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PubMed2006

Posttraumatic stress disorder: clinical features, pathophysiology, and treatment.

Posttraumatic stress disorder (PSTD), classified as an anxiety disorder, has become increasingly important because of wars overseas, natural disasters, and domestic violence. After trauma exposes the victim to actual or threatened death or serious injury, 3 dimensions of PTSD unfold: (1) reexperiencing the event with distressing recollections, dreams, flashbacks, and/or psychologic and physical distress; (2) persistent avoidance of stimuli that might invite memories or experiences of the trauma; and (3) increased arousal. Traumatic events sufficient to produce PTSD in susceptible subjects may reach a lifetime prevalence of 50% to 90%. The actual lifetime prevalence of PTSD among US citizens is approximately 8%, with the clinical course driven by pathophysiologic changes in the amygdala and hippocampus. Comorbid depression and other anxiety disorders are common. General principles of treatment include the immediate management of PTSD symptoms and signs; management of any trauma-related comorbid conditions; nonpharmacologic interventions including cognitive behavioral treatment; and psychopharmacologic agents including antidepressants (selective serotonin reuptake inhibitors most commonly), antianxiety medications, mood stabilizing drugs, and antipsychotics. This review of PTSD will provide the reader with a clearer understanding of this condition, an increased capacity to recognize and treat this syndrome, and a greater appreciation for the role of the internist in PTSD.

Cognitive Behavioral Therapy↗

PubMed1990

The biological equilibrium of base pairs.

An inherent feature of double-stranded DNA is the possible replacement of any base pair by another one upon replication. A replication-dependent substitution mutation of a matched base pair requires the temporary formation of a mismatched base pair (mispair). A functionally complementary pair of mispairs is ascribed to each of the four types of substitution mutations. Provided that all types of mispairs can be formed, a dynamic biological equilibrium between the four matched base pairs must exist in all DNA, which is directly related to the formation and stability of the corresponding eight mispairs in vivo. Each nucleotide position in a genome can therefore be described as a system of six dynamic equilibria between the four matched base pairs. After a sufficient number of replications, these equilibrium states will express an overall mutation-selection balance for each individual base pair. In a thermodynamic context, the mispairs represent intermediate states on the transformation pathways between the matched base pairs. Catalysts change the stability and probability of formation of intermediate states. Mutagenic proteins are proposed as hypothetical substitution mutation catalysts in vivo. Functionally, they would be capable of recognizing a particular DNA sequence, tautomerizing a nucleotide base thereof, and hence efficiently inducing a specific misincorporation. Phenomenologically such catalysts would accelerate the rates of substitution mutations and provide pathways for directional mutation pressure.

Base Composition↗

PubMed2000

Management of craniocervical junction dislocation.

The discovery of a craniocervical junction malformation requires management in three steps: (1) The patterns must be recognized using tomographic measurements (Chamberlain's line, Wackenheim's line). Dynamic flexion-extension studies are necessary to assess stability or instability. Stable patterns range from platybasia to basilar invagination, with gradual deformation, and are frequently associated with Chiari malformation. Unstable patterns characterized by odontoid instability are the equivalent of an odontoid fracture. The origin is malformative (hypoplasia, aplasia of the dens, os odontoidum), but the last may be difficult to distinguish from an old odontoid fracture. They are found in many syndromes (Down, Morquio, etc.). Unstable atlantoaxial patterns with atlas assimilation are hardly reducible; they evolve toward progressive instability. (2) The neurological consequences must be defined from the clinical features of the spinal cord and the cranial nerves. Both static and dynamic MRI scans must be performed; in this way identification of the neural abnormalities (hydromyelia, Chiari, etc.) and of the osseous compression is possible. (3) The most appropriate operative procedure must be selected: stable platybasia with a nervous compression by Chiari is cured only by posterior decompression; odontoid instability is cured by reduction and posterior fixation, using hooks and autologous bone grafts on the posterior arches of C-1 and C-2. Sometimes a transarticular screw fixation of C1-2 is necessary if there is a defect on the C-1 posterior arch. Craniocervical dislocations with assimilation of the atlas require posterior occipito-vertebral bony fixation with grafts and external halo immobilization or internal fixation with hooks or screws, with anterior transoral decompression in a second step.

