Effectiveness and safety of cholinesterase inhibitors in elderly subjects with Alzheimer's disease: a "real world" study.

Clinical trials have demonstrated the efficacy of cholinesterase inhibitors (ChEI) in improving cognitive status and disability in subjects with mild to moderate Alzheimer's disease (AD). However, little is known about the effectiveness of ChEI in clinical practice, and no large clinical trials comparing different ChEI are available at present. Aim of this study was to evaluate safety and effectiveness of ChEI in a sample of elderly outpatients diagnosed with mild to moderate AD. We selected 407 subjects for ChEI treatment (donepezil,rivastigmine or galantamine). Their cognitive function was evaluated by means of the mini mental state examination (MMSE), and the global functional status was estimated by using the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales at baseline (To), then after 1 (T1), 3 (T2) and 9 months (T3), respectively. T3 follow-up was completed by 212 subjects. The patients were considered as responders (R), if the MMSEscore at T2 was unchanged or improved, if compared to that of T0. In 35 patients (8.6 %)treatment was withdrawn because of mostly gastrointestinal adverse events. Compared to the other drugs, donepezil was associated with a lower incidence of withdrawals due to adverse events. Subjects who completed T3 follow-up (age 78 +/- 6 years, MMSE scores 18.8 +/- 3.9) showed an increase at T2 of 0.7 +/- 2.7 (p = 0.001) and a decrease at T3 of -0.6 +/- 3.4 (p = 0.008) in the MMSE scores, as compared to To . The ADL and IADL scores did not show significant changes at T2; however, both decreased significantly at T3. The patients Rat-T2 showed a better cognitive and functional outcome at T3 , compared to the nonresponders(NR-at-T2), displaying values of MMSE R-at-T2 0.4 +/- 3.1 vs. NR-at-T2 -3.0 +/- 2.5, p = 0.001, and ADL values of -0.3 +/- 1.2 vs. -0.7 +/- 1.3, p = 0.03, respectively. No significant difference was found in the changes of MMSE scores between donepezil and rivastigmine (galantamine was not included in the comparison due to the small number of treated subjects). In conclusion, in this sample of elderly subjects with mild to moderate AD,treated with ChEI, a small but significant decline in cognitive and functional status was observed after 9 months. Subjects who showed a good response to treatment after 3 months, had a better cognitive and functional outcome at 9 months. No significant difference in cognitive outcome was found between drugs, while donepezil was better tolerated.

Renal adaptive mechanisms in aged and hypertensive humans: possible effects of treatment.

BACKGROUND: In the aging kidney renal blood flow and glomerular filtration rate are reduced due to glomerulosclerosis. On this regard, hypertension has synergistic effects and may lead to end-stage renal disease in a significant proportion of cases. MATERIAL AND METHODS: To study the effects of antihypertensive drugs in an acute setting, we expressly designed an acute experiment to assess the renal response to mental stress (MS). In healthy elderly, the response was characterized by a prolonged and pronounced renal vasoconstriction, due to a reduction in renal autacoid modulatory capacity, particularly of prostaglandins. In older patients with isolated systolic hypertension, the response to MS was impaired, being characterized by a passive vasodilation with hyperfiltration. The effects of antihypertensive drugs were evaluated twice in adults patients with mild to moderate essential hypertension: after two weeks of pharmacological wash-out and after two weeks of treatment with the ACE-inhibitor trandolapril (4 mg), or the non-dihydropyridinic Ca2+ channel blocker verapamil (240 mg), or both (2 mg + 180 mg). RESULTS: While the three antihypertensive regimens reduced blood pressure to a similar extent, their effects on the renal response to MS were different. Each regimen re-established a renal vasoconstrictive response to adrenergic activation. However, with trandolapril, renal vasoconstriction was limited, as it occurs physiologically, to the period of blood pressure rise, while verapamil, or the combination of the two drugs, were associated with more prolonged vasoconstriction. CONCLUSIONS: Further studies are needed to confirm the nephroprotective effects of these drugs, particularly of ACE-inhibitors. These data may be a pathophysiological basis for future clinical trials.

Aminoguanidine and aortic wall mechanics, structure, and composition in aged rats.

