Time to pregnancy and life expectancy: a cohort study of 18 796 pregnant couples.

STUDY QUESTION: Is fecundity, measured as time to pregnancy (TTP), associated with mortality in parents? SUMMARY ANSWER: Prolonged TTP is associated with increased mortality in both mothers and fathers in a dose-response manner. WHAT IS KNOWN ALREADY: Several studies have linked both male and female fecundity to mortality. In women, infertility has been linked to several diseases, but studies suggest that the underlying conditions, rather than infertility, increase mortality. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was carried out on 18 796 pregnant couples, in which the pregnant women attended prophylactic antenatal care between 1973 and 1987 at a primary and tertiary care unit. The couples were followed in Danish mortality registers from their child's birth date until death or until 2018. The follow-up period was up to 47 years, and there was complete follow-up until death, emigration or end of study. PARTICIPANTS/MATERIALS, SETTING, METHODS: At the first antenatal visit, the pregnant women were asked to report the time to the current pregnancy. Inclusion was restricted to the first pregnancy, and TTP was categorised into <12 months, ≥12 months, not planned, and not available. In sub-analyses, TTP ≥12 was further categorized into 12-35, 36-60, and >60 months. Information for parents was linked to several Danish nationwide health registries. Survival analysis was used to estimate the hazard ratios (HRs) with a 95% CI for survival and adjusted for age at the first attempt to become pregnant, year of birth, socioeconomic status, mother's smoking during pregnancy, and mother's BMI. MAIN RESULTS AND THE ROLE OF CHANCE: Mothers and fathers with TTP >60 months survived, respectively, 3.5 (95% CI: 2.6-4.3) and 2.7 (95% CI: 1.8-3.7) years shorter than parents with a TTP <12 months. The mortality was higher for fathers (HR: 1.21, 95% CI: 1.09-1.34) and mothers (HR: 1.29, 95% CI: 1.12-1.49) with TTP ≥12 months compared to parents with TTP <12 months. The risk of all-cause mortality during the study period increased in a dose-response manner with the highest adjusted HR of 1.98 (95% CI: 1.62-2.41) for fathers and 2.03 (95% CI: 1.56-2.63) for mothers with TTP >60 months. Prolonged TTP was associated with several different causes of death in both fathers and mothers, indicating that the underlying causes of the relation between fecundity and survival may be multi-factorial. LIMITATIONS, REASONS FOR CAUTION: A limitation is that fecundity is measured using a pregnancy-based approach. Thus, the cohort is conditioned on fertility success and excludes sterile couples, unsuccessful attempts and spontaneous abortions. The question used to measure TTP when the pregnant woman was interviewed at her first attended prophylactic antenatal care: 'From the time you wanted a pregnancy until it occurred, how much time passed?' could potentially have led to serious misclassification if the woman did not answer on time starting unprotected intercourse but on the start of wishing to have a child. WIDER IMPLICATIONS OF THE FINDINGS: We found that TTP is a strong marker of survival, contributing to the still-emerging evidence that fecundity in men and women reflects their health and survival potential. STUDY FUNDING/COMPETING INTEREST(S): The authors acknowledge an unrestricted grant from Ferring. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. M.L.E. is an advisor to Ro, VSeat, Doveras, and Next. TRIAL REGISTRATION NUMBER: N/A.

Effect of exogenously administered glucagon versus spontaneous endogenous counter-regulation on glycaemic recovery from insulin-induced hypoglycaemia in patients with type 2 diabetes treated with a novel glucokinase activator, AZD1656, and metformin.

