De novo design methods.
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Chemistry, Pharmaceutical↗
Biomedical subjects
H Briem
Publications and source records attributed to H Briem.
Campylobacter spp. in Icelandic poultry operations and human disease.
We describe the observed relationship of campylobacter in poultry operations to human cases in a closed environment. During 1999 in Iceland, domestic cases of campylobacteriosis reached peak levels at 116/100,000 and in 2000 dropped to 33/100,000. Approximately 62% of broiler carcass rinses were contaminated with Campylobacter spp. in 1999. During 2000, only 15% of the broiler flocks tested Campylobacter spp. positive. In 2000, carcasses from flocks which tested positive on the farms at 4 weeks of age were subsequently frozen prior to distribution. We suggest that public education, enhanced on-farm biological security measures, carcass freezing and other unidentified factors, such as variations in weather, contributed to the large reduction in poultry-borne campylobacteriosis. There is no immediate basis for assigning credit to any specific intervention. We continue to seek additional information to understand the decline in campylobacteriosis and to create a risk assessment model for Campylobacter spp. transmission through this well defined system.
Abattoirs↗
A European outbreak of Salmonella enterica serotype Typhimurium definitive phage type 204b in 2000.
OBJECTIVE: To describe the clinical, epidemiologic and microbiological features of a large outbreak of infection with a multiresistant Salmonella enterica serotype Typhimurium definitive type DT204b infection involving at least 392 people in five European countries. METHODS: Icelandic public-health doctors responded to a report on an Internet news site of an outbreak of infection with a multiresistant strain of Typhimurium DT104 in England by contacting the Public Health Laboratory Service (PHLS) Communicable Disease Surveillance Centre (CDSC). An international alert was sent out through Enter-net. All strains from England & Wales, The Netherlands, Scotland and Germany, and 17 of the outbreak isolates from Iceland, were phage-typed, screened for antimicrobial resistance, and subjected to molecular typing. Hypothesis-generating interviews were conducted, followed by case-control studies performed in Iceland and England. RESULTS: Isolates from cases in Iceland, England and Wales, The Netherlands, Scotland and Germany were identified as Typhimurium DT204b. The antimicrobial resistance pattern was ACGNeKSSuTTmNxCpL. All strains tested displayed an identical plasmid profile. Strains from five cases in England & Wales and five cases in Iceland possessed identical pulsed-field profiles. Although a common source was suspected, only Iceland implicated imported lettuce as a vehicle, with an analytic epidemiologic study (OR = 40.8; P = 0.005; 95% CI 2.7-3175). CONCLUSION: The identification of international outbreaks, necessary for investigation and control, can be facilitated by standardized phage-typing techniques, the electronic transfer of molecular typing patterns, formal and informal links established through international surveillance networks, and the early reporting of national outbreaks to such networks.
Adolescent↗
[Quality control of antimicrobial usage in Reykjavik Hospital in 1994 - 1998: economic impact.].
AIMS: To investigate the effect of guidelines and supervision of the prescription of antimicrobial agents at Reykjavik Hospital on the cost and the amount used of these agents. MATERIAL AND METHODS: The investigation was conducted from 1994 to 1997. Guidelines were issued for the prescription of antimicrobial agents in empirical treatment and for prophylactics in surgery. The availability of these agents was reduced and the physicians had to order these drugs by filling out a special application form. These forms were later on used for the supervision by a pharmacist and an infectious disease physician of the use of antmicrobial agents and to monitor any change in the prescription of the agents. If needed the supervisors gave advice to the clinicians responsible for the patients care. The supervision took place at eight of the wards of the hospital and started at different times during May 1995 to March 1996. RESULTS: The cost of the usage of antimicrobial agents was reduced after the introduction of the supervision. However, as time passed from the implementation of the supervision the cost tended to increase again. The greatest cost reduction was achieved at the departments of surgery or 8.5 million Icelandic crowns. At the departments of medicine the cost reduction was 2.3 million crowns. By correcting for the cost of supervisory staff the real cost decrease was approximately 6 million crowns. The total amount of prescribed antimicrobial agents measured by the Standardised Daily Dosage was reduced in all the concerned wards by 3-14%. CONCLUSIONS: The real cost decreases after the implementation of supervision of the prescription of antimicrobial agents was approximately six million Icelandic crowns during 1994 to 1997. Also, the proportion of antimicrobial agents in the total cost of drugs was reduced after the supervision started in spite of increasing mean cost per Standardised Daily Dosage increased at the departments during the study period. The goal of reducing the amount of antimicrobial agents prescribed was also achieved.
