Karen Dawe

Maternal Mood and Neuroendocrine Programming: Effects of Time of Exposure and Sex

Adverse exposures that influence growth in prenatal and early postnatal periods are considered to influence vulnerability to chronic diseases via their effects on the neuroendocrine system. In humans, the assessment of the underlying mechanisms has been restricted. The present study aimed to investigate the effects of adverse early‐life exposures, specifically maternal mood, on hypothlamic‐pituitary‐adrenal (HPA) axis, sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) responses to an acute physiological stressor. In addition, we conducted a preliminary examination into whether these effects varied by time of exposure and sex. One hundred and thity‐nine individuals (mean age 15.12 years) were recruited from the ALSPAC (Avon Longitudinal Study of Parents and Children) birth cohort. Participants underwent the CO2 stress test and indices of the PNS, SNS and HPA axis were measured. Pre‐existing data on demographic and psychosocial factors of the mothers during pregnancy (18 and 32 weeks) and postnatally (8 weeks and 8 months) were extracted, as were participants’ clinical and demographic data at birth. Increases in both pre‐ and postnatal anxiety and depression were associated with greater SNS reactivity to the stressor and slower recovery, as well as blunted HPA axis responses. Programming effects on the SNS appeared to be restricted to male offspring only. No consistent relationships were evident for any of the measures of pre‐stress function. We have found preliminary evidence that both pre‐ and postnatal maternal anxiety and depression have sustained programming effects on the SNS and HPA axis. Effects on the SNS were restricted to male offspring.

Role of Nociceptin/Orphanin FQ and NOP Receptors in the Response to Acute and Repeated Restraint Stress in Rats

Central nociceptin/orphanin FQ (N/OFQ)‐expressing neurones are abundantly expressed in the hypothalamus and limbic system and are implicated in the regulation of activity of the hypothalamic‐pituitary‐adrenal axis (HPA) and stress responses. We investigated the role of the endogenous N/OFQ receptor (NOP) system using the nonpeptidic NOP antagonist, JTC‐801 [N‐(4‐amino‐2‐methylquinolin‐6‐yl)‐2‐(4‐ethylphenoxy‐methyl)benzamide monohydrochloride], during the HPA axis response to acute physical/psychological stress (60 min of restraint). Although i.v. JTC‐801 (0.05 mg/kg in 100 μl) had no significant effect on restraint‐induced plasma corticosterone release at 30 or 60 min post‐injection, i.v. JTC‐801 (0.05 mg/kg in 100 μl) in quiescent rats significantly increased basal plasma corticosterone at the 30‐min time‐point compared to i.v. vehicle (1% dimethysulphoxide in sterile saline). Central injection of JTC‐801 i.c.v. was associated with increased Fos expression in the parvocellular paraventricular nucleus 90 min after infusion compared to vehicle control. These findings contrast to the effects of i.c.v. UFP‐101, a NOP antagonist that we have previously shown to have no effect on HPA activity in quiescent rats. To determine whether restraint stress was associated with compensatory changes in N/OFQ precursor (ppN/OFQ) or NOP receptor mRNAs, in a separate study, we undertook reverse transcriptase‐polymerase chain reaction and in situ hybridisation analysis of ppN/OFQ and NOP transcripts in the brains of male Sprague–Dawley rats. In support of an endogenous role for central N/OFQ in psychological stress, we found that acute restraint significantly decreased preproN/OFQ transcript expression in the hippocampus 2 h after stress compared to unstressed controls. PpN/OFQ mRNA was also reduced in the mediodorsal forebrain 4 h after stress. NOP mRNA was reduced in the hypothalamus 2 h after restraint and at 4 h in mediodorsal forebrain and hippocampus. In situ hybridisation analysis showed that acute restraint significantly decreased ppNN/OFQ in the central amygdala, with significantly increased expression in bed nucleus and reticular thalamus associated with repeated restraint. There was a strong trend for reduced NOP mRNA in the bed nucleus of acute and repeated restraint groups, although there were no other significant changes seen. Although the exact mechanisms require elucidation, the findings obtained in the present study provide evidence indicating that the endogenous N/OFQ system is involved in both acute and chronic restraint stress responses. In summary, our findings confirm the significant role of endogenous NOP receptors and tonic N/OFQ function in the response to the psychological stress of restraint.

Endogenous nociceptin / orphanin FQ system involvement in hypothalamic-pituitary-adrenal axis responses: relevance to models of inflammation.

