Is age at menopause decreasing? - The consequences of not completing the generational cohort.

BACKGROUND: Due to contradictory results in current research, whether age at menopause is increasing or decreasing in Western countries remains an open question, yet worth studying as later ages at menopause are likely to be related to an increased risk of breast cancer. Using data from breast cancer screening programs to study the temporal trend of age at menopause is difficult since especially younger women in the same generational cohort have often not yet reached menopause. Deleting these younger women in a breast cancer risk analyses may bias the results. The aim of this study is therefore to recover missing menopause ages as a covariate by comparing methods for handling missing data. Additionally, the study makes a contribution to understanding the evolution of age at menopause for several generations born in Portugal between 1920 and 1970. METHODS: Data from a breast cancer screening program in Portugal including 278,282 women aged 45-69 and collected between 1990 and 2010 are used to compare two approaches of imputing age at menopause: (i) a multiple imputation methodology based on a truncated distribution but ignoring the mechanism of missingness; (ii) a copula-based multiple imputation method that simultaneously handles the age at menopause and the missing mechanism. The linear predictors considered in both cases have a semiparametric additive structure accommodating linear and non-linear effects defined via splines or Markov random fields smoothers in the case of spatial variables. RESULTS: Both imputation methods unveiled an increasing trend of age at menopause when viewed as a function of the birth year for the youngest generation. This trend is hidden if we model only women with an observed age at menopause. CONCLUSION: When studying age at menopause, missing ages must be recovered with an adequate procedure for incomplete data. Imputing these missing ages avoids excluding the younger generation cohort of the screening program in breast cancer risk analyses and hence reduces the bias stemming from this exclusion. In addition, imputing the not yet observed ages of menopause for mostly younger women is also crucial when studying the time trend of age at menopause otherwise the analysis will be biased.

Temporal Characterization of Behavioral and Hippocampal Dysfunction in the YAC128 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a genetic neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms. Emerging evidence suggests that emotional and cognitive deficits seen in HD may be related to hippocampal dysfunction. We used the YAC128 HD mouse model to perform a temporal characterization of the behavioral and hippocampal dysfunctions. Early and late symptomatic YAC128 mice exhibited depressive-like behavior, as demonstrated by increased immobility times in the Tail Suspension Test. In addition, YAC128 mice exhibited cognitive deficits in the Swimming T-maze Test during the late symptomatic stage. Except for a reduction in basal mitochondrial respiration, no significant deficits in the mitochondrial respiratory rates were observed in the hippocampus of late symptomatic YAC128 mice. In agreement, YAC128 animals did not present robust alterations in mitochondrial ultrastructural morphology. However, light and electron microscopy analysis revealed the presence of dark neurons characterized by the intense staining of granule cell bodies and shrunken nuclei and cytoplasm in the hippocampal dentate gyrus (DG) of late symptomatic YAC128 mice. Furthermore, structural alterations in the rough endoplasmic reticulum and Golgi apparatus were detected in the hippocampal DG of YAC128 mice by electron microscopy. These results clearly show a degenerative process in the hippocampal DG in late symptomatic YAC128 animals.

Selective transfer of nerve to supinator to restore digital extension in central cord syndrome: An anatomical study and a case report.

