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Recent genome-wide association studies have linked polymorphisms in two atophagy genes, Atg16L1 and IRGM, with Crohn's Disease. Now, experiments with Atg16L1 transgenic mice indicate multiple roles for autophagy in inflammatory bowel disease via effects on Paneth cells, a runaway inflammasome, and the proinflammatory cytokine IL-1beta.

This policy document was prepared by J Nunn, M Foster, S Master and S Greening on behalf of the British Society of Paediatric Dentistry (BSPD). Policy documents produced by the BSPD represent a majority view, based on a consideration of currently available evidence. They are produced to provide guidance with the intention that the policy be regularly reviewed and updated to take account of changing views and developments.

Interconversions of phosphoinositides play a pivotal role during phagocytosis and at the subsequent stages of phagosomal maturation into the phagolysosome. Several model systems have been used to study the role of phosphoinositides in phagosomal membrane remodelling. These include phagosomes formed by inanimate objects such as latex beads, or pathogenic bacteria, e.g. Mycobacterium tuberculosis. The latter category provides naturally occurring tools to dissect membrane trafficking processes governing phagolysosome biogenesis. M. tuberculosis persists in infected macrophages by blocking Rab conversion and affecting Rab effectors. One of the major Rab effectors involved in this process is the type III phosphatidylinositol 3-kinase hVPS34. The lipid kinase hVPS34 and its enzymatic product PtdIns3P are critical for the default pathway of phagosomal maturation into phagolysosomes. Mycobacteria block PtdIns3P production and thus arrest phagosomal maturation. PtdIns3P is also critical for the process of autophagy, recently recognized as an effector of innate immunity defenses. Induction of autophagy by pharmacological, physiological, or immunological means, overcomes mycobacterial phagosome maturation block in a PtdIns3P generation dependent manner and eliminates intracellular M. tuberculosis. PtdIns3P and PtdIns3P-dependent processes represent an important cellular nexus where fundamental trafficking processes, disease causing host-pathogen interactions, and innate and adaptive immunity defense mechanisms meet.

Autophagy is a newly recognized innate and adaptive immunity defense against intracellular pathogens, in keeping with its role as a cytoplasmic maintenance pathway. Induction of autophagy by physiological, pharmacological or immunological means can eliminate intracellular Mycobacterium tuberculosis, providing one of the first examples of the immunological role of autophagy. Under normal circumstances, M. Tuberculosis survives in macrophages by inhibiting phagolysosome biogenesis. Induction of autophagy overcomes the mycobacterial phagosome maturation block, and delivers the tubercle bacilli to degradative compartments where they are eliminated.

Background: Resting and squeeze pressures in the anal canal are thought to reflect the contributions of the internal anal sphincter (IAS) and the external anal sphincter (EAS) respectively. Role of the puborectalis muscle (PRM) in the genesis of anal canal pressure is not known., Objectives: To determine the functional correlates of anal canal anatomy., Methods: Seventeen asymptomatic nulliparous women were studied using simultaneous 3D ultrasound images and manometry of the anal canal. Ultrasound images were recorded using a transducer placed at the vaginal introitus and pressures were recorded with a side-hole manometry catheter using a station (every 5 mm) pull-through technique. Pressures were recorded at rest and during voluntary squeeze., Results: Anal canal high pressure zone was 39 +/- 1 mm in length. The IAS, EAS, and PRM were clearly visualized in the ultrasound images. EAS was located in the distal (length 19 +/- 1 mm) and PRM in the proximal part (length 18 +/- 1 mm) of the anal canal. The station pull-through technique revealed increases in pressure with voluntary squeeze in the proximal as well as distal parts of the anal canal. Proximal anal canal pressure, located in the PRM zone, showed greater circumferential asymmetry than the distal anal canal pressure, located in the EAS zone., Conclusions: (1) PRM contributes to the squeeze pressure in the proximal part of the anal canal and EAS to the distal anal canal. (2) PRM squeeze-related increase in anal canal pressure might be important in the anal continence mechanism.

