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Radiopharmaceuticals to image infection and inflammation.

Scintigraphic imaging of infection and inflammation is a powerful diagnostic tool in the management of patients with infectious or inflammatory diseases. Most infectious and inflammatory foci can be visualized accurately with radiolabeled autologous leukocytes. However, the preparation of this radiopharmaceutical is laborious and requires the handling of potentially contaminated blood. A few radiopharmaceuticals are available that could be used instead of radiolabeled leukocytes to scintigraphically visualize infectious and inflammatory foci, such as 67Ga-citrate and 99mTc-labeled antigranulocyte antibody preparations. Various agents labeled with 99mTc are currently developed for this application. Most of these newly developed agents are ligands that bind receptors on white blood cell subpopulations, ie, monoclonal antibodies, chemotactic peptides, and cytokines. Furthermore, agents are developed that potentially could distinguish between infection and nonmicrobial inflammation. In addition, 18F-fluorodeoxyglucose positron emission tomography imaging was proposed to visualize inflammatory foci when a high spatial resolution is required. In this article, the characteristics and diagnostic potential of established and experimental radiopharmaceuticals for infection and inflammation imaging are reviewed.

Animals↗

Polymorphonuclear neutrophilic leukocytes in protein deficiency.

The number of white blood cells and of polymorphonuclear leukocytes remained unchanged in vervet monkeys (Cercopithecus aethiops) receiving a "O" protein diet. The motility of the polymorphonuclear leukocytes and their phagocytic and killing indices with and without leukokinin stimulation decreased in protein-depleted animals. Acid cathepsin decreased, DNA relatively increased, and peroxidase, alkaline phosphatase, acid phenylphosphatase, and lysozyme reached higher levels in the polymorphonuclear leukocytes of animals on a "O" protein diet.

Animals↗

Inflammation: a quarter century of progress.

This report summarizes the progress of studies on inflammation during the past quarter century; it is a personal overview of the most important and salient accomplishments in this field. Except for a few references to review articles and textbooks in the field, much of the literature surveyed is not cited.

Acute Disease↗

Correlation of T-cell response and lymphokine profile with RESA peptides of Plasmodium falciparum containing a universal T-cell epitope and an immunopotentiator, polytuftsin.

Two RESA repeat sequences, (EENVEHDA)2 and (DDEHVEEPTVA)2, were chemically linked to a universal T-cell epitope, CS.T3 and polytuftsin, and a natural immunopotentiator, was physically mixed with these conjugates. The immunogens were studied for in vitro antigen-induced T-cell proliferation, and cytokine levels were measured in the culture supernatants. The RESA peptide(s)-CS.T3 conjugate containing polytuftsin showed the highest stimulation index (SI) as compared to the RESA peptide-CS.T3 conjugates or RESA peptides alone. Spleen cells from mice primed with either RESA peptide(s)-CS.T3 conjugate or RESA peptide-CS.T3 conjugate containing polytuftsin, when pulsed in vitro with the respective RESA peptide, showed a higher proliferation index as compared to spleen cells primed and pulsed in vitro with the respective RESA peptides. This observation has an important relevance during natural reinfection for boosting the immune response. The culture supernatants from the cells primed and pulsed in vitro with RESA peptide-CS.T3 conjugate and RESA peptide-CS.T3 conjugate containing polytuftsin showed higher IL-2 and IFN-gamma levels as compared to the RESA peptides alone. Very low IL-4 levels were detected with the above formulations. The cytokine profile is suggestive of a CD4+ TH1 type of immune response, which is ideal for the killing of intracellular pathogens like the malarial parasite.

Adjuvants, Immunologic↗

An active pseudopeptide analog of the leucokinin insect neuropeptide family.

A pseudopeptide analog of the active core of the leucokinin insect neuropeptide family was synthesized and found to retain myotropic activity. No reports of active pseudopeptide analogs of an insect or other invertebrate neuropeptide have previously appeared in the literature. The pseudopeptide (Phe psi [CH2-NH] Phe-Ser-Trp-Gly-NH2) contains a reduced-amide linkage between the two N-terminal Phe residues. Unlike its amide-bond containing counterpart, the activity of the pseudopeptide was not destroyed upon exposure to aminopeptidase M.

Amino Acid Sequence↗

Sequencing of peptide mixtures by Edman degradation and field-desorption mass spectrometry.

A new procedure is described for sequencing of peptide mixtures by a combination of Edman degradation and field-desorption mass spectrometry. The procedure involves measurement of the mass values of quasi-molecular ions ([M + H]+) of constituent peptides in the mixture and their fragments degraded by the Edman method. Calculation of all the possible mass differences of the mass values before and after degradation and identification of the phenylthiohydantoins released reveal the N-terminal amino acids of individual peptides in the mixture. Repetition of these operations gives the amino acid sequences of individual peptides in the mixture. As typical examples, the sequencing of peptide mixtures prepared by proteolytic digestion of glucagon are described. In addition, a computer program was designed for determining the possible sequences of proteins from the partial sequences and mass values of their proteolytic peptides. Output data showed that the entire amino acid sequence of glucagon can be determined by only four and two cycles of degradation of chymotryptic and tryptic peptides, respectively.

Amino Acid Sequence↗

Detection of splenosis and ectopic spleens with 99mTc-labelled heat damaged autologous erythrocytes in 90 splenectomized patients.

