An Easy Access to Furan-Fused Polyheterocyclic Systems.

Nitrostilbenes characterized by two different or differently substituted aryl moieties can be obtained from the initial ring-opening of 3-nitrobenzo[b]thiophene with amines. Such versatile building blocks couple the well-recognized double electrophilic reactivity of the nitrovinyl moiety (addition to the double bond, followed by, e.g., intramolecular replacement of the nitro group) with the possibility to exploit a conjugated system of double bonds within an electrocyclization process. Herein, nitrostilbenes are reacted with different aromatic enols provided by a double (carbon and oxygen) nucleophilicity, leading to novel, interesting naphthodihydrofurans. From these, as a viable application, aromatization and electrocyclization lead in turn to valuable polycondensed, fully aromatic O-heterocycles.

Densely Functionalized 2-Methylideneazetidines: Evaluation as Antibacterials.

Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common ß-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1-2 µg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 µM, MIC: 8.6 µM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure-activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile.

3-Aryl-4-nitrobenzothiochromans S,S-dioxide: From Calcium-Channel Modulators Properties to Multidrug-Resistance Reverting Activity.

Our research groups have been involved for many years in studies aimed at identifying new active organic compounds endowed with pharmacological properties. In this work, we focused our attention on the evaluation of cardiovascular and molecular drug resistance (MDR) reverting activities of some nitrosubstituted sulphur-containing heterocycles. Firstly, we have examined the effects of 4-nitro-3-(4-methylphenyl)-3,6-dihydro-2H-thiopyran S,S-dioxide 5, and have observed no activity. Then we have extended our investigation to the 3-aryl-4-nitrobenzothiochromans S,S-dioxide 6 and 7, and have observed an interesting biological profile. Cardiovascular activities were assessed for all compounds using ex vivo studies, while the MDR reverting effect was evaluated only for selected compounds using tumor cell lines. All compounds were shown to affect cardiovascular parameters. Compound 7i exerted the most effect on negative inotropic activity, while 6d and 6f could be interesting molecules for the development of more active ABCB1 inhibitors. Both 6 and 7 represent structures of large possible biological interest, providing a scaffold for the identification of new ABCB1 inhibitors.

Polypharmacy and sarcopenia in hospitalized older patients: results of the GLISTEN study.

BACKGROUND: Recently the Berlin Aging Study II (BASE-II) showed that polypharmacy is associated with clinically relevant sarcopenia among community-dwelling older persons. Here we report findings from the GLISTEN study about the association of polypharmacy with sarcopenia among older medical in-patients. METHODS: The GLISTEN study investigated prevalence and clinical correlates of sarcopenia in older patients admitted to geriatric and internal medicine acute care wards of 12 Italian hospitals. RESULTS: In this sample of older medical in-patients with high prevalence of sarcopenia (34.7%) and polypharmacy (70.2%) we did not observe a significant association of polypharmacy with sarcopenia. CONCLUSIONS: Present findings demonstrate that the association of polypharmacy with sarcopenia, observed in the BASE-II study, is not evident in the GLISTEN sample, being our patients significantly older, more multi-morbid, with high prevalence of sarcopenia and polypharmacy, suggesting that this association might vary according to the heterogeneous health, functional, and nutritional characteristics of older people.

Sequential Annulations to Interesting Novel Pyrrolo[3,2-c]carbazoles.

Herein we report a significant, valuable extension of a recently implemented pyrrole benzannulation methodology that, employing versatile nitrodienes from our lab as useful C4 building blocks, led to indole derivatives characterized by unusual patterns of substitution. The 6-nitro-7-arylindoles resulting from suitably derivatized, non-symmetric dienes are of foreseeable synthetic interest in search for new polyheterocyclic systems. As an example, pyrrolocarbazoles with a rarely reported ring fusion were synthesized with the classical Cadogan protocol. Furthermore, the proven easy reducibility of the nitro group to amine will surely open the way to further interesting elaborations.

