Early standardized clinical judgement for syncope diagnosis in the emergency department.

BACKGROUND: The diagnosis of cardiac syncope remains a challenge in the emergency department (ED). OBJECTIVE: Assessing the diagnostic accuracy of the early standardized clinical judgement (ESCJ) including a standardized syncope-specific case report form (CRF) in comparison with a recommended multivariable diagnostic score. METHODS: In a prospective international observational multicentre study, diagnostic accuracy for cardiac syncope of ESCJ by the ED physician amongst patients ≥ 40 years presenting with syncope to the ED was directly compared with that of the Evaluation of Guidelines in Syncope Study (EGSYS) diagnostic score. Cardiac syncope was centrally adjudicated independently of the ESCJ or conducted workup by two ED specialists based on all information available up to 1-year follow-up. Secondary aims included direct comparison with high-sensitivity cardiac troponin I (hs-cTnI) and B-type natriuretic peptide (BNP) concentrations and a Lasso regression to identify variables contributing most to ESCJ. RESULTS: Cardiac syncope was adjudicated in 252/1494 patients (15.2%). The diagnostic accuracy of ESCJ for cardiac syncope as quantified by the area under the curve (AUC) was 0.87 (95% CI: 0.84-0.89), and higher compared with the EGSYS diagnostic score (0.73 (95% CI: 0.70-0.76)), hs-cTnI (0.77 (95% CI: 0.73-0.80)) and BNP (0.77 (95% CI: 0.74-0.80)), all P < 0.001. Both biomarkers (alone or in combination) on top of the ESCJ significantly improved diagnostic accuracy. CONCLUSION: ESCJ including a standardized syncope-specific CRF has very high diagnostic accuracy and outperforms the EGSYS score, hs-cTnI and BNP.

Missed myocardial infarctions in ED patients prospectively categorized as low risk by established risk scores.

STUDY OBJECTIVES: Few studies have prospectively compared multiple cardiac risk prediction scores. We compared the rate of missed acute myocardial infarction (AMI) in chest pain patients prospectively categorized as low risk by unstructured clinical impression, and by HEART, TIMI, GRACE, and EDACS scores, in combination with two negative contemporary cardiac troponins (cTn) available in the U.S. METHODS: We enrolled 434 patients with chest pain presenting to one of seven emergency departments (ED). Risk scores were prospectively calculated and included the first two cTn. Low risk was defined for each score as HEART≤3, TIMI≤0, GRACE≤50, and EDACS≤15. AMI incidence was calculated for low risk patients and compared across scores using Χ2 tests and C statistics. RESULTS: The patients' median age was 57, 58% were male, 60% white, and 80 (18%) had AMI. The missed AMI rate in low risk patients for each of the scores when combined with 2 cTn were HEART 3.6%, TIMI 0%, GRACE 6.3%, EDACS 0.9%, and unstructured clinical impression 0%. The C-statistic was greatest for the EDACS score, 0.94 (95% CI, 0.92-0.97). CONCLUSIONS: Using their recommended cutpoints and non high sensitivity cTn, TIMI and unstructured clinical impression were the only scores with no missed cases of AMI. Using lower cutpoints (GRACE≤48, TIMI=0, EDACS≤11, HEART≤2) missed no case of AMI, but classified less patients as low-risk.

Treatment of ulcerated necrobiosis lipoidica with ovine forestomach matrix.

Necrobiosis lipoidica (NL) results from degradation of the collagen extracellular matrix; these recurring ulcerated lesions are an especially challenging condition to treat. Ovine forestomach matrix (OFM) is a decellularised extracellular matrix and was used to successfully close a pretibial ulcer resulting from NL. Complete closure of the wound was achieved in 22 weeks, after four applications of OFM. This suggests OFM may be considered for the treatment of these challenging wounds.

Preinjury characteristics of children with mild traumatic brain injury: Is "other injury" an appropriate comparison group"?

