Responsiveness and minimal clinically important difference of the Minnesota living with heart failure questionnaire.

BACKGROUND: The Minnesota Living with Heart Failure Questionnaire (MLHFQ) is one of the most widely used health-related quality of life questionnaires for patients with heart failure (HF). The objective of the present study was to explore the responsiveness of the MLHFQ by estimating the minimal detectable change (MDC) and the minimal clinically important difference (MCID) in Spain. METHODS: Patients hospitalized for HF in the participating hospitals completed the MLHFQ at baseline and 6 months, plus anchor questions at 6 months. To study responsiveness, patients were classified as having "improved", remained "the same" or "worsened", using anchor questions. We used the standardized effect size (SES), and standardized response mean (SRM) to measure the magnitude of the changes scores and calculate the MDC and MCID. RESULTS: Overall, 1211 patients completed the baseline and follow-up questionnaires 6 months after discharge. The mean changes in all MLHFQ domains followed a trend (P < 0.0001) with larger gains in quality of life among patients classified as "improved", smaller gains among those classified as "the same", and losses among those classified as "worsened". The SES and SRM responsiveness parameters in the "improved" group were ≥ 0.80 on nearly all scales. Among patients classified as "worsened", effect sizes were < 0.40, while among patients classified as "the same", the values ranged from 0.24 to 0.52. The MDC ranged from 7.27 to 16.96. The MCID based on patients whose response to the anchor question was "somewhat better", ranged from 3.59 to 19.14 points. CONCLUSIONS: All of these results suggest that all domains of the MLHFQ have a good sensitivity to change in the population studied.

Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: a post hoc analysis of the AWARD programme.

AIMS: To evaluate the effects of dulaglutide vs placebo on liver and glycaemic/metabolic measurements in a population with Type 2 diabetes and in a subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis. METHODS: A total of 1499 participants from AWARD-1, AWARD-5, AWARD-8 and AWARD-9 clinical trials were included in this analysis (dulaglutide 1.5 mg, n=971 and placebo, n=528). Thresholds of alanine aminotransferase levels ≥30 IU/l in men and ≥19 IU/l in women were used to determine the subgroup who had non-alcoholic fatty liver/non-alcoholic steatohepatitis. Objectives included changes from baseline to 6 months in: (1) alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels in the overall population and (2) alanine aminotransferase, aspartate transaminase, gamma-glutamyl transpeptidase and glycaemic/metabolic measurements (e.g. HbA1c , fasting serum glucose, body weight, lipids and homeostatic model assessment) in the non-alcoholic fatty liver/non-alcoholic steatohepatitis subgroup. RESULTS: In the overall population at 6 months, dulaglutide significantly reduced alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels vs placebo [least squares mean treatment differences: -1.7 IU/l (95% CI -2.8, -0.6), P=0.003; -1.1 IU/l (95% CI -2.1, -0.1), P=0.037; -6.6 IU/l (95% CI -12.4, -0.8), P=0.025, respectively]. In the subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis (alanine aminotransferase levels greater than or equal to the upper limit of normal), mean baseline liver enzyme values were 38.0 IU/l, 27.8 IU/l and 43.9 IU/l for alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase, respectively. In this population, more pronounced reductions from baseline in alanine aminotransferase were observed with dulaglutide vs placebo (-8.8 IU/l vs -6.7 IU/l). In the subgroup of people with alanine aminotransferase levels less than the upper limit of normal, changes from baseline in alanine aminotransferase did not significantly differ between treatment groups (0.0 IU/l vs 0.7 IU/l). CONCLUSIONS: Once-weekly dulaglutide improved alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels compared with placebo in a pattern consistent with liver fat reductions. Our results add further weight to the notion that glucagon-like peptide-1 receptor agonists may provide benefit in lowering liver fat in addition to their other metabolic actions.

Total knee replacement; minimal clinically important differences and responders.

