Plasma Neurokinin A Levels Predict Survival in Well-Differentiated Neuroendocrine Tumors of the Small Bowel.

OBJECTIVES: Elevated neurokinin A (NKA) levels are associated with poor prognosis in patients with small bowel neuroendocrine tumors. We hypothesized that patients with NKA levels that remain elevated despite treatment with surgical cytoreduction have a poor prognosis. METHODS: Patients diagnosed with small bowel neuroendocrine tumors who underwent surgical cytoreduction at our institution were identified. Demographics, histopathologic characteristics, and biochemical data were collected. Patients were grouped by the trend of their NKA levels (group 1, continuously normal; group 2, transiently elevated but normalized after therapy; group 3, remained elevated despite therapy). Survival rates were calculated from the date of the patient's first NKA level. RESULTS: Serial NKA values after surgical cytoreduction were monitored in 267 patients. Kaplan-Meier 2-year, 5-year, and 10-year survival rates were as follows: group 1 (n = 157), 97%, 89%, and 62%; group 2 (n = 78), 99%, 90%, and 78%; and group 3 (n = 32), 88%, 69%, and 0%. Survival rates were statistically significant between groups 1 and 3 and between groups 2 and 3 (P < 0.01). CONCLUSIONS: Serial monitoring of plasma NKA levels is useful in identifying patients who have a poor prognosis. Elevated NKA levels can indicate the need for immediate therapeutic intervention.

Colorectal and cardiovascular effects of [Lys5,MeLeu9,Nle10]-NKA(4-10) in anesthetized macaques.

The effects of the tachykinin NK2 receptor agonist LMN-NKA ([Lys5,MeLeu9,Nle10]-NKA(4-10)) on colorectal and arterial blood pressure were examined in anesthetized macaques. Intravenous (IV) administration of 1-100 µg/kg caused dose-related increases in colorectal pressure up to 120 mmHg above baseline, and area under the curve (AUC) up to 24,987 mmHg*s. This was accompanied at all doses by transient hypotension, with up to 26% reduction in mean arterial pressure (MAP) from baseline. Hypotension, but not the increase in colorectal pressure, was inhibited by a 10-min pretreatment with the NK1 receptor antagonist CP-99,994. In a pilot experiment using subcutaneous (SC) injection, a similar dose range of LMN-NKA (3-100 µg/kg) again appeared to increase colorectal pressure with a similar AUC (up to 18,546 mmHg*s) to that seen after IV injection, but lower peak amplitude (up to 49 mmHg). Unlike the effects of IV injection, hypotension was only present after the highest SC dose (100 µg/kg) in one of two animals. Pharmacokinetic analysis revealed markedly lower plasma exposures after SC compared with IV administration. Cmax was 39.6 versus 1070 ng/mL, and AUCinf was 627 versus 2090 ng/mL*min, respectively. These findings are consistent with previous observations in anesthetized dogs and indicate that the prokinetic effects of LMN-NKA may be achieved without hypotension using a route of administration that avoids unnecessarily high plasma exposures.

Evaluation of ADMA, carbonyl groups, CAT and NKA in depressed patients with and without posttraumatic stress disorder.

BACKGROUND: It has been shown that asymmetric dimethylarginine (ADMA), carbonyl groups, catalase (CAT) and neurokinin A (NKA) are actively involved in neuronal processes such as depression and posttraumatic stress disorder (PTSD). One of their roles is to protect the body from oxidative damage. This is done by affecting neuronal growth, development and plasticity. The study aimed at assessing the concentrations of ADMA, carbonyl groups, CAT and NKA in patients with varying levels of depression severity, PTSD, and depression concurrent with PTSD. METHODS: The study covered 460 people. Out of them, 120 suffered from different types of depression. The study groups comprised: 60 subjects with mild depression (MD), 60 subjects with moderate depression (MOD), 60 subjects with severe depression (SeD), 60 subjects with MD and PTSD (MD+PTSD), 60 subjects with MOD and PTSD (MOD+PTSD), 60 subjects with SeD and PTSD (SeD+PTSD), and 60 subjects with PTSD alone. Each group of 60 participants included 30 males and 30 females. The concentrations of all blood parameters were determined at 7 a.m. using the ELISA method. RESULTS: Depressive episodes became more severe as the concentration levels of studied markers increased. CONCLUSIONS: ADMA, carbonyl groups, CAT and NKA can be useful markers of chronic stress in both males and females with depression, PTSD, and depression concurrent with PTSD. They can be utilized when making an initial diagnosis and evaluating the severity of disease. Changes in their concentration levels may show a biological response to oxidative stress characteristic of depression.

