Treatment Outcome, Duration, and Costs: A Comparison of Performance Indicators Using Data from Eight Mental Health Care Providers in The Netherlands.

Assessing performance of mental health services (MHS) providers merely by their outcomes is insufficient. Process factors, such as treatment cost or duration, should also be considered in a meaningful and thorough analysis of quality of care. The present study aims to examine various performance indicators based on treatment outcome and two process factors: duration and cost of treatment. Data of patients with depression or anxiety from eight Dutch MHS providers were used. Treatment outcome was operationalized as case mix corrected pre-to-posttreatment change scores and as reliable change (improved) and clinical significant change (recovered). Duration and cost were corrected for case mix differences as well. Three performance indicators were calculated and compared: outcome as such, duration per outcome, and cost per outcome. The results showed that performance indicators, which also take process variability into account, reveal larger differences between MHS providers than mere outcome. We recommend to use the three performance indicators in a complementary way. Average pre-to-posttreatment change allows for a simple and straightforward ranking of MHS providers. Duration per outcome informs patients on how MHS providers compare in how quickly symptomatic relief is achieved. Cost per outcome informs MHS providers on how they compare regarding the efficiency of their care. The substantial variation among MHS providers in outcome, treatment duration and cost calls for further exploration of its causes, dissemination of best practices, and continuous quality improvement.

Efficacy of serology driven "test and treat strategy" for eradication of H. pylori in patients with rheumatic disease in the Netherlands.

The treatment of choice of H. pylori infections is a 7-day triple-therapy with a proton pump inhibitor (PPI) plus amoxicillin and either clarithromycin or metronidazole, depending on local antibiotic resistance rates. The data on efficacy of eradication therapy in a group of rheumatology patients on long-term NSAID therapy are reported here. This study was part of a nationwide, multicenter RCT that took place in 2000-2002 in the Netherlands. Patients who tested positive for H. pylori IgG antibodies were included and randomly assigned to either eradication PPI-triple therapy or placebo. After completion, follow-up at 3 months was done by endoscopy and biopsies were sent for culture and histology. In the eradication group 13% (20/152, 95% CI 9-20%) and in the placebo group 79% (123/155, 95% CI 72-85%) of the patients were H. pylori positive by histology or culture. H. pylori was successfully eradicated in 91% of the patients who were fully compliant to therapy, compared to 50% of those who were not (difference of 41%; 95% CI 18-63%). Resistance percentages found in isolates of the placebo group were: 4% to clarithromycin, 19% to metronidazole, 1% to amoxicillin and 2% to tetracycline.

Performance of various criteria sets in patients with inflammatory back pain of short duration; the Maastricht early spondyloarthritis clinic.

AIM: To describe how patients presenting with inflammatory back pain (IBP) of short duration can be classified by different sets of classification criteria for spondyloarthritis (SpA) and ankylosing spondylitis, and which clinical and imaging features are of discernible importance. METHODS: 68 patients with IBP of a maximum of 2 years' duration were included in the early spondyloarthritis cohort. Detailed history, clinical examination and imaging of sacroiliac joints by plain radiography and magnetic resonance imaging (MRI) were obtained. The Berlin criteria set for SpA that has a prominent place for MRI and human leucocyte antigen B27 was used to quantify the relative contribution of MRI in classifying SpA. RESULTS: 14 of the 68 patients had ankylosing spondylitis according to the modified New York criteria, 57 patients fulfilled the European Spondylarthropathy Study Group (ESSG) criteria for SpA, 48 patients fulfilled the Amor criteria for SpA (43 patients fulfilled both criteria sets) and 44 patients fulfilled the Berlin criteria for SpA. Only four patients did not fulfil any criteria set; 36 patients fulfilled ESSG, Amor and Berlin criteria. The 14 patients with ankylosing spondylitis fulfilled all three SpA criteria sets. CONCLUSION: Among our selected cohort of patients with early IBP, the prevalence of SpA according to three different criteria sets is high. The ESSG criteria were the most sensitive, followed by the Amor criteria and the Berlin criteria. The modified New York criteria for ankylosing spondylitis appeared to be the most specific. In this cohort, the contribution of MRI and human leucocyte antigen B27 to purely clinical criteria in making a diagnosis of axial SpA was limited.

