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Entomology is key to understanding terrestrial and freshwater ecosystems at a time of unprecedented anthropogenic environmental change and offers substantial untapped potential to benefit humanity in a variety of ways, from improving agricultural practices to managing vector-borne diseases and inspiring technological advances.We identified high priority challenges for entomology using an inclusive, open, and democratic four-stage prioritisation approach, conducted among the membership and affiliates (hereafter 'members') of the UK-based Royal Entomological Society (RES).A list of 710 challenges was gathered from 189 RES members. Thematic analysis was used to group suggestions, followed by an online vote to determine initial priorities, which were subsequently ranked during an online workshop involving 37 participants.The outcome was a set of 61 priority challenges within four groupings of related themes: (i) 'Fundamental Research' (themes: Taxonomy, 'Blue Skies' [defined as research ideas without immediate practical application], Methods and Techniques); (ii) 'Anthropogenic Impacts and Conservation' (themes: Anthropogenic Impacts, Conservation Options); (iii) 'Uses, Ecosystem Services and Disservices' (themes: Ecosystem Benefits, Technology and Resources [use of insects as a resource, or as inspiration], Pests); (iv) 'Collaboration, Engagement and Training' (themes: Knowledge Access, Training and Collaboration, Societal Engagement).Priority challenges encompass research questions, funding objectives, new technologies, and priorities for outreach and engagement. Examples include training taxonomists, establishing a global network of insect monitoring sites, understanding the extent of insect declines, exploring roles of cultivated insects in food supply chains, and connecting professional with amateur entomologists. Responses to different challenges could be led by amateur and professional entomologists, at all career stages.Overall, the challenges provide a diverse array of options to inspire and initiate entomological activities and reveal the potential of entomology to contribute to addressing global challenges related to human health and well-being, and environmental change., Competing Interests: Luke A. N. Tilley, Sajidha Mohammed, and Francisca Sconce are employed by the Royal Entomological Society (RES); Helen E. Roy, Chris D. Thomas, Simon Ward, Allan Watt, Lynn V. Dicks and Jane K. Hill play senior roles in the management of the RES, including as trustees, president, or former president; and the majority of co‐authors are members of the RES., (© 2023 The Authors. Insect Conservation and Diversity published by John Wiley & Sons Ltd on behalf of Royal Entomological Society.)

The Snail1 transcriptional factor is required for correct embryonic development, yet its expression in adult animals is very limited and its functional roles are not evident. We have now conditionally inactivated Snail1 in adult mice and analyzed the phenotype of these animals. Snail1 ablation rapidly altered pancreas structure: one month after Snail1 depletion, acinar cells were markedly depleted, and pancreas accumulated adipose tissue. Snail1 expression was not detected in the epithelium but was in pancreatic mesenchymal cells (PMCs). Snail1 ablation in cultured PMCs downregulated the expression of several β-catenin/Tcf-4 target genes, modified the secretome of these cells and decreased their ability to maintain acinar markers in cultured pancreas cells. Finally, Snail1 deficiency modified the phenotype of pancreatic tumors generated in transgenic mice expressing c-myc under the control of the elastase promoter. Specifically, Snail1 depletion did not significantly alter the size of the tumors but accelerated acinar-ductal metaplasia. These results demonstrate that Snail1 is expressed in PMCs and plays a pivotal role in maintaining acinar cells within the pancreas in normal and pathological conditions.

Objective: Treatment response and prognosis in glioblastoma (GBM) tumours can differ among patients, highlighting the growing relevance of genetic biomarkers to differentiate glioblastoma sub-types. The biomarker isocitrate dehydrogenase (IDH1) is currently receiving considerable attention. The objective of this work was to analyse the clinical and prognostic differences between glioblastomas with and without the IDH1 mutation., Methods: A retrospective study was performed on patients with GBM who underwent surgery between 2007 and 2012. The inclusion criteria were: patient age between 18-85 years who underwent surgery for the first time with complete macroscopic resection, complete adjuvant treatment with chemotherapy and radiotherapy, and a Karnofsky performance score>70., Results: A total of 61 patients (36 males/25 famales) were included and with a mean age of 62.3 years. An IDH1mutation was found in 14 patients (23%). Median survival in patients with the IDH1 mutation (IDH1-m) was 23.6 months compared with 11.9 months in those with the wild type IDH1 (IDH1-wt) (P=.028). Disease onset in IDH1-m patients tended to be at a younger age, 58.7 vs. 63.4 years, but this difference was not statistically significant., Conclusion: Glioblastomas with IDH1-m should be considered a different entity from the IDH1-wt, as their natural history and prognosis differ. In the near future we should be classified glioblastomas based on the presence of the IDH1 mutation., (Copyright © 2015 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.)

