Biomedical subjects
Publications and source records attributed to H Kessler.
Six diastereoisomeric cyclic hexapeptides of the partial sequence 39-44 of human thymopoietin III in which each residue was replaced with the D-amino acid were synthesized. In contrast to expectations, the yields from cyclization were not influenced by the location of the D-residue.
In an experiment with Wistar rats the question of whether oral vitamin C application has a protective effect in liver carcinogenesis caused by N-nitrosodiethylamine in drinking water (n = 104) was studied. When comparing four groups (without carcinogen, with carcinogen and carcinogen plus vitamin C alternately and concomitantly) significant statistical differences in the linear regression were noted. Ninety per cent of the rats developed hepatocellular carcinomas when only carcinogen was administered whereas the rate with additional administration of vitamin C alternately and concomitantly was 68% and 55%, respectively. Without carcinogen no tumour developed. The results suggest that vitamin C may delay the development of liver cancer upon oral administration of N-nitrosodiethylamine. The explanation for this fact is still hypothetical.
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OBJECTIVE: To determine the ability to recover human immunodeficiency virus type 1 (HIV-1) from the plasma and mononuclear cell (MNC) fractions of postmortem blood samples from patients with the acquired immunodeficiency syndrome. DESIGN: Blood was randomly cultured post mortem from 41 patients with the acquired immunodeficiency syndrome. Plasma and MNC cultures were performed as well as serum antigen assays. Evaluation parameters included MNC recovery, MNC viability, time of sample collection after death, time of inoculation of coculture following sample acquisition, and storage conditions of the body (ie, refrigeration vs nonrefrigeration). SETTING: Blood samples were obtained from patients with the acquired immunodeficiency syndrome being prepared for burial at metropolitan area funeral homes. PATIENTS: Postmortem samples were obtained from 41 patients with the acquired immunodeficiency syndrome. MAIN OUTCOME MEASURE: Virus recovery from either cells or plasma. RESULTS: Human immunodeficiency virus type 1 was recovered from 21 (51%) of 41 patients at 0.5 to 21.25 hours postmortem. Recovery of HIV-1 from plasma and/or MNC fractions was variable with 6 (15%) of 41 plasma+/MNC+, 12 (29%) of 41 plasma-/MNC+, three (7%) of 41 plasma+/MNC-, and 20 (49%) of 41 plasma-/MNC-. Plasma p24 levels (> 30 pg/mL) were detectable in 14 (48%) of 37 samples tested. Of those culture-positive patients, seven (33%) of 21 were refrigerated compared with the culture-negative group in which 10 (50%) of 20 were refrigerated. Time from death until specimen acquisition was the only factor significantly associated with recovery of HIV-1. CONCLUSION: These results should be useful for health care workers and others exposed to postmortem blood from HIV-infected individuals and should lead to changes in the processing practices of morticians and/or pathologists for HIV-1-infected cadavers.
Cyclic Arg-Gly-Asp-Phe-Val peptides with either D-Phe or D-Val residues were 20- to more than 100-fold better inhibitors of cell adhesion to vitronectin and/or laminin fragment P1 when compared to a linear variant or Gly-Arg-Gly-Asp-Ser. No or only little increase in inhibitory capacity was observed for fibronectin adhesion and for the binding of platelet receptor alpha IIb beta 3 to fibrinogen. NMR studies of the two most active cyclic peptides showed for both an all-trans conformation with a beta II' and gamma turn. Subtle conformational differences, however, exist between both peptides and may contribute to selectivity of inhibition.
We wished to determine the incidence of human immunodeficiency virus-related high-grade non-Hodgkin's lymphoma (NHL) and identify factors associated with the development of NHL in patients receiving zidovudine. Data are from a 2-year prospective, observational, multisite study of 1030 patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex who received zidovudine. Non-Hodgkin's lymphoma developed in 24 (2.3%) of 1030 patients who received zidovudine during 1463 person-years of follow-up (rate, 1.6 per 100 person-years of therapy). The relative hazard for development of NHL was stable throughout 2 years of therapy, with the risk of developing NHL 0.8% for each additional 6 months of therapy. Factors associated with development of NHL were a prior diagnosis of Kaposi's sarcoma, herpes simplex virus infection, or lower mean neutrophil count. Less strongly associated was a prior diagnosis of oral hairy leukoplakia or homosexual transmission of HIV. By Cox proportional hazards analysis, a prior diagnosis of Kaposi's sarcoma, cytomegalovirus disease, or oral hairy leukoplakia was most strongly associated with development of NHL. Our study demonstrates a relatively high incidence of NHL in patients with advanced human immunodeficiency virus disease who are undergoing antiretroviral therapy and suggests possible risk factors for development of NHL.