AIMS: To study the effect of exogenous i.m. glucagon on recovery from controlled insulin-induced hypoglycaemia in patients with type 2 diabetes treated with the novel glucokinase activator AZD1656, in combination with metformin. METHODS: This was a single-centre randomized, open, two-way crossover phase I, automated glucose clamp (Biostator(®); Life Science Instruments, Elkhart, MD, USA) study (NCT00817271) in eight patients (seven men and one woman, mean age 58.6 years, body mass index 28.1 kg/m(2)). All patients received a stable dose of metformin twice daily, ranging from 1000 to 2250 mg. A 2-day titration phase commenced with 40 mg AZD1656 twice daily, escalating to 80 mg twice daily if tolerated. This was followed by a single dose of 80 or 160 mg AZD1656, administered on days 5 and 8 when metabolic studies were performed. After an overnight fast on days 5 and 8, controlled hypoglycaemia was induced using an exogenous i.v. infusion of insulin. Plasma glucose was lowered in a stepwise fashion over 3 h to attain a target nadir of 2.7 mmol/l. This was sustained for 30 min, at the end of which the hypoglycaemic clamp was released. In random sequence, patients either received an i.m. injection of 1 mg glucagon or were allowed to recover from hypoglycaemia by endogenous counter-regulation. To avoid prolonged hypoglycaemia, a reverse glucose clamp was applied from 4 to 6 h post-dose. RESULTS: Three patients received 40 mg AZD1656 twice daily and five patients 80 mg twice daily. Mean plasma glucose at 20 min after release of the hypoglycaemic clamp was significantly lower (3.1 ± 0.3 mmol/l) for AZD1656 alone than for AZD1656 + glucagon (4.9 ± 0.8 mmol/l; p < 0.001 between the groups). Catecholamine and cortisol responses were similar on the AZD1656 + glucagon and AZD alone study days. Growth hormone response was 18% lower for AZD1656 alone (p = 0.01), consistent with the effect of a pharmacological dose of glucagon on growth hormone secretion. No safety or tolerability concerns were observed during treatment with AZ1656. CONCLUSIONS: Exogenous glucagon was effective as a rescue treatment for hypoglycaemia induced during treatment with AZD1656, given in combination with metformin in patients with type 2 diabetes.

Stem cell dynamics and heterogeneity: implications for epidermal regeneration and skin cancer.

The skin epithelium undergoes constant renewal, a process that is driven by stem cells (SCs) localising to the interfollicular epidermis and different regions of the hair follicle. Over the last years, tremendous progress has been made to unravel the physiological function of distinct stem and progenitor cell populations by using genetic lineage tracing in vivo, transplantation, clonogenicity approaches and live cell imaging. It turned out that these cell compartments constitute heterogeneous SC pools and that individual SCs respond differently to various signals sent by the microenvironment. Recent genetic manipulation experiments and elegant mouse models have shed light on the signalling pathways being crucial for self-renewal and lineage fate decisions during tissue homeostasis. Here, we summarise current concepts of SC function in mammalian skin and focus on the dynamic behaviour of SCs during morphogenesis and tissue regeneration of the skin epithelium. Clearly, understanding the cellular and molecular mechanisms of SC regulation and function during tissue homeostasis has enormous impact on our view of the pathogenesis of various skin diseases and will be beneficial for regenerative medicine. Recent experiments suggest an important role of tissue SCs in the process of skin tumour initiation and progression. For the future, the genuine challenge is to further dissect SC function in pathophysiological settings and to translate our knowledge to design novel efficient therapeutic strategies for treatment of cutaneous cancer.

Plasma galanin, vasopressin, and oxytocin in patients with Addison's disease.

Galanin is colocalized with adrenocorticotrophin (ACTH) in the human pituitary and with corticotrophin releasing hormone, arginine, vasopressin, and oxytocin in the hypothalamus. Galanin, vasopressin, and oxytocin influence the secretion of pituitary ACTH. The aim of this study was to investigate if the endogenous stimulation of ACTH release in Addison's disease was reflected in plasma galanin, vasopressin, and oxytocin. ACTH, galanin, vasopressin, and oxytocin were measured in plasma from 14 patients with Addison's disease, one patient with Nelson's syndrome, and 14 healthy controls. Eight patients had elevated plasma ACTH whereas six patients and all controls had ACTH levels within the reference-range. There was no difference in galanin or vasopressin between patients and controls or between samples with low or high ACTH concentrations. In contrast, oxytocin was higher in patients with elevated plasma ACTH compared to patients and controls with normal or low ACTH. No relation was found between galanin or oxytocin and age or sex. A tendency towards lower vasopressin with increasing age was found among the men (p=0.057). The highest ACTH and galanin levels were found in the patient with Nelson's syndrome. In conclusion, increased plasma ACTH was not reflected in elevated plasma galanin or vasopressin. In contrast, elevated ACTH levels were accompanied by higher oxytocin levels.

Effects of arginine-vasopressin and parathyroid hormone-related protein (1-34) on cell proliferation and production of YKL-40 in cultured chondrocytes from patients with rheumatoid arthritis and osteoarthritis.

