External amplitude and frequency modulation of a terahertz quantum cascade laser using metamaterial/graphene devices.

Active control of the amplitude and frequency of terahertz sources is an essential prerequisite for exploiting a myriad of terahertz applications in imaging, spectroscopy, and communications. Here we present a optoelectronic, external modulation technique applied to a terahertz quantum cascade laser which holds the promise of addressing a number of important challenges in this research area. A hybrid metamaterial/graphene device is implemented into an external cavity set-up allowing for optoelectronic tuning of feedback into a quantum cascade laser. We demonstrate powerful, all-electronic, control over the amplitude and frequency of the laser output. Full laser switching is performed by electrostatic gating of the metamaterial/graphene device, demonstrating a modulation depth of 100%. External control of the emission spectrum is also achieved, highlighting the flexibility of this feedback method. By taking advantage of the frequency dispersive reflectivity of the metamaterial array, different modes of the QCL output are selectively suppressed using lithographic tuning and single mode operation of the multi-mode laser is enforced. Side mode suppression is electrically modulated from ~6 dB to ~21 dB, demonstrating active, optoelectronic modulation of the laser frequency content between multi-mode and single mode operation.

Hyperuniform disordered terahertz quantum cascade laser.

Laser cavities have been realized in various different photonic systems. One of the forefront research fields regards the investigation of the physics of amplifying random optical media. The random laser is a fascinating concept because, further to the fundamental research investigating light transport into complex media, it allows us to obtain non-conventional spectral distribution and angular beam emission patterns not achievable with conventional approaches. Even more intriguing is the possibility to engineer a priori the optical properties of a disordered distribution in an amplifying medium. We demonstrate here the realization of a terahertz quantum cascade laser in an isotropic hyperuniform disordered distribution exhibiting unique features, such as the presence of a photonic band gap, low threshold current density, unconventional angular emission and optical bistability.

Investigation of hollow cylindrical metal terahertz waveguides suitable for cryogenic environments.

The field of terahertz (THz) waveguides continues to grow rapidly, with many being tailored to suit the specific demands of a particular final application. Here, we explore waveguides capable of enabling efficient and accurate power delivery within cryogenic environments (< 4 K). The performance of extruded hollow cylindrical metal waveguides made of un-annealed and annealed copper, as well as stainless steel, have been investigated for bore diameters between 1.75 - 4.6 mm, and at frequencies of 2.0, 2.85 and 3.4 THz, provided by a suitable selection of THz quantum cascade lasers. The annealed copper resulted in the lowest transmission losses, < 3 dB/m for a 4.6 mm diameter waveguide, along with 90° bending losses as low as ~2 dB for a bend radius of 15.9 mm. The observed trends in losses were subsequently analyzed and related to measured inner surface roughness parameters. These results provide a foundation for the development of a wide array of demanding low-temperature THz applications, and enabling the study of fundamental physics.

Efficient coupling of double-metal terahertz quantum cascade lasers to flexible dielectric-lined hollow metallic waveguides.

The growth in terahertz frequency applications utilising the quantum cascade laser is hampered by a lack of targeted power delivery solutions over large distances (>100 mm). Here we demonstrate the efficient coupling of double-metal quantum cascade lasers into flexible polystyrene lined hollow metallic waveguides via the use of a hollow copper waveguide integrated into the laser mounting block. Our approach exhibits low divergence, Gaussian-like emission, which is robust to misalignment error, at distances > 550 mm, with a coupling efficiency from the hollow copper waveguide into the flexible waveguide > 90%. We also demonstrate the ability to nitrogen purge the flexible waveguide, increasing the power transmission by up to 20% at 2.85 THz, which paves the way for future fibre based terahertz sensing and spectroscopy applications.

Hollow metallic waveguides integrated with terahertz quantum cascade lasers.