Arnold-Chiari Malformation↗

PubMed1984

A deletion analysis of transposon Tn9.

Tn9, like other transposable elements, promotes formation of deletions. This activity has been monitored using a plasmid (pAA3B101) on which deletions can be selected positively as galactose-resistant colonies. Measurements of deletion formation by a series of internal deletions of Tn9, generated by restriction endonucleases, show that the two IS1 elements of Tn9 are functionally non-equivalent. IS1-L is active while IS1-R is inactive. The inactive IS1-R element can, however, be reactivated by a deletion which specifically removes the cat promoter. This result indicates that the inactivity of IS1-R is not due to an altered sequence (Galas & Chandler, 1982), but due to inhibition by transcription from the cat promoter (Machida et al., 1983) which acts in a direction opposite to IS1-R transcription. The occurrence of non-equivalent IS in all transposons analysed suggests that this may be an important feature of organization required for the stability of these composite elements.

Chromosome Deletion↗

PubMed1986

Cytokeratin expression in simple epithelia. I. Identification of mRNA coding for human cytokeratin no. 18 by a cDNA clone.

To study the regulation of the expression of cytokeratins characteristic of simple epithelia, i.e., human cytokeratins nos. 7, 8, 18, and 19, we prepared several cDNA clones coding for these proteins and their bovine counterparts. In the present study, we describe a cDNA clone of the mRNA coding for human cytokeratin no. 18, which was isolated from an expression library using the monoclonal antibody, KG 8.13. This clone (756 nucleotides, excluding the polyA portion), encodes approximately one-half of the mRNA (approximately 1.4 kb), identifies one mRNA band in Northern-hybridization blots, and specifically selects one mRNA species coding for cytokeratin no. 18, as demonstrated by translation in vitro. Comparison of the deduced amino acid sequence--confirmed by direct amino-acid-sequence analyses of some polypeptide fragments produced by cleavage with cyanogen bromide--indicated that cytokeratin no. 18 is a member of the acidic (type I) subfamily of cytokeratins. It has only limited sequence homologies in common with other intermediate-sized filament proteins, and these are essentially restricted to certain domains of the alpha-helical rod portion. The carboxyterminal tail sequence does not contain glycine-rich elements, thus distinguishing this cytokeratin from those acidic (type I) cytokeratins that are characterized by this feature. The similarities and differences between cytokeratin no. 18 and previously described epidermal cytokeratins are discussed in relation to the differences in the stability of the complexes which this cytokeratin forms with basic (type II) cytokeratins, as well as in relation to possible functional differences of cytokeratins in simple and stratified epithelia.

Amino Acid Sequence↗

PubMed2005

Maxillary tooth splinting in periodontally compromised patients using fiber-reinforced composite: the Targis-Vectris method.

AIM: To show the Targis-Vectris retention technique, illustrating its features and clinical applications in periodontally compromised patients. METHODS: The Targis-Vectris technique is constituted by an esthetic external layer (Targis) combined with and supported by a metal-free structure (Vectris). An adult female with a full Class II malocclusion and compromised periodontal condition with significant bone loss on the maxillary central incisor was treated. Before debonding, a fiber-reinforced splint was placed on the palatal surface of the maxillary anterior teeth, using the Targis-Vectris method, to permit long-term stability. The final result remained stable at 5 years posttreatment. RESULTS: The correction of the Class II malocclusion took 24 months. The Targis-Vectris method ensured maintenance of tooth position and periodontal condition. CONCLUSION: The Targis-Vectris technique represents a useful procedure for splinting maxillary teeth in selected periodontally compromised patients. The 5-year posttreatment follow-up visit showed no relapse. Correct occlusal relationships are necessary to reduce the risk of breakage.