Combining information obtained from magnetic resonance imaging and conventional radiographs to detect sacroiliitis in patients with recent onset inflammatory back pain.

OBJECTIVE: To compare the contribution of changes on magnetic resonance imaging (MRI) and conventional radiography (CR) in the sacroiliac joints of patients with recent onset inflammatory back pain (IBP) in making an early diagnosis of spondyloarthritides. METHODS: The study involved 68 patients with IBP (38% male; mean (SD) age, 34.9 (10.3) years) with symptom duration less than two years. Coronal MRI of the sacroiliac joints was scored for inflammation and structural changes, and pelvic radiographs were scored by the modified New York (mNY) grading. Agreement between MRI and CR was analysed by cross tabulation per sacroiliac joint and per patient. RESULTS: A structural change was detected in 20 sacroiliac joints by MRI and in 37 by CR. Inflammation was detected in 36 sacroiliac joints by MRI, and 22 of these showed radiographic sacroiliitis. Fourteen patients fulfilled the mNY criteria based on CR. Classification according to the modified New York criteria would be justified for eight patients if it was based on MRI for structural changes only, for 14 if it was based on structural changes on CR, for 14 (partly) different patients if it was based on inflammation on MRI only, for 16 if it was based on inflammation and structural changes on MRI, for 19 if it was based on inflammation on CR combined with MRI, and for (the same) 19 if it was based on inflammation and structural damage on CR combined with MRI. CONCLUSIONS: CR can detect structural changes in SI joints with higher sensitivity than MRI. However, inflammation on MRI can be found in a substantial proportion of patients with IBP but normal radiographs. Assessment of structural changes by CR followed by assessment of inflammation on MRI in patients with negative findings gives the highest returns for detecting involvement of the SI joints by imaging in patients with recent onset IBP.

The role of a computerised case-based testing procedure in practice performance assessment.

INTRODUCTION: For postgraduate training of doctors there is a need for valid and reliable instruments to assess their daily performance. Various instruments have been suggested, some of which use incognito simulated patients (SPs). These methods are resource intensive. Computerised Case-based testing (CCT) is logistically simpler and may still predict performance well. The research question was to evaluate the predictive validity of CCT for performance. METHODS: Seventeen rheumatologists were each visited by eight incognito SPs presenting various rheumatological complaints, and scoring the performance of the rheumatologists using a predefined checklist. From this checklist a panel of experts identified essential items. In addition the rheumatologists sat a CCT test containing 55 cases with a total of 121 items. RESULTS: Negative correlations were found between the SP scores and the CCT scores. This was unexpected. Therefore, background variables on experience were used to compare both methods. The correlation between these and CCT were high and positive and with the SP scores high and negative. This pattern did not differ when using the essential items of the checklist. Reliabilities of the SP scores were markedly high. DISCUSSION: Although CCT was not predictive of SP scores, it was related to working experience. There are good reasons to assume that although SP-scores were more authentic, they were less valid than CCT scores, mainly because they focussed more on thoroughness than on efficiency in data gathering. The results underpin the assumption that for valid performance assessment the most important issue is what information about the candidate is collected and now how authentic the method is.

[Two patients with joint pain as initial presentation of a haematological malignancy]. / Twee patiënten met gewrichtsklachten als initiële presentatie van een hematologische maligniteit.

A 75-year-old man and a 53-year-old woman had longstanding joint pain, for which they had been treated with NSAIDs. When the symptoms worsened, a thorough diagnostic investigation was conducted that revealed myeloproliferative bone-marrow disorders in both patients. The man, who had polyarticular gout secondary to chronic myelomonocytic leukaemia, was able to maintain control of his joint pain with medical treatment. In the woman, with a history of stable joint pain due to polyarthritis, deterioration of the symptoms and the development of pancytopaenia led to a diagnosis of acute lymphocytic leukaemia; she died after receiving multiple courses of chemotherapy. The possibility of an underlying malignancy should be considered in patients with atypical symptoms in the locomotor system, an unexpected course or anomalous secondary symptoms.

Pustular skin lesions in patients treated with infliximab: report of two cases.

Two cases are presented in which repeated use of the TNF-alpha blocker infliximab may have led to development of pustular skin lesions. These findings might result in an improved understanding regarding the safety of infliximab with long-term usage.

Psoriatic arthritis: performance of rheumatologists in daily practice.

