Polypharmacy, common in older people, confers both risk of adverse outcomes and benefits. We assessed the relationship of commonly prescribed medications with anticholinergic and sedative effects to physical and cognitive performance in older individuals. The study population comprised 932 moderately to severely disabled community-resident women aged 65 years or older who were participants in the Women's Health and Aging Study I. A scale based on pharmacodynamic principles was developed and utilized as a measure of drug burden. This was related to measures of physical and cognitive function. After adjusting for demographics and comorbidities, anticholinergic drug burden was independently associated with greater difficulty in four physical function domains with adjusted odds ratios (95% confidence interval (CI)) of 4.9 (2.0-12.0) for balance difficulty; 3.2 (1.5-6.9) for mobility difficulty; 3.6 (1.6-8.0) for slow gait; 4.2 (2.0-8.7) for chair stands difficulty; 2.4 (1.1-5.3) for weak grip strength; 2.7 (1.3-5.4) for upper extremity limitations; 3.4 (1.7-6.9) for difficulty in activities of daily living; and 2.4 (95% CI, 1.1-5.1) for poor performance on the Mini-Mental State Examination. Sedative burden was associated only with impaired grip strength (3.3 (1.5-7.3)) and mobility difficulty (2.4 (1.1-5.3)). The burden of multiple drugs can be quantified by incorporating the recommended dose regimen and the actual dose and frequency of drug taken. Anticholinergic drug burden is strongly associated with limitations in physical and cognitive function. Sedative burden is associated with impaired functioning in more limited domains. The risk associated with exposure of vulnerable older women to drugs with anticholinergic properties, and to a lesser extent those with sedative properties, implies that such drugs should not be used in this patient group without compelling clinical indication.

Temporomandibular joint or related masticatory muscle pain represents the most common chronic orofacial pain condition. Patients frequently report this kind of pain after dental alterations in occlusion. However, lack of understanding of the mechanisms of occlusion-related temporomandibular joint and muscle pain prevents treating this problem successfully. To explore the relationship between improper occlusion (occlusal interference) and masticatory muscle pain, we created an occlusal interference animal model by directly bonding a crown to a maxillary molar to raise the masticating surface of the tooth in rats. We raised the occlusal surface to three different heights (0.2, 0.4, and 0.6mm), and for one month we quantitatively measured mechanical nociceptive thresholds of the temporal and masseter muscles on both sides. Results showed a stimulus-response relationship between the height of occlusal interference and muscle hyperalgesia. Removal of the crown 6 days after occlusal interference showed that the removal at this time could not terminate the 1 month duration of mechanical hyperalgesia in the masticatory muscles. Lastly, we systemically administered NMDA antagonist MK801 (0.2, 0.1, and 0.05 mg/kg) to the treated rats and found that MK801 dose dependently attenuated the occlusal interference-induced hyperalgesia. These findings suggest that occlusal interference is directly related to masticatory muscle pain, and that central sensitization mechanisms are involved in the maintenance of the occlusal interference-induced mechanical hyperalgesia.

Wnt5a and Ror2 may serve as tumor suppressor genes in the development of HCC, and may serve as clinicopathologic biomarkers for prognosis in HCC patients.

Our study suggests that the overexpression of UbcH10 gene plays a critical role in the carcinogenesis and tumor progression of colorectal cancer. It may be a new marker in diagnosis and prognosis of colorectal cancer, and the inhibition of UbcH10 may be a therapeutic potential for the treatment of colorectal cancer.

Acute cerebral ischemia causes hypoxic neuronal cell death by necrosis and apoptosis. Expression of anti-apoptotic transgenes in ischemic brainThrombotic vessel occlusion in the brain causes acute hypoxia in the respective vascular territory and subsequently induces neuronal death in the core and the penumbra of the ischemic lesion which is caused by necrosis and apoptosis. 1,2 The anti-apoptotic protein bcl-2 is known to protect most eukaryotic cells from apoptotic or necrotic cell death. 3 Bcl-2 also protects human neurons in cell culture against apoptosis induced by withdrawal of nerve growth factor (NGF) and by amyloid ␤-peptide, as well as against oxidative and hypoxic insults. [4][5][6] Delivery of the bcl-2 gene and expression of transgenic bcl-2 in ischemic brain tissue results in neuroprotection and may inhibit hypoxic cell death in vivo. [7][8][9][10] Most of the previous studies on neuroprotective gene transfer used genetically engineered virus vectors, such as herpes-simplex type I virus (HSV), adenovirus (AV), or adeno-associated virus (AAV). 8,9,11

The aim of this study was to determine whether pregabalin affects nociceptive behavior and central sensitization in a trigeminal neuropathic pain model. A partial infraorbital nerve transection (p-IONX) or sham operation was performed in adult male rats. Nociceptive withdrawal thresholds were tested with von Frey filaments applied to the bilateral vibrissal pads pre-operatively and post-operatively. On post-operative day 7, the behavioral assessment was conducted before and at 30 min, 60 min, 120 min, 180 min, and 24hr after pregabalin (0.1, 1, 10, 100 mg/kg, i.p.) or saline injection. The effects of pregabalin or saline were also examined on the mechanoreceptive field and response properties of nociceptive neurons recorded in the medullary dorsal horn at post-operative day 7–10. Reduced withdrawal thresholds reflecting bilateral mechanical allodynia were observed in p-IONX rats until post-operative day 28, but not in sham-operated rats. At post-operative day 7, pregabalin significantly and dose-dependently reversed the reduced mechanical withdrawal thresholds in p-IONX rats. Pregabalin also attenuated central sensitization of the neurons, as reflected in reversal of their reduced activation threshold, increased responses to pinch/pressure, and enhanced stimulus-response function. This study provides the first documentation that pregabalin attenuates the mechanical allodynia and central sensitization that characterize this trigeminal neuropathic pain model, and supports its clinical use for treating craniofacial neuropathic pain.

A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolar binding affinities for the alpha 4 beta 2 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds.

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