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This qualitative study explores player and stakeholder perceptions of menstrual health support in elite female soccer.Semi-structured interviews were conducted with 47 participants including players (n = 12), parents (n = 9), coaches (n = 9), sport scientists (n = 7), nutritionists (n = 5) and medical staff (n = 5).Via thematic analysis, data demonstrate that elite female soccer players experience a range of physical and psychological symptoms primarily at the onset of and during menses (as also perceived by stakeholders), with most participants perceiving these symptoms to impact performance. Nonetheless, menstrual health support is perceived as minimal and although players have their menstrual status tracked, they report little understanding as to why or how this information is used. This confusion was also present among stakeholders, often as a result of uncertainty about the evidence supporting the need for menstrual health support. The perceived lack of support may also be reflective of a culture where conversations about the menstrual cycle are not normalised. Overall, this may result in failure to identify and treat menstrual irregularities despite non-coaching staff members perceiving them to be common amongst players.These data support the need for individualised support based on the lived experiences of individual players and support staff. Furthermore, our research identifies the need for organisational, stakeholder, and player centred education programmes (led by experts in female athlete health) that create an environment where players receive personalised menstrual health support.

This qualitative study explores player and stakeholder perceptions of the role of nutrition in supporting player development and performance in elite female soccer. Semi-structured interviews (36 ± 18 mins in length) were conducted with 47 participants, including players (n = 12), parents (n = 9), coaches (n = 9), sport scientists (n = 7), nutritionists (n = 5) and medical staff (n = 5). Via thematic analysis, data provided an insight into the nutrition culture within elite women's soccer. Data demonstrate that considerable confusion and misconceptions exist amongst players and stakeholders regarding the theoretical underpinning and practical application of meeting energy requirements, colloquially referred to as "fuelling". As such, it is perceived that players "under-fuel", which is likely caused by misunderstandings about the impact of carbohydrate intake on body composition, a fear of weight gain and the associated impacts upon body image. The "carbohydrate fear" that is experienced by players is exacerbated by external pressures arising from social media, key stakeholders (e.g., coaches) and the skinfold culture surrounding measurement of body composition. Such cultural issues are amplified by the lack of full-time professionally accredited nutritionists overseeing the provision of nutrition support. Indeed, the infrastructure supporting the women's game (e.g. staffing resource, on-site food provision, player education programmes etc.) was considered incomparable to the men's game. When taken together, our data provide a platform for which to develop organisational, stakeholder and player centred education and behaviour change interventions that strive to promote a positive performance nutrition culture within the women's game.

Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain.SIGNIFICANCE STATEMENTEndogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline. The results demonstrate that meditation-based pain relief does not require endogenous opioids. Therefore, the treatment of chronic pain may be more effective with meditation due to a lack of cross-tolerance with opiate-based medications.

Understanding risk factors for locoregional recurrence (LRR) after accelerated partial breast irradiation (APBI) can help to guide patient selection for treatment with APBI. Published findings to date have not been consistent. More data are needed as these risk factors continue to be defined.A total of 277 women with early-stage invasive breast cancer underwent lumpectomy and were treated adjuvantly at our institution with APBI using high-dose rate brachytherapy. APBI was delivered using multicatheter interstitial brachytherapy (91 %) or single-entry catheter brachytherapy (9 %) to a dose of 32-34 Gy in 8-10 twice daily fractions. Failure patterns and risk factors for recurrence were analyzed.With a median follow-up of 61 months, the 5-year locoregional control rate was 94.4 %. Negative estrogen receptor (ER) status was strongly associated with LRR on multivariate analysis (p 0.005). Lobular histology, the presence of an extensive intraductal component, and lymphovascular invasion also were significant but to a lesser degree than ER-negative status. Patients with multiple risk factors were at highest risk for LRR. Age was not significantly associated with increased risk for LRR.The presence of specific pathological features, particularly ER negative status, was associated with increased risk of LRR in this cohort of women treated with APBI. Further investigation is warranted to determine whether patients with adverse pathological risk factors are at higher risk of LRR after APBI than after conventional whole breast irradiation (WBI), as these same features also may place women at risk for LRR after WBI.

Whole pelvic radiotherapy with concurrent chemotherapy is the standard of care for locally advanced cervical carcinoma. Published literature reports that the pelvic bone marrow (BM) dosimetric parameters of V10 > 90% and V20 > 80% are associated with higher rates of hematologic toxicities using this approach. Here, we investigate the ability of Tomotherapy based intensity modulated radiation therapy (IMRT) to reduce dose to pelvic BM while evaluating dose distribution to critical structures and planning target volume (PTV) coverage. Ten patients were selected for analysis. Normal structures, whole pelvic BM, PTV contours, and IMRT objects were standardized. Two whole pelvis Tomotherapy plans were created for each patient, one standard plan, and one with the addition of a BM sparing (BMS) constraint (V10

Purpose To evaluate outcomes among women with American Society for Radiation Oncology (ASTRO) consensus statement cautionary features treated with brachytherapy-based accelerated partial breast irradiation (APBI). Methods and Materials Between March 2001 and June 2006, 322 consecutive patients were treated with high-dose-rate (HDR) APBI at the University of Wisconsin. A total of 136 patients were identified who met the ASTRO cautionary criteria. Thirty-eight (27.9%) patients possessed multiple cautionary factors. All patients received 32 to 34 Gy in 8 to 10 twice-daily fractions using multicatheter (93.4%) or Mammosite balloon (6.6%) brachytherapy. Results With a median follow-up of 60 months, there were 5 ipsilateral breast tumor recurrences (IBTR), three local, and two loco-regional. The 5-year actuarial rate of IBTR was 4.8% ± 4.1%. The 5-year disease-free survival was 89.6%, with a cause-specific survival and overall survival of 97.6% and 95.3%, respectively. There were no IBTRs among 32 patients with ductal carcinoma in situ (DCIS) vs. 6.1% for patients with invasive carcinoma ( p = 0.24). Among 104 patients with Stage I or II invasive carcinoma, the IBTR rate for patients considered cautionary because of age alone was 0% vs. 12.7% in those deemed cautionary due to histopathologic factors ( p = 0.018). Conclusions Overall, we observed few local recurrences among patients with cautionary features. Women with DCIS and patients 50 to 59 years of age with Stage I/II disease who otherwise meet the criteria for suitability appear to be at a low risk of IBTR. Patients with tumor-related cautionary features will benefit from careful patient selection.