OBJECTIVE: Both arg-vasopressin (AVP) and parathyroid hormone-related protein (PTHrP) may act as proinflammatory hormones. In addition, they have been suggested to be involved in the pathophysiology of rheumatoid arthritis (RA). We therefore investigated the effects of AVP and PTHrP (1-34) on cell proliferation and secretion of the glycoprotein YKL-40 in human chondrocytes derived from healthy subjects as well as from patients with RA or osteoarthritis (OA). METHOD: Primary cultures of human chondrocytes were incubated with AVP (1-100 pmol/l) or PTHrP (1-34) (0.1-100 nmol/l). Cell proliferation was measured as [3H]thymidine incorporation. Intracellular cAMP and YKL-40 in cell medium were determined by commercially available kits. RESULTS: AVP and PTHrP (1-34) increased proliferation in chondrocytes derived from healthy donors as well as from RA and OA patients. PTHrP (1-34), but not AVP, increased intracellular levels of cAMP. PTHrP (1-34) did not change the amount of YKL-40 in chondrocytes from healthy subjects or patients with OA. AVP tended to decrease the secretion of YKL-40 from healthy chondrocytes. Both PTHrP (1-34) and AVP increased YKL-40 secretion from RA chondrocytes. In contrast, AVP decreased the secretion of YKL-40 in chondrocytes from patients with OA. CONCLUSION: AVP and PTHrP (1-34) stimulated proliferation in human chondrocytes derived from healthy subjects as well as from patients with RA or OA. However, the effects of AVP and PTHrP (1-34) on YKL-40 secretion varied depending on the origin of the chondrocytes.

The effects of arg-vasopressin on osteoblast-like cells in endothelial nitric oxide synthase-knockout mice and their wild type counterparts.

In the present study, we investigated whether nitric oxide (NO) could be involved in the effects of arg-vasopressin (AVP) on osteoblast-like cells. Cells derived from endothelial nitric oxide synthase (eNOS)-knockout mice and their wild type (WT) counterparts, and an osteosarcoma cell line (SaOS-2) were used. AVP (10-100 pmol/l) increased proliferation of osteoblast-like cells from WT mice. The effect was abolished by an AVP V1-receptor antagonist. AVP increased proliferation of cells from eNOSKO mice only when a NO donor, SNAP, was added. A nitric oxide synthase-inhibitor, L-NAME, antagonized the increase in cell proliferation in response to AVP in SaOS-2 cells. In conclusion, this study indicates that NO is involved in the effects of AVP on cell proliferation in osteoblast-like cells.

Inhibited anabolic effect of insulin-like growth factor-I on stromal bone marrow cells in endothelial nitric oxide synthase-knockout mice.

AIMS: Insulin-like growth factor-I (IGF-I), parathyroid hormone (PTH) and PTH-related protein (PTHrP) are hormones that have anabolic effects on bone formation. The aim of this study was to investigate whether production of nitric oxide (NO) is involved in the effect of IGF-I and PTH/PTHrP on osteoblast-like cells. METHODS: Bone marrow stromal cells from adult endothelial nitric oxide synthase (eNOS)-knockout (eNOSKO) mice and wild type (WT) counterparts were cultivated with osteogenic substances. The cells showed an osteoblastic phenotype measured as osteocalcin production and alkaline phosphatase activity. DNA synthesis was measured as [3H] thymidine incorporation in the bone marrow cells and in a human osteosarcoma cell-line (SaOS-2). RESULTS: The stimulatory effect of IGF-I on thymidine incorporation seen in WT animals was absent in eNOSKO mice. Addition of a NO donor to eNOSKO cells recovered the effect of IGF-I on thymidine incorporation. PTH/PTHrP stimulated cell proliferation in both WT and eNOSKO mice. In SaOS-2 cells, incubation with IGF-I together with a NOS inhibitor resulted in an inhibition of the anabolic effect of IGF-I on cell proliferation. CONCLUSIONS: The stimulatory effect of IGF-I on WT cell proliferation was abolished in eNOSKO cells, recovered by an NO donor and inhibited in osteosarcoma cells by a NOS inhibitor. The results indicate that the effect of IGF-I is dependent on NO production. The impaired IGF-I response may contribute to the bone defect formation seen in eNOSKO animals.

Tissue distribution and differential expression of melanocortin 1 receptor, a malignant melanoma marker.

