Underprescription of medications in older adults: causes, consequences and solutions-a narrative review.

PURPOSE: Under-prescription is defined as the omission of a medication that is indicated for the treatment of a condition or a disease, without any valid reason for not prescribing it. The aim of this review is to provide an updated overview of under-prescription, summarizing the available evidence concerning its prevalence, causes, consequences and potential interventions to reduce it. METHODS: A PubMed search was performed, using the following keywords: under-prescription; under-treatment; prescribing omission; older adults; polypharmacy; cardiovascular drugs; osteoporosis; anticoagulant. The list of articles was evaluated by two authors who selected the most relevant of them. The reference lists of retrieved articles were screened for additional pertinent studies. RESULTS: Although several pharmacological therapies are safe and effective in older patients, under-prescription remains widespread in the older population, with a prevalence ranging from 22 to 70%. Several drugs are underused, including cardiovascular, oral anticoagulant and anti-osteoporotic drugs. Many factors are associated with under-prescription, e.g. multi-morbidity, polypharmacy, dementia, frailty, risk of adverse drug events, absence of specific clinical trials in older patients and economic factors. Under-prescription is associated with negative consequences, such as higher risk of cardiovascular events, worsening disability, hospitalization and death. The implementation of explicit criteria for under-prescription, the use of the comprehensive geriatric assessment by geriatricians, and the involvement of a clinical pharmacist seem to be promising options to reduce under-prescription. CONCLUSION: Under-prescription remains widespread in the older population. Further studies should be performed, to provide a better comprehension of this phenomenon and to confirm the efficacy of corrective interventions.

Inappropriate Use of Proton Pump Inhibitors in Elderly Patients Discharged from Acute Care Hospitals.

BACKGROUND: Proton-pump inhibitors (PPI) are extensively prescribed in older patients. However, little information is available on factors associated to PPI prescribing patterns among older patients discharged from hospital. OBJECTIVE: To evaluate the appropriateness and clinical correlates of PPI prescription at discharge in a population of 1081 older patients discharged from acute care Italian hospitals. DESIGN: We used data from the CRiteria to Assess Appropriate Medication Use among Elderly Complex Patients (CRIME) study, a multicenter observational study. The appropriateness of PPI prescriptions was defined according to the Italian Medicines Agency (AIFA) rules. Correlates of overprescribing (i.e prescribing without recognized AIFA indications) and underprescribing (i.e. not prescribing despite the presence of recognized AIFA indications) were investigated by logistic regression analysis. RESULTS: Overprescribing was observed in 30% of patients receiving PPIs at discharge. Underprescribing was observed in 11% of patients not receiving PPIs at discharge. Overprescribing of PPIs at discharge was negatively associated with age (OR=0.88, 95%CI=0.85-0.91), depression (OR=0.58, 95%CI=0.35-0.96), use of aspirin (OR=0.03, 95%CI=0.02-0.06) and systemic corticosteroids (OR=0.02, 95%CI=0.01-0.04). The negative association with number of medications (OR=0.95, 95%CI=0.88-1.03) and overall comorbidities (OR=0.92, 95%CI=0.83-1.02) was nearly significant. Conversely, older age (OR=1.09, 95%CI=1.04-1.14), use of aspirin (OR=24.0, 95%CI=11.5-49.8) and systemic corticosteroids (OR=19.3, 95%CI=11.5-49.8) and overall comorbidities (OR=1.22, 95%CI=1.04-1.42) were independent correlates of underprescribing. CONCLUSION: Overprescribing of PPIs is more frequent in younger patients with lower burden of depression, whilst underprescribing is characterized by older age and greater burden of comorbidity and polypharmacy. Hospitalization should be considered as a clue to identify inappropriate use of PPIs and improve appropriateness of prescribing.

The impact of drug interactions and polypharmacy on antimicrobial therapy in the elderly.