We present the realization of a compact, monolithically integrated arrangement of terahertz quantum cascade lasers with hollow metallic cylindrical waveguides. By directly mounting a copper pipe to the end facet of a double metal waveguide, it was possible to significantly improve the far field emission from such a sub-wavelength plasmonic mode, while preserving the characteristic performance of the laser. Careful alignment of the quantum cascade laser and the hollow waveguide is required in order to prevent the excitation of higher order/mixed modes as predicted with a high degree of accuracy by a theoretical model. Finally, this approach proved to be a superior method of beam shaping when compared to other in situ arrangements, such as a silicon hyper-hemispherical lens glued to the facet, which are presented.

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 microg/rat) had no significant effect on LPS-induced (250 microg/rat i.p) plasma corticosterone release at 30 or 60 min post-i.c.v. injection, i.c.v. UFP-101 (1 microg/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.

Overnight variations in cortisol, interleukin 6, tumour necrosis factor alpha and other cytokines in people with rheumatoid arthritis.

OBJECTIVE: To investigate overnight variations in absolute values and patterns of cytokines including interleukin 6 (IL6) and tumour necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA), and to relate any changes to those occurring in blood cortisol. METHODS: A total of 16 people (8 female) with active RA and who had received no recent glucocorticoids were admitted overnight. Blood samples were obtained at 13 time points between 21.00 and 10.00. RESULTS: The geometric mean IL6 concentration rose significantly from 35 pg/ml at 22:00 to 64 pg/ml at 07:15 (repeated measures analysis of variance (ANOVA), p<0.001). The geometric mean cortisol concentration rose significantly overnight from 57 ng/ml at 01:00 to 229 ng/ml at 07:15 (repeated measures ANOVA, p<0.001). Neither TNFalpha nor the other cytokines measured changed significantly. Using cubic regression modelling IL6 began to rise before cortisol (range 0.01 to 4.83 h) in eight participants and after cortisol (range 1.11 to 5.14 h) in three participants. In a random coefficient model including data from all participants, the estimated mean IL6 value began to rise 3.05 h before the estimated mean cortisol value, with the IL6 peak occurring 0.70 h before the cortisol peak. CONCLUSION: The mean IL6 and cortisol concentrations showed a significant overnight variation. Neither TNFalpha nor the other cytokines measured changed significantly. In a random coefficient model IL6 began to rise approximately 3 h, and reached a peak about 40 min, before cortisol. These studies confirm that there are abnormalities in plasma cortisol and IL6 concentrations and dynamics. The data also link the overnight rise in IL6 to the circadian variation in symptoms.

Higher physical activity is associated with increased androgens, low interleukin 6 and less aortic calcification in peripheral obese elderly women.

The presence of peripheral fat mass (PFM) appears to counteract the atherogenic trends of central fat mass through mechanisms presently poorly understood. In elderly women with distinct forms of body fat distribution, we wanted to study whether physical activity and aortic calcification are related to plasma levels of cortisol, 17-alpha-hydroxyprogesterone (17-alpha-OHP), dehydroepiandrosterone (DHEA), androstenedione (ASD), and interleukin 6 (IL6) accomplishing an anti-atherogenic milieu. A total of 276 well-defined generally healthy women aged 60-85 years were included. Categorization of body fat distribution was based on the relative presence of central to PFM measured by dual-energy X-ray absorptiometry. Women meticulously reported weekly physical activity. Outcome measures were aortic calcification between lumbar vertebra L1 and L4, plasma levels of hormones, and IL6. In peripheral adipose women, plasma DHEA and ASD increased with the degree of physical activity. This was also mirrored in the ratios of cortisol/DHEA and cortisol/17-alpha-OHP. Peripheral adipose women with high DHEA relative to cortisol had less severe aortic calcification, and in the same group a higher level of physical activity was associated with lower levels of plasma IL6. In conclusion, this study demonstrates that high physical activity is associated with a high circulating androgen to cortisol ratio, low IL6, and less severe aortic calcification. Since androgens inhibit IL6 secretion, the activity-induced increase of these hormones might be an anti-atherogenic signal.