Neurokinin A monitoring of response to interferon alpha in a patient with an advanced small bowel neuroendocrine tumour uncontrolled by somatostatin analogue therapy.

A 52-year-old lady presented with a history of occasional, severe abdominal cramps, postprandial diarrhoea and weight loss. After routine gastrointestinal investigations, she was diagnosed with irritable bowel syndrome. Over six months, she developed occasional facial flushing prompting assessment of neuroendocrine tumour markers. Urinary 5HIAA, 5HT, chromogranin A and neurokinin A were significantly elevated. Scans showed extensive hepatic metastases but did not show the location of a primary tumour. Somatostatin analogue therapy was commenced but despite increasing doses, symptoms increased and biomarkers rose dramatically. Interferon alpha was introduced concomitant with somatostatin analogue therapy. Biomarkers were monitored regularly. Within six months, symptoms abated and biomarkers reduced, continuing to fall over the next year, close to reference range. To manage side-effects of interferon alpha, dose was reduced from time to time. During these short periods, neurokinin A showed significant transient increases (75-150 ng/L) and carcinoid symptoms returned. For more than seven years, and with the co-operation of the patient, a balance was achieved between interferon alpha side-effects and disease control. Scans showed tumour load to be stable. The patient survived for 10 years post diagnosis. She chose to discontinue interferon alpha and received peptide receptor radiation therapy in her final year. Throughout, neurokinin A remained the most sensitive monitor of her disease progression.

The levels of blood mercury and inflammatory-related neuropeptides in the serum are correlated in children with autism spectrum disorder.

Tachykinins (substance P, neurokinin A, and neurokinin B) are pro-inflammatory neuropeptides that may play an important role in some autoimmune neuroinflammatory diseases, including autism spectrum disorder (ASD). Mercury (Hg) is a neurotoxicant, and potentially one of the main environmental triggers for ASD as it induces neuroinflammation with a subsequent release of neuropeptides. This is the first study to explore the potentially causal relationship between levels of serum neurokinin A and blood mercury (BHg) in children with ASD. Levels of serum neurokinin A and BHg were measured in 84 children with ASD, aged between 3 and 10 years, and 84 healthy-matched children. There was a positive linear relationship between the Childhood Autism Rating Scale (CARS) and both serum neurokinin A and BHg. ASD children had significantly higher levels of serum neurokinin A than healthy controls (P < 0.001). Increased levels of serum neurokinin A and BHg were respectively found in 54.8 % and 42.9 % of the two groups. There was significant and positive linear relationship between levels of serum neurokinin A and BHg in children with moderate and severe ASD, but not in healthy control children. It was found that 78.3 % of the ASD patients with increased serum levels of neurokinin A had elevated BHg levels (P < 0.001). Neuroinflammation, with increased levels of neurokinin A, is seen in some children with ASD, and may be caused by elevated BHg levels. Further research is recommended to determine the pathogenic role of increased levels of serum neurokinin A and BHg in ASD. The therapeutic role of tachykinin receptor antagonists, a potential new class of anti-inflammatory medications, and Hg chelators, should also be studied in ASD.

Raised circulating Neurokinin A predicts prognosis in metastatic small bowel neuroendocrine tumours. Lowering Neurokinin A indicates improved prognosis.