Cerebral cortical activity is heavily influenced by interactions with the basal ganglia. These interactions occur via cortico-basal ganglia-thalamo-cortical loops. The putamen is one of the major sites of cortical input into basal ganglia loops and is frequently activated during pain. This activity has been typically associated with the processing of pain-related motor responses. However, the potential contribution of putamen to the processing of sensory aspects of pain remains poorly characterized. In order to more directly determine if the putamen can contribute to sensory aspects of pain, nine individuals with lesions involving the putamen underwent both psychophysical and functional imaging assessment of perceived pain and pain-related brain activation. These individuals exhibited intact tactile thresholds, but reduced heat pain sensitivity and widespread reductions in pain-related cortical activity in comparison with 14 age-matched healthy subjects. Using magnetic resonance imaging to assess structural connectivity in healthy subjects, we show that portions of the putamen activated during pain are connected not only with cortical regions involved in sensory-motor processing, but also regions involved in attention, memory and affect. Such a framework may allow cognitive information to flow from these brain areas to the putamen where it may be used to influence how nociceptive information is processed. Taken together, these findings indicate that the putamen and the basal ganglia may contribute importantly to the shaping of an individual subjective sensory experience by utilizing internal cognitive information to influence activity of large areas of the cerebral cortex.

Purpose: To investigate the reliability, validity and feasibility of a computer-assisted manual segmentation method for determining the synovial membrane volume as a surrogate measure for synovitis in patients with rheumatoid arthritis (RA). Materials and Methods: The 3 Tesla (T) MRI scans were acquired in 22 early RA and 16 established RA patients. Synovial membrane volumes in postcontrast T1w axial images at three wrist joint regions were determined by two nonradiologist observers using a computer-assisted manual segmentation method. Results: Intraobserver reliability, measured by intraclass correlation coefficients (ICCs), was excellent in the early (ICC = 0.99) and established (ICC = 0.99) RA cohorts. Interobserver reliability (mean ICC [95% Confidence Interval]) was moderate to excellent in the early and established RA groups (ICCs = 0.87 [0.68,0.94] and 0.88 [0.66, 0.96], respectively). There was a strong correlation between the synovial membrane volumes derived by segmentation and the RA MRI scoring system (RAMRIS) scores for synovitis at all joints in the early (Spearman rho = 0.86–0.96) and established (Spearman rho = 0.85–0.93) RA cohorts. The entire segmentation technique took 19 to 21 min per patient. Conclusion: Measurement of MRI synovitis using a computer-assisted manual segmentation method demonstrated excellent intraobserver and very good interobserver reliability, content validity (represented by its strong correlation with RAMRIS synovitis), and moderate feasibility. J. Magn. Reson. Imaging 2011;33:1106–1113. © 2011 Wiley-Liss, Inc.

The subjective experience of one's environment is constructed by interactions among sensory, cognitive, and affective processes. For centuries, meditation has been thought to influence such processes by enabling a nonevaluative representation of sensory events. To better understand how meditation influences the sensory experience, we used arterial spin labeling functional magnetic resonance imaging to assess the neural mechanisms by which mindfulness meditation influences pain in healthy human participants. After 4 d of mindfulness meditation training, meditating in the presence of noxious stimulation significantly reduced pain unpleasantness by 57% and pain intensity ratings by 40% when compared to rest. A two-factor repeated-measures ANOVA was used to identify interactions between meditation and pain-related brain activation. Meditation reduced pain-related activation of the contralateral primary somatosensory cortex. Multiple regression analysis was used to identify brain regions associated with individual differences in the magnitude of meditation-related pain reductions. Meditation-induced reductions in pain intensity ratings were associated with increased activity in the anterior cingulate cortex and anterior insula, areas involved in the cognitive regulation of nociceptive processing. Reductions in pain unpleasantness ratings were associated with orbitofrontal cortex activation, an area implicated in reframing the contextual evaluation of sensory events. Moreover, reductions in pain unpleasantness also were associated with thalamic deactivation, which may reflect a limbic gating mechanism involved in modifying interactions between afferent input and executive-order brain areas. Together, these data indicate that meditation engages multiple brain mechanisms that alter the construction of the subjectively available pain experience from afferent information.

Purpose To investigate the reliability, feasibility, and validity of a computer-assisted manual segmentation (outlining) technique for measuring magnetic resonance imaging (MRI) bone erosion and edema at the wrist in rheumatoid arthritis (RA). Materials and Methods The 3T MRI scans were obtained in 22 RA patients (

The inheritance of A-V conduction time in Polynesians has been examined, using ECGs taken from the population of the Tokelau Islands. As has been demonstrated in other racial groups, A-V conduction time was influenced by sex, age, and heart rate. Complex segregation analysis provides evidence for a significant polygenic influence on A-V conduction, but no evidence for a major gene. Familial correlations and commingling analysis are in agreement with this conclusion. The heritability of A-V conduction time was 0.46. The hypothesis of Moller & Heiberg (1980a) that a major gene could be influencing A-V conduction, is not supported by these data.