Chronic citalopram treatment does not sensitize the adrenal gland to ACTH (1-24) in rats.

We have previously reported that rats exposed chronically to citalopram are able to elicit a corticosterone but not adrenocorticotropic hormone (ACTH) response to restraint stress. Thus we proposed the hypothesis that the corticosterone response to restraint in citalopram-treated rats was maintained due to increased adrenal sensitivity to lower ACTH levels. To test this hypothesis, we intravenously injected ACTH (1-24) to rats (dose 3 ng/rat) exposed to citalopram through minipump infusion for 14 days and to control rats (no citalopram). ACTH significantly increased plasma corticosterone levels in both control and citalopram treated rats over a period of 120 min. There was no significant difference in plasma corticosterone between citalopram treated rats and control rats at any time point. Therefore we conclude that, under these experimental conditions, citalopram does not appear to sensitize the rodent adrenal gland to ACTH, and that other mechanisms may be responsible for the ACTH/corticosterone disconnection.

The nociceptin/orphanin FQ antagonist UFP-101 differentially modulates the glucocorticoid response to restraint stress in rats during the peak and nadir phases of the hypothalamo-pituitary-adrenal axis circadian rhythm.

The involvement of nociceptin (N/OFQ) and the nociceptin/orphanin FQ peptide (NOP) receptor in behavior associated with stress and anxiety has been established but their role in the regulation of the hypothalamo-pituitary-adrenal (HPA) axis under conditions of stress has not been fully investigated. We used the selective NOP receptor antagonist UFP-101 to examine the contribution of endogenous N/OFQ to HPA axis control under conditions of restraint stress in the morning and the evening. We found that in the morning during the HPA axis circadian nadir rats exposed to restraint stress in both the presence and absence of UFP-101 exhibited significantly elevated plasma corticosterone at 30 min post-i.c.v. injection compared to the home cage control group. Additionally, rats treated with UFP-101 and exposed to restraint had significantly elevated corticosterone levels at 60 min post-i.c.v. injection compared to all other treatment groups. Interestingly, while there was a significant increase in the expression of CRF mRNA in the paraventricular nucleus (PVN) of rats exposed to restraint stress only, there was no comparable increase in those co-treated with UFP-101. There was no change in the expression of AVP or POMC mRNA in any of the treatment groups. In contrast, when carried out in the evening we observed significantly elevated plasma corticosterone in the vehicle-treated restraint group only at 30 min post-i.c.v. injection. There was no significant difference between the UFP-101-treated restraint group and either of the home cage control groups or the vehicle-treated restraint group. Additionally, in contrast to the morning study, UFP-101 did not prolong glucocorticoid release at the 60 min time-point. These results demonstrate for the first time a differential effect of UFP-101 on restraint stress-induced HPA axis activity characterized by significant prolongation of stress-induced activity in the morning but no significant effect on the response to restraint in the evening.

Attenuated stress response to acute lipopolysaccharide challenge and ethanol administration in vasopressin V1b receptor knockout mice.

The arginine vasopressin (Avp) 1b receptor (Avpr1b) present on anterior pituitary corticotrophs is involved in the stimulation of adrenocorticotrophic hormone (ACTH) secretion, especially during times of stress. Corticotrophin-releasing hormone (CRH) is considered the major ACTH secretagogue during acute stress whereas Avp appears to be the more dominant mediator of the hypothalamic-pituitary-adrenal (HPA) axis response during chronic stress situations. To investigate the role of the Avpr1b in the HPA axis response to acute stress, we measured ACTH and corticosterone (CORT) plasma levels in Avpr1b knockout (KO) mice and wild-type controls in response to bacterial lipopolysaccharide (LPS) challenge and ethanol (EtOH) administration. Mice deficient in Avpr1b had markedly compromised plasma ACTH and CORT responses to acute (30 min) LPS, but normal ACTH and CORT response to more extended exposure (4 h) to the immune system activator. The plasma ACTH and CORT levels stimulated by intoxicating, sedative doses of EtOH (3.2 and 4 g/kg) were significantly decreased in the Avpr1b KO mice compared to wild-type littermates. Significantly higher EtOH-induced plasma ACTH and CORT secretion was measured in female than in male Avpr1b wild-type mice. There were no differences in the blood alcohol levels following acute EtOH administration in Avpr1b KO or wild-type mice of either gender. Our results clearly suggest that Avpr1b plays a significant role in the HPA axis response to acute immune stress and EtOH intoxication.

