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PubMed1999

Design, characterization and testing of tRNA3Lys-based hammerhead ribozymes.

A hammerhead ribozyme targeted against the HIV-1 env coding region was expressed as part of the anticodon loop of human tRNA3Lys without sacrificing tRNA stability or ribozyme catalytic activity. These tRNA-ribozymes were isolated from a library which was designed to contain linkers (sequences connecting the ribozyme to the anticodon loop) of random sequence and variable length. The ribozyme target site was provided in cis during selection and in trans during subsequent characterization. tRNA-ribozymes that possessed ideal combinations of linkers were expected to recognize the cis target site more freely and undergo cleavage. The cleaved molecules were isolated, cloned and characterized. Active tRNA-ribozymes were identified and the structural features conducive to cleavage were defined. The selected tRNA-ribozymes were stable, possessed cleavage rates lower or similar to the linear hammerhead ribozyme, and could be transcribed by an extract containing RNA polymerase III. Retroviral vectors expressing tRNA-ribozymes were tested in a human CD4+ T cell line and were shown to inhibit HIV-1 replication. These tRNA3Lys-based hammerhead ribozymes should therefore prove to be valuable for both basic and applied research. Special application is sought in HIV-1 or HIV-2 gene therapy.

Base Sequence↗

PubMed1997

Empiric antibiotic selection criteria for respiratory infections in pediatric practice.

BACKGROUND: Respiratory infections in children may occur as a consequence of resistant bacterial pathogens. Streptococcus pneumoniae organisms resistant to penicillin, trimethoprim/sulfamethoxazole and macrolides are increasingly prevalent. Amoxicillin- and macrolide-resistant Haemophilus influenzae and Moraxella (Branhamella) catarrhalis are also more commonly seen. Traditional agents such as amoxicillin and trimethoprim/sulfamethoxazole remain acceptable choices for most children with respiratory infections because currently most patients are not infected by resistant pathogens and there is a high spontaneous cure rate associated with these infections. OBJECTIVE: To analyze the criteria for the selection of extended spectrum antimicrobials as empiric therapy for respiratory infections. DISCUSSION: When an extended spectrum antimicrobial is appropriate for empiric therapy, selection should be based on: (1) efficacy; (2) adverse event profile; and (3) compliance-enhancing features (dosing with meals, once or twice daily administration, good palatability in suspension, shortened course of therapy and affordability). A new agent, ceftibuten, has recently joined other extended spectrum cephalosporins and newer macrolides (clarithromycin and azithromycin) as a choice to be considered for empiric therapy for respiratory infections. These antimicrobials are differentiated from each other and traditional agents by differences in activity in vitro against penicillin-resistant pneumococci, relative beta-lactamase stability against Gram-negative bacteria and pharmacodynamic properties. When resistant organisms are isolated or suspected in community-acquired respiratory infections, cautious use of newer antibiotics may have to be considered.

Anti-Bacterial Agents↗

PubMed1985

Common features of polyomavirus mutants selected on PCC4 embryonal carcinoma cells.

The genomic rearrangements of six polyomavirus mutants selected on PCC4 embryonal carcinoma cells have been compared and their common characteristics pointed out. All mutants show a duplication which includes at least the adenovirus type 5 (Ad5) E1A-like enhancer core sequence plus a deletion of variable size and location. The presence of the second enhancer core sequence, the SV40-like enhancer, is not required for expression of the PyEC PCC4 phenotype. Two of these mutants are also able to express polyomavirus T antigen on F9 and LT1 cells. Multiadaptation seems to require the duplication of the Ad5 E1A-like core sequence, the maintenance of the SV40-like core sequence and a local change in DNA stability.

Animals↗

PubMed1979

Electrophrenic respiration: report of six cases.

The development of electrophrenic respiration has permitted freedom from mechanical ventilation for patients who have irreversible respiratory failure in association with high-cervical spinal cord or brainstem lesions. There are three basic criteria for successful diaphragm pacing: (1) the need for long-term mechanical ventilatory assistance, (2) a functionally intact phrenic nerve-diaphragm axis, and (3) chest wall stability. Inability to achieve satisfactory pacing can be due to malfunction of equipment, instability of the chest wall, or inadequate neuromuscular responsiveness. These features of diaphragm pacing are exemplified in a series of six patients. Three achieved independence from mechanical ventilatory assistance with full-time phrenic pacing. In one patient, only limited electrophrenic respiration was achieved, and in another the method was entirely unsuccessful. Although functioning well, pacing systems were removed from the sixth patient because of infection. Diaphragm pacing can be a valuable form of respiratory support for carefully selected patients.