Infectious diseases are more prevalent in older people than in younger adults, and represent a major healthcare issue in older populations. Indeed, infections in the elderly are often associated with higher morbidity and mortality, and may present atypically. Additionally, older patients are generally treated with polypharmacy regimens, which increase the likelihood of drug-drug interactions when the prescription of an antimicrobial agent is needed. A progressive impairment in the functional reserve of multiple organs may affect either pharmacokinetics or pharmacodynamics during aging. Changes in body composition occurring with advancing age, reduced liver mass and perfusion, and reduced renal excretion may affect either pharmacokinetics or pharmacodynamics. These issues need to be taken into account when prescribing antimicrobial agents to older complex patients taking multiple drugs. Interventions aimed at improving the appropriateness and safety of antimicrobial prescriptions have been proposed. Educational interventions targeting physicians may improve antimicrobial prescriptions. Antimicrobial stewardship programmes have been found to reduce the length of hospital stay and improve safety in hospitalized patients, and their use in long-term care facilities is worth testing. Computerized prescription and decision support systems, as well as interventions aimed at improving antimicrobial agents dosage in relation to kidney function, may also help to reduce the burden of interactions and inherent costs.

Treating cancer in older and oldest old patients.

The so-called "silver tsunami" is a metaphor that the individuals 65 and older represent the most rapidly growing segment of the Western world population. Aging is an ongoing process that leads to the loss of functional reserve of multiple organ systems, increased susceptibility to stress, it is associated with increased prevalence of chronic disease, and functional dependence. Determined by a combination of genetic and environmental factors, this process is highly individualized and poorly reflected in chronologic age. The heterogeneity and the complexity of the older old population represent the main challenge to the treatment of cancer in those patients. We should discern "fit" elderly in whom standard cancer treatment appears to be comparable to a younger population and "unfit" or "frail" elderly, in which the risks of the treatment may overwhelm potential benefits. There are many aspects that have to be assessed before treating an elderly patient, or before to choose the treatment itself. In our review we will try to explain and describe the meaning and the most important aspects related to the oldest old complex patients, and how to manage those patients.

The Relationship of Hemoglobin Levels, Delirium and Cognitive Status in Hospitalized Geriatric Patients: Results from the CRIME Study.

OBJECTIVE: Delirium is a frequent clinical complication in geriatric patients admitted to the hospital, because of the simultaneous presence and synergistic effect of predisposing and precipitating factors. Also anaemia is a common concern in geriatric population. The aim of this study was to investigate the association between anaemia (precipitating factor) and delirium in a sample of Italian older hospitalized patients with different degree of cognitive impairment (predisposing factor). DESIGN, SETTING, PARTICIPANTS: Cross-sectional analysis of 1069 participants enrolled in the CRIME study, with assessment of hemoglobin levels at hospital admission. MEASUREMENTS: Delirium was assessed using DSM-IV criteria, whereas cognitive status was categorized as dementia, cognitive impairment or normal, according to clinical history, specific treatment and MMSE score. Anaemia was defined according to sex-specific WHO criteria. The association of hemoglobin levels and delirium was investigated with multivariable logistic regression models. RESULTS: Mean age of study participants was 81.4±7.2 years, 52.2% had prevalent anaemia, 6.1% had delirium. According to cognitive status 20.8% had dementia and 40.9% had cognitive impairment. Overall there was no association between anaemia and delirium. However, among patients with cognitive impairment (MMSE <24, no dementia) anaemia was significantly associated with the likelihood of delirium (p<0.006). Multivariate logistic regression analysis, adjusted for potential confounders, showed in these patients a graded increased risk of delirium according to anaemia severity with an almost six-fold increased risk of delirium in moderate-severe anaemia (OR 5.95, 95% CI:1.15-30.73). CONCLUSION: In older patients with cognitive impairment moderate-severe anaemia is independently associated with the likelihood of delirium. Further studies should investigate if anaemia correction would translate in delirium risk reduction.

Diabetes-related quality of life is enhanced by glycaemic improvement in older people.

