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Ageism refers to prejudice, stereotypes or discrimination based on a person's actual or perceived chronological age. While ageism can affect people at all stages of the human lifespan, ageism against older adults has emerged as the most pervasive and potentially harmful. Much is now understood about how ageism can impact older people's health and wellbeing via structural, organisational, and provider level biases that threaten the provision of equitable and ethical healthcare. Negative attitudes about age and ageing also contribute to workforce shortages in aged care sectors, such as residential aged care and nursing. However, often underappreciated is how self-directed ageism, which refers to ageism turned against oneself, can also be an important determinant of health and wellbeing. Relative to external sources of ageism, negative internalised ageist beliefs are not only experienced more frequently in older adults' everyday lives, but are also more strongly linked to their health and wellbeing. Here we highlight how this understanding means that eliminating ageism requires a multifaceted approach that targets not only health care systems and aged care professionals, but older people themselves. Because normal age-related cognitive changes in how we think, perceive and reason increase the risk of older people viewing themselves through a negative and ageist lens, we provide a novel discussion of how broader insights from cognitive ageing literature must play a central role in any agenda focused on breaking the links between ageism and health., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Multiple sclerosis (MS) is a leading cause of neurological disability in young and middle-aged populations, associated with substantial burden of illness. Because a growing literature now shows that this burden extends to poorer oral health, oral health-related quality of life (OHRQoL) may be reduced as well., Objectives: To test whether people with relapsing-remitting MS (RRMS) have poorer OHRQoL than demographically matched controls, and to establish which variables are associated with worse OHRQoL., Materials and Methods: In total, 64 people with RRMS and 69 demographically matched controls participated. Both groups completed the Oral Health Impact Profile (OHIP-14), a validated measure of OHRQoL, as well as an objective oral health examination performed by a qualified dentist, a measure of dental-related functionality and a measure of mental health., Results: OHRQoL was significantly poorer in the RRMS relative to the control group. However, although poorer OHRQoL in the RRMS group was moderately associated with objectively assessed oral health (r = .30), it was more strongly associated with mental health (r = .61). For the control group, the reverse pattern of association was evident, with OHRQoL more strongly associated with oral health (r = .48) relative to mental health (r = .20)., Conclusion: People with RRMS report poorer OHRQoL than demographically matched controls, but these appraisals are more strongly linked to mental health than to objective oral health indicators., (© 2022 The Authors. Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

Background: Oral health is often poorer in people living with acquired brain injury relative to non-clinical controls. However, although anxiety disorders become more common following stroke, no study to date has tested whether dental anxiety might contribute to stroke survivors' increased vulnerability to poorer oral health. This pilot study reports the first test of whether the anxiety disturbances that commonly present following stroke extend to dental anxiety, and if dental anxiety in this group is linked to poorer oral health., Materials and Methods: First-time stroke survivors (N = 35) and demographically matched controls (N = 35) completed validated measures of dental anxiety, oral health, negative affect, and life satisfaction., Results: Stroke survivors did not differ from controls in their overall levels of dental anxiety or oral health, but uniquely for the stroke group, dental anxiety was strongly associated with poorer oral health, and this effect remained significant even after controlling for negative affect and life satisfaction., Conclusion: Stroke survivors who have higher levels of dental-related anxiety may be at increased risk of poorer oral health., (© 2022. The Author(s).)

Background: Growing evidence suggests that there is an association between poor oral health and cognitive function in late adulthood. However, most studies to date have relied on cross-sectional research methods that do not permit inferences about the temporality of any association. Moreover, the few longitudinal studies that do exist have typically relied on small samples and quite limited cognitive or oral health assessments. The aim of the present study was therefore designed to provide the first direct evaluation of whether cognitive function is predictive of poor oral health in older adults., Methods: This longitudinal research included data from 339 participants aged 70 years or older from The Sydney Memory and Ageing Study (MAS), a large cohort of healthy community-dwelling older adults. Cognitive function was assessed using a battery of tests at baseline (Wave 1) in 2005 and six years later (Wave 4) in 2011. In 2015 (Wave 6), participants were assessed for oral health using the Oral Health Assessment Tool (OHAT), number of functional occluding pairs of natural teeth and sublingual resting saliva pH (SRSpH). Ordinal least squares regression analysis was used to model the effect of cognitive function on total OHAT score, and binomial logistic regression used for SRSpH and occluding pairs of functional teeth., Results: Two models were tested. In the partially adjusted model, age, gender and years of education were included. The fully adjusted model additionally included medical conditions, general health, depression, smoking, alcohol consumption, functionality, and dental care utilization. The key finding to emerge was that a six-year change in memory (from Wave 1 to Wave 4) was associated with lower sublingual resting saliva pH at Wave 6 in partially (Odds Ratio (OR) = 0.65) and fully adjusted model (OR = 0.63)., Conclusions: This longitudinal study provides further evidence that a relationship between cognitive function and oral health exists, and also points to this relationship potentially being bi-directional, as previous evidence suggests. The findings from the study also suggest that older adults who present with greater than normal memory decline at an earlier point in life were more likely to experience poor oral health when this was evaluated at a later time-point, four years later., (© 2022. The Author(s).)

