ß-Hairpin mimics containing a piperidine-pyrrolidine scaffold modulate the ß-amyloid aggregation process preserving the monomer species.

Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid ß peptides, with Aß1-42 being the most aggregative and neurotoxic one. We report herein the synthesis and conformational analysis of Aß1-42-amyloid related ß-hairpin peptidomimetics, built on a piperidine-pyrrolidine semi rigid ß-turn inducer and bearing two small recognition peptide sequences, designed on oligomeric and fibril structures of Aß1-42. According to these peptide sequences, a stable ß-hairpin or a dynamic equilibrium between two possible architectures was observed. These original constructs are able to greatly delay the kinetics of Aß1-42 aggregation process as demonstrated by thioflavin-T fluorescence, and transmission electron microscopy. Capillary electrophoresis indicates their ability to preserve the monomer species, inhibiting the formation of toxic oligomers. Furthermore, compounds protect against toxic effects of Aß on neuroblastoma cells even at substoichiometric concentrations. This study is the first example of acyclic small ß-hairpin mimics possessing such a highly efficient anti-aggregation activity. The protective effect is more pronounced than that observed with molecules which have undergone clinical trials. The structural elements made in this study provide valuable insights in the understanding of the aggregation process and insights to explore the design of novel acyclic ß-hairpin targeting other types of amyloid-forming proteins.

A many-body term improves the accuracy of effective potentials based on protein coevolutionary data.

The study of correlated mutations in alignments of homologous proteins proved to be successful not only in the prediction of their native conformation but also in the development of a two-body effective potential between pairs of amino acids. In the present work, we extend the effective potential, introducing a many-body term based on the same theoretical framework, making use of a principle of maximum entropy. The extended potential performs better than the two-body one in predicting the energetic effect of 308 mutations in 14 proteins (including membrane proteins). The average value of the parameters of the many-body term correlates with the degree of hydrophobicity of the corresponding residues, suggesting that this term partly reflects the effect of the solvent.

Pediatric blunt renal trauma with wide fragments dislocation: successful organ saving management by internal stenting and percutaneous perirenal drain.

Children have an high risk of renal damage as a result of blunt trauma. Conservative management is always recommended for lower grades (I to III) but is rather controversial whenever high grade injuries (grade IV and V) are concerned. We describe a case of successful conservative management in grade IV renal injury occurred in a 9-years-old girl with blunt trauma.

Multisite intracerebral microdialysis to study the mechanism of L-DOPA induced dopamine and serotonin release in the parkinsonian brain.

L-DOPA is currently one of the best medications for Parkinson's disease. It was assumed for several years that its benefits and side effects were related to the enhancement of dopamine release in the dopamine-depleted striatum. The use of intracerebral microdialysis combined with a pharmacological approach has led to the discovery that serotonergic neurons are responsible for dopamine release induced by L-DOPA. The subsequent use of multisite microdialysis has further revealed that L-DOPA-stimulated dopamine release is widespread and related to the serotonergic innervation. The present Review emphasizes the functional impact of extrastriatal release of dopamine induced by L-DOPA in both the therapeutic and side effects of L-DOPA.

Activity and structural changes of Euphorbia characias peroxidase in the presence of trifluoroethanol.

Activity assays, conformational changes and transitional switches between secondary structures of a peroxidase from Euphorbia characias were studied in the presence of trifluoroethanol and in the presence or absence of calcium ions. The addition of trifluoroethanol up to 10-20% first induced a drastic decrease of alpha-helix content followed by an increase of tryptophan fluorescence emission intensity, a progressive re-induction of the formation of alpha-helical elements concomitant with loss of enzyme activity. In the presence of calcium ions, the fluorescence of the enzyme almost remained unchanged in the trifluoroethanol concentration range 5-20%. Further increase in trifluoroethanol concentration led to a protein structure characterized by a progressive re-induction of alpha-helical elements, a remarkable increase of the tryptophan fluorescence and a loss of enzyme activity. These results indicate that calcium ions in Euphorbia peroxidase play an essential role in maintaining the hydrophobic interactions on the protein structure preserving enzymatic activity.

[Percutaneous endoscopic gastrostomy (PEG) in pediatric patients: our experience and proposal of follow-up methodology]. / Gastrostomia endoscopica percutanea (PEG) nei pazienti pediatrici: nostra esperienza e proposta operativa di metodologia osservazionale.

