Improved breakdown strength and electrical energy storage performance of γ-poly(vinylidene fluoride)/unmodified montmorillonite clay nano-dielectrics.

A remarkable improvement in the dielectric breakdown strength (Eb) and discharge energy density (U e) of flexible polymer nanocomposites is realized by the incorporation of unmodified smectite montmorillonite (MMT) nanoclay into a poly(vinylidene fluoride) (PVDF) matrix. The resulting PVDF/MMT clay nanocomposite (PCN) films stabilize the γ phase and increase the path tortuosity via strong intercalation of the PVDF matrix into inorganic layered silicates without sacrificing the quality of surface morphology. The PCN films exhibits superior dielectric properties (up to ε r ∼ 28 and tan δ ∼ 0.032 at 1 kHz) than those of pure PVDF. As a result, a large increase in E b of 873 MV m(-1) and U e of 24.9 J cm(-3) is achieved. Subsequently, the PCN films possess more than 60% charge-discharge efficiency even at higher electric field and thus provide a scope to develop high energy density flexible and transparent materials for energy storage technologies.

Greening the grid: A comprehensive review of renewable energy in Bangladesh.

The escalating global demand for energy has coincided with economic development, while Bangladesh's reliance on renewable energy remains modest at 4.59%. Investigating economically viable solutions such as solar, biomass, and other renewable sources, the research underscores the pivotal role of sound policies and a strategic plan in transforming the current energy landscape. Despite facing various challenges, particularly in technology, the implementation of sound policies and a strategic plan can substantially alter the current landscape. By reviewing the Renewable Energy Policy of 2008 and incorporating recommendations from United States Agency for International Development (USAID) in 2023, this paper not only delves into challenges and future prospects but also aligns with the Sustainable Development Goal (SDG) aimed at achieving affordable and clean energy. This study contributes valuable insights by proposing methodologies to generate renewable energy by offering a comprehensive overview of the present energy scenario in Bangladesh, with a focus on strategic policy recommendations, thus surpassing previous efforts in the literature. The paper, in its entirety, strives to foster the adoption of renewable energy while concurrently mitigating reliance on conventional fossil fuels.

Strategies of managing solid waste and energy recovery for a developing country - A review.

Solid waste is considered one of the major pollutants of both water and surface worldwide. The growing global population, urban expansion, and industrial growth are the main reasons for solid waste generation. This has become a major challenge with both regional and worldwide consequences. The yearly generation of municipal solid wastes around the world is 2.01 BT (billion tons) among which about 33 % are not ecologically handled. To address this, proper solid waste management, especially recycling waste products, is crucial to achieving sustainability. High-income countries are able to recycle 51 % of their waste, while low-income countries only recycle 16 % of their waste. Inadequate solid waste management practices can only compound environmental and social problems. To handle these issues thermochemical and biochemical methods are used to convert solid waste to energy. Thermochemical method is suitable for developing countries though it is energy extensive. This review provides a detailed analysis of developing countries' solid waste management and energy recovery. It explores energy recovery technologies, including thermochemical and biochemical waste conversion processes.

Anthropometric measures and the risk of endometrial cancer, overall and by tumor microsatellite status and histological subtype.

Obesity is an established risk factor for endometrial cancer, but this association is not well understood for subtypes of endometrial cancer. We evaluated the association of recent and adult-life obesity with subtypes of endometrial cancer based on microsatellite status (microsatellite-stable (MSS) vs. microsatellite-instable (MSI)) and histology (type I vs. type II). Analyses were based on a population-based case-control study (524 cases and 1,032 controls) conducted in Alberta, Canada (2002-2006) and included the following groupings of subtypes: MSS = 337 and MSI = 130; type I = 458 and type II = 66. Logistic and polytomous logistic regression were used to estimate odds ratios and 95% confidence intervals for overall endometrial cancer and subtypes of endometrial cancer, respectively. The risks of all subtypes of endometrial cancer, except type II, increased with an increase in all of the anthropometric characteristics examined. The risks for MSI tumors were suggestively stronger than those for MSS tumors; the risk with high (≥30) body mass index (weight (kg)/height (m)(2)) was significantly stronger for MSI tumors (odds ratio = 4.96, 95% confidence interval: 2.76, 8.91) than for MSS tumors (odds ratio = 2.33, 95% confidence interval: 1.66, 3.28) (P-heterogeneity = 0.02). Obesity is associated with most subtypes of endometrial cancer, and further studies are warranted to elucidate the biological mechanisms underlying the stronger risk for the MSI subtype with a high body mass index.