BACKGROUND: Assessing prognosis is important in patients with neuroendocrine tumours of the small bowel as disease progression and survival is variable. We previously identified raised Neurokinin A as an independent indicator of poor prognosis and have shown that prognosis worsens when circulating Neurokinin A rises ≥50 ng/L. In the present study we have examined survival in relation to Neurokinin A concentrations. METHODS: Patients in whom Neurokinin A rose ≥50 ng/L between January 1989 and December 2010 were identified. All circulating Neurokinin A concentrations were recorded and survival was followed up to 31 December 2014 or to death. RESULTS: Median survival, from the date when Neurokinin A was first ≥50 ng/L was 11.1 (2.0-117.8) months if Neurokinin A remained ≥50 ng/L and 72.4 (4.8-152.6) months when Neurokinin A was reduced below 50 ng/L and controlled below that concentration for ≥3 months (P < 0.001). Survival was significantly better for patients attending the neuroendocrine tumour specialist clinic than for those not attending (P = 0.009). Comparing patients identified during 1989-2000, and those during 2001-2010, Neurokinin A was successfully reduced in the earlier period in 30.3% patients with median survival 23.2 (2.0-152.6) months and this improved in 58.1% with median survival of 43.3 (2.0-141.1) months in the later period (P = 0.019). Significance was greater between the earlier and later periods when only patients attending the neuroendocrine tumour clinic were compared (P = 0.016). CONCLUSIONS: Circulating Neurokinin A ≥ 50 ng/L is a strong indicator of poor prognosis when Neurokinin A remains above this concentration. Lowering Neurokinin A below 50 ng/L indicates a significant improvement in prognosis (P < 0.001). This prognostic indicator reflects improved treatment and survival in more recent years.

Neuroendocrine tumours of the small bowel: interpretation of raised circulating chromogranin A, urinary 5 hydroxy indole acetic acid and circulating neurokinin A.

BACKGROUND: Neuroendocrine tumours (NETs) of the small bowel are difficult to diagnose as symptoms are non-specific and more often found in common gastrointestinal diseases. Chromogranin A (CGA), urinary 5 hydroxy indole acetic acid (U-5HIAA) and Neurokinin A (NKA) are used as laboratory diagnostic tests but results may be misleading or confusing. AIM: To clarify the relevance of NET biomarkers for diagnosis of small bowel NETs. DESIGN: A review of laboratory test results. METHODS: We reviewed 500 consecutive raised plasma CGA, U-5HIAA and plasma NKA, results from patients in N Ireland. The diagnosis of NET was confirmed by the Northern Ireland Cancer Registry. RESULTS: In 500 specimens recording raised CGA, 52.2% were from patients with NETs, 13.6% being small bowel tumours, 5.4% of specimens from patients with auto-immune atrophic gastritis and 15.4% from patients taking proton pump inhibitors. In 500 specimens with raised U-5HIAA, 87.8% were from patients with NETs, 68.2% being small bowel tumours. Lung NETs contributed 12.2% and NETs from other sites, 7.4%. Of 500 specimens with raised NKA (reference range (RR) > 20 ng/L), 72.6% were from patients with small bowel NETs and 6% specimens from patients with other NETs. In 20% of specimens NKA concentrations were 21-23 ng/L, within limits of assay precision. CONCLUSION: CGA remains the best general circulating marker for NETs although only half of raised test results are due to an NET. U-5HIAA is an excellent marker for small bowel and lung NETs with 80% of high test results confirming these diagnoses. NKA is the most specific biomarker for small bowel NETs.

A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection.

A critical requirement in neuroendocrine tumor (NET) management is a sensitive, specific and reproducible blood biomarker test. We evaluated a PCR-based 51 transcript signature (NETest) and compared it to chromogranin A (CgA), pancreastatin (PST) and neurokinin A (NKA). The multigene signature was evaluated in two groups: i) a validation set of 40 NETs and controls and ii) a prospectively collected group of NETs (n=41, 61% small intestinal, 50% metastatic, 44% currently treated and 41 age-sex matched controls). Samples were analyzed by a two-step PCR (51 marker genes) protocol and ELISAs for CgA, PST and NKA. Sensitivity comparisons included χ(2), non-parametric measurements, ROC curves and predictive feature importance (PFAI) analyses. NETest identified 38 of 41 NETs. Performance metrics were: sensitivity 92.8%, specificity 92.8%, positive predictive value 92.8% and negative predictive value 92.8%. Single analyte ELISA metrics were: CgA 76, 59, 65, and 71%; PST 63, 56, 59, and 61% and NKA 39, 93, 84, and 60%. The AUCs (ROC analysis) were: NETest: 0.96±0.025, CgA: 0.67±0.06, PST 0.56±0.06, NKA: 0.66±0.06. NETest significantly outperformed single analyte tests (area differences: 0.284-0.403, Z-statistic 4.85-5.9, P<0.0001). PFAI analysis determined NETest had most value (69%) in diagnosis (CgA (13%), PST (9%), and NKA (9%)). Test data were consistent with the validation set (NETest >95% sensitivity and specificity, AUC =0.98 vs single analytes: 59-67% sensitivity, AUCs: 0.58-0.63). The NETest is significantly more sensitive and efficient (>93%) than single analyte assays (CgA, PST or NKA) in NET diagnosis. Blood-based multigene analytic measurement will facilitate early detection of disease recurrence and can predict therapeutic efficacy.