OBJECTIVE: To provide new data on minimally clinical important difference (MCID) and percentages of responders on pain and functional dimensions of Western Ontario and McMaster Osteoarthritis Index (WOMAC) in patients who have undergone total knee replacement (TKR). METHODS: 1-year prospective multicentre study with two different cohorts. Consecutive patients on the waiting list were recruited. There were 415 and 497 patients included. Pain and function were collected by the reverse scoring option of the WOMAC (0-100, worst to best). Transition items (five point scale) were collected at 1-year and MCID was calculated through mean change in patients somewhat better, Receiver Operating Characteristic (ROC) and two other questions about satisfaction. Analysis was performed in the whole sample and by tertiles of baseline severity. Likewise were calculated the percentages of patients who attained cut-off values. RESULTS: Global MCID for pain were about 30 in both cohorts and 32 for. By ROC these values were about 20 and 24 respectively. According to the other two transitional questions these values were for pain 27 and 20 for function. By tertiles the worst the baseline score the higher the cut-off values. Percentage of responders does not change when comparing responders to the global MCID with their own tertile MCID and were about 61% for pain and 50% for function. CONCLUSION: Due to the wide variations, MCID estimates should be calculated and used according to the baseline severity score.

First Report of Powdery Mildew (Pseudoidium anacardii) of Mango Trees in Sinaloa, Mexico.

Powdery mildew of mango is an important disease in Mexico's northern Sinaloa state. Identification of the causal fungal agent has been hindered by the absence of information regarding its teleomorph, as well as a detailed morphometric analysis of the anamorph and molecular characterization. The first symptoms of the disease appear in mango inflorescences of early February, and it subsequently affects young fruits. The disease progresses during March and early April, causing significant fruit abortion and a scabby appearance in a high percentage of fruits that remain attached to the trees. We observed the disease on inflorescences but not in leaves during our sampling period. Powdery mildew specimens were collected during 2011 and 2012 and included Kent and Keith varieties from commercial orchards, and creole materials from backyards of private residences in the Ahome and Fuerte Counties of northern Sinaloa, Mexico. Symptomatic inflorescences were analyzed morphologically. Conidiophores and conidia were prepared by touching the whitish lesions with clear adhesive tape, which was then placed over microscope slides with a drop of distilled water and observed under a compound microscope. The anamorph structures of the pathogen were measured. The mycelium was septate and ramified on the surface of the host, forming a dense coat of branching hyphae. The mycelium had a diameter of 2.5 to 8.7 µm; conidiophores (Pseudoidium type) emerged from the superficial mycelium, were unbranched, and consisted of 1 to 3 cells with conidia forming singly from the apex. The length of the conidiophores varied from 30.0 to 77.5 µm; the foot cell of the conidiophores was straight, 10.0 to 47.5 µm long and with a diameter of 5.0 to 15.5 µm across its midpoint. Conidia without fibrosin bodies were borne singly, and were ellipsoid/ovoid, 22.5 to 46.2 µm long and 15.0 to 27.5 µm wide. Eighty percent of the germ tubes were forked (lobed); the rest were simple, emerged from the end, and were occasionally on the side of the conidia. Germ tubes ranged from 2.0 to 7.2 µm at the midpoint. The surface of the conidia appeared smooth under the scanning electron microscope, and elliptical conidia appeared constricted at their ends; this, however, was not observed in the ovoid conidia. In both cases, the terminal end of the conidia was smooth. The teleomorph was not found. Molecular and phylogenetic analysis of the ITS rDNA (2) region showed that samples are closely related to specimens of Pseudoidium anacardii (1) (teleomorph: Erysiphe quercicola [4]) collected from mango trees in diverse countries. Measurements of somatic and asexual structures are in agreement with descriptions of P. anachardii (formerly known as Oidium mangiferae) from India (3). The nucleotide sequences derived from this research were deposited in GenBank (Accession Nos. JX893951 to JX893957). To our knowledge, this is the first report of P. anacardii associated to mango inflorescences in Sinaloa, Mexico. Due to the economic importance of powdery mildew of mango trees in Sinaloa, future research directions should focus on finding the teleomorph of the fungus to support its identity. References: (1) U. Braun and R. T. A. Cook CBS Biodiversity Series No. 11, 2012. (2) S. Limkaisang et al. Mycoscience 47:327, 2006. (3) O. Prakash and K. C. Srivastava. Mango diseases and their management. A World Review Today and Tomorrow Publishers. New Delhi, India, 1987. (4) S. Takamatsu et al. Mycol. Res. 111:809, 2007.

International comparability of reference unit costs of education services: when harmonizing methodology is not enough (PECUNIA project).

