Novel 8-(furan-2-yl)-3-benzyl thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine-2(3H)-thione as selective adenosine A2A receptor antagonist

Adenosine A_2A receptor (A_2AR) antagonists have emerged as potential drug candidates to alleviate progression and symptoms of Parkinson's disease (PD), and reduce the dopaminergic side effects. The synthesis of novel compound 8-(furan-2-yl)-3-benzyl thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine-2-(3H)-thione (BTTP) was carried out to evaluate the potential of BTTP as A_2AR antagonist using SCH58261, a standard A_2AR antagonist. The strong interaction of BTTP with A_2AR (ΔG = −12.46 kcal/mol and K_i = 0.6 nM) in silico analysis was confirmed by radioligand receptor binding studies showing high affinity (K_i = 0.004 nM) and selectivity with A_2AR (A_2A/A₁ = 1155-fold). The effect of CGS21680 (selective A_2AR agonist) induced cAMP concentration (0.1 pmol/ml) in HEK293 cells was antagonized with BTTP (0.065 pmol/ml) and SCH58261 (0.075 pmol/ml). Furthermore, BTTP pre-treated (5, 10 and 20 mg/kg) haloperidol-induced mice demonstrated significant attenuation in catalepsy and akinesia. BTTP induced elevation in the striatal dopamine concentration (2.90 μM/mg of tissue) was comparable to SCH58261 (2.92 μM/mg of tissue) at the dose of 10 mg/kg. The results firmly articulate that BTTP possesses potential A_2AR antagonist activity and can be further explored for the treatment of PD.     

Cancer Pain: A Critical Review of Mechanism-based Classification and Physical Therapy Management in Palliative Care

Mechanism-based classification and physical therapy management of pain is essential to effectively manage painful symptoms in patients attending palliative care. The objective of this review is to provide a detailed review of mechanism-based classification and physical therapy management of patients with cancer pain. Cancer pain can be classified based upon pain symptoms, pain mechanisms and pain syndromes. Classification based upon mechanisms not only addresses the underlying pathophysiology but also provides us with an understanding behind patient's symptoms and treatment responses. Existing evidence suggests that the five mechanisms - central sensitization, peripheral sensitization, sympathetically maintained pain, nociceptive and cognitive-affective - operate in patients with cancer pain. Summary of studies showing evidence for physical therapy treatment methods for cancer pain follows with suggested therapeutic implications. Effective palliative physical therapy care using a mechanism-based classification model should be tailored to suit each patient's findings, using a biopsychosocial model of pain.     

Mechanism-based Classification of Pain for Physical Therapy Management in Palliative care: A Clinical Commentary

Pain relief is a major goal for palliative care in India so much that most palliative care interventions necessarily begin first with pain relief. Physical therapists play an important role in palliative care and they are regarded as highly proficient members of a multidisciplinary healthcare team towards management of chronic pain. Pain necessarily involves three different levels of classification-based upon pain symptoms, pain mechanisms and pain syndromes. Mechanism-based treatments are most likely to succeed compared to symptomatic treatments or diagnosis-based treatments. The objective of this clinical commentary is to update the physical therapists working in palliative care, on the mechanism-based classification of pain and its interpretation, with available therapeutic evidence for providing optimal patient care using physical therapy. The paper describes the evolution of mechanism-based classification of pain, the five mechanisms (central sensitization, peripheral neuropathic, nociceptive, sympathetically maintained pain and cognitive-affective) are explained with recent evidence for physical therapy treatments for each of the mechanisms.     

Blood supply to the first metatarsal head and vessels at risk with a chevron osteotomy