BACKGROUND: Mild traumatic brain injury (mTBI) has been associated with ongoing problems in children and young people. However, there remains to be considerable debate regarding whether outcomes are a result of brain impairment, or simply reflect preinjury characteristics of the child or family. To reliably assess outcomes, an appropriate control group is required. AIMS: This study aimed to identify the preinjury characteristics of children with mTBI, and to examine whether an "other injury to the head" group is an appropriate comparison to control for preinjury characteristics of children with mTBI. METHOD: Parents of 290 children admitted to the emergency department with either a diagnosis of mTBI (n = 186, M = 6.44 years) or a superficial injury to the head (SIH) (n = 104, M = 5.40 years) were assessed. Parents completed three questionnaires examining behavioral problems (Clinical Assessment of Behavior), parental stress (Parenting Stress Index), and background variables (e.g., medical issues, socioeconomic factors). RESULTS: A series of chi-square analyses and multivariate analysis of variance tests revealed no differences for behavior, parental stress, and other preexisting problems between children with mTBI and those with SIH. CONCLUSIONS: Children who experience a mTBI event present similarly to individuals with a SIH, and SIH is an appropriate comparison group to examine the outcomes of childhood mTBI, as it may help minimize any confounding effects of preexisting issues associated with mTBI.

Crystal structure of the first dissimilatory nitrate reductase at 1.9 A solved by MAD methods.

BACKGROUND: The periplasmic nitrate reductase (NAP) from the sulphate reducing bacterium Desulfovibrio desulfuricans ATCC 27774 is induced by growth on nitrate and catalyses the reduction of nitrate to nitrite for respiration. NAP is a molybdenum-containing enzyme with one bis-molybdopterin guanine dinucleotide (MGD) cofactor and one [4Fe-4S] cluster in a single polypeptide chain of 723 amino acid residues. To date, there is no crystal structure of a nitrate reductase. RESULTS: The first crystal structure of a dissimilatory (respiratory) nitrate reductase was determined at 1.9 A resolution by multiwavelength anomalous diffraction (MAD) methods. The structure is folded into four domains with an alpha/beta-type topology and all four domains are involved in cofactor binding. The [4Fe-4S] centre is located near the periphery of the molecule, whereas the MGD cofactor extends across the interior of the molecule interacting with residues from all four domains. The molybdenum atom is located at the bottom of a 15 A deep crevice, and is positioned 12 A from the [4Fe-4S] cluster. The structure of NAP reveals the details of the catalytic molybdenum site, which is coordinated to two MGD cofactors, Cys140, and a water/hydroxo ligand. A facile electron-transfer pathway through bonds connects the molybdenum and the [4Fe-4S] cluster. CONCLUSIONS: The polypeptide fold of NAP and the arrangement of the cofactors is related to that of Escherichia coli formate dehydrogenase (FDH) and distantly resembles dimethylsulphoxide reductase. The close structural homology of NAP and FDH shows how small changes in the vicinity of the molybdenum catalytic site are sufficient for the substrate specificity.

Validation of NICE diagnostic guidance for rule out of myocardial infarction using high-sensitivity troponin tests.

OBJECTIVE: To validate the National Institute for Health and Care Excellence (NICE) recommended algorithms for high-sensitivity troponin (hsTn) assays in adults presenting with chest pain. METHODS: International post hoc analysis of three prospective, observational studies from tertiary hospital emergency departments. The primary endpoint was cardiac death or acute myocardial infarction (AMI) within 24 hours of presentation, and the secondary endpoint was major adverse cardiac events (MACE) at 30 days. RESULTS: 15% of patients were diagnosed with non-ST elevation myocardial infarction (MI) on admission. The hsTnI algorithm classified 2506/3128 (80.1%) of patients as 'ruled out' with 50 (2.0%) missed MI. 943/3128 (30.1%) of patients had a troponin I level below the limit of detection on admission with 2 (0.2%) missed MI. For the hsTnT algorithm, 1794/3374 (53.1%) of patients were 'ruled out' with 7 (0.4%) missed MI. 490/3374 (14.5%) of patients had a troponin T below the limit of blank on admission with no MI. MACE at 30 days occurred in 10.7% and 8.5% of patients 'ruled out' defined by the hsTnI and hsTnT algorithms, respectively. CONCLUSIONS: The NICE algorithms could identify patients with low probability of AMI within 2 hours; however, neither strategy performed as predicted by the NICE diagnostic guidance model. Additionally, the rate of MACE at 30 days was sufficiently high that the algorithms should only be used as one component of a more extensive model of risk stratification. TRIAL REGISTRATION NUMBER: ACTRN12611001069943, NCT00470587; post-results.

