Actual and Missed Opportunities for End-of-Life Care Discussions With Oncology Patients: A Qualitative Study.

Importance: Early discussion of end-of-life (EOL) care preferences improves clinical outcomes and goal-concordant care. However, most EOL discussions occur approximately 1 month before death, despite most patients desiring information earlier. Objective: To describe successful navigation and missed opportunities for EOL discussions (eg, advance care planning, palliative care, discontinuation of disease-directed treatment, hospice care, and after-death wishes) between oncologists and outpatients with advanced cancer. Design, Setting, and Participants: This study is a secondary qualitative analysis of outpatient visits audio-recorded between November 2010 and September 2014 for the Studying Communication in Oncologist-Patient Encounters randomized clinical trial. The study was conducted at 2 US academic medical centers. Participants included medical, gynecological, and radiation oncologists and patients with stage IV malignant neoplasm, whom oncologists characterized as being ones whom they "…would not be surprised if they were admitted to an intensive care unit or died within one year." Data were analyzed between January 2018 and August 2020. Exposures: The parent study randomized participants to oncologist- and patient-directed interventions to facilitate discussion of emotions. Encounters were sampled across preintervention and postintervention periods and all 4 treatment conditions. Main Outcomes and Measures: Secondary qualitative analysis was done of patient-oncologist dyads with 3 consecutive visits for EOL discussions, and a random sample of 7 to 8 dyads from 4 trial groups was analyzed for missed opportunities. Results: The full sample included 141 patients (54 women [38.3%]) and 39 oncologists (8 women [19.5%]) (mean [SD] age for both patients and oncologists, 56.3 [10.0] years). Of 423 encounters, only 21 (5%) included EOL discussions. Oncologists reevaluated treatment options in response to patients' concerns, honored patients as experts on their goals, or used anticipatory guidance to frame treatment reevaluation. In the random sample of 31 dyads and 93 encounters, 35 (38%) included at least 1 missed opportunity. Oncologists responded inadequately to patient concerns over disease progression or dying, used optimistic future talk to address patient concerns, or expressed concern over treatment discontinuation. Only 4 of 23 oncologists (17.4%) had both an EOL discussion and a missed opportunity. Conclusions and Relevance: Opportunities for EOL discussions were rarely realized, whereas missed opportunities were more common, a trend that mirrored oncologists' treatment style. There remains a need to address oncologists' sensitivity to EOL discussions, to avoid unnecessary EOL treatment.

Encounter decision aids to facilitate shared decision-making with women experiencing heavy menstrual bleeding or symptomatic uterine fibroids: A before-after study.

OBJECTIVE: Is the level of shared decision-making (SDM) higher after introduction of a SDM package (including encounter decision aids on treatment options for heavy menstrual bleeding and training for clinicians) than before?. METHODS: This before-after study, performed in OB-GYN practice, compared consultations before and after introduction of a SDM package. The target sample size was 25 patients per group. Women seeking treatment for heavy menstrual bleeding were eligible. After their appointments, patients filled out a three-item patient-reported SDM measure. Treatment discussions were audio-recorded and rated for SDM using Observer OPTION5. Consultation transcripts in the 'after' group were checked for adherence to the steps required for intended use of decision aids. RESULTS: 16 gynaecologists participated. 25 patients participated before introduction of the decision aids and 28 after. The proportion of women reporting optimal SDM was higher after introduction (75 %) than before (50 %;p < 0.001). The mean observer-rated level of SDM was also significantly higher after than before (MD = 12.50,95 % CI 5.53-19.47). CONCLUSION: The level of SDM was higher after the introduction of the package than before. PRACTICE IMPLICATIONS: This study was conducted in a real-life setting in three clinics, both large academic and small rural, offering opportunities for implementation in different type of organizations.

Identification of Key Functional Motifs of Native Amelogenin Protein for Dental Enamel Remineralisation.

