Associations Between Hypertension, Angiotensin-Converting Enzyme Inhibitors, and Physical Performance in Very Old Adults: Results from the ilSIRENTE Study.

BACKGROUND: Results regarding the associations between hypertension-related parameters and physical performance in older adults are conflicting. A possible explanation for these divergent results is that investigations may not have adjusted their analyses according to the use of angiotensin-converting enzyme inhibitors (ACEIs). OBJECTIVES: To examine the associations between hypertension-related parameters, ACEI use, and a set of physical performance tests in very old adults. DESIGN: Cross-sectional study from the ilSIRENTE database. SETTING: Mountain community of the Sirente geographic area (L'Aquila, Abruzzo, Italy). PARTICIPANTS: All persons born in the Sirente area (13 municipalities) before 1 January 1924 and living in that region at the time of study were identified and invited to participate. The final sample included 364 older adults (mean age: 85.8 ± standard deviation [SD] 4.8). MEASUREMENTS: Physical performance was assessed using isometric handgrip strength (IHG), walking speed (WS) at normal and fast pace, 5-time sit-to-stand test (5STS), and muscle power measures. Blood pressure (BP) was measured after 20 to 40 min of rest, while participants sat in an upright position. Drugs were coded according to the Anatomical Therapeutic and Chemical codes. ACEIs were categorized in centrally (ACEI-c) and peripherally (ACEI-p) acting. Blood inflammatory markers, free insulin-like growth factor 1 (IGF-1), and IGF-binding protein 3 (IGFBP-3) were assayed. RESULTS: Results indicated that 5STS test was significantly and negatively associated with diastolic BP values. However, significance was lost when results were adjusted for ACEI use. Participants on ACEIs were more likely to have greater specific muscle power and higher blood levels of IGFBP-3 than non-ACEI users. When participants were categorized according to ACEI subtypes, those on ACEI-p had higher blood IGF-1 levels compared with ACEI-c users. CONCLUSIONS: The main findings of the present study indicate that ACEI use might influence the association between hypertension-related parameters and neuromuscular parameters in very old adults. Such results may possibly be linked to the effects of ACEI-p on the IGF-1 pathway.

Markers of community outbreak and facility type for mitigation of COVID-19 in long-term care homes in Ontario, Canada: Insights and implications from a time-series analysis.

PURPOSE: The resident deaths among Long Term Care Home (LTCH) accounted for more than 65% of total deaths in the province of Ontario, Canada, during March 29 to June 3, 2020, yet not all LTCHs were severely affected. METHODS: We carried out a retrospective cohort study, with case control for questions for which data allowed, with LTCH COVID-19 databases obtained from Ontario's Ministry of Long Term Care. We performed a combined temporal and spatial data analysis of COVID-19 cases and deaths among LTCH residents, identified trends, contributing factors, and early markers of LTCH outbreak severity. RESULTS: Our analysis shows that for-profit LTCHs had higher death-to-bed ratio, also with an average rate of increase of death-to-bed ratio higher for for-profit homes than other types of management. We find from uni- and multi-variable analyses (linear and nonlinear) that staff infection has the strongest association with death-to-bed ratio from among the descriptor variables considered, reflecting the risk of the disease in the health region/community. We also identify a delay of up to 8 days between the trends in fatalities among individuals outside LTCHs and that of LTCH residents. We did find an association between policy change to single LTCH/staff and reduction in weekly LTCH resident death, albeit with an expected time delay of about 7-10 days. CONCLUSIONS: The association between the risk of COVID-19 in the health region and the deaths among LTCH residents, and the delay between fatality among individuals residing outside and inside LTCHs suggests that fatality in a health region could be a predictor of outbreak in LTCHs within the same health region.

Protein Intake from Various Foods Sources Is Negatively Associated with Cardiometabolic Risk Markers in Italian Older Adults.

