[Orofacial and musculoskeletal disorders of professional musicians - Frequency and therapy principles]. / Orofaziale und muskuloskelettale Schmerzsyndrome bei professionellen Musikern ­ Häufigkeiten und Therapieprinzipien.

Playing-related musculoskeletal disorders are frequently found in the upper extremety and the spine. Moreover, orofacial pain syndromes and craniomandibular dysfunctions are important in upper string players and wind players. The treatment of musicians is based on a diagnostic process including the evaluation of specific musical aspects, a functional manual medicine examination and an evaluation of postural and movement characteristics while playing the musical instrument.

Safe Polycationic Dendrimers as Potent Oral In Vivo Inhibitors of Mycobacterium tuberculosis: A New Therapy to Take Down Tuberculosis.

The long-term treatment of tuberculosis (TB) sometimes leads to nonadherence to treatment, resulting in multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. Inadequate bioavailability of the drug is the main factor for therapeutic failure, which leads to the development of drug-resistant cases. Therefore, there is an urgent need to design and develop novel antimycobacterial agents minimizing the period of treatment and reducing the propagation of resistance at the same time. Here, we report the development of original and noncytotoxic polycationic phosphorus dendrimers essentially of generations 0 and 1, but also of generations 2-4, with pyrrolidinium, piperidinium, and related cyclic amino groups on the surface, as new antitubercular agents active per se, meaning with intrinsic activity. The strategy is based on the phenotypic screening of a newly designed phosphorus dendrimer library (generations 0-4) against three bacterial strains: attenuated Mycobacterium tuberculosis H37Ra, virulent M. tuberculosis H37Rv, and Mangora bovis BCG. The most potent polycationic phosphorus dendrimers 1G0,HCl and 2G0,HCl are active against all three strains with minimum inhibitory concentrations (MICs) between 3.12 and 25.0 µg/mL. Both are irregularly shaped nanoparticles with highly mobile branches presenting a radius of gyration of 7 Å, a diameter of maximal 25 Å, and a solvent-accessible surface area of dominantly positive potential energy with very localized negative patches arising from the central N3P3 core, which steadily interacts with water molecules. The most interesting is 2G0,HCl, showing relevant efficacy against single-drug-resistant (SDR) M. tuberculosis H37Rv, resistant to rifampicin, isoniaid, ethambutol, or streptomycin. Importantly, 2G0,HCl displayed significant in vivo efficacy based on bacterial counts in lungs of infected Balb/C mice at a dose of 50 mg/kg oral administration once a day for 2 weeks and superior efficacy in comparison to ethambutol and rifampicin. This series of polycationic phosphorus dendrimers represents first-in-class drugs to treat TB infection, could fulfill the clinical candidate pipe of this high burden of infectious disease, and play a part in addressing the continuous demand for new drugs.

Multivalent Copper(II)-Conjugated Phosphorus Dendrimers with Noteworthy In Vitro and In Vivo Antitumor Activities: A Concise Overview.

Dendrimers are macromolecules with well-defined, homogeneous, and monodispersed structures that form a branch-like structure. In general, they have a symmetric core, inner shells, and an outer shell. Over the past decade, metallodendritic architectures have developed into a new area in nanomedicine. Due to their versatility and facile customization, phosphorus dendrimers represent interesting platforms for biomedical applications. Metallo-conjugated phosphorus dendrimers have been developed within the dendrimer space, an important part of the chemical space. The first investigation was made using phosphorus dendrimers bearing copper(II) groups on their surface as the original anticancer drug candidates. The aim of this minireview is to present our powerful strategy to find and develop original multivalent copper(II)-conjugated phosphorus dendrimers. The most potent of them is G3 dendrimers with N-(pyridine-2-ylmethylene)ethanamine as the chelating motif complexed with Cu(II) (1G3-Cu), showing very good in vitro and in vivo antiproliferative efficacy. On the basis of these results, 1G3-Cu is a potential clinical candidate having progressed from hit to preclinical candidate status.

Anticancer copper(II) phosphorus dendrimers are potent proapoptotic Bax activators.

A multivalent phosphorus dendrimer 1G3 and its corresponding Cu-complex, 1G3-Cu have been recently identified as agents retaining high antiproliferative potency. This antiproliferative capacity was preserved in cell lines overexpressing the efflux pump ABC B1, whereas cross-resistance was observed in ovarian cancer cell lines resistant to cisplatin. Theoretical 3D models were constructed: the dendrimers appear as irregularly shaped disk-like nano-objects of about 22 Å thickness and 49 Å diameter, which accumulated in cells after penetration by endocytosis. To get insight in their mode of action, cell death pathways have been examined in human cancer cell lines: early apoptosis was followed by secondary necrosis after multivalent phosphorus dendrimers exposure. The multivalent plain phosphorus dendrimer 1G3 moderately activated caspase-3 activity, in contrast with the multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu which strikingly reduced the caspase-3 content and activity. This decrease of caspase activity is not related to the presence of copper, since inorganic copper has no or little effect on caspase-3. Conversely the potent apoptosis activation could be related to a noticeable translocation of Bax to the mitochondria, resulting in the release of AIF into the cytosol, its translocation to the nucleus and a severe DNA fragmentation, without alteration of the cell cycle. The multivalent Cu-conjugated phosphorus dendrimer is more efficient than its non-complexed analog to activate this pathway in close relationship with the higher antiproliferative potency. Therefore, this multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu can be considered as a new and promising first-in-class antiproliferative agent with a distinctive mode of action, inducing apoptosis tumor cell death through Bax activation pathway.

Impairment of postural stabilization systems in musicians with playing-related musculoskeletal disorders.

OBJECTIVE: Recent research demonstrates the importance of postural stabilization systems (PSS) in back pain. The purpose of this study was to examine the frequency of PSS disturbances in musicians experiencing playing-related musculoskeletal disorders (PRMDs). METHODS: Analysis for the presence of impaired PSS (lumbopelvic and scapular stabilizing system dysfunction, upper crossed syndrome) in 84 musicians. RESULTS: Analysis of clinical examination data revealed dysfunctions of the PSS to be present in 78 (93%) of these subjects. Eighty-five percent were found to have impairments of scapular, 71% impairments of lumbopelvic stabilization system, and 57% were found to have upper crossed syndrome. Subgroup analysis (upper strings, lower strings, wind and keyboard instruments) showed significantly more impairment of the lumbopelvic stabilization system for upper and lower strings (P = .008), whereas similar rates for disturbances of scapular stabilizers and upper crossed syndrome were seen across subgroups. Furthermore, significant sex differences with a higher frequency of scapular stabilizers (P = .014) and upper crossed syndrome (P < .001) in women were present. CONCLUSION: This study suggests that insufficiencies of the postural stabilization systems play an important role in the manifestation of musculoskeletal pain and PRMD in musicians. Although there are no prospective research data concerning PSS in musicians, the present authors' empirical observations and clinical experience support the notion that the clinical course and therapeutic outcomes of PRMD bear relationship to the function of the stabilization systems. We therefore argue for a greater emphasis on the examination and training of the postural systems in the integrated prevention, treatment, and rehabilitation of musicians.