The melanocortin 1 receptor is a G-protein-coupled receptor, described to be expressed on melanomas and melanocytes. Subsequent RT-PCR studies demonstrated the presence of melanocortin 1 receptor mRNA in other tissues such as pituitary gland and testis. Previously, we have demonstrated that three HLA-A2 binding nonamer peptides derived from melanocortin 1 receptor can elicit peptide-specific CTL which can recognize target cells transfected with the melanocortin 1 receptor gene and MHC class I matched melanoma lines. The potential of targeting melanocortin 1 receptor in therapy and diagnosis will depend on a preferential expression of this receptor in the majority of primary and metastatic melanomas vs normal tissues. We tested a panel of melanomas, carcinomas and other cell lines for the presence of melanocortin 1 receptor, using two monoclonal antibodies. The receptor was detected in 83% of the tested melanoma cell lines but not in other carcinoma lines. Immunohistochemistry revealed a strong expression of melanocortin 1 receptor in all tested primary and metastatic melanomas, but also demonstrated low levels of expression in adrenal medulla, cerebellum, liver and keratinocytes. Flow cytometry studies showed that melanocortin 1 receptor was expressed in in vitro activated monocytes/macrophages and in the THP-1 monocytic leukaemia line at levels of about 1 in 3 to 1 in 5 of that found in melanomas. Peripheral blood-derived dendritic cells, also express melanocortin 1 receptor in vitro. This extensive analysis of melanocortin 1 receptor tissue distribution may be of relevance not only for melanoma immunology, but also for research on the pathogenicity of inflammatory conditions in the skin and neurologic tissues. It remains to be seen if the over-expression of melanocortin 1 receptor in melanomas is sufficiently high to allow a 'therapeutic window' to be exploited in cancer immunotherapy.

Inhibition of activated/memory (CD45RO(+)) T cells by oxidative stress associated with block of NF-kappaB activation.

Impaired immune responses in cancer patients have been associated with oxidative stress. Increased levels of reactive oxygen species released from activated, tumor-infiltrating macrophages or granulocytes may therefore constitute a hurdle for effective immunotherapy against cancer. In this study, we investigated functional consequences and molecular events in T cells exposed to low levels of oxidative stress. We observed that cytokine production of human PBMC, upon stimulation with an HLA-A*0201-restricted influenza peptide and nonspecific receptor cross-linking, was reduced after exposure to micromolar levels of H2O2. Functional impairment as measured by IFN-gamma release occurred earlier and at lower doses of exogenously added H2O2 than required to induce apoptosis. This suggests that there is a dose window of oxidative stress leading to T cell unresponsiveness in the absence of apoptosis. The reduction of Th1 cytokines, induced by H2O2, was predominantly observed in memory/effector (CD45RO(+)) T cells and correlated with a block in NF-kappaB activation. IL-10 production was more profoundly influenced by low doses of H2O2 than IFN-gamma, TNF-alpha, and IL-2. The influence of H2O2 on production of IL-10 was not significantly different between memory/activated and naive T cells. These observations suggest that Th1 and Th2 cytokines are differently regulated under conditions of oxidative stress. Taken together, these findings may explain why Ag-experienced, CD45RO(+), T cells found in the tumor milieu are functionally suppressed.

Oxytocin decreases carrageenan induced inflammation in rats.

The effects of oxytocin on carrageenan-induced inflammation in rat hindpaw was examined. Oxytocin at 100 (P < 0.05) and 1000 microg/kg s.c. (P < 0.05), but not at 1 and 10 microg/kg s.c., reduced the edema of the paw when measured up to 10 h after the injection. An additional experiment showed that the effect was comparable to the effect of the glucocorticoid dexamethasone. No effect was found by oxytocin i.c.v. In addition, rats with carrageenan-induced inflammation given oxytocin (1000 microg/kg s.c.) responded differently to nociceptive mechanical stimulation (P < 0.05) and had a reduced amount of myeloperoxidase (marker for neutrophil recruitment) in the paw (P < 0.01).

Antagonistic oxytocin/alpha2-adrenoreceptor interactions in the nucleus tractus solitarii: relevance for central cardiovascular control.

The modulation of the central cardiovascular effects of alpha2-adrenoceptor activation by oxytocin in the nucleus tractus solitarii has been evaluated by cardiovascular analysis and by quantitative receptor autoradiography. Microinjections in the nucleus tractus solitarii of a threshold dose of oxytocin effectively and significantly counteracted the vasodepressor and bradycardic actions of an ED50 dose of the alpha2-adrenoceptor agonist clonidine. The coinjection of a threshold dose of oxytocin with a threshold dose of clonidine did not produce any changes in the mean arterial pressure but a tachycardic response was observed. Receptor autoradiographical experiments showed that oxytocin (3 nM) significantly increased the Kd and Bmax values of [3H]p-aminoclonidine binding sites in the nucleus tractus solitarii compatible with a possible antagonistic interaction with the alpha2-adrenoceptors, and this effect was blocked by the presence of the specific oxytocin receptor antagonist 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin. These findings suggest the existence of an antagonistic oxytocin/alpha2-adrenoceptor interaction in nucleus tractus solitarii that may be of relevance for the demonstrated modulation of alpha2-adrenoceptor induced cardiovascular responses by oxytocin.