BACKGROUND: Nerve transfers are increasingly used to restore upper extremity function in patients with spinal cord injury. However, the role of nerve transfers for central cord syndrome is still being established. The purpose of this study is to report the anatomical feasibility and clinical use of nerve transfer of supinator motor branches (NS) to restore finger extension in a central cord syndrome patient. MATERIALS AND METHODS: The posterior interosseous nerve (PIN), its superficial division, and branches were dissected in 14 fresh cadavers, with a mean age of 65 (58-79). Measurements included number and length of branches of donor and recipient, diameters, regeneration distance from coaptation site to motor entry point and axonal counts. A NS transfer to extensor carpi ulnaris (ECU), extensor digiti quinti (EDQ) and extensor digitorum communis (EDC) was performed in a 28-year-old patient, with central cord syndrome after a motorcycle accident, who did not recover active finger extension at 10 months post injury. RESULTS: The PIN consistently divided into a deep and superficial branch between 1.5 cm proximal to, and 2 cm distal to the distal boundary of the supinator. The superficial branch provided a first common branch to the ECU and EDQ. In 12/14 dissections, the EDC was innervated by a 4 cm long branch that entered the muscle on its radial deep surface. In all cases, the superficial branch of the PIN could be separated in a retrograde fashion from the PIN and coapted with NS. The mean myelinated fiber count in nerve to EDC was 401 ± 190 compared to 398 ± 75 in the NS. At 48 months after surgery, with the wrist at neutral, the patient recovered full metacarpophalangeal extension scoring M4. Supination was preserved with the elbow extended or flexed. CONCLUSIONS: Restoration of finger extension in central cord syndrome is possible with a selective transfer of the NS to EDC, and is anatomically feasible with a short regeneration distance and favorable axonal count ratio.

Triceps and cutaneous radial nerve branches investigated via an axillary anterior arm approach: new findings in a fresh-cadaver anatomical study.

OBJECTIVE: The authors sought to describe the anatomy of the radial nerve and its branches when exposed through an axillary anterior arm approach. METHODS: Bilateral upper limbs of 10 fresh cadavers were dissected after dyed latex was injected into the axillary artery. RESULTS: Via the anterior arm approach, all triceps muscle heads could be dissected and individualized. The radial nerve overlaid the latissimus dorsi tendon, bounded by the axillar artery on its superior surface, then passed around the humerus, together with the lower lateral arm and posterior antebrachial cutaneous nerve, between the lateral and medial heads of the triceps. No triceps motor branch accompanied the radial nerve's trajectory. Over the latissimus dorsi tendon, an antero-inferior bundle, containing all radial nerve branches to the triceps, was consistently observed. In the majority of the dissections, a single branch to the long head and dual innervations for the lateral and medial heads were observed. The triceps long and proximal lateral head branches entered the triceps muscle close to the latissimus dorsi tendon. The second branch to the lateral head stemmed from the triceps lower head motor branch. The triceps medial head was innervated by the upper medial head motor branch, which followed the ulnar nerve to enter the medial head on its anterior surface. The distal branch to the triceps medial head also originated near the distal border of the latissimus dorsi tendon. After a short trajectory, a branch went out that penetrated the medial head on its posterior surface. The triceps lower medial head motor branch ended in the anconeus muscle, after traveling inside the triceps medial head. The lower lateral arm and posterior antebrachial cutaneous nerve followed the radial nerve within the torsion canal. The lower lateral brachial cutaneous nerve innervated the skin over the biceps, while the posterior antebrachial cutaneous nerve innervated the skin over the lateral epicondyle and posterior surface of the forearm. The average numbers of myelinated fibers were 926 in the long and 439 in the upper lateral head and 658 in the upper and 1137 in the lower medial head motor branches. CONCLUSIONS: The new understanding of radial nerve anatomy delineated in this study should aid surgeons during reconstructive surgery to treat upper-limb paralysis.

Patterns of median nerve branching in the cubital fossa: implications for nerve transfers to restore motor function in a paralyzed upper limb.