OBJECTIVES: To examine the relationships between protein intake from various food sources and cardiometabolic risk markers in Italian older adults. DESIGN: Cross-sectional study. SETTING: Unconventional settings across Italy (e.g., exhibitions, health promotion campaigns). PARTICIPANTS: People 65+ years who provided a written informed consent. MEASUREMENTS: Blood pressure (BP), blood glucose, total blood cholesterol, and anthropometric indices were assessed. Daily protein intake was estimated for 12 food items listed in a food frequency questionnaire. RESULTS: Three-thousand four-hundred twenty-four older adults (mean age: 72.7 ± 5.7 years; 55% women) were included in the study. Results of linear regression analysis indicated that protein intake from several food sources was negatively associated with BP, waist and hip circumferences, and waist-to-hip ratio in both sexes. Blood glucose levels were inversely associated with many protein sources in women. Positive associations were observed between some protein sources and total blood cholesterol in both men and women. CONCLUSION: Our findings suggest that dietary protein is differentially associated with cardiometabolic risk factors depending on sex and food sources.

Global cardiovascular risk, COVID-19 severity and post-COVID-19 syndrome: a clinical study.

OBJECTIVE: Post-COVID-19 is a syndrome defined by signs and symptoms present until 12 weeks after COVID-19, lasting for more than 8 weeks, not explained by an alternative diagnosis. The present study aimed to assess whether the cardiovascular risk (CVR) of patients with COVID-19 correlates with symptoms and changes in respiratory function parameters in post-COVID-19. The association between CVR and the severity of acute disease was also considered. PATIENTS AND METHODS: Between 21/04/21-01/09/21, we enrolled 1,782 consecutive patients with COVID-19. We divided these subjects into (i) 4 levels, based on the severity of COVID-19 (home care; hospitalized/no oxygen therapy; hospitalized/oxygen therapy; hospitalized/NIV-ICU), (ii) 2 levels, according to CVR calculated with the European Society of Cardiology SCORE tables (low-intermediate risk; high or very high risk). All subjects underwent a 3-month follow-up considering post-COVID-19 symptoms. RESULTS: In post-COVID-19 patients, high or very-high CVR was associated with (i) increased risk of hospitalization for COVID-19 (p<0.0001), (ii) higher prevalence of severe clinical manifestations and ICU admission (p<0.0001), (iii) development of post-COVID-19 (p<0.0001) and (iv) increased risk of a larger post-COVID-19 burden of disease. CONCLUSIONS: We found a statistically significant association between CVR, severity of COVID-19, and post-COVID-19 syndrome three months after the end of acute disease.

Development of implantation substrates for the collection of radionuclides of medical interest produced via ISOL technique at INFN-LNL.

Accelerator-based techniques with electromagnetic mass separation are considered among the most innovative and promising strategies to produce non-conventional radionuclides for nuclear medicine. Such approach was successfully used at CERN, where the dedicated MEDICIS facility was built, and at TRIUMF, where the ISAC radioactive beam facility was used to produce unconventional α-emitters. In such framework, the Legnaro National Laboratories of the Italian Institute of Nuclear Physics (INFN-LNL) proposed the ISOLPHARM project (ISOL technique for radioPHARMaceuticals), which will exploit radionuclides producible with the SPES (Selective Production of Exotic Species) ISOL (Isotope Separation On-Line) facility to develop novel radiopharmaceuticals. The ISOL technique utilizes the irradiation with a primary beam of particles/nuclei of a production target where radionuclides are produced. A radioactive ion beam is subsequently extracted from the production target unit, and transported up to an analyzing magnet, where non-isobaric contaminants are filtered out. The so-obtained purified radioactive beam is dumped onto an implantation substrate, referred as collection target. Then, the desired nuclides can be chemically harvested from the collected isobars, and the isotopically pure atom collection can be employed to radiolabel high specific activity radiopharmaceuticals. Metallic deposition targets in the form of coated metal foils were mostly used at TRIUMF and CERN. At ISOLPHARM, a different approach is under investigation which foresees the use of soluble cold-pressed collection targets, possibly facilitating the chemical purification process of the collected radionuclides. In this study, the production and characterization of some of the ISOLPHARM collection targets is presented, in particular, soluble salts (NaCl and NaNO3) and organic materials widely used for pharmaceutical tablets production are considered. All such materials proved to be potentially suitable as collection targets, since solid samples were easily produced and resulted compatible with the vacuum conditions required for the ion implantation process. Furthermore, some of the selected substrates were used for proof-of-concept deposition tests with stable silver, to prove their suitability as ISOLPHARM deposition substrates for silver-111, a promising candidate for radiotherapy. Such tests highlighted possible scenarios useful for the development of new alternative materials, as the use of insoluble organic targets.