ABO blood group-incompatible kidney transplantation (ABOiKTx) outcomes are good, but complications are more common than in conventional transplantation. Regimens that use extracorporeal antibody removal therapy (EART) and enhanced immunosuppression are guided by titration of ABO blood group antibodies (using hemagglutination [HA] dilution assays), and these assays vary significantly in performance between centers. This study aims to describe the differences in titer measurement and the effect on clinical practice and outcomes.This multicentre, prospective cohort study of 100 ABOiKTx recipients assessed treatment and outcome data, including HA assay results measured retrospectively in a single central laboratory.Patient and allograft survival at 1 year was 99% and 94%, respectively. There were significant differences in the number of pretransplantation EART sessions in centers undertaking plasma exchange (PEx), compared with immunoadsorption (IA) (median, 6 vs. 4 sessions; p = 0.007). The pre-EART HA titer in both groups was the same when centrally assayed. The local HA assay used to guide treatment yielded significantly higher titers in centers undertaking PEx compared with IA (median, 128 vs. 32; p 0.005). Patients undergoing PEx rather than IA were significantly more likely to suffer postoperative hematoma (12.9% vs. 1.8%; p = 0.05) or any perioperative collection requiring drainage (19.4% vs. 3.6%; p = 0.02).The colinearity of HA assay sensitivity with the receipt of PEx and EART limits some conclusions regarding the likely direction of causation. However, the association of differences in clinical practice with recognized perioperative complications of ABOiKTx identifies targets for further investigation and quality improvement.

Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p< 0.05). Mindfulness meditation reduced pain intensity (p= 0.032) and pain unpleasantness (p< 0.001) ratings more than placebo analgesia. Mindfulness meditation also reduced pain intensity (p= 0.030) and pain unpleasantness (p= 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain modulation.SIGNIFICANCE STATEMENTRecent findings have demonstrated that mindfulness meditation significantly reduces pain. Given that the “gold standard” for evaluating the efficacy of behavioral interventions is based on appropriate placebo comparisons, it is imperative that we establish whether there is an effect supporting meditation-related pain relief above and beyond the effects of placebo. Here, we provide novel evidence demonstrating that mindfulness meditation produces greater pain relief and employs distinct neural mechanisms than placebo cream and sham mindfulness meditation. Specifically, mindfulness meditation-induced pain relief activated higher-order brain regions, including the orbitofrontal and cingulate cortices. In contrast, placebo analgesia was associated with decreased pain-related brain activation. These findings demonstrate that mindfulness meditation reduces pain through unique mechanisms and may foster greater acceptance of meditation as an adjunct pain therapy.

Our subjective sensory experiences are thought to be heavily shaped by interactions between expectations and incoming sensory information. However, the neural mechanisms supporting these interactions remain poorly understood. By using combined psychophysical and functional MRI techniques, brain activation related to the intensity of expected pain and experienced pain was characterized. As the magnitude of expected pain increased, activation increased in the thalamus, insula, prefrontal cortex, anterior cingulate cortex (ACC) and other brain regions. Pain-intensity-related brain activation was identified in a widely distributed set of brain regions but overlapped partially with expectation-related activation in regions, including the anterior insula and ACC. When expected pain was manipulated, expectations of decreased pain powerfully reduced both the subjective experience of pain and activation of pain-related brain regions, such as the primary somatosensory cortex, insular cortex, and ACC. These results confirm that a mental representation of an impending sensory event can significantly shape neural processes that underlie the formulation of the actual sensory experience and provide insight as to how positive expectations diminish the severity of chronic disease states.

Introduction Magnetic resonance imaging (MRI) is useful for detecting joint inflammation and damage in the inflammatory arthropathies. This study aimed to investigate MRI cartilage damage and its associations with joint inflammation in patients with gout compared with a group with rheumatoid arthritis (RA). Methods Forty patients with gout and 38 with seropositive RA underwent 3T-MRI of the wrist with assessment of cartilage damage at six carpal sites, using established scoring systems. Synovitis and bone oedema (BME) were graded according to Rheumatoid Arthritis MRI Scoring System criteria. Cartilage damage was compared between the groups adjusting for synovitis and disease duration using logistic regression analysis. Results Compared with RA, there were fewer sites of cartilage damage and lower total damage scores in the gout group (P = 0.02 and 0.003), adjusting for their longer disease duration and lesser degree of synovitis. Cartilage damage was strongly associated with synovitis in both conditions (R = 0.59, P

OBJECTIVES To determine parents9 views on autopsy after treatment withdrawal. DESIGN Face to face interviews with 59 sets of bereaved parents (108 individual parents) for whose 62 babies there had been discussion of treatment withdrawal. RESULTS All except one couple were asked for permission for postmortem examination; 38% refused. The main reasons for declining were concerns about disfigurement, a wish to have the child left in peace, and a feeling that an autopsy was unnecessary because the parents had no unanswered questions. The diagnosis, the age of the child, and the approach of the consultant appeared to influence consent rates. Of those who agreed to autopsies, 92% were given the results by the neonatologist concerned. Whether or not they had agreed to the procedure, at 13 months no parent expressed regrets about their decision. CONCLUSIONS Autopsy rates in the East of Scotland stand at 62%. Parents9 perceptions are an important element in consent to postmortem examination.

OBJECTIVE To explore parents9 experiences of bereavement care after withdrawal of newborn intensive care. DESIGN Face to face interviews with 108 parents of 62 babies born over two calendar years in the East of Scotland. RESULTS Only 22% were seen by six weeks after the death, 10% were not recalled before 6–11 months, and 8% were not seen at all in the first year. All except one couple saw the neonatologist who had cared for their baby. Only 33% remembered a neonatal nurse being present. Most (88%) were seen in the study hospital. Parents highlighted a number of specific needs. Appointments should be: ( a ) scheduled soon after the death of the baby and certainly within two months of the death irrespective of whether or not autopsy results are available; ( b ) with the named neonatologist; ( c ) in a setting away from the hospital if possible. Parents value: ( a ) efforts to find out how they are coping; ( b ) full frank information given sensitively to enable them to build up a cohesive picture of what happened and assess their future risks; ( c ) reassurance where possible, but half truths, false reassurances, and broken promises are unacceptable. CONCLUSIONS Follow up care is a crucial part of the management of families from whose babies treatment has been withdrawn. Resources devoted to it should be re-examined to provide a service more in tune with parental need. In choosing the place, timing, and conduct of the meeting, staff should be sensitive to the expressed wishes of the parents themselves.