A marquee feature of the powerful human pathogen Mycobacterium tuberculosis is its macrophage parasitism. The intracellular survival of this microorganism rests upon its ability to arrest phagolysosome biogenesis, avoid direct cidal mechanisms in macrophages, and block efficient antigen processing and presentation. Mycobacteria prevent Rab conversion on their phagosomes and elaborate glycolipid and protein trafficking toxins that interfere with Rab effectors and regulation of specific organellar biogenesis in mammalian cells. One of the major Rab effectors affected in this process is the type III phosphatidylinositol 3-kinase hVPS34 and its enzymatic product phosphatidylinositol 3-phosphate (PI3P), a regulatory lipid earmarking organellar membranes for specific trafficking events. PI3P is also critical for the process of autophagy, recently recognized as an effector of innate and adaptive immunity. Induction of autophagy by physiological, pharmacological or immunological signals, including the major antituberculosis Th1 cytokine IFN-gamma and its downstream effector p47 GTPase LRG-47, can overcome mycobacterial phagosome maturation block and inhibit intracellular M. tuberculosis survival. This review summarizes the findings centred around the PI3P-nexus where the mycobacterial phagosome maturation block and execution stages of autophagy intersect.

Background: One of the great difficulties in evaluating a voice is the judgment of quality through the perceptual auditive analysis--although frequently used--, as it is influenced by socioeconomic and cultural aspects as well as individual preferences. Many are the adjectives and methods used in this assessment, especially because of the subjectivity involved in the process, leading to incompatibilities between listeners and difficulties in reaching a consensus on the use of this or that terminology. In such a context, the voice laboratory and more specifically the acoustic computerized analysis, has guided and complemented speech-language treatments. Among the several possibilities of spectrographic analysis, the (Long-Term Average Spectrum--LTAS) quantifies the quality of voices, pointing differences between gender, age, professional--spoken and sang--and dysphonic voices. The LTAS has been used a lot in researches that investigate voice. As it evidences the contribution of the glottic source and of resonance to the quality of voice, it provides objective parameters for the evaluation of this aspect which usually depends on our auditive perception., Aim: to demonstrate how LTAS can be applied in voice research and in the speech-language therapy practice, describing both the technical aspects required for the production and interpretation of results, and its limitations., Conclusion: The area of voice research has developed a lot in these last two decades especially because of the advent of the voice and speech laboratory. For this reason, the knowledge about the applicability of more tools for voice analysis, as the LTAS, as well as the existing need for more studies in this area, will most certainly contribute for the creation of new research areas not only in the field of professional voice but also in the field of therapy.

The Neoproterozoic glaciations supposedly ended in a supergreenhouse environment, which led to rapid melting of the ice cover and precipitation of the so-called cap carbonates. If Earth was covered with ice, then extraterrestrial material would have accumulated on and within the ice and precipitated during rapid melting at the end of the glaciation. We found iridium (Ir) anomalies at the base of cap carbonates in three drill cores from the Eastern Congo craton. Our data confirm the presence of extended global Neoproterozoic glaciations and indicate that the duration of the Marinoan glacial episode was at least 3 million, and most likely 12 million, years.

Inhibition of phagolysosome biogenesis in infected macrophages is a classical pathogenesis determinant of Mycobacterium tuberculosis. In this review we primarily cover the cellular mechanisms of M. tuberculosis phagosome maturation arrest. A detailed picture is beginning to emerge, involving regulators of membrane trafficking in mammalian cells and phagosomal interactions with endosomal organelles and the trans-Golgi network. We also present a hypothesis that overlaps may exist between the mycobacterial interference with the host cell membrane trafficking processes and the targeting of the late endosomal sorting machinery by HIV during viral budding in macrophages. We propose that interference with the endosomal sorting machinery contributes to the synergism between the two significant human diseases--AIDS and tuberculosis.

Isoniazid (INH), a front-line antituberculosis agent, is activated by mycobacterial catalase-peroxidase KatG, converting INH into bactericidal reactive species. Here we investigated the requirements and the pathway of nitric oxide (NO*) generation during oxidative activation of INH by Mycobacterium tuberculosis KatG in vitro. We also provide in vivo evidence that INH-derived NO* can inhibit key mycobacterial respiratory enzymes, which may contribute to the overall antimycobacterial action of INH.

Isonicotinic acid hydrazide (INH) is a frontline antituberculosis agent. Once taken up by Mycobacterium tuberculosis, INH requires activation by the catalase-peroxidase KatG, converting INH from its prodrug form into a range of bactericidal reactive species. Here we used 15N-labeled INH together with electron paramagnetic resonance spin trapping techniques to demonstrate that nitric oxide (NO*) is generated from oxidation at the hydrazide nitrogens during the activation of INH by M. tuberculosis KatG. We also observed that a specific scavenger of NO* provided protection against the antimycobacterial activity of INH in bacterial culture. No significant increases in mycobacterial protein nitration were detected, suggesting that NOdot; and not peroxynitrite, a nitrating metabolite of NO*, is involved in antimycobacterial action. In conclusion, INH-derived NO* has biological activity, which directly contributes to the antimycobacterial action of INH.