OBJECTIVE: To evaluate effectiveness and acceptability of percutaneous endoscopic gastrostomy (PEG) in pediatric patients and to propose a data collection and follow-up methodology. MATERIALS AND METHODS: Observational retrospective and prospective study on 33 pediatric patients and 5 adults with PEG, placed using Gauderer "push" technique, between 2000 and 2007. By means of an appropriate questionnaire, the following parameters were evaluated: complications, factors of further risk, nutritional status, management and acceptability of PEG. RESULTS: No problems occurred during placement. Complications were few and easy to resolve. In 3 patients a stomal dehiscence occurred, strongly related to the tube gauge. During replacement, in 4 patients, bumper was not taken away because of difficult removal. 8 patients had pre-PEG Gastroesophageal reflux: In 2 of them, during the PEG placement, fundoplication was realized. Subsequently PEG procedure, only 1 patient needed fundoplication for worsening of GER. All of them continued gastroprotective treatment. Respiratory tract infections decreased in our 13 patients carries of tracheostomy. CONCLUSIONS: To prefer smaller gauge reduces risk of dehiscence. If the bumper's removal is hard, to leave it inside is acceptable and quite safe, on condition of a careful surveillance of gastrointestinal obstruction signs. GER is not a contraindication of PEG. A careful follow-up is important, by recording all the evaluated parameters and by questionnaire to the family, during every hospital admission. This study, even if on few patients, confi rms PEG as the technique of choice for long-term enteral feeding, also in children. Training of family and caregivers is important to care.

Isothiazoles. Part XV. A mild and efficient synthesis of new antiproliferative 5-sulfanylsubstituted 3-alkylaminoisothiazole 1,1-dioxides.

5-Sulfanyl-3-alkylaminoisothiazole dioxide derivatives have been identified as a new class of potent inhibitors of rat aortic myocite proliferation. They were prepared by applying a simple methodology able to introduce a heteroatom on C-5 of the 3-alkylaminoisothiazole dioxide system. 3-Aminosubstituted-5-chloroisothiazole dioxides react smoothly not only with S-nucleophiles but also with N- and O-nucleophiles affording the corresponding 5-heterosubstituted isothiazole dioxides through an addition-elimination reaction. The behavior of 3-alkylamino-4-bromo-isothiazole 1,1-dioxide with S-, N- and O-nucleophiles affording the same products has also been described. On the contrary, the 3-amino-4,5-unsubstituted isothiazole dioxide system reacts easily only with sulfur nucleophiles affording the corresponding 4,5-dihydro-5-sulfanylderivatives through a simple Michael addition reaction.

Clinical evaluation of St Jude Medical Hemodynamic Plus versus standard aortic valve prostheses: The Italian multicenter, prospective, randomized study.

OBJECTIVE: Hemodynamic and clinical performances of 21-mm and 23-mm St Jude Medical Hemodynamic Plus aortic valves (St Jude Medical, Inc, St Paul, Minn) were compared with those of 21-mm and 23-mm St Jude Medical standard cuff aortic valves in the first such multicenter, prospective, randomized study. Hemodynamic Plus valves are mechanical, bileaflet prostheses suitable for the small aortic anulus. METHODS: Patients with 21-mm and 23-mm anulus diameters were randomized to receive either a Hemodynamic Plus or a standard cuff valve. Postoperatively and at 6 months after the operation, patients underwent 2-dimensional Doppler echocardiography. Ejection fraction, cardiac output, peak gradient, mean gradient, effective orifice area, effective area index, and performance index were calculated. Postoperative and 6-month echocardiographic measurements and their variations across observation times were analyzed statistically. RESULTS: Of the 140 patients enrolled, 5 died at operation and 1 died of aortic dissection during the follow-up period. Eight patients were lost to follow-up. A total of 125 patients completed the study. In 1 patient a sewing cuff escaped intraoperatively. At 6 months the 21-mm and 23-mm Hemodynamic Plus valves showed significantly lower peak gradients and mean gradients than those of the 21-mm and 23-mm standard cuff valves. The 21-mm Hemodynamic Plus valves had gradients similar to those of the 23-mm Hemodynamic Plus valves. The effective orifice area did not differ significantly between the Hemodynamic Plus and standard cuff valves at either measurement. No valve mismatch was found in the 4 groups of patients. A more enhanced decrease of peak gradients and mean gradients and a more enhanced increase of effective orifice areas, effective area indices, and performance indices were found across observation times for patients with Hemodynamic Plus valves compared with those with standard cuff valves. CONCLUSIONS: Clinical hemodynamic performances of 21-mm and 23-mm St Jude Medical Hemodynamic Plus valves correspond closely with those of standard cuff valves, and gradients are substantially better than those of standard cuff valves of the same diameter. Therefore, use of this valve may minimize the need for aortic anulus enlargement. Early follow-up results with the Hemodynamic Plus valves were excellent, although more time is required to confirm this outcome.