Adolescent↗

PubMed1994

NMR-derived three-dimensional solution structure of protein S complexed with calcium.

BACKGROUND: Protein S is a developmentally-regulated Ca(2+)-binding protein of the soil bacterium Myxococcus xanthus. It functions by forming protective, multilayer spore surface assemblies which may additionally act as a cell-cell adhesive. Protein S is evolutionarily related to vertebrate lens beta gamma-crystallins. RESULTS: The three-dimensional solution structure of Ca(2+)-loaded protein S has been determined using multi-dimensional heteronuclear NMR spectroscopy. (Sixty structures were calculated, from which thirty were selected with a root mean square difference from the mean of 0.38 A for backbone atoms and 1.22 A for all non-hydrogen atoms.) The structure was analyzed and compared in detail with X-ray crystallographic structures of beta gamma-crystallins. The two internally homologous domains of protein S were compared, and hydrophobic cores, domain interfaces, surface ion pairing, amino-aromatic interactions and potential modes of multimerization are discussed. CONCLUSIONS: Structural features of protein S described here help to explain its overall thermostability, as well as the higher stability and Ca2+ affinity of the amino-terminal domain relative to the carboxy-terminal domain. Two potential modes of multimerization are proposed involving cross-linking of protein S molecules through surface Ca(2+)-binding sites and formation of the intramolecular protein S or gamma B-crystallin interdomain interface in an intermolecular content. This structural analysis may also have implications for Ca(2+)-dependent cell-cell interactions mediated by the vertebrate cadherins and Dictyostelium discoideum protein gp24.

Amino Acid Sequence↗

PubMed1999

The disulfide-coupled folding pathway of apamin as derived from diselenide-quenched analogs and intermediates.

The sequence of apamin, an 18 residue bee venom toxin, encloses all the information required for the correct disulfide-coupled folding into the cystine-stabilized alpha-helical motif. Three apamin analogs, each containing a pair of selenocysteine residues replacing the related cysteines, were synthesized to mimic the three possible apamin isomers with two crossed, parallel, or consecutive disulfides, respectively. Refolding experiments clearly revealed that the redox potential of selenocysteine prevails over the sequence encoded structural information for proper folding of apamin. Thus, selenocysteine can be used as a new device to generate productive and nonproductive folding intermediates of peptides and proteins. In fact, disulfides are selectively reduced in presence of the diselenide and the conformational features derived from these intermediates as well as from the three-dimensional (3D) structures of the selenocysteine-containing analogs with their nonnatural networks of diselenide/disulfide bridges allowed to gain further insight into the subtle driving forces for the correct folding of apamin that mainly derive from local conformational preferences.

Amino Acid Sequence↗

PubMed1996

Conserved features in the active site of nonhomologous serine proteases.

BACKGROUND: Serine protease activity is critical for many biological processes and has arisen independently in a few different protein families. It is not clear, though, the degree to which these protease families share common biochemical and biophysical properties. We have used a computer program to study the properties that are shared by four serine protease active sites with no overall structural or sequence homology. The program systematically compares the region around the catalytic histidines from the four proteins with a set of noncatalytic histidines, used as controls. It reports the three-dimensional locations and level of statistical significance for those properties that distinguish the catalytic histidines from the noncatalytic ones. The method of analysis is general and can be applied easily to other active sites of interest. RESULTS: As expected, some of the reported properties correspond to previously known features of the serine protease active site, including the catalytic triad and the oxyanion hole. Novel properties are also found, including the spatial distribution of charged, polar, and hydrophobic groups arranged to stabilize the catalytic residues, and a relative abundance of some residues (Val, Tyr, Leu, and Gly) around the active site. CONCLUSIONS: Our findings show that in addition to some properties common to all the proteases examined, there are a set of preferred, but not required, properties that can be reliably observed only by aligning the sites and comparing them with carefully selected statistical controls.

Animals↗

PubMedDate not supplied

[Post-radiotherapy lesions of the brachial plexus. Classification and results of surgical treatment].

A series of 60 cases with a follow-up of 3 to 13 years among 118 operations for post-radiation lesions of the brachial plexus performed between 1978 and 1990 was investigated as a function of three features: 1) anatomic classification according to 3 stages for per-operatory observations of extrinsic and intrinsic compression, 2) clinical classification according to 4 types of sensoro-motor neurological symptoms and 3) the different operative procedures used for decompression. It was concluded that post-radiation plexuses should be operated as early as possible as soon as paraesthesia appears and before the onset of pain since the aim of the operation is to stabilize the clinical course and not achieve cure. It was also found that the best operative procedure is a selective neurolysis of the plexus completed by a pedicled omentoplasty.