Thermus thermophilus cytochrome-c552: A new highly thermostable cytochrome-c structure obtained by MAD phasing.

The three-dimensional structure of cytochrome-c552 from Thermus thermophilus has been determined by the multiple anomalous dispersion technique using synchrotron radiation and refined to a resolution of 1.28 A. Data collection at 90 K and the recording of three data sets (f'-minimum: 7125 eV, f"-maximum: 7138 eV and reference for scaling: 10,077 eV) resulted in an initial electron density of very high quality at 2.1 A, which was readily interpretable for model building. The model was refined to an R value of 19.1% (Rfree=22.4%) at 1.28 A resolution using a fourth data set collected at a photon energy of 11,810 eV. Comparison of this thermophilic cytochrome with its mesophilic mitochondrial or bacterial counterparts reveals significant structural differences which are discussed with respect to their importance for thermostability and binding between this cytochrome and its corresponding ba3-oxidase. Amino acid sequence similarities to other class I cytochromes are very weak and entirely limited to the region around the CXXCH motif close to the N terminus. The N-terminal two-thirds of cytochrome-c552 cover spatial regions around the heme prosthetic group that are similar to those observed for other cytochromes. The actual secondary structural elements that are responsible for that shielding do not, however, correlate well to other structures. Only the N-terminal helix (containing the heme binding cysteine residues) aligns reasonably well with other class I cytochromes. The most striking differences that distinguish the present structure from all other class I cytochromes is the C-terminal one-third of the molecule that wraps around the remainder of the structure as a stabilizing clamp, the existence of an extended beta-sheet covering one edge of the heme and the lack of any internal water molecule.

Amino acid sequence, crystallization and structure determination of reduced and oxidized cytochrome c6 from the green alga Scenedesmus obliquus.

Cytochrome c6from the unicellular green alga Scenedesmus obliquus was sequenced, crystallized in its reduced and oxidized state and the three-dimensional structure of the protein in both redox states was determined by X-ray crystallography. Reduced cytochrome c6crystallized as a monomer in the space group P 21212, whereas the oxidized protein crystallized as a dimer in the space group P 3121. The structures were solved by molecular replacement and refined to 1. 9 and 2.0 A, respectively. Comparison of the structures of both redox states revealed only slight differences on the protein surface, whereas a distortion along the axis between the heme iron and its coordinating Met61 residue was observed. No redox-dependent movement of internal water molecules could be detected. The high degree of similarity of the surfaces and charge distributions of both redox states, as well as the dimerization of cytochrome c6as observed in the oxidized crystal, is discussed with respect to its biological relevance and its implications for the reaction mechanisms between cytochrome c6and its redox partners. The dimer of oxidized cytochrome c6may represent a molecular structure occurring in a binary complex with cytochrome b6f. This assembly might be required for the correct orientation of cytochrome c6with respect to its redox partner cytochrome b6f, facilitating the electron transfer within the complex. If the dimerization is not redox-dependent in vivo, the almost identical surfaces of both redox states do not support a long range differentiation between reduced and oxidized cyt c6, i.e. a random collision model for the formation of an electron transfer complex must be assumed.