The authors conducted four studies (total N = 292) about character and mate desirability. In Study 1, undergraduates judged stimuli for attractiveness-physically and as a casual or longterm date. The target was described as faithful, having cheated but stayed with mates, or having cheated and left. Contrary to the hypothesis, men and women were equally affected by both kinds of cheaters. Study 2 replicated Study 1 with nonstudent adults. In Study 3, undergraduates rated a stimulus on the same attractiveness variables. This target had $14 million from winning a lottery or selling a dot-com company. Women, but not men, found the dot-com creator to be more physically attractive than the lottery winner. In Study 4, undergraduates rated someone who sold a cookie-making company or profited from a lucky real estate transaction. Both men and women preferred the cookie-company seller on all three measures of attractiveness.

Mycobacterium tuberculosis persistence in human populations relies on its ability to inhibit phagosomal maturation. M. tuberculosis resides in a pathogen-friendly phagosome escaping lysosomal bactericidal mechanisms and efficient antigen presentation in the host phagocytic cell. M. tuberculosis phagosome maturation arrest includes the action of mycobacterial lipid products, which mimic mammalian phosphatidylinositols, targeting host cell membrane trafficking processes. These products interfere with membrane trafficking and organelle biogenesis processes initiated by Ca(2+) fluxes, and ending with host cell Rab GTP-binding proteins and their effectors. The block includes phosphatidylinositol 3-kinase and membrane tethering molecules that prepare phagosomes for fusion with other organelles. Understanding these processes could provide new targets for pharmacological intervention in tuberculosis.

Phenelzine (PLZ) is a non-selective monoamine oxidase inhibitor (MAOI) commonly used to treat depression and panic disorder. As expected, PLZ increases brain levels of dopamine, norepinephrine, and serotonin. Interestingly, PLZ also elevates brain levels of gamma-aminobutyric acid (GABA), and previous studies have suggested that these increases may also contribute to the anxiolytic effects of PLZ. Using in vivo microdialysis in conscious, freely moving rats, combined with high performance liquid chromatography, the present experiments determined that PLZ (15 or 30 mg/kg, free base weight) increases extracellular levels of GABA in the caudate-putamen and nucleus accumbens. The results also indicated that phenylethylidenehydrazine (PEH; 29.6 mg/kg, free base weight), a putative intermediate metabolite of PLZ that is not an MAOI, also significantly increases extracellular GABA levels in the caudate-putamen. These findings provide further evidence that GABA may play an important role in the actions of PLZ and suggest that PEH should be pursued further as a GABAergic drug in its own right.

In this report, we have analyzed the protein encoded by the murine Brca2 locus. We find that murine Brca2 shares multiple properties with human BRCA2 including its regulation during the cell cycle, localization to nuclear foci, and interaction with Brca1 and Rad51. Murine Brca2 stably interacts with human BRCA1, and the amino terminus of Brca2 is sufficient for this interaction. Exon 11 of murine Brca2 is required for its stable association with RAD51, whereas the carboxyl terminus of Brca2 is dispensable for this interaction. Finally, in contrast to human BRCA2, we demonstrate that carboxyl-terminal truncations of murine Brca2 localize to the nucleus. This finding may explain the apparent inconsistency between the cytoplasmic localization of carboxyl-terminal truncations of human BRCA2 and the hypomorphic phenotype of mice homozygous for similar carboxyl-terminal truncating mutations.

