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Background: Disease-related-malnutrition predicts poor clinical outcomes in elderly patients, and screening is pivotal for identifying patients at nutritional risk. The present study aimed to investigate nutrition screening rates in electronic patient records and validate the scores given. A secondary aim was to investigate whether the proportion of patients at risk differed between patients where screening was documented and those where no screening was documented., Methods: This cross-sectional observational study was conducted in a Danish university hospital during November 2020. Patients aged 65 years or more admitted to a medical department were included. The Nutrition Risk Screening 2002 (NRS-2002) tool was used to identify patients at nutritional risk, both in routine clinical care, where data were collected retrospectively, and during a validation process in a random patient sample, where data were collected prospectively., Results: In total, 817 patients were admitted for more than 24 h. Of these, an NRS-2002 score was documented in 294 (36%), among whom 177 (60%) were at nutritional risk. In 146 patients where no score was documented, 88 (60%) were at risk. Validation was possible in 91 patients where a record-based score and a validated score were documented. The specificity of the record-based score was 100%, whereas the sensitivity was 75%, indicating that routine screening underestimated nutritional risk (p < 0.001, proportion difference 19%; 95% confidence interval = 10%-28%)., Conclusions: Electronic documentation does not solve issues about compliance with nutritional risk screening. In patients where screening was not documented, the occurrence of nutritional risk was similar, indicating that omission of screening is not related to the score., (© 2022 The Authors. Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)

Vacuolar-type adenosine triphosphatases (V-ATPases) 1-3 are electrogenic rotary mechanoenzymes structurally related to F-type ATP synthases 4,5 . They hydrolyse ATP to establish electrochemical proton gradients for a plethora of cellular processes 1,3 . In neurons, the loading of all neurotransmitters into synaptic vesicles is energized by about one V-ATPase molecule per synaptic vesicle 6,7 . To shed light on this bona fide single-molecule biological process, we investigated electrogenic proton-pumping by single mammalian-brain V-ATPases in single synaptic vesicles. Here we show that V-ATPases do not pump continuously in time, as suggested by observing the rotation of bacterial homologues 8 and assuming strict ATP-proton coupling. Instead, they stochastically switch between three ultralong-lived modes: proton-pumping, inactive and proton-leaky. Notably, direct observation of pumping revealed that physiologically relevant concentrations of ATP do not regulate the intrinsic pumping rate. ATP regulates V-ATPase activity through the switching probability of the proton-pumping mode. By contrast, electrochemical proton gradients regulate the pumping rate and the switching of the pumping and inactive modes. A direct consequence of mode-switching is all-or-none stochastic fluctuations in the electrochemical gradient of synaptic vesicles that would be expected to introduce stochasticity in proton-driven secondary active loading of neurotransmitters and may thus have important implications for neurotransmission. This work reveals and emphasizes the mechanistic and biological importance of ultraslow mode-switching., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Non-sputum-based tests to accurately identify active tuberculosis (TB) disease and monitor response to therapy are urgently needed. This study examined the biomarker capacity of a panel of plasma proteins alone, and in conjunction with a previously identified miRNA signature, to identify active TB disease., Methods: The expression of nine proteins (IP-10, MCP-1, sTNFR1, RANTES, VEGF, IL-6, IL-10, TNF and Eotaxin) was measured in the plasma of 100 control subjects and 100 TB patients, at diagnosis (treatment naïve) and over the course of treatment (1-, 2- and 6-month intervals). The diagnostic performance of the nine proteins alone, and with the miRNA, was assessed., Results: Six proteins were significantly up-regulated in the plasma of TB patients at diagnosis compared to controls. Receiver operator characteristic curve analysis demonstrated that IP-10 with an AUC = 0.874, sensitivity of 75% and specificity of 87% was the best single biomarker candidate to distinguish TB patients from controls. IP-10 and IL-6 levels fell significantly within one month of commencing treatment and may have potential as indicators of a positive response to therapy. The combined protein and miRNA panel gave an AUC of 1.00. A smaller panel of only five analytes (IP-10, miR-29a, miR-146a, miR-99b and miR-221) showed an AUC = 0.995, sensitivity of 96% and specificity of 97%., Conclusions: A novel combination of miRNA and proteins significantly improves the sensitivity and specificity as a biosignature over single biomarker candidates and may be useful for the development of a non-sputum test to aid the diagnosis of active TB disease., Competing Interests: The authors report no conflicts of interest with regard to this publication., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Efforts to reduce the global TB burden are hindered by the lack of simple, reliable non-sputum based diagnostics. To date studies investigating the biomarker potential of circulating host proteins and mRNA have not shown sufficient diagnostic utility. Recently, there has been increasing interest in circulating miRNA as a biomarker of TB disease. This review examined all published miRNA-TB biomarker studies to determine if a reproducible miRNA signature of TB disease could be elucidated. From 15 miRNA profiling studies, 894 miRNA differentially expressed between TB patients and healthy controls were identified in at least one study. Of these, 143 miRNA were validated by qPCR with 53 differentially expressed between TB patients and controls. Interestingly, only 8 of these miRNA were identified in 2 or more studies, and no consensus on a reproducible miRNA signature for identification of TB disease could be identified. TB disease is clearly associated with a wide breadth of differentially expressed miRNA. This review highlights our recent progress and the multiple factors, including environment, source of tissue, ethnicity and extent of TB disease that may influence miRNA expression. Coordinated efforts are required to validate identified targets in multiple populations to progress miRNA biomarker development., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Prognostic uncertainty inhibits clinicians from initiating timely end-of-life discussions and advance care planning. This study evaluates the efficacy of the CriSTAL (Criteria for Screening and Triaging to Appropriate aLternative care) checklist in emergency departments., Methods: Prospective cohort study of patients aged ≥65 years with any diagnosis admitted via emergency departments in ten hospitals in Australia, Denmark and Ireland. Electronic and paper clinical records will be used to extract risk factors such as nursing home residency, physiological deterioration warranting a rapid response call, personal history of active chronic disease, history of hospitalisations or intensive care unit admission in the past year, evidence of proteinuria or ECG abnormalities, and evidence of frailty to be concurrently measured with Fried Score and Clinical Frailty Scale. Patients or their informal caregivers will be contacted by telephone around three months after initial assessment to ascertain survival, self-reported health, post-discharge frailty and health service utilisation since discharge. Logistic regression and bootstrapping techniques and AUROC curves will be used to test the predictive accuracy of CriSTAL for death within 90 days of admission and in-hospital death., Discussion: The CriSTAL checklist is an objective and practical tool for use in emergency departments among older patients to determine individual probability of death in the short-term. Its validation in this cohort is expected to reduce clinicians' prognostic uncertainty on the time to patients' death and encourage timely end-of-life conversations to support clinical decisions with older frail patients and their families about their imminent or future care choices., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Abstract: To determine the validity of the Australian clinical prediction tool Criteria for Screening and Triaging to Appropriate aLternative care (CRISTAL) based on objective clinical criteria to accurately identify risk of death within 3 months of admission among older patients., Methods: Prospective study of ≥ 65 year-olds presenting at emergency departments in five Australian (Aus) and four Danish (DK) hospitals. Logistic regression analysis was used to model factors for death prediction; Sensitivity, specificity, area under the ROC curve and calibration with bootstrapping techniques were used to describe predictive accuracy., Results: 2493 patients, with median age 78-80 years (DK-Aus). The deceased had significantly higher mean CriSTAL with Australian mean of 8.1 (95% CI 7.7-8.6 vs. 5.8 95% CI 5.6-5.9) and Danish mean 7.1 (95% CI 6.6-7.5 vs. 5.5 95% CI 5.4-5.6). The model with Fried Frailty score was optimal for the Australian cohort but prediction with the Clinical Frailty Scale (CFS) was also good (AUROC 0.825 and 0.81, respectively). Values for the Danish cohort were AUROC 0.764 with Fried and 0.794 using CFS. The most significant independent predictors of short-term death in both cohorts were advanced malignancy, frailty, male gender and advanced age. CriSTAL's accuracy was only modest for in-hospital death prediction in either setting., Conclusions: The modified CriSTAL tool (with CFS instead of Fried's frailty instrument) has good discriminant power to improve prognostic certainty of short-term mortality for ED physicians in both health systems. This shows promise in enhancing clinician's confidence in initiating earlier end-of-life discussions., Competing Interests: MC and KH developed the risk prediction tool in 2015 and have tested it retrospectively in several hospitals. This might be perceived by readers as non-financial conflict of interest given their knowledge of the subject matter or materials discussed in this manuscript. However, they have no affiliations with or involvement in any organisation or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; or expert testimony or patent-licensing arrangements), that may influence the validity of the study. All other authors certify that they have NO conflict of interest to report. The analyses were led by two co-authors (RMT and FG) who were not involved in the development of the tool, data collection or outcome ascertainment for this validation study.The study was approved in Australia by the hospital management teams and by the South Eastern Sydney Local Health District Ethics Committee [#15/026 HREC/15/POW/55 and data was stored in the UNSW secure server. The need for approval in Denmark was waivered by the Regional Ethics Committee of Southern Denmark, as this project was considered to be a quality improvement initiative without an intervention [42].Verbal information on the study preceded the request for written informed consent which was obtained from each individual if cognitively competent or their surrogate at the time of recruitment. Participants consented to being interviewed, giving access to hospital records during admission, and being contacted for follow-up outcome ascertainment. The original consent remained with the researchers and a copy went to the patient or their family.