The association of a panel of biomarkers with the presence and severity of carcinoid heart disease: a cross-sectional study.

PURPOSE: Metastatic neuroendocrine tumors secrete serotonin and other vasoactive substances that are responsible for carcinoid syndrome and carcinoid heart disease. We sought to evaluate the discriminatory utility of diagnostic biomarkers in determining the presence and severity of carcinoid heart disease in patients with metastatic neuroendocrine tumors. PATIENTS AND METHODS: A cross-sectional study of patients with neuroendocrine tumors with documented liver metastases and/or carcinoid syndrome between April 2009-October 2012 in 5 tertiary referral centers. Serum was analyzed for Chromogranin A, Chromogranin B and N-terminal pro Brain Natriuretic Peptide (NT-proBNP). Plasma was analyzed for Neurokinin A and 5-Hydroxyindoleacetic acid (5HIAA). Echocardiography was used to determine the presence and severity of carcinoid heart disease. Non-parametric receiver operating characteristic curves were constructed for biomarkers, and the area under the curve determined. The severity of cardiac involvement was correlated with the concentration of each biomarker. RESULTS: A total of 187 patients were identified of whom 37 (20%) had carcinoid heart disease. Significantly higher median values of all biomarkers were found in the patients with cardiac involvement. NT-proBNP and plasma 5HIAA had the highest areas under the curve for the prediction of carcinoid heart disease [NT-proBNP 0.82 (95% confidence interval 0.74-0.90, p<0.0001) and 5HIAA 0.85 (95% confidence interval 0.78-0.92, p<0.0001]. NT-proBNP was moderately correlated (r = 0.48, p<0.001) whereas plasma 5HIAA was only weakly correlated (r = 0.34, p<0.001) with the echocardiographic severity score. CONCLUSION: NT-proBNP and plasma 5HIAA are both sensitive and specific biomarkers for the presence of carcinoid heart disease whereas only NT-proBNP is moderately correlated with disease severity.

Neurokinin A levels predict survival in patients with stage IV well differentiated small bowel neuroendocrine neoplasms.

BACKGROUND: Recent European investigations have shown that persistently elevated (>50 pg/mL) plasma neurokinin A levels are associated with poor short-term survival in patients with midgut neuroendocrine neoplasms. We hypothesized that American patients with persistently elevated plasma neurokinin A levels (>50 pg/mL) will also have a poor short-term survival. METHODS: Serial plasma neurokinin A levels were collected from the charts of 180 patients with metastatic midgut neuroendocrine neoplasms. Patients were grouped according to their plasma neurokinin A values, and survival rates were calculated. Group 1 had plasma neurokinin A levels <50 pg/mL. Group 2 at one point had plasma neurokinin A levels >50 pg/mL, but are currently <50 pg/mL. Group 3 had plasma neurokinin A values consistently >50 pg/mL. RESULTS: Group 1 patients (n = 143) have not reached their median survival and have a 24-month survival of 93%. Thirteen of 14 (93%) group 2 patients are currently alive. Group 3 patients (n = 23) had a median survival of 20 months and a 24-month survival of 48%. CONCLUSION: Patients with midgut neuroendocrine neoplasms who have serial plasma neurokinin A levels <50 pg/mL have an excellent short-term prognosis, while patients with plasma neurokinin A levels >50 pg/mL have a poor short-term prognosis.