Adult↗

PubMedDate not supplied

The Canada Pension Plan's experience with investing its portfolio in equities.

For the past few years, the Canada Pension Plan (CPP) has been investing some of its assets in equities. Without changes, an imbalance between revenues and outlays would exhaust the CPP reserve fund by 2015. Creating an entity that was independent of government was one of several changes the federal and provincial governments enacted to achieve fuller funding. The governments created an independent Investment Board (the CPP Investment Board, or "CPPIB") to oversee the new investments. Because the plan already owned a large government bond portfolio, the CPPIB decided to invest new CPP funds in broad equity indices in March 1999. In 2000, the CPPIB began actively investing a portion of the CPP funds. Key features of that policy and some observations about its implementation include the following: In addition to investing CPP revenues in equities, reform also included contribution rate increases, benefit reductions, and a financing stabilizer. The new investment policy accounted for 25 percent of the total effect of all the reforms. It is premature to know if the investments will achieve their long-term performance objective. The new equity investments are projected by the Chief Actuary, in his most recent Actuarial Report, to earn a 4.5 percent real rate of return on Canadian equity and 5.0 percent real return on foreign equity for a blended real return of 4.65 percent based on an equity mix of 70 percent Canadian and 30 percent non-Canadian. However, it is too early to tell if the equity investments will achieve that goal over the long run. The Investment Board's mandate is to maximize returns. The Investment Board, which oversees the CPP's new investments, has broad discretion to pursue maximum returns on its assets without incurring undue risk of loss while keeping in mind the financial obligations and other assets of the CPP. Furthermore, it has developed into a professional investment organization staffed with private-sector experts in finance and investment. The board is designed to be independent of government. The federal and provincial governments designed the board to operate at arm's length from themselves. The process for selecting directors includes public- and private-sector participation, and the board is in compliance with several sets of governance guidelines for corporations. CPPIB management, with the support of its board of directors, has decided to implement a virtual corporation model involving a small team of senior executives setting strategies for implementation primarily by external professional firms. Consequently, as a virtual corporation, the board currently relies on external fund managers to make investments and vote proxies. Several measures are designed to ensure accountability to the public. The investment legislation subjects the board to overlapping layers of oversight to ensure accountability to the public. The features of this oversight include public meetings in each province as well as quarterly statements and annual reports to Parliament, the federal and provincial finance ministers, and the public. The 10 finance ministers review the CPPIB's mandate and regulations every 3 years, and the CPPIB is subject to a special examination every 6 years by an auditor appointed by the Federal Minister of Finance.

Canada↗

PubMed2005

The Diamond STING server.

Diamond STING is a new version of the STING suite of programs for a comprehensive analysis of a relationship between protein sequence, structure, function and stability. We have added a number of new functionalities by both providing more structure parameters to the STING Database and by improving/expanding the interface for enhanced data handling. The integration among the STING components has also been improved. A new key feature is the ability of the STING server to handle local files containing protein structures (either modeled or not yet deposited to the Protein Data Bank) so that they can be used by the principal STING components: (Java)Protein Dossier ((J)PD) and STING Report. The current capabilities of the new STING version and a couple of biologically relevant applications are described here. We have provided an example where Diamond STING identifies the active site amino acids and folding essential amino acids (both previously determined by experiments) by filtering out all but those residues by selecting the numerical values/ranges for a set of corresponding parameters. This is the fundamental step toward a more interesting endeavor-the prediction of such residues. Diamond STING is freely accessible at http://sms.cbi.cnptia.embrapa.br and http://trantor.bioc.columbia.edu/SMS.

Acid Anhydride Hydrolases↗

PubMedDate not supplied

Base-pairing potential identified by in vitro selection predicts the kinked RNA backbone observed in the crystal structure of the alfalfa mosaic virus RNA-coat protein complex.