English Abstract↗
Multiple-conformation and protonation-state representation in 4D-QSAR: the neurokinin-1 receptor system.
Using a 4D-QSAR approach (software Quasar) allowing for multiple-conformation, orientation, and protonation-state ligand representation as well as for the simulation of local induced-fit phenomena, we have validated a family of receptor surrogates for the neurokinin-1 (NK-1) receptor system. The evolution was based on a population of 500 receptor models and simulated during 40 000 crossover steps, corresponding to 80 generations. It yielded a cross-validated r(2) of 0.887 for the 50 ligands of the training set (represented by a total of 218 conformers and protomers) and a predictive r(2) of 0.834 for the 15 ligands of the test set (70 conformers and protomers). A series of five "scramble tests" (with an average predictive r(2) of -0.438) demonstrates the sensitivity of the surrogate toward the biological data, for which it should establish a QSAR. On the basis of this model, the activities of 12 new compounds - four of which have been synthesized and tested in the meantime - are predicted. For most of the NK-1 antagonists, the genetic algorithm selected a single entity - out of the up to 12 conformers or protomers - to preferably bind to the receptor surrogate. Moreover, the evolution converged at an identical protonation scheme for all NK-1 antagonists. This indicates that 4D-QSAR techniques may, indeed, reduce the bias associated with the choice of the bioactive conformation as each ligand molecule can be represented by an ensemble of conformations, orientations, and protonation states.
Combinatorial Chemistry Techniques↗
Flexsim-X: a method for the detection of molecules with similar biological activity
We describe the development of the method Flexsim-X, which can be used to detect molecules with similar biological activity. This procedure is based on comparing virtual affinity fingerprints made up from docking scores of the molecules with respect to a reference set of binding sites. Using a test data set consisting of ligands from five different activity classes and randomly chosen compounds, the reference panel of binding sites was optimized in terms of size and composition. Systematic approaches as well as genetic algorithm based (GA) optimization procedures have been evaluated. Additionally, the effectiveness of the method is illustrated.
Journal Article↗
TT virus infections among blood donors in Iceland: prevalence, genotypes, and lack of relationship to serum ALT levels.
BACKGROUND: The TT virus (TTV) is a newly identified blood-borne virus. Its association with disease is still unknown, and screening of blood donors has not been implemented. Several genotypes of the TTV have been identified. STUDY DESIGN AND METHODS: Three hundred seventy healthy blood donors were randomly selected and tested for TTV by the PCR method. Sequencing of a part of the genome was performed to identify various genotypes of the virus. ALT levels were determined in both infected and uninfected individuals. RESULTS: The TT virus (TTV), was detected in the sera of 23 (6.2%) of 370 healthy Icelandic blood donors; this prevalence is lower than that reported in Japan but higher than that in Scotland. The virus was found in all groups over the age of 19. Sequencing and phylogenetic analysis of 202 bp from open reading frame 1 demonstrated genotypes 1b and 2b 2c and genotype 4 isolates, with the latter bearing 89-percent nucleotide homology with other genotype 4 sequences deposited at GenBank. One sample showed a mixed genotype 1b/2c infection. Serum ALT levels were within normal limits in all infected individuals. CONCLUSION: The TTV carrier state does not cause significant liver injury.
Adolescent↗
[Food-borne Infections in a new Millennium [Editorial].].
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Journal Article↗
Tuberculosis in immigrants.
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Cohort Studies↗
Immunogenicity of two efficacious outer membrane protein-based serogroup B meningococcal vaccines among young adults in Iceland.
