Analysis of non-derivatized 2-(4-R-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine using short column gas chromatography - mass spectrometry.

The 25R-NBOH family is a group of thermally labile compounds that are relevant for forensic sciences and traditionally analyzed by GC-MS after derivatization - a step that is time consuming in a routine work. In this paper, the use of short analytical columns (4 and 10 m) showed to decrease compound degradation in the GC oven during chromatographic separation and to allow the analysis of non-derivatized 25R-NBOH compounds by GC-MS. A shorter column demanded a higher gas flow rate, and both factors decreased residence time of the analytes in the column and their degradation. The inlet temperature (250° C or 280°C) did not impact the response of 25R-NBOH. A 25R-NBOH fragmentation pathway by electron ionization was also presented for the first time. The GC-MS method with a 4 m column was successfully applied to other compounds of forensic interest, and it can be tested in the analysis of biological samples in toxicological investigations.

Do prostaglandin analogs affect eyelid position and motility?

PURPOSE: The authors aim at investigating the possible clinical effects of topical Prostaglandin Analogs on eyelid position and motility with this single masked protocol in a cross-sectional study. METHODS: A group (group A) of 182 patients on treatment for glaucoma with prostaglandin analogs (latanoprost, travoprost, and bimatoprost) and a group of 191 age-matched normal controls (group B) were enrolled in the study. Group A was subdivided into 3 subgroups according to the prostaglandin analogs used by the patients. Group A1: 84 patients on latanoprost, group A2: 56 patients on travoprost, and group A3: 42 patients on bimatoprost. Two positive control groups (group H of 115 patients with lower lid involutional entropion or ectropion secondary to horizontal lid laxity (HLL), and a group P of 137 patients with involutive aponeurotic blepharoptosis) were also enrolled in the study. For the upper eyelid, the following parameters were measured: margin-reflex distance (MRD), upper lid crease position, levator function. For the lower lid, the following parameters were used: HLL and lower lid excursion (LLE). Statistical analysis of the data was done to assess whether there was any statistical significant difference for each of the parameter between group A (and its subgroups) and, respectively, groups B, H, and P. Similarly, it was also compared with group B, with group H, and then with group P. Analysis of variance of the eyelid parameters was also carried out in the 3 subgroups A1, A2, and A3. RESULTS: There was no statistically significant difference for each studied parameter between group B and, respectively, groups A1, A2, A3 and group A, nor there was any statistically significant variance between parameters in the 3 subgroups A1, A2, and A3. The accuracy of the eyelid parameters was confirmed while obtaining statistically significant differences in LLE (P<0.05) and in HLL (P<0.001) comparing group A (and its subgroups) and group H and also in MRD and upper lid crest (P<0.001) comparing group A (and its subgroups) and group P. CONCLUSIONS: There is no evidence that prostaglandin analogs significantly affect the eyelids' tissues to produce eyelid malposition.

Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial.

BACKGROUND: Docetaxel (DTX) and zoledronic acid (ZOL) are effective in patients with hormone resistant prostate cancer (HRPC) with bone metastases. A phase I clinical trial of metronomic administration of Zoledronic Acid AN d TaxoterE combination (ZANTE trial) in 2 different sequences was conducted in HRPC. RESULTS: The maximum tolerated dose was not achieved with sequence A. Two patients at third level of sequence B developed dose limiting toxicity. A disease control was obtained in six out of nine patients treated with sequence A, where a decrease of biological markers and PSA were also observed. No evidence of anti-tumor activity was observed in patients treated with sequence B. PATIENTS AND METHODS: Twenty-two patients enrolled into the study (median age: 73 years; range: 43-80) received one of three escalated doses of DTX (30, 40 and 50 mg/m(2)) in combination with a fixed dose of ZOL (2 mg), both administered every 14 days in two different sequences: DTX at the day 1 followed by ZOL at the day 2 (sequence A) or the reverse (sequence B). Patients were evaluated for adverse events and serum IL-8, MMP-2 and MMP-9 were evaluated prior and after therapy with the two sequences of administration of DTX and ZOL. CONCLUSIONS: The bi-weekly combination of DTX (50 mg/m(2)) followed by ZOL was feasible and show promising anti-tumor activity.

Role of neuroendocrine pathways in cognitive decline during aging.

