein enriched in the blood and activates integrin receptors. VTN blood levels increase only in female mice 24 h after an ischemic stroke and exacerbate brain injury through IL-6-driven inflammation, but the VTN induction mechanism is unknown. Here, a 30 min middle cerebral artery occlusion (MCAO) in female mice induced VTN protein in the liver (normally the main source) in concert with plasma VTN. Male mice were excluded as VTN is not induced after stroke. MCAO also increased plasma VTN levels after de novo expression of VTN in the liver of VTN-/- female mice, using a hepatocyte-specific (SERPINA1) promoter. MCAO did not affect SERPINA1 or VTN mRNA in the liver, brain, or several peripheral organs, or platelet VTN, compared to sham mice. Thus, hepatocytes are the source of stroke-induced increases in plasma VTN, which is independent of transcription. The cholinergic innervation by the parasympathetic vagus nerve is a potential source of brain-liver signaling after stroke. Right-sided vagotomy at the cervical level led to increased plasma VTN levels, suggesting that VTN release is inhibited by vagal tone. Co-culture of hepatocytes with cholinergic neurons or treatment with acetylcholine, but not noradrenaline (sympathetic transmitter), suppressed VTN expression. Hepatocytes have muscarinic receptors and the M1/M3 agonist bethanechol decreased VTN mRNA and protein release in vitro via M1 receptors. Finally, systemic bethanechol treatment blocked stroke-induced plasma VTN. Thus, VTN translation and release are inhibited by muscarinic signaling from the vagus nerve and presents a novel target for lessening detrimental VTN expression.

Bethanechol used to prevent salivary gland dysfunction in patients submitted to radioactive iodine therapy: A double blind, placebo-controlled, randomized study.

Symptoms related to salivary gland damage are one of the most frustrating complications after radioactive iodine (131I) therapy. To the best of our knowledge, this is the first study that aimed to evaluate the prophylactic effect of Bethanechol on the radioiodine content of salivary gland. Fifty patients who were referred to 131I therapy were randomized into Bethanechol and placebo groups. Patients received Bethanechol or Placebo (25 mg, 2 times daily), starting 2 h after 131I therapy to 1-month.  Both groups were compared at baseline, 10, 30 and 90 days after 131I therapy based on the following: symptoms related to salivary gland damage; unstimulated whole saliva (UWS) and quality of life using University of Washington Quality of Life 4 questionnaire. Bethanechol group presented significantly lower complaints of dry mouth on 10 (p = 0.047) and 30 (p = 0.003) days compared with placebo. Salivary gland pain and swelling were more frequent among placebo patients at 10 days (p = 0.047). Comparison of the two groups by UWS, no statistical difference was found. Placebo group presented worse score related to activity (p = 0.034), saliva (p = 0.05) and humor (p = 0.05) at 10 days; palate (p = 0.05) and saliva (p = 0.05) at 1 month. Interestingly, Bethanechol patients who received 131I dose > 125mCi, showed better xerostomia indices when compared to the Placebo with same dose. Bethanechol during 131I therapy was found to be effective in decreasing the acute salivary gland damage with impact on patients' quality of life.

Pancreatic acinar cells utilize tyrosine to synthesize L-dihydroxyphenylalanine.

The pancreatic ß cells can synthesize dopamine by taking L-dihydroxyphenylalanine, but whether pancreatic acinar cells synthesize dopamine has not been confirmed. By means of immunofluorescence, the tyrosine hydroxylase -immunoreactivity and aromatic amino acid decarboxylase (AADC)- immunoreactivity were respectively observed in pancreatic acinar cells and islet ß cells. Treatment with L-dihydroxyphenylalanine, not tyrosine, caused the production of dopamine in the incubation of INS-1 cells (rat islet ß cell line) and primary isolated islets, which was blocked by AADC inhibitor NSD-1015. However, only L-dihydroxyphenylalanine, but not dopamine, was detected when AR42J cells (rat pancreatic acinar cell line) were treated with tyrosine, which was blocked by tyrosine hydroxylase inhibitor AMPT. Dopamine was detected in the coculture of INS-1 cells with AR42J cells after treatment with tyrosine. In an in vivo study, pancreatic juice contained high levels of L-dihydroxyphenylalanine and dopamine. Both L-dihydroxyphenylalanine and dopamine accompanied with pancreatic enzymes and insulin in the pancreatic juice were all significantly increased after intraperitoneal injection of bethanechol chloride and their increases were all blocked by atropine. Inhibiting TH with AMPT blocked bethanechol chloride-induced increases in L-dihydroxyphenylalanine and dopamine, while inhibiting AADC with NSD-1015 only blocked the dopamine increase. Bilateral subdiaphragmatic vagotomy of rats leads to significant decreases of L-dihydroxyphenylalanine and dopamine in pancreatic juice. These results suggested that pancreatic acinar cells could utilize tyrosine to synthesize L-dihydroxyphenylalanine, not dopamine. Islet ß cells only used L-dihydroxyphenylalanine, not tyrosine, to synthesize dopamine. Both L-dihydroxyphenylalanine and dopamine were respectively released into the pancreatic duct, which was regulated by the vagal cholinergic pathway. The present study provides important evidences for the source of L-dihydroxyphenylalanine and dopamine in the pancreas.