The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin.

Neuropathic pain results from damage to the peripheral sensory nervous system, which may have a number of causes. The calcium channel subunit alpha(2)delta-1 is upregulated in dorsal root ganglion (DRG) neurons in several animal models of neuropathic pain, and this is causally related to the onset of allodynia, in which a non-noxious stimulus becomes painful. The therapeutic drugs gabapentin and pregabalin (PGB), which are both alpha(2)delta ligands, have antiallodynic effects, but their mechanism of action has remained elusive. To investigate this, we used an in vivo rat model of neuropathy, unilateral lumbar spinal nerve ligation (SNL), to characterize the distribution of alpha(2)delta-1 in DRG neurons, both at the light- and electron-microscopic level. We found that, on the side of the ligation, alpha(2)delta-1 was increased in the endoplasmic reticulum of DRG somata, in intracellular vesicular structures within their axons, and in the plasma membrane of their presynaptic terminals in superficial layers of the dorsal horn. Chronic PGB treatment of SNL animals, at a dose that alleviated allodynia, markedly reduced the elevation of alpha(2)delta-1 in the spinal cord and ascending axon tracts. In contrast, it had no effect on the upregulation of alpha(2)delta-1 mRNA and protein in DRGs. In vitro, PGB reduced plasma membrane expression of alpha(2)delta-1 without affecting endocytosis. We conclude that the antiallodynic effect of PGB in vivo is associated with impaired anterograde trafficking of alpha(2)delta-1, resulting in its decrease in presynaptic terminals, which would reduce neurotransmitter release and spinal sensitization, an important factor in the maintenance of neuropathic pain.

The anti-allodynic alpha(2)delta ligand pregabalin inhibits the trafficking of the calcium channel alpha(2)delta-1 subunit to presynaptic terminals in vivo.

Neuropathic pain is caused by lesion or dysfunction of the peripheral sensory nervous system. Up-regulation of the voltage-gated Ca(2+) channel subunit alpha(2)delta-1 in DRG (dorsal root ganglion) neurons and the spinal cord correlates with the onset of neuropathic pain symptoms such as allodynia in several animal models of neuropathic pain. The clinically important anti-allodynic drugs gabapentin and pregabalin are alpha(2)delta-1 ligands, but how these drugs alleviate neuropathic pain is poorly understood. In the present paper, we review recent advances in our understanding of their molecular mechanisms.

Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain.

BACKGROUND: Descending facilitation, from the brainstem, promotes spinal neuronal hyperexcitability and behavioural hypersensitivity in many chronic pain states. We have previously demonstrated enhanced descending facilitation onto dorsal horn neurones in a neuropathic pain model, and shown this to enable the analgesic effectiveness of gabapentin. Here we have tested if this hypothesis applies to other pain states by using a combination of approaches in a rat model of osteoarthritis (OA) to ascertain if 1) a role for descending 5HT mediated facilitation exists, and 2) if pregabalin (a newer analogue of gabapentin) is an effective antinociceptive agent in this model. Further, quantitative-PCR experiments were undertaken to analyse the alpha 2 delta-1 and 5-HT3A subunit mRNA levels in L3-6 DRG in order to assess whether changes in these molecular substrates have a bearing on the pharmacological effects of ondansetron and pregabalin in OA. RESULTS: Osteoarthritis was induced via intra-articular injection of monosodium iodoacetate (MIA) into the knee joint. Control animals were injected with 0.9% saline. Two weeks later in vivo electrophysiology was performed, comparing the effects of spinal ondansetron (10-100 microg/50 microl) or systemic pregabalin (0.3 - 10 mg/kg) on evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimuli in MIA or control rats. In MIA rats, ondansetron significantly inhibited the evoked responses to both innocuous and noxious natural evoked neuronal responses, whereas only inhibition of noxious evoked responses was seen in controls. Pregabalin significantly inhibited neuronal responses in the MIA rats only; this effect was blocked by a pre-administration of spinal ondansetron. Analysis of alpha 2 delta-1 and 5-HT3A subunit mRNA levels in L3-6 DRG revealed a significant increase in alpha 2 delta-1 levels in ipsilateral L3&4 DRG in MIA rats. 5-HT3A subunit mRNA levels were unchanged. CONCLUSION: These data suggest descending serotonergic facilitation plays a role in mediating the brush and innocuous mechanical punctate evoked neuronal responses in MIA rats, suggesting an adaptive change in the excitatory serotonergic drive modulating low threshold evoked neuronal responses in MIA-induced OA pain. This alteration in excitatory serotonergic drive, alongside an increase in alpha 2 delta-1 mRNA levels, may underlie pregabalin's state dependent effects in this model of chronic pain.