Objectives: To compare the effects of two nutritional follow-up interventions with regard to preventing short-term deterioration in ADL, and to compare their effects on physical function, emotional health, and health-related quality of life., Design: Randomized clinical trial with two intervention groups and one control group, and a follow-up period of eight weeks., Setting: Intervention in the participants' homes after discharge from hospital., Participants: Inclusion: Malnourished geriatric patients and patients at risk of malnutrition (MNA<24), aged 75 years and older, living at home and alone. Exclusion: Nursing home residents and patients with terminal illnesses or cognitive impairment. Randomization: At discharge, the patients were assigned to one of three groups: 'home visit', 'telephone consultation', or 'control' group., Intervention: Individually tailored nutritional counselling of the patient and the patient's daily home carer by a clinical dietician one, two, and four weeks after discharge from hospital. The counselling was either in-person at the patients' homes, or by telephone. The control group received no follow-up after discharge., Measurements: Primary outcome: Change in ADL (Barthel-100 score) at discharge and eight weeks later., Secondary Outcomes: Change in physical performance (handgrip strength, 30-sec. chair stand test, CAS), quality of life and depression measurements (SF-36, Depression List, Geriatric Depression Score), and Avlund mobility-tiredness score (Mob-T)., Results: Two-hundred and eight participants were randomized, 73 to home visits and 68 to telephone consultations. The control group comprised 67 patients. The mean age of the participants was 86.1 years. At eight weeks after discharge, 157 completed the follow-up (home visit 52, telephone consultation 51, and control group 54). The mean age of these patients was 85.8 years. More patients in the home visit group improved or maintained their ADL (96%), compared to the telephone (75%) and control groups (72%), p<0.01. No difference was detected among the groups with regard to physical measurements, health-related quality of life, and emotional health., Conclusion: Early nutritional follow-up after discharge, performed as home visits, prevents deterioration of ADL in malnourished, independent, geriatric patients who live alone and thereby preserves their independence.