BACKGROUND: Health problems can lead to costs in the education sector. However, these costs are rarely incorporated in health economic evaluations due to the lack of reference unit costs (RUCs), cost per unit of service, of education services and of validated methods to obtain them. In this study, a standardized unit cost calculation tool developed in the PECUNIA project, the PECUNIA RUC Template for services, was applied to calculate the RUCs of selected education services in five European countries. METHODS: The RUCs of special education services and of educational therapy were calculated using the information collected via an exploratory gray literature search and contact with service providers. RESULTS: The RUCs of special education services ranged from €55 to €189 per school day. The RUCs of educational therapy ranged from €6 to €25 per contact and from €5 to €35 per day. Variation was observed in the type of input data and measurement unit, among other. DISCUSSION: The tool helped reduce variability in the RUCs related to costing methodology and gain insights into other aspects that contribute to the variability (e.g. data availability). Further research and efforts to generate high quality input data are required to reduce the variability of the RUCs.

Patient acceptable symptom state and OMERACT-OARSI set of responder criteria in joint replacement. Identification of cut-off values.

OBJECTIVE: To identify new cut-off values beyond which patients can be considered as satisfied or as responders through patient acceptable symptom state (PASS) and OMERACT-OARSI (Outcome Measures in Rheumatology-Osteoarthritis Research Society International) set of responder criteria in total joint replacement. METHODS: Secondary analysis of a 1-year prospective multicenter study of 861 patients, 510 with total knee replacement (TKR) and 351 with total hip prosthesis (THR). Pain and function data were collected by the reverse scoring option of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). PASS values were identified with the 25th centile estimation using an anchoring question about satisfaction with actual symptoms. OMERACT-OARSI set of responder criteria was based on a combination of absolute and relative change of pain, function and global patient's assessment. Receiver operating characteristic (ROC) analysis was used as a complementary approach. RESULTS: The values for PASS were about 80 and 69 for pain and function in THR, while these values were 80 and 68 when using OMERACT-OARSI criteria. Regarding TKR, PASS values were about 75 and 67 in pain and function with both criteria. ROC values were slightly lower in all cases. PASS and OMERACT-OARSI values varied moderately across tertiles of baseline severity. CONCLUSION: With the provided data we can establish when a patient can be considered as satisfied/responder in joint replacement. The scores achieved at 1 year were very similar according to both criteria.

A systematic review of specialised palliative care for terminal patients: which model is better?

There is evidence of improved effectiveness of specialised palliative care for terminally ill patients in comparison to conventional care. However, there is uncertainty about which model is better. The objective of this systematic review was to identify studies that compare specialised palliative care models between them assessing their effectiveness or cost-effectiveness. We searched studies published between 2003 and 2006 in several electronic databases and updated the search in MEDLINE up to 2008. Papers published before 2003 were identified by means of previous systematic reviews and manual search. Studies with broad designs comparing two or more specialised palliative care programmes in adults with terminal illness were selected. Six systematic reviews, three studies on effectiveness and one cost study were included. All systematic reviews drew the conclusion that specialised palliative care is more effective than conventional care. The methodological limitations of the original studies and the heterogeneity of programmes did not allow to draw conclusions about whether a specific model of specialised palliative care is more or less effective or cost-effective than other.

Total knee replacement: Are there any baseline factors that have influence in patient reported outcomes?

BACKGROUND: There is conflicting evidence about what factors influence outcomes after total knee replacement (TKR). The objective is to identify baseline factors that differentiate patients who achieve both, minimal clinically important difference (MCID) and a patient acceptable symptom state (PASS) in pain and function, measured by WOMAC, after TKR from those who do not attain scores above the cutoff in either of these dimensions. METHODS: One-year prospective multicentre study. Patients completed WOMAC, SF-12, EQ-5D, expectations, other joint problems and sociodemographic data while in the waiting list, and 1-year post-TKR. Dependent variable was a combination of MCID and PASS in both dimensions (yes/no). Univariate analysis was performed to identify variables associated. Exploratory factor analysis (EFA) was performed to study how these variables grouped into different factors. RESULTS: Total sample comprised 492 patients. Mean (SD) age was 71.3 (6.9), and there were a 69.7% of women. Of the total, 106 patients did not attain either MCID or PASS in either dimension, and 230 exceeded both thresholds in both dimensions. In the univariate analysis, 13 variables were associated with belonging to one group or another. These 13 variables were included in EFA; 3 factors were extracted: expectations, mental health, and other joints problems. The percentage of variance explained by the 3 factors was 80.4%. CONCLUSION: We have found 2 modifiable baseline factors, expectations and mental health, that should be properly managed by different specialist. Indication of TKR should take into account these modifiable factors for improving outcomes after TKR.