Objectives: Multiple sclerosis (MS) is often associated with reduced cognitive function, and there is also emerging evidence of a heightened vulnerability to oral health problems. However, although links between cognitive function and oral health have been identified in other special populations, it remains to be established whether this relationship is also evident for people with MS. The aim of this study was to provide the first empirical test of whether there is a relationship between cognitive function and oral health in people diagnosed with relapsing-remitting multiple sclerosis (RRMS)., Methods: One hundred and eleven individuals were evaluated: 56 people diagnosed with RRMS and 55 demographically matched healthy controls. All participants completed an objective oral health assessment as well as a standardized battery that assessed six distinct neurocognitive domains., Results: Relative to controls, people with RRMS presented with higher rates of decayed teeth and mild gingivitis, and also performed more poorly in three of the six neurocognitive domains assessed (language, complex attention, and executive function). However, for the RRMS group, no associations emerged between oral health with performance on any of the six neurocognitive domains., Conclusions: These data cross-validate previous research which shows people with RRMS are more likely to present with both reduced cognitive function and poorer oral health, but also extends this literature in a meaningful way by additionally showing for the first time that these clinical features are unrelated in RRMS., Clinical Relevance: The findings emphasize the need for early assessment of both oral health and cognitive function in people with RRMS so that appropriate interventions and support can be put in place for each of these clinical symptoms., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Episodic foresight refers to the ability to imagine future scenarios and to then use this imaginative capacity to guide future-directed behavior. Multiple sclerosis (MS) is associated with deficits generating the phenomenological characteristics of future events (the imaginative component of episodic foresight), but no study to date has tested whether MS is also associated with deficits using episodic foresight to appropriately guide future-directed behavior., Method: Forty people with relapsing-remitting MS (RRMS) and 40 demographically matched healthy participants completed a validated measure that met strict criteria for assessing the functional application of episodic foresight, Virtual-Week Foresight (VW-Foresight)., Results: Overall, people with RRMS did not differ significantly relative to comparison participants in how likely they were to spontaneously acquire items that would later allow a problem to be solved and were also just as likely to subsequently use these items to solve the problem. However, the latter group difference was large in magnitude and just failed to attain significance. Higher levels of depression were significantly related to performance on this same "use" component of foresight in the RRMS group, and depressed RRMS participants were significantly impaired in this aspect of foresight relative to both healthy participants and nondepressed RRMS participants. The depressed MS subgroup also differed from the nondepressed subgroup in their ability to perform instrumental activities of daily living., Conclusions: People with RRMS who present with heightened levels of depressive symptomatology also appear to be at greater risk of experiencing specific problems with episodic foresight. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background: Most evidence now indicates that cognitive function is related to poorer oral health in late adulthood, but that this relationship is not invariant across specific cognitive domains. Prospective memory (PM) is a core memory skill that refers to memory for future intentions and is known to be related to the formation of habits such as tooth flossing. However, the relationship between PM and oral health has been subject to only limited empirical study., Objective: The two studies reported in this paper were designed to test whether PM is related to oral health in older adults of varying vulnerability status., Methods: Study 1 sampled community-dwelling older adults (N = 172) living independently in the community; Study 2 sampled older adults living in a retirement village (N = 32). Participants in both studies were asked to complete a behavioural measure of PM, with their oral health indexed via self-report (Study 1) or an objective oral health exam (Study 2)., Results: In both studies, relationships emerged between event-based PM and oral health, with Study 2 showing that these relationships were specific to oral health measures of plaque and calculus., Conclusions: Older adults are particularly vulnerable to dental pathology, with important implications for their broader health and well-being. By showing that there is a relationship between oral health and a particular type of PM, this work will have potential implications for the development of more effective interventions focused on enhancing oral health outcomes in this group, such as those focused on strengthening habit formation., (© 2021 S. Karger AG, Basel.)

Objectives: Despite more than 25 years of research focused on this topic, it remains unclear whether people with multiple sclerosis are more likely to present with oral health problems. The aim of this study was to provide the first systematic review of this literature., Methods: A literature search for studies focused on oral health and multiple sclerosis was conducted using PRISMA guidelines. Electronic databases (PubMed, Scopus, Web of Science, MEDLINE and CINAHL) were searched up until February 2019. Two independent coders extracted data, and study quality graded using the Newcastle-Ottawa Scale (NOS)., Results: From 1281 articles identified, 17 met all the eligibility criteria. Of the seventeen studies, more than half included a nonclinical control group, and the majority were observational studies. The included studies were of poor to moderate quality. Taken together, the results provided only very limited evidence that people with multiple sclerosis are more likely to present with dental caries and gingival disease. There was suggestive evidence that people with multiple sclerosis may be at higher risk of periodontal disease and present with poorer oral hygiene, and moderate evidence for an association between multiple sclerosis and temporomandibular disorders., Conclusions: This systematic review provides evidence of an association between multiple sclerosis and at least some oral health problems. When temporomandibular disorders and periodontal status specifically have been assessed, most studies provide evidence of an association with multiple sclerosis. However, this review also clearly highlights the need for further, high-quality studies in this area., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose of Review: This article provides an overview of current literature focused on oral health and cognitive impairment in older adulthood, focusing in particular on whether oral inflammation, tooth loss and masticatory dysfunction might increase the risk of cognitive impairment in this age group., Recent Findings: There is now general acceptance that cognitive impairment contributes to poor oral health, largely through detrimental changes in behaviours related to maintaining good oral hygiene. There is more limited evidence for the reverse causal direction, but at least some studies now suggest that inflammatory mechanisms, tooth loss and masticatory dysfunction each have the potential to contribute to cognitive decline., Summary: Poorer oral health significantly correlates with cognitive dysfunction, and at least some studies suggest that there may be a bi-directional causal relationship. Randomized controlled trials assessing cognitive abilities in relation to oral hygiene or oral health interventions, or provision of removable or fixed (implant-supported) dentures, are encouraged.

