Advance care planning and proxy decision making for patients with advanced Parkinson disease.

OBJECTIVES: To examine advance care planning practices and proxy decision making by family healthcare proxies for patients with advanced Parkinson disease (PD). METHODS: Sixty-four spouses and adult children, self-designated as a/the healthcare proxy for advanced patients with PD, participated in a cross-sectional survey study. RESULTS: Sixty patients with PD (95%) had completed a living will, but only 38% had shared the document with a physician. Among three life-support treatments--cardiopulmonary resuscitation (CPR), ventilator, and feeding tube--47% of patients opted for CPR, 16% for ventilator, and 20% for feeding tube. Forty-two percent of proxies did not know patients' preferences for one or more of the three life-support treatments. Only 28% of proxies reported that patients wanted hospice. Patients who shared advance directives with a physician were significantly less likely to choose CPR and a feeding tube and they were more likely to choose hospice. In a hypothetical end-of-life (EOL) scenario, the majority of proxies chose comfort care as the EOL goal of care (53%) and pain and symptom management only as the course of treatment option (72%); these proxy choices for patients, however, were not associated with patients' preferences for life support. Patients' proxies preferred a form of shared decision making with other family members and physicians. CONCLUSIONS: Advance care planning is effective when patients, families, and healthcare professionals together consider future needs for EOL care decisions. Further efforts are needed by healthcare professionals to provide evidence-based education about care options and facilitate advanced discussion and shared decision making by the patient and families.

Dermal application of nitric oxide releasing acidified nitrite-containing liniments significantly reduces blood pressure in humans.

Vascular ischemic diseases, hypertension, and other systemic hemodynamic and vascular disorders may be the result of impaired bioavailability of nitric oxide (NO). NO but also its active derivates like nitrite or nitroso compounds are important effector and signal molecules with vasodilating properties. Our previous findings point to a therapeutical potential of cutaneous administration of NO in the treatment of systemic hemodynamic disorders. Unfortunately, no reliable data are available on the mechanisms, kinetics and biological responses of dermal application of nitric oxide in humans in vivo. The aim of the study was to close this gap and to explore the therapeutical potential of dermal nitric oxide application. We characterized with human skin in vitro and in vivo the capacity of NO, applied in a NO-releasing acidified form of nitrite-containing liniments, to penetrate the epidermis and to influence local as well as systemic hemodynamic parameters. We found that dermal application of NO led to a very rapid and significant transepidermal translocation of NO into the underlying tissue. Depending on the size of treated skin area, this translocation manifests itself through a significant systemic increase of the NO derivates nitrite and nitroso compounds, respectively. In parallel, this translocation was accompanied by an increased systemic vasodilatation and blood flow as well as reduced blood pressure. We here give evidence that in humans dermal application of NO has a therapeutic potential for systemic hemodynamic disorders that might arise from local or systemic insufficient availability of NO or its bio-active NO derivates, respectively.

Parkinson disease: research update and clinical management.

More than 1 million people in the United States have Parkinson disease (PD), more than are diagnosed as having multiple sclerosis, amyotrophic lateral sclerosis, muscular dystrophy, and myasthenia gravis combined. PD affects approximately 1 in 100 Americans older than 60 years. It burdens patients, their care partners, and the overall healthcare system. This article reviews the epidemiology, clinical features, putative environmental risk and protective factors, neuropathological aspects, heterogeneity, medical management, and recent studies regarding genetics and PD. The article suggests that based on new research, the prevalence of PD varies in different regions of the United States. Some progress has been made in identifying the risk and protective factors of PD, and a newly emphasized area of study in PD is genetics. Patient care recommendations, based on American Academy of Neurology practice guidelines, are outlined to show the state of contemporary medical management of PD and related disorders.

How much striving is too much? John Henryism active coping predicts worse daily cortisol responses for African American but not white female dementia family caregivers.