Review of economic studies and budget impact analysis of ocriplasmin as a treatment of vitreomacular traction. / Revisión de estudios económicos y análisis de impacto presupuestario de la ocriplasmina como tratamiento de la tracción vitreomacular.

OBJECTIVE: To review the evidence on the cost-effectiveness of ocriplasmin as a treatment for vitreomacular traction (VMT), and to estimate the impact on the Spanish National Health System (NHS). MATERIAL AND METHODS: 1) Systematic review. The following databases were searched in January 2015: MEDLINE, PREMEDLINE, EMBASE, CRD, the Cochrane Library, and key websites. Selection criteria were: full economic evaluations that compared ocriplasmin with usual care ('watch and wait' and/or vitrectomy) in patients with VMT. The outcomes to extract were costs of the alternatives and the incremental cost-effectiveness ratio. Studies of budget impact analysis were also included. The methodological quality was assessed, and a narrative synthesis of the included studies was carried out. 2) Estimation of budget impact. The impact on the budget as a result of the introduction of ocriplasmin in the NHS was estimated, including data from different sources. RESULTS: Six studies were identified, none of them performed in Spain. The two best studies concluded that ocriplasmin is cost-effective in their respective countries (Canada and United Kingdom), but only in patients with certain conditions (without epiretinal membrane, for example). The results of the budget impact analysis are different between countries. The analysis for Spain showed that the introduction of ocriplasmin would mean a saving over 1 million Euros for the NHS in 5 years. CONCLUSIONS: The cost-effectiveness of ocriplasmin has not been demonstrated in Spain. However, good studies performed in other countries found that ocriplasmin is cost-effective in selected patients. Given the current prices in Spain, ocriplasmin could involve a saving for the Spanish NHS.

[Safety and efficacy of growth hormone treatment: GeNeSIS study in Spain]. / Seguridad y efectividad del tratamiento con hormona de crecimiento: estudio GeNeSIS en España.

INTRODUCTION: Country-specific information on pediatric GH therapy is available from multi-national studies. METHODS: A total of 1294 children in Spain enrolled in the observational Genetics and Neuroendocrinology of Short-stature International Study (GeNeSIS). Adverse events were assessed in all GH-treated patients (n=1267) and effectiveness in those with GH deficiency (GHD, 78%). RESULTS: Mean age at time of entry to the study was 9.8 years. GH was initiated at a median (Q1-Q3) 0.22 (0.20-0.25) mg/kg/week and administered for 2.8 (1.6-4.4) years. For 262 patients with GHD and 4-year data, mean (95% CI) height velocity was 4.3 (4.1 - 4.6) cm/year at baseline, 9.0 (8.7 to 9.4) cm/year at 1-year, and 5.5 (5.2 to 5.8) cm/year at 4-years. Height standard deviation score (SDS) was -2.48 (-2.58 to -2.38) at baseline and -1.18 (-1.28 to -1.08) at 4 years. Final height SDS minus target height SDS (n=241) was -0.09 (-0.20 to 0.02). In 1143 GH-treated patients with ≥1 year follow-up, 93 (8.1%) reported treatment-emergent adverse events. Serious events were reported for 7 children, with 2 considered GH-related. CONCLUSION: These data confirm the benefit of GH replacement therapy on height gain for the patients in Spain. The safety profile was consistent with that already known for GH therapy.

Comparative pharmacoeconomic study of vancomycin and teicoplanin in intensive care patients.

