Structure-activity relationships in carboxamide derivatives based on the targeted delivery of radionuclides and boron atoms by means of peripheral benzodiazepine receptor ligands

The structure-activity relationship studies on 2-quinolinecarboxamide peripheral benzodiazepine receptor (PBR) ligands have been refined with the aim of using these ligands as carriers of radionuclides and boron atoms. Some new ligands show enhanced affinity and steroidogenic activity with respect to reference compound 1 and are interesting candidates for radiolabeling and PET studies. Moreover, carborane derivative 3q, representing the first example of PBR ligand bearing a carborane cage, can be useful to explore an alternative mechanism in BNCT.     

The role of anthracyclines in combination chemotherapy for the treatment of follicular lymphoma: retrospective study of the Intergruppo Italiano Linfomi on 761 cases

In order to elucidate the role of anthracycline based combination chemotherapy regimens for the treatment of follicular lymphoma we conducted a retrospective study on a large series of patients with a histologically confirmed diagnosis of follicular lymphoma. The Italian lymphoma intergroup (ILI) promoted a retrospective study of patients with follicular lymphoma treated in cooperative trials between 1985 and 1996. Six hundred and thirty three cases were treated with an anthracycline-containing regimen and 128 patients were treated without anthracyclines. The two groups were prognostically comparable; in particular, no difference was observed according to both IPI and ILI prognostic index. Results showed a complete remission (CR) rate for patients treated with anthracyclines was 69.2% and overall response rate was 92.5%. After a median follow-up of 51 months (54 months for patients still alive), the 5- and 10-year overall survival (OS) rates were 80 and 66%, respectively. Disease-free survival (DFS) and failure-free survival (FFS) rates at 5 years were 61 and 49%, respectively. In the group of patients treated with combination chemotherapy not including anthracyclines, the CR rate was 67.5% and the overall response rate was 85.4%. A longer OS (80% at 5 years) was observed in patients treated with anthracyclines compared to 67% OS rate in patients treated without anthracyclines (p = 0.0004). FFS was significantly longer in patients treated with anthracyclines (49 vs. 34% p = 0.006). Patients treated with anthracyclines with low or intermediate risk according to ILI prognostic index showed a significantly longer OS (p = 0.0001 andp = 0.0009, respectively); those in the high-risk group showed a trend for a longer survival. In conclusion, this retrospective study shows that patients with follicular lymphoma treated with an anthracycline containing regimen had a better outcome compared to patients treated with other combination regimens non including anthracyclines in terms of CRs, OS and FFS. On the basis of these results anthracycline-containing regimens (ACR) should be considered as the standard treatment of patients with advanced follicular lymphoma.     

The role of the ubiquitination-proteasome pathway in breast cancer: use of mouse models for analyzing ubiquitination processes

Turnover of several regulatory proteins results from targeted destruction via ubiquitination and subsequent degradation through the proteosome. The timely and irreversible degradation of critical regulators is essential for normal cellular function. The precise biochemical mechanisms that are involved in protein turnover by ubiquitin-mediated degradation have been elucidated using in vitro assays and cell culture systems. However, pathways that lead to ubiquitination of critical regulatory proteins in vivo are more complex, and have both temporal and tissue-specific differences. In vivo models will allow identification of substrates and enzymes of the ubiquitin-proteosome pathway that play important roles in selected tissues and diseases. In addition, assessment of the therapeutic efficacy of drugs designed to inhibit or enhance protein turnover by ubiquitination requires in vivo models. In the present review we describe selected examples of transgenic and knockout models of proteins that are known either to be regulated by ubiquitin-mediated degradation or to have a catalytic function in this process, and to play an important role in breast cancer. We outline the functions of these proteins in vivo and focus on knowledge gained in the comparison of in vivo behavior predicted from cell-free in vitro data or from experiments conducted in cell culture systems.     

