Search

Background: Aspiration pneumonia is common among frail elderly persons with dysphagia. Although interventions to prevent aspiration are routinely used in these patients, little is known about the effectiveness of those interventions.Objective: To compare the effectiveness of chin-down posture and 2 consistencies (nectar or honey) of thickened liquids on the 3-month cumulative incidence of pneumonia in patients with dementia or Parkinson disease.Design: Randomized, controlled, parallel-design trial in which patients were enrolled for 3-month periods from 9 June 1998 to 19 September 2005.Setting: 47 hospitals and 79 subacute care facilities.Patients: 515 patients age 50 years or older with dementia or Parkinson disease who aspirated thin liquids (demonstrated videofluoroscopically). Of these, 504 were followed until death or for 3 months.Intervention: Participants were randomly assigned to drink all liquids in a chin-down posture (n = 259) or to drink nectar-thick (n = 133) or honey-thick (n = 123) liquids in a head-neutral position.Measurements: The primary outcome was pneumonia diagnosed by chest radiography or by the presence of 3 respiratory indicators.Results: 52 participants had pneumonia, yielding an overall estimated 3-month cumulative incidence of 11%. The 3-month cumulative incidence of pneumonia was 0.098 and 0.116 in the chin-down posture and thickened-liquid groups, respectively (hazard ratio, 0.84 [95% CI, 0.49 to 1.45]; P = 0.53). The 3-month cumulative incidence of pneumonia was 0.084 in the nectar-thick liquid group compared with 0.150 in the honey-thick liquid group (hazard ratio, 0.50 [CI, 0.23 to 1.09]; P = 0.083). More patients assigned to thickened liquids than those assigned to the chin-down posture intervention had dehydration (6% vs. 2%), urinary tract infection (6% vs. 3%), and fever (4% vs. 2%).Limitations: A no-treatment control group was not included. Follow-up was limited to 3 months. Care providers were not blinded, and differences in cumulative pneumonia incidence between interventions had wide CIs.Conclusion: No definitive conclusions about the superiority of any of the tested interventions can be made. The 3-month cumulative incidence of pneumonia was much lower than expected in this frail elderly population. Future investigation of chin-down posture combined with nectar-thick liquid may be warranted to determine whether this combination better prevents pneumonia than either intervention independently. [ABSTRACT FROM AUTHOR]

Although it is well established that wildfire smoke exposure can increase cardiovascular morbidity and mortality, the combined effects of non-chemical stressors and wildfire smoke remains understudied. Housing is a non-chemical stressor that is a major determinant of cardiovascular health, however, disparities in neighborhood and social status have exacerbated the cardiovascular health gaps within the United States. Further, pre-existing cardiovascular morbidities, such as atherosclerosis, can worsen the response to wildfire smoke exposures. This represents a potentially hazardous interaction between inadequate housing and stress, cardiovascular morbidities, and worsened responses to wildfire smoke exposures. The purpose of this study was to examine the effects of enriched (EH) versus depleted (DH) housing on pulmonary and cardiovascular responses to a single flaming eucalyptus wildfire smoke (WS) exposure in male and female apolipoprotein E (ApoE) knockout mice, which develop an atherosclerosis-like phenotype. The results of this study show that cardiopulmonary responses to WS exposure occur in a sex-specific manner. EH blunts adverse WS-induced ventilatory responses, specifically an increase in tidal volume (TV), expiratory time (Te), and relaxation time (RT) after a WS exposure, but only in females. EH also blunted an increase in isovolumic relaxation time (IVRT) and the myocardial performance index (MPI) 1-week after exposures, also only in females. Our results suggest that housing alters the cardiovascular response to a single WS exposure, and that DH might cause increased susceptibility to environmental exposures that manifest in altered ventilation patterns and diastolic dysfunction in a sex-specific manner., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Living conditions are an important modifier of individual health outcomes and may lead to higher allostatic load (AL). However, housing-induced cardiovascular and immune effects contributing to altered environmental responsiveness remain understudied. This investigation was conducted to examine the influence of enriched (EH) versus depleted housing (DH) conditions on cardiopulmonary functions, systemic immune responses, and allostatic load in response to a single wildfire smoke (WS) exposure in mice. Male and female C57BL/6J mice were divided into EH or DH for 22 weeks, and cardiopulmonary assessments measured before and after exposures to either one-hr filtered air (FA) or flaming eucalyptus WS exposure. Male and female DH mice exhibited increased heart rate (HR) and left ventricular mass (LVM), as well as reduced stroke volume and end diastolic volume (EDV) one week following exposure to WS. Female DH mice displayed significantly elevated levels of IL-2, IL-17, corticosterone and hemoglobin A1c (HbA1c) following WS, while female in EH mice higher epinephrine levels were detected. Female mice exhibited higher AL than males with DH, which was potentiated post-WS exposure. Thus, DH increased susceptibility to extreme air pollution in a gender-dependent manner suggesting that living conditions need to be evaluated as a modifier of toxicological responses.