Alternative methods providing enhanced sensitivity and selectivity in capillary electroseparation experiments.

The study of alternative and novel techniques for altering selectivity and enhancing sensitivity as well as injection and detection protocols are important in the ongoing development of capillary electroseparation protocols. Some recent research from our laboratory in these fields is presented and discussed in this review. To improve sensitivity an off-line sample enrichment technique utilising solvent evaporation in a levitated drop or an on-line solid-phase extraction protocol was used. The selectivity was tuned by the use of protein gels or molecularly imprinted polymer mediated capillary electrochromatography. Furthermore, a picolitre droplet injection method is described as well as a detection protocol based on laser-induced fluorescence imaging.

T cell tolerance based on avidity thresholds rather than complete deletion allows maintenance of maximal repertoire diversity.

Given the flexible nature of TCR specificity, deletion or permanent disabling of all T cells with the capacity to recognize self peptides would severely limit the diversity of the repertoire and the capacity to recognize foreign Ags. To address this, we have investigated the patterns of CD8+ CTL reactivity to a naturally H-2Kb-presented self peptide derived from the elongation factor 1alpha (EF1alpha). EF1alpha occurs as two differentially expressed isoforms differing at one position of the relevant peptide. Low avidity CTLs could be raised against both variants of the EF1alpha peptide. These CTLs required 100-fold more peptide-H-2Kb complexes on the target cell compared with CTLs against a viral peptide, and did not recognize the naturally expressed levels of EF1alpha peptides. Thus, low avidity T cells specific for these self peptides escape tolerance by deletion, despite expression of both EF1alpha isoforms in dendritic cells known to mediate negative selection in the thymus. The low avidity in CTL recognition of these peptides correlated with low TCR affinity. However, self peptide-specific CTLs expressed elevated levels of CD8. Furthermore, CTLs generated against altered self peptide variants displayed intermediate avidity, indicating cross-reactivity in induction of tolerance. We interpret these data, together with results previously published by others, in an avidity pit model based on avidity thresholds for maintenance of both maximal diversity and optimal self tolerance in the CD8+ T cell repertoire.

Oxytocin/alpha(2)-Adrenoceptor interactions in feeding responses.

The modulation of alpha(2)-adrenoceptor-induced food intake by oxytocin has been evaluated in studies on food intake and by quantitative receptor autoradiography in the hypothalamus and the amygdala of the rat. The effects of lateral intracerebroventricular administration of clonidine and oxytocin were evaluated on food intake in satiated animals. Food consumption was measured at 30, 90, 240 min and 22 h (1,320 min) after injection. The coinjection of oxytocin and clonidine was found to counteract the increase in food intake produced by clonidine (p < 0.001) in satiated rats. Receptor autoradiographic experiments showed that oxytocin significantly increased the K(d) values of [(3)H]p-aminoclonidine alpha(2)-agonist-binding sites in the hypothalamus. Effective oxytocin concentrations ranged between 0.3 and 1 nM (p < 0.05) with a maximal action of 250% at 1 nM. The B(max) value was significantly increased (p < 0.05) for all concentrations of oxytocin. In the amygdala, oxytocin also increased both the K(d) of [(3)H]p-aminoclonidine-binding sites by about 190% at 1 nM and the B(max) values at 1 and 3 nM (p < 0.05). Oxytocin (1 nM) also significantly and substantially (p < 0.01) increased the K(d) and B(max) values of the [(3)H]UK 14.304 alpha(2)-agonist-binding sites in the hypothalamus and amygdala in agreement with the results obtained with the other agonist of the alpha(2)-adrenoceptor [(3)H]p-aminoclonidine. This effect was partially blocked by the presence of the specific oxytocin receptor antagonist, CAP. These findings suggest the existence of an antagonistic oxytocin/alpha(2)-receptor interaction in the hypothalamus and amygdala that may be of relevance for the demonstrated modulation of alpha(2)-adrenoceptor-induced feeding responses by oxytocin.

Systemic oxytocin treatment modulates alpha 2-adrenoceptors in telencephalic and diencephalic regions of the rat.