Serum bactericidal activity (SBA) and ELISA antibody levels elicited by two efficacious serogroup B meningococcal vaccines were measured in a controlled trial involving 408 15- to 20-year-olds. Subjects were given two doses at a 6-week interval of a serogroup B or control vaccine. Response was defined as > or = 4-fold rise in antibody level. After two doses of the Finlay Institute (Havana) vaccine at 12 months, the proportions of SBA and ELISA responders were not different from those of the control group (15% and 17% [vaccine] vs. 13% and 9% [control], P > .05). After two doses of the National Institute of Public Health (Oslo) vaccine, there were more SBA and ELISA responders than in the control group (47% and 34% [vaccine] vs. 10% and 1% [control]) or the Finlay Institute vaccine group (P < .05 for both). SBA and ELISA may be insensitive correlates for protective efficacy for some outer membrane protein-based serogroup B meningococcal vaccines.
Adolescent↗
Synthesis of cyclic dipeptide templates, their incorporation into peptides and studies on their conformational and biological properties.
This study investigated the diastereoselective synthesis of three dipeptide templates 1, 2 and 3, which may be regarded as conformationally restricted analogs of H-Gly-Xaa-OH, in which Xaa constitutes an aromatic amino acid. Bond formation between alpha-C of Gly and the aromatic moiety was achieved by proton-catalyzed intramolecular electrophilic aromatic substitution. The absolute configuration of the dipeptide templates was determined by single-crystal X-ray crystallography or by nuclear Overhauser enhancement measurements. A protective group strategy was elaborated to allow their incorporation into peptide sequences by liquid phase as well as by solid-phase peptide synthesis. The templates were used to generate an enkephalin analog 15, a modified peptidic neurokinin antagonist 20 and two dermorphin derivatives (24 and 33). Molecular dynamic simulations with 15 and 20 revealed the preference for a turn-like motif for 15. The biological activity, as investigated by respective receptor binding and functional assays, was strongly diminished with all four derivatives, indicating that their receptor-relevant molecular geometries lie outside the examined conformational space.
Crystallography, X-Ray↗
Molecular similarity based on DOCK-generated fingerprints.
An alternative method for defining molecular similarity is presented. By using the docking program DOCK and a reference panel of protein binding sites, fingerprints for a set of molecules have been generated, based on calculated interaction energies. These binding patterns allowed us to calculate matrices of similarity coefficients which subsequently were used for nearest-neighbor searches within the database. Our results indicate that the method is suitable for finding significant similarities of compounds of the same biological activity. Although the overall performance of a traditional 2D similarity method is better in the test systems investigated, our 3D approach can be regarded as complementary since it is able to detect similarities independent of the covalent structure of the compounds. Thus it should be a useful 3D database-searching tool for rational lead discovery.
Amino Acid Sequence↗
Characteristics of hepatitis C virus among intravenous drug users in Iceland.
According to antibody analysis, approximately two of every three intravenous drug users in Iceland have become infected with hepatitis C virus (HCV). In this study, serum samples from 55 HCV antibody-positive intravenous drug users (39 males and 16 females) were analyzed by polymerase chain reaction, and the viral strains were grouped into genotypes. Only three genotypes--1a, 3a, and 1b--were found among the drug users. Of 40 persons who were positive by polymerase chain reaction, 23 (57.5%) had type 1a, 15 (37.5%) had type 3a, and one (2.5%) had type 1b. One serum sample was untypeable. HCV viral RNA was detectable in 84.6% of the males and 43.7% of the females, which is a significant difference between the sexes (p < 0.01). In addition, 41 randomly selected HCV antibody-positive intravenous drug users (17 males and 24 females) were tested for HCV viral RNA with a commercially available polymerase chain reaction technique. In this subset of drug users, 76.4% of the males and 33.3% of the females had detectable HCV RNA in their serum, which is also a significant sex difference (p < 0.01). This study shows that two HCV genotypes predominate among intravenous drug users in Iceland, and the results indicate that women eliminate virus more effectively than men.
Adolescent↗
Synthesis of a new dipeptide template, its X-ray structure, and modeling studies on its conformational features.
The diastereoselective synthesis is reported of a dipeptide template which is closely related to H-Gly-Trp-OH. Intramolecular bond formation between alpha-C of Gly and ring position 2 of the Trp unit has been achieved by a Pictet-Spengler-type electrophilic aromatic substitution. The absolute configuration of the N-Moc protected dipeptide template 9.2H2O was determined by single-crystal X-ray crystallography and found to be (2S,5S). The cis orientation of the amino and carboxy termini prompted us to investigate the potential of 9 as a beta-turn mimic. MD calculations on the model pseudopeptide Ac-Ala-Gly-Trp-Ala-NHMe 11 suggest that an unusually tight turn should be favoured rather than a beta-turn. The proper protective situation as a pre-requisite for the incorporation of the template into a peptide has been established, and comments about its chemical properties are given.
