Cytotoxic activity of organotin(IV) derivatives with triazolopyrimidine containing exocyclic oxygen atoms

In this study cytotoxicity of organotin(IV) compounds with 1,2,4-triazolo[1,5-a]pyrimidines, Me3Sn(5tpO) (1), n-Bu3Sn(5tpO) (2), Me3Sn(mtpO) (3), n-Bu3Sn(mtpO) (4), n-Bu3Sn(HtpO2) (5), Ph3Sn(HtpO2) (6) where 5HtpO = 4,5-dihydro-5-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, HmtpO = 4,7-dihydro-5-methyl-7-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, and H2tpO2 = 4,5,6,7-tetrahydro-5,7-dioxo-[1,2,4]triazolo-[1,5-a]-pyrimidine, was assessed on three different human tumor cell lines: HCT-116 (colorectal carcinoma), HepG2 (hepatocarcinoma) and MCF-7 (breast cancer). While 1 and 3 were inactive, compounds 2, 4, 5 and 6 inhibited the growth of the three tumor cell lines with IC50 values in the submicromolar range and showed high selectivity indexes towards the tumor cells (SI > 90). The mechanism of cell death triggered by the organotin(IV) derivatives, investigated on HCT-116 cells, was apoptotic, as evident from the externalization of phosphatidylserine to the cell surface, and occurred via the intrinsic pathway with fall of mitochondrial inner membrane potential and production of reactive oxygen species. While compound 6 arrested the cell progression in the G2/M cell cycle phase and increased p53 and p21 levels, compounds 2, 4 and 5 blocked cell duplication in the G1 phase without affecting the expression of either of the two tumor suppressor proteins. Compounds 1 and 2 were also investigated using single crystal X-ray diffraction and found to be, in both cases, coordination polymers forming 1 D chains based on metal-ligand interactions. Interestingly, for n-Bu3Sn(5tpO)(2) H-bonding interactions between 5tpO− ligands belonging to adjacent chains were also detected that resemble the “base-pairing” assembly and could be responsible for the higher biological activity compared to compound 1. In addition, they are the first example of bidentate N(3), O coordination for the 5HtpO ligand on two adjacent metal atoms

Effect of multidisciplinary rehabilitation on sleep outcomes in individuals with preclinical Huntington disease: An exploratory study

Dear Editor Sleep disturbances are an early feature of Huntington disease (HD), which worsen as the disease progresses. Studies have documented increased sleep fragmentation, decreased rapid eye-movement (REM) sleep, reduced sleep efficiency, insomnia and an increase in periodic leg movements (PLMs) in individuals with HD [1], [2]. Disturbances in sleep are thought to exacerbate cognitive impairments and may hasten subcortical neurodegeneration [3], [4]. Hence, management of sleep disturbances in individuals with HD is imperative

Living with Parkinson's - Past, present and future: A qualitative study of the subjective perspective

Background: the social impact of Parkinson's is difficult to capture in quantitative research given the condition's variable presentation, so qualitative research is needed to support a person-centred approach. Aims: to describe how people with Parkinson's experience living with their condition over time. Methods: 27 audio-recorded verbatim-transcribed interviews were analysed through the grounded theory method. Findings: past, present and future were the core categories that emerged. Past is the dimension of regretted memories of past life overturned by the communication of diagnosis. Present is the time dimension in which patients concretely experience the hindrances associated with the condition (loss of autonomy, submissive acceptance and social embarrassment), and the resources (search for autonomy, serene or in-progress acceptance, and social support). Future is characterised by both positive visions of tomorrow and negative ones (worry, resignation, denial). Conclusion: these results, highlighting what living with Parkinson's means over time, may contribute to a better tailoring of nursing practice to the person's needs and rhythm, in a perspective of continuous adaptation

Towards proactive active living: Patients with Parkinson's disease experience of a multidisciplinary intensive rehabilitation treatment