Randomized clinical trials and meta-analyses have not demonstrated any statistically significant differences between teicoplanin and vancomycin with regard to efficacy. A cost-minimization analysis was conducted to compare the economical impact of the treatment with vancomycin and teicoplanin in intensive care patients. Information on resource utilization was retrospectively collected from 100 consecutive clinical histories of patients hospitalized in a Spanish Intensive Care Unit, who had been given a glycopeptide antibiotic (50 teicoplanin and 50 vancomycin) for the treatment of a suspected or proven infection. Although personnel, material, and monitoring costs were higher in the vancomycin group, the acquisition costs and the total costs were much lower in this group, so the resulting total costs per day were 5508 ptas (33 euros) for vancomycin-treated patients and 9893 ptas (59.5 euros) for teicoplanin-treated patients. The savings with vancomycin for a 10-day course of treatment would be approximately 40697 ptas (244.5 euros) per patient. Results were consistent for a variety of conditions that were included in the sensitivity analysis.

Effect of zaleplon on digoxin pharmacokinetics and pharmacodynamics.

The pharmacokinetics and pharmacodynamics of digoxin alone and digoxin plus zaleplon were studied. Healthy, nonsmoking men between 18 and 45 years of age were given a single oral dose of digoxin 0.375 mg daily on days 1 through 9. On days 10 through 14, the subjects received digoxin 0.375 mg plus oral zaleplon 10 mg daily. Blood samples were obtained on days 3, 5, 8, 9, and 14, and serum digoxin concentration data were analyzed by model-independent pharmacokinetic methods. Blood pressure, heart rate, PR interval, and QTc interval were recorded to determine the effect of zaleplon on digoxin pharmacodynamics. A total of 20 men completed the study. Maximum serum digoxin concentration and area under the serum digoxin concentration-versus-time curve from 0 to 24 hours met bioequivalence test criteria. There were no significant differences in QTc or PR interval between days 9 (digoxin alone) and 14 (digoxin plus zaleplon), and there were no clinically important changes from baseline to the study's end in vital signs, physical examination findings, or ECG results for individual subjects. Eighteen percent of the subjects who received digoxin alone and 35% of those who received digoxin plus zaleplon reported one or more adverse effects; all were mild and resolved quickly. Zaleplon had no significant effects on selected pharmacokinetic and pharmacodynamic properties of digoxin.

[Myocardial infarct in the geriatric patient: the short- and mid-term prognostic factors]. / El infarto de miocardio en el paciente geriátrico: factores pronósticos a corto y medio plazo.

The purpose of this study was to investigate the clinical features and the prognostic factors related to early and late mortality in the acute myocardial infarction (AMI) in the geriatric population. We have studied 208 consecutive patients with AMI admitted to the Coronary Care Unit at the Hospital General de Asturias. Two groups were selected: group A included 102 patients older than 65 years; and 106 were younger (group B). In the group A was found a significantly lower percentage of males (52.9% vs 89.6%; p less than 0.0001) and smokers (45.1% vs 89.6%; p less than 0.0001); and older patients showed a greater incidence of diabetes mellitus (30.7% vs 16%; p less than 0.01). In the geriatric group, the clinical course of AMI is characterized by a greater incidence of heart failure (50% vs 29.2%; p less than 0.002) and cardiogenic shock (22.5% vs 7.5%; p = 0.002). Early mortality (first month) was significantly higher in elderly patients (36.3% vs 7.5%; p less than 0.001); and this increased mortality rate is partially related to an increased incidence of heart pump failure, despite having a smaller enzymatic infarct size by CPK peak (1,062 +/- 1,017 U/l vs 1,579 +/- 1,428 U/l; p less than 0.005). The multivariate analysis by stepwise logistic regression, selected diabetes mellitus, heart failure and peri-infarct bundle branch blocks as the only independent predictive variables for the early mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Costs resulting from premature mortality due to cardiovascular causes: A 20-year follow-up of the DRECE study. / Mortalidad prematura cardiovascular y sus costes: 20 años de seguimiento del estudio DRECE.

OBJECTIVES: Cardiovascular diseases are still the leading cause of death in Spain. The DRECE study (Diet and Cardiovascular Disease Risk in Spain), based on a representative cohort of the Spanish general population, analyzed nutritional habits and lifestyle and their association with morbidity and mortality patterns. We estimated the impact, in terms of loss of productivity, of premature mortality attributed to cardiovascular diseases. METHODS: The loss of productivity attributed to premature mortality was calculated from 1991, based on the potential years of life lost and the potential years of working life lost. RESULTS: During the 20-year follow-up of a cohort of 4779 patients, 225 of these patients died (men, 152). Sixteen percent of the deaths were attributed to cardiovascular disease. The costs due to lost productivity by premature mortality exceeded 29 million euros. Of these, 4 million euros (14% of the total cost) were due to cardiovascular causes. CONCLUSIONS: Premature cardiovascular mortality in the DRECE cohort represented a significant social cost due to lost productivity.