The pineal and pituitary-adrenocortical secretions play an important role in adaptive responses of the organism acting as coordinating signals for both several biological rhythms and multiple neuroendocrine and metabolic functions. The more relevant neuroendocrine changes occurring with ageing affect the secretion of melatonin and of corticosteroids. These changes may be clearly appreciated by the study of their circadian rhythmicity. The circadian profile of plasma melatonin was clearly flattened in elderly subjects and even more in old individuals with dementia. Indeed, the impairment of melatonin signal occurring in aging was related either to age itself or to the cognitive performances of subjects. The biosynthetic dissociation between glucocorticoids and androgen secretion is responsible for the selective impairment of androgens, such as DHEA and DHEA-S, by comparison to cortisol. Due to the opposite effects of the two kinds of corticosteroids either in the periphery and in the CNS, the imbalance between glucocorticoids and androgens, well demonstrated by the evaluation of the cortisol/DHEA-S molar ratio, may be responsible for the occurrence in the CNS of a more neurotoxic steroidal milieu, already present in clinically healthy elderly subjects and especially in patients with dementia. The effects of that steroidal milieu are more prominent at the level of the hippocampal-limbic structure, involved both in the modulation of endocrine structures, such as the HPA axis, and in the control of cognitive, behavioral and affective functions.

Ab interno trabeculectomy: ultrastructural evidence and early tissue response in a human eye.

PURPOSE: To report the results of ultrastructural analysis of the postoperative effects of ab interno trabeculectomy in a human eye. SETTING: Department of Ophthalmology, Palmanova Hospital, Palmanova, Udine, Italy. METHODS: A 60-year-old woman with cataract and glaucoma had enucleation for a choroidal melanoma 10 days after ab interno trabeculectomy combined with phacoemulsification. A second ab interno trabeculectomy was performed after enucleation to evaluate the outcomes of the previous trabeculectomy. Light and transmission electron microscopy analyses were performed on samples excised from areas (1) not subjected to a procedure (control samples), (2) that had ab interno trabeculectomy before enucleation, and (3) that had ab interno trabeculectomy immediately after enucleation. RESULTS: Control samples showed normal trabecular features. Semithin sections of all ab interno trabeculectomy samples showed full-thickness removal of trabeculum segments, with Schlemm's canal lumen opening into the anterior chamber and apparent preservation of the adjacent structures. On ultrathin sections of samples that had ab interno trabeculectomy before enucleation, the endothelium lining the outer wall of Schlemm's canal and other angle components showed intact ultrastructural features. In trabecular beams that were not removed, the extracellular matrix appeared to have maintained its fine texture and was free of activated fibroblasts or leucocyte infiltrates. CONCLUSIONS: Observations confirm that ab interno trabeculectomy causes direct communication between Schlemm's canal lumen and the anterior chamber in vivo and immediately after enucleation during the early postoperative period. The absence of an evident inflammatory reaction in the examined case should be considered with caution because of possible tumor-induced immune suppression.

Stress and dementia: the role of the hypothalamicpituitary-adrenal axis.

Hippocampus plays a crucial role in learning and memory and, in spite of its remarkable plasticity, it is also particularly sensitive to stress hormones due to its high concentration of corticosteroid receptors. Indeed, adrenal steroids modulate hippocampal plasticity, acting on excitability and long term potentiation or depression. By a chronobiological approach, we studied the cortisol and DHEAS secretion in clinically healthy old subjects and in age-matched demented patients, including both the degenerative and the vascular type. When compared to young controls, both clinically healthy elderly subjects and demented patients, particularly those with AD, had significantly higher cortisol levels at night time, i.e. at the moment of the maximal sensitivity of HPA axis to stimulatory or inhibitory inputs. At the same time, a clear age- and disease-dependent reduction of DHEAS secretion was found. Thus the cortisol to DHEAS molar ratio was significantly higher in healthy old subjects, and even more in demented patients, when compared to young controls, and significantly linked to both age and cognitive impairment. Finally, the quantitative and qualitative changes of the adrenal secretory pattern were significantly correlated with the decline of hippocampal volumes, measured by MRI. In conclusion, several lines of evidence deal with a pathogenetic role of stress hormones in the occurrence and progression of cognitive disorders in elderly subjects. The consequent hippocampal neuronal impairment may in turn be responsible for the continuous activation of HPA axis and the increased hypothalamic expression of vasopressin and corticotropin releasing hormone.