Objectives: Living conditions play a major role in health and well-being, particularly for the cardiovascular and pulmonary systems. Depleted housing contributes to impairment and development of disease, but how it impacts body resiliency during exposure to environmental stressors is unknown. This study examined the effect of depleted (DH) versus enriched housing (EH) on cardiopulmonary function and subsequent responses to wildfire smoke. Materials and Methods: Two cohorts of healthy female mice, one of them surgically implanted with radiotelemeters for the measurement of electrocardiogram, body temperature (Tco) and activity, were housed in either DH or EH for 7 weeks. Telemetered mice were exposed for 1 h to filtered air (FA) and then flaming eucalyptus wildfire smoke (WS) while untelemetered mice, which were used for ventilatory assessment and tissue collection, were exposed to either FA or WS. Animals were continuously monitored for 5-7 days after exposure. Results: EH prevented a decrease in Tco after radiotelemetry surgery. EH mice also had significantly higher activity levels and lower heart rate during and after FA and WS. Moreover, EH caused a decreased number of cardiac arrhythmias during WS. WS caused ventilatory depression in DH mice but not EH mice. Housing enrichment also upregulated the expression of cardioprotective genes in the heart. Conclusions: The results of this study indicate that housing conditions impact overall health and cardiopulmonary function. More importantly, depleted housing appears to worsen the response to air pollution. Thus, non-chemical factors should be considered when assessing the susceptibility of populations, especially when it comes to extreme environmental events.