The hinge region links the antigen binding Fab part to the constant Fc domain in immunoglobulins. For the hinge peptide derivative [AcThr(OtBu)-Cys-Pro-Pro-Cys-Pro-Ala-ProNH2]2 the assignment of the 1H and 13C resonances was achieved by two-dimensional nmr techniques: total correlation spectroscopy (TOCSY), nuclear Overhauser enhancement spectroscopy (NOESY), rotating frame nuclear Overhauser enhancement spectroscopy (ROESY), heteronuclear multiple quantum coherence (HMQC) transfer, and a HSQC (modified Overbodenhausen experiment) with high resolution in F1, which was several times folded in F1 but still phase correctable. Conformational relevant parameters (78 nuclear Overhauser effect distance restraints, 3JHH for prochiral assignments, temperature gradients) were determined by nmr and served as input data for molecular dynamics (MD) structure refinement. A simulated model compound corresponding to the [Cys-Pro-Pro-Cys]2 core elongated by the peptide chains in the Fab and Fc direction served as a starting structure for the final MD run. The conformation calculated in in vacuo does not agree with the C2 symmetry required from nmr data, but the structure obtained by a water simulation fulfills the requirement. Here the core of the hinge peptide derivative adopts a polyproline II double helix as in the x-ray structure of IgG1. Hence, segments responsible for the internal flexibility are located outside the core as confirmed by the flexibility of the solvent exposed C termini.
A method to determine heteronuclear long-range couplings to carbon and nitrogen at natural abundance is presented and applied to two cyclic hexapeptides and the peptidomacrolide FK506. The method is applicable for proton-bearing heteronuclei. By introduction of heteronuclear half-filters in two- or three-dimensional experiments the spectra exhibit an E.COSY pattern when executed without heteronuclear decoupling. The extraction of the heteronuclear coupling constants is therefore independent of linewidth. In cyclo(-Ala-Ala-Ala-Pro-Ala-Pro-) a 13C-omega 1-half-filtered TOCSY spectrum yields the 3J(HN-C beta) coupling constant, which can be used to remove ambiguity in the phi angle determination from 3J(HN-H alpha). In cyclo(-D-Pro-Phe-Phe-Lys(Z)-Trp-Phe-) a 15N-omega 1-half-filtered TOCSY was applied to individually assign the diastereotopic beta-methylene protons via the 3J(H beta-N). In FK506 a 3D-HMQC-TOCSY without heteronuclear decoupling is used to obtain a number of heteronuclear coupling constants to carbons. These values have been applied for the assignment of diastereotopic methylene protons and determination of dihedral angles in the cyclic portion of the molecule.
In animal experiments with Wistar rats we attempted to determine if oral application of Vitamin C inhibits or delays carcinogenesis due to oral administered N-Nitrosopiperidine (NTP). One group of animals received NTP only, two other groups NTP and Vitamin C either alternating or simultaneously. A fourth group receiving only Vitamin C served as control. Carcinomas of the esophagus, stomach and liver developed in response to NTP application. The additional administration of Vitamin C neither inhibited nor delayed the development of carcinomas.
Among 587 patients with ductal pancreatic carcinoma who were examined between 1969 and 1987, 260 (44.3%) had distant metastases at the time of diagnosis. Tumour resections, mostly subtotal duodenopancreatectomies, were performed in 138 patients (23.5% of all patients, or 39.8% of all patients without distant metastases); in 91 patients the resection was for cure (R0). Operative mortality following tumour resection was 6% for all patients. The age-corrected 5-year survival rate was 2.9% for all patients and 16% where the resection was curative; of these 46% were in Stages I and II and 6% in Stage III. In non-curative resections, the median survival time was 7.2 months, which was significantly longer than the 3.4 months following bypass operation. Cure for pancreatic carcinoma can be achieved only through surgery, and a negative attitude towards surgery must be resisted.
The conformation of cyclosporin A was investigated in different environments. Whereas there was no distinct difference between the structure of CSA in CDCl3 and THF, the addition of LiCl caused a conformational change. Also, using polar solvents (DMSO, water) induced conformational changes in the backbone as well as the side chains.