"Say Ninetynine": It's Never too Late to Recover from COVID-19.

COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, showed higher severity and lethality in male older adults . There are currently no specific treatments. Studies are evaluating the efficacy of monoclonal antibodies against interleukin-6 receptor. Here we present the case of a 98-years old man admitted to our COVID-Hospital with acute respiratory failure. Comprehensive geriatric assessment showed no signs of frailty. First-line therapy with hydroxychloroquine and anticoagulants was not effective. Patient was administered intravenous monoclonal antibodies, and he showed remarkable clinical improvement. This case suggests that age alone should not preclude access to new therapeutic approaches. Comprehensive, multisciplinary, multidomain approaches are needed to develop patient-tailored treatments against COVID-19.

Animal-Derived Protein Consumption Is Associated with Muscle Mass and Strength in Community-Dwellers: Results from the Milan EXPO Survey.

OBJECTIVES: Behavioral factors, including protein intake, influence the quantity and quality of skeletal muscle. The aim of this study was to explore the relationship between animal-derived protein intake and muscle mass and function in a large sample of unselected community-dwellers. MATERIAL AND METHODS: The VIP (Very Important Protein) study, conducted during Expo 2015 in Milan, was a population survey aimed at assessing major health metrics in a population outside of the research setting, with a special focus on the relation between animal-derived protein intake and muscle mass and function. A brief questionnaire exploring lifestyle habits, dietary preferences and the consumption of selected foods was administered. Muscle mass was estimated by calf circumference (CC) and mid-arm muscle circumference (MAMC) of the dominant side. Muscle strength of upper and lower extremities was assessed through handgrip strength testing and repeated chair stand test, respectively. RESULTS: The mean age of the 1,853 participants was 50.3 years (standard deviation: 15.7; range: 18-98 years), of whom 959 (51.7%) were women. Participants in the highest tertile of protein consumption showed better performance at both the handgrip strength (p <0.001) and chair stand tests than those in the lowest tertile (p <0.01). The same results were found for CC (p <0.001) and MAMC (p <0.001). Participants with high protein intake and engaged in regular physical activity showed the higher scores in all the assessed domains. CONCLUSIONS: The results of the VIP survey suggest an association between animal-derived protein intake and muscle mass and strength across ages. Our findings also indicate a synergistic effect of animal-derived protein intake and physical activity on muscle-related parameters.

Intervenciones para optimizar el tratamiento farmacológico en ancianos hospitalizados: una revisión sistemática / Interventions to optimize pharmacologic treatment in hospitalized older adults: a systematic review

Objetivo. Resumir la evidencia sobre las intervenciones orientadas a optimizar el tratamiento farmacológico en ancianos hospitalizados. Material y métodos. Se realizó una búsqueda en las principales bases de datos bibliográficas, seleccionando estudios prospectivos en pacientes mayores de 65 años hospitalizados que realizaran intervenciones dirigidas a optimizar el tratamiento farmacológico, disminuir la polifarmacia y mejorar la adecuación terapéutica, los resultados en salud o el aprovechamiento del sistema sanitario. Resultados. Se seleccionaron 18 estudios. Las intervenciones consistieron en revisiones de medicación, detección de medicamentos predefinidos como potencialmente inadecuados en ancianos, asesoramiento de un equipo especializado en geriatría, uso de un sistema informático de apoyo a la prescripción o formación específica al equipo de enfermería. Hasta 14 estudios evaluaron la adecuación terapéutica, demostrando 13 de ellos una mejoría en alguno de los parámetros. Siete estudios midieron el impacto de la intervención sobre la polifarmacia, pero solo uno mejoró los resultados respecto al control. Otros siete estudios analizaron la mortalidad, no demostrándose una disminución de la misma en ninguno. Solo uno de seis estudios mostró una reducción de reingresos hospitalarios y uno de cuatro estudios una disminución de las visitas a urgencias. Conclusiones. Pese a la heterogeneidad de las intervenciones y de las variables analizadas, se obtuvieron mejores resultados en las variables de proceso, especialmente en la adecuación terapéutica, que en aquellas que midieron resultados en salud, donde hubo una mayor variabilidad (AU)