Long-term heart rate variability as a predictor of patient age.

Patients age has been estimated in healthy population by means of the heart rate variability (HRV) parameters to assess the potentiality of HRV indexes as a biomarker of age. A long-term analysis of HRV has been performed, computing linear time and frequency domain parameters as well as non-linear metrics, in a dataset of 113 healthy subjects (age range 20-85 years old). The principal component analysis has been used to capture age-related influence on HRV and then three different models have been applied to predict subjects age: a robust linear regressor (RLR), a feedforward neural network (FFNN) and a radial basis function neural network (RBFNN). A good prediction of patient age has been obtained (using all principal components, the Pearson correlation coefficient between predicted and real age: RLR=0.793; FFNN=0.872; RBFNN=0.829), even if an overestimation in younger subjects and an underestimation in older ones may be observed. The important and complementary contribution of non-linear indexes to aging related HRV modifications has also been underlined.

New emerging drugs in soft tissue sarcoma.

Doxorubicin and ifosfamide are the two most active drugs in the treatment of patients with advanced, soft tissue sarcoma (STS) of most histologic subtypes, aside from gastrointestinal stromal tumor (GIST). However, after failure of these drugs, alone or in combination, patients with advanced STS have few therapeutic options and the search for new active drugs is well worth pursuing. ET-743, a DNA minor groove binder, which blocks cell cycle progression in G2/M phase through a p53-independent apoptotic process, represents the most promising among novel compounds in STS, since recently completed phase II trials have consistently shown high survival, in spite of the relatively low incidence of major objective responses. The potential for combination with other active compounds further increases the appeal of ET-743. Imatinib mesylate is being tested also in STS other than GIST, which can overexpress one or more of the tyrosine kinases inhibited by imatinib; however, negative data have recently been presented. Clinical studies with a number of other compounds are ongoing or planned. However, investigators involved in the management of patients with advanced STS are to be increasingly aware of the emergence of new molecular targets and genetic profiles in different histologic subtypes, according to which treatment strategies should be adapted.

Cardiovascular, anthropometric and neurocognitive features of healthy postmenopausal women: effects of hormone replacement therapy.

UNLABELLED: Randomized clinical trials have not shown long-term benefit of postmenopausal hormone replacement therapy (PHT) nor have they shown conclusively that the harmful consequences outweighs the benefits of the treatment. Rather, it is possible that an individualized hormone replacement therapy in questionably clinically healthy postmenopausal women may lead to different results than randomized trials. DESIGN: In this cross-sectional study we evaluated anthropometric parameters, body composition, serum lipids, blood pressure, heart rate variability (HRV) and neurocognitive functions in 39 healthy postmenopausal women PHT users or not users (n=13, age 53.0+/-3.3 and n=26, age=53.3+/-5.0 SD, respectively) as well as in 27 younger controls (ages=33.3+/-7.1). RESULTS: Demographic parameters were similar in women PHT users and not users. Postmenopausal women showed a significantly increase of body mass index (BMI) as well as of waist circumference, compared to younger controls, but in PHT users the values of fat free mass were intermediate between the ones of not treated and younger women. The study of HRV showed a reduction in low frequency (LF) component (sympathetic modulation) during the day, and a reduction in high frequency (HF) component (parasympathetic modulation), particularly in postmenopausal women without PHT. PHT users were characterized by autonomic parameters intermediate between younger controls and age-matched women without PHT. CONCLUSIONS: The impact of PHT on the age-dependent changes of anthropometric features and body composition seems to be modest but positive. Furthermore, PHT seems to play a positive role on the autonomic modulation of cardiac function, through a shift of LF/HF ratio values towards those of young controls.

Second-line intra-arterial chemotherapy in advanced pancreatic adenocarcinoma.

