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Introduction: Proximal humerus fractures are the seventh most frequent fracture in adults, and the third in patients over 65 years old, 5.7% of whole diagnosed fractures. Most of these fractures can be treated conservatively and achieve good results. However, more and more frequently we are confronted with dislo-cated and multifragmentary fractures, and with elderly and high functional demanding patients. In patients with osteoporosis and poor general conditions external fixation can be performed as rapid and mininvasive procedure with good outcome and low complication rates. The authors investigated the use of external fixa-tion in the treatment of proximal humerus fractures. The objective is to demonstrate the effectiveness of this method as a valid alternative to other surgical techniques. Materials and Methods: A multicentre study was conducted at 7 hospitals in Italy from 2014 through 2018. We recruited all proximal humeral fractures (as classified with the Neer system) that are surgically treated with the same external fixator DOS, for a total of 110 patients, evaluated later with Oxford Shoulder Scale (OSS) and disability of the arm, shoulder and hand score (DASH) at 1, 2 and 6 months. Results:The patients have passed from a score of 75,37 in the first month to a score of 29,47in the sixth month at the DASH and from 47,02 to 27,71 at the OSS. The data further confirm the increased incidence of these fractures in women and in a mean age of about 65. Conclusions:Al-though it does not represent the golden standard in the treatment of fractures of the proximal humerus, in our experience the minimal osteosynthesis with external fixator turned out to be a very valid help especially for the simplicity and speed of the method, as well as for the exciting functional results. sometimes superior to other methods. The preliminary results from the different centers have confirmed this hypothesis. We hope this will be a good starting point for further in-depth studies.

Denture stomatitis (DS) is an inflammatory oral condition affecting most frequently the palatal mucosa covered by the fitting surface of a denture. The aim of this study was to determine the local cytokine profile generated in DS, as well as the level and identity of Candida involved. Palatal inflammation was determined by clinical indices in 93 upper denture-wearing subjects (42 with DS). The level of selected cytokines in palatal fluid was measured by cytometric bead array. Grouping of the cytokines associated with Th1, Th2, Th17 and regulatory T cell (Treg) responses, showed significant increases particularly for Th1 and Th17 responses. Using imprint culture, Candida was isolated from 48 patients (29 with DS). DS patients had significantly higher numbers of Candida isolated from the fitting surface of the denture (P=0.0113). However, there was significantly (P=0.03) higher numbers of Candida on the palate of non-DS patients. In summary, it would appear that an appropriate immune response is elicited in DS patients and whilst this appears to reduce Candida levels on inflamed mucosa, it is probable that Candida on the fitting surface of the denture remain protected from local immune responses which results in a continued reservoir of infection.

The aim of these clinical studies was to evaluate an in situ dentine tubule occlusion model, and to determine the occluding effect from novel occluding agents on patent dentine tubules compared to a positive control (8% strontium acetate--Sensodyne Mint) and negative control (a non-occluding agent) after four days of brushing treatment.These two in situ clinical studies were of single-center, randomized, crossover, single-blind design. Healthy participants wore two lower intra-oral appliances retaining four dentine samples for four treatment days for each period of the study. Samples were power-brushed each day with the test product. Assessment utilized surface topological analysis with a replica-based methodology under scanning electron microscopy (SEM).Both clinical trials demonstrated that the positive control (8% strontium acetate) occluded dentine tubules significantly better (p = 0.0007; p0.0009) than the negative controls in the two studies, respectively. The experimental occluding agents demonstrated varying degrees of success for occluding effect compared to the controls.The methodology clearly demonstrates that this in situ clinical model can robustly and reproducibly detect the dentine tubular occlusive effects of positive and negative controls in the treatment of dentine hypersensitivity brushed on the dentine surface. Using this methodology, new occlusion agents for the relief of dentine hypersensitivity can be assessed for occlusive effects on dentine.

Background: From February 21, the day of hospitalisation in ICU of the first diagnosed case of Covid-19, the social situation and the hospitals’ organisation throughout Italy dramatically changed. Methods: The CIO (Club Italiano dell’Osteosintesi) is an Italian society devoted to the study of traumatology that counts members spread in public and private hospitals throughout the country. Fifteen members of the CIO, Chairmen of 15 Orthopaedic and Trauma Units of level 1 or 2 trauma centres in Italy, have been involved in the study. They were asked to record data about surgical, outpatients clinics and ER activity from the 23rd of February to the 4th of April 2020. The data collected were compared with the data of the same timeframe of the previous year (2019). Results: Comparing with last year, overall outpatient activity reduced up to 75%, overall Emergency Room (ER) trauma consultations up to 71%, elective surgical activity reduced up to 100% within two weeks and trauma surgery excluding femoral neck fractures up to 50%. The surgical treatment of femoral neck fractures showed a stable reduction from 15 to 20% without a significant variation during the timeframe. Conclusions: Covid-19 outbreak showed a tremendous impact on all orthopaedic trauma activities throughout the country except for the surgical treatment of femoral neck fractures, which, although reduced, did not change in percentage within the analysed timeframe.