Protective effects of endotoxin in a rat model of chronic inflammation are accompanied by suppressed secretion of pro-inflammatory cytokines and biphasic alteration in hypothalamo-pituitary-adrenal axis activity.

We have previously demonstrated that Gram-negative bacterial endotoxin can exert long-term protective effects against the chronic inflammatory disease adjuvant arthritis in rats. The present study was designed to investigate the mechanisms and time-course of hypothalamo-pituitary-adrenocortical (HPA) axis activity and cytokine secretion underlying this phenomenon. Rats were injected with endotoxin (lipopolysaccharide) and blood was collected either 7 or 21 days later. Priming with endotoxin induced a biphasic alteration in secretion of adrenocorticotrophic hormone and corticosterone in response to a second injection of endotoxin, with decreased secretion observed after 7 days whereas robust secretion was observed at 21 days. Seven days following priming with endotoxin, plasma concentrations of pro-inflammatory cytokines interleukin (IL)-6 and interferon (IFN)-gamma were reduced by 90%, and tumour necrosis factor (TNF)-alpha by 70%, compared to saline-treated rats, whereas robust secretion of the anti-inflammatory cytokine IL-10 was maintained in both groups. A similar net change favouring an anti-inflammatory cytokine secretory milieu was also observed 21 days following priming with endotoxin. This study provides evidence that the long-term protective effects of endotoxin on inflammation are associated with a sustained reduction in secretion of pro-inflammatory cytokines. HPA axis hypoactivity at 7 days suggests that corticosterone is not involved in suppressing IL-6, IFN-gamma and TNF-alpha at this time point. Conversely, hypersecretion of corticosterone at 21 days may underlie synchronous suppression of IL-6 and IFN-gamma. These data provide novel insight into interactions between HPA axis activity and cytokine secretion following endotoxin priming prior to induction of inflammatory disease.

Stress in autoimmune disease models.

The release of endogenous glucocorticoids is critical in regulating the severity of disease activity in patients with inflammatory conditions such as rheumatoid arthritis (RA). Blocking cortisol production results in a flare-up in disease activity in RA patients, and surgical removal of the adrenals in patients with Cushing's disease has been reported to exacerbate autoimmune disease. In adjuvant-induced arthritis (AA; a rat model of RA), there is an activation of the hypothalamo-pituitary-adrenal (HPA) axis associated with the development of inflammation. In addition, there are profound changes in peptides within the paraventricular nucleus, which are responsible for regulating the HPA axis. These changes have profound implications on the ability of AA rats to respond to acute stress. Understanding the regulation of the HPA axis in health and disease holds out the promise of targeted therapy to alleviate inflammatory conditions. This article will consider the impact of stress on an individual and his or her susceptibility to inflammation. We wish to question the idea that stress is "all bad." As we shall see, exposure to a single acute stressor can alter the phenotype of the rat to change it from being susceptible to resistant in autoimmune disease models. This alteration in susceptibility takes days to manifest itself, but can last for weeks, suggesting beneficial effects of exposure to an acute stressor.

The nociceptin receptor antagonist [Nphe1,Arg14,Lys15]nociceptin/orphanin FQ-NH2 blocks the stimulatory effects of nociceptin/orphanin FQ on the HPA axis in rats.