The present study was conducted to evaluate activity and toxicity of the FLEC (folinic acid 100 mg/m2; 5-fluorouracil 1000 mg/m2; carboplatin 300 mg/m2; epirubicin 60 mg/m2) schedule as second-line treatment for progressive locally advanced or metastatic pancreatic cancer (LAMPC). FLEC was administered every 3 weeks with an angiographic catheter introduced into the tumor vascular bed. Thirty-two patients were enrolled. Twenty patients had a PS of 2. Twenty-five patients had metastatic disease to liver. Seven (21.9%) partial responses were observed (WHO criteria). Fifteen patients (46.9%) had stable disease and ten patients (31.2%) had progressive disease. The median OS from the diagnosis was 11.8 months. PS (p=0.0308) and pain (WHO scale, p=0.0222; analogic scale, p=0.0446) significantly improved after therapy. No patient discontinued treatment because of toxicity (NCI-CTC criteria). The current study shows that intraarterial chemotherapy is a good therapeutic option in second-line treatment of LAMPC.

Combined clear corneal phacoemulsification and ab interno trabeculectomy: three-year case series.

PURPOSE: To evaluate the efficacy and safety of a novel surgical approach, ab interno trabeculectomy, in a combined procedure (clear corneal phacoemulsification + ab interno trabeculectomy) for the management of concurrent cataract and glaucoma with prognostic factors for filtration failure. SETTING: Department of Ophthalmology, Palmanova Hospital, Udine, Italy. METHODS: A prospective noncomparative case series of 11 eyes of 11 consecutive cataract patients with medically uncontrolled primary open-angle glaucoma or pseudoexfoliation glaucoma was performed. Each patient had phacoemulsification + intraocular lens implantation + ab interno trabeculectomy, which consisted of a gonioscopically controlled ab interno removal of a quadrant (3 clock hours) of the trabecular meshwork. The main outcome measures were intraocular pressure (IOP), the number of antiglaucomatous medications used, and complications. RESULTS: Ten patients completed a 3-year follow-up. One patient had further surgery because of poor IOP control; in this case, the last valid observation was carried forward for IOP calculation. Mean preoperative IOP and IOPs measured 1, 3, 6, 12, 24, and 36 months after surgery were 25.0, 15.8, 15.4, 15.4, 15.2, 15.0, and 15.3 (-38.56%) mm Hg respectively. The number of medications averaged 2.4 before surgery and dropped to 0.8 at the end of follow-up. No major complications occurred during the follow-up period. CONCLUSIONS: The new surgical procedure combining phacoemulsification with ab interno trabeculectomy can induce a clinically relevant decrease in IOP in eyes with cataract and glaucoma with poor prognosis for filtering surgery. However, a randomized controlled clinical trial with a more extended follow-up and a larger series of patients is needed to ascertain the actual effectiveness and safety of this procedure.

Activity of chemotherapy in mucinous epithelial ovarian cancer: a retrospective study.

OBJECTIVE: Mucinous ovarian carcinoma has a poorer prognosis compared with other histological subtypes. The aim of this study was to evaluate, retrospectively, the activity of first-line and second-line chemotherapy in patients with mucinous ovarian cancer in a mono-institutional series. PATIENTS AND METHODS: In the period under survey (1996-2003), 225 new patients with ovarian cancer were treated. Twenty-one out of these patients (9.3%) received a diagnosis of mucinous ovarian cancer. The median age, performance status, stage at diagnosis and residual disease after surgery were similar in the mucinous compared to the other histological groups (P=NS). RESULTS: In mucinous ovarian cancer the grading of the tumors was 2 in 76% of the cases, while grade 3 was more frequent in the other subtypes (p<0.002). Eighty-five % of the patients had received carboplatin/paclitaxel, while the remaining cases had been treated with a cisplatin-based chemotherapy not containing paclitaxel. Two patients with early stage were treated with adjuvant chemotherapy and were not evaluable for response while 19 patients had measurable disease (12 pts) or were assessed at second-look (7 pts). Forty-seven % of the 19 patients experienced disease progression during first-line, while 31.5% and 10.5% complete and partial responses were recorded, respectively. Fifteen out of the 21 patients had progressed at the time of the analyses. Sixty % of the progressed patients were platinum-refractory, 3 cases were platinum-sensitive and 3 platinum-resistant. The 3 platinum-sensitive patients were treated with single agent carboplatin without any response. No response was recorded with topotecan or liposomal doxorubicin when given as second- or third-line treatment in platinum-refractory/resistant patients. CONCLUSION: Mucinous ovarian cancer has a poor response to chemotherapy both in the first-line and in the recurrence settings. Studies with alternative chemotherapy combinations are mandatory in this histological subgroup.