Risk factors for hospital readmissions in elderly patients: a systematic review.

Population ageing is associated with an increase in hospital admissions. Defining the factors that affect the risk of hospital readmission could identify individuals at high risk and enable targeted interventions to be designed. This aim of this study was to identify the risk factors for hospital readmission in elderly people. A systematic review of the literature published in English or Spanish was performed by electronically searching EMBASE, MEDLINE, CINAHL, SCI and SSCI. Some keywords were aged, elder, readmission, risk, etc. Selection criteria were: prospective cohort studies with suitable statistical analysis such as logistic regression, that explored the relationship between the risk of readmission with clinical, socio-demographic or other factors in elderly patients (aged at least 75 years) admitted to hospital. Studies that fulfilled these criteria were reviewed and data were extracted by two reviewers. We assessed the methodological quality of the studies and prepared a narrative synthesis. We included 12 studies: 11 were selected from 1392 articles identified from the electronic search and one additional reference was selected by manual review. Socio-demographic factors were only explanatory in a few models, while prior admissions and duration of hospital stay were frequently relevant factors in others. Morbidity and functional disability were the most common risk factors. The results demonstrate the need for increased vigilance of elderly patients who are admitted to hospital with specific characteristics that include previous hospital admissions, duration of hospital stay, morbidity and functional disability.

Costs of QuantiFERON-TB Gold versus tuberculin skin test in Spanish healthcare workers.

We compared the cost of the tuberculin skin test (TST) with the QuantiFERON-TB Gold (QFT-G) test when screening for latent tuberculosis in 134 healthcare workers in Spain. The QFT-G test cost euro42.5 per healthcare worker, while the TST cost euro39.5. The tests varied in cost structure; most (70%) TST costs were due to time demands on the participants, whereas the QFT-G was more expensive in terms of consumables (50% of the total cost). Accordingly, the results depend on the hourly wages of the participants and the time they must dedicate to the tests. In the Spanish healthcare system, the societal costs of QFT-G are comparable to those of the TST, although their cost structures are quite distinct.

Separation between cytosolic calcium and secretion in chromaffin cells superfused with calcium ramps.

This paper describes experiments in which cytosolic Ca2+ concentrations ([Ca2+]i) and catecholamine release were measured in two populations of chromaffin cells stimulated with a solution enriched in K+ (100 mM). Once depolarized, external Ca2+ or Ba2+ ions were offered to cells either as a single 2.5 mM step or as a ramp that linearly increased the concentration from 0 to 2.5 mM over a 10-min period. A clear separation between the changes of the [Ca2+]i and the time course of secretion was observed. Specifically, secretion and [Ca2+]i rose in parallel when a Ca2+ step was used to reach a peak in a few seconds; however, while secretion declined to the basal level, [Ca2+]i remained elevated at a plateau of 400 nM. With a Ca2+ ramp, only a transient small peak of secretion was observed, yet the [Ca2+]i remained elevated throughout the 10-min stimulation period. The separation between secretion and [Ca2+]i was observed even when voltage-dependent Ca2+ channels were expected to remain open (mild depolarization in the presence of 1 microM Bay K 8644). By using Ba2+ steps or ramps, sustained noninactivating secretory responses were obtained. The results suggest that the rate and extent of secretion are not a simple function of the [Ca2+]i at a given time; they are compatible with the following conclusions: (i) A steep extracellular-to-cytosolic Ca2+ gradient is required to produce a sharp increase in the [Ca2+]i at exocytotic sites capable of evoking a fast but transient secretory response. (ii) As a result of Cai(2+)-dependent inactivation of Ca2+ channels, those high [Ca2+]i are possible only at early times after cell depolarization. (iii) The Cai(2+)-dependent supply of storage granules to the secretory machinery cooperates with the supply of Ca2+ through Ca2+ channels to regulate the rate and extent of secretion.