Brachial Plexus↗

PubMed1999

Calcium-binding properties and molecular organization of bradykinin A solution 1H-NMR study.

The NMR features of bradykinin were investigated in dimethylsulfoxide containing 1% water. The temperature dependence of chemical shifts and ROESY maps were monitored for the major species where all X-Pro bonds are trans. The occurrence of a head-to-tail ionic interaction and intramolecular hydrogen bonds stabilizing a pseudo cyclic arrangement was inferred, a beta turn at the C-terminus being the main feature of the secondary structure. Calcium was shown to bind to the peptide with a dissociation constant Kd = 2.8 + 0.2 mm. 2Pro and 3Pro carbonyls, as well as the 9Arg carboxyl, were assigned as the metal-binding sites. A molecular model of the 1 : 1 metal-complex was obtained. In light of conformational changes experienced by the peptide upon interaction with calcium, a role for the metal was hypothesized in the process of conformational selection from the free to the receptor-bound state of bradykinin.

Bradykinin↗

PubMed2000

Heterogeneity of response to antipsychotics from multiple disorders in the schizophrenia spectrum.

BACKGROUND: Antipsychotic response after the initiation of neuroleptic treatment shows wide variation in schizophrenic patient populations. In this overview, the authors suggest that the variance in antipsychotic drug response within schizophrenia can be reduced by resolving the schizophrenias into several discrete "endophenotypes," each with different etiologic underpinnings. METHOD: Studies relating differences in the relative speed or completeness of antipsychotic response to differences in distribution of 2 biological markers with possible etiologic significance are reviewed. Such studies had assessed recently hospitalized, neuroleptic-free patients undergoing exacerbation of nonaffective psychotic disorders. Prior to initiation of neuroleptic, the cohort of patients had been assessed for the quantity of the dopamine metabolite homovanillic acid in plasma (pHVA) and had undergone the first of 2 magnetic resonance imaging (MRI) studies for analyses of ventricle volumes. A second MRI was subsequently performed during a period of (partial) remission to determine within-patient stability of ventricular volumes. These selected studies assessed the distribution of pHVA and distribution of rates of ventricular change, with non-normal distributions resolved by K-means clustering. The speed and completeness of neuroleptic-induced antipsychotic response were related to 3 clusters of patients delineated by modal distributions of pHVA and of apparent rates of ventricular change. RESULTS: At least 3 unique "endophenotypes" of the "group of the schizophrenias" can be defined with respect to speed and completeness of antipsychotic response. Each endophenotype appears to show at least one unique biological feature that differentiates it from a normal comparison group. A rapidly responsive psychosis was associated with excessive production of dopamine, as identifiable by elevation of pHVA and a "good-prognosis" course. A delayed-response psychosis had low-to-normal pHVA, clinically demonstrated persistent negative symptoms, and was associated with an excessive rate of change in ventricle volume between exacerbations of psychosis and (partial) remissions. Finally, a nonresponsive psychosis could be characterized as having both low-to-normal pHVA and rate of change of ventricle volumes similar to that of controls. Additional studies revealed that each of the endophenotypes had high rates of the psychoses in family members. The good-prognosis course of the rapidly responsive group of studied patients was also found in their family members who had psychotic disorders. Similarly, the prominent negative symptoms of the delayed-response probands were reflected as a prominent trait in their family members also afflicted with psychosis. The endophenotypes tended to "breed true" in terms of prognosis and negative symptoms. CONCLUSION: Major differences in antipsychotic response patterns appear to be associated with patient and family characteristics that may be related to differences in the etiology and consequent pathophysiology of illness.

Adolescent↗

PubMed1999

Human renal cell carcinoma xenografts in SCID mice: tumorigenicity correlates with a poor clinical prognosis.

To establish human renal cell carcinoma (RCC) xenografts for preclinical studies, 55 renal tumors (33 primary and 22 metastatic lesions) were transplanted subcutaneously into severe combined immunodeficient mice. Twenty of 49 evaluable tumors (40.8%) grew with a median latency period of 89 days (36 to 209 days) from the day of engraftment. Tumor growth was stabilized after the fifth passage with a median time between passages of 38 days (19 to 80 days). Tumorigenicity was correlated with the metastatic phenotype of the tumor (54% success rate, p = 0.007) and with reduced survival of patients. Despite a possible evolution of histological features and tumor grading, established RCC xenografts were comparable to parental tumors, as assessed by karyotype and DNA-ploidy analyses. Molecular cytogenetic analysis also revealed specific genetic alterations characterizing distinct RCC types that were constant in parental and corresponding xenografts. In addition, this xenograft model has permitted the selection of minor tumor subclones with a proliferative advantage and minimal overexpressed chromosomal regions. We conclude that severe combined immunodeficient mice are useful recipients for the establishment of long-term RCC xenografts that can be used as valuable tools to evaluate the activity of new therapeutic approaches and to study biological parameters determining in vivo aggressiveness of human RCC.