Cigarette, alcohol use and physical activity among Myanmar youth workers, Samut Sakhon Province, Thailand.

Over 1.2 million migrants from Myanmar are currently residing in Thailand. Little information is known about Myanmar youth risk behaviors. This cross-sectional study aimed to determine the prevalence and the factors associated with cigarette and alcohol use, and physical inactivity, among Myanmar youth working in a harbor town in Samut Sakhon Province, Thailand. One hundred and seventy-seven young workers aged 15-24 years, living in the study area, were interviewed by structured questionnaire. About 21.5% were current smokers, 25.4% were alcohol drinkers, and 36.7% were physically inactive. Univariate analysis indicated one variable was significantly associated with cigarette smoking: education level higher than primary school (OR=2.3, 95% CI 1.02-5.0), Three variables were significantly associated with alcohol drinking: married status (OR=2.2, 95%CI 1.02-4.5); non-seafood-processing workers, i e, street vendors, construction laborers, etc. (OR=3.4, 95% CI 1.7-7.1), and high job stress due to supervisor/boss (OR=2.1 95% CI 1.1-4.2). Two variables were significantly associated with physical inactivity: female youth (OR=3.9 95% CI 2.1-7.5), and education level higher than primary school (OR=0.4, 95% CI 0.2-0.8). The prevalence of smoking, alcohol drinking and physical inactivity among Myanmar migrant youths was quite high. Government and non-government organizations should co-operate to provide interventions to reduce youths' risk behaviors.

Combining presentation high-sensitivity cardiac troponin I and glucose measurements to rule-out an acute myocardial infarction in patients presenting to emergency department with chest pain.

BACKGROUND AND AIMS: The use of high sensitivity troponin (hs-Tn) may enable early rule out of acute myocardial infarction (AMI) for patients presenting to the emergency department (ED) with chest pain. This study evaluated two approaches to the early rule out of AMI; a combination of a presentation hs-Tn <4ng/L and normal glucose at presentation (dual testing) and a presentation hs-Tn troponin below the limit of detection (LoD). METHODS: We utilised prospectively collected data on adult patients presenting with suspected ACS in two EDs in Australia and New Zealand. Blood samples were taken on presentation and tested for glucose and high sensitivity troponin I. The primary endpoint was index AMI and the secondary endpoint was 30-day acute coronary syndrome (ACS). Sensitivity, specificity, positive and negative predictive values were used to assess the diagnostic accuracy of the dual testing and LoD approaches. RESULTS: Of the 1412 participants, 182 (12.9%) had index AMI. The LoD and the dual testing approach were 100% sensitive for index AMI. The specificity of the dual testing approach (25.2%) was slightly higher than that of the LoD (20.4%). Sensitivity for ACS was similar for the two approaches (96.5% for dual testing and 98.1% for the LoD). CONCLUSIONS: The dual testing and LoD approach identified all patients with index AMI and could be used to reduce the proportion of patients requiring lengthy assessment and inpatient admission. Further investigation is still required to rule out unstable angina pectoris in patients identified as low risk.

A novel troponin T peptide in humans: Assay, biochemistry and preliminary findings in acute coronary syndromes.

INTRODUCTION: High sensitivity assays for cardiac troponin (cTn) have reduced time to diagnosis of myocardial infarction (MI) but at costs to diagnostic specificity. We hypothesised that measurement of an upstream open reading frame peptide (uORF) from the human cTnT gene (TnTuORF) might improve cTn specificity in MI patients. METHODS: A novel immunoassay to TnTuORF was developed and used to document circulating concentrations in normal healthy volunteers (n=150); assess potential trans-organ secretion in patients undergoing cardiac catheterisation (n=16); characterise temporal TnTuORF concentrations during ST-elevation MI (STEMI, n=4) and assess the potential of TnTuORF to assist the diagnosis and prognosis of MI in patients presenting with chest pain suspicious of ACS (n=502). Plasma immunoreactive TnTuORF was characterised on reverse phase and size exclusion HPLC. RESULTS: In normal volunteers and suspected acute coronary syndrome (ACS) patients, TnTuORF had no relationship with TnI or TnT. Trans-organ venous sampling suggested TnTuORF secretion is not exclusively cardiac based. In STEMI patients, TnTuORF concentrations decreased for up to 12h after onset. In suspected ACS patients, TnTuORF could not diagnose MI (ROC AUC=0.446, P=0.117) but could diagnose cardiac disorders other than MI (AUC=0.79, P<0.001). CONCLUSION: This is the first evidence for a circulating uORF peptide. TnTuORF does not appear to aid the diagnosis of MI but further studies to assess its potential in cardiovascular disease are required.