Postoperative interventions for preventing bladder dysfunction after radical hysterectomy in women with early-stage cervical cancer.

BACKGROUND: Bladder dysfunction is a common complication following radical hysterectomy, caused by the damage to pelvic autonomic nerves that innervate the muscles of the bladder, urethral sphincter, and pelvic floor fasciae. Bladder dysfunction increases the rates of urinary tract infection, hospital visits or admission, and patient dissatisfaction. In addition, bladder dysfunction can also negatively impact patient quality of life (QoL). Several postoperative interventions have been proposed to prevent bladder dysfunction following radical hysterectomy. To our knowledge, there has been no systematic review evaluating the effectiveness and safety of these interventions for preventing bladder dysfunction following radical hysterectomy in women with cervical cancer. OBJECTIVES: To evaluate the effectiveness and safety of postoperative interventions for preventing bladder dysfunction following radical hysterectomy in women with early-stage cervical cancer (stage IA2 to IIA2). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 4) in the Cochrane Library, MEDLINE via Ovid (1946 to April week 2, 2020), and Embase via Ovid (1980 to 2020, week 16). We also checked registers of clinical trials, grey literature, conference reports, and citation lists of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating the effectiveness and safety of any type of postoperative interventions for preventing bladder dysfunction following a radical hysterectomy in women with stage IA2 to IIA2 cervical cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently selected potentially relevant RCTs, extracted data, assessed risk of bias, compared results, and made judgments on the quality and certainty of the evidence. We resolved any disagreements through discussion or consultation with a third review author. Outcomes of interest consisted of spontaneous voiding recovery one week after the operation, quality of life (QoL), adverse events, post-void residual urine volume one month after the operation, urinary tract infection over the one month following the operation, and subjective urinary symptoms. MAIN RESULTS: We identified 1464 records as a result of the search (excluding duplicates). Of the 20 records that potentially met the review criteria, we included five reports of four studies. Most of the studies had unclear risks of selection and reporting biases. Of the four studies, one compared bethanechol versus placebo and three studies compared suprapubic catheterisation with intermittent self-catheterisation. We identified two ongoing studies. Bethanechol versus placebo The study reported no information on the rate of spontaneous voiding recovery at one week following the operation, QoL, adverse events, urinary tract infection in the first month after surgery, and subjective urinary symptoms for this comparison. The volume of post-void residual urine, assessed at one month after surgery, among women receiving bethanechol was lower than those in the placebo group (mean difference (MD) -37.4 mL, 95% confidence interval (CI) -60.35 to -14.45; one study, 39 participants; very-low certainty evidence). Suprapubic catheterisation versus intermittent self-catheterisation The studies reported no information on the rate of spontaneous voiding recovery at one week and post-void residual urine volume at one month following the operation for this comparison. There was no difference in risks of acute complication (risk ratio (RR) 0.77, 95% CI 0.24 to 2.49; one study, 71 participants; very low certainty evidence) and urinary tract infections during the first month after surgery (RR 0.77, 95% CI 0.53 to 1.13; two studies, 95 participants; very- low certainty evidence) between participants who underwent suprapubic catheterisation and those who underwent intermittent self-catheterisation. Available data were insufficient to calculate the relative measures of the effect of interventions on QoL and subjective urinary symptoms. AUTHORS' CONCLUSIONS: None of the included studies reported rate of spontaneous voiding recovery one week after surgery, time to a post-void residual volume of urine of 50 mL or less, or post-void residual urine volume at 6 and 12 months after surgery, all of which are important outcomes for assessing postoperative bladder dysfunction. Limited evidence suggested that bethanechol may minimise the risk of bladder dysfunction after radical hysterectomy by lowering post-void residual urine volume. The certainty of this evidence, however, was very low. The effectiveness of different types of postoperative urinary catheterisation (suprapubic and intermittent self-catheterisation) remain unproven.

Airway cholinergic history modifies mucus secretion properties to subsequent cholinergic challenge in diminished chloride and bicarbonate conditions.