Introduction Dentists are frequently exposed to occupational stressors, including emotionally tense interactions with patients who are experiencing pain, anxiety and fear. Unsurprisingly, dentists are also a group that experience particularly high levels of occupational burnout. The present study provides the first empirical test of whether occupational burnout is higher, and general wellbeing is lower, for dental practitioners and students who have greater difficulties managing their own emotions (emotion dysregulation) and detecting and interpreting social cues from others (social cognitive difficulties).Materials and methods Ninety-six dental practitioners and 54 dental students completed validated measures of emotion regulation, social cognitive function, occupational burnout and wellbeing.Results Consistent with broader literature, rates of burnout were significantly higher in both dental practitioners and students, relative to normative standards. Importantly, the results also identified significant associations between rates of burnout with both emotion dysregulation, as well as one of the measures of social cognitive function: the empathic disposition to experience discomfort in response to the distress of others (personal distress). Ratings of emotion dysregulation and personal distress were also significantly higher for dental students relative to practitioners.Conclusion These data highlight the importance of being able to effectively manage difficult emotions in the dental practice.

Emotional stimuli, such as facial expressions, reliably evoke rapid, spontaneous and covert facial reactions in the perceiver that reflect the affective valence of the observed stimulus. These physiological reactions have been linked to a variety of social cognitive processes known to be disrupted in schizophrenia, such as emotion recognition and affective empathy. Moreover, individuals with schizophrenia exhibit atypical rapid facial reactions when observing emotional expressions. The current study aimed to determine if the disruption in schizophrenia is specific to facial expressions, or instead reflects more generalised emotional or motor impairments in the elicitation of this rapid facial response. Here we quantified activity in the corrugator supercilii and zygomaticus major muscle regions using electromyography while individuals with schizophrenia (n = 24) and controls (n = 21) viewed images of facial and non-facial emotional stimuli. The results indicate that schizophrenia is marked by a disruption in rapid facial responding to facial expressions, but intact responding to non-facial emotional stimuli. This dissociation between the processing of facial and non-facial emotional stimuli points to the need for a greater understanding of the degree to which facial emotion processing impairments contribute to disruptions in mimetic responding in this population., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: It has often been argued that there is a relationship between oral health and cognitive decline in late adulthood, but a recent systematic review concluded that it was unclear "how or whether" any relationship exists. However, most of the studies that contributed to this review operationalised cognitive function using a brief cognitive screen and/or dementia status., Objective: An updated systematic review was conducted that focused on how oral health relates to specific cognitive abilities in older adults (specifically, the neurocognitive domains specified in the DSM-5: learning and memory, perceptual motor function, language, executive function, complex attention, and social cognition)., Methods: A systematic review was undertaken and completed in August 2018. From a total of 1,304 potentially relevant articles, 23 were identified that assessed oral health and at least one of the specific cognitive domains in an older adult cohort., Results: The most consistent relationships were identified with learning and memory, complex attention, and executive function. For each of these cognitive domains, most studies identified significant unadjusted associations with oral health; where adjustments for covariates were made, at least one of the associations with oral health remained significant in half or more of the studies. Results were less clear for the domains of language and perceptual motor function. No study assessed the relationship between social cognition and oral health., Conclusions: This systematic review provides evidence of an association between learning and memory, complex attention, and executive function with oral health in old age. Gaining a detailed picture of how specific types of cognitive decline relate to oral health has potential implications for earlier identification of older adults who experience oral health problems, and may also inform the development of more effective interventions focused on enhancing oral health outcomes in this group., (© 2019 S. Karger AG, Basel.)

It has been suggested that an age-related positivity effect may only occur in the context of explicit information processing, but it is unclear whether this bias extends to the processing of rapid facial reactions. In addition, most studies that have looked for evidence of age-related implicit positivity have used attentional (as opposed to sensory) unawareness paradigms, or used broad-based indicators of attentional awareness that do not speak to the nature of the affective response. In the present study, younger and older adults were therefore asked to view non-facial images presented supraliminally (i.e., consciously) as well as outside of sensory awareness (i.e., subliminally) while their facial reactions were indexed using electromyography. The results indicated that both younger and older adults exhibited rapid facial reactions congruent with the emotional valence of non-facial images in both supraliminal and subliminal conditions. Relative to young, older adults did not respond with greater zygomaticus (cheek) activity to positive stimuli or reduced corrugator (brow) activity to negative stimuli in either condition. These data show that rapid facial reactions to emotional stimuli are intact in late adulthood, even in response to stimuli that activate more automatic and implicit forms of emotion processing. However, there is no evidence for any age-related positivity bias in these behavioral responses.

Objectives: It remains unclear whether there are age-related changes in the experience of strong self-conscious emotion, such as shame, guilt, pride and embarrassment. Because shame and guilt figure prominently in the aetiology of depressive symptoms and other mental health problems, a better understanding of how age affects the strong experience of these two negative self-conscious emotions is of particular importance., Methods: Thirty younger, 30 middle-aged and 30 older adults were compared on standardised cognitive assessments, in addition to an interview-based measure that assessed whether there are age differences in the likelihood of strongly experiencing four different types of self-conscious emotion within the past five years (shame, guilt, embarrassment and pride)., Results: The three groups did not differ in their likelihood of reporting an event that strongly elicited the positive self-conscious emotion of pride. However, older adults were more likely to report sources of pride that were other (as opposed to self) focused. Older adults were also less likely to report experiencing events that elicited all three negative self-conscious emotions, in particular, shame., Conclusions: Strong negative self-conscious emotion, and in particular shame, appears to be experienced less by older than younger adults.