With aging, the aortic wall becomes stiffer. This could be because of changes in wall stress or composition. We investigated whether a specific change in wall composition, ie, accumulation of advanced glycation end products (AGEs) on the extracellular matrix, is a major factor. We measured aortic mechanics, geometry, and composition in 3-, 10-, 15-, 20-, and 30-month-old inbred normotensive Wistar-Glaxo/Rijswick rats and in a group of 30-month-old rats treated from 20 months onward with aminoguanidine (AG, 42 mg/kg per day), an inhibitor of AGE formation. Thoracoabdominal aortic (pressure) pulse-wave velocity (PWV) increased progressively with age (44% from 3 to 30 months). This age-related increase in aortic PWV was not related to changes in wall stress. For all ages, central (and peripheral) aortic mean blood pressures were not statistically different. Dilatation occurred (18% increase in internal diameter from 3 to 30 months), but this was accompanied by outward hypertrophic remodeling, with an increase in the medial cross-sectional area of 95% and in the ratio of medial thickness to internal diameter of 29%. Wall stress decreased with age (-34%). There was an increase in the ratio of elastic modulus (calculated from the Moens-Korteweg equation) to wall stress (calculated from the Lamé equation, 117% from 3 to 30 months), suggesting that a change in the composition of the wall is responsible for the age-linked increase in wall stiffness. Dry weight decreased slightly but significantly (-14%) with age. Total protein, elastin, collagen, and nonscleroprotein protein [total-(elastin+collagen)] contents did not change with age, but calculated densities of all 4 were halved (as the medial cross-sectional area doubled). The elastin/collagen ratio was statistically similar at all ages. The only significant effect of AG treatment was a fall in PWV (-20%), leading to a fall in the elastic modulus/wall stress ratio (-27% at 10 months of AG treatment versus 30 months of no treatment). In conclusion, the age-related increase in aortic wall stiffness is prevented by 10 months of treatment with AG, which has no effect on wall stress or composition, suggesting that AG may improve aortic wall stiffness by lowering the degree of AGE-induced cross-linking of the extracellular matrix scleroproteins, such as collagen.

Changes in renal autacoids and hemodynamics associated with aging and isolated systolic hypertension.

The aging kidney is characterized by a decrease in renal blood flow and glomerular filtration rate mainly due to glomerulosclerosis. Nevertheless, even in the presence of these changes, the kidney maintains its functionality until advanced age. However, there is a tendency towards greater renal vasoconstriction in the elderly as compared with young individuals. This occurs either in physiological circumstances such as physical exercise, or in disease manifestations, such as the effective circulatory volume depletion that develops, for example, in heart failure. This tendency may be secondary to the reduction of renal autacoid modulatory capacity, particularly at the vasodilating prostaglandin level. In an acute experimental model we could demonstrate that, in the healthy elderly, the renal response to adrenergic activation by mental stress is characterized by a prolonged and pronounced vasoconstriction. In addition to this, in elderly patients affected by isolated systolic hypertension, we demonstrated an impairment of renal hemodynamic and humoral adaptation capacity in response to adrenergic activation and blood pressure increase. In the presence of sudden blood pressure increase, the kidney of these patients responds with a passive vasodilation and a glomerular filtration rate increase without any activation of humoral modulatory substances. The impairment in renal adaptation capacity may predispose these patients to renal injury, particularly in the presence of the many hypertensive peaks which characterize everyday life of elderly individuals. In conclusion, these results show that renal adaptation capacity of elderly patients with isolated systolic hypertension is completely lost. Further studies will elucidate whether antihypertensive treatment per se, or specific classes of antihypertensive drugs, are able to revert this impairment.

Changes in renal autacoids in aged human hypertensives.