Selective ablation of dorsal horn NK1 expressing cells reveals a modulation of spinal alpha2-adrenergic inhibition of dorsal horn neurones.

Activity in descending systems from the brainstem modulates nociceptive transmission through the dorsal horn. Intrathecal injection of the neurotoxin saporin conjugated to SP (SP-SAP) into the lumbar spinal cord results in the selective ablation of NK(1) receptor expressing (NK(1)+ve) neurones in the superficial dorsal horn (lamina I/III). Loss of these NK(1)+ve neurones attenuates excitability of deep dorsal horn neurones due to a disruption of both intrinsic spinal circuits and a spino-bulbo-spinal loop, which activates a descending excitatory drive, mediated through spinal 5HT(3) receptors. Descending inhibitory pathways also modulate spinal activity and hence control the level of nociceptive transmission relayed to higher centres. To ascertain the spinal origins of the major descending noradrenergic inhibitory pathway we studied the effects of a selective alpha2-adrenoceptor antagonist, atipamezole, on neuronal activity in animals pre-treated with SP-SAP. Intrathecal application of atipamezole dose dependently facilitated the mechanically evoked neuronal responses of deep dorsal horn neurones to low intensity von Frey hairs (5-15 g) and noxious thermal (45-50 degrees C) evoked responses in SAP control animals indicating a physiological alpha2-adrenoceptor control. This facilitatory effect of atipamezole was lost in the SP-SAP treated group. These data suggest that activity within noradrenergic pathways have a dependence on dorsal horn NK(1)+ve cells. Further, noradrenergic descending inhibition may in part be driven by lamina I/III (NK(1)+ve) cells, and mediated via spinal alpha2-adrenoceptor activation. Since the same neuronal population drives descending facilitation and inhibition, the reduced excitability of lamina V/VI WDR neurones seen after loss of these NK(1)+ve neurones indicates a dominant role of descending facilitation.

Peripheral nerve injury-induced changes in spinal alpha(2)-adrenoceptor-mediated modulation of mechanically evoked dorsal horn neuronal responses.

UNLABELLED: Peripheral nerve injury has been associated with changes in the modulatory action of noradrenergic pathways on nociceptive traffic through the spinal cord. Thus, the purpose of this study was to assess whether endogenous noradrenergic descending inhibition, acting via spinal alpha(2)-receptors, is altered after peripheral nerve damage. We investigated the effects of spinal administration of a selective alpha(2)-adrenoceptor antagonist, atipamezole, on the evoked activity of deep dorsal horn neurons in animals with selective spinal nerve ligation (SNL) compared with a sham-operated group. Intrathecal administration of atipamezole (1, 10, and 100 microg) did not produce any significant effects on the electrically evoked neuronal responses in either animal group, with the exception of a small but significant enhancement of the postdischarge in the sham control group only. Similarly, no significant effects were observed with the heat-evoked neuronal responses in either group. Interestingly, atipamezole significantly increased the evoked responses of neurons to low-intensity mechanical stimuli in the sham control group but was without effect in the SNL group. Thus, our findings suggest that peripheral nerve injury can result in the suppression of noradrenergic spinal alpha(2)-adrenoceptor-mediated inhibition of spinal dorsal horn neuronal activity evoked by low-intensity mechanical stimuli. PERSPECTIVE: These results suggest that a tonically active noradrenergic inhibition of mechanically evoked spinal dorsal horn neuronal responses is lost after nerve injury. This shift in the balance of noradrenergic controls may be one of the many underlying mechanisms by which behavioral symptoms of hypersensitivity develop after nerve damage.