Amino Acid Sequence↗
Immunogenicity and safety in adults of hepatitis A virus vaccine administered as a single dose with a booster 6 months later.
An inactivated vaccine against hepatitis A was administered as a single 1,440 enzyme-linked immunosorbent assay (ELISA) units dose at month 0 with a booster at month 6 to 200 subjects divided into two age groups: group 1, 20-39 years (n = 134) and group II, 40-62 years (n = 66). At day 15, the seropositivity rates were 90% and 77% in groups I and II, respectively. At month 1 the seropositivity rate was 97% in both groups. At month 6 the seropositivity rates were 94% and 88% in groups I and II, respectively. One month after the booster, at month 7, 100% in both groups had become seropositive. The vaccine was well tolerated and did not cause any severe reactions. The results indicate that a single high vaccine dose offers protection against hepatitis A virus (HAV) for at least 6 months in the majority of cases where rapid vaccination is required even in travellers of older age. A booster dose will ensure long-term protection.
Adult↗
Age specific prevalence of antibodies against Chlamydia pneumoniae in Iceland.
Chlamydia pneumoniae is a newly recognized common cause of respiratory tract infections. The aim of this study was to examine its prevalence in Iceland. The study was based on 1020 serum samples from individuals 0-99 years old. The samples were divided into 10-year age groups. IgG and IgM antibodies were determined with microimmunofluorescence assay. An IgG titer > or = 32 and IgM titer > or = 16 were considered positive. The prevalence of positive IgG titer in the study population was 53 +/- 16% (mean +/- SD, age group range 14-66%). Neither seasonal nor gender-based difference in IgG antibody prevalence was demonstrated. It was lowest in the youngest group, 0-9 years old (p < 0.001), but rose linearly to age 70 (p < 0.005). 34 samples were IgM positive on initial testing; most from the older age groups. 12 were rheumatoid factor positive as well. After treatment with caprine antihuman IgG antibodies all became negative. The prevalence of C. pneumoniae infections is high in Iceland according to these results and similar to that in neighbouring countries. The presence of IgM rheumatoid factor may cause false positive tests for pathogen-specific IgM by immune complex binding with pathogen-specific IgG, thereby requiring its removal before testing.
Adolescent↗
[Voluntary HIV testing in Iceland. Infection risk factors and prevalence of antibodies against HIV, hepatitis B and C viruses].
Subjects attending a semi-anonymous HIV testing site at Borgarspitalinn, Reykjavik, during a five year period (1987-1992) were asked to complete a questionnaire on several factors associated with increased risk of HIV infection and the reason for their request of being tested. Serum samples from the subjects were tested for antibodies against HIV, HBV and HCV. During the study period 475 sets of tests were performed on a total of 400 individuals. Three-hundred thirty six individuals returned 401 questionnaires. Sexual contact with prostitutes was reported by 30 males (in 40 instances) and one female: and 40 males (in 47 instances) and 18 females indicated promiscuous sexual behaviour. Homosexuality was reported by 15 males and one female. Seven individuals requested testing due to previous blood transfusion and 5 reported i.v. drug abuse. A request from a third party (significant other, insurance company, etc.) was stated by 32 subjects. Two of the 400 subjects tested were HIV-positive (0.5 per cent), and 9 (2.3 per cent) and 11 (2.8 per cent) were found to have markers for HBV and HCV infection, respectively. A significant correlation was observed between HIV infection and homosexuality (P < 0.05) and between HCV infection and i.v. drug abuse (p < 0.01). Overall, a total of 136 subjects (41 per cent) in the study reported behaviour associated with increased risk of HIV infection. This information supports the continued role of a semi-anonymous HIV testing site among the services offered by the health care system during the AIDS epidemic.
AIDS Serodiagnosis↗
[New findings in the molecular mechanisms of drugs].
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Animals↗