Background: Antibodies against acetylcholine receptors (AChRs) can also target nicotinic AChRs that are present throughout the central nervous system, thus leading to cognitive dysfunctions in patients with myasthenia gravis (MG). However, the presence of cognitive impairment in MG is controversial, and the factors that may influence this risk are almost completely unknown. In this study, the frequency of mild cognitive impairment (MCI) in MG, as well as the clinical, immunological, and behavioral correlates of MCI in MG were evaluated. Methods: A total of 52 patients with MG underwent a comprehensive assessment including motor and functional scales, serological testing, and neuropsychological and behavioral evaluation. Results: The frequency of MCI was 53.8%, and the most impaired cognitive domains were, in order, visuoconstructive/visuospatial skills, memory, and attention. After multivariate analysis, only pyridostigmine use was inversely associated with the presence of MCI, while a trend toward a positive association between MCI and disease severity and arms/legs hyposthenia was found. Correlation analyses showed that daily doses of prednisone and azathioprine significantly correlated with depressive symptomatology, while disease severity significantly correlated with depressive symptomatology and sleep disturbance. Conclusions: The presence of MCI is rather frequent in MG and is characterized by multidomain amnestic impairment. Such preliminary data need further confirmation on larger case series.

The ability of several N-phenyl-1H-pyrazole-4-carboxamide derivatives and other pyrazoles opportunely modified at the positions 3, 4 and 5, to reduce the formation of the biofilm in some Staphylococcus aureus strains (ATCC 29213, ATCC 25923 and ATCC 6538) were investigated. All the tested compounds were able, although to a different extent, to reduce the biofilm formation of the three bacterial strains considered. Among these, the 1-(2,5-dichlorophenyl)-5-methyl-N-phenyl-1H-pyrazole-4-carboxamide 14 resulted as the best inhibitor of biofilm formation showing an IC50 ranging from 2.3 to 32 μM, against all the three strains of S. aureus. Compound 14 also shows a good protective effect in vivo by improving the survival of wax moth larva (Galleria mellonella) infected with S. aureus ATCC 29213. These findings indicate that 14d is a potential lead compound for the development of new anti-virulence agents against S. aureus infections.

A natural like O -glycoconjugate polycyclic compound 4 was obtained by a multistep procedure starting from N -(3-methyl-1-(4-nitrophenyl)-1 H -pyrazol-5-yl)acetamide. The glycosyl derivative 4 showed antiproliferative activity against all the tumoral cell lines of the NCI panel in the range 0.47–5.43 μ M. Cytofluorimetric analysis performed on MDA-MB231, a very aggressive breast cancer cell line, which does not express estrogen, progesterone and HER-2/neu receptors, showed that 4 is able to induce prolonged cell cycle arrest at G2/M phase and morphological signs of differentiation. These events are correlated with down-regulation of both cyclin B1 and cdc2, the cyclins involved in G2/M transition, as well as up-regulation of cyclin-dependent kinase (CDK) inhibitor p21 Cip1/Waf1.

In the struggle against the emergence of the antibiotic resistance, new molecules targeting biofilm formation could be useful as adjuvant of conventional antibiotics. This study focused on a new class of 2-phenylhydrazinylidene derivatives as antivirulence agents. The compound 12e showed interesting activities against biofilm formation of all tested Staphylococcus aureus strains with IC50 ranging from 1.7 to 43 µM; compounds 12f and 13a resulted strong inhibitors of S. aureus ATCC 6538 and ATCC 29213 biofilm formation with IC50 of 0.9 and 0.8 µM, respectively. A preliminary study on the mechanism of action was carried on evaluating the inhibition of sortase A transpeptidase. Compound 12e resulted not to be toxic at 1 mg/ml by using an in vivo model (the wax moth larva model, Galleria mellonella).