The three-dimensional structure of the 3' terminus of alfalfa mosaic virus RNA in complex with an amino-terminal coat protein peptide revealed an unusual RNA fold with inter-AUGC basepairing stabilized by key arginine residues (Guogas, et al., 2004). To probe viral RNA interactions with the full-length coat protein, we have used in vitro genetic selection to characterize potential folding patterns among RNAs isolated from a complex randomized pool. Nitrocellulose filter retention, electrophoretic mobility bandshift analysis, and hydroxyl radical footprinting techniques were used to define binding affinities and to localize the potential RNA-protein interaction sites. Minimized binding sites were identified that included both the randomized domain and a portion of the constant regions of the selected RNAs. The selected RNAs, identified by their ability to bind full-length coat protein, have the potential to form the same unusual inter-AUGC Watson-Crick base pairs observed in the crystal structure, although the primary sequences diverge from the wild-type RNA. A constant feature of both the wild-type RNA and the selected RNAs is a G ribonucleotide in the third position of an AUGC-like repeat. Competitive binding assays showed that substituting adenosine for the constant guanosine in either the wild-type or selected RNAs impaired coat protein binding. These data suggest that the interactions observed in the RNA-peptide structure are likely recapitulated when the full-length protein binds. Further, the results underscore the power of in vitro genetic selection for probing RNA-protein structure and function.

Alfalfa mosaic virus↗

PubMed2006

Comparative studies of suppression of malignant cancer cell phenotype by antisense oligo DNA and small interfering RNA.

One of the distinguishing features of malignant tumor cells is the ability to proliferate in an anchorage-independent manner; methods that effectively suppress this phenotype may be applicable to the therapeutic inhibition of the malignancy of cancers. Interfering RNA is a potentially powerful tool for cancer therapy because of its specificity of target selection and remarkably high efficiency in target mRNA suppression. We studied the use of two knockdown strategies, antisense oligo DNA (AS-ODN) and small interfering RNA (siRNA), and showed how the anchorage-independent proliferation of malignant cells could be blocked efficiently. Anchorage-independent proliferation of rat fibroblasts transformed with v-src was suppressed with only a single 1-microM dose of AS-ODN; similar suppression using siRNA required treatment with 1 nM siRNA every 12 h. With our experimental system, the molecular stability of AS-ODN allowed the use of a simple treatment regimen to control the amount of the target molecule, providing that the treatment dose was sufficiently high. In comparison, siRNA treatment was effective at lower doses, but more frequent treatment was necessary to achieve the same suppression of proliferation.

Animals↗

PubMed2006

Utilising the left-helical conformation of L-DNA for analysing different marker types on a single universal microarray platform.

L-DNA is the perfect mirror-image form of the naturally occurring d-conformation of DNA. Therefore, L-DNA duplexes have the same physical characteristics in terms of solubility, duplex stability and selectivity as D-DNA but form a left-helical double-helix. Because of its chiral difference, L-DNA does not bind to its naturally occurring D-DNA counterpart, however. We analysed some of the properties that are typical for L-DNA. For all the differences, L-DNA is chemically compatible with the D-form of DNA, so that chimeric molecules can be synthesized. We take advantage of the characteristics of L-DNA toward the establishment of a universal microarray that permits the analysis of different kinds of molecular diagnostic information in a single experiment on a single platform, in various combinations. Typical results for the measurement of transcript level variations, genotypic differences and DNA-protein interactions are presented. However, on the basis of the characteristic features of L-DNA, also other applications of this molecule type are discussed.

Animals↗

PubMed2005

Heat shock protein 27 in chronic allograft nephropathy: a local stress response.