The prototypical neurotrophin, nerve growth factor (NGF), plays an important role in the development and maintenance of many neurons in both the central and peripheral nervous systems, and can promote functional recovery after peripheral nerve injury in adulthood. However, repair of peripheral nerve defects is hampered by the short half-life of NGF in vivo, and treatment with either NGF alone or NGF contained in synthetic nerve conduits is inferior to the use of nerve autografts, the current gold standard. We tested the reparative ability of a single local injection of a polyvalent coacervate containing polycation-poly(ethylene argininylaspartate diglyceride; PEAD), heparin, and NGF, in adult rats following sciatic nerve crush injury, using molecular, histological and behavioral approaches. In vitro assays demonstrated that NGF was loaded into the coacervate at nearly 100% efficiency, and was protected from proteolytic degradation. In vivo, the coacervate enhanced NGF bioavailability, leading to a notable improvement in motor function (track walking analysis) after 30days. The NGF coacervate treatment was also associated with better weight gain and reduction in atrophy of the gastrocnemius muscle. Furthermore, light and electron microscopy showed that the number of myelinated axons and axon-to-fiber ratio (G-ratio) were significantly higher in NGF coacervate-treated rats compared with control groups. Expression of markers of neural tissue regeneration (MAP-2, S-100β, MBP and GAP-43), as well as proliferating Schwann cells and myelin-axon relationships (GFAP and NF200), were also increased. These observations suggest that even a single administration of NGF coacervate could have therapeutic value for peripheral nerve regeneration and functional recovery., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The nerve growth factor (NGF) precursor, proNGF, is implicated in various neuropathological states. ProNGF signals apoptosis by forming a complex with the receptors p75 and sortilin, however, it can also induce neurite growth, proposed to be mediated by the receptor of mature NGF, tyrosine kinase receptor A (TrkA). The way in which these dual effects occur in adult neurons is unclear. We investigated the neurotrophic effects of proNGF on peptidergic sensory neurons isolated from adult mouse dorsal root ganglia and found that proNGF stimulated neurite extension and branching, requiring p75, sortilin and TrkA. Neurite growth rarely occurred in sortilin-expressing neurons but was commonly observed in TrkA-positive, sortilin-negative neurons that associated closely with sortilin-positive glia. ProNGF was unable to induce local trophic effects at growth cones where sortilin-positive glia was absent. We propose that in adult sensory neurons the neurotrophic response to proNGF is mediated by NGF and TrkA, and that peri-somatic glia may participate in sortilin- and p-75 dependent cleavage of proNGF. The potential ability of local glial cells to provide a targeted supply of NGF may provide an important way to promote trophic (rather than apoptotic) outcomes under conditions where regeneration or sprouting is required., (© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

Although general emotion coping difficulties are well documented in schizophrenia, there has been limited study of specific regulatory strategies such as suppression, reappraisal, and acceptance. In the present study, clinical and control participants were asked to watch video clips selected to elicit negative affect while engaging in one of these three different emotion regulation strategies (counterbalanced), versus a passive viewing condition. The experiential and expressive components of emotion were quantified using self-report and facial electromyography, respectively. A major finding was that, in contrast to control participants, individuals with schizophrenia did not report a greater willingness to reexperience negative emotion after engaging in acceptance. These data are discussed in the context of evidence highlighting the potentially important role of acceptance in understanding affective abnormalities in clinical conditions such as schizophrenia.

Introduction: Activation of the DNA repair enzyme, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), in response to hyperglycemia-driven oxidative/nitrosative stress, may be an important mechanism in the development of vascular and neural complications in diabetes mellitus. However, a role for PARP in diabetic erectile dysfunction (ED) has not been demonstrated., Aim: To assess whether treatment with a novel PARP-1 inhibitor, GPI 15427, could improve neurovascular dysfunction in corpus cavernosum (CC) from diabetic mice., Methods: Diabetes was induced by streptozotocin in male MF1 mice; duration was 6 weeks. Intervention GPI 15427 treatment (20mg/kg/day intraperitoneal [i.p.]) was given for 2 weeks following 4 weeks of untreated diabetes. CC strips were mounted in aerated organ baths for measurement of pharmacological or electrical stimulation-evoked changes in smooth muscle tension., Main Outcome Measures: Contractile responses to noradrenergic stimulation and to pharmacological agents stimulating endothelium-dependent and -independent relaxation, and nerve-mediated relaxations against a background precontraction., Results: Contractions in response to phenylephrine or activation of noradrenergic nerves were not significantly altered by diabetes. In contrast, maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted CC was approximately 28% reduced by diabetes: GPI 15427 treatment completely corrected this diabetic deficit. Similarly, maximal nitric oxide (NO)-mediated endothelium-dependent and -independent relaxations to acetylcholine and sodium nitroprusside, against phenylephrine precontraction, were attenuated approximately 37% and 23% by diabetes, respectively. These deficits were completely reversed by PARP-1 inhibition. Furthermore, GPI 15427 corrected a modest diabetic deficit in sensitivity to nitroprusside (EC(50) reduced by 0.14 log units); a similar trend was observed for acetylcholine-induced relaxation., Conclusions: GPI 15427 treatment provides marked benefits for NO-dependent neurovascular function in diabetic mouse CC. Therefore, PARP-1 inhibition may be worthy of further investigation for diabetes-associated ED., (© 2010 International Society for Sexual Medicine.)