Defect of a subpopulation of natural killer immune cells in Graves' disease and Hashimoto's thyroiditis: normalizing effect of dehydroepiandrosterone sulfate.

BACKGROUND: The study of the natural killer (NK) immune compartment could provide important findings to help in the understanding of some of the pathogenetic mechanisms related to autoimmune thyroid diseases (Graves' disease (GD) and Hashimoto's thyroiditis (HT)). Within this context, it was suggested that alterations in NK cell cytotoxicity (NKCC) and NK production of cytokines might occur in subjects with GD and HT, whereas the normalization of NK functions could potentially contribute to the prevention of the onset or the progression of both diseases. OBJECTIVE: Due to the hypothesis of alterations in NK in autoimmune thyroid diseases, we were interested to evaluate NKCC in GD and HT patients and to modulate NK function and secretory activity with cytokines and dehydroepiandrosterone sulfate (DHEAS) in an attempt to normalize NK cell defect. DESIGN: We studied 13 patients with recent onset Graves' disease, 11 patients with Hashimoto's thyroiditis at first diagnosis and 15 age-matched healthy subjects. METHODS: NK cells were concentrated at a density of 7.75x10(6) cells/ml by negative immunomagnetic cell separation and validated by FACScan as CD16+/CD56+cells. NK cells were incubated with interleukin-2 (IL-2) and interferon-beta (IFN-beta) and co-incubated with DHEAS at different molar concentrations for measuring NKCC and the secretory pattern of tumor necrosis factor-alpha (TNF-alpha) from NK cells. RESULTS: Lower spontaneous, IL-2- and IFN-beta-modulated NKCC was demonstrated in GD and HT patients compared with healthy subjects (P<0.001). A decrease in spontaneous and IL-2-modulated TNF-alpha release from NK cells was also found in both groups of patients (P<0.001). The co-incubation of NK cells with IL-2/IFN-beta+DHEAS at different molar concentrations (from 10(-8) to 10(-5) M/ml/NK cells) promptly normalized NKCC and TNF-alpha secretion in GD and HT patients. CONCLUSIONS: A functional defect of a subpopulation of NK immune cells, involving both NKCC and the secretory activity, was demonstrated in newly-diagnosed GD and HT patients. This defect can be reversed by a dose-dependent treatment with DHEAS. The impairment of NK cell activity in autoimmune thyroid diseases could potentially determine a critical expansion of T/B-cell immune compartments leading to the generation of autoantibodies and to the pathogenesis of thyroid autoimmunity.

Levofloxacin disposition over time in aqueous humor of patients undergoing cataract surgery.

The ocular disposition of levofloxacin in patients receiving two 500-mg oral doses 10 h apart before cataract surgery was assessed with the intent of defining drug ocular exposure over time. The mean aqueous humor concentrations persisted above 1.5 mg/liter between 1.5 and 6.0 h after the second dose, with average aqueous-to-plasma ratios ranging between 0.33 and 0.57. This favorable ocular disposition provides support for trials of systemic levofloxacin for prophylaxis of postoperative endophthalmitis in selected patients or as adjunctive therapy for the treatment of this potentially devastating infective complication.

Decreased release of the angiogenic peptide vascular endothelial growth factor in Alzheimer's disease: recovering effect with insulin and DHEA sulfate.