Dental caries or tooth decay is a preventable and multifactorial disease that affects billions of people globally and is a particular concern in younger populations. This decay arises from acid demineralisation of tooth enamel resulting in mineral loss from the subsurface. The remineralisation of early enamel carious lesions could prevent the cavitation of teeth. The enamel protein amelogenin constitutes 90% of the total enamel matrix protein in teeth and plays a key role in the biomineralisation of tooth enamel. The physiological importance of amelogenin has led to the investigation of the possible development of amelogenin-derived biomimetics against dental caries. We herein review the literature on amelogenin, its primary and secondary structure, comparison to related species, and its' in vivo processing to bioactive peptide fragments. The key structural motifs of amelogenin that enable enamel remineralisation are discussed. The presence of several motifs in the amelogenin structure (such as polyproline, N- and C-terminal domains and C-terminal orientation) were shown to play a critical role in the formation of particle shape during remineralization. Understanding the function/structure relationships of amelogenin can aid in the rational design of synthetic polypeptides for biomineralisation, halting enamel loss and leading to improved therapies for tooth decay.

Role of norms in variation in cancer centers' end-of-life quality: qualitative case study protocol.

BACKGROUND: A critical barrier to improving the quality of end-of-life (EOL) cancer care is our lack of understanding of the mechanisms underlying variation in EOL treatment intensity. This study aims to fill this gap by identifying 1) organizational and provider practice norms at major US cancer centers, and 2) how these norms influence provider decision making heuristics and patient expectations for EOL care, particularly for minority patients with advanced cancer. METHODS: This is a multi-center, qualitative case study at six National Comprehensive Cancer Network (NCCN) and National Cancer Institute (NCI) Comprehensive Cancer Centers. We will theoretically sample centers based upon National Quality Forum (NQF) endorsed EOL quality metrics and demographics to ensure heterogeneity in EOL intensity and region. A multidisciplinary team of clinician and non-clinician researchers will conduct direct observations, semi-structured interviews, and artifact collection. Participants will include: 1) cancer center and clinical service line administrators; 2) providers from medical, surgical, and radiation oncology; palliative or supportive care; intensive care; hospital medicine; and emergency medicine who see patients with cancer and have high clinical practice volume or high local influence (provider interviews and observations); and 3) adult patients with metastatic solid tumors and whom the provider would not be surprised if they died in the next 12 months and their caregivers (patient and caregiver interviews). Leadership interviews will probe about EOL institutional norms and organization. We will observe inpatient and outpatient care for two weeks. Provider interviews will use vignettes to probe explicit and implicit motivations for treatment choices. Semi-structured interviews with patients near EOL, or their family members and caregivers will explore past, current, and future decisions related to their cancer care. We will import transcribed field notes and interviews into Dedoose software for qualitative data management and analysis, and we will develop and apply a deductive and inductive codebook to the data. DISCUSSION: This study aims to improve our understanding of organizational and provider practice norms pertinent to EOL care in U.S. cancer centers. This research will ultimately be used to inform a provider-oriented intervention to improve EOL care for racial and ethnic minority patients with advanced cancer. TRIAL REGISTRATION: Clinicaltrials.gov ; NCT03780816 ; December 19, 2018.

End-of-life quality metrics among medicare decedents at minority-serving cancer centers: A retrospective study.