AIMS: To investigate the validity and reliability of the Audit of Diabetes-Dependent Quality of Life instrument in older Italians with diabetes and to test the association of diabetes-related quality of life with glycaemic control over time. METHODS: A total of 558 outpatients with Type 2 diabetes from the Diabetic Unit of the Italian National Research Centre on Aging Hospital in Ancona were enrolled to complete questionnaires (Audit of Diabetes-Dependent Quality of Life-19 and the Short-Form-12), and to undergo clinical and biochemical testing at baseline and at 12 months of follow-up. The overall impact of diabetes using the average weighted impact score from the Audit of Diabetes-Dependent Quality of Life questionnaire was calculated. Participants were categorized according to this score as having either less or more negative diabetes-related quality of life. RESULTS: Participants had a mean ± SD age of 67.7 ± 9.2 years and 51.8% were male. Factor analysis and Cronbach's coefficient of internal consistency (Cronbach's α = 0.931) confirmed that the 19 domain-specific Audit of Diabetes-Dependent Quality of Life items could be combined into a single scale in this Italian population. The impact score correlated with the physical (r = 0.275; P < 0.001) and mental components (r = 0.291; P < 0.001) of the Short-Form-12 questionnaire. Significant differences were found according to diabetic complications in specific Audit of Diabetes-Dependent Quality of Life items and impact scores. Insulin use had a greater association with a more negative quality of life compared with other antidiabetic agents. A multivariate linear regression model with restricted linear spline application showed that the relationship between HbA1c and impact score was not linear and that the change in the impact score was associated with improved glycaemic control in those with a less negative diabetes-related quality of life at 12 months. CONCLUSIONS: The Audit of Diabetes-Dependent Quality of Life-19 is a valid tool for measuring the impact of diabetes on quality of life in older Italians. Perception of diabetes-related quality of life is associated with glycaemic control over time.

Physical performance measures and polypharmacy among hospitalized older adults: results from the CRIME study.

OBJECTIVE: To investigate the association of polypharmacy and physical performance measures in a sample of elderly patients aged ≥65 years admitted to acute care hospitals. DESIGN, SETTING AND PARTICIPANTS: Prospective study conducted among 1123 hospitalized older adults participating to the CRiteria to Assess Appropriate Medication Use among Elderly Complex Patients (CRIME) project. MEASUREMENTS: Physical performance was measured at hospital admission by the 4-meter walking speed (WS) and the grip strength (GS). Polypharmacy was defined as the use of ≥10 drugs during hospital stay. RESULTS: Mean age of 1123 participants was 81.5±7.4 years and 576 (51.3%) were on polypharmacy. Prevalence of polypharmacy was higher in patients with low WS and GS. After adjusting for potential confounders, participants in the highest tertile of WS were less likely to be on polypharmacy as compared with those in the lowest tertile (OR 0.58; 95% CI 0.35 - 0.96). Similarly, participants in the highest tertile of GS had a significantly lower likelihood of polypharmacy as compared with those in the lowest tertile (OR 0.55; 95% CI 0.36 - 0.84). When examined as continuous variables, WS and GS were inversely associated with polypharmacy (WS: OR 0.77 per 1 SD increment; 95% CI 0.60 - 0.98; GS: OR 0.71 per 1 SD increment; 95% CI 0.56 - 0.90). CONCLUSION: Among hospitalized older adults WS and GS are inversely related to polypharmacy. These measures should be incorporated in standard assessment of in-hospital patients.

Relationship between use of proton pump inhibitors and IGF system in older subjects.

OBJECTIVES: to investigate the effects of proton pump inhibitors (PPIs) on the insulin-like-growth factor 1(IGF-1) system in the elderly. DESIGN: cross-sectional. SETTING: InCHIANTI study. PARTICIPANTS: 938 older subjects (536 women, 402 men, mean age 75.7±7.4 years). MEASUREMENTS: complete data on age, sex, BMI, liver function, medications, dietary intake, IGF-1, IGF-binding protein-1 and -3 (IGFBP-1, IGFBP-3). RESULTS: Participants were categorized by PPI use, identifying 903 PPI non users and 35 users. After adjusting for age, male PPI users (107.0 ± 69.6 vs. 127.1 ± 55.8, p<0.001) and female PPI users (87.6 ± 29.1 vs. 107.6 ± 52.3, p=0.03) had lower IGF-1 levels than non-users. IGFBP-1 levels were similar in the two groups in both sexes. In whole population, after adjustment for age and sex, PPI users had lower IGF-1 levels 81.9 [61.1-113.8] than non-users 110 [77.8-148.6], p=0.02. After further adjustment for BMI, albumin, liver function, C-reactive protein, Interleukin-6, number of medications, ACE-inhibitors use, caloric intake, protein intake, physical activity, glycemia, and IGFBP-1, the use of PPIs remained significantly and negatively associated with IGF-1 levels (ß±SE = -19.60±9.83, p=0.045). CONCLUSION: Use of PPIs was independently and negatively associated with IGF-1 levels.