A new heptavalent conjugate vaccine (PCV7-TT) is under development in Cuba. PCV7-TT contains 2 μg of serotypes 1, 5, 14, 18C, 19F, 23F and 4 μg of 6B, each one conjugated to tetanus toxoid (TT). This vaccine was designed with the serotypes that cause most invasive pneumococcal diseases (IPD) worldwide. In the present study, we investigated the safety and explored the immunogenicity of PCV7-TT during a controlled, randomized and double blind clinical trial phase I in 4-5-year-old children. PCV7-TT was well tolerated and as safe as Synflorix used as control vaccine. Following a single-dose vaccination, all individual serotypes included in PCV7-TT induced statistically significant increase of IgG GMC and OPA GMT. These are the first clinical results of PCV7-TT in children and they pave the way toward next clinical trials in children and infants. This clinical trial was published in the Cuban Public Register of Clinical Trials with code RPCEC00000173., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Water-soluble humic substances (denoted by LN) extracted at alkaline pH from leonardite are proposed to be used as complexing agents to overcome micronutrient deficiencies in plants such as iron chlorosis. LN presents oxidized functional groups that can bind Fe(2+) and Fe(3+). The knowledge of the environment of Fe in the Fe-LN complexes is a key point in the studies on their efficacy as Fe fertilizers. The aim of this work was to study the Fe(2+)/Fe(3+) species formed in Fe-LN complexes with (57)Fe Mössbauer spectroscopy under different experimental conditions in relation to the Fe-complexing capacities, chemical characteristics, and efficiency to provide iron in hydroponics. A high oxidation rate of Fe(2+) to Fe(3+) was found when samples were prepared with Fe(2+), although no well-crystalline magnetically ordered ferric oxide formation could be observed in slightly acidic or neutral media. It seems to be the case that the formation of Fe(3+)-LN compounds is favored over Fe(2+)-LN compounds, although at acidic pH no complex formation between Fe(3+) and LN occurred. The Fe(2+)/Fe(3+) speciation provided by the Mössbauer data showed that Fe(2+)-LN could be efficient in hydroponics while Fe(3+)-LN is suggested to be used more effectively under calcareous soil conditions. However, according to the biological assay, Fe(3+)-LN proved to be effective as a chlorosis corrector applied to iron-deficient cucumber in nutrient solution.

In recent years mounting problems related to antibiotic-resistant bacteria have resulted in the prediction that we are entering the preantibiotic era. A way of preventing such a development would be to introduce novel antibacterial medicines with modes of action distinct from conventional antibiotics. Recent studies of bacterial virulence factors and toxins have resulted in increased understanding of the way in which pathogenic bacteria manipulate host cellular processes. This knowledge may now be used to develop novel antibacterial medicines that disarm pathogenic bacteria. The type III secretion system (T3SS) is known to be a potent virulence mechanism shared by a broad spectrum of pathogenic Gram-negative bacteria that interact with human, animal and plant hosts by injecting effector proteins into the cytosol of host cells. Diseases, such as bubonic plague, shigellosis, salmonellosis, typhoid fever, pulmonary infections, sexually transmitted chlamydia and diarrhoea largely depend on the bacterial proteins injected by the T3SS machinery. Recently a number of T3SS inhibitors have been identified using screening-based approaches. One class of inhibitors, the salicylidene acylhydrazides, has been subjected to chemical optimization and evaluation in several in vitro and ex vivo assays in multiple bacterial species including Yersinia spp., Chlamydia spp., Salmonella spp. and Pseudotuberculosis aeruginosa. Reports published up to date indicate that T3SS inhibitors have the potential to be developed into novel antibacterial therapeutics.