Ultrasound-guided percutaneous laser ablation is safe and effective in the treatment of small renal tumors in patients at increased bleeding risk.

PURPOSE: The aim of this retrospective study was to assess the safety and effectiveness of laser ablation (LA) in patients with small renal cell carcinomas (RCC) and increased risk of bleeding. MATERIAL AND METHODS: From 2013 to 2017, nine patients (six males, three females, aged 68.5 ± 12.2 years) at high risk of bleeding underwent ultrasonography-guided LA for an RCC. Patients were considered at increased risk of bleeding because of impairment of coagulation parameters, concomitant antiplatelet therapy, or at-risk location of the tumor (one, five, and three patients, respectively). RCC diameter ranged from 11 to 23 mm. According to tumor size, two or three laser fibers were introduced through 21-gauge needles and 1800 J per fiber were delivered in 6 min with a fixed power of 5 W. Major and minor complications, technical success, and primary and secondary technical effectiveness and tumor recurrence were recorded. RESULTS: Just one Grade 1 complication was observed: a small asymptomatic hematoma that spontaneously resolved. Technical success was 100%, 1 month technical efficacy was 88.9% (8/9 patients). One patient with residual tumor was successfully retreated 1 month later, and secondary efficacy rate was 100%. No local tumor recurrence occurred during a median follow-up of 26 months (range 11-49 months). CONCLUSIONS: LA is safe and effective in the treatment of small RCC and might represent a valid option in patients with increased risk of bleeding.

Nitro-substituted tetrahydroindolizines and homologs: Design, kinetics, and mechanism of α-glucosidase inhibition.

A series of 1-[(methylsulfonyl)methyl]-2-nitro-5,6,7,8-tetrahydroindolizines and homologs were designed, prepared, and evaluated as non-sugar-type α-glucosidase inhibitors. The inhibitory activity appeared to be related to cyclo homologation with the best congeners being tetrahydroindolizines. The introduction of a methoxycarbonyl group as an additional hydrogen bond acceptor into the exocyclic methylene group was beneficial affording the most potent congener 3e (half maximal inhibitory concentration, IC50=8.0±0.1µM) which displayed 25-fold higher inhibitory activity than 1-deoxynojirimycin (2, IC50=203±9µM)-the reference compound. Kinetic analysis indicated that compound 3e is a mixed inhibitor with preference for the free enzyme over the α-glucosidase-substrate complex (Ki,free=3.6µM; Ki,bound=7.6µM). Molecular docking experiments were in agreement with kinetic results indicating reliable interactions with both the catalytic cleft and other sites. Circular dichroism spectroscopy studies suggested that the inhibition exerted by 3e may involve changes in the secondary structure of the enzyme. Considering the relatively low molecular weight of 3e together with its high fraction of sp3 hybridized carbon atoms, this nitro-substituted tetrahydroindolizine may be considered as a good starting point towards new leads in the area of α-glucosidase inhibitors.

Physical disability in the elderly with diabetes: epidemiology and mechanisms.

Diabetes mellitus is a common chronic condition worldwide, especially in the elderly population. Several epidemiologic studies in the last 2 years have consistently associated diabetes with physical disability, a condition that may profoundly affect the quality of life of older people. Although in older people with diabetes, the pathogenesis of functional limitation and disability has not been completely elucidated, it is certainly complex and involves multiple potential pathways. In this narrative review, we described the most recent epidemiologic and clinical evidence supporting the association between diabetes and impaired physical function in older persons focusing on emerging biological mechanisms explaining the excess risk of disability associated with diabetes.

Reactivity of ethyl nitrosoacrylate toward pyrrole, indole and pyrrolo[3,2-c]carbazole: an experimental and theoretical study.