Aim: Interleukin-6 (IL-6), a member of the neuropoietic cytokine family, participates in neural development and has neurotrophic activity. Recent research has also indicated actions to improve vasa nervorum function in diabetes. Both these facets are potentially relevant for treatment of diabetic neuropathy. The aim of this study was to determine whether IL-6 treatment corrected changes in neurovascular function in streptozotocin-induced diabetic rats., Methods: After 1 month of diabetes, rats were given IL-6 for 1 month. The rats were subjected to sensory testing and measurements of nerve conduction velocities and nerve blood flow by hydrogen clearance microelectrode polarography. Further groups were used to study responses of the isolated gastric fundus and renal artery. Results were statistically analysed using ANOVA and post hoc tests., Results: Diabetic rats showed mechanical hyperalgesia, thermal hyperalgesia, and tactile allodynia. The former was unaffected by IL-6 treatment, whereas the latter two measures were corrected. Immunohistochemical staining of dorsal root ganglia for IL-6 did not reveal any changes with diabetes or treatment. The results showed that 22 and 17.4% slowing of sciatic motor and saphenous sensory nerve conduction velocities, respectively, with diabetes were improved by IL-6. Sciatic endoneurial perfusion was halved by diabetes and corrected by IL-6. A 40.6% diabetic deficit in maximal non-adrenergic, non-cholinergic relaxation of gastric fundus to nerve stimulation was unaffected by IL-6. Renal artery endothelium-dependent relaxation was halved by diabetes, the endothelium-derived hyperpolarizing factor (EDHF) component being severely attenuated. IL-6 did not affect nitric oxide-mediated vasorelaxation, but markedly improved EDHF responses., Conclusions: IL-6 improved aspects of small and large nerve fibre and vascular endothelium dysfunction in diabetic rats. The functional benefits related to increased nerve blood flow via an EDHF mechanism, and IL-6 could have therapeutic potential in diabetic neuropathy and vasculopathy, which should be further evaluated.

Introduction: The metabolic syndrome is a cluster of cardiovascular risk factors that predispose toward the development of diseases such as diabetes. Erectile dysfunction (ED) is common in men with metabolic syndrome, but its etiology is poorly understood. Pro-erectile nitrergic nerves innervating penile erectile tissue are also susceptible to mechanical injury during pelvic surgical procedures, which can lead to sexual dysfunction., Aims: The aims of this article are: (i) to examine erectile function in an experimental model of metabolic syndrome, the phosphoenolpyruvate carboxykinase (PEPCK)-overexpressing rat; and (ii) to study function and cavernous reinnervation after penile nerve crush injury, which permits regeneration, in transgenic rats., Methods: We analyzed the density of noradrenergic and nitrergic nerves and performed organ bath pharmacology to assess neurogenic activity., Main Outcome Measures: By analyzing changes in neural structure, function, and pharmacologic responses of cavernous tissue after nerve crush injury, we were able to reveal neurologic deficits in rats with metabolic syndrome., Results: Animals with features of metabolic syndrome did not develop notable changes in cavernous autonomic nerve density or nerve-evoked smooth muscle activity. However, regeneration of nitrergic nerves after crush injury in transgenic rats was impaired compared with injured controls. This was manifested as a deficit in axon regrowth and responses to axon activation. However, unlike injured controls, injured PEPCK-overexpressing rats did not develop a reduced maximal response to the nitric oxide (NO) donor, sodium nitroprusside. This suggests preserved NO responsiveness in tissues from rats with metabolic syndrome, despite impaired regeneration and return of function., Conclusions: This study revealed that rats with features of metabolic syndrome display impaired cavernous nerve regeneration after penile nerve injury, but the degree of functional impairment may be attenuated due to reduced plasticity of NO signaling. This reinnervation deficit may be of clinical relevance for understanding why ED persists in some (particularly aged) men after pelvic surgery.

Although older adults have difficulty recognizing all facial emotions, they have particular difficulty decoding expressions of anger. Since disruption of facial mimicry impairs emotion recognition, electromyography of the corrugator supercilii (i.e., brow) muscle region was used to test whether there are age differences in anger mimicry. Associations between mimicry and emotion recognition were also assessed. The results indicated that although there were no age differences in anger mimicry, older (but not young) adults' corrugator responses to angry expressions were associated with reduced anger recognition. Implications for understanding emotion recognition difficulties in older adulthood are discussed.

The pelvic ganglia provide autonomic innervation to pelvic viscera and urogenital organs. These neurons are susceptible to axonal injury during pelvic surgical procedures, yet their regenerative mechanisms are poorly understood. The AP-1 transcription factor component, c-Jun, has been strongly linked to regenerative events in injured sensory, sympathetic and somatic motor neurons and is considered to be required for regeneration. Our aims were: (1) to identify whether c-Jun was upregulated by injury in pelvic parasympathetic neurons, and (2) whether injury was required for c-Jun upregulation, by performing deafferentation (i.e., severance of lumbar and sacral spinal inputs), which elicits sprouting of axon collaterals from pelvic ganglion neurons but does not injure them. A week after penile nerve axotomy in rats and mice, upregulation of c-Jun occurred in numerous glia within pelvic ganglia and almost half of the retrogradely-labelled penis-projecting neurons but also occurred in many uninjured noradrenergic neurons. We also identified upregulation of c-Jun in many pelvic ganglion neurons and glia a week after deafferentation, suggesting that c-Jun expression is activated in sprouting but uninjured neurons. A c-Jun response was retained in injured or deafferented parasympathetic neurons in neurturin knockout mice. In summary, neurturin-independent c-Jun expression within pelvic ganglion neurons does not require a direct injury and may instead be causally linked to axonal sprouting, regardless of stimulus. This study revealed mechanisms involved in structural remodelling of pelvic autonomic nerve circuits that may be modulated to improve regenerative processes.