The pharmaceutical industry has long been heavily reliant on natural products, and today more than half of the twenty best-selling pharmaceuticals are derived from natural sources. Hitherto sample collection from fauna and flora has been based on an ethnobotanical approach involving traditional healers and oral histories of indigenous peoples as sources of information on folk uses of plants and organisms. In the future, however, random sampling combined with automated high-throughput screening (HTS) may come to the forefront in drug design, enabling extensive libraries of active compounds to be built up, and rendering local knowledge largely irrelevant. New technological advances in chemistry, molecular biology and data processing are combined in automated systems whereby HTS, based on bioassay-guided fractionation procedures, is used to isolate active compounds, and enabling the chemical structure of isolated compounds to be determined within 24 hours. The combination of the speed of HTS, and a remarkable decrease in the amount of sample required for the isolation and structure determination of natural compounds, has improved our ability to find unique natural products for drug development. Moreover, it has already been demonstrated that, owing to the relatively minute amounts of material required for HTS, this random sampling approach to bioprospecting for the purposes of drug will benefit efforts to conserve such sensitive biosystems as the rain forests and marine ecosystems. Thus, this technology would seem to be more compatible with the needs of modern drug design in the pharmaceutical industry that the ethnobotanical approach.

Substance P is widely distributed in the nervous system. In brain and spinal cord it may act as a transmitter, for example at the central branches of primary sensory neurons. It may also be released from the sensory nerve endings and is thought to be involved in antidromic vasodilatation and in synaptic transmission in autonomic ganglia. In some central neurons substance P is stored together with 5-hydroxytryptamine and thyrotropin-releasing hormone. These neurons project to the ventral horn of the spinal cord, amongst other places. In another system substance P coexists with a cholecystokinin-like peptide. These neurons are localized in the periaqueductal central grey matter and also project to the spinal cord. Finally, injection of a substance P antagonist into the ventral mesencephalon causes marked morphological changes in neurons that contain dopamine, substance P and gamma-aminobutyric acid (GABA).

Our experimental data show that neurotensin or a metabolite satisfies the rigid physiological criteria that should be met before a substance is classified as a true hormone with endocrine function. The gastrointestinal actions are produced by very small concentrations; the release into the blood is produced by a physiological stimulus (ingestion of food, especially fat); and the plasma concentrations of NTLI following the ingestion of food are comparable to those obtained by giving exogenous neurotensin at doses which produce effects in the gastrointestinal tract.

The aim of the present study in man was to investigate the influence of cigarette smoking on basal plasma concentrations of neurotensin-like immunoreactivity (p-NTLI), as well as on fat-induced elevation of p-NTLI levels. On three separate occasions, habitual tobacco smokers either ingested fat (55 ml Intralipid 20%) or smoked three cigarettes, or ingested fat and smoked. The subjects were fasted overnight and told no to smoke during the fasting period. Smoking of one cigarette at one hour intervals (0, 60, and 120 min) did not change the p-NTLI levels (n = 6). Ingestion of fat caused a significant increase (n = 16) and when these two procedures were combined (n = 16), the mean integrated p-NTLI response (nM0-180 min) was 56% larger than the response after fat ingestion alone. The results show that cigarette smoking potentiates the fat-induced elevation of p-NTLI levels, whereas cigarette smoking per se has no effect.

In dogs with innervated fundic pouches an intravenous infusion of (Gln4)-neurotensin, 60 pmol X kg-1 X min-1, reduced the pentagastrin-stimulated acid secretion to 40% of the control secretory rate. After vagal denervation of the fundic pouches the same dose of (Gln4)-neurotensin did not significantly change the secretion. These findings suggest that (Gln4)-neurotensin does not act directly on parietal cells but inhibits acid secretion at a presynaptic level.

The effect of ingestion of amino acids (Vamin N), glucose, and fat (Intralipid) on the concentration of neurotensin-like immunoreactivity (NTLI) in plasma was determined in 6 healthy male volunteers. After ingestion of Intralipid (55 ml, 200 mgxml-1) there was a significant increase in the plasma concentration of NTLI. The calculated integrated total NTLI response (6.7 +/- 2.5 nM over 180 min) was statistically significant. Although isocaloric amounts of Vamin and glucose also increased the plasma concentration of NTLI, these increases were not statistically significant. The data indicate that fat is an important stimulus for the release of NTLI from the small intestine. It is suggested that neurotensin, or a metabolite, in blood may be a hormone involved in the postprandial inhibition of gastric motility and gastric acid secretion elicited from the small intestine.