OBJECTIVE: The purpose of this study was to describe the anatomy of donor and recipient median nerve motor branches for nerve transfer surgery within the cubital fossa. METHODS: Bilateral upper limbs of 10 fresh cadavers were dissected after dyed latex was injected into the axillary artery. RESULTS: In the cubital fossa, the first branch was always the proximal branch of the pronator teres (PPT), whereas the last one was the anterior interosseous nerve (AIN) and the distal motor branch of the flexor digitorum superficialis (DFDS) on a consistent basis. The PT muscle was also innervated by a distal branch (DPT), which emerged from the anterior side of the median nerve and provided innervation to its deep head. The palmaris longus (PL) motor branch was always the second branch after the PPT, emerging as a single branch together with the flexor carpi radialis (FCR) or the proximal branch of the flexor digitorum superficialis. The FCR motor branch was prone to variations. It originated proximally with the PL branch (35%) or distally with the AIN (35%), and less frequently from the DPT. In 40% of dissections, the FDS was innervated by a single branch (i.e., the DFDS) originating close to the AIN. In 60% of cases, a proximal branch originated together with the PL or FCR. The AIN emerged from the posterior side of the median nerve and had a diameter of 2.3 mm, twice that of other branches. When dissections were performed between the PT and FCR muscles at the FDS arcade, we observed the AIN lying lateral and the DFDS medial to the median nerve. After crossing the FDS arcade, the AIN divided into: 1) a lateral branch to the flexor pollicis longus (FPL), which bifurcated to reach the anterior and posterior surfaces of the FPL; 2) a medial branch, which bifurcated to reach the flexor digitorum profundus (FDP); and 3) a long middle branch to the pronator quadratus. The average numbers of myelinated fibers within each median nerve branch were as follows (values expressed as the mean ± SD): PPT 646 ± 249; DPT 599 ± 150; PL 259 ± 105; FCR 541 ± 199; proximal FDS 435 ± 158; DFDS 376 ± 150; FPL 480 ± 309; first branch to the FDP 397 ± 12; and second branch to the FDP 369 ± 33. CONCLUSIONS: The median nerve's branching pattern in the cubital fossa is predictable. The most important variation involves the FCR motor branch. These anatomical findings aid during nerve transfer surgery to restore function when paralysis results from injury to the radial or median nerves, brachial plexus, or spinal cord.

Peripheral receptors and neuromediators involved in the antihyperalgesic effects of acupuncture: a state-of-the-art review.

The present study aims to describe state-of-the-art of preclinical studies that have investigated peripheral receptors and neuromediators involved in the antihyperalgesic effects of acupuncture. The PubMed, Scopus, and Web of Science databases were searched using the integrative review method. Preclinical articles that involved the study of peripheral receptors and neuromediators on the pain control effects of acupuncture in rats or mice were selected using a predefined search strategy. From this search, 456 articles were found, and 29 of them met the inclusion criteria of the study. The selected articles addressed the following peripheral receptors: opioid (n = 9), adenosine (n = 5), cannabinoid (n = 5), transient receptor potential vanilloid (TRPV) (n = 3), histamine (n = 2), adrenergic (n = 1), muscarinic (n = 1), corticotrophin-releasing factor (CRF) (n = 2), IL-1 (n = 1), and endothelin (n = 1) receptors. The peripheral neuromediators correlated with the peripheral pain control effect were as follows: opioid peptides (n = 4), adenosine (n = 3), histamine (n = 1), substance P (n = 1) calcitonin gene-related peptide (CGRP) (n = 1), anandamide (n = 1), nitric oxide (n = 1), and norepinephrine (n = 1). This review summarizes the methods used to investigate the peripheral effects of acupuncture and discusses the main findings on each family of receptors and neuromediators. Ten families of peripheral receptors and 8 types of neuromediators were correlated with the antihyperalgesic effects of acupuncture in preclinical studies. Considering the benefits of a better understanding of the role of peripheral receptors and neuromediators in the context pain management, the findings of the present study highlight the importance of deepening the exploration of the peripheral mechanisms of acupuncture.

Medium- and long-term functional behavior evaluations in an experimental focal ischemic stroke mouse model.