Penile (cavernous) nerves are readily damaged during radical prostatectomy, invariably causing impotence. Erectile function can return, however this may take months or years and capacity often remains poor. Many studies have attempted to improve penile nerve regeneration but have not explored mechanisms underlying the delay in functional recovery. This is assumed to be due to slow growth of axons, although penile tissues also change following loss of erectile activity. We have asked whether delayed recovery of the nitrergic nerve-evoked erectile response is due to pre-synaptic (slow axonal growth) or post-synaptic (changes in tissue responsiveness) mechanisms. These components were dissected in vitro following penile nerve injury in adult rats. Following crush of both penile nerves, excellent regeneration of nitrergic axons occurred after 10-12 weeks but neurogenic relaxation of cavernosum muscle was still relatively poor. This was at least partly due to attenuated tissue responsiveness to nitric oxide (using sodium nitroprusside as a donor) from 3 weeks after injury. Western blotting also revealed a modest reduction of soluble guanylyl cyclase. A second model of penile nerve injury, unilateral cut, completely denervated one side but retained potential for penile erection. Some anatomical and functional recovery occurred after 9-11 weeks (probably due to sprouting from contralateral uninjured axons), but nitroprusside-evoked relaxations were unaltered from at least 3 weeks onward. These data suggest that erectile dysfunction following extensive nerve injury may be exacerbated by postsynaptic changes in nitric oxide signaling, even when nerve regeneration occurs. This may be prevented by continued activation of penile tissues to retain normal perfusion.

Kilham's rat virus (KRV) is a parvovirus commonly known to affect laboratory rats. Qualitative immunohistochemical analysis revealed that aorta isolated from KRV-infected streptozotocin (STZ)-induced diabetic adult rats expressed markedly greater levels of inducible nitric oxide synthase (iNOS) than aorta from KRV-infected controls. In contrast with the prevailing literature, nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was not blunted by STZ-diabetes, but was comparable to relaxations of aorta from controls. However, with increasing ex vivo duration, a decreased response to acetylcholine was observed in the STZ-diabetic aorta. In addition, whereas contraction responses to phenylephrine were not significantly altered over time in control tissue, aorta from STZ-diabetic rats developed increased tensions. The data suggest that increased iNOS-derived nitric oxide masks expected acetylcholine-mediated relaxation deficits as a result of KRV-infection, and that the deficit is unmasked by iNOS turnover ex vivo.

Objectives: Oxidative or glyco-oxidative stress-induced activation of the transcription factor, nuclear factor (NF)-kappaB, is associated with the neurovascular complications of diabetes mellitus. Antioxidant treatment has beneficial effects in diabetic patients; however, delineating a possible role for NF-kappaB deactivation against direct antioxidant effects has been difficult. NF-kappaB is negatively regulated by the inhibitor of kappaB (IkappaB) complex that, in turn, is activated by specific kinases. Thus, the aim was to investigate the effects of the IkappaB kinase 2 inhibitor, AS602868, on corpus cavernosum function in diabetic mice., Methods: Diabetes was induced by streptozotocin; the duration was 6 weeks. Intervention AS602868 treatment (100 mg/kg/day) was given for 2 weeks after 4 weeks of untreated diabetes. Corpora cavernosum were isolated in organ baths for measurement of agonist-evoked or electrical stimulation-evoked smooth muscle tensions., Results: The maximal nitrergic nerve-mediated relaxation of phenylephrine-precontracted cavernosum was reduced approximately 30% by diabetes (P <0.001). AS602868 treatment completely reversed the deficit (P <0.001). Maximal nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated approximately 32% by diabetes (P <0.05). This was completely restored by IkappaB kinase 2 inhibition (P <0.01). Furthermore, AS602868 treatment also completely corrected (P <0.01) an approximate 20% diabetic deficit (P <0.001) in maximal endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside., Conclusions: Inhibition of IkappaB kinase 2 can correct nitric oxide-dependent indexes of diabetic erectile dysfunction. This suggests that NF-kappaB activation is important in the development of diabetic cavernosum nitrergic neuropathy and vasculopathy.

The neurotrophic factor, neurturin (NTN), plays an important role in parasympathetic neural development. In the penis, parasympathetic nitrergic/cholinergic nerves mediate the erectile response. However, despite reduced parasympathetic penile innervation in mice lacking the NTN receptor, glial cell line-derived neurotrophic factor family receptor alpha (GFRalpha)2, they are capable of erection and reproduction. Our aim was to assess neural regulation of erectile tissues from mice lacking NTN. Responses of cavernosal smooth muscle were studied in vitro, monitoring agonist- and nerve-evoked changes in tension. Frequency-dependent nerve-evoked relaxations in the presence of guanethidine were markedly reduced in the mutant mice compared to wild types (19 vs 72% of phenylephrine pre-contraction). Atropine reduced the amplitude in wild-type mice to 61%, but abolished relaxations in knockout mice. In wild-type and knockout animals, nitric oxide synthase inhibition abolished neurogenic relaxations. In NTN knockout animals, EC(50) values for nitric oxide-dependent relaxations to acetylcholine and muscarine were increased approximately 0.5 log units. In contrast, contractions to electrical stimulation or phenylephrine, and relaxations to bradykinin or the nitric oxide donor, sodium nitroprusside, were unaltered. Immunohistochemistry confirmed that nerves immunoreactive for nitric oxide synthase, vesicular acetylcholine transporter and vasoactive intestinal polypeptide were substantially reduced in cavernosum of NTN knockout mice. Parallel immunohistochemical and pharmacological studies in GFRalpha2 knockout animals showed the same changes from their wild types as the NTN knockout animals. The data demonstrate that NTN is essential for normal development of penile erection-inducing nerves and that its absence leads to increased responsiveness to muscarinic agonists, possibly as a compensatory mechanism.