BACKGROUND: Heat shock protein (HSP) 27 plays a cytoprotective role through its antioxidant, antiapoptotic, and actin-stabilizing properties during cell stress. The authors hypothesized that HSP27 is involved in chronic allograft nephropathy (CAN), a chronic state of inflammation and stress. METHODS: The authors used the Fisher 344-to-Lewis model of CAN. Transplants were performed in 3-month-old recipient rats. HSP27 mRNA and protein levels were determined using semiquantitative polymerase chain reaction, microarray (stress-toxicity, GEArray) analyses, gene sequencing, immunoblotting, and immunohistochemical analyses at 10 days and 6 months posttransplant. P38 mitogen-activated protein kinase (MAPK), manganese (Mn) superoxide dismutase (SOD), copper-zinc (CuZn) SOD, FasL, Bax, hypoxia-inducible factor (HIF)-1alpha, and CD3 lymphocytes were studied in parallel as selective biomarkers of oxidative stress (OS), apoptosis, hypoxia, and graft-infiltrating immune cells. RESULTS: Six months after transplantation, kidney allografts displayed histologic and functional features of CAN, including tubular atrophy, interstitial fibrosis, glomerulosclerosis, and increased proteinuria and serum creatinine levels. HSP27 mRNA and protein levels in CAN were reduced by 50% and 85%, respectively (P=0.04). Immunohistochemical analyses revealed a "shift" in HSP27 from the medulla to the cortex in allografts with CAN. Bax, phosphorylated p38-MAPK, HIF-1alpha, and MnSOD followed a parallel relocation pattern. CD3 lymphocyte density and tubular FasL expression were also greater in the cortex of allografts with CAN. Time-course analyses revealed that most of these changes were present as early as 10 days posttransplant. CONCLUSIONS: The shift of HSP27 from the medulla to the cortex, combined with greater CD3, p38-MAPK, Bax, FasL, HIF-1alpha, and MnSOD immunoreactivity in this area of the kidney, likely represents an allograft-level response to CAN-related OS-hypoxia.

Animals↗

PubMed1984

Lineage switch in acute leukemia.

Conversions of leukemic cell lineage (lymphoid or myeloid) have been reported only rarely. Our review of the cytochemical and immunophenotypic features of 89 cases of childhood leukemia in marrow relapse indicated lineage switch (lymphoid to myeloid or the reverse) in six patients (6.7%). Five patients with acute lymphoblastic leukemia (ALL) at diagnosis had converted to acute nonlymphoblastic leukemia (ANLL), and one had converted from ANLL to ALL. Each child received lineage-specific multiagent chemotherapy when initially diagnosed, and all achieved a complete remission. After conversion, four patients readily achieved second remissions with treatment for the phenotype evident at lineage switch. Two patients with ANLL at conversion failed ALL-directed reinduction, while one of the two responded to high-dose cytarabine but died during bone marrow hypoplasia, emphasizing the importance of prompt recognition of lineage switch and selection of an appropriate plan of retreatment. Cytogenetic studies disclosed evidence of clonal selection in one patient and clonal stability in two. These findings indicate an unexpectedly high frequency of lineage switch in patients who relapse in the bone marrow after intensive chemotherapy. Although specific causative factors could not be identified, our observations suggest at least two general mechanisms for lineage switch in acute leukemia. In one, chemotherapy appears to eradicate the dominant clone present at diagnosis, permitting expansion of a secondary clone with a different phenotype. In the second, drug-induced changes in the original clone may either amplify or suppress differentiation programs so that phenotypic shift is possible.

Acute Disease↗

PubMed2004

Molecular docking of the scorpion toxin Tc1 to the structural model of the voltage-gated potassium channel Kv1.1 from human Homo sapiens.