BACKGROUND: Chevron osteotomy, a commonly performed procedure for the treatment of hallux valgus, results in osteonecrosis of the first metatarsal head in 0% to 20% of cases. The aim of this study was to map out the arrangement of the vascular supply to the first metatarsal head and its relationship to the limbs of the chevron osteotomy. METHODS: Ten cadaveric lower limbs were injected with an India ink-latex mixture, and the feet were dissected to assess the blood supply to the first metatarsal head. The dissection was carried out by tracing the branches of the dorsalis pedis and posterior tibial vessels. A distal chevron osteotomy was mapped, with the limbs of the osteotomy set at an angle of 60 degrees from the geometric center of the first metatarsal head. The relationship of the limbs of the osteotomy to the blood vessels was recorded. RESULTS: The first metatarsal head was found to be supplied by branches from the first dorsal metatarsal, first plantar metatarsal, and medial plantar arteries. The first dorsal metatarsal artery was the dominant vessel among the three arteries in eight specimens. All of the vessels formed a plexus at the plantar-lateral aspect of the metatarsal neck, just proximal to the capsular attachment, with a varying number of branches from the plexus then entering the metatarsal head. The plantar limb of the proposed chevron cuts exited through this plexus of vessels in all specimens. Contrary to the widely held view, only minor vascular branches could be found entering the dorsal aspect of the neck. CONCLUSIONS: The identification of the plantar-lateral corner of the metatarsal neck as the major site of vascular ingress into the first metatarsal head suggests that constructing the chevron osteotomy with a long plantar limb exiting well proximal to the capsular attachment may decrease the postoperative prevalence of osteonecrosis of the first metatarsal head.     

A high-resolution large area serotonin map of a live rat brain section

We employ three-photon microscopy to produce a high-resolution map of serotonin autofluorescence in a rat midbrain section (covering more than half of the brain), to quantitatively characterize serotonin distribution and release in different areas of a live brain slice. The map consists of a tiling of approximately 160 contiguous optical images (covering an area of approximately 27 mm with sub-mum resolution in 20 min), and is recorded before and after inducing depolarization. We observe that the total serotonin exocytosed from the somata in the raphe is quantitatively comparable with regions containing a high density of serotonergic processes. Our results demonstrate that high-resolution, wide-area, dynamic neurotransmitter mapping is now possible.     

Critical analysis of outcome measures used in the assessment of carpal tunnel syndrome

Clinicians and researchers are confounded by the various outcome measures used for the assessment of carpal tunnel syndrome (CTS). In this study, we critically analysed the conceptual framework, validity, reliability, responsiveness and appropriateness of some of the commonly used CTS outcome measures. Initially, we conducted an extensive literature search to identify all of the outcome measures used in the assessment of CTS patients, which revealed six different carpal tunnel outcome measures [Boston Carpal Tunnel Questionnaire (BCTQ), Michigan Hand Outcome Questionnaire (MHQ), Disability of Arm, Shoulder and Hand (DASH), Patient Evaluation Measure (PEM), clinical rating scale (Historical-Objective (Hi-Ob) scale) and Upper Extremity Functional Scale (UEFS)]. We analysed the construction framework, development process, validation process, reliability, internal consistency (IC), responsiveness and limitations of each of these outcome measures. Our analysis reveals that BCTQ, MHQ and PEM have comprehensive frameworks, good validity, reliability and responsiveness both in the hands of the developers, as well as independent researchers. The UEFS and Hi-Ob scale need validation and reliability testing by independent researchers. Region-specific measures like DASH have good frameworks and, hence, a potential role in the assessment of CTS but they require more validation in exclusive carpal tunnel patients.     

Locations of bone tissue at high risk of initial failure during compressive loading of the human vertebral body

Knowledge of the location of initial regions of failure within the vertebra - cortical shell, cortical endplates vs. trabecular bone, as well as anatomic location--may lead to improved understanding of the mechanisms of aging, disease and treatment. The overall objective of this study was to identify the location of the bone tissue at highest risk of initial failure within the vertebral body when subjected to compressive loading. Toward this end, micro-CT-based 60-micron voxel-sized, linearly elastic, finite element models of a cohort of thirteen elderly (age range: 54-87 years, 75+/-9 years) female whole vertebrae without posterior elements were virtually loaded in compression through a simulated disc. All bone tissues within each vertebra having either the maximum or minimum principal strain beyond its 90th percentile were defined as the tissue at highest risk of initial failure within that particular vertebral body. Our results showed that such high-risk tissue first occurred in the trabecular bone and that the largest proportion of the high-risk tissue also occurred in the trabecular bone. The amount of high-risk tissue was significantly greater in and adjacent to the cortical endplates than in the mid-transverse region. The amount of high-risk tissue in the cortical endplates was comparable to or greater than that in the cortical shell regardless of the assumed Poisson's ratio of the simulated disc. Our results provide new insight into the micromechanics of failure of trabecular and cortical bone within the human vertebra, and taken together, suggest that, during strenuous compressive loading of the vertebra, the tissue near and including the endplates is at the highest risk of initial failure.