Nociceptin/orphanin FQ (N/OFQ) is an opioid-related peptide that stimulates corticosterone release after i.c.v. administration in non-stressed rats. We employed in situ hybridization histochemistry to investigate N/OFQ-stimulated activation of the HPA axis at the hypothalamic and pituitary level. We have demonstrated that N/OFQ-induced activation of the HPA axis is mediated via the central N/OFQ peptide receptor (NOP) using the recently described selective NOP antagonist [Nphe(1),Arg(14),Lys(15)]nociceptin/orphanin FQ-NH(2) (UFP-101). We found that, at 30 min post-i.c.v. injection, N/OFQ dose-dependently increased plasma adrenocorticotrophin hormone and corticosterone compared with the vehicle-injected controls. N/OFQ (1.0 microg) significantly increased CRF mRNA but not AVP mRNA within the parvocellular hypothalamic paraventricular nucleus compared with the control group, and significantly increased pro-opiomelanocortin (POMC) mRNA in the anterior pituitary. While UFP-101 (1.0 microg) alone had no significant effect on plasma corticosterone concentration it blocked the effect of N/OFQ (1.0 microg) on plasma corticosterone levels when compared with N/OFQ administered alone. UFP-101 also blocked the N/OFQ-induced increase in CRF mRNA and POMC mRNA. These results demonstrate that centrally administered N/OFQ activates the HPA axis via up-regulation of CRF and POMC mRNA and stimulation of corticosterone release in rats. Further, we have demonstrated for the first time that the selective NOP receptor antagonist UFP-101 blocks these effects indicating that N/OFQ-induced HPA axis activation is mediated via central NOP receptors.

Differential effects of acute and chronic social defeat stress on hypothalamic-pituitary-adrenal axis function and hippocampal serotonin release in mice.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) stress axis and disturbances in serotonin (5-HT) neurotransmission have been implicated in the pathogenesis of depressive disorder. Repeated social defeat of male NMRI mice has been shown to induce increases in core body temperature and corticosterone, indicative of a state of chronic stress in subordinate animals. The present study further characterised the HPA axis response to social defeat stress, and also examined hippocampal extracellular 5-HT release during the stress. Exposure to an acute social defeat elicits increases in plasma adrenocorticotrophic hormone and corticosterone levels, peaking at 15 and 30 min, respectively, and enhances corticotrophin-releasing factor (CRF) mRNA, but not arginine vasopressin (AVP) mRNA within the medial parvocellular division of the hypothalamic paraventricular nucleus. A concomitant increase in hippocampal corticosterone and 5-HT levels is observed. By contrast, although chronic social defeat is associated with greatly elevated corticosterone levels, the predominant drive appears to be via parvocellular AVP rather than CRF. Furthermore, subordinate animals allowed to recover for 9 days after chronic social defeat display an increase in immobility in the forced swimming model of depression, indicating that animals previously exposed to the homotypic defeat stress are sensitised to the behavioural effects of a novel stressor. These results demonstrate that social defeat induces prolonged activation of the HPA axis and alterations in 5-HT neurotransmission that could be of relevance to some of the pathological abnormalities observed in clinical depression.

Differential actions of acute and chronic citalopram on the rodent hypothalamic-pituitary-adrenal axis response to acute restraint stress.