Introduction Cartilage damage impacts on patient disability in rheumatoid arthritis (RA). The aims of this magnetic resonance imaging (MRI) study were to investigate cartilage damage over three years and determine predictive factors. Methods A total of 38 RA patients and 22 controls were enrolled at t = 0 (2009). After 3 years, clinical and MRI data were available in 28 patients and 15 controls. 3T MRI scans were scored for cartilage damage, bone erosion, synovitis and osteitis. A model was developed to predict cartilage damage from baseline parameters. Results Inter-reader reliability for the Auckland MRI cartilage score (AMRICS) was high for status scores; intraclass correlation coefficient (ICC), 0.90 (0.81 to 0.95) and moderate for change scores (ICC 0.58 (0.24 to 0.77)). AMRICS scores correlated with the Outcome MEasures in Rheumatoid Arthritis Clinical Trials (OMERACT) MRI joint space narrowing (jsn) and X-Ray (XR) jsn scores (r =0.96, P

The brain mechanisms by which sensory cues become transformed into expectations of impending events are a critical component of cognitive tuning of sensory processing. However, distinctions among the afferent processing of cue-related activity itself versus those mechanisms supporting the contextual meaning imparted to the cue remain limited. Do sensory cues with equal meaning engage similar patterns of brain activations even if they are delivered in separate modalities? To address this question, we used functional magnetic resonance imaging of an expectation paradigm in which cues were delivered with visual or innocuous thermal stimuli. Cues were designed to be highly meaningful because they predicted the delivery of high and low painful stimuli. As expected, the cues themselves activated unimodal sensory cortices. This cue modality-specific activation was transformed into a pattern of activity reflecting cue meaning. Cues signaling high pain produced greater activity in the left dorsolateral prefrontal cortex and anterior cingulate cortex. Such activity is consistent with the graded encoding of the magnitude of expected pain. In contrast, cues signaling low pain produced greater activity in the right intraparietal sulcus. This activation may reflect processes directing spatial attention to the stimulated body region in order to more accurately evaluate the relatively weak, low pain stimulus. Taken together, these findings indicate that cues arising from different sensory modalities ultimately engage common brain mechanisms that reflect the meaning of the cue. This meaning-related activity is presumably critical for preparing sensory systems to optimally process afferent information.

Anxiety is the cognitive state related to the inability to control emotional responses to perceived threats. Anxiety is inversely related to brain activity associated with the cognitive regulation of emotions. Mindfulness meditation has been found to regulate anxiety. However, the brain mechanisms involved in meditation-related anxiety relief are largely unknown. We employed pulsed arterial spin labeling MRI to compare the effects of distraction in the form of attending to the breath (ATB; before meditation training) to mindfulness meditation (after meditation training) on state anxiety across the same subjects. Fifteen healthy subjects, with no prior meditation experience, participated in 4 d of mindfulness meditation training. ATB did not reduce state anxiety, but state anxiety was significantly reduced in every session that subjects meditated. Meditation-related anxiety relief was associated with activation of the anterior cingulate cortex, ventromedial prefrontal cortex and anterior insula. Meditation-related activation in these regions exhibited a strong relationship to anxiety relief when compared to ATB. During meditation, those who exhibited greater default-related activity (i.e. posterior cingulate cortex) reported greater anxiety, possibly reflecting an inability to control self-referential thoughts. These findings provide evidence that mindfulness meditation attenuates anxiety through mechanisms involved in the regulation of self-referential thought processes.

Using an ovine model of polycystic ovary syndrome (PCOS), (pregnant ewes injected with testosterone propionate (TP) (100 mg twice weekly) from day (d)62 to d102 of d147 gestation (maternal injection – MI-TP)), we previously reported female offspring with normal glucose tolerance but hyperinsulinemia. We therefore examined insulin signalling and pancreatic morphology in these offspring using quantitative (Q) RT-PCR and western blotting. In addition the fetal pancreatic responses to MI-TP, and androgenic and estrogenic contributions to such responses (direct fetal injection (FI) of TP (20 mg) or diethylstilbestrol (DES) (20 mg) at d62 and d82 gestation) were assessed at d90 gestation. Fetal plasma was assayed for insulin, testosterone and estradiol, pancreatic tissue was cultured, and expression of key b-cell developmental genes was assessed by QRT-PCR. In female d62MI-TP offspring insulin signalling was unaltered but there was a pancreatic phenotype with increased numbers of b-cells (P,0.05). The fetal pancreas expressed androgen receptors in islets and genes involved in b-cell development and function (PDX1, IGF1R, INSR and INS) were up-regulated in female fetuses after d62MI-TP treatment (P,0.05–0.01). In addition the d62MI-TP pancreas showed increased insulin secretion under euglycaemic conditions (P,0.05) in vitro. The same effects were not seen in the male fetal pancreas or when MI-TP was started at d30, before the male programming window. As d62MI-TP increased both fetal plasma testosterone (P,0.05) and estradiol concentrations (P,0.05) we assessed the relative contribution of androgens and estrogens. FI-TP (commencing d62) (not FIDES treatment) caused elevated basal insulin secretion in vitro and the genes altered by d62MI-TP treatment were similarly altered by FI-TP but not FI-DES. In conclusion, androgen over-exposure alters fetal pancreatic development and b-cell numbers in offspring. These data suggest that that there may be a primary pancreatic phenotype in models of PCOS, and that there may be a distinct male and female pancreas.

To determine the safety, tolerability, and report on secondary efficacy endpoints of motexafin gadolinium (MGd) in combination with whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) for patients with ≤ 6 brain metastases. We conducted an international study of WBRT (37.5 Gy in 15 fractions) and SRS (15-21 Gy) with the addition of MGd (5 mg/kg preceding each fraction beginning week 2). The primary endpoint was to evaluate the rate of irreversible grade 3 or any grade ≥ 4 neurotoxicity and establish feasibility in preparation for a phase III trial. Sixty-five patients were enrolled from 14 institutions, of which 45 (69%) received SRS with MGd as intended and were available for evaluation. Grade ≥ 3 neurotoxicity attributable to radiation therapy within 3 months of SRS was seen in 2 patients (4.4%), including generalized weakness and radionecrosis requiring surgical management. Immediately following the course of MGd plus WBRT, new brain metastases were detected in 11 patients (24.4%) at the time of the SRS treatment planning MRI. The actuarial incidence of neurologic progression at 6 months and 1 year was 17 and 20%, respectively. The median investigator-determined neurologic progression free survival and overall survival times were 8 (95% CI: 5-14) and 9 months (95% CI: 6-not reached), respectively. We observed a low rate of neurotoxicity, demonstrating that the addition of MGd does not increase the incidence or severity of neurologic complications from WBRT with SRS boost.