INTRODUCTION: The John Henryism active coping (JHAC) hypothesis suggests that striving with life challenges predicts increased risk for cardiovascular disease for those with scarce coping resources. This study examined the moderating role of JHAC in the associations of 1) caregiver status and 2) care recipient functional status with diurnal salivary cortisol patterns among 30 African Americans (AAs) and 24 white female dementia caregivers and 63 noncaregivers (48 AAs). METHODS: Caregiver participants completed the JHAC-12 scale, Activities of Daily Living (ADL) scale, and Revised Memory and Behavior Problem checklist (RMBPC) and collected five saliva samples daily (at awakening, 9 A.M., 12 P.M., 5 P.M., and 9 P.M.) for 2 successive days. RESULTS: Univariate analysis of variance tests with mean diurnal cortisol slope as the outcome illustrated that among AA caregivers, higher JHAC scores were related to flatter (or more dysregulated) cortisol slopes. The JHAC by ADL and JHAC by RMBPC interactions were each significant for AA caregivers. Among AA caregivers who reported higher ADL and RMBPC scores, higher JHAC scores were associated with flatter cortisol slopes. CONCLUSIONS: These findings extend recent studies by showing that being AA, a caregiver, and high in JHAC may elevate the risk for chronic disease, especially for those with higher patient ADL and behavioral problems. Thus, it is imperative that interventions appreciate the pernicious role of high-effort coping style, especially for AA caregivers, to minimize the stressful side effects of patient ADL and memory and behavioral problems for the caregiver.

NO detection in biological samples: differentiation of 14 NO and 15 NO using infrared laser spectroscopy.

Accurate characterization of the biochemical pathways of nitric oxide (NO) is essential for investigations in the field of NO research. To analyze the different reaction pathways of enzymatic and non-enzymatic NO formation, determination of the source of NO is crucial. Measuring NO-related products in biological samples distinguishing between (14)NO and (15)NO offers the opportunity to specifically analyze NO signaling in blood and tissue. The aim of this study was to establish a highly sensitive technique for the specific measurement of NO in an isotopologue-selective manner in biological samples. With the cavity leak-out spectroscopy setup (CALOS) a differentiation between (14)NO and (15)NO is feasible. We describe here the employment of this method for measurements in biological samples. Certified gas mixtures of (14)NO/N(2) and (15)NO/N(2) were used to calibrate the system. (14)NO2- and (15)NO2- of aqueous and biological samples were reduced in a triiodide solution, and the NO released was detected via CALOS. Gas-phase chemiluminescence detection (CLD) was used for evaluation. The correlation received for both methods for the detection of NO in the gas phase was r=0.999, p<0.0001. Results obtained using aqueous and biological samples verified that CALOS enables NO measurements with high accuracy (detection limit for (14)NO2- 0.3 pmol and (15)NO2- 0.5 pmol; correlation (14)NO: p<0.0001, r=0.975, (15)NO: p<0.0001, r=0.969). The CALOS assay represents an extension of NO measurements in biological samples, allowing specific investigations of enzymatic and non-enzymatic NO formation and metabolism in a variety of samples.

Is exhaled carbon monoxide level associated with blood glucose level? A comparison of two breath analyzing methods.

The level of exhaled carbon monoxide (eCO) is considered a marker of oxidative stress in diabetes. Previous findings indicated that eCO levels correlated with blood glucose level. The aim of this work was to apply and compare two independent analyzing methods for eCO after oral glucose administration. Glycemia, eCO, and exhaled hydrogen were measured before and after oral administration of glucose. Six healthy nonsmoking volunteers participated. For eCO analysis, we used two methods: a commercially available electrochemical sensor, and a high-precision laser spectrometer developed in our laboratory. The precision of laser-spectroscopic eCO measurements was two orders of magnitude better than the precision of the electrochemical eCO measurement. eCO levels measured by laser spectrometry after glucose administration showed a decrease of 4.1%+/-1.5% compared to the baseline (p<0.05). Changes in the eCO measured by the electrochemical sensor were not significant (p=0.08). Exhaled hydrogen levels increased by 40% within the first 10 min after glucose administration (p<0.05). The previous finding that the glycemia increase after glucose administration was associated with a significant increase in eCO concentrations was not confirmed. We propose that previous eCO measurements with electrochemical sensors may have been affected by cross sensitivity to hydrogen.

Alzheimer's disease and smoking: bias in cohort studies.