Splenosis or ectopic spleens were detected in 22 of 45 patients splenectomized after either abdominal trauma or accidental lesions of the spleen during operation. The incidence of ectopic spleen tissue in various groups of splenectomized patients has been investigated by a sensitive scanning method employing reinjection of 99mTc-labelled heat damaged autologous erythrocytes. In comparison 7 cases were found among 45 patients who underwent splenectomy for haematological reasons. The time span between the operation and a positive scan varied between 3 months and 11 years. None of the patients in the haematological group with reoccurrence of spleen tissue presented any signs of relapse of their primary disorder. The only patient with overwhelming infection was a girl in whom splenectomy was performed for hereditary spherocytosis. She recovered from the sepsis and her scan was negative. It is concluded that recurrence of spleen tissue is frequent after traumatic lesions of the spleen but rare after selective splenectomy for haematological reasons. This may account for the lesser tendency to overwhelming sepsis after post-traumatic splenectomy.

Adolescent↗

Differential chemical protection of mammalian cells from the exotoxins of Corynebacterium diphtheriae and Pseudomonas aeruginosa.

Many drugs or chemicals had markedly different effects on the cytotoxicity induced by Pseudomonas aeruginosa exotoxin A (PE) or Corynebacterium diphtheriae exotoxin (DE). The glycolytic inhibitor NaF protected cells from DE but potentiated the cytotoxicity of PE. Another energy inhibitor, salicylic acid, also protected cells from DE but had no effect with PE. Colchicine and colcemid did not affect the cytotoxicity of either toxin. Cytochalasin B exhibited a modest protection from DE but no effect with PE. Ouabain, a specific inhibitor of the Na+, K+-dependent adenosine 5'-triphosphatase (ATPase), did not affect the cytotoxicity of either toxin. Ruthenium red, a specific inhibitor of the Ca2+, Mg2+,-dependent ATPase, conferred marked protection from DE-induced cytotoxicity but did not affect PE-induced cytotoxicity. A number of local anesthetics were tested, and they too presented differential results with PE and DE. Most chemicals that affected toxin-induced cytotoxicity had little or no influence on the in vitro adenosine 5'-diphosphate-ribosylation catalyzed by either toxin. This work presents further evidence that PE and DE have different mechanisms of intoxication and suggests that these differences lie in the attachment or internalization stages of intoxication.

4-Aminobenzoic Acid↗

Stimulation of neutrophil oxygen-dependent metabolism by human leukocytic pyrogen.

The ability of highly purified human leukocytic pyrogen (LP) to stimulate neutrophil oxygen-dependent metabolism was studied. Human peripheral blood neutrophils exposed to leukocytic pyrogen in vitro demonstrated an increase in the percentage of neutrophils reducing nitroblue tetrazolium (NBT) dye and a marked stimulation of superoxide dismutase inhibitable reduction of ferricytochrome c. LP stimulation of neutrophil oxygen-dependent metabolism was dose and time dependent. Procedures that destroyed the pyrogenicity of LP also abolished the effects on neutrophil metabolism. Neutrophil hexose monophosphate shunt activity was also stimulated by LP. In a rabbit model, the effect of in vivo LP on neutrophil superoxide generation was also studied. There was a consistent increase in the percent and absolute number of NBT positive neutrophils. Peak stimulation of neutrophil metabolism occurred after defervescence suggesting several possible mechanisms. The observations reported here may, in part, explain the nonspecificity of the NBT test in febrile, noninfected patients and provide further understanding of neutrophil physiology during acute inflammation.

Adult↗

Pharmacological activities of a kinin released from rat plasma by catheptic enzyme in rat stomach.

A kinin (material c), which was different from kallidin, methionyl-lysyl-bradykinin (MLBK), bradykinin (BK) and neurotensin, released from rat plasma by the kinin-forming enzyme in rat stomach was pharmacologically compared with BK and histamine or serotonin (5-HT) in various in vitro and in vivo systems. Material c produced contraction of isolated rat uterus, rat fundic strip, isolated guinea-pig ileum and guinea-pig tracheal chain; increased the vascular permeability of guinea-pig skin to circulating Evans blue; and produced a fall in rabbit blood pressure. Such effects were also produced by BK, but both were clearly discriminated by their quantitatively different activities. Histamine was not effective on isolated rat uterus, isolated rat duodenum, rat fundic strip, and rabbit blood pressure; produced contraction of isolated guinea-pig ileum and guinea-pig tracheal chain; and increased the vascular permeability of guinea-pig skin; but these activities were quantitatively different from those of material c. The contraction of isolated guinea-pig ileum elicited by histamine was sustained until it was removed from the bath, but those provoked by material c and BK gradually faded. 5-HT was qualitatively different from material c and BK with respect to contracting isolated rat duodenum. 5-HT also produced contraction of isolated rat uterus and rat fundic strip and produced a fall in rabbit blood pressure, but these activities were quantitatively different from those of material c and BK. As mentioned above, material c was quantitatively and qualitatively different from histamine and 5-HT.

Animals↗

Reverse turns in peptides and proteins.

The evidence that reverse turns frequently occur as structural components of proteins, as well as of linear and cyclic peptides, is overwhelming. This review summarizes and examines critically the experimental evidence derived from physical methods such as 1H and 13C nuclear magnetic resonance spectroscopy, spin-lattice relaxation time, circular dichroism, IR spectroscopy, and X-ray crystallography. Secondly, theoretical evidence obtained from energy calculations, which rely on empirical energy functions, and correlative methods, which rely on algorithms based on the frequency of occurrence of amino acids, is evaluated. In particular, those theoretical studies for which complementary physical studies have been completed are emphasized. Finally, examples of structure-function relationships involving reverse turns and their biological recognition are demonstrated.

Amines↗