Objective. To summarise the evidence on interventions aimed at optimising the drug treatment of hospitalised elderly patients. Material and methods. We conducted a search in the main medical literature databases, selecting prospective studies of hospitalised patients older than 65 years who underwent interventions aimed at optimising drug treatment, decreasing polypharmacy and improving the medication appropriateness, health outcomes and exploitation of the healthcare system. Results. We selected 18 studies whose interventions consisted of medication reviews, detection of predefined drugs as potentially inappropriate for the elderly, counselling from a specialised geriatric team, the use of a computer support system for prescriptions and specific training for the nursing team. Up to 14 studies assessed the medication appropriateness, 13 of which showed an improvement in one or more of the parameters. Seven studies measured the impact of the intervention on polypharmacy, but only one improved the outcomes compared with the control. Seven other studies analysed mortality, but none of them showed a reduction in that rate. Only 1 of 6 studies showed a reduction in the number of hospital readmissions, and 1 of 4 studies showed a reduction in the number of emergency department visits. Conclusions. Despite the heterogeneity of the analysed interventions and variables, we obtained better results in the process variables (especially in medication appropriateness) than in those that measured health outcomes, which had greater variability (AU)

[Interventions to optimize pharmacologic treatment in hospitalized older adults: a systematic review]. / Intervenciones para optimizar el tratamiento farmacológico en ancianos hospitalizados: una revisión sistemática.

OBJECTIVE: To summarise the evidence on interventions aimed at optimising the drug treatment of hospitalised elderly patients. MATERIAL AND METHODS: We conducted a search in the main medical literature databases, selecting prospective studies of hospitalised patients older than 65 years who underwent interventions aimed at optimising drug treatment, decreasing polypharmacy and improving the medication appropriateness, health outcomes and exploitation of the healthcare system. RESULTS: We selected 18 studies whose interventions consisted of medication reviews, detection of predefined drugs as potentially inappropriate for the elderly, counselling from a specialised geriatric team, the use of a computer support system for prescriptions and specific training for the nursing team. Up to 14 studies assessed the medication appropriateness, 13 of which showed an improvement in one or more of the parameters. Seven studies measured the impact of the intervention on polypharmacy, but only one improved the outcomes compared with the control. Seven other studies analysed mortality, but none of them showed a reduction in that rate. Only 1 of 6 studies showed a reduction in the number of hospital readmissions, and 1 of 4 studies showed a reduction in the number of emergency department visits. CONCLUSIONS: Despite the heterogeneity of the analysed interventions and variables, we obtained better results in the process variables (especially in medication appropriateness) than in those that measured health outcomes, which had greater variability.

Confocal Raman spectroscopy: In vivo biochemical changes in the human skin by topical formulations under UV radiation.