Adult↗

PubMed1990

Placing patients in the queue for coronary revascularization: evidence for practice variations from an expert panel process.

A panel of 16 cardiologists and cardiac surgeons rated 438 case scenarios for the maximum acceptable delay prior to revascularization, using a scale with seven interventional time frames and two nodes for designating dubious or inappropriate cases. If consensus was defined as agreement by 12 or more panelists, only 1.4 percent of the case scenarios showed consensus on a single rating. Dividing the scale into three broad clinical categories (revascularize promptly, place on a waiting list, or no intervention), 11.4 percent of scenarios showed all 16 panelists agreeing on a single category, rising to 59.4 percent of scenarios if agreement by 12 panelists was accepted as a consensus. The mean difference between the panelists' highest and lowest urgency ratings yielded waiting time differences of two weeks for scenarios of very unstable angina, and more than three months for those with stable angina. However, in a regression model, individual panelist factors on average had less effect than clinical features such as severity and stability of angina, or stenosis of major coronary arteries. These findings strongly support the need for consensus criteria to ensure that triage practices are consistent and fair, and also suggest that widespread adoption of a standardized approach to revascularization priorities may be feasible.

Coronary Artery Bypass↗

PubMed2000

DNA replication fidelity.

DNA replication fidelity is a key determinant of genome stability and is central to the evolution of species and to the origins of human diseases. Here we review our current understanding of replication fidelity, with emphasis on structural and biochemical studies of DNA polymerases that provide new insights into the importance of hydrogen bonding, base pair geometry, and substrate-induced conformational changes to fidelity. These studies also reveal polymerase interactions with the DNA minor groove at and upstream of the active site that influence nucleotide selectivity, the efficiency of exonucleolytic proofreading, and the rate of forming errors via strand misalignments. We highlight common features that are relevant to the fidelity of any DNA synthesis reaction, and consider why fidelity varies depending on the enzymes, the error, and the local sequence environment.

Base Pair Mismatch↗

PubMed1996

N-peptidyl, O-acyl hydroxamates: comparison of the selective inhibition of serine and cysteine proteinases.

Two series of N-aminoacyl, O-benzoyl hydroxamates were designed to investigate the influence of the substituted benzoyl residue on the hydrolytic stability and the reactivity of these potential inhibitors towards selected cysteine and serine proteinases. The inactivators react more rapidly with cysteine proteinases than with the serine enzymes tested. While Z-Phe-Gly-NHO-Nbz is the most reactive inhibitor of cathepsin L, inhibiting the target protein by a second order rate constant of 932.000 M-1 s-1, the bacterial serine proteinase thermitase is inhibited best by Z-Gly-Phe-NHO-Nbz, exhibiting a second-order rate constant of 1.170 M-1 s-1. Thiolsubtilisin, having the thiol-group as the reactive nucleophile instead of serine, exhibits specificity constants of the inactivation two orders of magnitude smaller than subtilisin. The degree of selectivity of the inhibitors relative to cathepsin B, cathepsin L, cathepsin S and papain varies up to two orders of magnitude with respect to their second order rate constant of inactivation. The inhibitory reactivity of these compounds varies only up to sixfold depending on the benzoyl substituent. Similarly, the rate constants for the hydrolytic decomposition of the compounds vary by a factor of about 6, suggesting that the structural and mechanistic features of the compounds which are responsible for decomposition as well as for the enzyme inhibition are the same. Comparing both reactions, the data allow the calculation of an acceleration factor of 2.4 x 10(10) for the inhibition of cathepsin L by its most effective inhibitor, clearly characterizing this enzyme inhibition reaction as enzyme-activated.

Cathepsins↗

PubMed1988

Comparative separation of human plasma proteins on polysulphated chromatographic media.