Comparison of BD Vacutainer® Rapid Serum Tube and plasma for haemolysis markers in the emergency department.

BACKGROUND: In recent years, a rapid-clotting serum tube, BD Vacutainer® Rapid Serum Tube (RST™), was introduced to improve turn-around times for serum samples. Previous studies reported reduced concentrations of some markers of haemolysis in RST specimens compared to other serum or plasma samples. We aimed to compare RST to plasma tubes for haemolysis markers in an emergency department (ED) setting, where increased rates of haemolysis are commonly seen. METHODS: Patients presenting to ED over an eight-day period had an RST, BD Vacutainer® PST™ II (plasma) Tube and BD Vacutainer® Heparin (non-gel, plasma) Tube collected. Blood was drawn from an intravenous cannula, and samples were promptly analysed for haemolysis index, potassium, phosphate, aspartate aminotrasferase (AST), magnesium and lactate dehydrogenase (LD). RESULTS: A total of 347 patient samples were included, and 9.2% of the PST samples were haemolysed. The RST tubes had small increases in all of the haemolysis markers compared to both plasma tubes (P ≤ 0.005), except LD which was lower in the RST group. There were no significant differences in the proportion of results above the upper reference limit between the tubes, except for LD which had a lower proportion in RST samples (P ≤ 0.002). CONCLUSION: Compared to plasma, RST specimens show small increases in several haemolysis markers, consistent with known differences between serum and plasma, but the proportion of elevated haemolysis markers is similar to plasma. In a setting with a high haemolysis rate such as ED, RST specimens provide a non-inferior sample type for markers of haemolysis.

Primary structure of a novel subunit in ba3-cytochrome oxidase from Thermus thermophilus.

The bax-type cytochrome c oxidase from Thermus thermophilus is known as a two subunit enzyme. Deduced from the crystal structure of this enzyme, we discovered the presence of an additional transmembrane helix "subunit IIa" spanning the membrane. The hydrophobic N-terminally blocked protein was isolated in high yield using high-performance liquid chromatography. Its complete amino acid sequence was determined by a combination of automated Edman degradation of both the deformylated and the cyanogen bromide cleaved protein and automated C-terminal sequencing of the native protein. The molecular mass of 3,794 Da as determined by MALDI-MS and by ESI requires the N-terminal methionine to be formylated and is in good agreement with the value calculated from the formylmethionine containing sequence (3,766.5 Da + 28 Da = 3,794.5 Da). This subunit consits of 34 residues forming one helix across the membrane (Lys5-Ala34), which corresponds in space to the first transmembrane helix of subunit II of the cytochrome c oxidases from Paracoccus denitrificans and bovine heart, however, with opposite polarity. It is 35% identical to subunit IV of the ba3-cytochrome oxidase from Natronobacterium pharaonis. The open reading frame encoding this new subunit IIa (cbaD) is located upstream of cbaB in the same operon as the genes for subunit I (cbaA) and subunit II (cbaB).

Anti-inflammatory effect of synthetic somatostatin analogues in the rat.