A new approach to the study of the effects on human skin of mycosporine-like amino acids (MAAs) and gadusol (Gad) incorporated in polymer gel is proposed in this work. The depth profile and photoprotector effects of Pluronic F127® gels containing each of the natural actives were evaluated by in vivo confocal Raman spectroscopy aiming at the analysis of the biochemical changes on human skin. Hierarchical cluster analysis (HCA) showed that the data corresponding to different depths of the skin, from surface to 4 µm, and from 6 to 16 µm, remained in the same cluster. In vivo Raman spectra, classified into five different layers of epidermis according to their similarities, indicated that the amount of Gad gel increased by about 26% in the outermost layer of the stratum corneum (SC) and that MAAs gel at 2 µm depth was 103.4% higher than in the outermost layer of the SC. Variations in the SC of urocanic acid at 1490-1515 cm(-1) and 1652 cm(-1) and histidine at 1318 cm(-1) were calculated, before and after UV exposure with or without gels. With the application of gels the vibrational modes that correspond to lipids in trans conformation (1063 and 1128 cm(-1)) increased with respect to normal skin, whereas gauche conformation (1085 cm(-1)) disappeared. Our studies suggest that gels protected the skin against the stress of the natural defense mechanism caused by high levels of UV exposure.

Operationalization of the physical frailty & sarcopenia syndrome: rationale and clinical implementation.

Over the years, different operational definitions have been elaborated to identify frail older persons, but none of them has received unanimous consensus. This, in turn, has hampered the clinical implementation of frailty as well as the design of targeted interventions. To overcome the current limitations in the field, a novel operationalization of physical frailty (PF) is proposed which grounds its roots in the recognition of sarcopenia as its central biological substrate. This conceptualization is based on the fact that the clinical picture of PF overlaps substantially with that of sarcopenia. The two conditions may therefore be merged into a new clinical entity, the PF & sarcopenia (PF&S) syndrome, in which muscle loss represents both the biological substrate for the development of PF and a major pathway whereby the negative health outcomes of PF occur. All of the components defining the PF&S syndrome are measurable in an objective manner, which will facilitate its incorporation into standard practice. The recognition of a precise biological substratum for PF&S (i.e., skeletal muscle decline) also opens new venues for the development of preventive and therapeutic interventions.

Effects of anorexia on mortality among older adults receiving home care: an observation study.

PURPOSE: We describe the prevalence of secondary anorexia in a population of older people living in community and receiving home care. In addition, we examined the relationship between secondary anorexia and mortality. METHODS: We analyzed data from a large collaborative observational study group, the Italian Silver Network Home Care project, that collected data on patients admitted to home care programs. A total of twelve Home Health Agencies participated in such project evaluating the implementation of the Minimum Data Set for Home Care (MDS-HC) instrument. A total of 2757 patients were enrolled in the present study. The main outcome measures were the prevalence of anorexia, weight loss and survival. RESULTS: More than 25% (744 subjects) of the study sample suffered from anorexia. During a mean follow-up of 10 months from initial MDS-HC assessment, 468 patients (17%) died. There was uneven distribution of the risk. After adjusting for age, gender and for all other possible risk factors for death (living alone, physical and cognitive disability, behavior problems, urinary incontinence, pressure ulcer, hearing impairment, congestive heart failure, hypertension, depression, diabetes, renal failure, cancer), subjects with anorexia were more likely to die relative to patients without anorexia (RR, 1.83; 95% CI 1.45-2.31). Even though the risk of mortality was higher among subjects suffering from anorexia and weight loss, the anorexia per se was associated with higher risk compared with subjects without anorexia (RR, 1.45; 95% CI 1.01-2.19). CONCLUSIONS: Anorexia is associated with a significant higher risk of all-cause mortality. The present findings support the possibility that anorexia has an independent effect on survival even among old people receiving home care.

Quasi-trapezoidal pulses to selectively block the activation of intrinsic laryngeal muscles during vagal nerve stimulation.

The stimulation of the vagus nerve has been used as an anti-epileptic treatment for over a decade, and its use for depression and chronic heart failure is currently under investigation. Co-activation of the intrinsic laryngeal muscles may limit the clinical use of vagal stimulation, especially in the case of prolonged activation. To prevent this, the use of a selective stimulation paradigm has been tested in seven acute pig experiments. Quasi-trapezoidal pulses successfully blocked the population of the largest and fastest vagal myelinated fibers being responsible for the co-activation. The first response in the vagus compound action potential was reduced by 75 +/- 22% (mean +/- SD) and the co-activated muscle action potential by 67 +/- 25%. The vagal bradycardic effects remained unchanged during the selective block, confirming the leading role of thin nerve fibers for the vagal control of the heart. Quasi-trapezoidal pulses may be an alternative to rectangular pulses in clinical vagal stimulation when the co-activation of laryngeal muscles must be avoided.