Serotonin re-uptake inhibitors (SSRIs) can affect the basal activity of the hypothalamic-pituitary-adrenal (HPA) axis in rats. A single injection of citalopram has been shown to stimulate the HPA axis while repeated administration leads to attenuation of the corticosterone response to the SSRI. The purpose of this work was to investigate the rodent HPA axis response to restraint stress, following acute and chronic treatment with the SSRI citalopram. We have demonstrated that a single injection of citalopram is able to prolong acute restraint-induced increases in plasma levels of corticosterone and adrenocorticotrophin (ACTH). This is possibly mediated by arginine vasopressin (AVP) in the parvocellular cells of the paraventricular nucleus (pPVN), as treatment with citalopram or restraint alone did not increase AVP mRNA in pPVN while the combination of treatments resulted in a significant increase in AVP mRNA in the pPVN. In contrast, the increase in corticotrophin-releasing factor (CRF) mRNA in the pPVN in response to acute restraint stress was not altered by citalopram. Oxytocin (OT) mRNA was also increased in the magnocellular PVN (mPVN) by the solo treatments of citalopram and restraint, and was not further enhanced by the dual treatment of restraint and citalopram. Chronic treatment with citalopram did not alter basal plasma levels of corticosterone or ACTH. However, the ACTH response to acute restraint was attenuated following chronic citalopram treatment. AVP mRNA in the pPVN was significantly elevated in response to chronic citalopram compared with saline controls suggesting an effect mediated through the AVP subset of pPVN neurones. The CRF mRNA response to acute restraint was not altered in rats treated chronically with citalopram. OT mRNA was not enhanced in the mPVN following chronic infusion of citalopram but was increased by acute restraint stress. We conclude from these data that both acute and chronic citalopram treatment has the potential to alter the rodent response to acute restraint stress. These effects appear to be regulated by the AVP-containing subset of CRF neurons in the pPVN and thus suggest that parvocellular AVP may have an important role in mediating the actions of SSRIs.

Gonadectomy reverses the sexually diergic patterns of circadian and stress-induced hypothalamic-pituitary-adrenal axis activity in male and female rats.

Enhanced corticosterone release by female compared to male rats under basal and stress conditions is well documented. The demonstration that gonadectomy enhances stress-induced corticosterone secretion in male rats, but reduces such levels in female rats, suggests a causal association between gonadal steroids and corticosterone release. The present study examined the corticosterone profile of sham gonadectomized and gonadectomized female and male rats under basal and stress conditions. An automated sampling system collected blood from each freely moving, unanaesthetized rat every 10 min (i) over a 24-h period; (ii) following noise stress; and (iii) following an immune-mediated stress (lipopolysaccharide, LPS). Plasma was analysed for corticosterone content using radioimmunoassay. Castration resulted in a significant increase in basal corticosterone release compared to the sham-castrated male rats. Pulsar analysis revealed a significant two-fold increase in the number of corticosterone pulses over 24 h. Corticosterone increases in response to noise stress and to LPS injection were enhanced following castration. Conversely, ovariectomy resulted in a two-fold reduction in the number of corticosterone pulses as well as the stress response compared to sham-ovariectomized female rats. Arginine vasopressin (AVP), corticotrophin-releasing hormone (CRH) and glucocorticoid receptor mRNAs in the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary were analysed post-LPS administration by in situ hybridization. Significantly higher values were found for AVP, CRH and POMC mRNAs examined for sham females and castrated males compared to sham males and ovariectomized females. This study confirms previous reports concerning the influence of gonadal factors in regulating HPA axis activity and stress responsiveness. The present results extend these observations to the regulation of the dynamic pattern of corticosterone release under basal conditions and suggests that this alteration in pulsatility is important for the differences in stress responsiveness when comparing males and females.

Immunohistochemical staining of endomorphin 1 and 2 in the immune cells of the spleen.

Endomorphin 1 (EM-1) and EM-2 have been widely reported in the cells of the central nervous system (CNS) but limited research has been done regarding their distribution in the peripheral system. The occurrence of EM-1 and -2 in the spleen as measured by RIA and their ability to mediate immune function imply a role for EMs in this area. The current study examines the localization of EM-1 and -2 in the immune cells of the spleen of male and female rats via an immunohistochemical procedure. In both genders, EM-1 and -2 immunoreactive staining was predominantly present in macrophages and B cells with minimal EM immunoreactive staining in T cells. This is the first evidence of a differential distribution of EM-1 and -2 in cells of the immune system.