The strategy and tactics of conformational analysis of cyclic peptides in solution is demonstrated by the example of cyclo(-D-Pro-Phe-Thr-Phe-Trp-Phe-). Spin-locked experiments like rotating frame nuclear Overhauser enhancement spectroscopy (ROESY), ROTO, and TOCSY are successfully applied to assign all proton signals and to obtain distance information. A crude conformational model was built using the nmr data. This starting model was refined by restrained molecular dynamics (MD) calculations using ROE derived distances and fixed bond angles as determined from homo- and heteronuclear coupling constants. To mimic the solvent and to reduce artifacts in an in vacuo calculation the charges of the solvent-exposed NH protons were gradually reduced according to the temperature gradients. The thus obtained "conformation" (mean of a 40 ps MD trajectory) shows very close similarity to x-ray structures in an orthorhombic and in two monoclinic crystal modifications of the same compound. The main difference is the breaking of an intermolecular hydrogen bond of the threonine hydroxyl group on dissolution of the crystal and forming an intramolecular hydrogen bond in solution.
A new method for the surgical treatment of ulcerative colitis and polyposis coli is described. Instead of preparing a pelvic pouch, the natural rectal pouch stripped of the diseased mucosa was used experimentally in dogs. The undisturbed muscular cuff of the rectum (12 cm from the anal verge) was covered by healthy vascularized mucosa of small bowel in such a manner that the dog could use its rectum as usual before surgery. The results are encouraging. The rectal reservoir is spared, with its sensitivity, continence and motor activity covered by healthy mucosa. The dogs thrived.
In recent years methods for deriving spatial molecular structure from atom-atom distance information have gained in importance due to the emergence of two-dimensional nuclear magnetic resonance (n.m.r) techniques, which make it possible to obtain such distance information for polypeptides, small proteins, sugars, and DNA fragments in solution. Distance geometry (DG) and restrained molecular dynamics (MD) refinement are applied to a cyclic polypeptide, the immunosuppressive drug cyclosporin A, and the results are compared. Two different procedures, DG followed by restrained MD, and straightforward restrained MD starting from the X-ray structure, both lead to a unique conformation that satisfies the 58 experimentally determined distance constraints. The results nicely show the relative merits of DG and restrained MD techniques for determining spatial molecular structure from distance information.
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Cyclo(-Phe(p-NH[1-14C]Ac)-Thr-Lys-(CO(p-N3)C6H4)-Trp-Phe-DPro++ +), in the following named azidobenzamido-008, was synthesized in order to identify binding sites for c(Phe-Thr-Lys-Trp-Phe-DPro), named 008, (a cyclosomatostatin with retro sequence) in liver cell plasma membranes. In the dark the above photolabel was taken up into isolated hepatocytes, inhibiting the sodium dependent uptake of cholate and taurocholate in a competitive manner (Ki for cholate uptake inhibition = 1 microM; Ki for taurocholate uptake inhibition = 5 microM). When activated by flashed light the inhibition became irreversible (IC50 for cholate uptake inhibition = 2 microM; IC50 for taurocholate uptake inhibition = 9 microM) and the activated cyclopeptide bound chiefly to hepatocellular membrane proteins of 67, 54, 50, 37 kDa. Excess of the initial 008, or of cholate or phalloidin partially protected the above membrane components against labeling with 14C-labeled azidobenzamido-008. In contrast AS 30 D ascites hepatoma cells, known to be deficient in bile acid and cyclosomatostatin transport, could not be specifically labeled by azidobenzamido-008. The membrane proteins preferentially labeled in hepatocytes (50 and 54 kDa) are integral glycoproteins. The 67 kDa protein is a hydrophilic nonglycosylated membrane component. Independent of labeling with 14C-labeled azidobenzamido-008 or with 14C-labeled azidobenzamido-taurocholate, the main radioactive peaks in the pH region of 7, 5.5, 5.25 were identical after solubilization with Nonidet P-40 and subsequent isoelectric focusing. Proteins of 67, 54, 50 and 37 kDa could be enriched by use of 008-containing gels in affinity electrophoresis. Binding sites for 008 were not destroyed by SDS or Nonidet P-40 treatment of plasma membranes.
Various aspects of monocyte-associated function were evaluated in the peripheral blood mononuclear cells of male homosexuals who were infected with the human immunodeficiency disease virus (HIV). The functional assessments included indomethacin-sensitive regulation of blastogenesis and lymphokine-activated killer (LAK)-cell induction, chemiluminescent responses of mononuclear leukocytes to opsonized zymosan, and the expression of HLA-DR antigen on CD-14-positive monocytes. The results obtained demonstrate that each of these functions is abnormal in asymptomatic individuals who have HIV core antigen (p24) in their circulation. These results suggest that monocyte abnormalities which could contribute to immune dysfunction in HIV-infected patients can be detected early during the course of HIV infection and are associated with the expression of serum HIV antigen.