The actions of the tridecapeptides neurotensin and (Gln4)-neurotensin have been studied on the heart and on the blood flow in subcutaneous adipose tissue, skin and small intestine of anesthetized dogs. In addition, their possible actions have been investigated on blood glucose concentration and lipolysis in subcutaneous adipose tissue. The two peptides were found to be approximately equipotent. Intravenous infusion of 20-120 ng X kg-1 X min-1 produced slight hypotension, an initial vasodilatation in the small intestine and a delayed vasoconstriction in denervated subcutaneous adipose tissue and to a lesser extent in the skin and small intestine. At this infusion rate, neurotensin and (Gln4)-neurotensin did not elicit vasodilatation in the skin or adipose tissue and had no effect on heart rate. The delayed vasoconstriction in adipose tissue was not inhibited by local alpha-receptor blockade. Both neurotensin and (Gln4)-neurotensin increased glucose concentration in the upper dose range. No effects on lipolysis were observed, either in vivo or in vitro. These experiments show that neurotensin and (Gln4)-neurotensin have both vasodilator and vasoconstrictor actions in the peripheral vasculature but seem to be without cardiac actions. They also increase blood glucose concentration. It remains to be shown whether these actions are direct or whether some are indirectly mediated.

The effects of (D-Pro2, D-Trp7,9)-substance P, a structural analogue of substance P, were examined in two models on cerebrovascular responses to substance P(SP) in cats; in vitro using segments of the middle cerebral artery and in situ by microapplication of the peptides close to pial arterioles. (D-Pro2, D-Trp7,9)-SP in concentrations up to 6.6 x 10(-6) M was without significant effect upon isolated middle cerebral arteries under normal conditions and in arteries contracted with prostaglandin F2 alpha. SP caused concentration-dependent relaxations of middle cerebral arteries contracted by prostaglandin F2 alpha (mean +/- SE; EC50: 2.0 +/- 1.6 x 10(-9) M). The presence of (D-Pro2, D-Trp7,9)-SP shifted the concentration-response curve of SP towards higher concentrations without significantly effecting the maximum response of the arteries to SP. A relaxation by 24.2 +/- 4.0% (n = 6) was obtained in prostaglandin F2 alpha contracted arteries by increasing the potassium concentration with 2 mM in the buffer solution. This response to potassium was unaltered in the presence of 6.6 x 10(-6)M of (D-Pro2, D-Trp7,9)-SP (25.0 +/- 7.1%, n = 5). Perivascular microapplication of SP around individual pial arterioles in situ effected dose-dependent increases in vascular calibre (mean response 14.5 +/- 2% with SP, 10(-7)M). The concomitant perivascular administration of (D-Pro2, D-Trp7,9)-SP (6.6 x 10(-6)M), which alone did not alter the arteriolar calibre, attenuated significantly the cerebrovascular response to SP (mean response 1.5 +/- 3.2%). On the basis of the agonist-antagonist relation found, these observations point to the possibility of a specific SP receptor site in cerebral arteries and arterioles.

Substance P (SP) and the C-terminal sequences octa- and penta-SP produced dose-dependent vasopressor responses, and the action was associated with mild tachycardia. The vasopressor effect of SP was counteracted by the SP antagonist [D-Pro2,D-Phe7,D-Trp9]SP given intracisternally, suggesting that central SP receptors were involved. Experiments with different sodium contents in the vehicle and with naloxone pretreatment indicate that central naloxone-sensitive opiate receptors may exist, capable of modulating the effects of SP receptor activation.