Only a few smaller studies have addressed the effect of psychosocial factors on risk of chronic obstructive pulmonary disease (COPD) in spite of the potential for psychosocial stress to affect development of the disease through immunological and behavioural pathways. The aim of this study is to determine the relation between various psychosocial risk factors, individually and accumulated, and COPD hospitalisation and deaths. A total of 8728 women and men free of asthma and COPD participating in the Copenhagen City Heart Study, were asked comprehensive questions on major life events, work-related stress, social network, vital exhaustion, economic hardship, and sleep medication in 1991-1993 and followed in nationwide registers until 2009, with <2% loss to follow-up. During follow-up, 461 women and 352 men were hospitalized with or died from COPD. Major life events in adult life and vital exhaustion were both associated with a higher risk of COPD in an exposure-dependent manner, with high vital exhaustion being associated with a hazard ratio [HR] of 2.31 (95% CI 1.69-3.16) for women and 2.48 (1.69-3.64) for men. A higher risk of COPD was also found in participants who experienced economic hardship or had a dysfunctional social network. Furthermore, the accumulation of psychosocial risk factors was associated with a higher risk of COPD in both women (HR = 2.40, 1.78-3.22) and men (HR = 1.93, 1.33-2.80). Psychosocial vulnerability may be important to consider both in clinical practice and when planning future preventive strategies against COPD.

Purpose of Review: Neurostimulation has emerged as a viable treatment for intractable chronic cluster headache. Several therapeutic strategies are being investigated including stimulation of the hypothalamus, occipital nerves and sphenopalatine ganglion. The aim of this review is to provide an overview of the rationale, methods and progress for each of these., Latest Findings: Results from a randomized, controlled trial investigating sphenopalatine ganglion stimulation have just been published. Reportedly the surgery is relatively simple and it is apparently the only therapy that provides relief acutely., Summary: The rationale behind these therapies is based on growing evidence from clinical, hormonal and neuroimaging studies. The overall results are encouraging, but unfortunately not all patients have benefited. All the mentioned therapies require weeks to months of stimulation for a prophylactic effect to occur, suggesting brain plasticity as a possible mechanism, and only stimulation of the sphenopalatine ganglion has demonstrated an acute, abortive effect. Predictors of effect for all modes of neurostimulation still need to be identified and in the future, the least invasive and most effective strategy must be preferred as first-line therapy for intractable chronic cluster headache.

Background: Animal models have shown histamine to be released from the skin during the acute phase of a burn injury. The role of histamine during the early phase of thermal injuries in humans remains unclear., Purpose: The objectives of this trial were to study histamine release in human skin during the acute phase of a standardized thermal injury in healthy volunteers., Methods: Histamine concentrations in human skin were measured by skin microdialysis technique. Microdialysis fibers were inserted into the dermis in the lower leg in male healthy volunteers. A standardized superficial thermal injury was elicited by a heating thermode (49 degrees C) applied to the skin for 5 min. Histamine in dialysate was analyzed for up to 2 h after the injury using two different analytical methods., Results: Spectrofluorometric assay of histamine showed no histamine release in separate studies using 2-min samples over 20 min (n = 6) and 5-10-min samples over 120 min (n = 8). The histamine values were at the limits of the quantification limit of the spectrofluorometric assay. Confirmatory studies using a sensitive radioimmunoassay confirmed no histamine release within the first hour of a thermal injury (baseline 11.6 +/- 1.8 nM vs. post-burn values of 14.8 +/- 1.8 nM, n = 8)., Conclusions: Histamine is not released in human skin during the acute phase of a thermal injury.

In this study, we examined the onset and duration of local analgesic effects of bupivacaine incorporated into biodegradable microcapsules (extended-duration local anesthetic; EDLA) administered as subcutaneous infiltrations in different doses in humans. In 18 volunteers, the skin on the medial calf was infiltrated with 10 mL of EDLA, and the opposite calf was infiltrated with 10 mL of aqueous bupivacaine (5.0 mg/mL) in a double-blinded, randomized manner. Three different concentrations of EDLA were tested (6.25, 12.5, and 25 mg/mL), with 6 subjects in each group. Pain responses to mechanical and heat stimuli and sensory thresholds (touch, warm, and cold detection thresholds) were examined by von Frey hairs and contact thermodes. Assessments were made before and 2, 4, 6, 8, 24, 48, 72, 96, and 168 h after the injections. Safety evaluations were performed daily for the first week and at 2 wk, 6 wk, and 6 mo after the injections. The time to maximum effects was significantly shorter for aqueous bupivacaine (2-6 h) than for EDLA (4-24 h), but there were no significant differences between the maximum effects of EDLA and aqueous bupivacaine. From 24 to 96 h after the injections, EDLA was significantly more efficient than aqueous bupivacaine for all variables, and significant effects of EDLA were demonstrated for at least 96 h for all variables. In general, a dose-response gradient was seen in the EDLA group for 5 of 7 variables when the curves expressing effect over time for the different concentrations were evaluated. No serious side effects were observed for up to 6 mo after administration. In conclusion, bupivacaine incorporated in microcapsules provided analgesia for 96 h after subcutaneous infiltration.