Cerebrovascular accident (CVA) is one of the leading causes of death and disability worldwide, as well as a major financial burden for health care systems. CVA rodent models provide experimental support to determine possible in vivo therapies to reduce brain injury and consequent sequelae. This study analyzed nociceptive, motor, cognitive and mood functions in mice submitted to distal middle cerebral artery (DMCA) occlusion. Male C57BL mice (n = 8) were randomly allocated to control or DMCA groups. Motor function was evaluated with the tests: grip force, rotarod and open field; and nociceptive threshold with von Frey and hot plate assessments. Cognitive function was evaluated with the inhibitory avoidance test, and mood with the tail suspension test. Evaluations were conducted on the seventh- and twenty-eighth-day post DMCA occlusion to assess medium- and long-term effects of the injury, respectively. DMCA occlusion significantly decreases muscle strength and spontaneous locomotion (p < 0.05) both medium- and long term; as well as increases immobility in the tail-suspension test (p < 0.05), suggesting a depressive-type behavior. However, DMCA occlusion did not affect nociceptive threshold nor cognitive functions (p > 0.05). These results suggest that, medium- and long-term effects of DMCA occlusion include motor function impairments, but no sensory dysfunction. Additionally, the injury affected mood but did not hinder cognitive function.

Prophylactic effect of physical exercise on Aß1-40-induced depressive-like behavior and gut dysfunction in mice.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease that is highly comorbid with depression. Gut dysfunction has been proposed as a possible risk factor for both clinical conditions. In the present study, we investigated the ability of treadmill exercise for 4 weeks (5 days/week, 40 min/day) to counteract amyloid ß1-40 peptide (Aß1-40)-induced depressive-like behavior, alterations in morphological parameters of the duodenum, and the abundance of Firmicutes and Bacteroidetes phyla. Aß1-40 administration (400 pmol/mouse, i.c.v.) increased immobility time in the tail suspension test (TST) and reduced time spent sniffing in the female urine sniffing test (FUST), indicating behavioral despair and impairment in reward-seeking behavior. These behavioral alterations, indicative of depressive-like behavior, were accompanied by reduced villus width in the duodenum. Moreover, photomicrographs obtained by transmission electron microscopy revealed abnormal epithelial microvilli in the duodenum from sedentary Aß1-40-exposed mice, characterized by shorter microvilli and heterogeneity in the length of these structures that exhibit a disordered packing. Regarding the ultrastructure of Paneth cells, Aß1-40 administration caused a reduction in the secretory granule diameter, as well as an enlarged peripheral halo. These animals also presented reduced Firmicutes and increased Bacteroidetes abundance, and increased Bacteroidetes/Firmicutes ratio. Most of the alterations observed in Aß1-40-exposed mice were prevented by the practice of physical exercise. Altogether the results provide evidence of the prophylactic effect of physical exercise on Aß1-40-induced depressive-like behavior and gut dysfunction in mice, suggesting that physical exercise could be useful for preventing depression associated with AD.

Transfer of the Distal Anterior Interosseous Nerve for Thumb Motion Reconstruction in Radial Nerve Paralysis.

PURPOSE: With nerve or tendon surgery, the results of thumb reconstruction to treat radial nerve paralysis are suboptimal. The goals of this study were to describe the anatomy of the deep branch of the posterior interosseous nerve (PIN) to the thumb extensor muscles (DBPIN), and to report the clinical results of transferring the distal anterior interosseous nerve (DAIN) to the DBPIN. METHODS: The PIN was dissected in 12 fresh upper limbs. Myelinated nerve fibers in the DBPIN and DAIN were counted. Five patients with radial nerve paralysis underwent transfer of the motor branch to the flexor carpi radialis to the PIN and a motor branch of the pronator teres to the extensor carpi radialis brevis. In addition, these patients had selective reconstruction of thumb motion by transferring the DAIN to the DBPIN, through either a combined volar and dorsal approach (n = 2) or a single dorsal approach (n = 3) with division of the interosseous membrane. RESULTS: At the origin of the abductor pollicis longus, the DBPIN divided into a lateral branch that innervated the abductor pollicis longus and extensor pollicis brevis, and a medial branch that innervated the extensor pollicis longus and extensor index proprius. The number of myelinated nerve fibers in the DAIN corresponded to 65% of that of the DBPIN. In each of the 5 patients, full thumb motion at the trapeziometacarpal joint was restored with no, or minimal, extension lag at the metacarpophalangeal (MCP) joint. CONCLUSIONS: The anatomy of the DBPIN is predictable. Transferring the DAIN to the DBPIN is feasible through a single dorsal approach, allowing full recovery of thumb motion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Distal pronator teres motor branch transfer for wrist extension restoration in radial nerve paralysis.