Ingestion of fat causes a pronounced decrease in lower esophageal sphincter (LES) pressure. This may be due in part to effects of neurotensin (NT), which is released postprandially after the ingestion of fat. The aim of the present investigation was to establish whether the LES pressure decreases at physiological plasma concentrations of NT(1-13). In addition, we have compared the effects and metabolism of NT(1-13) and (Gln4)NT(1-13). The experiments were performed in 3 healthy male volunteers who had fasted for at least 11 hours prior to the study. NT(1-13) or (Gln4)NT(1-13) were infused intravenously at a dose of 12 pmoles X kg-1 X min-1. LES pressure was monitored by a continuous pull-through method with a perfused catheter. The concentrations of chromatographically identified tridecapeptides were determined using NH2 and COOH-terminal directed antisera. Already one min after the start of the infusions the LES pressure had decreased by 43% of the control value. At that time the plasma concentration of the neurotensin tridecapeptide was about 15 pM. NT(1-13) and (Gln4)NT(1-13) had similar half-lives in plasma (2.5 min). NT(1-8) and (Gln4)NT(1-8) were found to be the main metabolites of NT(1-13) and (Gln4)NT(1-13) respectively. The results indicate that the increase in the plasma concentration of NT(1-13) seen after the ingestion of food is sufficient for neurotensin to function as a hormone of the endocrine type. NT(1-13) and (Gln4)NT(1-13) have the same effects on LES pressure in humans and show the same pharmacokinetic characteristics.

Nine of 34 (26%) consecutive patients with different endocrine gastrointestinal tumors had increased levels of plasma neurotensinlike immunoreactivity in the fasting state. This was the case in 6 of 18 (33%) patients with endocrine pancreatic tumors and in 3 of 16 (19%) patients with gut tumors. Only 1 of 13 patients with midgut tumors had increased plasma-neurotensinlike immunoreactivity, despite the fact that most of the normal neurotensin-containing cells are located in the midgut. In 3 of 4 cases the concentration of plasma-neurotensinlike immunoreactivity decreased after streptozotocin or surgical treatment. In 1 patient, increasing levels of plasma-neurotensinlike immunoreactivity were found several months before the onset of clinical symptoms or signs of relapse after surgical treatment. Neurotensin was found in extracts of primary tumors and metastases. Plasma-neurotensinlike immunoreactivity in patients with "neurotensinomas" represents more than one molecular form, including neurotensin(1-13) and neurotensin(1-8). Neurotensin(1-8) in plasma may be a degradation product of neurotensin(1-13) released from the tumor tissue. We have not been able to relate any specific symptoms to elevated plasma-neurotensinlike immunoreactivity.

Neurogenic factors released by antidromic nerve stimulation are thought to be in part responsible for the vasodilation and breakdown of the blood-aqueous barrier that follows trauma to the eye. Substance P is one candidate for the mediation of the inflammatory response since it is thought to be a neurotransmitter in sensory afferents and since exogenous substance P is capable of eliciting a response characteristic of inflammation. In rabbits, intravitreal or topical application onto the eye of a specific substance P antagonist, [d-Pro2, D-Trp7,9]SP, inhibited not only the irritant effects of exogenous substance P but also the inflammatory response to a standardized trauma (infrared irradiation of the iris). These observations suggest that substance P, or a related peptide, is a neurogenic mediator of the inflammatory response in the eye.

The effect of nephrectomy and ureter ligation on the concentration of endogenous plasma neurotensin-like immunoreactivity (p-NTLI) was studied in conscious rats by means of antiserum 17-8201 which detects NT (1-13) only, and antiserum 0-7709 which detects NT(1-13) and NT(1-8). The unstimulated p-NTLI concentration did not change significantly during a 25-h observation period following nephrectomy in comparison with sham operation. However, stimulation of the release of NTLI by intraduodenal administration of oleic acid (0.2 ml) resulted in significantly higher p-NTLI levels in the nephrectomized rats than in the sham operated rats. Ureter ligation did not significantly affect basal or stimulated p-NTLI. The data indicate that the kidneys play an important part in the elimination of p-NTLI released after fat ingestion.

The purpose of this study was to evaluate the pharmacological properties of a substance P (SP) analogue [D-Arg, D-Pro, D-Trp, Leu]SP as an SP antagonist. This analogue, blocked the SP-induced contractions of the isolated guinea-pig ileum and the rat urinary bladder and it exhibited no spasmogenic activity on these preparations. The affinity constant (pA2) for [D-Arg, D-Pro, D-Trp, Leu]SP versus SP was 6.31 on the guinea-pig ileum preparation and 5.30 on the rat urinary bladder preparation. The slopes of the regression lines of the Schild plots were close to unity. These data indicate that [D-Arg, D-Pro, D-Trp, Leu]SP blocks SP receptors in a simple competitive manner and suggest that there are at least two subpopulations of SP receptors. The contractions caused by the closely related tachykinins eledoisin and physalaemin were also blocked by the SP analogue. However, the slopes of the regression lines were significantly different from unity. Moreover, when tested on the hamster urinary bladder, which contracts at low concentrations of eledoisin but is rather insensitive to physalaemin and SP, [D-Arg, D-Pro, D-Trp, Leu]SP did not block the contractile actions of eledoisin or of physalaemin and SP. Compared to SP eledoisin and physalaemin may bind to SP receptors in a different manner. Eledoisin also seems to interact with receptors different from the SP receptors.