The possible link between the elevated serum levels of neurokinin A and anti-ribosomal P protein antibodies in children with autism.

BACKGROUND: Neurogenic inflammation is orchestrated by a large number of neuropeptides. Tachykinins (substance P, neurokinin A and neurokinin B) are pro-inflammatory neuropeptides that may play an important role in some autoimmune neuroinflammatory diseases. Autoimmunity may have a role in the pathogenesis of autism in some patients. We are the first to measure serum neurokinin A levels in autistic children. The relationship between serum levels of neurokinin A and anti-ribosomal P protein antibodies was also studied. METHODS: Serum neurokinin A and anti-ribosomal P protein antibodies were measured in 70 autistic children in comparison to 48 healthy-matched children. RESULTS: Autistic children had significantly higher serum neurokinin A levels than healthy controls (P < 0.001). Children with severe autism had significantly higher serum neurokinin A levels than patients with mild to moderate autism (P < 0.001). Increased serum levels of neurokinin A and anti-ribosomal P protein antibodies were found in 57.1% and 44.3%, respectively of autistic children. There was significant positive correlations between serum levels of neurokinin A and anti-ribosomal P protein antibodies (P = 0.004). CONCLUSIONS: Serum neurokinin A levels were elevated in some autistic children and they were significantly correlated to the severity of autism and to serum levels of anti-ribosomal P protein antibodies. However, this is an initial report that warrants further research to determine the pathogenic role of neurokinin A and its possible link to autoimmunity in autism. The therapeutic role of tachykinin receptor antagonists, a potential new class of anti-inflammatory medications, should also be studied in autism.

Validation of neurokinin a assays in the United States and Europe.

OBJECTIVES: International cooperative group trials require specific, sensitive biomarker assays that are validated between continents. Neurokinin A (NKA) has been shown to be a powerful independent predictor of a poor prognosis in well-differentiated midgut neuroendocrine tumors. We hypothesized that NKA concentrations of clinical specimens evaluated in NKA assays in the United States and the United Kingdom would be equivalent, even though assay techniques were significantly different. METHODS: Frozen clinical specimen aliquots were shipped from the United States to the United Kingdom (n = 67), and from United Kingdom to the United States (n = 50). In addition, spiked plasma standards and medium-spiked standards were exchanged. Samples from the United States were directly assayed in a radioimmunoassay, whereas the UK specimens were extracted, and the reconstituted specimens assayed in the radioimmunoassay. Neurokinin A values from the 2 studies were analyzed by regression analysis. RESULTS: The NKA values from the US and UK laboratories were essentially identical (United States to United Kingdom, r = 0.88, P < 0.0001; and United Kingdom to United States, r = 0.96, P < 0.0001). CONCLUSIONS: Validation of biomarker assays across continents will ensure that laboratory observations made by researchers are equivalent and that prediction of clinical outcomes based on these assays is also reliable.

Normative values of substance P and neurokinin A in neonates.

BACKGROUND: Substance P (SP) and neurokinin A (NKA) are neuropeptides that have been researched as pain markers in adults, as they are involved in transmission and modulation of pain signals. There is a potential role for them as neurochemical markers of pain in neonates, but this has never previously been investigated. AIM: To establish normative values of SP and NKA in neonates. METHODS: Longitudinal once-daily morning blood samples were collected over two weeks from 142 neonates, gestation 23-40 weeks. Peptides were extracted, and then quantified using an in-house radioimmunoassay. Infants with presumed painful conditions were excluded. RESULTS: SP concentrations ranged from <0.98 to 11.2 pmol/L (median 1.7 pmol/L) and NKA concentrations from <1.95 to 74.6 pmol/L (median 6.0 pmol/L). Gestation and birth weight had no significant correlation with peptide concentrations. Postnatally, there was a gradual rise in median SP during the first three days, which decreased again by day 14. Median NKA showed a similar rise, but was not statistically significant. This postnatal rise and fall were more apparent in preterm infants < or = 32 weeks gestation. CONCLUSIONS: This is the first description of normative values of SP and NKA in neonates. SP and NKA show changes with postnatal age, which are more marked in preterm infants.