The discrepancy between cohort and case-control studies regarding the association between smoking and Alzheimer's disease (AD) has been attributed to the competing risk of early mortality of smokers. A simulation study was conducted to show that the bias favoring smokers acts also on cohort studies. In the model, individuals {grow older} and have smoking habits according to published year-age-gender-specific patterns, with morbidity and mortality according to their demographic and smoking profiles. Those individuals dying of smoking-related causes ("phantoms") remain at risk of AD and of death from other causes. Three scenarios were considered: no association of AD and smoking, increased risk for smokers, and decreased risk for smokers. For each simulation of a cohort study, two incidence density ratios (IDR) were computed: one including the phantoms that developed AD (thus ignoring smoking-related deaths) and another excluding them (thus mimicking real-life studies). For all scenarios, the simulations show that smoking-related death creates a bias, resulting in smokers having an understated risk of AD compared to non-smokers. The speculation that the conflicting results of case-control and cohort studies are solely due to the increased mortality in smokers thus appears unjustified. Other factors must also be considered to explain the discrepancy in results.

Height and Alzheimer's disease: findings from a case-control study.

The purpose of this study is to examine the relationship of height, Apolipoprotein E genotype (APOE) and Alzheimer's disease (AD). Using a case-control design, subjects were recruited from the research registry of the University Memory and Aging Center of Case Western Reserve University and University Hospitals of Cleveland. On entry to the study, height was measured on 239 probable or possible AD patients and 341 healthy controls living in northeast Ohio. Risk of AD was modeled as a function of quartile of height, APOE genotype, years of education and year of birth. Analyses were stratified by gender. For men, cases were more likely to be shorter when compared to controls (p=0.001). There was only a small difference in mean height between AD cases and controls among women (p=0.05). For men, height in the highest quartile [>179.7 cm (70.75 in)] had a 59% lower risk of developing AD that in the lowest quartile [< 169.5 cm (66.75 in)], controlling for year of birth, and education (p=0.03). For women without an APOE epsilon4 allele, increasing height was associated with lower risk for AD (OR=0.88; p=0.01) but no significant association was found for women with at least one epsilon4 allele (OR=1.03; p=0.56).

Cognitive functioning in healthy aging: the role of reserve and lifestyle factors early in life.

PURPOSE: According to the reserve perspective on cognitive aging, individuals are born with or can develop resources that help them resist normal and disease-related cognitive changes that occur in aging. The reserve perspective is becoming more sophisticated, but gaps in knowledge persist. In the present research, we considered three understudied questions about reserve: Is reserve primarily static (unchangeable) throughout the life course or dynamic (changeable, in terms of increases or decreases)? Can reserve be increased at any point in life, or are there optimal time periods--such as early life, midlife, or late life--to increase it? Does participation in different types of leisure and occupational activities in early life and midlife have different effects depending on specific domains of late-life cognitive functioning? Here we link early cognitive and activity data--gathered from archival sources--with cognitive data from older adults to examine these issues. DESIGN AND METHODS: 349 participants, all mid-1940s graduates of the same high school, underwent telephone cognitive screening. All participants provided access to adolescent IQ scores; we determined activity levels from yearbooks. We used path analysis to evaluate the complex relationships between early life, midlife, and late-life variables. RESULTS: Adolescent IQ had strong direct effects on global cognitive functioning, episodic memory, verbal fluency, and processing speed. Participants' high school mental activities had direct effects on verbal fluency, but physical and social activities did not predict any cognitive measure. Education had direct effects on global cognitive functioning, episodic memory, and, most strongly, processing speed, but other midlife factors (notably, occupational demands) were not significant predictors of late-life cognition. There were weak indirect effects of adolescent IQ on global cognitive functioning, episodic memory, and processing speed, working through high school mental activities and education. Verbal fluency, in contrast, was affected by adolescent IQ through links with high school mental activities, but not education. IMPLICATIONS: Our study suggests that reserve is dynamic, but it is most amenable to change in early life. We conclude that an active, engaged lifestyle, emphasizing mental activity and educational pursuits in early life, can have a positive impact on cognitive functioning in late life.

The role of adolescent IQ and gender in the use of cognitive support for remembering in aging.