Intracellular pathogenic bacteria, including Mycobacterium tuberculosis, frequently have multitiered defense mechanisms ensuring their survival in host phagocytic cells. One such defense determinant in M. tuberculosis is the katG gene, which encodes an enzyme with catalase, peroxidase, and peroxynitritase activities. KatG is considered to be important for protection against reactive oxygen and nitrogen intermediates produced by phagocytic cells. However, KatG also activates the front-line antituberculosis drug isoniazid, hence rendering M. tuberculosis exquisitely sensitive to this compound. In this context, katG expression represents a double-edged sword, as it is an important virulence determinant but at the same time its activity levels determine sensitivity to INH. Thus, it is important to delineate the regulation and expression of katG, as this not only can aid understanding of how M. tuberculosis survives and persists in the host but also may provide information of relevance for better management of INH therapy. Here, we report the first extensive analysis of the katG promoter activity examined both in vitro and in vivo. Using S1 nuclease protection analysis, we mapped the katG mRNA 5' ends and demonstrated that two promoters, P(1)furA and P(1)katG, control transcription of katG. The furA and katG genes are cotranscribed from P(1)furA. Both P(1)furA and P(1)katG promoters show induction upon challenge with hydrogen peroxide and cumene hydroperoxide. Studies carried out using the transcriptional fusions P(1)furA-gfp, P(1)katG-gfp, and P(1)furA-P(1)katG-gfp confirmed the existence of two katG promoters. In addition, we showed that both promoters are expressed in vivo during intracellular growth of virulent M. tuberculosis H37Rv. P(1)furA is induced early upon infection, and P(1)katG becomes active only upon extended growth in macrophages. These studies delineate the transcriptional organization of the furA-katG region and indicate differential regulation in vivo of the two katG promoters. These phenomena most likely reflect the differing demands at sequential stages of the infection cycle and may provide information for improved understanding of host-pathogen interactions in tuberculosis and for further optimization of INH chemotherapy.

Both human and mouse cells express an alternatively spliced variant of BRCA1, BRCA1-Delta11, which lacks exon 11 in its entirety, including putative nuclear localization signals. Consistent with this, BRCA1-Delta11 has been reported to reside in the cytoplasm, a localization that would ostensibly preclude it from playing a role in the nuclear processes in which its full-length counterpart has been implicated. Nevertheless, the finding that murine embryos bearing homozygous deletions of exon 11 survive longer than embryos that are homozygous for Brca1 null alleles suggests that exon 11-deleted isoforms may perform at least some of the functions of Brca1. We have analyzed both the full-length and the exon 11-deleted isoforms of the murine Brca1 protein. Our results demonstrate that full-length murine Brca1 is identical to human BRCA1 with respect to its cell cycle regulation, DNA damage-induced phosphorylation, nuclear localization, and association with Rad51. Surprisingly, we show that endogenous Brca1-Delta11 localizes to discrete nuclear foci indistinguishable from those found in wild-type cells, despite the fact that Brca1-Delta11 lacks previously defined nuclear localization signals. However, we further show that DNA damage-induced phosphorylation of Brca1-Delta11 is significantly reduced compared to full-length Brca1, and that gamma irradiation-induced Rad51 focus formation is impaired in cells in which only Brca1-Delta11 is expressed. Our results suggest that the increased viability of embryos bearing homozygous deletions of exon 11 may be due to expression of Brca1-Delta11 and suggest an explanation for the genomic instability that accompanies the loss of full-length Brca1.

In vivo microdialysis, using dialysis probes inserted into discrete brain areas and subsequent analysis of neurotransmitters and related substances in the dialysates (usually with HPLC), has yielded a great deal of important information about the actions of psychotropic drugs and endogenous neurotransmitter systems and about the functional interactions between various brain areas. This paper reviews the principles involved in in vivo microdialysis, its advantages and disadvantages, and recent innovations in methodology and applications. The first section includes brief discussions of principles and applications of dialysis, use of anesthetized versus conscious freely moving animals, and methods used to determine the neural origin of neurotransmitters in the dialysate. The subsequent sections provide detailed descriptions, based largely on our own studies in rats, of stereotaxic surgery, in vivo microdialysis, and dialysate analysis, with an emphasis on amino acids and biogenic amines and their metabolites. A discussion of methodological problems which may be encountered in the analysis of amino acids and biogenic amines is also included., (Copyright 2001 Academic Press.)