Propofol has a greater amnesic effect than thiopental. In this study we tested whether different brain regions were affected by propofol and thiopental at similar drug effects. Changes in regional cerebral blood flow (rCBF) were identified by using SPM99 analysis of images obtained with positron emission tomography with (15)O water. Ten right-handed male volunteers (age, 35 +/- 10 yr; weight, 74.1 +/- 7.5 kg; mean +/- sd) were randomized to receive thiopental (n = 4) or propofol (n = 6) to target sedative and hypnotic concentrations with bispectral index (BIS) monitoring. Four positron emission tomography images were obtained during various tasks at baseline and with sedative and hypnotic effects. Two participants receiving propofol were unresponsive at sedative concentrations and were not included in the final analyses. Median serum concentrations were 1.2 and 2.7 microg/mL for sedative and hypnotic propofol effects, respectively. Similarly, thiopental concentrations were 4.8 and 10.6 microg/mL. BIS decreased similarly in both groups. The pattern of rCBF change was markedly different for propofol and thiopental. Propofol decreased rCBF in the anterior (right-sided during sedation) brain regions, whereas thiopental decreased rCBF primarily in the cerebellar and posterior brain regions. At similar levels of drug effect, propofol and thiopental affect different regions of the brain. These differences may help to identify the loci of action for the nonsedative effects of propofol, such as amnesia.

One of the oldest methods of pain relief following a burn injury is local application of ice or cold water. Experimental data indicate that cooling may also reduce the severity of tissue injury and promote wound healing, but there are no controlled studies in humans evaluating the anti-inflammatory or anti-hyperalgesic potential of early cooling after thermal injury. Twenty-four healthy volunteers participated in this randomized, single-blinded study. Following baseline measurements, which included inflammatory variables (skin temperature, erythema index) and sensory variables (thermal and mechanical detection thresholds, thermal and mechanical pain responses, area of secondary hyperalgesia), first degree burn injuries were induced on both calves by contact thermodes (12.5 cm(2), 47 degrees C for 7 min). Eight minutes after the burn injury, contact thermodes (12.5 cm(2)) were again applied on the burns. One of the thermodes cooled the burn (8 degrees C for 30 min) whereas the other thermode was a non-active dummy on the control burn. Inflammatory and sensory variables were followed for 160 min after end of the cooling procedure. The burn injury induced significant increases in skin temperature (P<0.0005), erythema index (P<0.0001), thermal pain responses (P<0.0005), mechanical pain responses (P<0.005) and secondary hyperalgesia, and significant decreases in heat pain threshold (P<0.0005) and mechanical pain threshold (P<0.0005). There were no post-cooling effects on skin temperature (P>0.5), erythema (P>0.9), heat pain threshold (P>0.5), thermal or mechanical pain responses (P>0.5) or the development of secondary hyperalgesia (P>0.4) compared with the control burn. However, a significant, albeit transient, increase in cold detection threshold was observed on the cooled burn side (P<0.0001). In conclusion, cooling with 8 degrees C for 30 min following a first degree burn injury in humans does not attenuate inflammatory or hyperalgesic responses compared with a placebo-treated control burn.

Background: Quantitative reviews of postoperative pain management have demonstrated that the number of patients needed to treat for one patient to achieve at least 50% pain relief (NNT) is 2.7 for ibuprofen (400 mg) and 4.6 for paracetamol (1000 mg), both compared with placebo. However, direct comparisons between paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) have not been extensively reviewed. The aims of this review are (i) to compare the analgesic and adverse effects of paracetamol with those of other NSAIDs in postoperative pain, (ii) to compare the effects of combined paracetamol and NSAID with those of either drug alone, and (iii) to discuss whether the adverse effects of NSAIDs in short-term use are justified by their analgesic effects, compared with paracetamol., Methods: Medline (1966 to January 2001) and the Cochrane Library (January 2001) were used to perform a systematic, qualitative review of postoperative pain studies comparing paracetamol (minimum 1000 mg) with NSAID in a double-blind, randomized manner. A quantitative review was not performed as too many studies of high scientific standard (27 out of 41 valid studies, including all major surgery studies) would have been excluded., Results: NSAIDs were clearly more effective in dental surgery, whereas the efficacy of NSAIDs and paracetamol seemed without substantial differences in major and orthopaedic surgery, although firm conclusions could not be made because the number of studies was limited. The addition of an NSAID to paracetamol may confer additional analgesic efficacy compared with paracetamol alone, and the limited data available also suggest that paracetamol may enhance analgesia when added to an NSAID, compared with NSAIDs alone., Conclusion: Paracetamol is a viable alternative to the NSAIDs, especially because of the low incidence of adverse effects, and should be the preferred choice in high-risk patients. It may be appropriate to combine paracetamol with NSAIDs, but future studies are required, especially after major surgery, with specific focus on a potential increase in side-effects from their combined use.

Background and Objectives: The aim of the study was to examine the analgesic effects of the anticonvulsant, gabapentin, in a validated model of acute inflammatory pain., Methods: Twenty-two volunteers were investigated in a double-blind, randomized, placebo-controlled cross-over study. Gabapentin 1,200 mg or placebo was given on 2 separate study days. Three hours after drug administration, a first-degree burn injury was produced on the medial aspect of the nondominant calf (12.5 cm(2), 47 degrees C for 7 minutes). Quantitative sensory testing (QST) included pain ratings to thermal and mechanical stimuli (visual analog scale [VAS]), assessments of thermal and mechanical detection thresholds, and areas of secondary hyperalgesia. Side effects drowsiness and postural instability were assessed by subjective ratings (VAS)., Results: The burn injury induced significant primary and secondary hyperalgesia (P <.0001). Gabapentin diminished the decrease in mechanical pain threshold in the burn area (P =.04) and reduced secondary hyperalgesia, but the reduction was not significant (P =.06). Heat pain thresholds, pain during the burn, and mechanical pain in the area of secondary hyperalgesia were not significantly changed by gabapentin (P <.2). Ratings of drowsiness and unsteadiness during walking were significantly higher for gabapentin than for placebo (P <.05)., Conclusions: The study indicates that gabapentin has no analgesic effect in normal skin, but may reduce primary mechanical allodynia in acute inflammation following a thermal injury. These observations suggest a clinical potential of gabapentin in the treatment of postoperative pain.