Influence of stimulus color on the control of reaching-grasping movements

This kinematic study aimed to determine whether color is a stimulus property involved in the control of reaching-grasping movements. Subjects reached and grasped a target-object, located either on the right or on the left of the subject's midline. A distractor, placed along the subject's midline, could be randomly presented. The colors, i.e., both chromaticity (red and green stimuli were presented) and lightness, of the target and distractor were varied in experiment 1. Only stimulus lightness and only stimulus chromaticity were varied in experiments 2 and 3, respectively. In experiment 4 subjects matched with their thumb and index finger the size of the target-stimuli presented in experiment 1. Chromaticity (experiments 1 and 3) of the target and distractor influenced grasp, but not reach. Maximal finger aperture was larger during grasping the red than the green target. Data collected in the matching task (experiment 4) confirmed a trend to overestimate the red target and to underestimate the green one. During grasp, hand shaping was influenced by distractor chromaticity when it was different from target chromaticity. Distractor lightness affected reach, but not grasp (experiments 1 and 2). Reach was slower when the distractor was lighter and arm trajectory veered away from it. The results of the present study suggest that color, that is the ensemble of chromaticity and lightness, is a stimulus property involved in the control of reaching-grasping. The different effects of target color on reach and grasp support the notion that intrinsic object properties, such as color, affect grasp more than reach. In addition, the different effects of distractor chromaticity and lightness on reach and grasp confirm that target-objects are visually extracted from surrounding cues by means of different processes, according to the required motor response.     

Antimicrobial activity of a new intact skin antisepsis formulation

Different antiseptic formulations have shown limitations when applied to disinfecting intact skin, notably short-term tolerability and/or efficacy. The purpose of this study was optimizing a new antiseptic formulation specifically targeted at intact skin disinfection and evaluating its in vitro microbicidal activity and in vivo efficacy. METHODS: The biocidal properties of the antiseptic solution containing 0.5% chloramine-T diluted in 50% isopropyl alcohol (Cloral; Eurospital SpA Trieste, Italy) were measured in vitro versus gram-positive-, gram-negative-, and acid-alcohol-resistant germs and fungi with standard suspension tests in the presence of fetal bovine serum. Virus-inhibiting activity was evaluated in vitro against human cytomegalovirus, herpes simplex virus, poliovirus, hepatitis B virus, and hepatitis C virus. Tests used different methods for the different biologic and in vitro replication capacity of these human viruses. Lastly, Cloral tolerability and skin colonization retardation efficacy after disinfection were studied in vivo. RESULTS: The antiseptic under review showed fast and sustained antimicrobial activity. The efficacy of Cloral against clinically important bacterial and viral pathogens and fungi was highlighted under the experimental conditions described in this article. Finally, microbial regrowth lag and no side effects were documented in vivo after disinfection of 11 volunteers. CONCLUSIONS: A stable chloramine-T solution in isopropyl alcohol may be suggested for intact skin antisepsis.     

Sleep-related changes in baroreflex sensitivity and cardiovascular autonomic modulation

OBJECTIVE: We examined the effects of the various sleep stages on baroreflex sensitivity (BRS), and heart rate and blood pressure (BP) variability, and tested the hypothesis that there is a different behavior of the baroreflex control of the sinus node in response to hypertensive and hypotensive stimuli and in relation to different cycles of the overnight sleep. DESIGN: Polygraphic sleep recordings were performed in 10 healthy males. The BP and the RR interval were continuously recorded during sleep. METHODS: BRS was calculated by the sequences method. Autoregressive power spectral analysis was used to investigate the RR-interval and BP variabilities. RESULTS: During rapid eye movement (REM) sleep BRS significantly increased in response to hypertensive stimuli in comparison with non-rapid eye movement (NREM) sleep and the awake state, whereas it did not change in response to hypotensive stimuli. In the first sleep cycle, BRS significantly increased during NREM in comparison with wakefulness, whereas during REM BRS in response to hypertensive stimuli did not show significant changes as compared with the awake state and/or with NREM. During REM occurring in the sleep cycle before morning awakening, BRS showed a significant increase in response to hypertensive stimuli in comparison with both NREM and the awake state. CONCLUSIONS: During sleep, arterial baroreflex modulation of the sinus node is different in response to hypotensive and hypertensive stimuli particularly during REM. Furthermore, baroreflex control of the sinus node shows a non-uniform behavior during REM occurring in different nocturnal sleep cycles. These findings suggest that the arterial baroreflex is more effective in buffering the increased sympathetic activation associated with REM at the end of sleep than in the early night.     

Allelic variants of natriuretic peptide receptor genes are associated with family history of hypertension and cardiovascular phenotype