BACKGROUND: We calculated the performance of National Cancer Institute (NCI)/National Comprehensive Cancer Network (NCCN) cancer centers' end-of-life (EOL) quality metrics among minority and white decedents to explore center-attributable sources of EOL disparities. METHODS: We conducted a retrospective cohort study of Medicare beneficiaries with poor-prognosis cancers who died between April 1, 2016 and December 31, 2016 and had any inpatient services in the last 6 months of life. We attributed patients' EOL treatment to the center at which they received the preponderance of EOL inpatient services and calculated eight risk-adjusted metrics of EOL quality (hospice admission ≤3 days before death; chemotherapy last 14 days of life; ≥2 emergency department (ED) visits; intensive care unit (ICU) admission; or life-sustaining treatment last 30 days; hospice referral; palliative care; advance care planning last 6 months). We compared performance between patients across and within centers. RESULTS: Among 126,434 patients, 10,119 received treatment at one of 54 NCI/NCCN centers. In aggregate, performance was worse among minorities for ED visits (10.3% vs 7.4%, P < .01), ICU admissions (32.9% vs 30.4%, P = .03), no hospice referral (39.5% vs 37.0%, P = .03), and life-sustaining treatment (19.4% vs 16.2%, P < .01). Despite high within-center correlation for minority and white metrics (0.61-0.79; P < .01), five metrics demonstrated worse performance as the concentration of minorities increased: ED visits (P = .03), ICU admission (P < .01), no hospice referral (P < .01), and life-sustaining treatments (P < .01). CONCLUSION: EOL quality metrics vary across NCI/NCCN centers. Within center, care was similar for minority and white patients. Minority-serving centers had worse performance on many metrics.

End-of-Life Spending and Healthcare Utilization Among Older Adults with Chronic Obstructive Pulmonary Disease.

BACKGROUND: End-of-life spending and healthcare utilization among older adults with COPD have not been previously described. METHODS: We examined data on Medicare beneficiaries aged 65 years or older with chronic obstructive pulmonary disease (COPD) who died during the period of 2013-2014. End-of-life measures were retrospectively reviewed for 2 years prior to death. Hospital referral regions (HRRs) were categorized into quintiles of age-sex-race-adjusted overall spending during the last 2 years of life. Geographic quintile variation in spending and healthcare utilization was examined across the continuum. RESULTS: We investigated data on 146,240 decedents with COPD from 306 HRRs. Age-sex-race-adjusted overall spending per decedent during the last 2 years of life varied significantly nationwide ($61,271±$11,639 per decedent; range: $48,288±$3,665 to $79,453±$9,242). Inpatient care accounted for 40.2% of spending ($24,626±$6,192 per decedent). Overall, 82%±4% of decedents were admitted to the hospital for 13.7±3.1 days, and 55%±11% were admitted to an intensive care unit for 5.4±2.5 days. Compared with HRRs in the lowest spending quintile, HRRs in the highest spending quintile had a 1.5-fold longer hospital length of stay. Skilled nursing facilities accounted for 11.6% of spending ($7101±$2403 per decedent), and these facilities were utilized by 38%±7% of decedents for 18.7±4.9 days. Hospice accounted for 10.3% of spending ($6,307±$2,201 per decedent) and was utilized by 47%±9% of decedents for 39.7±14.8 days. Significant geographic variation in hospice utilization existed nationwide. CONCLUSIONS: End-of-life spending and healthcare utilization among older adults with COPD varied substantially nationwide. Decedents with COPD frequently utilized acute care near the end of life. Hospice utilization was higher than expected, with significant geographic disparities.

Are Urinary Biomarkers Better Than Acute Kidney Injury Duration for Predicting Readmission?

BACKGROUND: Acute kidney injury (AKI) is a common complication of cardiac surgery. Postprocedural AKI is a risk factor for 30-day readmission. We sought to examine the association of AKI and kidney injury biomarkers with readmission after cardiac surgery. METHODS: Patients alive at discharge who underwent cardiac surgery from the Translational Research Investigating Biomarker Endpoints-AKI cohort were enrolled from six medical centers in the United States and Canada. AKI duration was defined as the total number of days AKI was present during index admission (no AKI, 1-2, 3-6, and 7+ days). Preoperative and postoperative urinary levels were collected for interleukin-18, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, liver-fatty-acid-binding protein, cystatin C, microalbumin, creatinine, and albumin-to-creatinine ratio. Readmission and death events were identified through US (Medicare) and Canadian administrative databases at 30 days and 365 days after discharge. RESULTS: Of 968 patients 15.9% were readmitted or died within 30 days of discharge and 35.9% were readmitted or died within 365 days. AKI duration of 3 to 6 days was significantly associated with 30-day readmission or death (adjusted odds ratio, 1.82%; 95% confidence interval, 1.08-3.05). Patients with AKI duration ≥ 7 days had increased odds of readmission or death at both 30 days (adjusted odds ratio, 2.49%; 95% confidence interval, 1.15-5.43) and 365 days (adjusted odds ratio, 3.67%; 95% confidence interval, 1.73-7.79). Urinary biomarkers had no association with readmission and death. CONCLUSIONS: AKI duration ≥ 3 days, and not kidney biomarkers, was strongly associated with readmission or death. These clinical outcomes are potentially due to cardiovascular or hemodynamic causes rather than intrinsic injury to the kidney parenchyma.