ObjectivesTo develop and test an MRI cartilage scoring system for use at the wrist in rheumatoid arthritis (RA).MethodsMRI scans were obtained using a 3T MRI scanner with dedicated wrist coil in 22 early and 16 established RA patients plus 22 controls. Axial and coronal T1-weighted (precontrast and postcontrast) and T2-weighted turbo spin echo sequences were obtained. Eight wrist joints were scored for cartilage narrowing: distal radioulnar, radiolunate, radioscaphoid, triquetrum-hamate, capitate-lunate, scaphotrapezoid, second metacarpal base-trapezoid and third metacarpal base-capitate, using a system based on the Sharp van der Heijde x-ray joint space narrowing (JSN) score by three radiologists. Fifteen sites at the wrist were also scored for synovitis, bone oedema and erosion using the RA MRI score.ResultsInterobserver (three-reader) and intraobserver reliability (readers 1 and 2) for the cartilage score were excellent: intraclass correlations (ICC (95% CI)) 0.91, (0.86 to 0.94), 0.98 (0.96 to 1.00) and 0.94 (0.87 to 1.00), respectively. Cartilage scores (median, range) were higher in the established RA group (11.9, 2.3–27.3) than the early RA group (2.15, 0–6) (p≤0.001) but early RA scores did not differ from healthy controls (2.3, 1–8.7). Cartilage scores correlated with synovitis (R=0.52), bone oedema (R=0.63) and erosion scores (R=0.66), pConclusionThis MRI cartilage score demonstrated excellent reliability when tested in a three-reader system. However, cartilage loss in early RA could not be distinguished from that seen in healthy controls.

That having a baby in hospital undergoing intensive care is a stressful experience is beyond dispute. Every parent, no matter how well-developed their own personal resources, depends to some extent on the support of others within their social system to cope with this stress. Grandparents occupy a special place in support networks and their role was studied in families with a very low birthweight baby. Both professional and lay perspectives were investigated and 93 families participated. Questionnaires were sent to family members 1 month after the baby's birth and 1 month after discharge home. There was a general consensus that the principal role of grandparents was to provide emotional support. Many practical forms of help were seen to be expressions of their care and concern. There were, however, discrepancies between professional and parental expectations where both protection from problems and obtaining information on behalf of the parents were concerned. More was expected of grandmothers than of grandfathers and maternal grandmothers in particular were key figures. There were a number of areas of potential conflict of needs and rights and a recommendation has been made to give parents a greater voice on who they choose to support them.

Pain can be very intense or only mild, and can be well localized or diffuse. To date, little is known as to how such distinct sensory aspects of noxious stimuli are processed by the human brain. Using functional magnetic resonance imaging and a delayed match-to-sample task, we show that discrimination of pain intensity, a nonspatial aspect of pain, activates a ventrally directed pathway extending bilaterally from the insular cortex to the prefrontal cortex. This activation is distinct from the dorsally directed activation of the posterior parietal cortex and right dorsolateral prefrontal cortex that occurs during spatial discrimination of pain. Both intensity and spatial discrimination tasks activate highly similar aspects of the anterior cingulate cortex, suggesting that this structure contributes to common elements of the discrimination task such as the monitoring of sensory comparisons and response selection. Together, these results provide the foundation for a new model of pain in which bidirectional dorsal and ventral streams preferentially amplify and process distinct sensory features of noxious stimuli according to top-down task demands.

International audience; Much of the evidence linking the short-latency phasic signaling of midbrain dopaminergic neurons with reward-prediction errors used in learning and habit formation comes from recording the visual responses of monkey dopaminergic neurons. However, the information encoded by dopaminergic neuron activity is constrained by the qualities of the afferent visual signals made available to these cells. Recent evidence from rats and cats indicates the primary source of this visual input originates subcortically, via a direct tectonigral projection. The present anatomical study sought to establish whether a direct tectonigral projection is a significant feature of the primate brain. Injections of anterograde tracers into the superior colliculus of macaque monkeys labelled terminal arbors throughout the substantia nigra, with the densest terminations in the dorsal tier. Labelled boutons were found in close association (possibly indicative of synaptic contact) with ventral midbrain neurons staining positively for the dopaminergic marker tyrosine hydroxylase. Injections of retrograde tracer confined to the macaque substantia nigra retrogradely labelled small- to medium-sized neurons in the intermediate and deep layers of the superior colliculus. Together, these data indicate that a direct tectonigral projection is also a feature of the monkey brain, and therefore likely to have been conserved throughout mammalian evolution. Insofar as the superior colliculus is configured to detect unpredicted, biologically salient, sensory events, it may be safer to regard the phasic responses of midbrain dopaminergic neurons as 'sensory prediction errors' rather than 'reward prediction errors', in which case dopamine-based theories of reinforcement learning will require revision.

Pain is a uniquely individual experience that is heavily shaped by evaluation and judgments about afferent sensory information. In visual, auditory, and tactile sensory modalities, evaluation of afferent information engages brain regions outside of the primary sensory cortices. In contrast, evaluation of sensory features of noxious information has long been thought to be accomplished by the primary somatosensory cortex and other structures associated with the lateral pain system. Using functional magnetic resonance imaging and a delayed match-to-sample task, we show that the prefrontal cortex, anterior cingulate cortex, posterior parietal cortex, thalamus, and caudate are engaged during evaluation of the spatial locations of noxious stimuli. Thus, brain mechanisms supporting discrimination of sensory features of pain extend far beyond the somatosensory cortices and involve frontal regions traditionally associated with affective processing and the medial pain system. These frontoparietal interactions are similar to those involved in the processing of innocuous information and may be critically involved in placing afferent sensory information into a personal historical context.