1. Somatostatin (6.11 nmol kg(-1) i.p.) inhibited neurogenic plasma extravasation evoked by 1% mustard oil and non-neurogenic oedema induced by 5% dextran in the rat skin. 2. Cyclic synthetic octapeptide (TT-248 and TT-250) and heptapeptide (TT-232) somatostatin analogues proved to be more effective in reducing neurogenic and non-neurogenic inflammatory reactions but octreotide had no influence on either neurogenic or non-neurogenic inflammation. 3. TT-232 administered i.p. or i.v. (1.06 - 42.40 nmol kg(-1)) inhibited in a dose-dependent manner the plasma extravasation evoked by mustard oil in the rat's paw. Neither diclofenac (15.78 - 315.60 micromol kg(-1)) nor the selective COX-2 inhibitor meloxicam (2.95 - 569.38 micromol kg(-1)) attenuated the mustard oil-induced neurogenic plasma extravasation. 4. TT-232, diclofenac and meloxicam dose-dependently diminished non-neurogenic dextran-oedema of the paw the ED(35) values were 1.73 nmol kg(-1) for TT-232 and 34.37 micromol kg(-1) for diclofenac. 5. TT-232 inhibited in the dose range of 1.06 - 21.21 nmol kg(-1) the bradykinin-induced plasma extravasation in the skin of the chronically denervated paw. 6. Mustard oil-induced cutaneous plasma extravasation was dose-dependently diminished by s.c. TT-232 1, 2, 4, 6 or 16 h after the treatment. TT-232 (2 x 106, 2 x 212 and 2 x 530 nmol kg(-1) per day s.c. for 18 days) caused dose-dependent inhibition of chronic Freund adjuvant-induced arthritis during the experimental period. 7. TT-232 (200 and 500 nM) inhibited the release of SP, CGRP and somatostatin from the rat isolated trachea induced by electrical field stimulation (40 V, 0.1 ms, 10 Hz, 120 s) or by capsaicin (10(-7) M), but did not influence the basal, non-stimulated peptide release. 8. It is concluded that somatostatin analogues without endocrine functions as TT-232 are promising compounds with a novel site of action for inhibition of non-neurogenic and neurogenic inflammatory processes.

Systemic anti-inflammatory effect of somatostatin released from capsaicin-sensitive vagal and sciatic sensory fibres of the rat and guinea-pig.

The systemic anti-inflammatory effect induced by antidromic sensory nerve stimulation was investigated in rats and guinea-pigs. In atropine-pretreated rats, bilateral antidromic stimulation of vagal afferent fibres (8 Hz, 20 min, at C-fibre strength) inhibited plasma extravasation induced by 1% mustard oil on the acutely denervated hindlegs by 36.45+/-3.95%. Both the prevention of this inhibitory effect by cysteamine pretreatment and the stimulation-evoked rise of plasma somatostatin-like immunoreactivity in the two species suggest a mediator role of neural somatostatin. Since this response was blocked by systemic capsaicin pretreatment and slightly reduced after subdiaphragmal vagotomy, participation of thoracic capsaicin-sensitive afferents is indicated. In guinea-pigs pretreated with guanethidine and pipecuronium, antidromic sciatic nerve stimulation induced 45.46+/-5.08% inhibition on the contralateral leg and increased plasma somatostatin-like immunoreactivity. It is concluded that somatostatin released from the activated vagal capsaicin-sensitive sensory nerve terminals of the rat and somatic nerves of the guinea-pigs exerts a systemic humoral function.

Decreased sensory neuropeptide release from trachea of rats with streptozotocin-induced diabetes.