Mutational and computational analysis of the alpha(1b)-adrenergic receptor. Involvement of basic and hydrophobic residues in receptor activation and G protein coupling.

To investigate their role in receptor coupling to G(q), we mutated all basic amino acids and some conserved hydrophobic residues of the cytosolic surface of the alpha(1b)-adrenergic receptor (AR). The wild type and mutated receptors were expressed in COS-7 cells and characterized for their ligand binding properties and ability to increase inositol phosphate accumulation. The experimental results have been interpreted in the context of both an ab initio model of the alpha(1b)-AR and of a new homology model built on the recently solved crystal structure of rhodopsin. Among the twenty-three basic amino acids mutated only mutations of three, Arg(254) and Lys(258) in the third intracellular loop and Lys(291) at the cytosolic extension of helix 6, markedly impaired the receptor-mediated inositol phosphate production. Additionally, mutations of two conserved hydrophobic residues, Val(147) and Leu(151) in the second intracellular loop had significant effects on receptor function. The functional analysis of the receptor mutants in conjunction with the predictions of molecular modeling supports the hypothesis that Arg(254), Lys(258), as well as Leu(151) are directly involved in receptor-G protein interaction and/or receptor-mediated activation of the G protein. In contrast, the residues belonging to the cytosolic extensions of helices 3 and 6 play a predominant role in the activation process of the alpha(1b)-AR. These findings contribute to the delineation of the molecular determinants of the alpha(1b)-AR/G(q) interface.

[Surgery of large ventral hernias. Personal experience in 1990-1997]. / La chirurgia dei grandi laparoceli. Esperienza di scuola 1990-1997.

BACKGROUND: The surgical treatment of large wall defects conventionally defined as an extension over 10 cm is discussed. The difficulty to contain the bowels that have lost law of domicile in the abdominal hollow, constitutes motive for notable increase of the endo-abdominal Pressure with serious consequences in the postoperative course and this leads to the use of prothesis meshes that allow the closing of the abdominal hollow with the Tension-Free technique. METHODS: Personal experience embraces 45 patients, with large wall defects, divided into 21 patients with overumbilical location, 14 with umbilical location, 10 with periumbelical location; a simple suture has been used in 7 cases, the reconstruction of the wall according to Stoppa in 36 cases and the apposition of Goretex net internally and Marlex net externally in 2 cases. RESULTS: There have been neither mortality, neither recidivists of illness, but only some complications: 9 cases of superficial infection, 1 case of intestinal occlusion and 2 of subcutaneous seroma. CONCLUSIONS: According to their experience and wide literature review, the authors draw some conclusions: an accurate toilet and a careful evaluation of the respiratory functionality are fundamental; it's necessary to postpone surgical intervention in presence of local inflammation and, where this is improrogable it's opportune to avoid the use of prothesis meshes or refold on readsorbible prothesis; special care must be taken to the hemostasis and an aspirative drain for 24-48 hrs preserves from the risk of postoperative hematomas and following local infections. The submuscular mesh permits a Tension-Free suture and for this reason it would have nowdays a more extensive use. Finally it's pointed out the choice of a PTFEe mesh in contact with the intestinal skein.

[Essential varicocele. Which treatment?]. / Il varicocele essenziale. Quale trattamento?