BACKGROUND: Non-pharmacological approaches to PD disease management seem to be a growing and promising field of investigation. Indeed interesting new perspectives are forthcoming from studies on physical rehabilitation and on physical exercise. AIM: To qualitatively describe the rehabilitation experience of Parkinson Disease patients taking part in a multidisciplinary intensive rehabilitation treatment (MIRT) consisting of four weeks of physical therapy and exercise, with three daily sessions, five days a week. DESIGN: Data from a qualitative observational study with patients' interviews were analyzed. SETTING: PD inpatients of a Neurorehabilitation Department. POPULATION: Convenient sample of 27 PD patients (13 male, 14 female), mean age 70.3±8.5 and mean disease duration 8.25±6.9 years; Hoehn-Yahr stage 3, hospitalized for the 4-week MIRT. METHODS: Verbatim transcriptions of 27 semi-structured interviews were analysed using the Grounded Theory methodology. RESULTS: Depressive symptoms were present in 55.5% of the patients measured by Geriatric Depression Scale: mild (N.=8; 30.0%), moderate (N.=6; 22.2%), severe (N.=1; 3.7%). The core category Efficacy of active living identified the becoming conscious of the usefulness of a proactive lifestyle to counterattack disease degeneration. The category Satisfaction described patients' satisfaction upon MIRT, resulting in a perceived enhanced functionality (coherently with quantitative functional parameters improvement at discharge) and a rediscovered autonomy. The category Future described the intention to continue the rehabilitation prescription at home embracing a more dynamic lifestyle. Of interest is that the majority in the interview used body related terms and described perceived changes through the body itself. Verbs of perception (to see, to feel, to perceive) were used in a spontaneous way by all inpatients. The inpatients experienced not only through their mind but also by means of body perceptions how a proactive lifestyle could become a means of disease control. CONCLUSIONS: The positive subjective response to rehabilitation described qualitatively in this study, opens perspectives for tailoring interventions focusing also on patients' self, self-efficacy and perceived efficacy of active living. CLINICAL REHABILITATION IMPACT: Patients' proactive disposition may widen the perspective on patients' motivation to rehabilitation. A multidisciplinary intervention may act both on physical and subjective disease aspects; paying attention to patients' subjective feedbacks could contribute reliably to guide for medical decisions in managing tailored and detailed interventions

A statistical approach for the assessment of muscle activation patterns during gait in parkinson\u2019s disease

Recently, the statistical analysis of muscle activation patterns highlighted that not only one, but several activation patterns can be identified in the gait of healthy adults, with different occurrence. Although its potential, the application of this approach in pathological populations is still limited and specific implementation issues need to be addressed. This study aims at applying a statistical approach to analyze muscle activation patterns of gait in Parkinson\u2019s Disease, integrating gait symmetry and co-activation. Surface electromyographic signal of tibialis anterior and gastrocnemius medialis were recorded during a 6-min walking test in 20 patients. Symmetry between right and left stride time series was verified, different activation patterns identified, and their occurrence (number and timing) quantified, as well as the co-activation of antagonist muscles. Gastrocnemius medialis presented five activation patterns (mean occurrence ranging from 2% to 43%) showing, with respect to healthy adults, the presence of a first shorted and delayed activation (between flat foot contact and push off, and in the final swing) and highlighting a new second region of anticipated activation (during early/mid swing). Tibialis anterior presented five activation patterns (mean occurrence ranging from 3% to 40%) highlighting absent or delayed activity at the beginning of the gait cycle, and generally shorter and anticipated activations during the swing phase with respect to healthy adults. Three regions of co-contraction were identified: from heel strike to mid-stance, from the pre-to initial swing, and during late swing. This study provided a novel insight in the analysis of muscle activation patterns in Parkinson\u2019s Disease patients with respect to the literature, where unique, at times conflicting, average patterns were reported. The proposed integrated methodology is meant to be generalized for the analysis of muscle activation patterns in pathologic subjects

Dopamine replacement therapy, learning and reward prediction in Parkinson’s disease: implications for rehabilitation

The principal feature of Parkinson’s disease (PD) is the impaired ability to acquire and express habitual-automatic actions due to the loss of dopamine in the dorsolateral striatum, the region of the basal ganglia associated with the control of habitual behavior. Dopamine replacement therapy (DRT) compensates for the lack of dopamine, representing the standard treatment for different motor symptoms of PD (such as rigidity, bradykinesia and resting tremor). On the other hand, rehabilitation treatments, exploiting the use of cognitive strategies, feedbacks and external cues, permit to “learn to bypass” the defective basal ganglia (using the dorsolateral area of the prefrontal cortex) allowing the patients to perform correct movements under executive-volitional control. Therefore, DRT and rehabilitation seem to be two complementary and synergistic approaches. Learning and reward are central in rehabilitation: both of these mechanisms are the basis for the success of any rehabilitative treatment. Anyway, it is known that “learning resources” and reward could be negatively influenced from dopaminergic drugs. Furthermore, DRT causes different well-known complications: among these, dyskinesias, motor fluctuations, and dopamine dysregulation syndrome (DDS) are intimately linked with the alteration in the learning and reward mechanisms and could impact seriously on the rehabilitative outcomes. These considerations highlight the need for careful titration of DRT to produce the desired improvement in motor symptoms while minimizing the associated detrimental effects. This is important in order to maximize the motor re-learning based on repetition, reward and practice during rehabilitation. In this scenario, we review the knowledge concerning the interactions between DRT, learning and reward, examine the most impactful DRT side effects and provide suggestions for optimizing rehabilitation in PD