NEW FINDINGS: What is the central question of this study? What is the impact of airway cholinergic history on the properties of airway mucus secretion in a cystic fibrosis-like environment? What is the main finding and its importance? Prior cholinergic challenge slightly modifies the characteristics of mucus secretion in response to a second cholinergic challenge in a diminished bicarbonate and chloride transport environment. Such modifications might lead to retention of mucus on the airway surface, thereby potentiating exacerbations of airway disease. ABSTRACT: Viral infections precipitate exacerbations in many airway diseases, including asthma and cystic fibrosis. Although viral infections increase cholinergic transmission, few studies have examined how cholinergic history modifies subsequent cholinergic responses in the airway. In our previous work, we found that airway resistance in response to a second cholinergic challenge was increased in young pigs with a history of airway cholinergic stimulation. Given that mucus secretion is regulated by the cholinergic nervous system and that abnormal airway mucus contributes to exacerbations of airway disease, we hypothesized that prior cholinergic challenge would also modify subsequent mucus responses to a secondary cholinergic challenge. Using our established cholinergic challenge-rechallenge model in pigs, we atomized the cholinergic agonist bethanechol or saline control to pig airways. Forty-eight hours later, we removed tracheas and measured mucus secretion properties in response to a second cholinergic stimulation. The second cholinergic stimulation was conducted in conditions of diminished chloride and bicarbonate transport to mimic a cystic fibrosis-like environment. In pigs previously challenged with bethanechol, a second cholinergic stimulation produced a mild increase in sheet-like mucus films; these films were scarcely observed in animals originally challenged with saline control. The subtle increase in mucus films was not associated with changes in mucociliary transport. These data suggest that prior cholinergic history might modify mucus secretion characteristics with subsequent stimulation in certain environmental conditions or disease states. Such modifications and/or more repetitive stimulation might lead to retention of mucus on the airway surface, thereby potentiating exacerbations of airway disease.

The beneficial effects of a muscarinic agonist on pancreatic ß-cells.

The brain and nervous system play an important role in pancreatic ß-cell function. This study investigated the role of muscarinic agonists or acetylcholine, which is the major neurotransmitter in the vagal nerve, in regulating pancreatic ß-cell mass and glucose homeostasis. Administration of the muscarinic agonist bethanechol increased insulin secretion and improved glucose tolerance in insulin-receptor substrate 2 (IRS2)-knockout (IRS-2-/-) mice and diet-induced obesity mice. Oral administration of bethanechol increased ß-cell mass and proliferation in wild-type mice, but not IRS-2-/- mice. The muscarinic agonist also increased the incorporation of 5-bromo-2'-deoxyuridine (BrdU) into islets isolated from wild-type mice and pancreatic ß-cell line MIN6. The phosphorylation of protein kinase B (Akt) induced by oral administration of bethanechol was observed in wild-type mice, but not IRS-2-/- mice. The secretion of glucagon-like peptide-1 (GLP-1) was also stimulated by bethanechol in wild-type mice, and a GLP-1 antagonist partially inhibited the bethanechol-induced increase in ß-cell mass. These results suggest that the muscarinic agonist exerted direct and indirect effects on ß-cell proliferation that were dependent on the IRS-2/Akt pathway. The bethanechol-stimulated release of GLP-1 may be indirectly associated with ß-cell proliferation.

Bethanechol: Is it still being prescribed for bladder dysfunction in women?

PURPOSE: Few medical treatment options exist for detrusor underactivity or urinary retention in women. Bethanechol, a cholinergic agonist, may improve detrusor contractility in these conditions; however, its clinical efficacy is limited. We sought to examine the patterns of Bethanechol use by physicians in an ambulatory care setting using a national database to determine if it is still prescribed for patients with bladder dysfunction. MATERIALS AND METHODS: The National Ambulatory Medical Care Survey (NAMCS) database was queried for a sample of patient visits to office-based physicians from 2003-2013. Visits were included for women aged 18 years or older with diagnosed lower urinary tract symptoms (LUTS), neurogenic bladder, or urinary retention based on ICD-9-CM codes. Visits in which Bethanechol was prescribed were analysed with descriptive statistics. Sampling weights were adjusted for nonresponders to yield an unbiased national estimate of ambulatory care visits. RESULTS: Out of a weighted sample of 17 321 630 included patient visits, 132 281 (0.8%) visits included a prescription for Bethanechol. Patients prescribed Bethanechol had a mean age of 62.3 ± 2.1 and were predominantly Caucasian (67%) followed by African American (18%). The primary diagnosis associated with Bethanechol was atony of bladder (35%), urinary retention (20%), neurogenic bladder (18%), urinary incontinence (16%), and incomplete bladder emptying (10%). Visits were primarily for chronic conditions (63%). It was typically prescribed as a continued medication (79%) most often by urologists (92%) followed by internal medicine clinicians (8%). CONCLUSIONS: Bethanechol continues to be prescribed in elderly women primarily for detrusor atony, urinary retention, or incomplete bladder emptying.