The concentration of neurotensin-like immunoreactivity in plasma (p-NTLI) increases after the ingestion of food, and fat seems to be the most important nutrient. It is essential to characterize the NT species that are responsible for this postprandial rise of p-NTLI. After an overnight fast, two male and two female subjects therefore ingested 300 ml of cream (containing 40% (w/w) milk fat). Unextracted plasma samples were subjected to column chromatography and the eluates were analysed using four NT antisera having different specificities. The concentration of chromatographically identified NT(1-13) in peripheral plasma increased significantly from 3 pM in the fasting state to 26 pM 30 min after the ingestion of fat. The concentration of NT(1-8), which is probably a metabolite of NT(1-13), also increased markedly. No significant increase of smaller COOH-terminal sequences of NT was found. The results show that the plasma concentration of NT(1-13) may increase about tenfold following the ingestion of fat. This is further support for the hypothesis that NT(1-13) may function as a hormone.

Radioimmunoassays based on antisera raised against the tachykinins eledoisin (antiserum E7) and kassinin (antiserum K12) were used to measure the concentration of tachykinin-like immunoreactivity (TKLI) in plasma from 52 healthy subjects. 65 patients with carcinoid tumors (of which 46 had symptoms of both flushing and diarrhoea), and 6 patients with endocrine pancreatic tumors. The antisera did not crossreact with substance P (SP). Elevated concentrations of TKLI, as compared with healthy subjects, were found in 75% of the carcinoid patients, but in none of the patients with pancreatic tumors. Tumor metastases from 8 of the carcinoid patients all contained TKLI. Ion-exchange chromatography of plasma samples and tumor tissue extracts indicated the presence of several immunoreactive molecular forms. The elution patterns of the immunoreactivity detected by antisera E7 and K12 were similar, indicating that the same molecular species are measured by these antisera. None of the components coeluted with synthetic SP. One of the immunoreactive components in carcinoid tumor extracts coeluted with synthetic NKA. The major immunoreactive components in plasma from the patients eluted in a position different from that of all currently known mammalian tachykinins. Tachykinin immunoreactive material detected in tumor tissue and plasma of patients with carcinoid tumor may play a role in the symptomatology of the carcinoid syndrome.

Studies with the SP-analogues (D-Pro2, D-Phe7, D-Trp9)-SP and (D-Pro2, D-Trp7,9)-SP show that they inhibit the action of SP in a variety of organs both in vitro and in vivo. They also block several non-cholinergic, non-adrenergic effects of nerve activation. Experimental evidence suggest that (D-Pro2, D-Phe7, D-Trp9)-SP and (D-Pro2, D-Trp7,9)-SP are specific SP-antagonists of the competitive type with little or no agonist activity. The present data show that SP-antagonists will be of great importance in clarifying functions of SP.

Radioimmunoassays were developed for the tachykinins eledoisin (ELE) and kassinin (KAS) using antisera raised in rabbits. The antisera exhibited low (less than 0.1%) cross-reactivities to substance P (SP) and physalaemin (PHY), but crossreacted (with one exception, antiserum K7) to varying extents with neurokinin A (NKA) and neurokinin B (NKB). In the rat, the tissue distribution of the immunoreactive material detected by antiserum (E7) raised against ELE and by another antiserum (K1) raised against KAS both resembled that previously described for SP. Using the highly KAS-specific antiserum K7, no or only very low levels of immunoreactivity could be detected in extracts of various rat tissues. Gel permeation chromatography and ion-exchange chromatography of tissue extracts indicated that all antisera (except K7) detected the same population of immunoreactive molecules. One of the components was chromatographically indistinguishable from NKA. The tissue distribution of this component also resembled that of SP. Another immunoreactive component co-chromatographed with NKB at cation exchange chromatography. Acid tissue extracts, but not neutral tissue extracts, were found to contain immunoreactive components which appeared more basic than NKA and NKB. The total levels of immunoreactivity were higher in neutral than in acid tissue extracts. However, the ratio between the amounts of immunoreactivities in the two types of extracts varied considerably between tissues, indicating that tachykinin immunoreactive components may be present in different relative proportions in various tissues.