OBJECTIVE: Abnormalities in the natriuretic peptide system could play a key role in the genesis of hypertension. We evaluated the associations between a family history of hypertension, cardiovascular phenotype and allelic variants of Npr1 and Npr3, two candidate genes that codify for natriuretic peptide receptors. METHODS: We genotyped 45 young normotensive subjects (19 males, 26.8 +/- 3.7 years) with accurately assessed family history of hypertension (FH+) and 52 (26 males, 26.1 +/- 3.1 years) without (FH-) for the known variants of Npr1 and Npr3 genes, and for a novel length difference (3C/4C) polymorphism at position 15129 in the 3'-untranslated region of the Npr1 gene. Blood pressure, echocardiography and plasma brain natriuretic peptide were assessed. RESULTS: Both the novel Npr1 3C allele (59 versus 33%, P < 0.001) and the 3C/3C genotype (31 versus 8%; P < 0.001) were significantly more frequent in FH+ than in FH-. The inverse distribution of the 4C/4C genotype suggested that a casual association was very unlikely. Moreover, the 3C/3C homozygous had significantly higher systolic blood pressure (121.1 +/- 6.3 versus 115.6 +/- 7.8 mmHg in 4C/4C; P < 0.05) and a longer left ventricular isovolumic relaxation time (67 +/- 10 versus 61 +/- 9 ms; P < 0.05). The Npr3 C(-55) allele variant was also more frequent in FH+ (88 versus 76%, P < 0.05), but was not associated with the cardiovascular phenotype. CONCLUSIONS: The novel Npr1 gene 3C variant and the Npr3 gene C(-55) allele are associated with hypertensive family history. Moreover, the functional Npr1 3C variant, when homozygous, is also associated with higher systolic blood pressure and prolonged ventricular relaxation.     

Aerobic exercise physiology in a professional rugby union team

INTRODUCTION: In professional rugby, different positional roles may require different levels of aerobic fitness. Forward and backline players from a team of elite rugby players were tested to evaluate the differences between the two groups. METHODS: 28 male players, 15 backs and 13 forwards, underwent maximal treadmill cardiopulmonary exercise testing (CPX), lung spirometry, a 3 km timed run, and body fat measurement. RESULTS: Peak oxygen uptake was higher in backs than in forwards (peak VO(2) 48.3+/-2.1 vs. 41.2+/-2.7 ml kg(-1) min(-1), P<0.05) with no significant difference in peak respiratory exchange ratio (1.08+/-0.02 vs. 1.07+/-0.02, P=NS), exercise time (1306+/-39.7 vs. 1217+/-25.1 s, P=NS) or time for 3 km run (667.5+/-14.1 vs. 699.0+/-20.7 s, P=NS). However, the forwards were taller and heavier (height 190.2+/-2.2 vs. 179.5+/-1.3 cm, P<0.001, body mass 104+/-2.4 vs. 86.3+/-1.7 kg, P<0.0001) and had a higher fat content (body fat percentage 12.8+/-0.8 vs. 9.7+/-0.6%, P<0.01) and forced expiratory volume in 1 s (FEV1, 4.9+/-0.1 vs. 4.5+/-0.2 l, P<0.05). There was a significant negative correlation between peak VO(2), 3 km run time (r=-0.45, P<0.05) and weight (r=-0.54, P<0.003) for all subjects. CONCLUSION: Backline players have a higher peak oxygen uptake per kilogram than forwards, although the cardiopulmonary exercise test duration, degree of anaerobic metabolism and 3 km run time are not significantly different. These results could be due to the two groups' different body structure, being shorter, lighter and having a lower percentage body fat. These differences, which are likely to be a result of selection for specific roles in the game, should be taken into account when evaluating aerobic fitness within a rugby team.     

Evaluation and management of metabolic and coagulative disorders in HIV-infected patients receiving highly active antiretroviral therapy

A number of metabolic disorders, including hypercholesterolemia, hypertriglyceridemia, insulin resistance, elevated fasting glucose and diabetes mellitus, were reported in a high proportion of HIV-infected patients receiving highly active antiretroviral therapy (HAART). Less frequently, coagulative disorders were described in patients receiving HAART. Since all these metabolic disorders may predispose to coronary heart disease, an early evaluation and treatment is advisable. Existing guidelines for uninfected patients may be applied, taking into account, however, the potential for drug interactions and accumulated toxicity. It may be helpful to stratify all patients in three risk groups to plan regular diagnostic screening. Treatment of dyslipidemia and diabetes mellitus should include a first-line approach with non-pharmacological interventions. Statins and fibrates are proposed for HIV-infected patients with HAART-related hyperlipidemia, but concern has been raised on their potential for interaction with antiretrovirals and hepatic and muscle toxicity. Metformin and thiazolidenediones (or glitazones), hypoglycemic agents that increase insulin sensitivity, are presently under evaluation in diabetic and glucose-intolerant HIV-infected patients treated with HAART. Glitazones also have a potential for ameliorating the lipodystrophic syndrome. The routine evaluation of coagulative parameters is probably not advisable until a benefit of widespread screening is assessed in prospective studies. A heightened awareness of the possiblity of coagulative disorders, together with controlled trials and basic research, is needed.