OBJECTIVES: To assess, using standardised patients (SPs), how rheumatologists diagnose psoriatic arthritis, whether the diagnostic efficiency is influenced by specific characteristics of the rheumatologists, and to study the relationship with costs. METHODS: Twenty three rheumatologists were each visited by one of two SPs (one male, one female) presenting as a patient with psoriatic arthritis. SPs remained incognito for all meetings for the duration of the study. Immediately after the encounter, SPs completed case-specific checklists on the medical content of the encounter. Information on ordered laboratory and imaging tests was obtained from each hospital. RESULTS: Fourteen rheumatologists diagnosed psoriatic arthritis correctly. They inspected the skin for psoriatic lesions more often than those rheumatologists who established other diagnoses. Rheumatologists diagnosing psoriatic arthritis spent more on additional laboratory and imaging investigations. These were carried out after the diagnosis to confirm it and to record the extent and severity of the disease. No differences in type of practice, number of outpatients seen each week, working experience, or sex were found between rheumatologists who made the correct diagnosis and those who made other diagnoses. The correct diagnosis was more often missed by rheumatologists who saw the male SP, who presented with clear distal interphalangeal DIP joint arthritis only, causing confusion with osteoarthritis of the DIP joints. CONCLUSION: There is a considerable amount of variation in the delivery of care among rheumatologists who see an SP with psoriatic arthritis. Rheumatologists focusing too much on the most prominent features (DIP joint arthritis) sometimes seem to forget "the hidden (skin) symptoms".

Prevalence of vertebral deformities and symptomatic vertebral fractures in corticosteroid treated patients with rheumatoid arthritis.

OBJECTIVE: This study was designed to determine whether the prevalence of vertebral deformities in patients with rheumatoid arthritis (RA) treated with corticosteroids (Cs) is higher than in RA patients not receiving Cs therapy. PATIENTS AND METHODS: This multicentre cross-sectional study included 205 patients with RA who were receiving Cs orally on a daily basis and 205 patients with RA who did not receive Cs, matched for sex and age. Vertebral deformities were scored according to the Kleerekoper method. RESULTS: Vertebral deformities were found in 52 (25%) patients on Cs and in 26 (13%) patients not on Cs. Sixteen (8%) patients in the group on Cs had experienced clinical manifestations of an acute vertebral fracture in the past vs only three patients (1.5%) among those not on Cs. The use of Cs tended to increase the risk of developing a vertebral deformity [adjusted odds ratio (OR) 1.56, 95% confidence interval (CI) 0.81-2.99] and symptomatic vertebral fracture (adjusted OR 1.42, 95% CI 0.24-8.32). Each 1-mg increase in the current daily Cs dose increased the risk of a vertebral deformity (adjusted OR 1.05, 95% CI 0.98-1.13) and of a symptomatic vertebral fracture (adjusted OR 1.05, 95% CI 0.89-1.24). CONCLUSION: There is a higher prevalence of vertebral deformities and clinical manifestations of vertebral fractures in patients on Cs than in those not on Cs. Our data indicate that the use of Cs and each 1-mg increase in the current daily Cs dose may increase the risk of development of a vertebral deformity and symptomatic vertebral fracture in patients with RA.

Minimal clinically important difference in radiological progression of joint damage over 1 year in rheumatoid arthritis: preliminary results of a validation study with clinical experts.

To determine the minimal clinically important difference (MCID) between hand and foot films with a 1 year interval assessed with the Sharp/van der Heijde or Larsen/Scott scoring method. Progression scores of the 2 methods were compared with the opinion of an international expert panel on clinical relevance of radiological joint damage in 4 predefined clinical settings. The expert panel consisted of 3 rheumatologists, who evaluated 46 pairs of hand and foot films, taken with 1 year intervals, of patients with early rheumatoid arthritis. Receiver operating characteristics curves analyzed the accuracy of different threshold values (progression scores) of the 2 scoring methods to detect the presence or absence of clinically important difference, as defined by the expert panel as external criterion. The threshold value with the highest accuracy was subsequently chosen as the score representing the MCID. Five Sharp/van der Heijde units and 2 Larsen/Scott units were the best cutoffs. The accompanying sensitivities ranged from 77% to 100% for the Sharp/van der Heijde method and from 73% to 84% for the Larsen/Scott method for the 4 clinical settings. The specificities were between 78% and 84% for the Sharp/van der Heijde method and between 74% and 94% for the Larsen/Scott method. The smallest progression score that can be detected apart from interobserver measurement error, the smallest detectable difference (SDD), was equal to or larger than the calculated MCID, 5 Sharp/van der Heijde units and 6 Larsen/Scott units in our study, if the mean progression scores of the same 2 observers were used. The SDD is a conservative estimate of the MCID; our panel rated progression at or below this level as clinically significant.