Mental health care in Italy: organisational structure, routine clinical activity and costs of a community psychiatric service in Lombardy region.

The Magenta Community Mental Health Centre (CMHC) is the public agency responsible for providing adult psychiatric care to about 85,000 adult residents. In 1995, it had 1,145 clients and incurred costs of Euro 1.9 millions. Average cost per patient and per adult resident were Euro 1,661 and Euro 22.2, respectively. These values mask large variation across diagnosis: while patients with schizophrenia and related disorders had an average cost of Euro 3,771, those with neurotic and related disorders had an average cost of Euro 439. Patients with schizophrenia and related disorders (28% of the patients) absorbed about 60% of total costs and made extensive use of several types of services (hospital, outpatient, domiciliary, social and rehabilitative care). Since integrating different types of services is the key element of Italian psychiatric care, the new fee-for-service system adopted by the NHS to fund providers does not appear appropriate, particularly for schizophrenic patients.

Health care costs of therapy-refractory schizophrenic patients treated with clozapine: a study in a community psychiatric service in Italy.

This study evaluates the utilization of clozapine in the treatment of therapy-refractory schizophrenia in terms both of patterns of care and of health care costs in a community psychiatric service in Italy. Data covering the year prior to commencing clozapine and the year following the initiation of the therapy were collected. Clinical outcome was assessed by means of the Clinical Global Impression (CGI) and Global Assessment of Functioning (GAF) scales. Cost analysis followed a two-step procedure: (i) to record all health care services provided to patients and (ii) to assign a monetary value to each service. Three of the 15 patients enrolled in the study dropped out before the end of the 12-month period of therapy. Considering the 12 patients on clozapine treatment for at least 1 year, clinical improvements are associated with a substantial modification of the pattern of care. While patients in the pre-clozapine period were mainly managed in hospital settings, patients on clozapine were prevalently placed in the community and participated in intensive rehabilitative programmes. The higher costs of drug therapy and community services in the post-clozapine period were more than offset by the lower costs of acute hospital care.

[Cost of psychiatric patients by disability type]. / Il costo dei pazienti psichiatrici per classi di gravità.

OBJECTIVE: The study of the relation between treatment costs and disability of psychiatric patient groups. DESIGN: Perspective assessment of costs and disability of 1371 adult psychiatric patients in charge at two Operative Psychiatric Units (OPU), followed during an average period of 9 months. Data are related to all OPU's psychiatric services, including ambulatory, full or half-residential and psychiatric departments of acute hospital services. SETTING: OPUs of Magenta (MI) and Desio (MI). METHOD: The disability level has been measured by Health of the Nation Outcome Scales (HoNOS) filled in at the inclusion of the patient in the study and every three-months on average thereafter. Besides other HoNOSs have been filled in both at admission and discharge from psychiatric departments of acute hospitals, Residential Centres of psychiatric Therapies and Rehabilitation and Guarded Communities. All patients have been grouped using the main psychiatric diagnosis (first digit ICD-10) and the maximum disability level shown in the whole period of the study. Direct costs of publicly financed psychiatric services have only been considered. Their attribution to each patient has been made applying standard costs or tariffs (diagnostic procedures) to the data perspectively collected by the regional Register and a purposely designed protocol. RESULTS: Total cost of 1371 patients has been 9771.1 million lire with a cost per patient of 7,127,000 lire (sd 19,499,000) and a cost per "day in charge" of 27,172 lire (sd 68,358). The cost per day has been found unrelated with the length of observed time frame. At the inclusion the mean level of disability has been 4.26 points (sd 3.73) and 3.19 points (sd 3.26) at the end of the study. Its value, measured at maximum level shown by each problem in the whole period of study, has been 6.00 points (sd 4.64). Disability and treatment cost of each patient did result directly related (r = 0.626, p = 0.0001). All patients have been grouped in 12 classes with a significant (p = 0.0001) overall difference on both their disability level and treatment cost. CONCLUSIONS: All adult psychiatric patients could be grouped in disability related classes which sometimes have also a different treatment cost. A study on a greater number of patients is needed to confirm these results. It may also provide a more reliable basis for a new financing system of psychiatric services.