The oxygen therapy.

Oxygen (O(2)) is a vital element. Shortage of O(2) results in deranged metabolism and important changes in vascular tone with opposite effects on the systemic and pulmonary circulation. During hypoxemia, oxidative stress exposes the organism to a sort of accelerated senescence as well as to several acute untoward effects. Thus, hypoxemia should be promptly recognized and treated, hopefully by measures tailored to the pathophysiological mechanisms underlying hypoxemia. However, O(2) therapy remains the most common therapy of hypoxemia, but it must be carefully tailored to relieve hypoxemia without provoking hyperoxia or hypercarbia. Then, the individual response to O(2) as well as changing needs of O(2) during sleep or exercise must be evaluated to provide the best O(2) therapy. Hyperoxia, the effect of overcorrection of hypoxia, can dramatically impact the health status and threaten the survival of the newborn and, through different mechanisms and effects, the adult. A thorough knowledge of the pathophysiological bases of hypoxemia and O(2) storage and delivery devices is then mandatory to administer O(2) therapy guaranteeing for optimal correction of hypoxemia and minimizing the risk of hyperoxia. Consistent with this aim also is a careful scrutiny of instruments and procedures for monitoring the individual response to O(2) over time. Thus, at variance from classical pharmacological therapy, performing O(2) therapy requires a vast array of clinical and technical competences. The optimal integration of these competences is needed to optimize O(2) therapy on individual bases.

Ageing and COPD affect different domains of nutritional status: the ECCE study.

Chronic obstructive pulmonary disease (COPD) and ageing may contribute to malnutrition. We aimed to explore whether COPD and ageing determine malnutrition in different manners. 460 stable COPD outpatients (376 males and 84 females) from the Extrapulmonary Consequences of COPD in the Elderly (ECCE) study database were investigated (age 75.0±5.9 yrs; forced expiratory volume in 1 s 54.7±18.3% predicted). Nutritional status was evaluated using the Mini Nutritional Assessment® (MNA) questionnaire. From the MNA, three scores exploring the domains of the nutritional status were calculated: body composition, energy intake and body functionality scores. Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages were negatively correlated with five MNA items exploring mobility, patient's perception of own nutrition and health status, and arm and calf circumferences (lowest Spearman's rho (rs)=-0.011; highest p=0.039). GOLD stages were independently correlated with body composition and body functionality scores (model r2=0.073). Age was negatively correlated with four MNA items exploring loss of appetite, fluid intake, mobility and autonomy in daily life (lowest rs=-0.013; highest p=0.030). Age was independently correlated with body functionality score (model r2=0.037). Severe COPD and ageing are independent and probably concurrent conditions leading to malnutrition. The MNA questionnaire allows a valuable insight into the complexity of components of nutritional status and may provide useful clues for treatment strategies.

Frailty and muscle metabolism dysregulation in the elderly.

The frailty syndrome is increasingly recognized by geriatricians to identify elders at an extreme risk of adverse health outcomes. The physiological changes that result in frailty are complex and up to now have been extremely difficult to characterize due to the frequent coexistence of acute and chronic illness. Frailty is characterized by an decline in the functional reserve with several alterations in diverse physiological systems, including lower energy metabolism, decreased skeletal muscle mass and quality, altered hormonal and inflammatory functions. This altered network leads to an extreme vulnerability for disease, functional dependency, hospitalization and death. One of the most important core components of the frailty syndrome is a decreased reserve in skeletal muscle functioning which is clinically characterized by a loss in muscle mass and strength (sarcopenia), in walking performance and in endurance associated with a perception of exhaustion and fatigue. There are a number of physiological changes that occur in senescent muscle tissues that have a critical effect on body metabolism. The causes of sarcopenia are multi-factorial and can include disuse, changing hormonal function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. In this review, we will explore the dysregulation of some biological mechanisms that may contribute to the pathophysiology of the frailty syndrome through age-related changes in skeletal muscle mass and function.