The purpose of this study was to examine the role of adolescent IQ (AIQ) and gender in older adults' ability to use cognitive support to enhance memory. Subjects were 269 mid-1940s graduates of the same high school. Adolescent IQ scores were gathered from archives, and subjects' memory for words was tested with tasks that provided increasing cognitive support. Overall, subjects benefited from support; women recalled more words than men; and persons with a high AIQ remembered more words than persons with a lower AIQ. However, while all subjects showed gains from cognitive support, men with a lower AIQ performed worse than men with a high AIQ. Women's performance was not dependent on their AIQ. Analysis of qualitative memory indicators suggested that women and persons with a high AIQ had better encoding and retrieval operations. Men with a lower AIQ appear to be particularly vulnerable to memory deficits in aging. This may be due to low "cognitive reserve" or generally poorer episodic memory function.

Associations between dementia/mild cognitive impairment and cognitive performance and activity levels in youth.

OBJECTIVES: To study the associations between dementia/mild cognitive impairment (MCI) and cognitive performance and activity levels in youth. DESIGN: Retrospective cohort study. SETTING: Research volunteers living throughout the United States. PARTICIPANTS: A total of 396 persons (mean age 75) who were graduates of the same high school in the mid-1940s. MEASUREMENTS: Adolescent intelligence quotient (IQ) scores were gathered from archived student records, and activity levels were determined from yearbooks. A two-stage telephone screening procedure (Modified Telephone Interview for Cognitive Status or Informant Questionnaire on Cognitive Decline in the Elderly followed by Dementia Questionnaire) was used to determine adult cognitive status. Data were analyzed using logistic regression to model the risk of cognitive impairment (dementia/MCI) versus no cognitive impairment as a function of IQ and activity level, adjusting for sex and education. RESULTS: High adolescent IQ and greater activity level were each independently associated with a lower risk for dementia/MCI (odds ratio (OR) for a 1-standard deviation increase in IQ=0.51, 95% confidence interval (CI)=0.32-0.79; OR for a unit increase in activity=0.32, 95% CI=0.12-0.84). No association was found between sex or education and adult cognitive status in this model. CONCLUSION: High IQ and greater activity levels in youth reduce the risk for cognitive impairments in aging. The mechanism(s) underlying these associations are unknown, but intelligence may be a marker for cognitive/neurological "reserve," and involvement in activities may contribute to "reserve." Early neuropathology and ascertainment bias are also possible explanations for the observed associations.

Participation in novelty-seeking leisure activities and Alzheimer's disease.

The objective was to study the associations between participation in different types of mentally stimulating leisure activities and status as Alzheimer's disease (AD) case or normal control. Research suggests that participation in leisure activities, especially mentally stimulating activities, is associated with a lower risk for AD. However, no study has yet evaluated associations between AD and different types of mental leisure activities, especially those involving "novelty seeking." The authors used a case-control design to compare participation in activities across the life span in persons with AD and normal controls. Cases (n = 264) were recruited from clinical settings and from the community. Controls were drawn from 2 populations. Control group A members (n = 364) were the friends or neighbors of the cases or members of the same organizations to which the cases belonged. Control group B members (n = 181) were randomly drawn from the community. The 2 control groups did not differ in their responses to most activity questions, so they were combined. Factor analysis of activity questions identified 3 activity factors: (1) novelty seeking; (2) exchange of ideas; and (3) social. Logistic regression analysis indicated that, adjusting for control variables, greater participation in novelty-seeking and exchange-of-ideas activities was significantly associated with decreased odds of AD. The odds of AD were lower among those who more often participated in activities involving exchange of ideas and were lower yet for those who more frequently participated in novelty-seeking activities. We conclude that participation in a variety of mental activities across the life span may lower one's chances of developing AD.

Development of a scale to predict decline in patients with mild Alzheimer's disease.

OBJECTIVES: To develop a scale that can assist in predicting likelihood of decline from mild dementia over 1 year in patients with Alzheimer's disease (AD). DESIGN: Retrospective cohort study. SETTING: University Memory and Aging Center. PARTICIPANTS: Patients with probable or possible AD and Clinical Dementia Rating (CDR) of 1 at baseline, divided into development and validation cohorts (n = 118 each). MEASUREMENTS: The CDR and neurological and neuropsychological assessments were given at baseline and 1 year later. RESULTS: In the development cohort, high education, low Mini-Mental State Examination score, poor insight, psychotic symptoms, and greater activity of daily living impairment predicted decline in CDR from 1 to 2 or 3. Receiver operating characteristics (ROC) curve analysis identified cutoff scores that maximized sensitivity and specificity for each significant predictor of decline. Based on the cutoff, raw scores were recoded to reflect risk for decline, weighted, and summed to create a final scale score. ROC curve analysis established a cutoff to indicate risk for decline on the final scale score. Sensitivity, specificity, and area under the ROC were 0.76, 0.74, and 0.83 in the development cohort and 0.77, 0.69, and 0.80 in the validation cohort, respectively. Positive and negative predictive values were 0.71 and 0.78 in the development cohort and 0.68 and 0.78 in the validation cohort, respectively. CONCLUSIONS: Decline from mild to moderate or severe impairment represents significant clinical change, with implications for patient and caregiver quality of life and treatment options. The clinical scale developed uses data to enhance prediction about change from mild to moderate or severe stages of AD.