Superficial NK1 expressing spinal dorsal horn neurones modulate inhibitory neurotransmission mediated by spinal GABA(A) receptors.

Lamina 1 projection neurones which express the NK1 receptor (NK1R+) drive a descending serotonergic pathway from the brainstem that enhances spinal dorsal horn neuronal activity via the facilitatory spinal 5-HT3 receptor. Selective destruction of these cells via lumbar injection of substance P-saporin (SP-SAP) attenuates pain behaviours, including mechanical and thermal hypersensitivity, which are mirrored by deficits in the evoked responses of lamina V-VI wide dynamic range (WDR) neurones to noxious stimuli. To assess whether removing the origin of this facilitatory spino-bulbo-spinal loop results in alterations in GABAergic spinal inhibitory systems, the effects of spinal bicuculline, a selective GABA(A) receptor antagonist, on the evoked neuronal responses to electrical (Abeta-, Adelta-, C-fibre, post-discharge and Input) and mechanical (brush, prod and von Frey (vF) 8 and 26 g) stimuli were measured in SAP and SP-SAP groups. In the SAP control group, bicuculline produced a significant dose related facilitation of the electrically evoked Adelta-, C-fibre, post-discharge and input neuronal responses. The evoked mechanical (prod, vF8 g and 26 g) responses were also significantly increased. Brush evoked neuronal responses in these animals were enhanced but did not reach significance. This facilitatory effect of bicuculline, however, was lost in the SP-SAP treated group. The generation of intrinsic GABAergic transmission in the spinal cord appears dependent on NK1 bearing neurons, yet despite the loss of GABAergic inhibitory controls after SP-SAP treatment, the net effect is a decrease in spinal cord excitability. Thus activation of these cells predominantly drives facilitation.

Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin.

Not all neuropathic pain patients gain relief from current therapies that include the anticonvulsant, gabapentin, thought to modulate calcium channel function. We report a neural circuit that is permissive for the effectiveness of gabapentin. Substance P-saporin (SP-SAP) was used to selectively ablate superficial dorsal horn neurons expressing the neurokinin-1 receptor for substance P. These neurons project to the brain as shown by retrograde labelling and engage descending brainstem serotonergic influences that enhance spinal excitability via a facilitatory action on 5HT(3) receptors. We show the integrity of this pathway following nerve injury contributes to the behavioural allodynia, neuronal plasticity of deep dorsal horn neurons and the injury-specific actions of gabapentin. Thus SP-SAP attenuated the tactile and cold hypersensitivity and abnormal neuronal coding (including spontaneous activity, expansion of receptive field size) seen after spinal nerve ligation. Furthermore the powerful actions of gabapentin after neuropathy were blocked by either ablation of NK-1 expressing neurones or 5HT(3) receptor antagonism using ondansetron. Remarkably, 5HT(3) receptor activation provided a state-dependency (independent of that produced by neuropathy) allowing GBP to powerfully inhibit in normal uninjured animals. This circuit is therefore a crucial determinant of the abnormal neuronal and behavioural manifestations of neuropathy and importantly, the efficacy of gabapentin. As this spino-bulbo-spinal circuit contacts areas of the brain implicated in the affective components of pain, this loop may represent a route by which emotions can influence the degree of pain in a patient, as well as the effectiveness of the drug treatment. These hypotheses are testable in patients.

Emerging targets and therapeutic approaches for the treatment of osteoarthritis pain.

PURPOSE OF REVIEW: Osteoarthritis is a complex and often painful disease that is inadequately controlled with current analgesics. This review discusses emerging targets and therapeutic approaches that may lead to the development of better analgesics. RECENT FINDINGS: Aberrant excitability in peripheral and central pain pathways drives osteoarthritis pain, reversing this via modulation of nerve growth factor, voltage-gated sodium channel, voltage-gated calcium channel and transient receptor potential vanilloid one activity, and increasing inhibitory mechanisms through modulation of cannabinoid and descending modulatory systems hold promise for osteoarthritis pain therapy. Somatosensory phenotyping of chronic pain patients, as a surrogate of putative pain generating mechanisms, may predict patient response to treatment. SUMMARY: Identification of new targets will inform and guide future research, aiding the development of more effective analgesics. Future clinical trial designs should implement sensory phenotyping of patients, as an inclusion or stratification criterion, in order to establish an individualized, mechanism-based treatment of osteoarthritis pain.