Based on the encouraging results found for 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 7 previously tested by us, as well as the consideration that heterocycle fused tetrazepinones bearing the 2-chloroethyl substituent show a better cytotoxic profile than temozolomide and mitozolomide against human cancer cell lines which express the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), in this paper we report the multistep synthesis and the biological study of 3-(2-cloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 10. Like compound 7, it was active on P-glycoprotein expressing cells (MDR) HL60 and on K562 cell line that are resistant to apoptosis induced by different stimuli, showing GI50 values of 14 and 18 µM respectively. As an antiproliferative agent against the above cells compound 10 was about 2.2 times more active than compound 7. Compound 10 was also tested against WiDR cells which are overexpressing the DNA repair protein MGMT, showing a GI50 value of 2.3 µM. Finally, concerning the effect on cell cycle we observed an evident difference between compounds 7 and 10. In fact, compound 7 induces a block of cell cycle in G0-G1, therefore acting as phase-specific drug, in contrast, compound 10 is a not phase-specific agent. Both the compounds are able to increase the apoptotic sub G0-G1 peak of cell cycle.

In this review we report the recent advances in anticancer activity of the family of natural occurring flavonoids, covering the time span of the last five years. The bibliographic data will be grouped, on the basis of biological information, in two great categories: reports in which the extract plants bioactivity is reported and the identification of each flavonoid is present or not, and reports in which the anticancer activity is attributable to purified and identified flavonoids from plants. Wherever possible, the targets and mechanisms of action as well as the structure-activity relationships of the molecules will be reported. Also, in the review it was thoroughly investigated the recent discovery on flavonoids containing the 2-phenyl-4H-chromen-4-one system even if some examples of unusual flavonoids, bearing a non-aromatic B-ring or other ring condensed to the base structure are reported.

New N-methyl and N-ethyl substitutions in the indazole nucleus are reported by reacting 3-(2-aminobenzamido)indazole and the appropriate trimethyl/triethyl orthobenzoate. Single crystal X-ray analysis confirms the N-ethylation position for the 3-(1-ethyl-1H-indazol-3-yl)-2-phenylquinazolin-4(3H)-one derivative 3f. Compounds 11a-d and 3a-d were tested to evaluate their antimicrobial, their antiproliferative activity and their COX inhibitory activities showing scarce or moderately antiproliferative activity and some inhibitory activity against COX-1 and COX-2.

The multistep synthesis of 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4(3H)-one 15 has been carried out. The compound showed antiproliferative and apoptotic effects against K562, K562-R (imatinib mesilate resistant), HL60 and multidrug resistant (MDR) HL60 cell lines. Compound 15 showed a pro-apoptotic activity against HL60 and K562 resistant cell lines markedly higher than etoposide and busulfan, respectively. Flow cytometry studies carried out on K562 cells allowed to establish that 15 induces G0-G1 phase arrest followed by apoptosis.

Several new 2-(2-phenoxyacetamido)benzamides 17a-v, 21 and 22 were synthesized by stirring in pyridine the acid chlorides 16a-e and the appropriate5-R-4-R1-2-aminobenzamide 15a-e and initially evaluated in vitro for antiproliferative activity against the K562 (human chronic myelogenous leukemia) cell line. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). The most active compounds caused an arrest of K562 cells in the G0-G1 phase of cell cycle and induction of apoptosis, which was mediated by caspase activation.

The diazonium salt derived from 4-amino-N,1,3-trimethyl-N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1H-pyrazole-5-carboxamide (14) was reacted with a mixture of CuSO4 and NaCl, with ascorbic acid as an initiator to afford the planar derivative 4,6-dihydro-1,4,6,8-tetramethyl-3-phenyldipyrazolo[3,4-b:4′,3′-d]pyridin-5(3H)-one (16) and its unexpected isomer 4,6-dihydro-3,4,6,8-tetramethyl-1-phenyldipyrazolo[4,3-b:4′,3′-d]pyridin-5(1H)-one (17), as well as the epimers (3S,4S)- (or (3S,4R)-) and (3S,4R)- (or (3S,4S)-) 4-chloro-2,4-dihydro-1′,3′,5,5′-tetramethyl-2-phenylspiro[pyrazole-3,4′(1′H)-pyrrolo[3,4-c]pyrazol]-6′(5′H)-one (18a and b, respectively). Epimers 18a and b were converted under basic conditions to 4′-chloro-N,1,3,3′-tetramethyl-1′-phenyl-[4,5′-bi-1H-pyrazole]-5-carboxamide (19). The structures of isomers 16 and 17 determined by single-crystal X-ray analysis are also reported. Linear dichroism (LD) measurements for the above isomers suggest that 17 intercalates into DNA, and 17 exhibited antiproliferation activity against human NCI-H460 pulmonary carcinoma cells.