Salivary and serum levels of substance P, neurokinin A and calcitonin generelated peptide in burning mouth syndrome

Background: Burning mouth syndrome (BMS) is an enigmatic condition with the etiopathogenesis remaininglargely obscure. However, a neuropathic basis for BMS continues to be an area of active clinical and researchinterest.Aim: It is becoming increasingly evident that certain oral disorders may be modulated by imbalances in certainneuropeptides such as substance P (SP), neurokinin A (NKA) and calcitonin gene-related peptide (CGRP) thereforewe measured SP, NKA and CGRP in the saliva and sera of BMS patients as well as controls.Subjects and Methods: Salivary and serum SP, NKA and CGRP were determined in the 26 female patients withburning mouth syndrome (age range 51-78, mean 65.69 yrs), and in the 22 female controls (age range 24-82, mean49.72 yrs). Serum and salivary SP, NKA, CGRP levels were determined by commercial competitive enzyme immunoassaykits. Statistical analysis was performed by use of descriptive statistics and analysis of variance.Results and Conclusions: No significant differences in salivary SP, NKA and CGRP as well as serum SP andCGRP between BMS patients and controls could be found. However, significantly decreased serum neurokinin A(p<0.05) in BMS patients may reflect an inefficient dopaminergic system (AU)

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Salivary and serum levels of substance P, neurokinin A and calcitonin gene related peptide in burning mouth syndrome.

BACKGROUND: Burning mouth syndrome (BMS) is an enigmatic condition with the aetiopathogenesis remaining largely obscure. However, a neuropathic basis for BMS continues to be an area of active clinical and research interest. AIM: It is becoming increasingly evident that certain oral disorders may be modulated by imbalances in certain neuropeptides such as substance P (SP), neurokinin A (NKA) and calcitonin gene-related peptide (CGRP) therefore we measured SP, NKA and CGRP in the saliva and sera of BMS patients as well as controls. SUBJECTS AND METHODS: Salivary and serum SP, NKA and CGRP were determined in the 26 female patients with burning mouth syndrome (age range 51-78, mean 65.69 yrs), and in the 22 female controls (age range 24-82, mean 49.72 yrs). Serum and salivary SP, NKA, CGRP levels were determined by commercial competitive enzyme immunoassay kits. Statistical analysis was performed by use of descriptive statistics and analysis of variance. RESULTS AND CONCLUSIONS: No significant differences in salivary SP, NKA and CGRP as well as serum SP and CGRP between BMS patients and controls could be found. However, significantly decreased serum neurokinin A (p<0.05) in BMS patients may reflect an inefficient dopaminergic system.

[Evaluation and correction of the pain syndrome in premature newborns with CNS infringement].

Premature newborn may feel different kinds of pain, thus incomplete diagnostics and unjustified therapy may lead to unfavourable physiological effects. All the pain feelings that a child experiences are acute and recurrent or persistent leading to a pain syndrome if there is no intervention. Currently a huge arsenal of pharmacological drugs is available to control pain. There are a lot of researches described in the literature on the effectiveness of the pharmacodynamics, pharmacokynetics and complications related to administration of different analgetics in newborns. However the unfavorable complications identified prevent their use in newborns. Analgesic effect can be made not only by proper analgetics, but combined homeopathic medications as well. One of such medications, which has no side effects is traumel S. The current paper reflects outcomes of the clinical research took place over the 79 pre-term newborns with infringement of the CNS who are subject of a big number of the prescribed treatment manipulation and procedures whereas most of them are quite painful. There is necessity of applying anesthesia treatment for avoiding clinical and biochemical consequences of the pain syndrome. Application of the traumel C intramuscularly or traumel C ointment per os just before and during painful manipulation affect drop pain level of a newborn. Appreciation of pain is subject to the level of CNS lesions because during severe disorders behavioral reaction to pain is certainly reduced. Premature newborns from control group, in the dynamics of neonatal period, manifested reliable reduction (R<0,05) of neurokinin A from 17.52 to 2.08 ng/ml, substance P from 2.5 to 0.3 n/ml compare to seek newborns. During comparison of the results it was revealed that premature newborns, with hypoxemic-ischemic lesion of CNS, treated based on traditional allopathic therapy from the first day of life, manifest significantly high level of neurokinin A and substance P, maintained until the end of first month of life. It was also determined that during the use of allopathic therapy on 7-10th days of life neurokinin A and substance P form 76.86 and 14.46 ng/ml respectively, confirming the development of pain syndrome.