Descending facilitatory control of mechanically evoked responses is enhanced in deep dorsal horn neurones following peripheral nerve injury.

Pain resulting from peripheral nerve injury, characterised by ongoing pain, hyperalgesia and allodynia arises from peripheral and central processes. Here, we studied the potential role of central facilitations in nerve injury by investigating the effect of blocking the excitatory 5HT3 receptor with ondansetron. 5HT3 receptors play a pronociceptive role in the spinal cord and ondansetron has previously been shown to produce antinociception in behavioural studies. We investigated the effects of spinally administered ondansetron (10, 50 and 100 microg) on the responses of deep dorsal horn neurones, evoked by peripheral electrical stimuli and a range of natural (mechanical punctate and heat) stimuli, 2 weeks after nerve injury induced through tight ligation of L5/6 spinal nerves (SNL). Comparisons were made between SNL rats and a sham-operated group. Ondansetron produced little effect on the electrically evoked responses (Abeta-, Adelta- and C-fibre-evoked responses, postdischarge); however, responses to mechanical punctate stimuli (von Frey filaments 1-75 g) were markedly reduced in both SNL and control groups. Furthermore, the drug effect was significantly enhanced after SNL (p<0.05). In particular, the lowest dose (10 microg) now became effective after SNL. Ondansetron produced less marked effects on thermal responses. Our results demonstrate that neuropathic pain states are associated with an enhanced descending facilitatory control of mechanical responses of spinal neurones, mediated through the activation of spinal 5HT3 receptors. These excitatory influences are likely to contribute to the development and maintenance of central sensitisation in the spinal cord, and furthermore, to the behavioural manifestation of tactile allodynia.

Descending serotonergic facilitation mediated through rat spinal 5HT3 receptors is unaltered following carrageenan inflammation.

A descending facilitatory drive originating from superficial dorsal horn NK1-expressing neurones and relaying through parabrachial and rostroventral medial medulla to act on deep dorsal horn neurones, mediated through spinal 5HT3 receptors, was recently documented. To determine if this pathway plays a role in the pathophysiology of inflammation, we investigated the effects of spinally administered ondansetron (a selective 5HT3 receptor antagonist) on deep dorsal horn neuronal responses in carrageenan inflamed and naïve animals using in vivo electrophysiology. The mechanical and thermal evoked responses of spinal neurones were dose dependently attenuated by ondansetron to a similar degree in both groups. In contrast, the electrically evoked responses (Abeta-, Adelta-, C-fibre evoked response and post-discharge) remained unaltered in both groups. Thus 5HT3 receptor mediated descending facilitation remains unaltered at this stage after tissue injury.

Antinociceptive effects of lacosamide on spinal neuronal and behavioural measures of pain in a rat model of osteoarthritis.

INTRODUCTION: Alterations in voltage-gated sodium channel (VGSC) function have been linked to chronic pain and are good targets for analgesics. Lacosamide (LCM) is a novel anticonvulsant that enhances the slow inactivation state of VGSCs. This conformational state can be induced by repeated neuronal firing and/or under conditions of sustained membrane depolarisation, as is expected for hyperexcitable neurones in pathological conditions such as epilepsy and neuropathy, and probably osteoarthritis (OA). In this study, therefore, we examined the antinociceptive effect of LCM on spinal neuronal and behavioural measures of pain, in vivo, in a rat OA model. METHODS: OA was induced in Sprague Dawley rats by intraarticular injection of 2 mg of monosodium iodoacetate (MIA). Sham rats received saline injections. Behavioural responses to mechanical and cooling stimulation of the ipsilateral hind paw and hindlimb weight-bearing were recorded. In vivo electrophysiology experiments were performed in anaesthetised MIA or sham rats, and we recorded the effects of spinal or systemic administration of LCM on the evoked responses of dorsal horn neurones to electrical, mechanical (brush, von Frey, 2 to 60 g) and heat (40°C to 50°C) stimulation of the peripheral receptive field. The effect of systemic LCM on nociceptive behaviours was assessed. RESULTS: Behavioural hypersensitivity ipsilateral to knee injury was seen as a reduced paw withdrawal threshold to mechanical stimulation, an increase in paw withdrawal frequency to cooling stimulation and hind limb weight-bearing asymmetry in MIA-treated rats only. Spinal and systemic administration of LCM produced significant reductions of the electrical Aß- and C-fibre evoked neuronal responses and the mechanical and thermal evoked neuronal responses in the MIA group only. Systemic administration of LCM significantly reversed the behavioural hypersensitive responses to mechanical and cooling stimulation of the ipsilateral hind paw, but hind limb weight-bearing asymmetry was not corrected. CONCLUSIONS: Our in vivo electrophysiological results show that the inhibitory effects of LCM were MIA-dependent. This suggests that, if used in OA patients, LCM may allow physiological transmission but suppress secondary hyperalgesia and allodynia. The inhibitory effect on spinal neuronal firing aligned with analgesic efficacy on nociceptive behaviours and suggests that LCM may still prove worthwhile for OA pain treatment and merits further clinical investigation.