Pragmatic and internal validity issues in sampling in caregiver studies: a comparison of population-based, registry-based, and ancillary studies.

OBJECTIVES: Studies of caregivers illustrate a classic sampling dilemma: maximizing recruitment without compromising study validity. Because caregivers are defined in relation to a care recipient, sampling methods are often determined by pragmatic decisions such as access, efficiency, and costs. However, overlooking validity may result in selection bias, misclassification of caregiver status, and the confounding of results. Validity and pragmatic concerns were compared in four caregiver studies that used different sampling frames: community based, Alzheimer's disease registry, and ancillary studies to existing epidemiologic studies. METHODS: Systematic comparison of validity and of pragmatic aspects of sampling frames, recruitment methods, and participation rates, with attention to caregiver identification, inclusion criteria, and sample restriction. RESULTS: All studies used task-based inclusion criteria. Caregiver participation rates ranged from 81% to 96%, with higher rates in community-based and registry-based studies than in ancillary studies. The latter studies benefited from unbiased selection of noncaregivers. DISCUSSION: Regardless of sampling frame, standard task-based inclusion criteria to define caregivers may enhance validity.

Prevalence and Cognitive Bases of Subjective Memory Complaints in Older Adults: Evidence from a Community Sample.

Objectives. To estimate the prevalence of subjective memory complaints (SMCs) in a sample of community-dwelling, older adults and to examine cognitive bases of these complaints. Participants. 499 community-dwelling adults, 65 and older. Measurements. A telephone survey consisting of cognitive tests and clinical and sociodemographic variables. SMCs were based on subjects' evaluations and subjects' perceptions of others' evaluations. Analysis. Logistic regression was used to model the risk for SMCs as a function of the cognitive, clinical, and sociodemographic variables. We tested for interactions of the cognitive variables with age, education, and gender. Results. 27.1% reported memory complaints. Among the younger age, better objective memory performance predicted lower risk for SMCs, while among the older age, better memory had no effect on risk. Among the better-educated people, better global cognitive functioning predicted lower risk for SMCs, while among the less-educated people, better global cognitive functioning had no effect on SMC risk. When predicting others' perceptions, better objective memory was associated with lower risk for SMCs. Conclusion. Objective memory performance and global cognitive functioning are associated with lower risk for SMCs, but these relationships are the strongest for the younger age and those with more education, respectively. Age and education may affect the ability to accurately appraise cognitive functioning.

Assessing executive function in Parkinson disease: the alternating names test. Part I. Reliability, validity, and normative data.

OBJECTIVES: To evaluate psychometric properties (convergent and divergent validity; alternate forms reliability) and provide normative data for the Alternating Names Test (ANT), a new bedside test of set-switching, a component of executive function (EF). The test was specifically designed for use in persons with Parkinson disease (PD). DESIGN: Cross-sectional study. SETTING: Clinic-based PD Research Registry. PARTICIPANTS: Data were gathered from two samples: 829 patients with idiopathic PD enrolled in our clinic registry and 253 caregivers and family members of patients. MEASUREMENTS: In the ANT, patients are asked to produce the names of children, switching back and forth from boys' to girls' names. Outcome measures include the time to complete ten correct pairs and the number of errors made. RESULTS: Correlations between the ANT and similar constructs were high (mean Spearman rank-order correlation coefficient, rho=.67), indicating good convergent validity. Measures of divergent validity were low (mean Spearman's rho=.31), demonstrating good divergent validity. Alternate forms reliability was high for time (rho=.76), but low for errors (rho=.37). Normative data are presented in a look-up table. CONCLUSION: Our test is a valid and reliable measure of set-switching in PD. Its ease of administration and effectiveness in identifying executive deficits suggests that the test could be useful in clinical practice and warrants further study.