Calpains, a superfamily of Ca(2+)-activated proteases, are associated with an array of physiological and pathological events, including susceptibility to diabetes. Recently, increased calpain activity has been linked to reduced endothelium-derived nitric oxide-mediated vasodilatation in diabetes. However, a similar mechanism for neuronal-derived nitric oxide has not been examined. Thus, the aim was to investigate effects of the calpain inhibitor A-705253, N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethyl-aminomethylphenyl)ethen-1-yl]benzamide, on nitrergic neurovascular function in diabetic mice. Diabetes was induced by streptozotocin; duration was 6 weeks. Intervention A-705253 treatment (30 mg/kg/day) was given for 2 weeks following 4 weeks of untreated diabetes. After 6 weeks of diabetes, corpus cavernosa were isolated in organ baths for measurement of agonist- and electrical stimulation-evoked smooth muscle tensions. Adrenergic nerve- and phenylephrine-mediated contractions were not altered by diabetes or calpain inhibition. In contrast, maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted cavernosum was approximately 29% reduced by diabetes (P<0.001). This neurological deficit was 66% corrected by A-705253 treatment (P<0.05). Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated approximately 39% by diabetes (P<0.01). Similarly, maximum endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside, was blunted approximately 23% by diabetes (P<0.001). A-705253 treatment partially improved endothelium-dependent relaxation to acetylcholine but had no effect on the deficit in response to nitroprusside. The data suggest that calpain contributes to the aetiology of diabetic nitrergic autonomic neuropathy and endothelial dysfunction, which may provide a novel therapeutic target for neurovascular complications.

Increased p38 mitogen-activated protein kinase (MAPK) in response to stress stimuli, including hyperglycemia, contributes to diabetic somatic neuropathy. However, effects on autonomic nerve and vascular function have not been determined. The aim of this study was to investigate the effects of the p38 MAPK inhibitor, LY2161793, on penile neurovascular function in streptozotocin-induced diabetic mice. Diabetes duration was 6 weeks and intervention LY2161793 treatment was given for the final 2 weeks. In vitro measurements on phenylephrine-precontracted corpus cavernosum revealed a 32% reduction in maximum nitrergic nerve-mediated relaxation with diabetes that was 74% corrected by LY2161793 treatment. Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was 42% attenuated by diabetes and 88% restored by LY2161793. Moreover, treatment partially corrected a diabetic deficit in endothelium-independent relaxation to a nitric oxide donor. Thus, p38 MAPK inhibition corrects nitric oxide-dependent indices of diabetic erectile autonomic neuropathy and vasculopathy, a therapeutic approach potentially worthy of consideration for clinical trials.

Advanced glycation and lipoxidation end products (AGEs/ALEs) have been implicated in the pathogenesis of the major microvascular complications of diabetes mellitus: nephropathy, neuropathy, and retinopathy. This article reviews the evidence regarding the peripheral nerve and its vascular supply. Most investigations done to assess the role of AGEs/ALEs in animal models of diabetic neuropathy have used aminoguanidine as a prototypic inhibitor. Preventive or intervention experiments have shown treatment benefits for motor and sensory nerve conduction velocity, autonomic nitrergic neurotransmission, nerve morphometry, and nerve blood flow. The latter depends on improvements in nitric oxide-mediated endothelium-dependent vasodilation and is responsible for conduction velocity improvements. A mechanistic interpretation of aminoguanidine's action in terms of AGE/ALE inhibition is made problematic by the relative lack of specificity. However, other unrelated compounds, such as pyridoxamine and pyridoxamine analogues, have recently been shown to have beneficial effects similar to aminoguanidine, as well as to improve pain-related measures of thermal hyperalgesia and tactile allodynia. These data also stress the importance of redox metal ion-catalyzed AGE/ALE formation. A further approach is to decrease substrate availability by reducing the elevated levels of hexose and triose phosphates found in diabetes. Benfotiamine is a transketolase activator that directs these substrates to the pentose phosphate pathway, thus reducing tissue AGEs. A similar spectrum of improvements in nerve and vascular function were noted when using benfotiamine in diabetic rats. Taken together, the data provide strong support for an important role for AGEs/ALEs in the etiology of diabetic neuropathy.

Peroxynitrite, the reaction product of nitric oxide and superoxide, may contribute to vascular tissue oxidant stress in diabetes mellitus. The aim was to establish whether the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron III (FeTMPyP) could improve nitric oxide-dependent autonomic nerve and microvascular penile function in the diabetic mouse. Diabetes was induced by streptozotocin; duration was 6 weeks. Intervention FeTMPyP treatment (25 mg kg(-1) day(-1)) was given for 2 weeks following 4 weeks untreated diabetes. Corpus cavernosum were isolated in organ baths for measurement of agonist or electrical stimulation-evoked nerve-mediated tension responses. Maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted cavernosum was approximately 35% reduced by diabetes; FeTMPyP treatment reversed this deficit by 45%. The concentration response-curve for nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated by diabetes; FeTMPyP restored the deficit to the nondiabetic range. Sensitivity (EC50) to the nitric oxide donor, sodium nitroprusside, was reduced by approximately 0.56 log10 M units in diabetes; however, FeTMPyP treatment failed to significantly reverse this deficit. Therefore, the peroxynitrite mechanism contributes to nitric oxide-dependent diabetic autonomic neuropathy and vasculopathy and may be a potential target for clinical trials using peroxynitrite decomposition catalysts.