Background: Postpartum anxiety is a mental health problem that has largely been ignored by maternity care providers despite an estimated incidence as high as 28.9%. Though postpartum anxiety may or may not be accompanied by depression, and while screening for postpartum depression has become more common place, postpartum anxiety is often not assessed or addressed., Purpose: The purpose of this pilot quality improvement project was to implement a screening, treatment and referral program for postpartum anxiety in the birth centre environment., Procedures: Midwives from 10 geographically diverse birth centres, and all members of the American Association of Birth Centres, were recruited to participate in the project. An online video was developed which detailed postpartum anxiety, screening through use of the anxiety subscale of the Edinburgh Postnatal Depression Scale and a toolkit for treatment and/or referral for screen positive patients. Participants entered patient scores into the Perinatal Data Registry of the American Association of Birth Centres. Individual interviews of midwives were conducted following the 10-week pilot period., Main Findings: There were a total of 387 participants across 9 participating sites. Among all screened participants with follow-up data, (n = 382), 9.69% (n = 37) were lost to follow-up. Among all participants screened with the Edinburgh Postpartum Depression Scale -3A and Edinburgh Postpartum Depression Scale (n = 318), 12.58% (n = 40) had a positive Edinburgh Postpartum Depression Scale -3A score of greater than six. Of all screened participants with an Edinburgh Postpartum Depression Scale score, 15 (6.98%) had a Edinburgh Postpartum Depression Scale score of less than 12 and an Edinburgh Postpartum Depression Scale -3A score greater than six, and would have not received follow up care if only screened for postpartum depression. Midwife participants expressed heightened awareness of the need to screen and felt screening was easy to integrate into clinical practice., Conclusions: The Edinburgh Postpartum Depression Scale -3A is a valid, easy-to-use tool which should be considered for use in clinical practice. Modification of the electronic health record can serve as an important impetus triggering screening and treatment. It is important that clinicians are educated on the prevalence of postpartum anxiety, its risk factors, symptoms and implications., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: We evaluated the efficacy and tolerability of the nicotinic channel modulator dexmecamylamine for overactive bladder., Materials and Methods: This was a randomized, double-blind, placebo controlled trial in 768 randomized subjects. Those with at least a 6-month history of overactive bladder were randomized to 0.5, 1 or 2 mg dexmecamylamine or placebo in a ratio of 1:1:1:2, respectively. Subjects completed a 3-day diary before each visit associated with the 12-week treatment period. They were required to have 8 or more micturitions per day and 3 or more urinary urge incontinent episodes per day if overactive bladder wet at the end of a placebo run-in period. Co-primary end points for the study included a change from baseline 1) in micturition frequency per 24 hours at week 12 and 2) in urge urinary incontinence episodes per 24 hours at week 12. Secondary end points were voided volume, nocturia episodes, OABq (Overactive Bladder Questionnaire) and urgency questionnaire., Results: Dexmecamylamine (2 mg) produced a statistically significant decrease in micturition frequency (p = 0.03) but did not produce a statistically significant decrease in urge incontinence (wet) episodes (p = 0.38). Secondary end points, including volume voided in the 1 mg group only, CGI-I (Clinical Global Impression of Improvement), visual analog scale urgency impact, intensity and severity, were statistically significant at week 12 for the 2 mg dose. Dexmecamylamine was well tolerated in this subject population with a low incidence of discontinuations due to adverse effects. Constipation, dry mouth and urinary tract infection showed a dose dependent increase in frequency., Conclusions: Dexmecamylamine does not appear to offer an enhanced therapeutic profile for the treatment of overactive bladder relative to current therapies., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Dexmecamylamine (TC-5214) is a nicotinic channel modulator that was evaluated as a potential adjunct treatment to an antidepressant for patients with major depressive disorder. Dexmecamylamine is almost completely eliminated via the kidneys, with more than 90 % of a given dose excreted unchanged in urine. The aim of this study was to assess the single-dose pharmacokinetics of dexmecamylamine in subjects with various degrees of renal impairment and subjects undergoing hemodialysis., Methods: A single-dose, open-label, parallel-group study was conducted at two study centers in the USA. There were four treatment groups with eight subjects in each, receiving a single dose of dexmecamylamine 8 mg (subjects with normal renal function and mild renal impairment) or TC-5412 2 mg [subjects with moderate renal impairment and end-stage renal disease (ESRD)]. The pharmacokinetics of dexmecamylamine in plasma, urine, and dialysate were evaluated using non-compartmental analysis., Results: The plasma pharmacokinetics of dexmecamylamine were influenced by renal function. The increase in dose-normalized area under the plasma concentration-time curve (AUC) was statistically significant with an approximately doubled exposure in subjects with moderate renal impairment compared with subjects with normal renal function. The maximum plasma concentration was not impacted by renal function. Plasma clearance of dexmecamylamine in ESRD subjects appeared negligible, with flat plasma concentration-time profiles. Hemodialysis had a relatively modest effect on reduction of dexmecamylamine plasma concentrations. There was no discernable relationship between renal clearance and urinary pH., Conclusion: Renal impairment increased the AUC, prolonged the elimination half-life, and decreased the clearance of dexmecamylamine following administration as a single oral dose. It is likely that renal function would need to be taken into account when setting the dose. Dexmecamylamine administration should be avoided or the dose significantly reduced in patients with severe renal impairment and ESRD.

TC-5214 (dexmecamylamine) is a nicotinic channel modulator that has previously been evaluated for treatment of major depression disorder (MDD) and is currently being evaluated by Targacept as a treatment for overactive bladder. A comprehensive population pharmacokinetic (POP PK) model of TC-5214 was developed using nonlinear mixed-effects modeling of pooled plasma concentration data from 6 early phase I studies in 179 healthy participants or patients with non-MDD and 1 phase II study in 68 MDD patients. Concentration-time profiles of TC-5214 after either single or multiple oral doses of TC-5214 was described by a one-compartment model with first-order absorption with lag time and first-order elimination. Covariate analysis revealed that creatinine clearance was a significant covariate on clearance and that body weight significantly influenced the central volume of distribution. The final model (with identified covariates) was used to simulate steady-state exposure for patients with impaired renal function. Results from forest plots reveal that patients with moderate to severe renal impairment or end stage renal disease are associated with significantly higher Cssmax and AUC compared to patients with normal renal function. The proposed final POP PK model could be employed in defining a TC-5214 dosage regimen in patients with impaired renal function., (© 2014, The American College of Clinical Pharmacology.)