Several studies have demonstrated the presence of opioid inducible receptors on peripheral nerves and peripheral antinociceptive effects of opioids. However, the effects of peripheral opioid administration in man are controversial. Our study used a randomized, double-blind, placebo-controlled, three-way crossover design in a human model of acute inflammatory pain (heat injury). We studied 18 healthy volunteers who each received morphine locally (2 mg), morphine systemically (2 mg), or placebo on three separate study days. The subjects received morphine infiltration subcutaneously (s.c.). 1 h before heat injury (47 degrees C, 7 min) and naloxone infiltration s.c. (0.2 mg) 2.5 h after the heat injury. Hyperalgesia to mechanical and heat stimuli were examined using von Frey hairs and thermodes, and pain was rated using a visual analogue scale. The burns produced significant hyperalgesia, but local morphine infiltration neither reduced pain during the burn, nor primary or secondary hyperalgesia to mechanical and heat stimuli after the burn. In conclusion, peripherally applied morphine had no acute antinociceptive effects in this human model of acute inflammatory pain.

Human experimental pain models are important tools in pain research. The primary aims of pain research in normal man is 1) to provide insight in pain mechanisms, 2) to provide a rational basis for clinical trials of pain relieving interventions, and 3) to confirm the anti-nociceptive effects demonstrated in animal models. Most often clinical pain is due to tissue damage leading to acute inflammation and hyperalgesia, but only few human pain models have examined pain responses in injured tissues. Therefore, models with controlled and reversible tissue trauma are needed. The human burn model is an example of such a model, and several groups have performed studies of analgesics and pain mechanisms based on the model. The thesis aims to provide a critical review of the human burn model as a tool in pain research, and to give suggestions for development of the model and future research. The pain and inflammatory responses to superficial thermal burns in skin have been studied in healthy volunteers. Burns have the potential for releasing most of the inflammatory and chemical mediators that produce sensitisation and excitation of nociceptors, and the intense nociceptive input during injury produces sensitisation of central neurones in the nociceptive pathway. Pain and hyperalgesia have been evaluated in the model by thermal, various mechanical, and electrical stimuli. The different methods of pain assessments are discussed to clarify the underlying neural mechanisms, the questions that can be addressed by the measurements, and the discrepancies in results between studies. Inflammation has been evaluated in the model by skin erythema intensity, area of flare, and blister formation. The major determinant of skin erythema intensity is the amount of blood in the most superficial part of the dermis, and burn-induced erythema may be primarily due to congestion of capillary loops and postcapillary venules. The area of flare may be used to evaluate the efferent function of heat-sensitive A delta- and C-fibre nociceptors, whereas blisters may be used to assess edema formation and the degree of injury. Hyperalgesia is induced immediately by the burns and lasts about 24 h dependent on the intensity of the heat stimulus. The burns heal without sequela. A study of the reproducibility of pain assessments in the burn model has shown that measures based on repeated measurements were significantly more reproducible than measures based on single time points. Further, within-day reproducibility was better than between-day reproducibility. Within-day variations of heat pain responses to 45 degrees C and 47 degrees C were smaller than that of pain responses to 43 degrees C, suggesting that assessments using clearly painful stimuli may be more reproducible. A methodological study also demonstrated that habituation to experimental pain developed as the study proceeded. Habituation is common in experimental pain models, and dividing analgesics and placebo evenly between the study days is one way of eliminating the effects of habituation. The use of simultaneous right-left comparisons represents the ideal design when possible. The burn model has been a valuable tool in the study of pain mechanisms. Hyperalgesia to heat in the burned area (primary hyperalgesia) is mediated by sensitisation of C-fibre mechano-heat-sensitive (CMH) nociceptors and A delta-fibre mechano-heat-sensitive (AMH) nociceptors of type I in hairy skin. A contribution from sensitised CNS neurones is likely, and the sensitisation of nociceptors is confined to the injured area. The presence of hyperalgesia to heat in normal skin surrounding a burn (secondary hyperalgesia) has been demonstrated in several studies, but the pain threshold may be unaltered. The mechanisms for primary hyperalgesia to mechanical stimuli may be both peripheral and central, but the importance of peripheral mechanisms is unclear and central mechanisms may account for mechanical hyperalgesia in both the primary and th

Riluzole modulates several transmitter systems which may be involved in nociception. Antinociceptive effects have been shown in animal studies, but there are no human data. Therefore, we have examined the acute analgesic effect of riluzole in a human model of inflammatory pain induced by a thermal injury on the distal leg (47 degrees C, 7 min, 12.5 cm2) in 20 healthy volunteers. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and thermodes. We used a randomized, double-blind, placebo-controlled design, and subjects received riluzole 100 mg or placebo for 2 days with a 14-day interval. The burns produced significant hyperalgesia, but riluzole had no acute analgesic effects in normal or hyperalgesic skin.