Systemic subchronic oxytocin treatment significantly and substantially increased the B(max) values of the alpha 2 agonist [(3)H]UK14.304 binding sites in the hypothalamus, the amygdala and the paraventricular thalamic nucleus of the rat as shown by quantitative receptor autoradiography. These results suggest that long-term modulation of autonomic and neuroendocrine functions and emotional behaviours elicited by brain oxytocin may involve enhancement of central alpha 2-adrenoceptor function.

Context and methodological decontextualization in nursing research with examples from phenomenography.

In both human science and nursing research the concept of context is important. However, context can be understood in different ways. The aim of this article is to elucidate, discuss and problematize context, decontextualization and recontextualization in some health care-related phenomenographical studies. A further aim is to problematize the concept of context in a wider perspective of human science, in order to gain a better understanding of phenomenographical research related to nursing care. Our analysis indicates that the complex phenomena which characterize nursing research demand a broad contextual understanding. Both the local or immediate context and the global or mediated context must be considered, as they are dialectically related. This includes the informants' experiences of the phenomenon of interest as well as the socio-cultural discourse. A balance between openness and pliability to the phenomenon is suggested. Reflection is considered an important tool in this process. Within phenomenography, the interest is directed towards conceptions of certain aspects of the world. Thus, context in a wider sense is given a subordinate role. Accordingly, phenomenography is considered to have limited applicability in nursing research when complex phenomena are to be studied.

Oxytocin enhances the effects of clonidine on blood pressure and locomotor activity in rats.

Oxytocin treatment decreases blood pressure and changes the pattern of spontaneous motor activity. The aim of this study was to explore if alpha 2-adrenoreceptors that are involved in the regulation of blood pressure and spontaneous motor activity are influenced by oxytocin treatment. For this purpose, male rats were pretreated with oxytocin (1 mg/kg subcutaneously (s.c.)) or saline once a day during 5 days. Clonidine (alpha 2-adrenoreceptor agonist) decreased blood pressure (2.5 microg/kg intracerebroventricularly (i.c.v.) and 100 microg/kg s.c.) and changed spontaneous motor activity (100 microg/kg s.c.), observed in an open field arena, significantly more in oxytocin pretreated rats compared to saline pretreated controls (P < 0.05). In contrast, idazoxan (alpha 2-adrenoreceptor antagonist) (50 microg/kg i.c.v.) caused a significantly smaller elevation of blood pressure in the oxytocin pretreated rats (P < 0.05). In addition, the effect on blood pressure of an alpha 1-adrenoreceptor agonist, phenylephrine, was evaluated. It increased blood pressure equally in the oxytocin- and saline pretreated rats. The present study shows that subchronic oxytocin treatment increases the effects of clonidine on blood pressure and spontaneous motor activity in rats. These findings imply that alpha 2-adrenoreceptors are involved in the effects of oxytocin treatment on blood pressure and spontaneous motor activity.

A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy.

The objective of this study was to investigate the central processing of dynamic mechanical allodynia in patients with mononeuropathy. Regional cerebral blood flow, as an indicator of neuronal activity, was measured with positron emission tomography. Paired comparisons were made between three different states; rest, allodynia during brushing the painful skin area, and brushing of the homologous contralateral area. Bilateral activations were observed in the primary somatosensory cortex (S1) and the secondary somatosensory cortex (S2) during allodynia compared to rest. The S1 activation contralateral to the site of the stimulus was more expressed during allodynia than during innocuous touch. Significant activations of the contralateral posterior parietal cortex, the periaqueductal gray (PAG), the thalamus bilaterally and motor areas were also observed in the allodynic state compared to both non-allodynic states. In the anterior cingulate cortex (ACC) there was only a suggested activation when the allodynic state was compared with the non-allodynic states. In order to account for the individual variability in the intensity of allodynia and ongoing spontaneous pain, rCBF was regressed on the individually reported pain intensity, and significant covariations were observed in the ACC and the right anterior insula. Significantly decreased regional blood flow was observed bilaterally in the medial and lateral temporal lobe as well as in the occipital and posterior cingulate cortices when the allodynic state was compared to the non-painful conditions. This finding is consistent with previous studies suggesting attentional modulation and a central coping strategy for known and expected painful stimuli. Involvement of the medial pain system has previously been reported in patients with mononeuropathy during ongoing spontaneous pain. This study reveals a bilateral activation of the lateral pain system as well as involvement of the medial pain system during dynamic mechanical allodynia in patients with mononeuropathy.