The pharmacokinetic and safety profiles of clinical drug candidates are greatly influenced by their requisite physicochemical properties. In particular, it has been shown that 2D molecular descriptors such as fraction of Sp3 carbon atoms (Fsp3) and number of stereo centers correlate with clinical success. Using the proteomic off-target hit rate of nicotinic ligands, we found that shape-based 3D descriptors such as the radius of gyration and shadow indices discriminate off-target promiscuity better than do Fsp3 and the number of stereo centers. We have deduced the relevant descriptor values required for a ligand to be nonpromiscuous. Investigating the MDL Drug Data Report (MDDR) database as compounds move from the preclinical stage toward the market, we have found that these shape-based 3D descriptors predict clinical success of compounds at preclinical and phase1 stages vs compounds withdrawn from the market better than do Fsp3 and LogD. Further, these computed 3D molecular descriptors correlate well with experimentally observed solubility, which is among well-known physicochemical properties that drive clinical success. We also found that about 84% of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas withdrawn and discontinued compounds fail to meet the same criteria. Our studies suggest that spherical compounds (rather than their elongated counterparts) with a minimal number of aromatic rings may exhibit a high propensity to advance from clinical trials to market.

Accurate detection and classification of aspiration is a critical component of videofluoroscopic swallowing evaluation, the most commonly utilized instrumental method for dysphagia diagnosis and treatment. Currently published literature indicates that interjudge reliability for the identification of aspiration ranges from poor to fairly good depending on the amount of training provided to clinicians. The majority of extant studies compared judgments among clinicians. No studies included judgments made during the use of a postural compensatory strategy. The purpose of this study was to examine the accuracy of judgments made by speech-language pathologists (SLPs) practicing in hospitals compared with unblinded expert judges when identifying aspiration and using the 8-point Penetration/Aspiration Scale. Clinicians received extensive training for the detection of aspiration and minimal training on use of the Penetration/Aspiration Scale. Videofluoroscopic data were collected from 669 patients as part of a large, randomized clinical trial and include judgments of 10,200 swallows made by 76 clinicians from 44 hospitals in 11 states. Judgments were made on swallows during use of dysphagia compensatory strategies: chin-down posture with thin liquids and head-neutral posture with thickened liquids (nectar-thick and honey-thick consistencies). The subject population included patients with Parkinson's disease and/or dementia. Kappa statistics indicate high accuracy for all interventions by SLPs for identification of aspiration (all kappa > 0.86) and variable accuracy (range = 69-76%) using the Penetration/Aspiration Scale when compared to expert judges. It is concluded that while the accuracy of identifying the presence of aspiration by SLPs is excellent, more extensive training and/or image enhancement is recommended for precise use of the Penetration/Aspiration Scale.

Purpose: This study was designed to identify which of 3 treatments for aspiration on thin liquids-chin-down posture, nectar-thickened liquids, or honey-thickened liquids-results in the most successful immediate elimination of aspiration on thin liquids during the videofluorographic swallow study in patients with dementia and/or Parkinson's disease., Method: This randomized clinical trial included 711 patients ages 50 to 95 years who aspirated on thin liquids as assessed videofluorographically. All patients received all 3 interventions in a randomly assigned order during the videofluorographic swallow study., Results: Immediate elimination of aspiration on thin liquids occurred most often with honey-thickened liquids for patients in each diagnostic category, followed by nectar-thickened liquids and chin-down posture. Patients with most severe dementia exhibited least effectiveness on all interventions. Patient preference was best for chin-down posture followed closely by nectar-thickened liquids., Conclusion: To identify best short-term intervention to prevent aspiration of thin liquid in patients with dementia and/or Parkinson's disease, a videofluorographic swallow assessment is needed. Evidence-based practice requires taking patient preference into account when designing a dysphagic patient's management plan. The longer-term impact of short-term prevention of aspiration requires further study.