In this study, structural model of the pore loop region of the voltage-gated potassium channel Kv1.1 from human Homo sapiens was constructed based on the crystallographic structure of KcsA by structural homology. The pore loop region of Kv1.1 exhibits similar folds as that of KcsA. The structural feature of the selectivity filter of Kv1.1 is nearly identical to that of KcsA, whereas most of the structural variations occur in the turret as well as in the inner and outer helices. Molecular docking experiments of the scorpion toxin Tc1 from Tityus cambridgei to the outer vestibule of KcsA as well as Kv1.1 were subsequently performed with various initial Tc1 orientations. Tc1 was found to form the most stable complexes with these two K+ channels when the side chain of Lys14 occupies the pore of the selectivity filter through electrostatic interaction. Tc1 binds preferentially towards Kv1.1 than KcsA due to stronger hydrophobic and electrostatic interactions formed between the toxin and the selectivity filter and outer vestibule of Kv1.1. Furthermore, surface complementarity of the outer vestibules of the channels to the Tc1 spatial conformations also plays an important role in stabilizing both the Tc1/KcsA and Tc1/Kv1.1 complexes.

Amino Acid Sequence↗

PubMed1980

Regulation of promoter selection by the bacteriophage T7 RNA polymerase in vitro.

During bacteriophage T7 infection a phage-specified RNA polymerase transcribes the late phage genes in two temporal classes (class II and class III). In this report, we show that the purified phage polymerase discriminates between the class II and class III promoters in vitro as a function of variables that alter the stability of the DNA helix. These variables include ionic strength, temperature, and the presence of denaturing agents such as dimethyl sulfoxide. In general, initiation at the class II promoters is preferentially inhibited as helix stability is increased. Conditions required for the establishment of salt-resistant transcription complexes by the T7 RNA polymerase have been determined; the establishment of stable complexes at the class II promoters requires the synthesis of a longer nascent RNA transcript than does formation of such complexes at the class III promoters. A comparison of the nucleotide sequences of several class II and class III promoters suggests certain features that may be responsible for the different responses of these promoters to helix destabilization. The conservation of structural features that are peculiar to the class II or class III promoters indicates that these features are important in regulation of T7 transcription in vivo. Experiments which bear on the physiological significance of these features are discussed.

DNA, Viral↗

PubMed1995

Registration of three-dimensional compound ultrasound scans of the breast for refraction and motion correction.

Use of multiple look directions, that is, compound imaging, has been shown previously to increase detection of specular reflectors and averaging of speckle noise in gray-scale images, often at the expense of spatial resolution and other misregistration errors. In color flow imaging, additional view angles can fill in vessels missed due to Doppler angle dropout and increase quantitative and visual Doppler accuracy by triangulation or a simple peak-frequency-shift combination algorithm. Image registration and unwarping throughout multiple three-dimensional (3D) volume sets should correct for many refraction artifacts, motion between and during compounded image sets and even, possibly, positioning errors between image sets, acquired months apart, to display growth of abnormalities. The registration described here does not provide sufficient accuracy for formation of enhanced coherent apertures, but shows promise in some cases to provide superior compound images and possibly comparisons of current and prior studies. In this study, the breast is stabilized by mild compression between a flat plate and a scanning membrane. Registration and unwarping is performed retrospectively on two separate volumetric data sets by defining pairs of corresponding points and, in some cases, line and plane segments. Three-dimensional linear affine transforms are performed using identified points, lines and planes. 3D nonlinear warped transforms are also possible given adequate numbers of identifiable points. More than two data sets are registered by selecting one as the standard, and registering the remainder to match. The most appropriate algorithm, such as averaging or maximum amplitude, may be used to combine the data sets for display. Significant success has been achieved in compound display of a test object and of the breast in vivo, even when there was relative motion or warping between image sets. In pulse-echo imaging, homologous feature registration for compounding appears to have advantages over mechanically registered compounding methods previously employed in the breast and significant increases in lesion and structural conspicuity are noted due to a reduction in speckle noise. The improvements from compounding in 3D, surface-rendered Doppler imaging of vasculature are striking.

Adenocarcinoma↗

PubMed2005

HIF-2alpha expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia.