The aging process determines several modifications of the kidney, that, however, do not provoke any dysfunction in normal conditions. But in the elderly--in the presence of stressful situations and particularly when adrenergic activation is present--the kidney is more vulnerable than in the young, and renal failure may arise. Variations typical of the aging kidney are accelerated when hypertension overlaps the physiological renal process, because both senescence and hypertension weight on the same structures, i.e. glomeruli. We studied renal hemodynamic adaptation capacity both in the healthy elderly and in patients affected by isolated systolic hypertension, in an acute experiment which requires the application of a mental stress-induced adrenergic activation. In hypertensive patients we have already demonstrated a total lack of renal adaptation capacity. In fact, while the elderly normotensives react with a prolonged and pronounced vasoconstriction, in those with isolated systolic hypertension, adrenergic activation induces a passive renal vasodilation and glomerular hyperfiltration. The anomalous adaptation capacity of renal hemodynamics is probably due to an impairment in the paracrine response of renal vasculature. Indeed in the hypertensive elderly, unlike in the normotensive one, no variations of autacoid production occur during the adrenergic activation. Following on from this, pattients affected by isolated systolic hypertension passively suffer the many hypertensive peaks which characterize their every day life. The altered renal autoregulation of the elderly with isolated systolic hypertension may explain the accelerated glomerulosclerosis and the greater incidence of renal damage and end-stage renal disease which characterize this condition. These aspects underline the primary role of the antihypertensive treatment of isolated systolic hypertension, not only for the prevention of cardiovascular mortality but also of renal damage and/or end-stage renal disease.

Impaired renal adaptation to stress in the elderly with isolated systolic hypertension.

The aim of this study was to evaluate the renal response in the elderly with isolated systolic hypertension (ISH) when an adrenergic activation, as induced by mental stress, is applied. Renal hemodynamics and kidney neurohumoral response to mental stress were studied in 8 elderly patients with ISH (aged 63 to 82 years) along with 8 elderly normotensive subjects. The study encompassed four 30-minute experimental periods (baseline, mental stress, and recovery I and II). In these patients, the mental stress-induced blood pressure rise was associated with a significant increase in both effective renal plasma flow ((131)I-labeled hippurate clearance) and glomerular filtration rate ((125)I-labeled iothalamate clearance) (+42% and +29%, respectively; P<0.01 for both), without variations in filtration fraction, while elderly normotensives reacted to adrenergic stimulation with renal vasoconstriction but with the glomerular filtration rate constant. Variations in renal vasoactive substances, which paralleled hemodynamics of the kidney, differed in the 2 groups. In normotensives, excretion (radioimmunoassay) of endothelin-1, prostaglandin E(2), and cGMP increased during the stimulus (+50%, +54%, and +59%, respectively; P<0.05). In ISH patients the release of these autacoids did not vary in any of the experimental periods. In conclusion, in patients with ISH the renal adaptive capacity to sympathetic activation is impaired, and the data may suggest that the glomerulus passively suffers the blood pressure increase, probably because of the insufficiency of the neurohumoral response, particularly in regard to the increase of endothelin-1. This hemodynamic pattern may predispose ISH patients to a higher risk of renal injury.

Excessive vasoconstriction after stress by the aging kidney: inadequate prostaglandin modulation of increased endothelin activity.

The adaptive capacity of the aging kidney to stimulation of the sympathetic nervous system, as induced by a 30-minute mental stress (MS), was assessed in 8 elderly healthy women (68 to 82 years of age) and compared with that of 8 younger women (24 to 40 years of age). The study encompassed 4 consecutive 30-minute periods (baseline, mental stress, recovery 1, and recovery 2). In the elderly subjects, baseline effective renal plasma flow (ERPF)(iodine 131-labeled hippurate clearance) was lower and glomerular filtration rate (GFR)(iodine 125-labeled iothalamate clearance) was proportionally less reduced than in the younger group; the filtration fraction (FF) was higher. The elderly group excreted more endothelin 1 (ET-1) (P < .05), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1alpha (6-keto PGF1alpha)(P < .001 for both)(radioimmunoassay). Mental stress induced similar increases in blood pressure, heart rate, and plasma catecholamines in the 2 age groups, limited to the stimulation period. In the elderly group, mental stress caused a prolonged decrease in ERPF that reached its maximum 60 minutes after mental stress (-33%, P < .05), while GFR remained constant during the whole experiment, so that FF increased. In the younger subjects, renal hemodynamic changes were limited to the mental stress period. ET-1 increased during mental stress and the first recovery period in the elderly group (+50% and +25%, P < .05) as it did in the younger group, but the elderly group differed from the younger in that vasodilating prostaglandins increased only during mental stress. In conclusion, the aging kidney reacts to adrenergic stimulation with more-pronounced and -prolonged vasoconstriction that is probably caused by a defect in prostaglandin modulation of endothelin activity. Autoregulation of GFR is maintained at the expense of increased intraglomerular pressure.