Two mechanisms may account for brain edema in fulminant hepatic failure: the osmotic effects of brain glutamine, a product of ammonia detoxification, and a change of cerebral blood flow (CBF). We have shown brain edema, a marked increase in brain glutamine, and a selective rise in CBF in rats after portacaval anastomosis receiving an ammonia infusion. In this study, we inhibited the activity of glutamine synthetase with methionine-sulfoximine (MSO) and examined ammonia levels, brain water and CBF. Four groups received either a continuous ammonium acetate or control infusion; half of the animals had been pretreated with MSO or vehicle. The ammonia group exhibited brain edema (79.97 +/- 0.04 vs. 81.11 +/- 0. 13% water), an increase in cerebrospinal fluid (CSF) glutamine (1.29 +/- 0.21 vs. 2.84 +/- 0.39 mmol/L) and CBF (63 +/- 11 vs. 266 +/- 45 mL/min/100 g brain). When MSO was added to the ammonia infusion, ammonia levels rose further (928 +/- 51 vs. 1,293 +/- 145 mmol/L, P <.05) but CSF glutamine decreased (2.84 +/- 0.39 vs. 1.61 +/- 0.2 mmol/L, P <.01). Brain edema (80.48 +/- 0.11%) and cerebral hyperemia (140 +/- 25 mL/min/100 g brain) were significantly ameliorated in the ammonia plus MSO group. Brain output of circulating nitric oxide (NO(x)) was increased in the ammonia-infused group but normalized in the ammonia plus MSO group. In this model, the rise of CBF reflects intracranial events that occur after glutamine synthesis. Activation of nitric oxide synthase in the brain could account for these findings.

The M.AluI DNA-(cytosine C5)-methyltransferase (5mC methylase) acts on the sequence 5'-AGCT-3'. The amino acid sequences of known 5mC methylases contain ten conserved motifs, with a variable region between Motifs VIII and IX that contains one or more "target-recognizing domains" (TRDs) responsible for DNA sequence specificity. Monospecific 5mC methylases are believed to have only one TRD, while multispecific 5mC methylases have as many as five. M.AluI has the second-largest variable region of all known 5mC methylases, and sequence analysis reveals five candidate TRDs. In testing whether M.AluI is in fact monospecific it was found that AGCT methylation represents only 80-90% of the methylating activity of this enzyme, while control experiments with the enzyme M.HhaI gave no unexplained activity. Because individual TRDs can be deleted from multispecific methylases without general loss of activity, a series of insertion and deletion mutants of the M.AluI variable region were prepared. All deletions that removed more than single amino acids from the variable region caused significant loss of activity; a sensitive in vivo assay for methylase activity based on McrBC restriction suggested that the central portion of the variable region is particularly important. In some cases, multispecific methylases can accommodate a TRD from another multispecific methylase, thereby acquiring an additional specificity. When TRDs were moved from a multispecific methylase into two different locations in the variable region of M.AluI, all hybrid enzymes had greatly reduced activity and no new specificities. M.AluI thus behaves in most respects as a monospecific methylase despite the remarkable size of its variable region.

The muscle myosins and hexomeric proteins consisting of two heavy chains and two pairs of light chains, the latter called essential (ELC) and regulatory (RLC). The light chains stabilize the long alpha helical neck of the myosin head. Their function in striated muscle, however, is only partially understood. We report here the identification of distinct missense mutations in a skeletal/ventricular ELC and RLC, each of which are associated with a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle. We show that myosin containing the mutant ELC has abnormal function, map the mutant residues on the three-dimensional structure of myosin and suggest that the mutations disrupt the stretch activation response of the cardiac papillary muscles.

The authors evaluated the test protocols used most frequently to screen the peripheral visual field of driving applicants to determine whether they are suitable for detecting peripheral field loss in patients with retinitis pigmentosa (RP). The peripheral vision tests available on the Keystone View Tester and the Titmus Vision Tester were administered to 23 subjects with RP, 3 subjects with Type 2 Usher's syndrome, and 1 subject who was a partially affected carrier of X-linked recessive RP. The subjects had varying degrees and types of visual field loss. Tests were administered using the standard protocol of the State of Illinois, which is a standard procedure used by state licensing bureaus nationwide. Results demonstrate that the screening protocols use stimulus conditions that are primarily sensitive only to appreciable field losses and examine locations that typically lie within an RP patient's remaining visual field rather than at locations that characteristically are scotomatous. The authors suggest that the current test protocols could determine peripheral field impairment more accurately by assessing additional locations in the visual field, and by introducing a background field and/or by reducing the luminance of the test targets.