The Association between Cytokines and 365-Day Readmission or Mortality in Adult Cardiac Surgery.

Cardiac surgery results in a multifactorial systemic inflammatory response with inflammatory cytokines, such as interleukin-10 and 6 (IL-10 and IL-6), shown to have potential in the prediction of adverse outcomes including readmission or mortality. This study sought to measure the association between IL-6 and IL-10 levels and 1-year hospital readmission or mortality following cardiac surgery. Plasma biomarkers IL-6 and IL-10 were measured in 1,047 patients discharged alive after isolated coronary artery bypass graft surgery from eight medical centers participating in the Northern New England Cardiovascular Disease Study Group between 2004 and 2007. Readmission status and mortality were ascertained using Medicare, state all-payer claims, and the National Death Index. We evaluated the association between preoperative and postoperative cytokines and 1-year readmission or mortality using Kaplan-Meier estimates and Cox's proportional hazards modeling, adjusting for covariates used in the Society of Thoracic Surgeons 30-day readmission model. The median follow-up time was 1 year. After adjustment, patients in the highest tertile of postoperative IL-6 values had a significantly increased risk of readmission or death within 1 year (HR: 1.38; 95% CI: 1.03-1.85), and an increased risk of death within 1 year of discharge (HR: 4.88; 95% CI: 1.26-18.85) compared with patients in the lowest tertile. However, postoperative IL-10 levels, although increasing through tertiles, were not found to be significantly associated independently with 1-year readmission or mortality (HR: 1.25; 95% CI: .93-1.69). Pro-inflammatory cytokine IL-6 and anti-inflammatory cytokine IL-10 may be postoperative markers of cardiac injury, and IL-6, specifically, shows promise in predicting readmission and mortality following cardiac surgery.

Utility of Biomarkers to Improve Prediction of Readmission or Mortality After Cardiac Surgery.

BACKGROUND: Hospital readmission within 30 days is associated with higher risks of complications, death, and increased costs. Accurate statistical models to stratify the risk of 30-day readmission or death after cardiac surgery could help clinical teams focus care on those patients at highest risk. We hypothesized biomarkers could improve prediction for readmission or mortality. METHODS: Levels of ST2, galectin-3, N-terminal pro-brain natriuretic peptide, cystatin C, interleukin-6, and interleukin-10 were measured in samples from 1,046 patients discharged after isolated coronary artery bypass graft surgery from eight medical centers, with external validation in 1,194 patients from five medical centers. Thirty-day readmission or mortality were ascertained using Medicare, state all-payer claims, and the National Death Index. We tested and externally validated the clinical models and the biomarker panels using area under the receiver-operating characteristics (AUROC) statistics. RESULTS: There were 112 patients (10.7%) who were readmitted or died within 30 days after coronary artery bypass graft surgery. The Society of Thoracic Surgeons augmented clinical model resulted in an AUROC of 0.66 (95% confidence interval: 0.61 to 0.71). The biomarker panel with The Society of Thoracic Surgeons augmented clinical model resulted in an AUROC of 0.74 (bootstrapped 95% confidence interval: 0.69 to 0.79, p < 0.0001). External validation of the model showed limited improvement with the addition of a biomarker panel, with an AUROC of 0.51 (95% confidence interval: 0.45 to 0.56). CONCLUSIONS: Although biomarkers significantly improved prediction of 30-day readmission or mortality in our derivation cohort, the external validation of the biomarker panel was poor. Biomarkers perform poorly, much like other efforts to improve prediction of readmission, suggesting there are many other factors yet to be explored to improve prediction of readmission.