Nociceptin/orphanin FQ (N/OFQ) peptide and its receptor (NOP) function in the neuromodulation of anxiety, stress and hypothalamic‐pituitary‐adrenal (HPA) axis activity. We investigated the endogenous NOP system using the selective NOP antagonist, UFP‐101, during the HPA axis response to bacterial endotoxin, lipopolysaccharide (LPS). Although i.c.v. N/OFQ (1 μg/rat) had no significant effect on LPS‐induced (250 μg/rat i.p) plasma corticosterone release at 30 or 60 min post‐i.c.v. injection, i.c.v. UFP‐101 (1 μg/rat)/LPS significantly attenuated plasma adrenocorticotrophic hormone and corticosterone at the 30‐min time‐point compared to i.c.v saline (0.9%)/LPS. Parvocellular paraventricular nucleus (PVN) corticotrophin‐releasing factor (CRF) and corticotrophic pro‐opiomelanocortin (POMC), but not parvocellular PVN arginine vasopressin (AVP), mRNA expression was significantly increased by LPS compared to non‐LPS control. Intracerebroventricular UFP‐101/LPS treatment was associated with increased POMC mRNA expression 4 h after injection and a clear trend towards increased parvocellular CRF mRNA. Furthermore, i.c.v. UFP‐101 was selectively associated with an LPS‐induced increase in parvocellular AVP mRNA, an effect that was absent in the i.c.v saline/LPS group. To determine whether LPS challenge was associated with compensatory changes in N/OFQ precursor or NOP receptor mRNAs, in a separate study, we undertook reverse transcriptase‐polymerase chain reaction analysis of preproN/OFQ and NOP transcripts. In support of an endogenous role for central N/OFQ in inflammatory stress, we found that LPS significantly increased preproN/OFQ transcript expression in the hypothalamus 4 h after injection compared to the saline control. No changes in preproN/OFQ mRNA level in the hippocampus or basal forebrain (including bed nucleus of stria terminalis) were seen, albeit at 4 h. LPS was associated with a significant attenuation of NOP mRNA in the basal forebrain at 4 h, possibly as a compensatory response to increased N/OFQ release. Although the exact mechanisms require elucidation, the findings obtained in the present study provide evidence indicating that the endogenous NOP system is involved in the acute HPA axis response to immune challenge.

Opportunities to say ‘yes’: Rare speech automatisms in a case of progressive nonfluent aphasia and apraxia

We describe the investigation of speech automatisms in a man with progressive nonfluent aphasia and apraxias. Occurrence of the automatisms yes and right, were analysed across a range of speech tasks varying in length, propositionality, lexical and articulatory complexity, whether tasks engaged internal generation or external triggering and articulatory distortions, and while completing pantomimes/gestures. No differences were found in occurrence across most tasks but there was a significant interaction between automatism production and apraxic speech errors and during limb praxic tasks, suggesting that production of the automatism was unrelated to linguistic or lexical variables, but was related to the presence of speech apraxia coupled with disinhibition.

Reducing the burden of chronic wounds: Prevention and management of the diabetic foot in the context of clinical guidelines:

Objectives: Chronic wounds such as diabetic foot and venous leg ulcers are a major burden for health services. Our programme was developed to explore the psychological and behavioural factors that may influence both the incidence of chronic wounds and their progression. The present article focuses on two particular aspects of the programme: patient knowledge of diabetic foot ulceration and factors influencing foot-related behaviour in patients with and without foot ulcers; and patient and podiatrist perspectives of consultations for diabetic foot ulcers. Methods: Two independent qualitative studies were undertaken: one with diabetic patients without a history of ulceration; and the other with diabetic patients with active ulceration and podiatrists treating these patients. Results: We found that patients may find it difficult understanding the rationale underlying prevention and treatment of foot ulcers; ulcerated patients may find it difficult to engage in the management of their foot ulcer outside consultations; and some podiatrists feel frustrated and unsupported in their attempts at empowering and building partnerships with patients. Conclusion: Patient and practitioner factors may contribute to the effective implementation of clinical guidelines regarding education, partnership building and shared decision-making. These findings are discussed in relation to patient education, partnership building and shared decision-making as recommended in NICE guidelines.

Phonetic and phonological analysis of progressive speech degeneration: a case study

In this paper we report on an adult male participant with a rare form of progressive speech degeneration. We present acoustic phonetic data on his vowel and consonant production, and describe his prosody and syllable structure. We suggest possible phonological analyses of his speech, concluding that a gestural approach to phonology best characterizes his speech production and its degeneration.

Nociceptin/orphanin FQ and the regulation of neuronal excitability in the rat bed nucleus of the stria terminalis: interaction with glucocorticoids.