Unlabelled: BACKGROUND. This study examined the analgesic effect of local ketamine infiltration, compared with placebo and systemic ketamine, in a human model of inflammatory pain., Methods: Inflammatory pain was induced by a burn (at 47 degrees C for 7 min; wound size, 2.5 x 5 cm) on the calf in 15 volunteers on 3 separate days with 7-day intervals. They received either (1) subcutaneous infiltration with ketamine in the burn area (local treatment) and contralateral placebo injections, or (2) subcutaneous ketamine contralateral to the burn (systemic treatment) and placebo in the burn area, or (3) placebo on both sides. The study was double-blinded and the order of the treatments was randomized. Hyperalgesia to mechanical and heat stimuli was examined by von Frey hairs and contact thermodes (3.75 and 12.5 cm2), and pain was rated using a visual analog scale (0-100)., Results: The burns produced significant hyperalgesia. Local ketamine infiltration reduced pain during the burn injury compared with systemic treatment and placebo (P < 0.01). Heat pain thresholds were increased by local ketamine treatment compared with placebo immediately after injection (P < 0.03), and so were the mechanical pain thresholds (P = 0.02). Secondary hyperalgesia and suprathreshold pain responses to heat and mechanical stimuli were not significantly affected by local ketamine. No difference between local ketamine and placebo could be detected 1 h and 2 h after the burn., Conclusions: Ketamine infiltration had brief local analgesic effects, but several measures of pain and hyperalgesia were unaffected. Therefore, a clinically relevant effect of peripheral ketamine in acute pain seems unlikely.

The aim of the study was to examine the presence of hyperalgesia to heat stimuli within the zone of secondary hyperalgesia to punctate mechanical stimuli. A burn was produced on the medial part of the non-dominant crus in 15 healthy volunteers with a 50 x 25 mm thermode (47 degrees C, 7 min), and assessments were made 70 min and 40 min before, and 0, 1, and 2 h after the burn injury. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and contact thermodes (3.75 and 12.5 cm2), and pain responses were rated with a visual analog scale (0-100). The area of secondary hyperalgesia to punctate stimuli was assessed with a rigid von Frey hair (462 mN). The heat pain responses to 45 degrees C in 5 s (3.75 cm2) were tested in the area just outside the burn, where the subjects developed secondary hyperalgesia, and on the lateral crus where no subject developed secondary hyperalgesia (control area). The burns decreased pain thresholds and increased pain responses to both thermal and mechanical stimuli within the burn (P < 10(-5)). Further, the burns induced secondary hyperalgesia (mean 89 cm2) to punctate mechanical stimuli (P < 10(-5)), and increased the pain response to mechanical stimuli in the areas of secondary hyperalgesia (P < 10(-5)). The pain response to heat stimuli increased over time in the area of secondary hyperalgesia (P < 10(-5)), and so did the pain response to heat on the lateral part of the crus (P < 10(-3)). However, the heat pain response increased more (P = 0.006) and was more intense (P = 0.001) within the zone of secondary hyperalgesia than on the lateral part of the crus. Further, the heat pain response was more intense in the zone of primary hyperalgesia than in the zone of secondary hyperalgesia (P = 0.004), in contrast to the mechanical pain response, which was not significantly different between the two zones of hyperalgesia. In conclusion, secondary hyperalgesia in man is not restricted to mechanical stimuli, as significant hyperalgesia to heat developed within the zone of secondary hyperalgesia to punctate mechanical stimuli. The data, combined with other evidence, suggest differences in the mechanisms accounting for primary hyperalgesia to heat and mechanical stimuli, whereas secondary hyperalgesia to heat and mechanical stimuli may be explained by a common central mechanism.

The aim of the study was to examine reproducibility of primary and secondary hyperalgesia in a psychophysical model of human inflammatory pain. Mild burns were produced on the crura of 12 volunteers with a 50 x 25 mm thermode (47 degrees C, 7 min). Assessments of (i) cold and warm detection thresholds, (ii) mechanical and heat pain thresholds, (iii) pain to heat (43 degrees C and 45 degrees C, 5 s), (iv) secondary hyperalgesia, and (v) skin erythema were made 1.75 and 0.5 h before, and 0, 1, 2, 4, and 6 h after a burn injury. Sensory thresholds and hyperalgesia to heat and mechanical stimuli were examined by contact thermodes and von Frey hairs, and pain intensity was rated with a visual analog scale (0-100). To describe between-day reproducibility, the subjects were examined three times at intervals of 21 days. Within-day comparisons showed that a 20% change could be detected as significant for all variables with fewer than 12 subjects in a cross-over design (2alpha = 5% and power = 80%). Between-day comparisons demanded up to 25 subjects to detect changes of the same magnitude. The burns caused mild to moderate pain (VAS: mean 29, SD 14) and the subjects (all right-handed) were more sensitive to heat pain on their left side (P < 0.03). Hyperalgesia was induced instantaneously by the burn and outlasted the study period (6 h). However, no spontaneous pain was observed after the injury, and a brief period of hypoesthesia to warm and cold stimuli was induced by the burn. The painful measurements themselves evoked hyperalgesia to heat and mechanical stimuli on the arm, but only to mechanical stimuli on the legs. including secondary hyperalgesia. Hyperalgesia evoked by the measurements was significantly less intense than that induced by injury. Habituation to the painful stimuli was demonstrated by significantly higher pain thresholds and lower pain responses on the second and third day of the study. The burn model is a sensitive psychophysical model of acute inflammatory pain, when cross-over designs and within-day comparisons are used, and the model is suitable for double-blind, placebo-controlled studies of analgesics. In similar models, we recommend that analgesic and placebo are evenly divided between right and left sides and study days.