Renal adaptation to stress: a possible role of endothelin release and prostaglandin modulation in the human subject.

The aim of this study was to define the neurohumoral response associated with the renal hemodynamic perturbations induced by mental stress acting as an adrenergic stimulus. In 8 healthy women, the effects of mental stress were studied during four consecutive 30-minute periods (baseline, mental stress, recovery I, recovery II). Mental stress induced sympathetic activation as evidenced by increases in blood pressure, heart rate, and plasma norepinephrine level. Effective renal plasma flow (iodine 131-labeled hippurate clearance) decreased only during mental stress (-22%, p < 0.05 vs baseline); glomerular filtration rate (iodine 125-labeled iotalamate clearance) remained constant during the entire experiment; the filtration fraction increased significantly during mental stress and recovery I (+30% and +22%, respectively, p < 0.02 for both). Complex neuroendocrine responses were associated with the hemodynamic changes. Urinary excretion of endothelin-1 and 6-keto-PGF(1alpha) increased during mental stress (+53%, p < 0.01, and +20%, p < 0.01, respectively) and recovery I (+49% and +29%, respectively, p < 0.01 for both). Urinary cyclic guanosine monophosphate rose only during mental stress (+77%, p < 0.05), whereas excretion of PGE2 showed a stepwise increase throughout recovery I and II (+292%, p < 0.01, and +360%, p < 0.001, respectively). In conclusion, the present experiments demonstrate that renal hemodynamic response induced by mental stress is a complex reaction in which endothelin-1, prostaglandins, and presumably nitric oxide take part.

Molecular cloning of mannose-6-phosphate reductase and its developmental expression in celery.

Compared with other primary photosynthetic products (e.g. sucrose and starch), little is known about sugar alcohol metabolism, its regulation, and the manner in which it is integrated with other pathways. Mannose-6-phosphate reductase (M6PR) is a key enzyme that is involved in mannitol biosynthesis in celery (Apium graveolens L.). The M6PR gene was cloned from a leaf cDNA library, and clonal authenticity was established by assays of M6PR activity, western blots, and comparisons of the deduced amino acid sequence with a celery M6PR tryptic digestion product. Recombinant M6PR, purified from Escherichia coli, had specific activity, molecular mass, and kinetic characteristics indistinguishable from those of authentic celery M6PR. Sequence analyses showed M6PR to be a member of the aldo-keto reductase superfamily, which includes both animal and plant enzymes. The greatest sequence similarity was with aldose-6-phosphate reductase (EC 1.1.1.200), a key enzyme in sorbitol synthesis in Rosaceae. Developmental studies showed M6PR to be limited to green tissues and to be under tight transcriptional regulation during leaf initiation, expansion, and maturation. These data confirmed a close relationship between the development of photosynthetic capacity, mannitol synthesis, and M6PR activity.

Increased renal formation of thromboxane A2 and prostaglandin F2 alpha in heart failure.

Renal formation of the vasoconstrictor prostaglandins thromboxane A2 (TXA2) and prostaglandin F2 alpha (PGF2 alpha) was investigated in 25 patients with cardiac failure, divided into New York Heart Association functional classes I to IV, and in eight healthy control subjects. Plasma renin activity (PRA) and hemodynamic parameters were also investigated. Renal vasoconstrictor eicosanoid formation, measured in urinary daily excretion, was not different between patients in class I and control subjects. Class II to IV patients showed progressively increasing production of PGF2 alpha (F = 49.8, p < 0.001, analysis of variance) and TXA2 (F = 37.8, p < 0.002). PGF2 alpha excretion peaked in class IV (+ 1266% vs class I, p < 0.001). Compared with class I, urinary excretion of thromboxane B2 was + 816% in class III and + 1561% in class IV (both p < 0.001). PRA was significantly increased only in class IV (+ 1558%, p < 0.001). The current results indicate a progressive increase in renal production of vasoconstrictor eicosanoids directly related to New York Heart Association class and suggest that these prostanoids may have a role in deterioration of renal function.

Collateral circulation in occlusion of lower limbs arteries: an anatomical study and statistical research in 35 old subjects.