Malaria, the clinical disease resulting from infection with Plasmodium, has haunted mankind with illness and death for thousands of years. As Plasmodia's ancient ancestor evolved from a mixotroph to an intracellular parasite, subsiding on amino acids obtained from hemoglobin, it encountered increased oxidative stress. To compensate for this oxidative stress, Plasmodia reduced its own production of reactive oxygen species by becoming largely fermentative and adapted novel methods to assuage oxidative injury. One such method appears to have been accomplished through the acquisition, retention and exploitation of an ancient red algal endosymbiote, now denoted the apicoplast. The apicoplast, located in close proximity to mitochondria, appears to synthesize the potent antioxidant lipoic acid. Lipoic acid may be utilized by Plasmodium as an antioxidant, a shuttle for reducing potentials and as a mitochondrial cofactor. Inhibition or alteration of the apicoplast leads to a curious phenomena known as "delayed death", whereby parasites die not in the present generation but in the ensuing one. Apicoplast inhibition may produce lipoic acid "starvation", increasing oxidative stress/mitochondrial injury during the subsequent asexual reproductive cycle. Collectively, data available to date indicate that the apicoplast was retained as an obligate endosymbiote, under evolutionary selective pressure, to assuage oxidative stress and plays a critical role in maintaining parasite viability during the Plasmodial shizont blood stage.

Growth hormone secretagogues (GHSs) represent attractive therapeutic alternatives to recombinant growth hormone (GH), given their ability to amplify pulsatile hormone secretion in a relatively physiologic manner. CP-424,391 (391) is a novel, orally active pyrazolinone-piperidine [corrected] GHS. In rat pituitary cell cultures, 391 stimulated GH release with an EC50 = 3 nM. The addition of 391 to rat pituitary cells activated intracellular calcium signaling but did not elevate intracellular cyclic adenosine monophosphate (cAMP). 391 also modulated the effects of GH-releasing hormone and somatostatin on pituitary cell GH-release and intracellular signaling. In nonpituitary cell lines, the ability of 391 to stimulate intracellular signaling was dependent on the expression of recombinant human GHS receptor. Acute administration of 391 to anesthetized rats or to conscious dogs induced pulsatile release of G H in a dose-dependent manner. Plasma insulin-like growth factor-I (IGF-I) was elevated progressively over a 5-d course of daily oral dosing in dogs. Chronic oral administration of 391 augmented body weight gain in rats and dogs. Thus, the peptidomimetic GHS 391 has potential utility for the treatment of clinical conditions that could benefit from systemic augmentation of GH and IGF-I levels.

1. Utilizing a validated ultrasensitive hplc assay (lower limit of quantitation 25 pg/ml), we characterized the disposition profile of droloxifene in the female Sprague-Dawley rat following intravenous, oral and intraportal administration. 2. The site and extent of first-pass metabolism and the extent of enterohepatic recirculation were investigated. 3. Our findings suggest that the intestine is neither a metabolic nor an absorptive barrier to the bioavailability of droloxifene in the female Sprague-Dawley rat and that first-pass hepatic extraction is approximately 70-80% following an oral dose of 1 mg/kg. 4. Employment of a modified linked-rat model revealed that droloxifene is subject to enterohepatic recirculation (approximately 5%) in the rat.

Throughout history, athletes have searched for performance-enhancing agents. Recently, creatine (N-[aminoiminomethyl]-N-methyl glycine) has been marketed as an ergogenic dietary supplement. There appears to be scientific merit to the claim that creatine is ergogenic when taken in large amounts. However, several issues regarding its use need to be addressed.