Solid tumors are frequently necrotic and hypoxic due to poor vascularization. Tumor cells adapt to hypoxia by modulating their phenotype. Key players in this process are the hypoxia-inducible factors (HIF-1alpha to 3alpha). HIFs are also expressed during normal development; for example, HIF-2alpha is specifically expressed and appears to be involved in the development of the murine sympathetic nervous system (SNS). Here, we demonstrate that HIF-2alpha protein is selectively present in human fetal week 8.5 SNS paraganglia. Neuroblastoma is derived from SNS precursors. In a subset of neuroblastomas, a spontaneous neuronal to neuroendocrine differentiation occurs in areas adjacent to necrotic zones. As HIF-2alpha activity has been associated not only with hypoxic but also with hypoglycemic conditions, we have investigated putative effects of hypoxia, glucose depletion, and HIF-2alpha on the neuroblastoma phenotype. HIF-2alpha was detected in hypoxic and in well-oxygenized neuroblastoma cells and tissue, presumably reflecting their embryonic features. With regard to differentiation, hypoxic cells lost their neuronal/neuroendocrine features and gained marker gene expression associated with an immature, neural crest-like phenotype. Low glucose potentiated the effect of hypoxia. These findings suggest that poorly vascularized neuroblastomas become immature and maintain a more aggressive phenotype, which possibly could involve a sustained stabilization and activation of HIF-2alpha.

Base Sequence↗

PubMed2000

Structure-activity studies including a Psi(CH(2)-NH) scan of peptide YY (PYY) active site, PYY(22-36), for interaction with rat intestinal PYY receptors: development of analogues with potent in vivo activity in the intestine.

Peptide YY (PYY) is a gut hormone that inhibits secretion and promotes absorption and growth in the intestinal epithelium. We have performed structure-activity studies with the active site, N-alpha-Ac-PYY(22-36)-NH(2), for interaction with intestinal PYY receptors. Investigation of aromatic substitutions at position 27 resulted in analogues that exhibited potent in vitro antisecretory potencies with N-alpha-Ac-[Trp(27)]PYY(22-36)-NH(2) exhibiting even greater potency than intact PYY. In vivo studies in dogs revealed that this analogue also promoted intestinal absorption of water and electrolytes during continuous intravenous and intraluminal infusion. Investigations carried out to identify features that would enhance stability revealed that incorporation of Trp(30) increased affinity for PYY receptors. A "CH(2)-NH" scan revealed that incorporation of reduced bonds at position 28-29 or 35-36 imparted greater receptor affinity. In general, disubstituted analogues designed based on the results of single substitutions exhibited good receptor affinity with N-alpha-Ac-[Trp(27),CH(2)-NH(35-36)]PYY(22-36)-NH(2) having the greatest affinity (IC(50) = 0.28 nM). Conservative multiple substitutions with Nle-->Leu and Nva-->Val also imparted good affinity. An analogue designed to encompass most of the favored substitutions, N-alpha-Ac-[Nle(24,28),Trp(30),Nva(31), CH(2)-NH(35-36)]PYY(22-36)-NH(2), exhibited a proabsorptive effect in dogs comparable to, but longer lasting than, that of intact hormone. Selected analogues also exhibited good antisecretory potencies in rats with N-alpha-Ac-[Trp(30)]PYY(22-36)-NH(2) being even more potent than PYY. However, the potencies did not correlate well with the PYY receptor affinity or the proabsorptive potencies in dogs. These differences could be due to species effects and/or the involvement of multiple receptors and neuronal elements in controlling the in vivo activity of PYY compounds. PYY(22-36) analogues exhibited good affinity for neuronal Y2 receptors but poor affinity for Y1 receptors. Also, crucial analogues in this series hardly bound to Y4 and Y5 receptors. In summary, we have developed PYY(22-36) analogues which, via interacting with intestinal PYY receptors, promoted potent and long-lasting proabsorptive and antisecretory effects in in vivo models. These compounds or analogues based on them may have useful clinical application in treating malabsorptive disorders observed under a variety of conditions.

Animals↗