Age-related pharmacokinetic and pharmacodynamic changes and related risk of adverse drug reactions.

Aging is known to be associated with an increased prevalence of multiple chronic diseases, which frequently causes the use of complex therapeutic regimens. The aging process is characterized by relevant changes in drug handling, physiological reserve, and pharmacodynamic response. Hepatic drug clearance of several drugs decreases with aging, mainly due to reduced blood flow, and hepatocyte mass. Renal function also declines with aging, mainly due to sclerotic changes in the glomeruli. Furthermore, due to reduced muscle mass, older subjects frequently have depressed glomerular filtration rate despite normal serum creatinine, and such a concealed renal insufficiency may impact significantly the clearance of hydrosoluble drugs. Changes in pharmacodynamics are also well documented in the cardiovascular and nervous system. Age-related changes in pharmacokinetics and pharmacodynamics, together with comorbidity and polypharmacy, make elderly patients at special risk for adverse drug reactions, which in turn are cause of relevant health burden and costs. Selected measures can assist in preventing or detecting timely such adverse events.

Relationship between socio-economic features and health status in elderly hospitalized patients.

We aimed at investigating the relationship between socioeconomic (SES) and health status in the context of an observational multicenter study of elderly hospitalized patients. Our series consisted of 473 patients aged 70 years or more. K-means cluster analysis was used to generate 3 clusters on the basis of age, gender, education, perception of personal economic situation, difficulty to reach health services, need for formal or informal support, family arrangement, and population density of residence municipality. Logistic regression analysis was used to identify correlates of "negative" SES. Correlates of "negative" SES cluster were older age (odds ratio=OR=5.19, 95% Cl=2.28-11.8), cognitive impairment (OR=6.36, 95%CI=3.11-13.0), emergency hospital admission (OR=3.11; 95%CI=1.52-6.35), and dependency in at least 1 BADL (OR=4.36, 95%CI=1.53-12.4). In conclusion, "negative" SES is associated with age and selected indices of frailty in elderly hospitalized patients. The evaluation of socio-economic problems should be routinely addressed in elderly hospitalized patients in order to tailor appropriately post-discharge use of health care resources.

Metabolic syndrome, psychological status and quality of life in obesity: the QUOVADIS Study.

OBJECTIVE: We aimed to investigate the association of the clinical variables of the metabolic syndrome (MS) and psychological parameters on health-related quality of life (HRQL) in obesity. In particular, our aim was to investigate the relative impact of physical symptoms, somatic diseases and psychological distress on both the physical and the mental domains of HRQL. DESIGN: Cross-sectional study. SUBJECTS: A cohort of 1822 obese outpatients seeking treatment in medical centers. MEASUREMENTS: HRQL was measured by the standardized summary scores for physical (PCS) and mental (MCS) components of the Short Form 36 Health Survey (SF-36). Patients were grouped according to tertiles of PCS and MCS. Metabolic and psychological profiles of PCS and MCS tertiles were compared by discriminant analysis. RESULTS: The profile of metabolic and psychological variables was tertile-specific in 62.4 and 68.3% of patients in the lowest and highest tertiles of PCS, respectively, while concordance was low in the mid-tertile (32.8%). Concordance was very high in the lowest (74.4%) and in the highest (75.5%) tertiles of MCS, and was fair in the mid-tertile (53.2%). The main correlates of PCS were obesity-specific and general psychological well-being, BMI, body uneasiness, binge eating, gender and psychiatric distress. Only hypertension and hyperglycemia qualified as correlates among the components of MS. The components of MS did not define MCS. CONCLUSIONS: Psychological well-being is the most important correlate of HRQL in obesity, both in the physical and in the mental domains, whereas the features of MS correlate only to some extent with the physical domain of HRQL.

Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients.