Head trauma produces debilitating injuries that affect millions of people each year. Such injuries lead to a cascade of physiologic sequelae resulting in a hypercatabolic/hypermetabolic state. Current information describing changes in hepatic drug metabolism as a result of head trauma is limited. In this study, the effect of craniotomy and craniotomy plus cerebral percussive injury (impact) were investigated and compared with anesthesia control. Steady-state mRNA levels for CYP2C11 and CYP3A were suppressed to 50% of control values 24 hr following injury for the impact treatments. Craniotomy treatments also demonstrated a 50% decline in steady-state levels of mRNA for CYP3A 24 hr following injury. However, Western blot analysis of the CYP3A enzyme revealed no change at 6, 24, or 48 hr following injury. In addition, activities for 2 alpha- and 6 beta-testosterone hydroxylase did not differ from control values at any time point. Spectral analysis of total P-450 demonstrated a very small decline of 15% for the impact treatment 48 hr following injury. Total cytochrome P-450 content did not differ from control values at any other time point. Head injury produces a profound decline in steady-state mRNA concentrations for CYP2C11 and CYP3A that do not translate into altered protein expression.

Alterations in plasma protein binding may alter patient response to pharmaceutical agents because only free drug is considered to be pharmacologically active. Such alterations appear to be more significant with highly bound agents such as phenytoin. Traditionally, most drug assays monitor total drug concentrations and do not quantitate free drug. When binding alterations are present, total drug concentrations may mislead clinicians in evaluating patient response. We describe a case in which profound hypoalbuminemia (0.2 g/dL), associated with focal segmental glomerulosclerosis, produced toxic free phenytoin concentrations (4.9 micrograms/mL) in an HIV-positive 25-year-old black woman. At such a high serum concentration of free phenytoin, the patient exhibited seizure-like effects. Renal abnormalities and hypoalbuminemia associated with acquired immunodeficiency syndrome (AIDS) may place patients at risk for elevated free fractions of phenytoin and subsequent toxicity.

The accuracy and precision of a fluorescence polarization immunoassay for diluted gentamicin serum samples in the presence of fluorescein dye is described.

Evaluated the sensitivity and specificity of the Pediatric Early Elementary Examination (PEEX), a test designed to identify children at risk for learning problems. Using a sample of 299 seven- to nine-year-old "disadvantaged" children, the number of "areas of concern" identified by the PEEX and a school record indicating whether a child was receiving special educational services were used to compute test sensitivity and specificity. For two areas of concern, the sensitivity was 76.9% and specificity was 59.9%. The findings indicate that the PEEX correctly identified only 64.3% of children receiving special educational services. The test has a high rate of false positives while still failing to identify 6-7.5% of the children receiving special education services. Other issues relating to the utility of the PEEX are discussed.

A study was conducted to determine the efficacy of utilizing Leach's interrogation model as a means for analyzing question types used by mothers and their children's responses to various interrogative forms. Data analyzed consisted of language samples obtained from three preschool children and their mothers during mother-child interactions plus each child's responses to a 90-item probe containing questions representing the 15 question forms delineated by the model. The interrogation model was an effective and reliable tool in the analysis of data. The question forms most frequently used by the mothers were (1) wh- interrogative nominal segment, (2) auxiliary + no infinitive, and (3) tag questions. All three subjects displayed similarities of performance in response to wh- interrogative nominal segment and auxiliary + no infinitive questions. Two of the subjects appeared capable of appropriately answering all of the question forms tested during the interrogative probe. Similarities of performance during the mother-child interaction and the interrogative probe were found to exist for two of the three subjects in certain categories. A high percentage of the questions posed by the mothers during the mother-child interactions were of forms which their children consistently answered appropriately during the interrogative probe.

Several studies in the last decade have demonstrated the importance of considering an information seeking versus information avoiding coping dimension in adult medical patients. However, there have been few empirical demonstrations of such a dimension in children. The present study utilized the Coping Strategies Interview to assign an information seeking score to child elective surgery patients. This information seeking score was related to several parent-rated variables, including the child's historical success in coping with medical procedures, the child's typical preference for information acquisition, and the child's typically emitted coping behaviors. In addition, the information seeking score was related to question asking and discussion of medical procedures as rated by an objective observer during the blood test, by the nurse during anesthesia induction, and by the parent during recovery from surgery. It was strongly related to the information acquired prior to hospitalization. Information seeking was also related to stress responses, such that high information seeking scores predicted more adaptive behaviors prior to the blood test. This cross-rater and cross-situation validation suggests the existence of an information seeking dimension in children and the utility of considering this dimension in future research.