One of the goals of human functional imaging studies is to interpret brain activation in the context of an individual's subjective experience. However, functional magnetic resonance imaging (fMRI) studies usually employ a block design that consists of multiple epochs of stimulation; this strategy does not readily allow subjective responses to be assessed on a stimulus-by-stimulus basis. To address this issue, we developed a "single-epoch" design, consisting of a single stimulation period presented between two baseline periods. This allows subjective ratings to be acquired after each stimulus, while minimizing rating-induced confounds. To evaluate its sensitivity and utility, we obtained fMRI data using single-epoch and block designs (five stimuli between six baselines) and assessed regional brain activations evoked by both visual (a checkerboard pattern) and painful (noxious heat to right calf) stimuli. For both types of stimulation, data collected using the single-epoch design displayed activation patterns that were generally similar to those detected with the block design. Furthermore, only one single-epoch acquisition series was sufficient to detect bilateral activation in the visual cortex during visual stimulation and activation in the primary somatosensory cortex, the anterior cingulate cortex, and other regions during painful stimulation. In addition, analyses of a series of single-epoch data from a single individual revealed a stimulus-by-stimulus decrease in the activation in the anterior cingulate cortex that paralleled the decrease in the subject's psychophysical responses. These findings confirm that the single-epoch design is sensitive to regional signal changes and serves as a viable alternative to the block design when the collection of subjective responses is of critical importance.

Some individuals claim that they are very sensitive to pain, whereas others say that they tolerate pain well. Yet, it is difficult to determine whether such subjective reports reflect true interindividual experiential differences. Using psychophysical ratings to define pain sensitivity and functional magnetic resonance imaging to assess brain activity, we found that highly sensitive individuals exhibited more frequent and more robust pain-induced activation of the primary somatosensory cortex, anterior cingulate cortex, and prefrontal cortex than did insensitive individuals. By identifying objective neural correlates of subjective differences, these findings validate the utility of introspection and subjective reporting as a means of communicating a first-person experience.

Injections of formalin into the rodent paw elicit a rapid orientation of the head and mouth to the source of discomfort, followed by licking and biting the injected area. Previous work has shown this response is dependent on the integrity of the midbrain superior colliculus. The present experiments were initiated to examine the ontogeny of this oral nocifensive reaction and to determine whether it is correlated with the functional maturation of collicular responses to noxious stimuli (as indicated by c-fos immunohistochemistry). Rat pups at various postnatal ages received formalin injections in either the hindpaw or perioral regions. Behaviour was videotaped, and after 120 min, animals were killed and the brain and spinal cord processed for Fos-like immunoreactivity. Uninjected controls were treated identically. Formalin-induced oral responses following injections into the hindpaw and the expression of Fos in the superior colliculus were virtually absent until 10 days postnatal, despite the presence of Fos-like immunoreactivity in many other structures (e.g. spinal cord, parabrachial area, periaqueductal grey). In contrast, animals from day 1 were able to use limbs to localise the perioral injection site. From day 10 onward, there was a progressive increase in oral nocifensive behaviours and Fos expression in the superior colliculus. Our observations are consistent with the hypothesis that the normal elaboration of pain-induced oral behaviour is initiated only after a functionally active superior colliculus has developed, and support previous observations that link the colliculus particularly with oral nocifensive behaviours.

Multiple sensory inputs to the superior colliculus (SC) play an important role in guiding head and eye movements toward or away from biologically significant stimuli. Much is now known about the visual, auditory, and somatosensory response properties of SC neurones that mediate these behavioural reactions. Rather less is known about the responses of SC neurones to noxious stimuli, and thus far, most of this information has been obtained in anaesthetised animals. Therefore, the purpose of the present study was to use the c-fos immunohistochemical technique and standard extracellular electrophysiology as parallel measures of nociceptive activity in the SC under different conditions of anaesthesia. In unanaesthetised animals, experimental and control treatments induced a qualitatively similar pattern of Fos-like immunoreactivity (FLI) in the SC, which was quantitatively related to the severity or biologic salience of the treatment; thus, baseline controlcontrol injections of salinea nonpainful stressor (immobilisation)noxious injections of formalin. Compared with baseline levels, urethane and avertin anaesthesia induced FLI expression in the SC intermediate layers, although the FLI response to both noxious stimulation and control conditions was differentially suppressed in different layers of the SC by anaesthesia. Parallel electrophysiologic recordings found that anaesthesia was associated with high levels of spontaneous activity in the SC intermediate layers, often in neurones which were also nociceptive. High rates of background spike activity were also induced in the SC intermediate layers by noxious stimulation in chronically recorded awake animals. Although these results point to some differences between the nociceptive responses of SC neurones in anaesthetised and unanaesthetised animals, both data sets support the view that there are different populations of nociceptive neurones in the rodent SC that may be related to different adaptive functions of pain.

Lateral suprasylvian cortex (LS) is an important source of visual projections to both the striatum and superior colliculus. Although these two LS efferent systems are likely to be involved in different aspects of visual processing, little is known about their functional properties. In the present experiments, 86 neurons in halothane-anesthetized, paralyzed cats were recorded along the posterior aspects of the medial and lateral banks of LS (PMLS and PLLS). Neurons were selected for analysis on the basis of antidromic activation from electrodes chronically implanted in the superior colliculus and caudate nucleus. The segregated nature of corticostriatal and corticotectal neurons was apparent; in no instance could a neuron be antidromically activated from both the superior colliculus and the caudate nucleus. Many common features were revealed between corticotectal and corticostriatal neurons; the majority of neurons in both populations were binocular and contralaterally dominant, showed similar responses to stationary flashed light, and expressed within-field spatial summation and surround inhibition. However, a number of information-processing features distinguished between corticotectal and corticostriatal neurons; the former were generally tuned to lower velocities than were the latter, and, for a given eccentricity in visual space, corticotectal neurons had smaller receptive fields than did corticostriatal neurons. Moreover, most corticotectal neurons displayed a marked preference for movements toward temporal visual space, whereas corticostriatal neurons revealed no specialization for a particular direction of movement. In addition, whereas corticotectal neurons were selective for receding stimuli, corticostriatal neurons were selective for approaching stimuli. The presence of these two corticofugal pathways is discussed in relation to their presumptive functional roles in the facilitation of attentive and orientation behaviors.