Rhemulatologists' performance in dailiy practice.

OBJECTIVE: To assess rheumatologists' performance for 8 rheumatologic conditions and to explore possible explanatory factors. METHODS: After written informed consent was obtained, 27 rheumatologists (21% of all Dutch rheumatologists) practicing in 16 outpatient departments were each visited by 8 incognito "standardized patients" (SPs). The diagnoses of these 8 cases account for about 23% of all new referred patients in the Netherlands. Results for ordered lab tests as well as real radiographs with corresponding results from a radiologist were simulated. Information from the visits was obtained from the SPs, who completed predefined case-specific checklists, and by collecting data on resource utilization. Feedback was provided. RESULTS: Altogether 254 encounters took place, of which 201 were first visits and 53 were followup visits. SPs were unmasked twice during a visit. There was considerable variation in resource utilization (lab tests and imaging) between cases and between rheumatologists. Mean costs per rheumatologist ranged from US $ 4.67 to $ 65.36 per visit for lab tests and from US $ 33.15 to $ 226.84 per visit for imaging tests. No significant correlations were seen between resource utilization costs and number of years of clinical experience or performance on checklist scores. Rheumatologists with longer experience had lower total item checklist scores (r = -0.47; P < 0.05). CONCLUSION: A considerable variation in resource utilization was found among 27 Dutch rheumatologists. The information obtained is an excellent source for discussion on the appropriateness of care.

Developing case-specific checklists for standardized-patient-based assessments in internal medicine: A review of the literature.

PURPOSE: To review the literature on the methods used in writing case-specific checklists for studies of internal medicine physicians' performances that were assessed by standardized patients. METHOD: The authors searched Medline, Embase, Psychlit, and ERIC for articles in English published between 1966 and February 1998. The following search string was used: "[(standardi(*) or simulat(*) or programm(*)) near (patient(*) or client(*) or consultati(*))] and internal medicine." The authors then searched the reference lists of papers retrieved from the database searches, as well as those from seven proceedings of the International Ottawa Conference on Medical Education and Assessment. RESULTS: The procedure yielded 29 relevant articles: database searches yielded 14 published reports dealing with case-specific checklists, 11 articles were culled from the reference lists of these papers, and the Ottawa Conference proceedings yielded four articles. Only 12 articles reported specifically on the development of checklists. In general, there were three sources used for developing checklists: panels of experts, the investigators themselves, and responses from expert physicians to written protocols. No article indicated that researchers had relied exclusively on data from the literature to compose their checklists. Only three articles indicated that literature sources had informed their checklist development. All articles except one relied on explicit criteria for the inclusion of items on the checklists. In 21 of the 29 articles, the checklists had been scored by SPs, but the scoring of specific items on the checklists varied according to the purpose of the SP-physician encounter. Only four of the articles made the checklists available or indicated that the checklists could be obtained from the authors. CONCLUSION: The development of case-specific checklists for SP examinations of physicians' performance has received little attention. To judge the validity of studies of physicians' performances that use SPs, the development processes for the checklists need to be more fully described to enable readers to evaluate the validity and reliability of the studies.

Effect of low-dose prednisone (with calcium and calcitriol supplementation) on calcium and bone metabolism in healthy volunteers.