OBJECTIVE: To verify whether platelet responsiveness to leptin is associated with metabolic syndrome risk factors. DESIGN: Cross-sectional study. SUBJECTS: We studied 169 consecutive patients, mean age=43.6+/-9.9 years, with overweight (N=57) or obesity (N=112). MEASUREMENTS: Cluster analysis was used to generate three clusters based on platelet responsiveness to increasing doses of leptin. Profiles of metabolic syndrome risk factors of the three clusters were compared by discriminant analysis. RESULTS: Platelet responsiveness to leptin was absent in cluster 1, whereas cluster 3 had the greatest platelet aggregation response to leptin pre-incubation. Plasma leptin levels significantly decreased from cluster 1 to cluster 3 in both gender. Patients in cluster 2 had an intermediate profile of leptin responsiveness. Highest body mass index (BMI) values were more frequent in non-responders, whereas the prevalence of high waist circumference, as well as hypertriglyceridemia and hypertension, increased with increasing responsiveness to leptin from cluster 1 to cluster 3. Pattern of metabolic syndrome risk factors qualified as group specific in 69.0% of the cluster 1, 54.9% of the cluster 2 and 55.8% of the cluster 3. Circulating leptin, waist circumference, plasma triglycerides and BMI defined distinctive patterns of metabolic syndrome risk factors in the clusters. CONCLUSIONS: In overweight and obese outpatients, metabolic syndrome risk factors parallel to some extent platelet responsiveness to leptin. Such a correlation involves plasma leptin levels, waist circumference, plasma triglycerides and BMI, and may contribute to the excess risk of cardiovascular events in overweight and obese patients.

Effects of magnesium sulphate on leptin-dependent platelet aggregation: an ex vivo study.

Magnesium sulphate has well known antiplatelet properties. Its effect on leptin-dependent platelet aggregation has not been studied previously. Thus, we performed this ex vivo study to investigate whether magnesium sulphate is able to inhibit leptin-dependent aggregation of human platelets. We obtained platelet rich plasma (PRP) from venous blood samples of 16 healthy male volunteers, and we measured ADP-induced platelet aggregation in the presence of leptin alone (5-500 ng/mL) or leptin and magnesium sulphate (0.25-8 mM). Platelet pre-incubation with leptin led to a significant and dose-dependent increase in ADP-induced platelet aggregation. Magnesium sulphate was able to inhibit the pro-aggregating effect of leptin in a dose-dependent manner. The inhibitory effect was apparent at 1 mM of magnesium sulphate concentration (% maximal aggregation=38.1 +/- 12.2) and reached its maximum at 8 mM (% maximal aggregation=20.0 +/- 7.8). Our results demonstrate that leptin-dependent platelet aggregation is inhibited by magnesium sulphate in a dose-dependent manner. It seems conceivable that the blocking of hydrolysis of phosphoinositide and of intracellular calcium mobilization by magnesium sulphate may be involved in these findings.

Identifying pathways involved in leptin-dependent aggregation of human platelets.

OBJECTIVE: To investigate the role of phospholipase C (PLC), phospholipase A(2) (PLA(2)), calcium, and protein kinase C (PKC) in mediating leptin-enhanced aggregation of human platelets. DESIGN: In vitro, ex vivo study. SETTING: Outpatient's Service for Prevention and Treatment of Obesity at the University Hospital of Messina, Italy. SUBJECTS: In total, 14 healthy normal-weight male (age 31.4+/-1.9 y; body mass index 22.7+/-0.6 kg/m2) subjects. MEASUREMENTS: Adenosine diphosphate-(ADP-) induced platelet aggregation and platelet free calcium were measured after incubation of platelets with leptin alone (5-500 ng/ml), or leptin (50 and 100 ng/ml) in combination with anti-human leptin receptor long form antibody (anti-ObRb-Ab, 1:800-1:100 dilutions), PLC inhibitor U73122 (3.125-25 microM), PLA(2) inhibitor AACOCF3 (1.25-10 microM), or PKC inhibitor Ro31-8220 (1.25-10 microM). RESULTS: Platelet stimulation with leptin leads to a significant and dose-dependent increase in ADP-induced platelet aggregation and platelet free calcium concentrations. Leptin effects on both platelet aggregation and calcium mobilization were completely abated by the co-incubation with leptin and anti-ObRb-Ab. Leptin-induced platelet aggregation was dose-dependently inhibited by U73122, AACOCF3, or Ro31-8220. The effect of leptin on intracellular calcium was inhibited in a dose-dependent manner by incubation with U73122 and AACOCF3, but not with Ro31-8220. CONCLUSIONS: Our study confirms that leptin is able to enhance ADP-induced aggregation of human platelets, and raise the possibility that PLC, PKC, PLA(2), and calcium could play a relevant role in mediating the proaggregating action of leptin.