Hypernatremic dehydration (mean plasma sodium, 184 mEq/L) was produced over a 3-5 d period in 71 rabbits. The dehydrated animals were divided into groups and rehydrated by intravenous (4, 6, and 8 h duration) or oral (4 and 24 h duration) solutions in amounts calculated to return plasma Na to 140 mEq/L. Plasma was obtained serially from each animal for electrolyte and osmolality determinations during dehydration and rehydration. Samples of brain hemisphere and cortex were obtained for chemical analysis from every animal immediately after death. The incidence of seizures was significantly less (P less than 0.025) in rabbits rehydrated orally when compared with rabbits rehydrated by the intravenous route. Brain water content was significantly greater in rabbits rehydrated intravenously when compared with normal rabbits and rabbits rehydrated orally. In addition, the amount of brain water was greater in rabbits with seizures when compared with those which did not have seizure manifestations. The mechanism underlying the significant reduction in seizures when the animals were rehydrated orally may relate to an integration of drinking behavior with rehydration status. Administration of oral fluids may provide an effective method of therapy for some patients with hypernatremic dehydration.

This study tested Albert Ellis' Rational Emotive Therapy (RET) theory which predicts that cognitive beliefs, not the stimulus situation, generate human emotions. According to RET, emotions created by rational beliefs are adaptive, while irrational beliefs result in an unadaptive anxiety level. Results demonstrated that at high levels of problem relevance there was (1) a significantly greater GSR in direct response to the stimulus situation, and also to irrational statements, than to rational and control statements, and (2) no significant difference between rational and neutral control statements. The authors argue that these results are more parsimoniously explained by conditioning theory than by RET theory.

One hundred patients receiving parenteral nutrition with lipids and hypertonic amino acids and glucose were divided into five groups of 20, depending on the type of intravenous catheter used for the infusion. Least satisfactory were the short Butterfly needles (average 3.3 days in place) and the long peripherally inserted polyvinyl central venous catheters (average 6.2 days in place). Subclavian catheters of polyvinyl (average 15.3 days) or silicone elastomer (average 17.5 days) were equally efficacious. A new long silicone elastomer catheter inserted peripherally was most satisfactory (average 29.5 days). Problems common with polyvinyl catheters (phlebitis, thrombosis, and sepsis) rarely occurred with either the long or short silicone elastomer catheter.

Hypernatremic dehydration was induced in rabbits during a 3- to 5-day period resulting in mean plasma sodium concentrations of 187 meq/liter. The animals were then rehydrated during a 4-h period by intravenous administration of a 2.5% glucose or fructose solution. The water content of four regions of brain sample showed a significant (P less than 0.05) increase in brain water content above normal in the rehydrated groups. Brain water content was significantly (P less than 0.01) greater in those animals with seizures compared with those without seizures, suggesting the importance of water intoxication in the pathogenesis of seizure activity. Changes in muscle Na, K, Cl, and water content were not similar to those of brain, indicating that muscle content of these substances was not an accurate reflection of the brain content specific time. The incidence of seizures was significantly (P less than 0.05) greater when glucose solution was used for rehydration (49%) compared with the use of fructose solution (25%). The mechanism(s) by which fructose resulted in a lower incidence of seizures is not known. The frequency of seizure activity was directly proportional to the rate of administration of intravenous solutions utilized to correct hypernatremia. In addition, the specific carbohydrate of the solution appeared to play an important role in the pathophysiology of the development of seizures.

The rapid single intravenous injection of the cholecystokinin preparation Cecekin (Vitrum) was found to inhibit the responses of Heidenhain pouch dogs to stimulation by gastrin extract or synthetic gastrin-like penta-peptide at both submaximal and supramaximal dose rates, to histamine, to the stable cholinergic drug Amechol, and to feeding a meat meal. The pattern of inhibition suggested that the inhibitor effect was exerted in the region of the acid secreting cell. Pure cholecystokinin was capable of inhibiting the acid response of the Heidenhain pouch dogs to histamine. Although both pure secretin and pure cholecystokinin have now been demonstrated to be possible inhibitor agents arising from duodenal mucosa, it is likely that endogenous duodenal acidification releases a further as yet unidentified humoral inhibitor agent, or that secretin and/or cholecystokinin may act in collaboration with each other or a further inhibitor agent. In dogs with both a Heidenhain pouch and a simple fistula into the normally vagally innervated gastric remnant and in which antrectomy had been performed, a single rapid intravenous injection of the Cecekin had no effect on the Heidenhain pouch responses to the continuous intravenous infusion of histamine. The acid output from the main gastric remnant, however, was increased by the Cecekin injection. Several hypotheses to account for the difference in behaviour in the two preparations are discussed. The possibility is raised that Cecekin contains some gastrin-like activity.