Temporal summation of pain occurs when repeated stimuli become increasingly painful in spite of unchanged stimulus intensity. Summation can be quantified as the difference in pain between the first and the last stimulus in a train of stimuli. The aim of the study was to compare temporal summation of pain in normal skin with summation of pain in skin with primary and secondary hyperalgesia evoked by a heat injury. A heat injury was produced on the crus of 12 volunteers with a 50 x 25 mm thermode (47 degrees C, 7 min). Measurements were made before, and 0, 1, 2, and 4 h after the heat injury, in three areas: primary and secondary mechanical hyperalgesia induced by the heat injury, and in a mirror image of the injury on the opposite leg. Temporal summation of pain was induced by repeated electrical stimuli (five stimuli at 2 Hz) and assessed by visual analog scale (VAS). Primary hyperalgesia was evaluated by von Frey hairs and electrical stimuli, and the areas of secondary hyperalgesia with a rigid von Frey hair (314 mN). Significant primary (P < 0.000001) and secondary (P < 0.00006) mechanical hyperalgesia were evoked by the heat injury. The pain threshold to single electrical stimuli was reduced within the injury (P < 0.03), but not outside. The pain responses to single and repeated electrical stimuli were not significantly altered by the injury. Temporal summation of pain occurred in 418 stimulus trains out of 576 (73%), but no significant changes in summation developed in skin with primary or secondary mechanical hyperalgesia compared with normal skin (baseline measurements). Temporal summation at high stimulus intensities was more pronounced than at lower intensities (P < 0.0002). We found no correlation between either temporal summation and area of secondary hyperalgesia, or temporal summation and pain intensity during the induction of heat injury. We conclude that the development of primary and secondary mechanical hyperalgesia after heat injury in man was not associated with changes in temporal summation of painful electrical stimuli.

Background: Sympathetic nerve blocks relieve pain in certain chronic pain states, but the role of the sympathetic pathways in acute pain is unclear. Thus the authors wanted to determine whether a sympathetic block could reduce acute pain and hyperalgesia after a heat injury in healthy volunteers., Methods: The study was made as a randomized, single blinded investigation, in which the volunteers served as their own controls. A lumbar sympathetic nerve block and a contralateral placebo block were performed in 24 persons by injecting 10 ml bupivacaine (0.5%) and 10 ml saline, respectively. The duration and quality of blocks were evaluated by the sympatogalvanic skin response and skin temperature. Bilateral heat injuries were produced on the medial surfaces of the calves with a 50 x 25 mm thermode (47 degrees C, 7 min) 45 min after the blocks. Pain intensity induced by heat, pain thresholds to thermal and mechanical stimulation, and secondary hyperalgesia were assessed before block, after block, and 1, 2, 4, and 6 h after the heat injuries., Results: Of the 24 volunteers, eight were excluded because of somatic block or incomplete sympathetic block. The study revealed no significant differences between sympathetic block and placebo for pain or mechanical allodynia during injury, or pain thresholds, pain responses to heat, or areas of secondary hyperalgesia after the injury. The comparisons were done for the period when the block was effective., Conclusion: Sympathetic nerve block did not change acute inflammatory pain or hyperalgesia after a heat injury in human skin.

Pain relief may be improved by reducing sensitization of nociceptive pathways caused by tissue injury. Such a reduction depends mainly on inhibition of local inflammatory changes and the relation between duration of nociceptive block and nociceptive input. In this study we examined if prolonged topical treatment with local anaesthetics could reduce late hyperalgesia and local inflammation after burn injury in healthy volunteers. The effects of EMLA treatment for 8 h after burn on hyperalgesia, inflammation and wound healing were compared with the contralateral placebo-treated leg for 48 h after bilateral burn injuries (15 x 25 mm, 49 degrees C for 5 min) in a double-blind, randomized study in 12 healthy volunteers. Wound healing was studied 1 and 2 weeks after injury. Neither mechanical nor thermal primary hyperalgesia were affected significantly by prolonged EMLA treatment. Secondary hyperalgesia and skin erythema were also not changed. Seven of 12 placebo-treated legs developed blisters, in contrast with four of 12 EMLA-treated legs. Wound healing showed no apparent differences. Our data suggest that prolonged, topical treatment with local anaesthetics did not reduce local inflammation and late hyperalgesia.

Background: Postoperative pain relief may be improved by reducing sensitization of nociceptive pathways caused by surgical trauma. Such a reduction may depend on the timing and efficacy of analgesia and the duration of the nociceptive block versus the duration of the nociceptive input. We examined whether a prolonged nerve block administered before a superficial burn injury could reduce local inflammation and late hyperalgesia after recovery from the block., Methods: The effects of a preemptive saphenous nerve block on primary and secondary hyperalgesia, skin erythema, and blister formation, were compared to the opposite unblocked leg for 12 h after bilateral thermal injuries (15 x 25 mm, 49 degrees C for 5 min) in 20 healthy volunteers. Recovery from the block was identified by return of sensation to cold., Results: Six subjects were excluded because of insufficient initial block (2 subjects) or because the block lasted beyond the study period (4 subjects). The remaining 14 subjects experienced significantly reduced primary (P = 0.005) and secondary hyperplasia (P = 0.01) in the blocked leg after return of cold sensation compared to the unblocked leg. Erythema intensity and blister formation were not significantly affected by the blockade (P = 0.94 and P = 0.07, respectively)., Conclusions: These data suggest that a prolonged, preemptive nerve block reduced late hyperalgesia after thermal injury, whereas the erythema and blister formation were not significantly affected.