Nitrosoalkenes react with 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole to give both 2- and 3-alkylated products via hetero-Diels-Alder reaction followed by the cycloadduct ring-opening. Quantum chemical calculations, at DFT level of theory, were carried out to investigate the regioselectivity of the cycloaddition of ethyl nitrosoacrylate with 1,6-dihydropyrrolo[3,2-c]carbazoles as well as with pyrrole and indole, allowing a more comprehensive analysis of the reactivity pattern of nitrosoalkenes with five-membered heterocycles. Furthermore, theoretical calculations confirmed that ethyl nitrosoacrylate reacts with these heterocycles via a LUMOheterodiene-HOMOdienophile controlled cycloaddition. The reactivity of one of the oxime-functionalized 1,6-dihydropyrrolo[3,2-c]carbazole was explored and a new hexahydropyrido[4',3':4,5]pyrrolo[3,2-c]carbazole system was obtained in high yield via a one-pot, two-step procedure.

Non-traumatic emergency abdominal surgery in nonagenarian patients: a retrospective study.

PURPOSE: The primary aim of this study was to evaluate the 30-day survival of nonagenarian patients who underwent non-traumatic emergency abdominal surgery. Other aims were: 90-day and 12-month survival rates, the postoperative complications rate, the impact of the emergency operation on postoperative functional status, the accuracy of the P-POSSUM in predicting 30-day postoperative mortality and changes in care services after surgery. METHODS: This was a retrospective cohort study of nonagenarian patients who underwent non-traumatic emergency abdominal surgery between January 2010 and June 2017. Patients were divided in two groups according to the 30-day survival status to compare the distribution of patients' characteristics and postoperative outcomes. Overall survival was estimated using the Kaplan-Meier method. To assess the accuracy of P-POSSUM to predict 30-day mortality, a receiver operating characteristic curve and the Hosmer-Lemeshow goodness of fit test were used. RESULTS: 85 nonagenarian patients were enrolled in this study; of these, 27 (31.8%) died within 30 days. The Kaplan-Meier curve showed a rapid decline in survival over the first 30 postoperative days, followed by a more gradual reduction during the rest of the first year. The majority of patients (92.6%) who died within 30 days experienced a medical complication, with a preponderance of respiratory failure (48.2%) and multiple organ failure (33.3%). In the surviving patients, the postoperative functional status had worsened, and 64.2% of patients did not return to their original housing situation or were institutionalized. The accuracy of P-POSSUM in predicting 30-day mortality in nonagenarian patients was poor. CONCLUSIONS: This study may help doctors convey the postoperative risks of morbidity and mortality, and also to adequately inform relatives about the possible adverse discharge destination of surviving nonagenarian patients with a consequent increase in care needs.

Ring-opening/ring-closing protocols from nitrothiophenes: six-membered versus unusual eight-membered sulfur heterocycles through Michael-type addition on nitrobutadienes.

When Ar is a low-aromaticity homo- or heterosystem, the sulfonyl-stabilized anion of nitrobutadienes 4 (which derive from the initial ring opening of 3-nitrothiophene) undergoes a rather surprising addition onto the aromatic ring itself, thereby leading to the construction of an unusual eight-membered sulfur heterocycle condensed with the original Ar ring. The competitiveness of such a pathway with respect to the formation of the thiopyran ring (i.e., addition onto the nitrovinyl moiety) is favored at low temperatures, thus revealing its nature as a kinetically controlled process.

Liver-directed therapies for liver metastases from neuroendocrine neoplasms: Can laser ablation play any role?

Aggressive cytoreduction can prolong survival in patients with unresectable liver metastases (LM) from neuroendocrine neoplasms (NEN), and minimally invasive, liver-directed therapies are gaining increasing interest. Catheter-based treatments are used in disseminated disease, whereas ablation techniques are usually indicated when the number of LM is limited. Although radiofrequency ablation (RFA) is by far the most used ablative technique, the goal of this opinion review is to explore the potential role of laser ablation (LA) in the treatment of LM from NEN. LA uses thinner needles than RFA, and this is an advantage when the tumors are in at-risk locations. Moreover, the multi-fiber technique enables the use of one to four laser fibers at once, and each fiber provides an almost spherical thermal lesion of 12-15 mm in diameter. Such a characteristic enables to tailor the size of each thermal lesion to the size of each tumor, sparing the liver parenchyma more than any other liver-directed therapy, and allowing for repeated treatments with low risk of liver failure. A recent retrospective study reporting the largest series of LM treated with LA documents both safety and effectiveness of LA, that can play a useful role in the multimodality approach to LM from NEN.