Predictive Ability of Novel Cardiac Biomarkers ST2, Galectin-3, and NT-ProBNP Before Cardiac Surgery.

BACKGROUND: Current preoperative models use clinical risk factors alone in estimating risk of in-hospital mortality following cardiac surgery. However, novel biomarkers now exist to potentially improve preoperative prediction models. An assessment of Galectin-3, N-terminal pro b-type natriuretic peptide (NT-ProBNP), and soluble ST2 to improve the predictive ability of an existing prediction model of in-hospital mortality may improve our capacity to risk-stratify patients before surgery. METHODS AND RESULTS: We measured preoperative biomarkers in the NNECDSG (Northern New England Cardiovascular Disease Study Group), a prospective cohort of 1554 patients undergoing coronary artery bypass graft surgery. Exposures of interest were preoperative levels of galectin-3, NT-ProBNP, and ST2. In-hospital mortality and adverse events occurring after coronary artery bypass graft were the outcomes. After adjustment, NT-ProBNP and ST2 showed a statistically significant association with both their median and third tercile categories with NT-ProBNP odds ratios of 2.89 (95% confidence interval [CI]: 1.04-8.05) and 5.43 (95% CI: 1.21-24.44) and ST2 odds ratios of 3.96 (95% CI: 1.60-9.82) and 3.21 (95% CI: 1.17-8.80), respectively. The model receiver operating characteristic score of the base prediction model (0.80 [95% CI: 0.72-0.89]) varied significantly from the new multi-marker model (0.85 [95% CI: 0.79-0.91]). Compared with the Northern New England (NNE) model alone, the full prediction model with biomarkers NT-proBNP and ST2 shows significant improvement in model classification of in-hospital mortality. CONCLUSIONS: This study demonstrates a significant improvement of preoperative prediction of in-hospital mortality in patients undergoing coronary artery bypass graft and suggests that biomarkers can be used to identify patients at higher risk.

The Association Between Novel Biomarkers and 1-Year Readmission or Mortality After Cardiac Surgery.

BACKGROUND: Novel cardiac biomarkers including soluble suppression of tumorigenicity 2, galectin-3, and the N-terminal prohormone of brain natriuretic peptide may be associated with long-term adverse outcomes after cardiac surgery. We sought to measure the association between cardiac biomarker levels and 1-year hospital readmission or mortality. METHODS: Plasma biomarkers from 1,047 patients discharged alive after isolated coronary artery bypass graft surgery from 8 medical centers were measured in a cohort from the Northern New England Cardiovascular Disease Study Group between 2004 and 2007. We evaluated the association between preoperative and postoperative biomarkers and 1-year readmission or mortality using Kaplan-Meier estimates and Cox proportional hazards modeling, adjusting for covariates used in The Society of Thoracic Surgeons 30-day readmission model. RESULTS: The median follow-up time was 365 days. After adjustment for established risk factors, above-median levels of postoperative galectin-3 (median 10.35 ng/mL; hazard ratio, 1.40; 95% confidence interval, 1.08 to 1.80; p = 0.010) and N-terminal prohormone of brain natriuretic peptide (median = 15.21 ng/mL, hazard ratio, 1.42; 95% confidence interval, 1.07 to 1.87; p = 0.014) were each significantly associated with 1-year readmission or mortality. CONCLUSIONS: In patients undergoing cardiac surgery, novel cardiac biomarkers were associated with readmission or mortality independent of established risk factors. Measurement of these biomarkers may improve our ability to identify patients at highest risk for readmission or mortality before discharge. This will also allow resource allocation accordingly, while implementing strategies for personalized medicine based on the biomarker profile of the patient.