Polysulphated chromatographic media, particularly Heparin Sepharose, are generally used to purify a variety of different plasma proteins. Heparin Sepharose, dextran sulphate Sepharose and sulphated dextran are compared with two recently available sulphated cellulose chromatographic media. The potential influence of structural features of different polysaccharides on the interaction with selected plasma proteins has been evaluated with the particular objective of developing an alternative medium for the preparation of specific therapeutic factor concentrates. The studies indicate that the degree of sulphation of the matrix is an important but not a critical determinant for resolution of factors IX and X. Despite large differences in the carbohydrate structure of the matrices, the new sulphated cellulose gel 5.2 had a total protein capacity and specific binding profile comparable to Heparin Sepharose. The sulphated cellulose which is competitively priced, and has excellent stability, is a potential alternative to Heparin Sepharose especially for larger scale industrial processing of factor IX concentrate.

Blood Proteins↗

PubMed2000

A distinctive clade B HIV type 1 is heterosexually transmitted in Trinidad and Tobago.

HIV-1 transmission worldwide is predominantly associated with heterosexual activity, and non-clade B viruses account for the most spread. The HIV-1 epidemic in Trinidad/Tobago and the Caribbean shares many features with such heterosexual epidemics, including a prominent role for coincident sexually transmitted diseases. This study evaluates the molecular epidemiology of HIV-1 in Trinidad/Tobago during a period when abrupt transition from homosexual to heterosexual transmission occurred in the absence of injecting drug use, concomitant with a rapid rise in HIV-1 prevalence in the heterosexual population. Of 31 viral isolates studied during 1987-1995, all cluster with subtype B reference strains. In the analysis of full env genes from 22 early seroconverters, the Trinidad isolates constitute a significant subcluster within the B subtype. The Trinidad V3 consensus sequence differs by a single amino acid from the prototype B V3 consensus and demonstrates stability over the decade of this study. In the majority of isolates, the V3 loop of env contains a signature threonine deletion that marks the lineage of the Trinidad HIV-1 clade B epidemic from pre-1984. No phenotypic features, including syncitium induction, neutralization profiles, and chemokine receptor usage, distinguish this virus population from other subtype B viruses. Thus, although the subtype B HIV-1 viruses being transmitted in Trinidad are genetically distinguishable from other subtype B viruses, this is probably the result of a strong founder effect in a geographically circumscribed population rather than genetic selection for heterosexual transmission. These results demonstrate that canonical clade B HIV-1 can generate a typical heterosexual epidemic.

Amino Acid Sequence↗

PubMed1999

Continuous mixed venous (SvO2) monitoring. Too expensive or indispensible?

Based on theoretic principles and clear literature support, SvO2 (mixed venous oxyhemoglobin) monitoring offers an important advantage over traditional hemodynamic parameters. SvO2 allows more precise understanding of the adequacy of cardiac and pulmonary function than traditional parameters. SvO2 values do not replace the need to measure individual parameters of oxygen delivery or consumption but serves as the standard for assessing the impact of each parameter on tissue oxygenation. SvO2 has the ability to reflect a threat to tissue oxygenation that is unmatched by other parameters. Its ability to give a real time indication of tissue oxygenation makes it a preferred parameter for monitoring the adequacy of hemodynamics. Its use as an end point for determining the adequacy of hemodynamics (BP, CO/CI), measurement of Qs/Qt, and prediction of potential hemodynamic instability make this parameter invaluable for the knowledgeable clinician. SvO2 catheters cost more than traditional PA catheters, a factor that has limited their acceptance as the standard PA catheter. The added cost of the SvO2 catheter has not been adequately addressed in the research literature. However, research does support SvO2 allows more rapid termination of drug therapies, may improve movement out of the ICU, and reduces the incidence of mechanical ventilator manipulation. These features increase the cost-effectiveness of SvO2 catheters. The cost-effectiveness of the catheter, like any technology, is predicated on the clinician. Clinicians++ must be educated to use SvO2 as a primary end point for treatment decisions regarding hemodynamic therapy and patient stability. If used properly, every PAC should use fiberoptic SvO2 capabilities.

Adolescent↗

PubMed1990

Inheritance of species-specific behaviors in the paradise fish (Macropodus opercularis): a diallel study.

Species-specific elements of the paradise fish's ethogram were recorded in one familiar and three different unfamiliar environments, which were designed to model certain features of this species' natural habitat: (1) a densely vegetated home range, (2) a novel open field, (3) a small novel place, and (4) a small novel place with a predator. The inheritance of the behavioral elements was investigated employing a five-times-replicated diallel cross among three inbred strains. A detailed Hayman analysis of variance and a variance-covariance analysis were performed to uncover the genetic architectures of these phenotypes. Additive genetic effects and/or ambidirectional dominance was found to be characteristic of most species-specific behavioral elements studied, suggesting an evolutionary history of stabilizing selection.

Animals↗