Comparing EWGSOP2 and FNIH Sarcopenia Definitions: Agreement and 3-Year Survival Prognostic Value in Older Hospitalized Adults: The GLISTEN Study.

BACKGROUND: Sarcopenia is common among older hospitalized adults but estimates vary according to definitions used. Aims of this study were to investigate the agreement between the European Working Group on Sarcopenia in Older People (EWGSOP2) and the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project criteria and to compare the predictive value of both definitions for 3-year mortality. METHODS: Analysis was performed on 610 older hospitalized patients enrolled in the GLISTEN study. Participants were categorized as sarcopenic or not sarcopenic according to EWGSOP2 and FNIH definitions separately and in a four-group variable (neither criterion positive, only EWGSOP2, only FNIH, and both criteria). RESULTS: Sarcopenia prevalence was 22.8% and 23.9% using EWGSOP2 and FNIH criteria, respectively, with a low classification agreement (Cohen's kappa statistic: 0.29). Sarcopenic participants by each definitions had higher mortality rate when compared to those not sarcopenic (both log-rank test: p < .001). Participants who met both positive criteria had the shorter survival as compared with the other three groups. Cox models showed that, after adjustment for potential confounders, only EWGSOP2 definition predicted 3-year mortality (hazard ratio [HR] 1.84; 95% confidence interval [CI] 1.33-2.57). When the four-group variable was used, compared with the NO EWGSOP2/NO FNIH group, significant mortality risk was found for the EWGSOP2 (HR 2.08; 95% CI 1.38-3.16) and the combined EWGSOP2/FNIH group (HR 1.75; 95% CI 1.11-2.79). CONCLUSIONS: Agreement between EWGSOP2 and FNIH definitions is poor. Sarcopenia on hospital admission is associated with increased risk of 3-year mortality and EWGSOP2 criteria seem to have the highest predictive value.

Percutaneous Laser Ablation of Liver Metastases from Neuroendocrine Neoplasm. A Retrospective Study for Safety and Effectiveness.

PURPOSE: To retrospectively assess safety and efficacy of laser ablation (LA) of multiple liver metastases (LM) from neuroendocrine neoplasms (NEN). METHODS: Twenty-one patients with NEN and at least 3 LM ≤ 4 cm in diameter underwent ultrasonography-guided LA. Up to seven LM were ablated in a single session; if the number of LM exceeded seven, the remaining LM were ablated in further LA sessions with a time interval of 3-4 weeks. LA was performed according to the multifiber technique. The patients underwent contrast-enhanced CT 1 month after LA, and were subsequently monitored every 3 months for the first 2 years and then every 6 months. RESULTS: In total, 189 LM were treated in 21 patients (mean 9 ± 8.2, median 6) in 41 LA sessions (range 1-5). The diameter of LM ranged from 5 to 35 mm (median 19 mm, mean 17.9 ± 6.4 mm). One grade 4 complication occurred (0.53%): a bowel perforation managed by surgery. Technical efficacy was 100%, primary efficacy rate 94.7%, and secondary efficacy rate 100%. Complete relief of hormone-related symptoms was obtained in all the 13 symptomatic patients. Median follow-up was 39 months (range 12-99). 1-, 2-, 3-, and 5-year survival rates were 95%, 86%, 66%, and 40%, respectively. Overall survival resulted higher for patients with Ki-67 expression ≤ 7% than for those with Ki-67 > 7% (p = 0.0347). CONCLUSIONS: LA is a promising and safe technique to treat LM from NEN. A longer follow-up should provide definitive information on the long-term efficacy of this liver-directed therapy. LEVEL OF EVIDENCE: Retrospective study, local non-random sample, level 3.