Preoperative serum ST2 level predicts acute kidney injury after adult cardiac surgery.

OBJECTIVE: The purpose of this study was to evaluate the relationship between preoperative levels of serum soluble ST2 (ST2) and acute kidney injury (AKI) after cardiac surgery. Previous research has shown that biomarkers facilitate the prediction of AKI and other complications after cardiac surgery. METHODS: Preoperative ST2 proteins were measured in 1498 patients undergoing isolated coronary artery bypass graft surgery at 8 hospitals participating in the Northern New England Biomarker Study from 2004 to 2007. AKI severity was defined using the Acute Kidney Injury Network (AKIN) definition. Preoperative ST2 levels were measured using multiplex assays. Ordered logistic regression was used to examine the relationship between ST2 levels and levels of AKI severity. RESULTS: Participants in this study showed a significant association between elevated preoperative ST2 levels and acute kidney risk. Before adjustment, the odds of patients developing AKIN stage 2 or 3, compared with AKIN stage 1, are 2.43 times higher (95% confidence interval, 1.86-3.16; P < .001) for patients in the highest tercile of preoperative ST2. After adjustment, patients in the highest tercile of preoperative ST2 had significantly greater odds of developing AKIN stage 2 or 3 AKI (odds ratio, 1.99; 95% confidence interval, 1.50-2.65; P < .001) compared with patients with AKIN stage 1. CONCLUSIONS: Preoperative ST2 levels are associated with postoperative AKI risk and can be used to identify patients at higher risk of developing AKI after cardiac surgery.

Meta-Analysis of Individual Patient Data of Sodium Bicarbonate and Sodium Chloride for All-Cause Mortality After Coronary Angiography.

We sought to examine the relation between sodium bicarbonate prophylaxis for contrast-associated nephropathy (CAN) and mortality. We conducted an individual patient data meta-analysis from multiple randomized controlled trials. We obtained individual patient data sets for 7 of 10 eligible trials (2,292 of 2,764 participants). For the remaining 3 trials, time-to-event data were imputed based on follow-up periods described in their original reports. We included all trials that compared periprocedural intravenous sodium bicarbonate to periprocedural intravenous sodium chloride in patients undergoing coronary angiography or other intra-arterial interventions. Included trials were determined by consensus according to predefined eligibility criteria. The primary outcome was all-cause mortality hazard, defined as time from randomization to death. In 10 trials with a total of 2,764 participants, sodium bicarbonate was associated with lower mortality hazard than sodium chloride at 1 year (hazard ratio 0.61, 95% confidence interval [CI] 0.41 to 0.89, p = 0.011). Although periprocedural sodium bicarbonate was associated with a reduction in the incidence of CAN (relative risk 0.75, 95% CI 0.62 to 0.91, p = 0.003), there exists a statistically significant interaction between the effect on mortality and the occurrence of CAN (hazard ratio 5.65, 95% CI 3.58 to 8.92, p <0.001) for up to 1-year mortality. Periprocedural intravenous sodium bicarbonate seems to be associated with a reduction in long-term mortality in patients undergoing coronary angiography or other intra-arterial interventions.

Maternal body mass index and risk of testicular cancer in male offspring: a systematic review and meta-analysis.