Leptin-dependent platelet aggregation in healthy, overweight and obese subjects.

OBJECTIVE: To investigate the effects of leptin on platelet aggregation and platelet free calcium (Ca(2+)) concentrations, and the role of the long form of leptin receptor (ObRb) and the phospholipase C (PLC) in mediating leptin effects on platelet function. DESIGN: Cross-sectional, clinical study. SETTING: Outpatient's Service for Prevention and Treatment of Obesity at the University Hospital of Messina, Italy. SUBJECTS: A total of 19 healthy, 14 overweight, and 16 obese male subjects. MEASUREMENTS: ADP-induced platelet aggregation and platelet Ca(2+) were measured after incubation of platelet-rich plasma with leptin alone 5-200 ng/ml, leptin 200 ng/ml and anti-human leptin receptor long-form antibody (ObRb-Ab) 5-10 microl, or leptin 200 ng/ml and PLC inhibitor U73122 0.5-1 nmol/l. RESULTS: Platelet stimulation with leptin lead to a significant and dose-dependent increase in platelet aggregation in healthy subjects. This effect was blunted in overweight, and strongly reduced in obese subjects. Similarly, the incubation with leptin induced a significant and dose-dependent increase in platelet free calcium, which was blunted in overweight and obese patients. The effect of leptin on platelet aggregation and platelet Ca(2+) was completely abated by the anti-ObRb-Ab and the PLC inhibitor U73122. CONCLUSIONS: Leptin produces a dose-dependent enhancement of ADP-induced platelet aggregation in humans. Platelet aggregation response to leptin is blunted, but not completely abolished in overweight/obese subjects, thus suggesting that platelet may represent a site of leptin resistance in human obesity. Leptin increases platelet free calcium in a dose-dependent manner. The inhibition of PLC completely abates the effect of leptin on both platelet aggregation and Ca(2+) levels. These findings suggest that signaling pathway other than JAK-STAT tyrosine phosphorylation (ie PLC and calcium) may be involved in mediating the prothrombotic action of leptin.

The study of APOA1, APOC3 and APOA4 variability in healthy ageing people reveals another paradox in the oldest old subjects.

The genes coding for apolipoprotein A1 (APOA1), apolipoprotein C3 (APOC3) and apolipoprotein A4 (APOA4) are tandemly organised within a short region on chromosome 11q23-q24. Polymorphisms of these genes have been extensively investigated in lipoprotein disorders and cardiovascular diseases, but poorly investigated in healthy ageing. The aim of this study was to describe possible modifications of the APOA1, APOC3, and APOA4 gene pool by cross-sectional studies carried out in a healthy ageing population whose ages ranged from 18 to 109 years (800 subjects, 327 males and 473 females, free of clinically manifested disease, and with emato-chemical parameters in the norm). APOA1-MspI-RFLP (-75 nt from the transcription starting site), APOC3-SstI-RFLP (3'UTR, 3238 nt), and APOA4-HincII-RFLP (Asp127/Ser127) were analysed according to age and sex. A significant age-related variation of the APOA1 gene pool was observed in males. An analysis of the allele average effect exerted by APOA1-MspI-RFLP A/P alleles (Absence/Presence of the restriction site) on lipidemic parameters in 46-80 year old males showed that allele A decreased, while allele P significantly increased, serum LDL-cholesterol. Unexpectedly, the P allele was over-represented in the group of the oldest old subjects, thus giving evidence of another "genetic paradox of centenarians".