OBJECTIVE: The authors describe the anatomy of the motor branches of the pronator teres (PT) as it relates to transferring the nerve of the extensor carpi radialis brevis (ECRB) to restore wrist extension in patients with radial nerve paralysis. They describe their anatomical cadaveric findings and report the results of their nerve transfer technique in several patients followed for at least 24 months postoperatively. METHODS: The authors dissected both upper limbs of 16 fresh cadavers. In 6 patients undergoing nerve surgery on the elbow, they dissected the branches of the median nerve and confirmed their identity by electrical stimulation. Of these 6 patients, 5 had had a radial nerve injury lasting 7-12 months, underwent transfer of the distal PT motor branch to the ECRB, and were followed for at least 24 months. RESULTS: The PT was innervated by two branches: a proximal branch, arising at a distance between 0 and 40 mm distal to the medial epicondyle, responsible for PT superficial head innervation, and a distal motor branch, emerging from the anterior side of the median nerve at a distance between 25 and 60 mm distal to the medial epicondyle. The distal motor branch of the PT traveled approximately 30 mm along the anterior side of the median nerve; just before the median nerve passed between the PT heads, it bifurcated to innervate the deep head and distal part of the superficial head of the PT. In 30% of the cadaver limbs, the proximal and distal PT branches converged into a single trunk distal to the medial epicondyle, while they converged into a single branch proximal to it in 70% of the limbs. The proximal and distal motor branches of the PT and the nerve to the ECRB had an average of 646, 599, and 457 myelinated fibers, respectively.All patients recovered full range of wrist flexion-extension, grade M4 strength on the British Medical Research Council scale. Grasp strength recovery achieved almost 50% of the strength of the contralateral side. All patients could maintain their wrist in extension while performing grasp measurements. CONCLUSIONS: The distal PT motor branch is suitable for reinnervation of the ECRB in radial nerve paralysis, for as long as 7-12 months postinjury.

Correction to: Electroacupuncture induces antihyperalgesic effect through endothelin-B receptor in the chronic phase of a mouse model of complex regional pain syndrome type I.

The original version of this article contains an error. The Author Francisco José Cidral-Filho incorrectly listed as Francisco José Cidra-Filho. The correct spelling is presented above. The original article has been corrected.

Antidepressant Effects of Probucol on Early-Symptomatic YAC128 Transgenic Mice for Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HD gene, resulting in an extended polyglutamine tract in the protein huntingtin. HD is traditionally viewed as a movement disorder, but cognitive and neuropsychiatric symptoms also contribute to the clinical presentation. Depression is one of the most common psychiatric disturbances in HD, present even before manifestation of motor symptoms. Diagnosis and treatment of depression in HD-affected individuals are essential aspects of clinical management in this population, especially owing to the high risk of suicide. This study investigated whether chronic administration of the antioxidant probucol improved motor and affective symptoms as well as hippocampal neurogenic function in the YAC128 transgenic mouse model of HD during the early- to mild-symptomatic stages of disease progression. The motor performance and affective symptoms were monitored using well-validated behavioral tests in YAC128 mice and age-matched wild-type littermates at 2, 4, and 6 months of age, after 1, 3, or 5 months of treatment with probucol (30 mg/kg/day via water supplementation, starting on postnatal day 30). Endogenous markers were used to assess the effect of probucol on cell proliferation (Ki-67 and proliferation cell nuclear antigen (PCNA)) and neuronal differentiation (doublecortin (DCX)) in the hippocampal dentate gyrus (DG). Chronic treatment with probucol reduced the occurrence of depressive-like behaviors in early- and mild-symptomatic YAC128 mice. Functional improvements were not accompanied by increased progenitor cell proliferation and neuronal differentiation. Our findings provide evidence that administration of probucol may be of clinical benefit in the management of early- to mild-symptomatic HD.

Electroacupuncture induces antihyperalgesic effect through endothelin-B receptor in the chronic phase of a mouse model of complex regional pain syndrome type I.