A wealth of evidence implicates the crossed descending projection from the superior colliculus (SC) in orientation and approach behaviours directed towards novel, non-noxious stimuli. In our preceding paper, we identified a population of nociceptive neurones in the rat SC that have axons that project to the contralateral brainstem via this output pathway. The purpose of the present study was, therefore, to evaluate the prediction that the crossed descending projection of the SC is also involved in the control of orientation and approach movements of the head and mouth made during the localisation of persistent noxious stimuli. An independent-groups design was used to test the effects of interrupting the contralateral descending projection from the SC on the behavioural reactions elicited by noxious mechanical stimuli presented to the tail and hindpaws. In different groups of animals, a microwire knife was used to cut the contralateral descending fibres at two different locations : (I) a sagittal cut at the level of the dorsal tegmental decussation; (2) a bilateral coronal cut of the predorsal bundle at the level of the medial pontine reticular formation. Retrograde anatomical tracing techniques were then used to evaluate the effectiveness of the cuts and to assess possible involvement of non-collicular fibre systems in both lesioned and control animals. Additional behavioural procedures were performed to test for general neurological status and responsiveness of animals to non-noxious stimuli. Anatomical tracing data indicated that the largest population of neurones with fibres severed by both cuts were the cells-of-origin of the contralateral descending projection in the intermediate white layer of the SC. Behavioural results showed that significantly more animals in both lesion groups failed to locate and bite a mechanical clip placed on the tail. Instead of switching to motor behaviours to localise and remove noxious stimuli, they persisted with defensive reactions, which included freezing, vocalisation or forward and backward escape. In contrast, when the clip was placed on the hindpaws, it was successfully localised by most lesioned and control animals ; however, lesioned animals had reliably longer latencies and spent less time in close contact with the clip. Consistent with the established role of the contralateral descending projection in non-noxious orientation, lesioned animals also showed orienting deficits to a range of non-noxious sensory stimuli. These data suggest that, under certain behavioural circumstances, nociceptive information from the SC is integral to the elaboration of orienting and approach movements of the head and mouth elicited by persistent noxious stimuli.

Discussion on the efficacy of the clinical involvement and credibility of nurse educators has been ongoing for a considerable time. The author sheds new light on the subject by referring to a survey of nurse education on HIV/AIDS in the UK. She concludes that while a measure of clinical experience is desirable in teaching, it is not always possible to have all the necessary qualities wrapped up in one person, and calls for carefully integrated team effort to take nurse education forward.

1. The onset of visual activity in the superficial layers of the cat superior colliculus begins abruptly at about 6 days postnatal (DPN), just before natural eye opening. Despite the presence of many inactive sites at this time, the systematic nature of the superior colliculus visuotopy is already evident. The number of inactive sites across the horizontal dimension of the superficial layers decreases rapidly so that by 9–10 DPN most sites are visually responsive. 2. Initially, visual activity is restricted to the topmost portion of the superficial gray layer, where W-cell terminals predominate, but rapidly extends down to include Y-cell territory at 10 DPN. 3. In contrast to what might have been expected based on earlier behavioral observations, there was no physiological evidence for a central-to-peripheral gradient in the development of the superior colliculus visuotopy. Rather, the entire visual field is well represented long before the expression of any visually initiated behaviors. 4. In contrast to the rapidity of the appearance and organization of the visual representation in superficial layers, deep layers remain refractory to visual stimuli for weeks.

OBJECTIVE--To evaluate the clinical and echocardiographic results of mitral valve repair done within an 11 year period. DESIGN--Retrospective review of case notes and clinical and echocardiographic examination of survivors. Analysis was made according to the intention to treat principle. PATIENTS--A consecutive series of 94 patients with mitral valve disease who had mitral reconstruction between 1980 and 1991. INTERVENTIONS--Mitral repair according to the techniques of Carpentier or Duran. MAIN OUTCOME MEASURES--Operative mortality, actuarial survival, rates of freedom from reoperation, thromboembolism, infective endocarditis, clinical state, and echocardiographic findings. RESULTS--There were equal numbers of males and females (mean (range) age 49 (4-74) years). The aetiology of mitral disease was degenerative in 59% and rheumatic in 30% of the patients. Operative mortality was 3%. The 10 year actuarial and valve related survival rates were 67% and 75%. At 10 years, 84% of the patients were free from thromboembolism, 94% free from haemorrhage related to anticoagulation, 88% free from infective endocarditis, and 73% free from reoperation. Of 75 survivors with completed follow up, 96% were in New York Heart Association functional class I or II and 64% were in sinus rhythm. Of 55 survivors who had an echocardiogram at follow up, normal left ventricular end diastolic dimension was shown in 76% and normal left ventricular shortening fraction in 89%. Doppler studies showed no mitral regurgitation in 36%, trivial or mild in 42%, moderate in 14%, and severe in 7% of patients. In stepwise logistic analysis previous myocardial infarction was associated with poor outcome (odds ratio: 13.7, p < 0.05). CONCLUSION--The results are comparable with similar studies and support the value of mitral valve repair. There is reservation about the use of repair for patients with previous myocardial infarction.

to review the utilisation of 2-D and Doppler echocardiography between 1984 and 1990.analysis of request forms and echocardiogram reports for patient demographics, major clinical indications and principal echocardiogram findings.between May 1984 and December 1990 11,701 studies were done in 8101 patients. Requests for scans increased by an average of 225 per year. Most frequently scanned were male (55%), inpatients (52%) and patients aged 60-69 yr (19%). In 1984 cardiologists made 100% of the requests and did 78% of the studies. In 1990 noncardiologists requested 48% of scans and 91% of studies were done by technicians. Echocardiograms were requested most often for assessment of valve disease (39%), left ventricular function (18%) and congenital heart disease (15%). Thirty-five percent of studies showed valve disease, 17% myocardial disorders and 10% congenital heart disease. Normal findings were shown in 25%.in this 6.5 year period there was a rapid increase in the utilisation of echocardiography and the practice changed from one requested by and done by cardiologists to a generally available service provided by technicians. The greatest application for scanning was in the assessment of acquired valvar disease and myocardial disorders. One-quarter of echocardiograms showed normal cardiac structure and function.