The administration of moderate to high doses of corticosteroids is associated with bone loss. This probably results from the uncoupling of bone formation (decreased) and bone resorption (unchanged or increased). We examined the effect of low-dose (10 mg/day) prednisone (LDP) and the possible mitigating effects of calcium and 1.25 (OH)2 vitamin D (calcitriol) on calcium and bone metabolism in eight healthy, young male volunteers. The study consisted of four observation periods: in the first period, LDP was prescribed during 1 week; in the second, third and fourth periods, calcium (500 mg/day), calcitriol (0.5 micrograms b.i.d.) and calcium in combination with calcitriol, respectively, were added to LDP. Bone formation was measured by means of serum osteocalcin, carboxy-terminal propeptide of type 1 procollagen (P1CP) and alkaline phosphatase, bone resorption by means of urinary excretion of calcium, hydroxyproline, (free and total) pyridinoline, (free and total) deoxypyridinoline and serum carboxy-terminal cross-linked telopeptide of type 1 collagen (1CTP). Dietary calcium and sodium intake were maintained at a stable level during the entire study period. Treatment with LDP led to a decrease in osteocalcin, P1CP and alkaline phosphatase (all P < 0.01). Urinary excretion of pyridinolines, hydroxyproline and serum 1CTP did not increase, but remained unchanged or slightly reduced (P < 0.05), depending on the time of measurement and the marker of bone resorption. Parathyroid hormone (PTH) (insignificantly) increased during LDP (+19%) and LDP plus calcium (+14%), but decreased during supplementation with calcitriol (-16%) and calcium/calcitriol (-44%; P < 0.01). Urinary excretion of calcium increased during treatment with LDP and calcitriol (P < 0.05) and calcium/calcitriol (P < 0.05). It is concluded that LDP has a negative effect on bone metabolism, since bone formation decreased while bone resorption remained unchanged or decreased slightly. The increase in PTH during LDP could be prevented by calcitriol combined with calcium supplementation.

Is addition of sodium fluoride to cyclical etidronate beneficial in the treatment of corticosteroid induced osteoporosis?

OBJECTIVE: To investigate whether administration of sodium fluoride (NaF) in addition to cyclical etidronate has a positive effect on bone mineral density (BMD) in patients with established osteoporosis during continued treatment with corticosteroids. PATIENTS AND METHODS: 47 patients who were receiving treatment with corticosteroids were included in a two year randomised, double blind, placebo controlled trial. Established osteoporosis was defined as a history of a peripheral fracture or a vertebral deformity, or both, on a radiograph. All patients were treated with cyclical etidronate, calcium, and either NaF (25 twice daily) or placebo. Vitamin D was supplemented in the case of a low serum 25 (OH) vitamin D concentration. BMD of the lumbar spine and hips was measured at baseline and at 6, 12, 18, and 24 months. RESULTS: After two years of treatment, the BMD of the lumbar spine in the etidronate/NaF group had increased by +9.3% (95% confidence intervals (CI): +2.3% to +16.2%, p < 0.01), while the BMD in the etidronate/placebo group was unchanged: +0.3% (95% CI: -2.2% to +2.8%). The difference in the change in BMD between groups was +8.9% (95% CI: +1.9% to +16.0%, p < 0.01). For the hips, no significant changes in BMD were observed in the etidronate/NaF group after two years: -2.5% (95% CI: -6.8% to +1.8%); in the etidronate/placebo group BMD had significantly decreased: -4.0% (95% CI: -6.6% to -1.4%; p < 0.01). The difference between the groups was not significant: +1.5% (95% CI: -3.4% to +6.4%). No significant differences in number of vertebral deformities and peripheral fractures were observed between the two groups. CONCLUSION: The effect of combination treatment with NaF and etidronate on the BMD of the lumbar spine in corticosteroid treated patients with established osteoporosis is superior to that of etidronate alone.

Evolution of the Martian water cycle.

The current Martian water cycle is extremely asymmetric, with large amounts of vapor subliming off a permanent north polar water ice cap in northern summer, but with no apparent major source of water vapor in the southern hemisphere. Detailed simulations of this process with a three-dimensional circulation model indicate that the summertime interhemispheric exchange (Hadley cell) is very much stronger than transport by eddies in other seasons. As a result, water ice would be distributed globally were it not for the buffering action of regolith soil adsorption which limits the net flux of water vapor off the north polar cap to amounts that are insignificant even on the scale of thousands of years. It has been suggested that the polar layered deposits are the result of exchange on these long time scales, driven by changes in Martian orbital parameters. We therefore are conducting simulations to test the effect of varied orbital parameters on the Martian water cycle. We find that when the perihelion summer pole is charged with a polar water ice cap, large quantities of water are quickly transfered to the aphelion summer pole, setting up an annual cycle that resembles the present one. Thus, the adsorptivity of the Martian regolith may be in the narrow range where it can limit net transport from the aphelion but not the perihelion pole.