Metacarpophalangeal pattern profile in Marfan syndrome and Marfan-like patients.

Marfan syndrome (MFS) is an autosomal dominant trait due to mutations in the fibrillin gene (FBN1). The MFS expressivity is variable, and its diagnosis relies completely on clinical criteria. Atypical cases and Marfan-like (marfanoid) clinical presentations are commonly found. The metacarpophalangeal pattern profile (MCPP), a radiological method in which the 19 tubular hand bones are assessed, has been used in the diagnosis of various syndromes. To investigate whether the MCPP was adequate to discriminate between MFS and Marfan-like subjects, we studied 38 patients who were referred to our service because they had an MFS diagnosis, diagnostic hypothesis, or differential diagnosis or had arachnodactyly with dolichostenomelia. Two groups were formed: 1) MFS: 21 patients with a mean age of 18.3 (10.8 S.D.) years and 2) Marfan-like syndromes: 16 patients who did not meet the current criteria, with a mean age of 14.6 (4.6 S.D.) years. The MCPP was performed in each case following the classical technique, and a characteristic mean profile was obtained for group I (MFS), with Z scores ranging from 0.69 to 2.73 (1.80+/-0.50; mean+/-S.D.). In group I, three cases had no correlation with the typical MFS pattern. In group II, three cases had an MFS pattern. The correlation with the mean MCPP of MFS permitted the differential diagnosis of MFS and marfanoid syndromes with 86% sensitivity, 81% specificity, and 86% positive and 81% negative predictive values. The results suggest that MCPP can be used effectively as an auxiliary tool in the nosology of these conditions and, because there is no change in MCPP with age, can be helpful in early diagnosis.

[Costs of psychiatric services: a study performed at a public mental center in the Lombardy Region, Italy]. / I costi delle prestazioni in psichiatria: un'analisi condotta in un Centro Psico-Sociale (CPS) pubblico in Lombardia.

OBJECTIVE: The implementation of a simple methodology to estimate full costs of services provided by a public mental health centre. SETTING: CPS (NHS Mental Centre) Ussl 35, Magenta, Lombardy Region. METHOD: To estimate full costs of 16 types of service we followed a two step procedure. The first step was to estimate all costs attributable to the CPS. In the second one, we allocated this estimate to each type of service provided. We attributed to the CPS the following cost items: personnel, utilities (telephone, electricity, water, heating and cleaning), land & building, transports (for services provided outside the clinic) and a share of general cost of the USSL to which the CPS belongs. Full cost of each service was then calculated on the base of the yearly number of services provided and the time spent by each health professional. RESULTS: In 1995, the CPS provided 14,562 services. Total costs amounted to L 1,356 million, and more than three quarters of this amount was attributable to the personnel working at the CPS. Unit costs ranged from L 5,300 (drug administration) to L 442,400 (family therapy involving two professionals for 90 minutes) The unit cost of psychiatric visits, psychologist consultations and nurse domiciliary visits were L 105,300, L 106,600 and L 78,000, respectively. CONCLUSIONS: This approach requires accessible data and is relatively simple to manage. Some refinements are required, especially to improve the methodology for the determination and the allocation of overheads. However, we are convinced that this cost accounting procedure provides acceptable estimates of the services provided by the CPS. These estimates suggest that charges to be used to fund NHS providers may be too low, especially if fee-for-service will be the main funding source.

Dermatophilosis in sheep: first report in Italy, experimental reproduction and evaluation of immune response.

A severe exudative-crustous and proliferous dermatitis in a 2 year old sheep caused by Dermatophilus congolensis (observed for the first time in Italy), is reported. The disease was reproduced experimentally in sheep, goats, rabbits and guinea pigs, whose skin was treated in different ways before infection. E.L.I.S.A. and Immunoblotting tests carried out in experimentally infected sheep, showed the antigenic complexity of the pathogen and the existence of cross-immunity to the protein components. Intradermoreaction tests were carried out in all animals. The development of a positive reaction only in rabbits and guinea pigs, confirmed that these animals have a cellular immunity against Dermatophilus congolensis.

Ectopic expression of bioactive peptides and serotonin in the sacciform gland cells of teleost skin.

Immunohistochemical methods identified serotonin, and the peptides bombesin and caerulein, in the skin of the teleosts Lepadogaster candollei and Mastacembelus erytrotaenia. In both species, the secretory content of epidermal sacciform cells reacted positively for all three substances. These results are compared with studies on the skin glands of amphibians, which also contain multiple active compounds, and on various neuroendocrine cells of fish. The precise functions of the secretions are not known.