In order to ascertain the relative contribution of the endothelial and neuronal nitric oxide (NO) synthase isoforms on NO-dependent vascular and nerve function in vitro, aorta and corpus cavernosum from mice deficient in their expression (eNOS-/- and nNOS-/-) were isolated in organ baths for tension measurements. Agonist or electrical field stimulation (EFS) evoked nerve-mediated responses were compared against wild-type controls. In aortas from nNOS-/- mice, contraction responses to phenylephrine were increased. Conversely, endothelium-dependent relaxation (EDR) to acetylcholine (ACh) was decreased. In contrast, eNOS-/- aortas showed decreased sensitivity to phenylephrine and developed a flurbiprofen-sensitive contraction to ACh, and sensitivity to the NO-donor sodium nitroprusside was increased. In cavernosum from eNOS-/- and nNOS-/- mice, maximum contractions to phenylephrine and EFS, and relaxation responses to nitroprusside, were increased. As in aorta, ACh addition led to a contractile response in eNOS-/- cavernosum. Maximum EFS induced non-adrenergic, non-cholinergic (NANC) nerve-mediated relaxation was increased in eNOS-/-, whilst being decreased in nNOS-/- cavernosum. These data suggest that whilst NO-dependent vascular function is primarily eNOS mediated, and nerve function nNOS mediated, aorta function may be at least partially reliant on nNOS-related mechanisms. In addition, mechanisms of physiological compensation were observed, which require further study.

Nitric oxide (NO), produced by NO-synthase (NOS), serves as an important vasodilator and inhibitory neurotransmitter. Inducible NOS (iNOS) is expressed in response to cytokine stimulation and is therefore not ordinarily present in healthy tissue. However, iNOS has been identified in certain organs, including the penis. The development of mice deficient in the iNOS gene (iNOS -/-) has provided a useful tool for the study of iNOS function. Therefore, an in vitro examination of vascular and nerve-mediated responses of corpus cavernosum (CC) and vascular responses of aorta from iNOS -/- mice and their wild-type controls was undertaken. Tissues were mounted in organ baths for agonist- and/or electrical field stimulation (EFS)-induced responses under isometric tension. CC from iNOS -/- mice developed increased sensitivity to phenylephrine (PE) and an increased maximum EFS-induced noradrenergic contraction of approximately 31%. Following PE precontraction, maximum relaxation to acetylcholine was reduced by approximately 39%; conversely, there was a 23% increase in relaxation to the NO-donor sodium nitroprusside. EFS-induced non-adrenergic, non-cholinergic (NANC) nerve-mediated relaxation was unaltered compared to control. Agonist-induced responses of aorta did not significantly differ between iNOS -/- and control mice. These results suggest that iNOS-derived NO may play a role in modulating erectile function and confirm that iNOS does not play a significant role in macrovascular function under normal physiological conditions.

Elevated plasma lipids contribute to neurovascular dysfunction in diabetes. Statins have lipid-lowering properties and can modulate endothelial nitric oxide (NO) bioavailability. The aim was to assess the impact of these factors on autonomic nitrergic nerve and endothelial function. Thus, the effects of diabetes and treatment with the HMG-CoA reductase inhibitor rosuvastatin (RSV) were examined on corpus cavernosum and aorta from streptozotocin-induced diabetic mice in a 4-week prevention study and a 2-week intervention study, following 4 weeks of untreated diabetes. Cotreatment with mevalonate was used to assess the dependence of RSV's effects on HMG-CoA reductase blockade. Diabetes caused a 25% reduction in NO-mediated endothelium-dependent relaxation to acetylcholine for aorta and cavernosum. Relaxations of cavernosum were in the nondiabetic range following prevention or reversal treatment. The aortic deficit was completely prevented and 60% reversed by RSV. Maximum NO-dependent nonadrenergic, noncholinergic nerve-mediated relaxations of cavernosum were reduced 25-33% by diabetes. RSV treatment prevented 75% and reversed 71% of this diabetic deficit. Cotreatment with mevalonate inhibited the beneficial actions of RSV on aorta and cavernosum. Total plasma cholesterol was unaltered by diabetes or treatment. Thus, RSV corrected defective NO-mediated nerve and vascular function in diabetic mice independent of cholesterol lowering but via effects dependent on cholesterol biosynthesis pathway inhibition.

Increased activity of the beta-isoform of protein kinase C (PKC) has been linked to the vascular and neural complications of diabetes mellitus. Treatment with the PKCbeta inhibitor, (s)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione, (LY333531), improves somatic nerve function and blood flow in diabetic rats. The aim was to assess whether LY333531 treatment could prevent nitric oxide-dependent autonomic nerve and vascular dysfunction in a diabetic mouse model. Diabetes was induced by streptozotocin; duration was 4 weeks. Aorta and corpus cavernosum were isolated and mounted in organ baths and agonist or electrical stimulation-evoked nerve-mediated tension responses were examined. Maximum nitric oxide-mediated endothelium-dependent relaxation of phenylephrine-precontracted aorta and cavernosum to acetylcholine were more than 30% reduced by diabetes. LY333531 treatment (10 mg kg(-1) day(-1)) completely prevented the diabetic deficit in cavernosum, and 75% prevented the deficit in aorta. Maximum nitric oxide-dependent non-adrenergic, non-cholinergic (NANC) nerve-mediated relaxation of phenylephrine-precontracted cavernosum was approximately 43% reduced by diabetes; LY333531 attenuated the deficit by 44%. For diabetic aorta, but not cavernosum, sensitivity (EC50) to phenylephrine-mediated contraction was increased by approximately 0.85 log10 M units; LY333531 treatment completely prevented this effect. Thus, PKCbeta activation contributes to nitric oxide-dependent vascular and autonomic nerve dysfunction in diabetic mice and could prove suitable for further study in clinical trials of diabetic autonomic neuropathy and vasculopathy.