Several new 4-(3,3-dimethyltriazeno)-5-benzamidopyrazole derivatives were prepared by reacting 4-diazo-5-benzamidopyrazole derivatives with dimethylamine. The compounds were tested at 10 microM for their vitro antileukemic activity against K562 (Human chronic myelogenous leukemia) and Raji (human Burkitt limphoma ) cell lines. Dacarbazine and methotrexate were used for comparative purpose. The 3-methyl-4-(3,3-dimethyltriazeno)-5-(substituted benzamido)pyrazoles, bearing the pyrazole nucleus free at 1 position, resulted more active than the 1-(substituted phenyl)-3-methyl-4-(3,3-dimethyltriazeno)-5-benzamidopyrazoles. Dacarbazine at 10 microM showed no activity in the above tests. The observed difference among Dacarbazine and the active 4-triazenopyrazoles migth be explained admiting that these last compounds, differently by Dacarbazine, did not follow a mechanism of action based on the cytochrome P-450 induced demethylation. The most active compound 2d showed growth inhibition values of 97.8 and 99.4% against K562 and Raji cell lines respectively. Methotrexate inhibition values at 0.2 microM against the above cell lines were 86.7 and 75.1% respectively.

In order to study the influence of 3-substitution on the cytotoxic activity of 2-styrylquinazolinones, new 6-chloro-2-styryl-3-(heteroaryl)-4(3H)-quinazolinones were synthesized by refluxing equimolar amounts of 6-chloro-2-methyl-3-(heteroaryl)-4(3H)-quinazolinones and benzaldehyde in glacial acetic acid. At 1 microg ml(-1) concentration, almost all 2-styrylquinazolinones showed some cytotoxic activity against the L1210 and K562 leukemia cell lines. However, only 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone inhibited the growth of these cells by over 50%. This last compound was also the only member of the series that inhibited tubulin polymerization, with an IC(50) value of 5.8 versus 3.2 microM for colchicine. It was also examined for effects on the growth of human MCF7 breast carcinoma cells and Burkitt lymphoma CA46 cells, which had IC(50) values of 0.34 and 1.0 microM, respectively. At 10 microM 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone induced G2/M arrest (66%) in Burkitt cells, with a mitotic index of 20%. At 3.4 microM, it caused disruption of the cellular microtubule system of the MCF7 cells. Both these cellular effects are consistent with its mechanism of action resulting from its inhibitory effect on tubulin assembly.

N-(1-Phenyl-4-carbetoxypyrazol-5-yl)-, N-(indazol-3-yl)- and N-(indazol-5-yl)-2-iodobenzamides 6, with a Benodanil-like structure, were synthesized by refluxing in acetic acid the corresponding benzotriazinones 5 with potassium iodide for 1 h in order to study the role on the antifungal activity of the N-substitution with an aromatic heterocyclic system on benzamide moiety. Among the tested iododerivatives, compounds 6d,f,g,h possess interesting activities toward some phytopathogenic fungal strains.

Neurons are highly polarized cells, composed of one axon and several branching dendrites. One important issue in neurobiology is to understand the molecular factors that determine the neuron to develop polarized structures. A particularly early event, in neurons still lacking a discernible axon, is the segregation of IGF-1 (Insulin like Growth Factor-1) receptors in one neurite. This receptor can be activated by insulin in bulk, but, it is not known if changes of insulin organization as a monomolecular film may affect neuron polarization. To this end, in this work we developed solid-supported Langmuir–Blodgett films of insulin with different surface packing density. Hyppocampal pyramidal neurons, in early stage of differentiation, were cultured onto those substrates and polarization was studied after 24 h by confocal microscopy. Also we used surface reflection interference contrast microscopy and confocal microscopy to study attachment patterns and morphology of growth cones. We observed that insulin films packed at 14 mN/m induced polarization in a similar manner to high insulin concentration in bulk, but insulin packed at 44 mN/m did not induce polarization. Our results provide novel evidence that the neuron polarization through IGF-1 receptor activation can be selectively modulated by the lateral packing of insulin organized as a monomolecular surface for cell growth. Fil: Grasso, Ernesto Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina Fil: Oliveira, Rafael Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina Fil: Oksdath Mansilla, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina Fil: Quiroga, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina Fil: Maggio, Bruno. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina

Several new 4-diazopyrazole derivatives 6a – g and 9a – c were obtained by the reaction of 1-(R-substituted-phenyl)-3-(1,3-dimethyl-1 H -pyrazol-5-yl)ureas 5a – g and N -(1,3-dimethyl-1 H -pyrazol-5-yl)-2-(R-substituted-phenyl)acetamides 8a – c respectively with a sevenfold excess of nitrous acid in acetic acid solution. The compounds were assayed for their activity against the Staphylococcus aureus reference strains ATCC 25923, ATCC 29213 and ATCC 6538, as well as six veterinary strains. The best anti-staphylococcal profile was showed by [(R-substituted-phenyl)acetyl](4-diazonio-1,3-dimethyl-1 H -pyrazol-5-yl)azanides 9a , c . Compound 9c was also able at 3.1 μg mL −1 to inhibit of 45.7% the biofilm formation of the strains S. aureus ATCC 29213.

The pyrazolo[3,4-d]pyrimidine system shows a multitude of interesting pharmacological properties. Owing to the potential anti-inflammatory activity of 5-benzamido-pyrazolo[3,4-d]pyrimidin- 4-one derivatives and considering the easy synthesis of this class of compounds, a set of new 5- benzamido-1H-pyrazolo[3,4-d]pyrimidin-4-ones has been prepared in 42-80% yields by reacting 5- aminopyrazole-4(N-benzoyl)carbohydrazide derivatives and the opportune triethylorthoesters. Compounds 8a, b, 10a–d, and 11a, b revealed a superior inhibitory profile against COX-2, when compared to that of reference standards NS398 and indomethacin. Molecular modelling studies confirmed the obtained biological results.

3-(3-Methylisoxazol-5-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones 8a–l and 9a,c–e,h–l were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 6 and 8 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 8a–l and 9a,c–e,h–l were tested in vitro for their antileukemic activity against L-1210 (murine leukemia), K-562 (human chronic myelogenous leukemia) and HL-60 (human leukemia) cell lines showing in some cases good activity.

Several triazenoindazoles and triazenopyrazoles were prepared transforming the appropriate aminoindazoles and aminopyrazoles in the corresponding diazonium salts which were reacted with dimethylamine, diethylamine and pyrrolidine. All the triazenes were tested for their antiproliferative activity against K562, HL60, L1210 and MCF7 cell lines. The biological data showed that the benzocondensation plays a positive role on the antiproliferative activity. The (1)H-NMR spectra showed that the rotational barrier around the N(2)-N(3) bond in the triazene group can be influenced both by the position of this group in the indazole nucleus and by the substitution pattern in the benzene moiety.

3-(1-Phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones 14a–q and 15a–q were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 12 and 13 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 14a–q and 15a–q were tested in vitro for their antileukemic activity against L1210 (murine leukemia), K562 (human chronic myelogenous leukemia) and HL60 (human leukemia) cell lines showing in some cases good activity.

2-(Methyl(3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)thiophene-3-diazonium hydrogen sulfate 20, 2-(methyl(3-methyl-isoxazol-5yl)carbamoyl)-benzenediazonium hydrogen sulfate 21 and 2-(methyl(phenyl)carbamoyl)-benzenediazonium hydrogen sulphate 22 were synthesized and reacted with a CuSO4/NaCl/ascorbic acid combination to give complex mixtures. The structures of the reaction products were elucidated, depending upon the pathways followed. Compound 20 almost exclusively afforded an Ar-5 cyclization product and trace amounts of the product derived from a competing Ar-6 Pschorr closure. In the case of compound 21, the Ar-6 cyclization was not observed, while the Ar-5 cyclization and 1,5-hydrogen radical transfer processes equally occurred. Finally, the Ar-6 cyclization was observed as the main process for compound 22, accompanied by the Ar-5 cyclization and, in a much lesser extent, by an 1,5-hydrogen radical transfer process.

The central eight-membered ring of the title compound, C40H36N8O2, deviates from the ideal boat conformation because the bond between the exo-ethylene group and the adjacent N atom is twisted by 60.0 (4)° due to steric hindrance. Its adjacent benzene and pyrazole rings are oriented almost perpendicular to each other, making a dihedral angle of 85.8 (3)°. In the crystal, the molecules are linked by C(ar)—H...O hydrogen bonds, generating a three-dimensional network.