Differential upregulation in DRG neurons of an α2δ-1 splice variant with a lower affinity for gabapentin after peripheral sensory nerve injury.

The α2δ-1 protein is an auxiliary subunit of voltage-gated calcium channels, critical for neurotransmitter release. It is upregulated in dorsal root ganglion (DRG) neurons following sensory nerve injury, and is also the therapeutic target of the gabapentinoid drugs, which are efficacious in both experimental and human neuropathic pain conditions. α2δ-1 has 3 spliced regions: A, B, and C. A and C are cassette exons, whereas B is introduced via an alternative 3' splice acceptor site. Here we have examined the presence of α2δ-1 splice variants in DRG neurons, and have found that although the main α2δ-1 splice variant in DRG is the same as that in brain (α2δ-1 ΔA+B+C), there is also another α2δ-1 splice variant (ΔA+BΔC), which is expressed in DRG neurons and is differentially upregulated compared to the main DRG splice variant α2δ-1 ΔA+B+C following spinal nerve ligation. Furthermore, this differential upregulation occurs preferentially in a small nonmyelinated DRG neuron fraction, obtained by density gradient separation. The α2δ-1 ΔA+BΔC splice variant supports CaV2 calcium currents with unaltered properties compared to α2δ-1 ΔA+B+C, but shows a significantly reduced affinity for gabapentin. This variant could therefore play a role in determining the efficacy of gabapentin in neuropathic pain.

Voltage gated sodium and calcium channel blockers for the treatment of chronic inflammatory pain.

The inflammatory response is a natural response of the body that occurs immediately following tissue damage, which may be due to injury, infection or disease. The acute inflammatory response is an essential mechanism that promotes healing and a key aspect is the ensuing pain, which warns the subject to protect the site of injury. Thus, it is common to see a zone of primary sensitization as well as consequential central sensitization that generally, is maintained by a peripheral drive from the zone of tissue injury. Inflammation associated with chronic pain states, such as rheumatoid and osteoarthritis, cancer and migraine etc. is deleterious to health and often debilitating for the patient. Thus there is a large unmet clinical need. The mechanisms underlying both acute and chronic inflammatory pain are extensive and complex, involving a diversity of cell types, receptors and proteins. Among these the contribution of voltage gated sodium and calcium channels on peripheral nociceptors is critical for nociceptive transmission beyond the peripheral transducers and changes in their distribution, accumulation, clustering and functional activities have been linked to both inflammatory and neuropathic pain. The latter has been the main area for trials and use of drugs that modulate ion channels such as carbamazepine and gabapentin, but given the large peripheral drive that follows tissue damage, there is a clear rationale for blocking voltage gated sodium and calcium channels in these pain states. It has been hypothesized that pain of inflammatory origin may evolve into a condition that resembles neuropathic pain, but mixed pains such as low back pain and cancer pain often include elements of both pain states. This review considers the therapeutic potential for sodium and calcium channel blockers for the treatment of chronic inflammatory pain states.

Hormonal and reproductive risk factors for sporadic microsatellite stable and unstable endometrial tumors.