Neurokinin A level in hypoxic-ischemic encephalopathy.

BACKGROUND: The present study was performed to investigate the effect of neonatal hypoxic-ischemic encephalopathy (HIE) on the neurotransmitter neurokinin A (NKA) and determine its relation to the severity of neonatal hypoxia. METHODS: Eighteen neonates suffering from HIE were compared to 10 clinically healthy full-term neonates acting as the control group. Maternal history of each neonate was collected, then deliveries were attended, resuscitation details including the Apgar score and thorough clinical examination of the neonates were performed. Routine laboratory work-up was done for the enrolled neonates, including complete blood count and C-reactive protein as well as estimation of NKA by enzyme-linked immunosorbent assay in the cord blood and after clinical stabilization. RESULTS: NKA was significantly lower in HIE patients compared to the controls at delivery with improvement in the follow-up sample. Additionally, the maximum decrease was detected in the neonates who suffered severe hypoxia compared to those who suffered mild hypoxia. Significant positive correlations were demonstrated between NKA at birth and Apgar scores at the 10th and 15th min. Regression showed that stage of HIE was the strongest determinant factor for the level of NKA at birth. CONCLUSION: NKA levels are decreased in HIE and this is more profound in the severe degrees of hypoxia compared to the mild ones. This emphasizes its role in pathogenesis of HIE and further proves that an imbalance in the central neuropeptide system results from HIE in the neonatal period.

Circulating markers of prognosis and response to treatment in patients with midgut carcinoid tumours.

BACKGROUND AND AIMS: Midgut carcinoid tumours are uncommon tumours with an unpredictable clinical behaviour and few useful prognostic markers. Somatostatin analogues are widely used in treatment but a survival advantage has not been proven. We analysed features associated with poor prognosis and assessed the clinical implications of the biochemical response to therapy. METHODS: Clinical and biochemical data were collected for patients with midgut carcinoid tumours attending a tertiary referral neuroendocrine clinic from 1978 to 2000. Using death as the end point, univariate and multivariate survival analyses were performed to identify prognostic indicators. The significance of altering biomarkers with therapy was also studied by including repeated measurements of the most prognostic biochemical parameter in a time dependent covariate survival analysis. RESULTS: We identified 139 patients with sufficient data for our analyses. Factors associated with a poor outcome on univariate analysis included: plasma neurokinin A (NKA), urinary 5-hydroxyindolacetic acid output, age, and >/=5 liver metastases. Plasma NKA was the strongest and only independent predictor of outcome on multivariate analysis. Patients in whom NKA continued to rise despite somatostatin analogues had a significantly worse survival than those in whom NKA stabilised or fell (one year survival rate 40% v 87%). Time dependent covariate analysis concluded that survival was better predicted by the most recent plasma NKA value rather than by the initial value. CONCLUSIONS: Plasma NKA is an accurate marker of prognosis for midgut carcinoid tumours. This is the first paper to support a survival advantage in patients in whom plasma NKA is altered by somatostatin analogues.

Clinical-biochemical correlates of migraine attacks in rizatriptan responders and non-responders.