OBJECTIVES: To date a number of studies have examined the association between maternal weight and testicular cancer risk although results have been largely inconsistent. This systematic review and meta-analysis investigated the nature of this association. METHODS: Search strategies were conducted in Ovid Medline (1950-2009), Embase (1980-2009), Web of Science (1970-2009), and CINAHL (1937-2009) using keywords for maternal weight (BMI) and testicular cancer. RESULTS: The literature search produced 1689 hits from which 63 papers were extracted. Only 7 studies met the pre-defined criteria. Random effects meta-analyses were conducted. The combined unadjusted OR (95% CI) of testicular cancer in the highest reported category of maternal BMI compared with the moderate maternal BMI was 0.82 (0.65-1.02). The Cochran's Q P value was 0.82 and the corresponding I(2) was 0%, both indicating very little variability among studies. The combined unadjusted OR (95% CI) for testicular cancer risk in the lowest reported category of maternal BMI compared to a moderate maternal BMI category was 0.88 (0.65-1.20). The Cochran's Q P value was 0.05 and the corresponding I(2) was 54%, indicating evidence of statistical heterogeneity. The combined unadjusted OR (95% CI) of testicular cancer risk per unit increase in maternal BMI was 1.01 (0.97-1.06). The Cochran's Q test had a P value of 0.05 and the corresponding I(2) was 55% indicating evidence of statistical heterogeneity. CONCLUSION: This meta-analysis, which included a small number of studies, showed that a higher maternal weight does not increase the risk of testicular cancer in male offspring. Though an inverse association between high maternal BMI and testicular cancer risk was detected, it was not statistically significant. Further primary studies with adjustment for appropriate confounders are required.

Synthesis and spectral characterization of CoxMg1-xAl2O4 as new nano-coloring agent of ceramic pigment.

New nano-blue ceramic pigments of Co(x)Mg(1-x)Al(2)O(4) (0< or =x< or =0.1) have been prepared by co-precipitate-combustion as a hybrid method using urea as a fuel at 500 degrees C in open furnace in air atmosphere. The structure of pigment is assigned based on TGA/DTA/DrTGA analyses, X-ray diffraction (XRD) and transmission electron microscopy (TEM). Also, electronic spectra, infrared (IR) and diffuse reflectance spectroscopy (DRS) using CIE L*a*b* parameter measurement techniques were used. The results revealed that the nano-particle size of pigments were obtained in the range 30-38 nm as well as the varying colors and particle size as a result of different calcinations temperatures within the range of 500-1200 degrees C for 2h.

Spectrophotometric microdetermination of nefopam, mebevrine and phenylpropanolamine hydrochloride in pharmaceutical formulations using alizarins.

Simple and rapid spectrophotometric procedures have been established for quantitation of nefopam hydrochloride (NF) mebevrine hydrochloride (MB) and phenylpropanolamine hydrochloride (PP). The procedures are based on the reaction between the examined drugs (NF, MB and PP) and alizarin (I), alizarin red S (II), alizarin yellow G (III) and quinalizarin (IV) producing ion-pair complexes which can be measured at the optimum wavelength. The optimization of the reaction conditions is investigated. Beer's law is obeyed in the concentration ranges 0.5-30.0 microg ml(-1). The molar absorptivity, Sandell sensitivity, detection and quantification limits are also calculated. The correlation coefficient was > or =0.9988 (n=6) with a relative standard deviation (R.S.D.) of < or =1.3, for six determinations of 20 microg ml(-1). The methods are successfully applied to the determination of NF, MB and PP in their pharmaceutical formulations.

Spectrophotometric determination of phenylephrine HCl and orphenadrine citrate in pure and in dosage forms.

A simple and rapid spectrophotometric methods have been estimated for the microdetermination of phenylephrine HCl (I) and orphenadrine citrate (II). The proposed methods are based on the formation of ion-pair complexes between the examined drugs with alizarine (Aliz), alizarine red S (ARS), alizarine yellow G (AYG) or quinalizarine (Qaliz), which can be measured at the optimum lambda(max). The optimization of the reaction conditions is investigated. Beer's law is obeyed in the concentration ranges 2-36 microgram ml(-1), whereas optimum concentration as adopted from Ringbom plots was 3.5-33 microgram ml(-1). The molar absorptivity, Sandell sensitivity, and detection limit are also calculated. The correlation coefficient was >/=0.9988 (n=6) with a relative standard deviation of

Determination of the thermodynamic parameters and stability constants of UO2(2+), Th4+, and Ce3+ complexes with some azo-benzene-N-malonic acid derivatives.