Bronchoscopy in neonates with severe bronchopulmonary dysplasia in the NICU.

OBJECTIVES: To describe the findings, resulting changes in management, and safety profile of flexible bronchoscopy in the neonates with severe bronchopulmonary dysplasia. STUDY DESIGN: This was a retrospective case series of twenty-seven neonates with severe bronchopulmonary dysplasia who underwent flexible bronchoscopy in the neonatal intensive care unit. RESULTS: Flexible bronchoscopy revealed airway pathology in 20/27 (74%) patients. Tracheomalacia 13/27 (48%), bronchomalacia 11/27 (40.7%), and airway edema 13/27 (48%) were the most common findings. Bronchoalveolar lavage (BAL) was performed in 17 patients. BAL culture revealed a microorganism in 12/17 (70.5%) cases. Findings from bronchoscopy resulted in change in clinical management in 17/27 (63%) patients. Common interventions included initiation of antibiotics (37%) and treatment of tracheobronchomalacia with bethanechol (22.2%), atrovent (18.5%), and PEEP titration (18.5%). Bronchoscopy was performed without significant complication in 26/27 (97%) patients. CONCLUSION: Flexible bronchoscopy can be a safe and useful tool for the management of neonates with severe bronchopulmonary dysplasia.

New technology assessment and current and upcoming therapies for underactive bladder.

BACKGROUND AND AIMS: Stakeholders from around the world came together to address the unmet needs of underactive bladder (UAB) at the 3rd International Congress for Underactive Bladder. METHODS: The main recommendation from the regulatory working group is a need for a meeting of UAB stakeholders and regulatory agencies including the FDA to discuss guidance for regulatory trial design for devices, drugs, and/or biologics for UAB. RESULTS: The following issues to be discussed and agreed upon for UAB trials: 1) Appropriate inclusion and exclusion criteria. 2) Should residual urine volume be the primary outcome parameter and how often should it be measured? 3) Are there secondary measures that should have a place in UAB trials, such as change in the number of catheterizations, quality of life measures, etc.? 4) Use and format of bladder voiding and catheterization diary for trials. 5) Define role and technique of urodynamics in UAB trials. Are urodynamics required to monitor, and possibly exclude, individuals with high pressure voiding induced by bladder prokinetic therapies? 6) Development and use of UAB questionnaires. DISCUSSION AND CONCLUSION: The UAB regulatory working group recognizes the path forward should include engaging the FDA and other regulatory organizations that may harmonize and formalize guidance for regulatory trial designs for therapeutics for UAB.

Salivary hypofunction: An update on therapeutic strategies.

OBJECTIVE: To perform a literature review addressing the therapeutic strategies for salivary hypofunction. BACKGROUND: Qualitative and quantitative salivary dysfunctions predispose to changes in the oral mucosa and teeth, cause impairment to oral functions and negative impact on quality of life. MATERIALS AND METHODS: A MEDLINE/PubMed search was conducted using the terms "Xerostomia" AND, "Saliva Artificial" OR, "Citric Acid," "Malic Acid," "Chewing Gum," "Acupuncture" OR, "Pilocarpine" OR, "Bethanechol" OR, "Cevimeline" OR, "Hyperbaric Oxygen Therapy" OR, "Stem Cell Therapy" OR "Genetic Therapy" and their Mesh Terms. RESULTS: We selected 25 clinical trials investigating the effects of salivary substitutes, chewing gum, malic and citric acids, pilocarpine, cevimeline, bethanechol, acupuncture, hyperbaric oxygen therapy and regenerative therapies on salivary hypofunction. In most studies, the number of participants was low and the follow-up times short. The therapeutic modalities were classified according to the level of evidence on salivary dysfunction. CONCLUSIONS: Pilocarpine and cevimeline had the strongest evidence of beneficial effect on salivary hypofunction. Citric and malic acids increase salivary flow but also increase the risk of erosion and dental caries. There are no controlled clinical trials supporting the efficacy of acupuncture, stem cell therapy and gene therapy on salivary dysfunction, although clinical observations suggest a promising effect. There is no evidence supporting salivary substitutes, chewing gum, bethanechol or hyperbaric oxygen on the treatment of salivary hypofunction.