Nociceptin (N/OFQ) peptide has regulatory roles in neuroendocrine responses to stress. We sought to clarify the roles of nociceptin and its receptors (NOP receptors) in the regulation of rat bed nucleus of the stria terminalis (BNST) neurones in vitro. The effect of nociceptin (75 nM) across subregions of the anterior BNST was determined using extracellular single-unit recordings in rat brain slices. Firing patterns of the neurones were recorded in the presence of N-methyl-D-aspartate (NMDA, 10 μm) for the classification of putative cell types. Based on the firing patterns, four cell types were identified. The distribution of cell types differed between the dorsal and ventral BNST. Nociceptin inhibited the activity of 53.2% of all the neurones tested (n = 47), regardless of the cell type or subregion. The duration of nociceptin-mediated inhibition of cell firing was significantly attenuated by pre-treatment with the NOP receptor antagonist, UFP-101 (750 nM), indicating that nociceptin-induced suppression of firing rate involves NOP receptor activation in the BNST. Pre-treatment of slices with 100-nM corticosterone (CORT) vs. dimethylsulphoxide (DMSO) for 20 min significantly abolished the nociceptin-induced inhibition of firing rate (P < 0.001) when tested 2 h later. We did not, however, observe a significant effect of CORT on baseline firing rate or pattern in BNST neurones. We suggest that the interaction between nociceptin and glucocorticoids in the BNST may be essential for normal adaptive stress responses.

The association of maternal prenatal psychosocial stress with vascular function in the child at age 10-11 years: findings from the Avon longitudinal study of parents and children

Objective To investigate whether (1) maternal psychosocial stress (depression/anxiety) during pregnancy is associated with offspring vascular function and (2) whether any association differs depending on the gestational timing of exposure to stress. We also investigated whether any association is likely to be due to intrauterine mechanisms by (3) comparing with the association of paternal stress with offspring vascular function and (4) examining whether any prenatal association is explained by maternal postnatal stress. Methods and results Associations were examined in a UK birth cohort, with offspring outcomes (systolic and diastolic blood pressure, SBP and DBP, endothelial function assessed by brachial artery flow-mediated dilatation (FMD); arterial stiffness assessed by carotid to radial pulse wave velocity (PWV), brachial artery distensibility (DC), and brachial artery diameter (BD) assessed at age 10–11 years (n = 4318). Maternal depressive symptoms and anxiety were assessed at 18 and 32 weeks gestation and 8 months postnatally. Paternal symptoms were assessed at week 19. With the exception of DBP and BD, there were no associations of maternal depressive symptoms with any of the vascular outcomes. Maternal depressive and anxiety symptoms were associated with lower offspring DBP and wider BD, though the latter attenuated to the null with adjustment for confounding factors. Paternal symptoms were not associated with offspring outcomes. Maternal postnatal depressive symptoms were associated with lower offspring SBP. Conclusions We found no evidence to support the hypothesis that maternal stress during pregnancy adversely affects offspring vascular function at age 10–12 years via intrauterine mechanisms.

Illness beliefs predict mortality in patients with diabetic foot ulcers

Background Patients’ illness beliefs have been associated with glycaemic control in diabetes and survival in other conditions. Objective We examined whether illness beliefs independently predicted survival in patients with diabetes and foot ulceration. Methods Patients (n = 169) were recruited between 2002 and 2007. Data on illness beliefs were collected at baseline. Data on survival were extracted on 1st November 2011. Number of days survived reflected the number of days from date of recruitment to 1st November 2011. Results Cox regressions examined the predictors of time to death and identified ischemia and identity beliefs (beliefs regarding symptoms associated with foot ulceration) as significant predictors of time to death. Conclusions Our data indicate that illness beliefs have a significant independent effect on survival in patients with diabetes and foot ulceration. These findings suggest that illness beliefs could improve our understanding of mortality risk in this patient group and could also be the basis for future therapeutic interventions to improve survival.

The effects of initiation, termination and inhibition impairments on speech rate in a case of progressive nonfluent aphasia with progressive apraxia of speech with frontotemporal degeneration

Recent research into nonfluent forms of primary progressive aphasia and progressive apraxia of speech has highlighted the importance of speech rate as a diagnostic feature. We describe detailed investigation and comparison of speech rate (latencies and utterance length in single word/nonword production and speech rate in connected speech) on a range of experimental tasks in a man with progressive speech deterioration of 10 years duration from Picks Disease. C.S. had a progressive nonfluent aphasia (PNFA) together with progressive apraxia of speech (pAOS) with an absence of significant interlectual, phonological or semantic impairment. C.S. showed increased latencies but reduced word length compared to matched controls on single word and nonword repetition and reading, an absence of a syllabic length effect in either single word/nonword tasks or connected speech tasks. Further investigation suggested that underlying his speech production impairments were problems with speech initiation, termination and inhibition. Most impairments worsened with progression over a 12-month period. Results provide support for the view that progressive apraxia of speech presents differently to apraxia of speech following stroke and, especially at advanced stages, involves deterioration in more central and supportive cognitive processes.