Hormonal and reproductive factors modulate bioavailable estrogen to influence endometrial cancer risk. Estrogen affects the microsatellite status of tumors, but the relation between these estrogen-related factors and microsatellite instability (MSI) status of endometrial tumors is not known. We evaluated associations between hormonal and reproductive factors and risks of microsatellite stable (MSS) and MSI endometrial cancer among postmenopausal women (MSS cases = 258, MSI cases = 103, and controls = 742) in a population-based case-control study in Alberta, Canada (2002-2006). Polytomous logistic regression was used to estimate ORs and 95% confidence intervals (95% CI). We observed a significant trend in risk reduction for MSI (Ptrend = 0.005) but not MSS (Ptrend = 0.23) cancer with oral contraceptive use; with 5-year use or more, the risk reduction was stronger for MSI (OR = 0.42; 95% CI, 0.23-0.77) than for MSS cancer (OR = 0.80; 95% CI, 0.54-1.17; Pheterogeneity = 0.05). For more recent use (<30 years), the risk reduction was stronger for MSI (OR = 0.36; 95% CI, 0.19-0.69) than for MSS cancer (OR = 0.77; 95% CI, 0.51-1.15; Pheterogeneity = 0.032). No differential risk associations were observed for menopausal hormone use, parity and age at menarche, menopause or first pregnancy. We found limited evidence for statistical heterogeneity of associations of endometrial cancer risk with hormonal and reproductive factors by MSI status, except with oral contraceptive use. This finding suggests a potential role for the MMR system in the reduction of endometrial cancer risk associated with oral contraceptive use, although the exact mechanism is unclear. This study shows for the first time that oral contraceptive use is associated with a reduced risk for MSI but not for MSS endometrial cancer.

Characterisation of a peripheral neuropathic component of the rat monoiodoacetate model of osteoarthritis.

Joint degeneration observed in the rat monoiodoacetate (MIA) model of osteoarthritis shares many histological features with the clinical condition. The accompanying pain phenotype has seen the model widely used to investigate the pathophysiology of osteoarthritis pain, and for preclinical screening of analgesic compounds. We have investigated the pathophysiological sequellae of MIA used at low (1 mg) or high (2 mg) dose. Intra-articular 2 mg MIA induced expression of ATF-3, a sensitive marker for peripheral neuron stress/injury, in small and large diameter DRG cell profiles principally at levels L4 and 5 (levels predominated by neurones innervating the hindpaw) rather than L3. At the 7 day timepoint, ATF-3 signal was significantly smaller in 1 mg MIA treated animals than in the 2 mg treated group. 2 mg, but not 1 mg, intra-articular MIA was also associated with a significant reduction in intra-epidermal nerve fibre density in plantar hindpaw skin, and produced spinal cord dorsal and ventral horn microgliosis. The 2 mg treatment evoked mechanical pain-related hypersensitivity of the hindpaw that was significantly greater than the 1 mg treatment. MIA treatment produced weight bearing asymmetry and cold hypersensitivity which was similar at both doses. Additionally, while pregabalin significantly reduced deep dorsal horn evoked neuronal responses in animals treated with 2 mg MIA, this effect was much reduced or absent in the 1 mg or sham treated groups. These data demonstrate that intra-articular 2 mg MIA not only produces joint degeneration, but also evokes significant axonal injury to DRG cells including those innervating targets outside of the knee joint such as hindpaw skin. This significant neuropathic component needs to be taken into account when interpreting studies using this model, particularly at doses greater than 1 mg MIA.

Recent Developments in Neuropathic Pain Mechanisms: Implications for Treatment.

Neuropathic pain is defined as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system".Characteristic symptoms include an increased evoked pain response to noxious (hyperalgesia) and innocuous (allodynia) stimuli, spontaneous pain, shooting electric shock like pain. Sensory deficits can also exist.Available treatments are not adequate in many patients due to many factors including the complexity of the pain state, disease progression, intolerable side effects and low analgesic efficacy.A number of peripheral, spinal and supraspinal mechanisms of hyperexcitability underlie neuropathic pain, these include changes in the activity and expression of voltage gated sodium, calcium and potassium channels, as well as TRPV1 channels and alterations in the activity of neuroimmue pathways.NeP patients often experience depression, anxiety, sleep disturbances etc. alongside their pain. These co-morbidites significantly reduce quality of life and as such are key treatment considerations..Improved understanding of NeP mechanisms is encouraging targeting of treatment to the mechanisms that produce painful symptoms as opposed to the etiology of disease.