Hand grip strength assessment in older people: is the supine position valid and reliable?

PURPOSE: Muscle strength evaluation is important in older people's functional assessment. We investigated the validity of grip strength measurement in a supine position as compared to the traditional one. METHODS: Cross-sectional study conducted in older people hospitalized in a medical unit. Patients underwent measurements of grip strength in both supine and sitting positions. Agreement between results was evaluated using Pearson correlation and Infraclass correlation coefficient. The two measurements techniques were graphically compared with Bland-Altman plot. RESULTS: Forty four participants enrolled (21 females), mean age 80.6. Correlation coefficients demonstrated a strong positive relationship between the two different measurement positions (all values greater than 0.9). Results were consistent and similar across gender, body side and were not affected by cognitive impairment. Infraclass correlation analyses demonstrate a very good inter-rate reliability. CONCLUSIONS: Grip strength assessed in the supine position can be considered a valid alternative in bedridden individuals.

Association between hospitalization-related outcomes, dynapenia and body mass index: The Glisten Study.

OBJECTIVE: To compare the prognostic value of dynapenia, as evaluated by handgrip, and body mass index (BMI) on length of stay (LOS), days of bed rest, and other hospitalization-related outcomes in a population of older adults admitted to 12 italian acute care divisions. METHODS: Data on age, weight, BMI, comorbidities, ADL, physical activity level, muscle strength, were recorded at hospital admission. LOS, days of bed rest, intrahospital falls, and discharge destination were also recorded during the hospitalization. Subjects with BMI <18.5 kg/m2 were classified as underweight, subjects with BMI 18.5-24.9 as normal weight, subjects with BMI ≥25 as overweight-obese. RESULTS: A total of 634 patients, mean age 80.8 ± 6.7 years and 49.4% women, were included in the analysis. Overall dynapenic subjects (D) showed a longer period of LOS and bed rest compared with non-dynapenic (ND). When the study population was divided according to BMI categories, underweight (UW), normal weight (NW), and overweight-obese (OW-OB), no significant differences were observed in hospital LOS and days of bed rest. When analysis of covariance was used to determine the difference of LOS across handgrip/BMI groups, D/OW-OB and D/UW subjects showed significantly longer LOS (11.32 and 10.96 days, both p 0.05) compared to ND/NW subjects (7.69 days), even when controlling for age, gender, baseline ADL, cause of hospitalization and comorbidity. After controlling for the same confounding factors, D/OW-OB, D/NW and D/UW subjects showed significantly longer bed rest (4.7, 4.56, and 4.05 days, respectively, all p 0.05, but D/OW-OB p 0.01) compared to ND/NW subjects (1.59 days). CONCLUSION: In our study population, LOS is longer in D/UW and D/OW-OB compared to ND/NW subjects and days of bed rest are mainly influenced by dynapenia, and not by BMI class.

Sensitivity of different resistant tumour cell lines to the two novel compounds (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate and (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene.

The inhibition of cell proliferation by methyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (1-Naph-NMCB) and (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene (2-Naph-DNB) has been studied in vitro against four cell lines selected for their resistance to doxorubicin, cisplatin, taxol and 5-fluorouracil. In previous experiments both compounds showed good in vitro antiproliferative, cytotoxic and pro-apoptotic activities against cell lines of different histologic origin. The results of the experiments presented here suggest that 1-Naph-NMCB is able to overcome all of the different mechanisms of resistance showed by the resistant cell lines used for our experiments. On the contrary, when we used the taxol-resistant A549-T12 cell line, characterized by a mechanism of resistance due to a mutation of the target site of taxol on microtubules, it displayed a partial but significant cross-resistance to 2-Naph-DNB. Although the actual mechanism of this cross-resistance has not yet been definitively elucidated, our results from immunostaining of microtubules suggest that it may be linked to the presence of a shared target site for taxol and 2-Naph-DNB on microtubules.