Changes of vascular endothelial growth factor (VEGF) secretion have recently been demonstrated in patients with Alzheimer's disease (AD). Since VEGF has been involved in brain angiogenesis, neuroprotection and cerebromicrovascular exchange of substrates and nutrients, the study of VEGF could have important relapses into the pathogenesis and treatment of AD. Within this context, 35 healthy subjects (16 of young and 19 of old age), 18 patients with dementia of the vascular type (VAD) and 22 with dementia of the Alzheimer's type (AD) were included in the study. VEGF levels were determined in the supernates of circulating natural killer (NK) immune cells isolated by immunomagnetic separation (pure CD16 + CD56 + NK cells at a final density of 7.75 x 10(6) cells/ml). VEGF was measured in spontaneous conditions (without modulation) and after exposure of NK cells with IL-2, lipopolysaccharide (LPS), dehydroepiandrosterone sulfate (DHEAS), LPS + insulin, amyloid-beta (Abeta) fragment 1-42, the inactive sequence Abeta(40-1) and Abeta(1-42) + insulin. A significant decrease in VEGF released by NK cells was demonstrated in AD subjects compared to the other groups. No differences of VEGF levels were found between healthy subjects of old age and the VAD group. The incubation with LPS and DHEAS significantly increased, in a dose-dependent manner, VEGF levels in AD as well as in healthy subjects of young and old age and in VAD patients. The incubation of NK cells with Abeta(1-42) completely suppressed VEGF generation in AD subjects, also reducing VEGF release in the other groups. The co-incubation of NK with LPS + insulin, at different molar concentrations, significantly restored (4- and 6-fold increase from LPS alone) VEGF in AD, also enhancing VEGF secretion in healthy subjects and the VAD group, while the co-incubation of NK with Abeta(1-42) + insulin promptly abolished the negative effects of Abeta(1-42) on VEGF release. These data might suggest that the decreased VEGF secretion by peripheral immune cells of AD subjects could have a negative role for brain angiogenesis, neuroprotection and for brain microvascular permeability to nutrients, increasing brain frailty towards hypoxic injuries. On the contrary, insulin and DHEAS could have beneficial effects in AD, as well as in VAD and in physiological aging, by increasing, in a dose-dependent fashion, VEGF availability by peripheral and resident immune and endothelial cells, so contributing to increase its circulating pool.

Endocrine pancreatic dysfunction in HIV-infected children: association with growth alterations.

BACKGROUND: The pancreatic endocrine system normally guarantees a quick and efficient response to daily metabolic perturbations, but associated data for human immunodeficiency virus (HIV)-infected patients are lacking. A prospective study was performed to evaluate pancreatic endocrine secretion and its possible association with failure to thrive among HIV-infected children. METHODS: Fourteen well-nourished, prepubertal, HIV-infected children (6 boys and 8 girls; age range, 5-11 years), none of whom were receiving protease inhibitors, and 16 clinically healthy sex- and age-matched children formed the patient group and the control group, respectively. At yearly follow-up examinations, insulin, glucagon, C-peptide, and glucose levels were measured; the ratio of insulin to glucose, the ratio of insulin to glucagon, and the homeostasis model assessment (HOMA) index were calculated; the glucagon test was administered; and growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, cortisol, and lipid patterns were evaluated. RESULTS: Insulin, glucagon, C-peptide, glucose, and HOMA measurements were significantly higher among patients, compared with control subjects, at all 3 follow-ups performed to date. The glucagon test revealed a normal glycemic response in all the healthy control subjects and a significantly impaired response in 11 patients. A significant correlation emerged between the ratio of insulin to glucagon and the growth velocity of HIV-infected children. CONCLUSION: To our knowledge, the present study provides the first evidence of altered pancreatic endocrine secretion and its association with growth failure among HIV-infected children.

Decreased membrane fluidity and altered susceptibility to peroxidation and lipid composition in overweight and obese female erythrocytes.

The increased generation of reactive oxygen species that occurs in the condition of obesity may be responsible for oxidative injury to erythrocyte membranes, which could lead to a decrease in tissue oxygenation. Therefore, we have looked into the effects of obesity on both indexes of oxidative damage and physical-chemical properties of erythrocyte membranes in 50 overweight or obese [25 < body mass index (BMI) < 33], normotensive, nondiabetic women and 50 age-matched lean healthy women (BMI < 25). In the obese group compared with the lean group, we found that a) the onset of free radical-induced erythrocyte hemolysis and the ratio between reduced and oxidized glutathione were reduced, whereas the rate of free radical-induced damage increased; b) the n-3 fatty acid and the phospholipid contents decreased; c) the ratio between cholesterol and phospholipids increased; and d) the membrane fluidity decreased. These findings suggest an impairment of erythrocyte membrane physical-chemical properties in overweight and obese people as a consequence of oxidative injury that might be part of a pathogenetic mechanism responsible for obesity-related pathologies such as atherosclerosis and hypertension.

Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians.