We studied the release of somatostatin, calcitonin gene-related peptide (CGRP) and substance P in response to electrical field stimulation from isolated tracheas of rats following 4 weeks of streptozotocin (50 mg/kg i.v.)-induced diabetes. Field stimulation (40 V, 0.1 ms, 10 Hz for 120 s) increased the release of somatostatin, CGRP and substance P from the baseline 0.18+/-0.029, 0.17+/-0.027, and 1.77+/-0.086 to 0.51+/-0.022, 0.69+/-0.115, and 5.96+/-0.377 in control preparations and 0.31+/-0.081, 0.41+/-0.142, and 3.14+/-0.443 fmol/mg wet tissue weight in preparations from diabetic rats as measured by radioimmunoassay (control vs. diabetic P<0.01 for each). The results show a simultaneous decrease in release of the three sensory neuropeptides and an enhanced plasma somatostatin level in rats with streptozotocin-induced diabetes.

Inhibition of nociceptin on sensory neuropeptide release and mast cell-mediated plasma extravasation in rats.

Nociceptin (20 microg/kg i.p.) strongly inhibited cutaneous Evans blue accumulation in the chronically denervated hindpaw of the rat in response to mast cell degranulating peptide (MCDP, 0.25 microg in 100 microl) but it had no and marginal effect on plasma extravasation induced by 5-hydroxytryptamine (5-HT, 0.5 microg in 100 microl) and histamine (0.1 microg in 100 microl), respectively. Release of sensory neuropeptides such as substance P, calcitonin gene-related peptide (CGRP) and somatostatin from the rat isolated trachea in response to capsaicin (10(-8) M) or bradykinin (10(-7) M) were also attenuated by nociceptin (100 and 300 nM). It is concluded that chemically induced discharge of mediators from mast cells and from capsaicin-sensitive afferent nerve terminals are both inhibited by nociceptin that participates in the anti-inflammatory effect of the peptide.

Impairment of neurogenic inflammatory and anti-inflammatory responses in diabetic rats.

The effect was studied of a primary (preconditioning) neurogenic inflammatory challenge induced by electrical stimulation of the peripheral stump of the sciatic nerve (20 V, 0.5 ms, 5 Hz, for 5 min) on neurogenic oedema (5 min later) induced by stimulation of the contralateral sciatic nerve. Plasma extravasation due to the second stimulation was decreased by 52.7+/-3.1% (P<0.01) in normal animals and by 29.7+/-2.2 and 18.1+/-1.5% with 50 mg/kg streptozotocin pretreatment i.v. 4 and 8 weeks previously, respectively. Subsequently, bilateral sciatic nerve stimulation increased baseline plasma somatostatin levels from 6.4+/-0.3, 11. 7+/-1.4, and 16.8+/-3.8 to 28.3+/-2.9 (P<0.01), 17.9+/-3.7, and 25. 1+/-1.7 pmol/l in normal, and 4- and 8-week diabetic animals, respectively. We conclude that experimental diabetes impairs the capability of a preconditioning neurogenic inflammatory episode to elicit a systemic anti-inflammatory effect. This is accompanied by a deficiency in elevation of the plasma somatostatin level in response to nerve stimulation, although the baseline plasma somatostatin level increases proportionally to the duration of experimental diabetes.

Anti-nociceptive effect induced by somatostatin released from sensory nerve terminals and by synthetic somatostatin analogues in the rat.

In rats anaesthetized with urethan and pretreated with pipecuronium bromide nocifensive reaction of blood pressure elevation evoked by intraarterial capsaicin injection was inhibited over 40 min by bilateral antidromic stimulation of the sensory fibres of the sciatic nerves. Rise in blood pressure, heart rate and respiratory frequency evoked by capsaicin were markedly diminished after smearing 1% mustard oil on the acutely denervated hindpaws indicating a release of mediators with anti-nociceptive action from cutaneous nociceptors. Intravenous injection of the putative mediator somatostatin (10 microg/kg) or its analogues RC-160 and TT-232, but not octreotide inhibited the cardiorespiratory and blood pressure responses evoked by topical cutaneous application of mustard oil or capsaicin instillation into the eye. It is concluded, that the endocrine and the anti-nociceptive effects of somatostatin are mediated through distinct receptor subtypes and therefore, TT-232, a novel heptapeptide analogue without endocrine action, is a promising analgesic compound.