The collateral circles formed following lower limbs arterial occlusion and their hemodynamic function have been described; 35 subjects (23 men and 12 women; age range 65 to 80), with symptomatic lower limbs obstructive arteriopathy (Fontaine's stage II) following occlusion of vessels downstream the subrenal aorta have been studied by means of Contrast Angiography and Color Doppler Echography of the vascular district including the terminal aorta and the lower limbs arteries. The hemodynamic significance of the collateral circles was assessed by calculating the Windsor index. In this population, the collateral circles for each level of obstruction were explored. Occlusion of the terminal abdominal aorta: the collateral circle was mainly established through the inferior mesenteric and ischiatic arteries and through the lumbar, ilio-lumbar and gluteal arteries; occlusion of the iliac tract: the collateral circulation was established through the spermatic or ovaric artery and through the funicular, external pudendal and middle sacral arteries; occlusion of the ilio-femoral tract: the collateral circulation was formed by the internal and external pudendal arteries and by the ilio-lumbar, obturating, gluteal and circumflex iliac arteries; occlusion of first tract of the superficial femoral artery: collateral circulation was established through the deep femoral artery and through the perforating arteries; occlusion of the terminal tract of the superficial femoral artery: collateral circulation was formed by the articular branches of the same artery originating proximal to the occlusion and through branches of the deep femoral artery; occlusion of the superficial and deep femoral arteries at their origin: collateral circulation was established through the ischiatic artery (directly and, indirectly, through the perforating arteries), and through the tegumental arteries. The hemodynamic significance, as measured by Windsor index was higher the more proximal was the occlusion, in accord with the lower caliber and/or number of vessels involved in the collateral circles.

Vesical-renal reflex: diuresis and natriuresis activated by intravesical capsaicin.

In the last years the role of capsaicin sensitive innervation, in the activation of the micturition reflex, has been reported in many papers. In our experience, upon the intravesical administration of capsaicin in humans, we noticed an increase of diuresis. No interaction is known about the sensory innervation of the bladder and renal function, so we studied the possibility of the existence of a vesical-renal reflex arc. Twenty-one patients (9 men and 12 women) were randomised to receive intravesical infusion of saline solution containing 10 microM capsaicin. Urine output, glomerular renal filtrate (GRF) and effective plasma renal flow (EPRF), measured by Technetium-99m diethylenetetramine-penta-acetic acid (DTPA) renal scintigraphy, were recorded over twenty minutes before and after the intravesical administration of capsaicin. Urine density, [Na+] and [K+] concentration, and prostaglandin E2 excretion were also determined before and after intravesical administration of capsaicin or vehicle. Installation of saline solution containing 10 microM capsaicin produced a significant increase of mean urine output, an increase of GRF, of EPRF and of [Na+] and [K+] urine concentration. An increase, not statistically significant, was observed of PgE2 excretion. None of the patients treated with vehicle showed any modification of parameters examined. The present findings demonstrate a hitherto unrecognized effect: increased diuresis following selective chemical stimulation of bladder efferents with capsaicin. The renal diuretic response to intravesical capsaicin represents a working hypothesis about the possible involvement of a vesical-renal reflex arc organized at spinal or supraspinal level.

[Care of oncologic child and his family: viewpoint of the pediatrician]. / L'assistenza al bambino oncologico e alla sua famiglia, vista dal pediatra.

The authors report their considerations on the care of the oncologic childhood and their families. Various psychologic aspects are discussed, first of all the child and his cancer, how the parents and siblings face the disease, death and after. Finally they outline the role of pediatrician and the hospital staff.

Intercellular glycosaminoglycans in human cancer.

Intercellular glycosaminoglycans (GAGs) from various tissues were analyzed by cellulose acetate electrophoresis and enzymatic treatment with specific mucopolysaccharidases. Each tissue exhibits a particular composition of sulfate and unsulfated molecular species. Invariably, malignant human neoplasias and their metastases show striking variations in the electrophoretic pattern typical of the corresponding normal tissue. An absolute or relative increase in surface ChS A/C and HA seems to be a consistent feature of neoplastic transformation. On the other hand, the GAGs composition of benign noninfiltrative tumors does not vary greatly with respect to the original normal tissue.