This study investigated the antinociceptive and anti-inflammatory effect of a topical non-steroidal anti-inflammatory drug in human thermal injury. Twelve healthy unmedicated volunteers had identical burn injuries produced on the medial side of both calves with a 49 degrees C 15 x 25 mm thermode. Ketorolac gel or placebo were randomly applied on the right or left calf 1.5 h before burn injury, immediately after burn injury and 6 and 12 h later in a double-blind trial where every subject served as his own control. Heat pain detection thresholds (HPDT), head pain tolerance (HPT), mechanical pain detection thresholds (MPDT) and the intensity of burn-induced erythema (erythema index, EI) were assessed in the area of the thermal injury, and areas of hyperalgesia to pin prick were determined outside the injury before and 3, 6 and 24 h after the burn injury. Burn injury led to a decrease in HPDT, HPT and MPDT, an increase in EI and development of mechanical hyperalgesia (P < 0.05). Ketorolac gel had no effect on any of the nociceptive or inflammatory variables studies (P > 0.2).

We report spermaturia in two normal boys with testicular volumes of 3 ml and no other signs of puberty. This supports the hypothesis that spermatogenesis can begin before any other signs of puberty and indicates that the definition of start of puberty as testicular volumes of 4 ml or more may be too rigorous.

We have studied the antinociceptive and anti-inflammatory effects of topical glucocorticoids in human thermal injury. The right and left legs of 12 healthy volunteers were allocated randomly to be treated with either 0.05% clobetasol propionate cream or placebo in a double-blind trial. Thermal injuries were induced with a thermode, which was heated to 49 degrees C for 5 min under standardized pressure. Clobetasol propionate or placebo cream was applied to the skin 1 h before burn injury, immediately after the injury and every 12 h for the next 3 days. Heat pain detection thresholds (HPDT), heat pain tolerance (HPT), mechanical pain detection thresholds (MPDT) and the intensity of burn-induced erythema (erythema index, EI) were assessed inside the thermal injury and areas of hyperalgesia to pinprick outside the injury were determined before and regularly for 72 h after the burn injury. Burn injury caused a decrease in HPDT, HPT and MPDT, an increase in EI and development of mechanical, secondary hyperalgesia. Clobetasol propionate had no effect on any of the nociceptive or inflammatory variables studied.

The pattern of spermaturia in boys at different stages of puberty was investigated. Fractionated 24 hour urine was collected for nine consecutive days from eight boys aged 13-14 years and 10 boys aged 15-17 years. Spermatozoa were detected by microscopic examination of the sediment. Sex characteristics were recorded. Fifty five per cent of all urine samples were positive for sperm and all boys showed spermaturia. A large variation in spermaturia was found between and within boys at the same stage of puberty. Spermaturia was a more common and regular event during early and mid-puberty than in more mature subjects. This indicates that the mechanism of spermaturia in early and late puberty could be different. It is suggested that spermaturia in non-virilised boys could be a result of a spontaneous, continuous flow of spermatozoa to the urethra in contrast with the peristaltic flow during ejaculation occurring at a later stage of puberty.

An iron-sulfur protein has been isolated from bovine brain mitochondria and purified 200-fold. The optical spectrum (peaks at 412 and 455 nm which disappear upon reduction) and the EPR spectrum (g values at 1.94 and 2.02) were typical for a ferredoxin. In reconstitution experiments, the protein could replace adrenodoxin in the cholesterol side chain cleavage reaction. The additional detection of cytochrome P-450 in brain mitochondria indicates that the isolated ferredoxin is part of a cytochrome P-450-dependent hydroxylation system.

TPN mixtures should contain all nutritional element necessary in the nutritional therapy--including unstable vitamins. In this study the stability of ascorbic acid and folic acid was investigated in a TPN mixture containing 12 vitamins by HPLC and microbiological assays. The degradation of both vitamins proceeded by first order kinetics. Half-lives for ascorbic acid were 1.1 h, 2.9 h, and 8.9 h when stored at 24 degrees C by daylight, 24 degrees C protected from light, and 4 degrees C protected by light, respectively. Under similar conditions half-lives for folic acid were 2.7 h, 5.4 h, and 24 h. The degradation rates found make pre-addition of these two vitamins to TPN mixtures questionable, storage for longer periods is inappropriate. For TPN patients receiving additional fluid intravenously it was found that addition of multivitamins to isotonic NaCl-solution was advisable. For other TPN patients alternative ways of vitamin administration might be preferable. When testing the stability of vitamins in TPN mixtures it was found that the brand of multivitamin preparation used was of importance. It should be stressed that data on the stability of vitamins derived from studies on the addition of a single vitamin cannot be extrapolated to multivitamin preparations because of possible mutual vitamin interactions.

Human and bovine serum albumin bound to silica or aminopropyl silica were used as chiral stationary phases (CSPs). D,L-Thyronine, D,L-tryptophan, N-benzoyl-D,L-phenylalanine, D,L-warfarin and D,L-benzoin could be resolved on these CSPs using a mobile phase of 0.05 M phosphate buffer, pH 7.0. The capacity factor of D-thyronine was higher than that of L-thyronine. The resolution of D,L-thyronine was completely lost by the presence of bilirubin in the mobile phase, but only little affected by caprylate. By contrast, the resolution of D,L-tryptophan was not affected by bilirubin, but lost by the presence of caprylate. These results are consistent with binding of D-thyronine to the bilirubin binding site and L-tryptophan to the caprylate binding site in albumin, respectively, and suggests that such "displacement chromatography" can be used for the determination of binding sites. The optical purity of D-thyroxine in tablets was determined indirectly after de-iodination by catalytic hydrogenation.