Design, synthesis, and in vitro evaluation of new naphthylnitrobutadienes with potential antiproliferative activity: toward a structure/activity correlation.

On the grounds of previous encouraging results on the antitumor activity of (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1), we have designed and synthesized two new molecules [(1E,3E)-1,4-bis(4-carboxy-1-naphthyl)-2,3-dinitro-1,3-butadiene (2) and methyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (3)] characterized by a common naphthylnitrobutadiene array but with different structural properties, with the aim of approaching to some structure-activity correlation. When 2 and 3 were analyzed in vitro for their inhibition of cell proliferation and pro-apoptotic properties, the carboxyderivative 2 did not furnish appreciable results. In contrast, 3 (which contains only one of the two naphthylnitroethenyl moieties of the original compound 1) showed remarkable activities in the range of micromolar concentrations (in six over eight cell lines its IC(50)s are in the 1-3 microM range), with a significant improvement compared to 1. In particular, 3 proved able to bind to DNA, to upregulate p53, to block cells in the G2/M phase of their cycle, and to induce apoptosis. Thus, very interestingly, the performance of 3 with respect to 1 shows that a single 1-(1-naphthyl)-2-nitroethene moiety is able to ensure better (on four out of eight of the cell lines tested) or comparable levels of activity. This result suggests that the 'molecular-simplification strategy' could furnish a useful instrument for future design in our antitumor research.

Contrast-enhanced ultrasonography of post-interventional hematoma: the bleeding mushroom is growing inside.

Catheter ablation is an effective treatment in patients with symptomatic atrial fibrillation. Complications are infrequent and usually resolve with minimal or no intervention, but active bleeding due to arterial injury during the vascular access can sometimes represent a life-threatening complication. Contrast-enhanced computed tomography is the standard technique to detect active bleeding, but it may not be immediately available. We report a case of iatrogenic hemorrhage after catheter ablation, in which contrast-enhanced ultrasonography played a decisive role in the recognition of active arterial bleeding due to injury to the right common femoral artery.

Association of Anticholinergic Drug Burden with Cognitive and Functional Decline Over Time in Older Inpatients: Results from the CRIME Project.

BACKGROUND: Medications with anticholinergic properties, although widely used, may negatively affect cognitive and functional status in older patients. To date there is still no standardized method to quantify anticholinergic exposure. We analyzed the relationship of two different tools for the evaluation of the anticholinergic drug burden with cognitive and functional impairment in a sample of older hospitalized patients. METHODS: A retrospective and longitudinal analysis with 1-year follow-up of 1123 older hospitalized patients enrolled in seven Italian acute care wards was conducted. We assessed anticholinergic burden with the Anticholinergic Cognitive Burden (ACB) and Anticholinergic Risk Scale (ARS). Cognitive and functional status were evaluated at hospital discharge and during follow-up (3, 6, 12 months) using the Mini Mental State Examination (MMSE) and five basic activities of daily living (ADLs). Associations between anticholinergic burden and cognitive decline and incident disability were estimated using linear regression models for repeated measures and logistic models, respectively. RESULTS: The mean age of the study population was 81 ± 7.5 years. ACB and ARS classifications showed low correlation (Spearman's rho = 0.39-0.43). Anticholinergic burden increased during hospitalization and was associated with cognitive and functional status. Patients with an ARS of ≥ 1 at discharge had  significantly lower baseline MMSE scores (ARS = 0: 23.1; ARS ≥ 1: 20.8; p = 0.002) and during follow-up presented a  significantly steeper MMSE score decline (- 0.15/month). Moreover, patients with an ACB of ≥ 1 at discharge had an almost threefold increased risk of developing disability (odds ratio 2.77, 95% confidence interval 1.39-5.54). CONCLUSIONS: ACB and ARS have only a moderate degree of correlation. Use of drugs with anticholinergic properties in elderly patients is independently associated with cognitive and functional decline.