Developmental regulation of lectin-binding patterns in Paracentrotus lividus gonads, gametes, and early embryos.

By use of several lectins (ConA, WGA, SBA, GS I, PNA), a study was carried on gametes and developing embryos of the sea urchin Paracentrotus lividus, to investigate developmental changes in cell surface, leading to changements in cell-environment interactions. ConA, WGA, and SBA, with high affinity, bind to the vitelline membrane of unfertilized eggs, while PNA labelling at the same site is weak; GS I-binding is only present in the cytoplasm and cortical region of the unfertilized eggs. Immediately after fertilization, no ConA-binding is present in the membrane, while WGA- and SBA-binding molecules are located in the fertilization layer. In zygotes, 40 min after fertilization, ConA affinity sites were again present in both cytoplasm and cortical region. During cleavages and gastrulation, ConA binds to the blastomere cytoplasm and cortical region, to the intercellular matrix, and to the cytoplasm of mesenchyme cells. WGA binds to the cortical region of cleaving blastomeres, including the hyaline layer, up to the unhatched blastula. Then it labels the gastrula inner and outer surfaces. SBA binds to the blastomere membranes; no GS I- and PNA-binding was detected during embryonic development. Sperms are bound by all the lectins, except GS I. Mannose and glucose conjugates are the most represented throughout the whole development of P. lividus, and their origin and locations are developmentally regulated. Galacto-residues are scarcely represented or are masked by other terminal sugars (e.g. sialic acid), and become functional during particular developmental events (cell movements).

Serotonin-like immunoreactivity in the epidermal club cells of teleost fishes.

The present immunocytochemical study concerns the distribution of serotonin in the epidermis of three species of teleost fish. Serotonin-like immunoreactivity was found in the club cells of Heteropneustes fossilis and Carapus acus but not in those from the sea eel Conger conger. This study is the first immunocytochemical identification of serotonin in the club cells of teleost epidermis. By comparing data from the literature (Zaccone et al. 1986, 1987, 1988) regarding the occurrence of serotonin and GRP/bombesin in the exocrine sacciform gland cells of piscine skin, it is worthy mentioning here that the serotonin contained in the club cells of the species studied may have the ability to affect the pheromonal or other possible functions of these cells. The presence of serotonin in these systems has been correlated with the capacity of the exocrine glands of fish skin to secrete, ectopically, amine messengers in contrast to those produced eutopically i.e. in the neuron-paraneuron system in some vertebrates (Fujita et al. 1988).

[Action of evening primrose oil on cardiovascular risk factors in insulin-dependent diabetics]. / L'azione dell'olio di "evening primrose" sui fattori di rischio cardiovascolare dei diabetici insulino-dipendenti.

In an open study, the authors compared two groups of insulin-dependent diabetics matched for age and metabolic control, one of which was given a linoleic-gamma-linolenic acid mixture (3 g daily), the other served as control. The effect, attributed to gamma-linolenic acid only, was evaluated as explained in the text and is shown in the table. At the end of two months no change was found in the control group while favorable changes of HDL-cholesterol and platelet adhesiveness were observed in the experimental group.

Localization of calmodulin positive immunoreactivity in the surface epidermis of the brown trout, Salmo trutta.

Calmodulin is a Ca2+-dependent modulatory protein which is required in the general regulation of a large number of key processes of cellular metabolism. In the present study, the localization of calmodulin positive immunoreactivity in the epidermis of the brown trout, Salmo trutta was investigated using a specific mouse monoclonal antibody to calmodulin of IgG2 class. The immunoreaction was found only in the superficial epithelial cells that constitute the main histological site for the production of calmodulin positive substances. Because of its distribution, this protein might have a physiological significance in the activation of the microvillar skeleton and in the control of the permeability of the skin epithelium.

Food and nutrient consumption of two rural Italian population groups followed for twenty years.

The food and nutrient consumption was examined in two rural population groups of 22 middle age men of Italy in connection with a longitudinal study of coronary heart disease. Most of the data were collected with use of the individual weighing method. In the 20 year interval increases and decreases were observed in the consumption of various foods, reflecting the influence of economic and biological factors. In regard to nutrients, in Crevalcore (Bologna) the original high level of some macronutrients and vitamin A progressively decreased. In Montegiorgio (Marche) the original high level of fat intake - in relation to recommended intake - progressively increased, while energy was throughout close to recommended values. The endemic deficit in riboflavin intake progressively decreased, while that for vitamin A remained practically constant.