A prospective study was conducted to investigate the perceptions of 21 mothers of singleton babies weighing 1500 g or less. Six in-depth interviews were held with each respondent from 1 week after delivery to 3 months after the baby's discharge from hospital. Diaries and Neonatal Perception Inventories supplied additional data. Six phases were identified each characterized by certain critical factors related to the mother's emotional state, her perceptions of the baby, and family responses. Significant statistical differences were found between those mothers who did not feel ready to take the infant home and the rest of the sample. Those who were not ready demonstrated a marked difficulty in establishing and maintaining relationships and held very inappropriate perceptions of the baby. These findings have important implications for the discharge of very low birthweight babies after a prolonged stay in hospital.

Twenty-four patients with subacute massive pulmonary embolism were studied both during their initial illness and up to nine years after it. The most common mode of presentation was progressive dyspnoea over a two to 12 week period, which in some, but not all, patients was accompanied by pleuritic chest pain and haemoptysis. Physical signs at diagnosis usually suggested right heart strain and ventilation/perfusion mismatch and in the five patients with the highest pulmonary artery pressures the pulmonary component of the second sound was accentuated. The chest x-ray and electrocardiogram provided useful diagnostic information in most patients though occasionally they were normal. Early response to thrombolytic treatment was poor when compared with patients with acute pulmonary embolism but was occasionally dramatically successful, and heparin alone provided satisfactory treatment in the eight patients receiving it. Pulmonary embolectomy provided poor results and four of the five patients undergoing this form of treatment died. Nine patients died during the initial illness and in seven death was directly related to embolic disease. One patient died from neoplastic disease during follow-up. Though the prolonged illness, poor initial response to treatment, and absence of predisposing factors suggest that recurrent embolic disease and late pulmonary hypertension might occur three was no evidence of this during a follow-up period of one to nine years (median five years).

Heart rate at rest and during increasing workloads was measured in a double blind study of 12 patients with chronic atrial fibrillation when serum concentrations of digoxin were nil and at low and high therapeutic values. Twelve normal subjects were studied for comparison. The heart rate at all levels of exercise in most patients with atrial fibrillation was not adequately controlled by any serum digoxin concentration tested despite a reduction in heart rate with increasing serum digoxin concentrations. Control of the resting heart rate, even in patients with high serum digoxin concentrations, did not ensure adequate control of the heart rate during work rates equivalent to regular daily activities.

Six patients in sinus rhythm with congestive heart failure due to either myocardial infarction or cardiomyopathy, were given oral frusemide to eliminate oedema. Symptomatic relief occurred as body weight was reduced, and after a 'dry' basal weight had been achieved, progressive-load exercise testing was done to examine any benefit that derived from adding oral digoxin to the diuretic. Three pairs of sub-maximal exercise tests were done at intervals over three months, and the responses of each patient when using digoxin and diuretics were compared with those when using diuretics alone. One patient did not complete this study, because more frequent premature beats and increased angina followed the withdrawal of digoxin. For the five patients who completed three pairs of tests, there was no significant change in symptoms, in workload achieved, or in heart rate, respiratory rate, ventilation and respiratory quotient, whether digoxin was added or removed. It is concluded that in these patients where salt and water retention was controlled with diuretics, digoxin did not improve the capacity for exercise, and it is suggested that for such patients with myocardial disease in sinus rhythm, treatment should begin with diuretics.

1. Psychophysical experiments were initiated to determine the possible influence of increasing stimulus size on perceived pain intensity. Six trained human subjects (5 male, 1 female) made visual analogue scale (VAS) ratings for pain-sensation intensity and unpleasantness in response to nociceptive thermal stimuli. Test stimuli consisted of 5-s duration heat pulses (45-50 degrees C in 1 degrees increments) delivered by one, two, or three contact thermal probes (1 cm2 each) applied to the medial aspect of the anterior forearm. 2. The area of skin receiving noxious thermal stimuli was changed by randomly varying the number of thermodes activated. The effects of varying the distance between the thermal probes also were evaluated. In the first series of experiments, thermal-probe separation was kept close to 0; in subsequent experimental series, the thermodes were separated by either 5 or 10 cm. 3. In each experimental series, considerable spatial summation occurred in both pain-sensation intensity and unpleasantness dimensions of pain. This summation occurred throughout the nociceptive thermal range of 45-50 degrees C and was larger at suprathreshold temperatures (greater than or equal to 47 degrees C) than those near threshold (less than or equal to 46 degrees C). Unlike spatial summation of perceived warmth, that of pain was not characterized by systematic changes in power-function exponents but as approximately upward parallel displacements in double-logarithmic coordinates. 4. Thermal-probe separation over a range of 0-10 cm had no effects on spatial summation of pain-sensation intensity or pain unpleasantness. In contrast, increasing thermal-probe separation increased the subjects' ability to discriminate differences in stimulus size and their ability to detect correctly the number of thermal probes activated. 5. Because affective VAS ratings of unpleasantness were linearly related to, but distinctly and systematically less than, VAS ratings of pain-sensation intensity, it was clear that subjects responded quite differently to these two pain dimensions. Affective judgements were not additionally influenced by thermal probe separation and hence by the ability to perceive stimulus size or number of thermal probes activated. 6. The results indicate that powerful spatial-summation mechanisms exist for heat-induced pain. Spatial summation of pain is likely to be subserved both by local integration mechanisms at the level of single spinothalamic-tract neurons and by recruitment of central nociceptive neurons, because spatial summation of pain occurred to approximately equal extents under conditions of thermode separations over a distance of at least 20 cm.