Effect of sodium fluoride on the prevention of corticosteroid-induced osteoporosis.

To investigate whether sodium fluoride (NaF) is able to prevent bone loss in patients treated with corticosteroids (Cs), we performed a randomized double-masked, placebo-controlled trial with 44 Cs-treated patients without established osteoporosis, defined as the absence of previous peripheral fractures and vertebral deformities on radiographs. The effects of NaF (25 mg twice daily) and placebo on the bone mineral density (BMD) of the lumbar spine and hips were compared at baseline and at 6, 12, 18 and 24 months. After 2 years, the BMD of the lumbar spine had decreased in the placebo group by 3.0% (95% CI: -4.9% to -1.0%; p < 0.01); in the NaF group there was a statistically insignificant increase in BMD of 2.2% (95% CI: -0.8% to +5.3%). The difference in the changes in BMD between the two groups was +5.2% (95% CI: +1.8% to +8.6%; p < 0.01). In the hips, BMD had decreased after 2 years in both groups: in the placebo group by -3.0% (95% CI: -5.0% to -1.0%; p < 0.05) and in the NaF group by 3.8% (95% CI: -6.1% to -1.5%; p < 0.01). The difference in the changes in BMD between the two groups was not significant: +0.8% (95% CI: -2.1% to +3.8%). Three vertebral deformities were observed in the placebo group and one in the NaF group (insignificant difference), while no peripheral fractures occurred during the study period. It is concluded that in Cs-treated patients without established osteoporosis NaF prevents bone loss in the lumbar spine but does not have a positive effect on the BMD of the hips.

Autoradiographic demonstration of 125I-Tyr4-bombesin binding sites on rat anterior pituitary cells.

Because several direct effects of bombesin related peptides on pituitary hormone release have been demonstrated, we chose to study the presence of bombesin binding sites in the adult male rat anterior pituitary in aggregate cell culture by autoradiographic localization of 125I-tyrosine4-bombesin (125I-Tyr4-BBN) binding and immunocytochemical localization of the anterior pituitary hormones. When aggregates were cultured in medium without hormonal supplements, the number of cells with detectable 125I-Tyr4-BBN binding was below 1%. In cell aggregates cultured in the presence of 1 nM estradiol (E2) 125I-Tyr4-BBN binding was detected on 5.4 +/- 0.8% of the cells after redispersion and on 5.8 +/- 1.1% of the cells in sections of paraffin embedded aggregates. The binding cell types were mainly lactotrophs and somatotrophs. The binding of 125I-Tyr4-BBN (3 or 5 nM) was specific because it was inhibited by the addition of an excess of unlabelled Tyr4-BBN or the bombesin receptor antagonist L686,095. In aggregates cultured in the presence of 1 nM E2 and 4 nM dex, the percentage of cells with detectable 125I-Tyr4-BBN binding was significantly lower than that in aggregates cultured in the presence of 1 nM E2 alone. Binding on somatotrophes almost completely disappeared. The present data show that specific 125I-Tyr4-BBN binding sites are present on anterior pituitary cells, are detectable mainly on a small subpopulation of lactotrophs and somatotrophs, and are affected by hormonal conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioactive peptides in anterior pituitary cells.

The anterior pituitary (AP) has been shown to contain a wide variety of bioactive peptides: brain-gut peptides, growth factors, hypothalamic releasing factors, posterior lobe peptides, opioids, and various other peptides. The localization of most of these peptides was first established by immunocytochemical methods and some of the peptides were localized in identified cell types. Although intracellular localization of a peptide may be the consequence of internalization from the plasma compartment, there is evidence for local synthesis of most of these peptides in the AP based on the identification of their messenger-RNA (mRNA). In several cases the release of the peptide from the AP cell has been shown and regulation of synthesis, storage and release have also been described. Because the amount of most of the AP peptides is very low (except for POMC peptides and galanin), endocrine functions are not expected. There is more evidence for paracrine, autocrine, or intracrine roles in growth, differentiation, and regeneration, or in the control of hormone release. To demonstrate such functions, in vitro AP experiments have been designed to avoid the interference of hypothalamic or peripheral hormones. The strategy is first to show a direct effect of the peptide after adding it to the in vitro system and, secondly, to explore if the endogenous AP peptide has a similar action by using blockers of peptide receptors or antisera immunoneutralizing the peptide.