Complex regional pain syndrome (CRPS) is a disorder that involves abnormal inflammation and nerve dysfunction frequently resistant to a broad range of treatments. Peripheral nerve stimulation with electroacupuncture (EA) has been widely used in different clinical conditions to control pain and inflammation; however, the use of EA in the treatment of CRPS is under investigation. In this study, we explore the effects of EA on hyperalgesia and edema induced in an animal model of chronic post-ischemia pain (CPIP model) and the possible involvement of endothelin receptor type B (ETB) in this effect. Female Swiss mice were subjected to 3 h hind paw ischemia/reperfusion CPIP model. EA treatment produced time-dependent inhibition of mechanical and cold hyperalgesia, as well as edema in CPIP mice. Peripheral administration (i.pl.) of BQ-788 (10 nmol), an ETB antagonist, prevented EA-induced antihyperalgesia while intrathecal administration prolonged EA's effect. Additionally, peripheral pre-treatment with sarafotoxin (SRTX S6c, 30 pmol, ETB agonist) increased EA anti-hyperalgesic effect. Furthermore, the expression of peripheral ETB receptors was increased after EA treatments, as measured by western blot. These results may suggest that EA's analgesic effect is synergic with ETB receptor activation in the periphery, as well as central (spinal cord) ETB receptor blockade. These data support the use of EA as a nonpharmacological approach for the management of CRPS-I, in an adjuvant manner to ETB receptor targeting drugs.

Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats.

In this study, we used an experimental model of congenital hypothyroidism to show that deficient thyroid hormones (TH) disrupt different neurochemical, morphological and functional aspects in the cerebral cortex of 15-day-old offspring. Our results showing decreased glutamine synthetase (GS) activity and Ca2+ overload in the cerebral cortex of hypothyroid pups suggest misregulated glutamate metabolism associated with developmentally induced TH deficiency. The 14C-MeAIB accumulation indicates upregulated System A activity and glutamine uptake by neurons. Energy metabolism in hypothyroid cortical slices was preserved, as demonstrated by unaltered glucose metabolism. We also found upregulated acetylcholinesterase activity, depleting acetylcholine from the synaptic cleft, pointing to disrupted cholinergic system. Increased reactive oxygen species (ROS) generation, lipid peroxidation, glutathione (GSH) depletion, which were associated with glutathione peroxidase, superoxide dismutase and gamma-glutamyltransferase downregulation suggest redox imbalance. Disrupted astrocyte cytoskeleton was evidenced by downregulated and hyperphosphorylated glial fibrillary acidic protein (GFAP). Morphological and structural characterization of the sensorimotor cerebral cortex (SCC) showed unaltered thickness of the SCC. However, decreased size of neurons on the layers II & III and IV in the right SCC and increased NeuN positive neurons in specific SCC layers, suggest that they are differently affected by the low TH levels during neurodevelopment. Hypothyroid pups presented increased number of foot-faults in the gridwalk test indicating affected motor functions. Taken together, our results show that congenital hypothyroidism disrupts glutamatergic and cholinergic neurotransmission, Ca2+ equilibrium, redox balance, cytoskeleton integrity, morphological and functional aspects in the cerebral cortex of young rats.

Studying the relationship between a woman's reproductive lifespan and age at menarche using a Bayesian multivariate structured additive distributional regression model.

Studies addressing breast cancer risk factors have been looking at trends relative to age at menarche and menopause. These studies point to a downward trend of age at menarche and an upward trend for age at menopause, meaning an increase of a woman's reproductive lifespan cycle. In addition to studying the effect of the year of birth on the expectation of age at menarche and a woman's reproductive lifespan, it is important to understand how a woman's cohort affects the correlation between these two variables. Since the behavior of age at menarche and menopause may vary with the geographic location of a woman's residence, the spatial effect of the municipality where a woman resides needs to be considered. Thus, a Bayesian multivariate structured additive distributional regression model is proposed in order to analyze how a woman's municipality and year of birth affects a woman's age of menarche, her lifespan cycle, and the correlation of the two. The data consists of 212,517 postmenopausal women, born between 1920 and 1965, who attended the breast cancer screening program in the central region of Portugal.