The influence of neurotensin, substance P and methionine-enkephalin (met-enkephaline) on proximal and distal colonic motility was studied in anesthetized cats. When administered i.v, at a dose of 14 pmol x kg-1 x min-1, neurotensin increased basal smooth muscle tone and antiperistaltic activity in the proximal colon. After higher doses of neurotensin the basal muscle tone also increased in the distal colon. Substance P at a dose of 17 pmol x kg-1 x min-1 selectively and powerfully stimulated the distal colon, thus causing a mass contraction pattern with a concomitant decrease in peristaltic amplitude. In the proximal part of the colon 17 pmol x kg -1 x min-1 of substance P exerted an inhibitory action on the peristaltic amplitude in animals with a high level of spontaneous activity. In addition, the basal muscle tone was slightly decreased. In animals with sluggish spontaneous activity, however, no effects were detected in the proximal colon. With increasing doses of substance P forceful contractions of the proximal colon were also registered. Met-enkephalin at a dose of 40 pmol x kg-1 x min-1 increased the smooth muscle basal tone with no effect on the peristaltic activity in the proximal or distal segments. The effect on basal tone was blocked by naloxone. Thus, neurotensin, substance P and met-enkephalin have distinct motor actions on the colon. At low doses neurotensin may stimulate the churning and mixing functions of the proximal colon. Substance P exerts its major effects on the distal part with a mass contraction response and met-enkepahlin increases the basal muscle tone equally in the proximal and distal parts of the colon.

The effect of intraduodenal administration of various types of lipids on the concentration of p-NTLI has been studied on anesthetized rats. Oleic acid, sodium oleate, triolein, linoleic acid, linolenic acid, arachidonic acid, butyric acid, liquid paraffin, phosphatidyl choline (lecithin) and saline were administered. Oleic acid, triolein, linoleic acid and linolenic acid significantly increased the integrated response of p-NTLI. The maximal concentration of p-NTLI was reached 40 min after administration of oleic acid. However after instillation of triolein, the maximal concentration was reached at 100 min which was significantly later. The results indicate that the response of p-NTLI following administration of fat into the duodenum of rats is a specific event caused by fatty acids rather than by lipophilic substances in general. Of the substances tested 18-carbon fatty acids were the most effective in increasing the concentration of p-NTLI. Shorter- or longer-chain fatty acids were less effective. The degree of unsaturation, i.e. the presence of one or more double bounds is also of importance. Triglycerides seem to be hydrolysed to fatty acids before they may bring about an increase in the concentration of p-NTLI. The charge of lipids seems to be critical since the sodium salt of oleic acid had limited effects. Arachidonic acid did not change the integrated response of p-NTLI indicating that products of cyclooxygenase and lipoxygenase pathways are not involved in the fatty acid induced release of NTLI.

Two novel neuropeptides, neurokinin alpha and beta isolated from porcine spinal cord, were announced. We have synthesized neurokinin alpha as Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2, which were 98-99% pure by HPLC. Assays on the isolated guinea pig ilium showed neurokinin alpha to have 81% and neurokinin beta to have 65% of the activity of Substance P. Knowledge of these three related peptides having a common activity opens new considerations of their intrinsic physiological roles in neurotransmission versus pharmacological activities, and reappraisal of the diverse activities of Substance P including that in the inflammatory response of the eye.

Ten analogs of substance P (SP) were designed and synthesized. The agonist and antagonist activities against SP were assayed on the isolated guinea pig ileum. The prime designs were changes of the important Met11 to include Leu11, Thr11, D-Leu11 and D-Ala11. Step-wise designs of changing D-Arg1 and D-Pro2 to the corresponding L-configurations resulted in decreasing antagonist activity. Changing Leu11 to D-Leu11 and D-Ala11 reduced antagonist activity. [D-Arg1,D-Pro2,D-Trp7,D-Trp9,Leu11]-SP is the most potent antagonist of this group of analogs, and required a 100-fold increase in the concentration of SP to give 50% of the maximal response caused by SP.