Melatonin secretion is an endogenous synchronizer, and it may possess some anti-aging properties. Thus we examined melatonin levels in physiological aging, in extreme senescence and in senile dementia. In healthy old (age 66-94 yr) and young subjects (age 23-39 yr) and in demented patients (age 68-91 yr) plasma melatonin was measured by radioimmunoassay in eight serial blood samples. In centenarians (age 100-107 yr) melatonin levels were estimated by assaying urinary 6-hydroxymelatonin sulfate (aMT6s) in two different urine samples collected from 08:00 to 20:00 hours and from 20:00 to 08:00 hours. These data were compared with the aMT6s excretion of old and young controls. Elderly subjects, demented or not, exhibited a flattened circadian profile of plasma melatonin, because of the suppression of the nocturnal peak. An age-related decline of the circadian amplitude of the melatonin rhythm occurred in old subjects, especially in demented individuals. Furthermore, the melatonin nocturnal peak was significantly correlated with the severity of the cognitive impairment. aMT6s urinary excretion also declined with age. However, as in young controls, in centenarians the aMT6s excretion was significantly higher at night than during the day. In conclusion, pineal melatonin secretion is affected by age and by the degree of cognitive impairment. In centenarians the maintenance of the circadian organization of melatonin secretion may suggest that the amplitude of the nocturnal peak and/or the persistence of a prevalent nocturnal secretion may be an important marker of biological age and of health status.

Metabolic effects of orally administered amino acid mixture in elderly subjects with poorly controlled type 2 diabetes mellitus.

The reduction of muscle mass and increased protein catabolism in aging can determine the occurrence of metabolic alterations-such as hyperglycemia and reduced insulin sensitivity-in elderly subjects with diabetes mellitus. Therefore, the aim of the study was to evaluate the effect of nutritional supplementation with oral amino acid mixture (OAAM) in elderly subjects with type 2 diabetes. This approach was conducted in an attempt to antagonize muscle catabolism by means of increased endogenous protein synthesis and to improve glucose metabolism and insulin sensitivity. A randomized, open-label, crossover study was conducted in poorly controlled (glycosylated hemoglobin level [HbA(1c)] >7%) elderly subjects (age range, 65 to 85 years) with type 2 diabetes. OAAM significantly reduced fasting and postprandial blood glucose and HbA(1c), whereas all parameters remained substantially unchanged in the group treated with placebo. Fasting insulin levels and insulin resistance increased at baseline in all subjects with diabetes and decreased during OAAM supplementation. These results persisted also after crossover from OAAM to placebo. No changes in blood lipid levels, creatinine, homocysteine, and urinary albumin excretion rate were observed throughout the study, whereas a mild but significant increase of high-density lipoprotein cholesterol was found after OAAM supplementation. We suggest that increased amino acid availability for skeletal muscle function and strength could ameliorate metabolic control and insulin sensitivity in elderly patients with poorly controlled type 2 diabetes.

Comparative effects of lercanidipine, lacidipine, and nifedipine gastrointestinal therapeutic system on blood pressure and heart rate in elderly hypertensive patients: the ELderly and LErcanidipine (ELLE) study.

This study was conducted to compare the antihypertensive efficacy and safety of lercanidipine with those of lacidipine and nifedipine gastrointestinal therapeutic systems in patients aged 65 years or above with mild-to-moderate hypertension. Patients were randomized to receive lercanidipine 5 mg, lacidipine 2 mg, or nifedipine 30 mg for 24 weeks. After 2 weeks, the dose was doubled in non-responding patients. At 24 weeks, blood pressure was significantly reduced in the three treatment groups. The decrease in systolic blood pressure was similar in all three groups. The decrease in diastolic blood pressure in the lercanidipine group (-18.3 mmHg) was comparable to that in the nifedipine group (-17.7 mmHg), but exceeded that in the lacidipine group (-16.6 mmHg). The incidence of adverse drug reactions (ADRs) was lowest in the lercanidipine group (19.4%) compared with the nifedipine group (28.4%) and the lacidipine group (27.1%). In particular, edema was least frequent in the lercanidipine group (2.8%) compared with the lacidipine group (7.5%) and the nifedipine group (10.1%). These data demonstrate that lercanidipine is effective in lowering blood pressure in older adult hypertensive patients while maintaining a superior tolerability and safety profile.