Proton-ligand dissociation and metal-ligand formation constants of azobenzene-N-malonic acid (I), p-Cl-azobenzene-N-malonic acid (II), p-Br-azobenzene-N-malonic acid (III) and p-COOH- azobenzene-N-malonic acid (IV) with UO2(2+), Th4+ and Ce3+ were evaluated potentiometrically using Bjerrum's method at 25, 35 and 45 +/- 0.5 degrees C and ionic strength 0.1 M in 40% v/v ethanol-water medium. The order of stability constants was found to be Ce3+ > Th4+ > UO2(2+). The effect of temperature on the dissociation and stability constants of the formed complexes was studied and the corresponding thermodynamic functions were derived and discussed. The ratio of metal-ligand was determined conductometrically. The structure of the ligands under investigation as well as their metal complexes has been elucidated by elemental analysis, IR and 1HNMR spectroscopy.

Role of RAS2 in recovery from chronic stress: effect on yeast life span.

The replicative life span of Saccharomyces cerevisiae was previously shown to be modulated by the homologous signal transducers Ras1p and Ras2p in a reciprocal manner. We have used thermal stress as a life span modulator in order to uncover functional differences between the RAS genes that may contribute to their divergent effects on life span. Chronic exposure of cells throughout life to recurring heat shocks at sublethal temperatures decreased their replicative life span. ras2 mutants, however, suffered the largest decrease compared to wild-type and ras1 mutant cells. The decrease was correlated with a substantial delay in resumption of budding upon recovery from these heat shocks, indicating an impaired renewal of cell cycling. Detailed analysis of gene expression showed that, during recovery, ras2 mutants were selectively impaired in down-regulation of stress-responsive genes and up-regulation of growth-promoting genes. Our results suggest that one of the functions of RAS2 in maintaining life span, for which RAS1 does not substitute, is to ensure renewal of growth and cell division after bouts of stress that cells encounter during their life. This activity of RAS2 is effected by the cyclic AMP pathway. Overexpression of RAS2, but not RAS2(ser42) which is deficient in the activation of adenylate cyclase, completely reversed the effect of chronic stress on life span. Thus, RAS2 is limiting for longevity in the face of chronic stress. Since RAS2 is known to down-regulate stress responses, this demonstrates that for longevity the ability to recover from stress is at least as important as the ability to mount a stress response.

Heat stress-induced life span extension in yeast.

The yeast Saccharomyces cerevisiae has a limited life span that can be measured by the number of times individual cells divide. Several genetic manipulations have been shown to prolong the yeast life span. However, environmental effects that extend longevity have been largely ignored. We have found that mild, nonlethal heat stress extended yeast life span when it was administered transiently early in life. The increased longevity was due to a reduction in the mortality rate that persisted over many cell divisions (generations) but was not permanent. The genes RAS1 and RAS2 were necessary to observe this effect of heat stress. The RAS2 gene is consistently required for maintenance of life span when heat stress is chronic or in its extension when heat stress is transient or absent altogether. RAS1, on the other hand, appears to have a role in signaling life extension induced by transient, mild heat stress, which is distinct from its life-span-curtailing effect in the absence of stress and its lack of involvement in the response to chronic heat stress. This distinction between the RAS genes may be partially related to their different effects on growth-promoting genes and stress-responsive genes. The ras2 mutation clearly hindered resumption of growth and recovery from stress, while the ras1 mutation did not. The HSP104 gene, which is largely responsible for induced thermotolerance in yeast, was necessary for life extension induced by transient heat stress. An interaction between mitochondrial petite mutations and heat stress was found, suggesting that mitochondria may be necessary for life extension by transient heat stress. The results raise the possibility that the RAS genes and mitochondria may play a role in the epigenetic inheritance of reduced mortality rate afforded by transient, mild heat stress.