The present study was aimed at verifying the clinical characteristics of a typical attack in 20 migraine patients, 10 responders and 10 non-responders to rizatriptan, and at investigating any differences in the levels of neuropeptides of the trigeminovascular or parasympathetic systems [calcitonin gene-related peptide (CGRP), neurokinin A (NKA) and vasoactive intestinal peptide (VIP) measured by radioimmunoassay methods in external jugular blood] between responders and non-responders. In all responders to rizatriptan, pain was unilateral, severe, and pulsating, and in five of them at least one sign suggestive of parasympathetic system activation was recorded. Five patients who were non-responders to rizatriptan referred bilateral and non-pulsating pain, even though severe in most of them. CGRP and NKA levels measured before rizatriptan administration were significantly higher in responders than in non-responders (P < 0.0001 and P < 0.002, respectively). In the five patients with autonomic signs among rizatriptan responders, detectable VIP levels were found at baseline. One hour after rizatriptan administration, a decrease in CGRP and NKA levels was evident in the external jugular venous blood of rizatriptan responders, and this corresponded to a significant pain relief and alleviation of accompanying symptoms. VIP levels were also significantly reduced at the same time in the five patients with autonomic signs. After rizatriptan administration, CGRP and NKA levels in non-responder patients showed less significant variations at all time points after rizatriptan administration compared with rizatriptan responders. The present study, although carried out on a limited number of patients, supports recent clinical evidence of increased trigeminal activation associated with a better triptan response in migraine patients accompanied by parasympathetic activation in a subgroup of patients with autonomic signs. In contrast, the poor response seems to be correlated with a lesser degree of trigeminal activation, lower variations of trigeminal neuropeptides after triptan administration, and no evidence of parasympathetic activation at baseline.

[Effect of glucocorticoid on neurokinin A in plasma and lungs of guinea pigs with asthma and molecular mechanism of the effect].

OBJECTIVE: Bronchial asthma is a chronic inflammatory disorder of the airways caused by many complicated elements. Recently, a close attention has been paid to the neurogenic inflammation in airways, which is mediated by sensory neuropeptides secreted by sensory nerve. Neurokinin A (NKA) is an important transmitter of non-cholinergic excitatory nerves in the lung which is an important sensory neuropeptide causing airway neurogenic inflammation. The purpose of this study was to investigate the effect of glucocorticoid (dexamethasone) on neurokinin A in plasma and lungs of guinea pigs with asthma and to explore its molecular mechanism. METHODS: Thirty guinea pigs (1.5 months old and weighed 200 - 225 g) were sensitized by exposure to aerosolized ovalbumin and challenged with the same antigen to establish asthma model. These animals were divided randomly into dexamethasone-treatment group and non-dexamethasone-treatment group (15 guinea pigs in each group). Normal control group animals (n = 15) were treated with normal saline (NS) instead of aerosolized ovalbumin. The guinea pigs in the dexamethasone-treatment group were treated with dexamethasone (5.0 mg/kg, intraperitoneal injection) one day before asthma-inducement, on the day of inducement and 24 h after inducement. The non-dexamethasone-treatment group animals were treated with NS (5.0 mg/kg, intraperitoneal injection) on the same days as the dexamethasone-treatment group was treated. The normal control group animals were treated with NS (5.0 mg/kg, intraperitoneal injection). The contents of NKA in the plasma and lung tissues were detected by ELISA; the expression of NKA mRNA in lung tissues was examined by RT-PCR. RESULTS: (1) The contents of NKA in the plasma (2.20 +/- 0.46 ng/ml), lung tissues (5.02 +/- 2.11 ng/g x protein) and the NKA mRNA expression in the lung tissues (1.10 +/- 0.06) of guinea pigs with induced asthma were significantly higher than those of the normal control group (plasma 0.84 +/- 0.33 ng/ml, lung tissues 2.56 +/- 0.80 ng/g x protein, mRNA 0.30 +/- 0.04; P < 0.001, respectively). (2) The contents of NKA in the plasma, lung tissues and the NKA mRNA expression in the lung tissues of guinea pigs with induced asthma were significantly lower in dexamethasone-treatment group (plasma 0.98 +/- 0.23 ng/ml, lung tissues 2.71 +/- 0.50 ng/g x protein, mRNA 0.35 +/- 0.07) than those in the non-dexamethasone-treatment group (plasma 2.20 +/- 0.46 ng/ml, lung tissues 5.02 +/- 2.11 ng/g x protein, mRNA 1.10 +/- 0.06; P < 0.001, respectively). No significant difference was found between the dexamethasone-treatment group and the normal control group (P > 0.05, respectively). CONCLUSIONS: (1) NKA mRNA expression in the lungs of guinea pigs with asthma was up-regulated and NKA contents were higher in plasma and lungs; (2) Glucocorticoid could significantly decrease the contents of NKA in plasma, lung tissues of guinea pigs with induced asthma; the mechanism of the effect may be related to down-regulation of NKA mRNA expression in lung tissues caused by glucocorticoid.