Purpose of the paper is to sum up the problem of surgery of idiopathic varicocele according to the present possibilities, both surgical and sclerotic. A wide review of the literature underlines a high rate of relapses and persistence of the disease (with a percentage from 10 to and 10%) following the two most used technique: retrograde sclerotic therapy under radioscopic control and surgical retroperitoneal or inguinal ligature of the internal spermatic vein; this technique was preferred by us until 1997. The percentage of failures, high with reference to the benign form of the disease (over 10% in our series of more than 100 patients submitted to clinical and flow-meter examinations) let the authors suggest a combined and simultaneous operation of ligature both internal and external of the spermatic vein at the level of the internal inguinal ring. Anatomical reasons confirm the opportunity of this procedure since the involvement of the system of the external spermatic vein is present in about the 20% of the cases of idiopathic varicocele in accordance with various flebografic studies. The possibility of escape through the external spermatic vein is eliminated in the case in which such vessel is preserved, and it seems frequent above all in 3rd degree idiopathic varicocele where many anastomotic vessels between the two systems are present. This procedure can be made both in general or local anaesthesia, it doesn't involve postoperative hospital stay and present the same acceptable postoperative complication of other proposed operations. The laparoscopic treatment even if easily performed at the level of the internal inguinal ring, doesn't seem justified for the higher cost and equal compliance for the patient. Besides, it is not possible to proceed laparoscopically under local anaesthesia.

Mutational analysis of the highly conserved arginine within the Glu/Asp-Arg-Tyr motif of the alpha(1b)-adrenergic receptor: effects on receptor isomerization and activation.

We have suggested previously that both the negatively and positively charged residues of the highly conserved Glu/Asp-Arg-Tyr (E/DRY) motif play an important role in the activation process of the alpha(1b)-adreneric receptor (AR). In this study, R143 of the E/DRY sequence in the alpha(1b)-AR was mutated into several amino acids (Lys, His, Glu, Asp, Ala, Asn, and Ile). The charge-conserving mutation of R143 into lysine not only preserved the maximal agonist-induced response of the alpha(1b)-AR, but it also conferred high degree of constitutive activity to the receptor. Both basal and agonist-induced phosphorylation levels were significantly increased for the R143K mutant compared with those of the wild-type receptor. Other substitutions of R143 resulted in receptor mutants with either a small increase in constitutive activity (R143H and R143D), impairment (R143H, R143D), or complete loss of receptor-mediated response (R143E, R143A, R143N, R143I). The R413E mutant displayed a small, but significant increase in basal phosphorylation despite being severely impaired in receptor-mediated response. Interestingly, all the arginine mutants displayed increased affinity for agonist binding compared with the wild-type alpha(1b)-AR. A correlation was found between the extent of the affinity shift and the intrinsic activity of the agonists. The analysis of the receptor mutants using the allosteric ternary complex model in conjunction with the results of molecular dynamics simulations on the receptor models support the hypothesis that mutations of R143 can drive the isomerization of the alpha(1b)-AR into different states, highlighting the crucial role of this residue in the activation process of the receptor.

Constitutively active mutants of the beta1-adrenergic receptor.

We provide the first evidence that point mutations can constitutively activate the beta(1)-adrenergic receptor (AR). Leucine 322 of the beta(1)-AR in the C-terminal portion of its third intracellular loop was replaced with seven amino acids (I, T, E, F, C, A and K) differing in their physico-chemical properties. The beta(1)-AR mutants expressed in HEK-293 cells displayed various levels of constitutive activity which could be partially inhibited by some beta-blockers. The results of this study might have interesting implications for future studies aiming at elucidating the activation process of the beta(1)-AR as well as the mechanism of action of beta-blockers.

[The diagnosis and therapy of dysphagic disorders of the LES]. / Diagnosi e terapia dei disturbi disfagici del LES.

Primary motor disorders of LES causing dysphagia consist in cardial achalasia and intermedius motor disorder (IMD), the last one different from achalasia because of normal motor pattern of the esophageal body. In this paper diagnostic and therapeutic procedures are examined according to an experience of 94 surgically treated cases (22 rioperations for surgical failures). Cardial dilatation as treatment of choice is recognized only for IMD in which a normal peristaltic behaviour of the esophagus can avoid the high danger of GER. Surgical procedure, now laparoscopically performed, consisting in Heller's myotomy + Dor partial fundoplication is to be preferred in cases of true achalasia.