Hydroalcoholic crude extract of Casearia sylvestris Sw. reduces chronic post-ischemic pain by activation of pro-resolving pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Casearia sylvestris Sw. is widely used in popular medicine to treat conditions associated with pain. AIM OF THE STUDY: The present study investigated the influence of hydroalcoholic crude extract of Casearia sylvestris (HCE-CS) and contribution of pro-resolving mediators on mechanical hyperalgesia in a mouse model of chronic post-ischemia pain (CPIP). METHODS AND RESULTS: Male Swiss mice were subjected to ischemia of the right hind paw (3h), then reperfusion was allowed. At 10min, 24h or 48h post-ischemia/reperfusion (I/R), different groups of animals were treated with HCE-CS (30mg/Kg, orally [p.o]), selected agonists at the pro-resolving receptor ALX/FPR2 (natural molecules like resolvin D1 and lipoxin A4 or the synthetic compound BML-111; 0.1-1µg/animal) or vehicle (saline, 10mL/Kg, s.c.), in the absence or presence of the antagonist WRW4 (10µg, s.c.). Mechanical hyperalgesia (paw withdrawal to von Frey filament) was asseseed together with histological and immunostainning analyses. In these settings, pro-resolving mediators reduced mechanical hyperalgesia and HCE-CS or BML-111 displayed anti-hyperalgesic effects which was markedly attenuated in animals treated with WRW4. ALX/FPR2 expression was raised in skeletal muscle or neutrophils after treatment with HCE-CS or BML-111. CONCLUSION: These results reveal significant antihyperalgesic effect of HCE-CS on CPIP, mediated at least in part, by the pathway of resolution of inflammation centred on the axis modulated by ALX/FPR2.

Diacerein reduces joint damage, pain behavior and inhibits transient receptor potential vanilloid 1, matrix metalloproteinase and glial cells in rat spinal cord.

AIM: To investigate the antinociceptive, antiedematogenic and chondroprotective effects of diacerein (DIA) in a model of joint inflammation induced by complete Freund's adjuvant (CFA), as well as to investigate the involvement of metalloproteinase (MMP)-9, transient receptor potential vanilloid 1 (TRPV1) and glial cells in DIA's action mechanism. METHODS: Complete Freund's adjuvant was injected into the knee joint of male rats. We observed mechanical and cold hypersensitivity, vocalization and spontaneous pain-related behaviors, as well as edema of the knee. Tissue samples of the knee were stained with Cason`s technique and the thickness of the condilus cartilage was measured. Immunohistochemical analysis was performed on the spinal cord using anti-GFAP (glial fibrillary acidic protein), anti-MMP and anti-TRPV1 antibodies. Sections of the dorsal horns of the spinal cord were captured and an optical density was obtained. RESULTS: Complete Freund's adjuvant induced mechanical and thermal hypersensitivity, as well as joint edema and changes in the synovial membrane and cartilage. DIA (30 mg/kg, orally, daily) significantly inhibited mechanical (58 ± 10-87 ± 3%) and thermal (66 ± 12-87 ± 8%) hypersensitivity, vocalization (83 ± 5-41 ± 11%), spontaneous pain score, joint swelling (60 ± 6-40 ± 9%), as well as the histological changes induced by CFA. In addition, DIA inhibited astrocyte activation, and prevented the increase of MMP-9 and TRPV1 expression in the spinal cord of the animals subjected to CFA injections. CONCLUSIONS: In short, this study shows that DIA reduces joint damage and hypersensitivity associated with inflammation induced by CFA through the inhibition of astroglial activation and decreases the expression of TRPV1 and MMP-9 in the rat spinal cord.

Intervention with the mother-infant relationship reduces cell proliferation in the Locus Coeruleus of female rat pups.