A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease.

OBJECTIVES: To evaluate the safety of the peroxisome proliferator-activated receptor gamma agonist pioglitazone in nondiabetic patients with Alzheimer disease (AD) and to explore treatment effect sizes on clinical outcomes. DESIGN: Double-blind, placebo-controlled randomized controlled trial of 18-month duration. SETTING: Two academic medical center outpatient clinics. PATIENTS: Nondiabetic patients meeting research criteria for probable AD were enrolled. Twenty-five of 29 subjects completed the study; no withdrawals were attributable to adverse effects. INTERVENTION: Subjects received pioglitazone (Actos), titrated to 45 mg daily, or matching placebo, and 200 IU of vitamin E daily. Patients maintained treatment with cholinesterase inhibitors and could begin memantine therapy when it became available during the study. MAIN OUTCOME MEASURES: The primary outcome was frequency of reported adverse effects (AEs). Secondary outcomes were measures of cognition, activities of daily living, neuropsychiatric symptoms, and global function. RESULTS: Peripheral edema was the principal AE occurring more frequently in subjects taking pioglitazone than placebo (28.6% vs 0%). This is consistent with the known AE profile of pioglitazone. No group differences in laboratory measures were identified. No significant treatment effect was observed on exploratory analysis of clinical efficacy. CONCLUSIONS: Pioglitazone was generally well tolerated in this pilot study. There were no serious or unanticipated adverse events or clinical laboratory changes attributable to pioglitazone over a long-term exposure in nondiabetic patients with AD. The tolerability of pioglitazone in this population and peroxisome proliferator-activated receptor gamma effects in laboratory models of AD support further study of this drug class in earlier disease stages. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00982202.

Impact of TimeSlips, a creative expression intervention program, on nursing home residents with dementia and their caregivers.

PURPOSE: Creative expression (CE) programs are emerging interventions to improve the quality of care and life of persons with dementia (PWDs) in long-term care settings. However, limited empirical evidence exists to support the effectiveness of these programs. Here, we report the findings from an assessment of the impact of TimeSlips (TS), a group storytelling program that encourages CE among PWDs and those who care for them. DESIGN AND METHODS: Instruction in TS was provided through a 10-week on-site training. An observational study using an experimental design was conducted in 20 nursing home facilities in 2 states, 10 of which were randomly selected to implement TS. Two weeks after the implementation of TS at the intervention sites, we conducted 4 days of direct observation, using a time-sampling approach, of residents and staff in each facility. Using surveys, we also assessed staff job satisfaction, attitudes toward residents, and burnout. RESULTS: Compared with residents in the control facilities, those in the TS facilities were more engaged and more alert. In TS facilities, there were more frequent staff-resident interactions, social interactions, and social engagement. Also, staff who participated in the TS program had more positive views of residents with dementia and devalued residents less than did the control group staff. There were no differences in staff job satisfaction and burnout among staff in the TS and non-TS facilities. IMPLICATIONS: Implementing the TS program in nursing facilities improves the care environment for PWDs. However, additional studies are needed to offer further insights into the mechanisms by which TS improves both staff and resident outcomes.

Infrared laser spectroscopy for online recording of exhaled carbon monoxide-a progress report.

Despite the growing number of reports on breath CO measurements, the development of rapid and sensitive analysis techniques for measurements of this breath constituent still remains a challenge. We demonstrate the application of infrared laser spectroscopy for exhaled CO analysis. The breath samples are analyzed in real-time during single exhalations by means of cavity ring-down spectroscopy. This is an ultra-sensitive laser-based method for the analysis of trace gases with precision on the ppb level (parts per billion). The noise-equivalent CO level of this method is 7 ppb Hz(-1/2); the time resolution is around 1 s. The expirograms were recorded with exhalation flow rates varying from 4 l min(-1) up to 50 l min(-1). Alveolar phase (phase III) of expiration shows a remarkable flow-rate dependence. Also, expirograms were recorded after a breath holding time between 0 s and 60 s. The normalized slope of the alveolar plateau (S(n)) was determined, which is between 0.004 l(-1) and 0.15 l(-1).