The Locus Coeruleus (LC) is a noradrenergic nucleus involved in several neuroendocrine and behavioral functions. During the neonatal period, the LC is critical for olfactory learning. Full development occurs during the early postnatal period. Environmental interventions after birth may affect neurogenesis. In rats, the neonatal handling procedure has been used as a model to analyze the effects of environmental intervention early in life. It has been related to several long-lasting behavioral and neuroendocrine changes. The present study analyzed the effects of handling on the number of neurons, cellular proliferation, and apoptosis in the LC of 11-day-old female rats. Wistar rat pups were submitted to brief maternal separation followed by handling (1 min per day from postnatal day [PND] 1 to 10). On PND 11, the LC was analyzed using immunohistochemistry for NeuN and BrdU, TUNEL staining, and electron microscopy. The intervention reduced the number of neurons in the LC but showed no significant change in the number of apoptotic cells, as measured by the TUNEL technique. However, the number of proliferating cells was significantly lower in the handled rat pups as compared with the nonhandled ones. This study demonstrates that the infant LC is sensitive to changes in maternal behavior. A seemingly mild environmental intervention during the neonatal period may reprogram the development of the LC, altering cell proliferation. (PsycINFO Database Record

Neonatal hypoxic-ischemic encephalopathy reduces c-Fos activation in the rat hippocampus: evidence of a long-lasting effect.

The effect of neonatal hypoxic-ischemic encephalopathy (HIE) on maturation of nociceptive pathways has been sparsely explored. To investigate whether neonatal HIE alters neuronal activity, nociceptive behavior, and serum neuroplasticity mediators (brain-derived neurotrophic factor [BDNF] and tumor necrosis factor-α [TNF]) in the short, medium, and long term. Neonate male Wistar rats were randomized to receive a brain insult that could be either ischemic (left carotid artery ligation [LCAL]), hypoxic (8% oxygen chamber), hypoxic-ischemic (LCAL and hypoxic chamber), sham-ischemic, or sham-hypoxic. Neuronal activity (c-Fos activation at region CA1 and dentate gyrus of the hippocampus), nociceptive behavior (von Frey, tail-flick, and hot-plate tests), neuroplasticity mediators (BDNF, TNF), and a cellular injury marker (lactase dehydrogenase [LDH]) were assessed in blood serum 14, 30, and 60 days after birth. Neonatal HIE persistently reduced c-Fos activation in the ipsilateral hippocampal region CA1; however, contralateral c-Fos reduction appeared only 7 weeks after the event. Neonatal HIE acutely reduced the paw withdrawal threshold (von Frey test), but this returned to normal by the 30th postnatal day. Hypoxia reduced serum LDH levels. Serum neuroplasticity mediators increased with age, and neonatal HIE did not affect their ontogeny. Neonatal HIE-induced reduction in neuronal activity occurs acutely in the ipsilateral hippocampal region CA1 and persists for at least 60 days, but the contralateral effect of the insult is delayed. Alterations in the nociceptive response are acute and self-limited. Serum neuroplasticity mediators increase with age, and remain unaffected by HIE.

Histopathology of motor cortex in an experimental focal ischemic stroke in mouse model.

Experimental ischemia results in cortical brain lesion followed by ischemic stroke. In this study, focal cerebral ischemia was induced in mice by occlusion of the middle cerebral artery. We studied cortical layers I, II/III, V and VI in the caudal forelimb area (CFA) and medial agranular cortex (AGm) from control and C57BL/6 mice induced with ischemic stroke. Based on our analysis of CFA and AGm motor cortex, significant differences were observed in the numbers of neurons, astrocytes and microglia in the superficial II/III and deep V cortical layers. Cellular changes were more prominent in layer V of the CFA with nuclear pyknosis, chromatin fragmentation, necrosis and degeneration, as well as, morphological evidence of apoptosis, mainly in neurons. As result, the CFA was more severely impaired than the AGm in this focal cerebral ischemic model, as evidenced by the proliferation of astrocytes, potentially resulting in neuroinflammation by microglia-like cells.