Search PubMed⌕ Search

Biomedical subjects

W D Wilson

Publications and source records attributed to W D Wilson.

At least 73 records · Page 4Linked to original sources
PubMed1997

Equine herpesvirus 1 myeloencephalopathy.

Myeloencephalopathy is an uncommon manifestation of equine herpesvirus 1 (EHV-1), but it can cause devastating losses during outbreaks on individual farms. Clinical signs of neurologic disease reflect a diffuse multifocal hemorrhagic myeloencephalopathy secondary to vasculitis and thrombosis. Sudden onset and early stabilization of signs, including ataxia, paresis, and urinary incontinence; involvement of multiple horses on the premises; and recent history of fever, abortion, or viral respiratory disease in the affected horse or herdmates are typical features, although there is considerable variation between outbreaks in epidemiologic and clinical findings. Prevention is difficult because many asymptomatic horses are infected latently with EHV-1 myeloencephalopathy and because vaccines do not confer protection against neurologic manifestations of infection. This article reviews the pathogenesis, pathology, clinical manifestations, diagnosis, and treatment of EHV-1 myeloencephalopathy and discusses prevention and control of equine herpesviral infections in the context of their epidemiology.

Animals↗
PubMed1997

Design and analysis of molecular motifs for specific recognition of RNA.

Selective targeting of RNA has become a recent priority in drug design strategies due to the emergence of retroviruses, the need for new antibiotics to counter drug resistance, and our increased awareness of the essential role RNA and RNA structures play in the progression of disease. Most organic compounds known to specifically target RNA are complex, naturally occurring antibiotics that are difficult to synthesize or derivatize and modification of these compounds to optimize interactions with structurally unique RNAs is difficult. The de novo design of synthetically accessible analogues is one possible alternative; however, little is known about the RNA recognition principles on which to design new compounds and limited information on RNA structure in general is available. To contribute to the growing body of knowledge on RNA recognition principles, we have prepared two series of polycationic RNA-binding agents, one with a linear scaffold, the other with a macrocyclic scaffold. We evaluated these compounds for their ability to bind to DNA and RNA, as well as to a specific RNA, the regulatory sequence, RRE, derived from HIV-1, by using thermal melting, circular dichroism, and electrophoresis gel shift methods. Out results suggest that cationic charge centers of high pKa that are displayed along a scaffold of limited flexibility bind preferentially to RNA, most likely within the major groove. Related derivatives that bind more strongly to DNA more closely mimic classical DNA minor-groove binding agents. Several of the macrocyclic polycations expand on a new binding motif where purine bases in duplex RNA are complexed within the macrocyclic cavity, enhancing base-pair opening processes and ultimately destabilizing the RNA duplex. The results in this report should prove a helpful addition to the growing information on molecular motifs that specifically bind to RNA.

Amino Acid Sequence↗
PubMed1997

Modulation of the Rev-RRE interaction by aromatic heterocyclic compounds.

The HIV-1 Rev protein regulates the nucleocytoplasmic distribution of viral precursor RNAs that encode HIV-1 structural proteins. Rev-mediated viral RNA expression requires a sequence-specific interaction between Rev and a viral RNA sequence, the Rev responsive element (RRE). Because the Rev-RRE interaction is essential for HIV-1 replication, anti-viral agents that selectively block this interaction may be effective anti-HIV-1 therapeutics. Here, we show that certain aromatic heterocyclic compounds, in particular, a tetracationic diphenylfuran, AK.A, can block binding of Rev to its high-affinity viral RNA binding site. AK.A abolishes Rev-RRE interactions at concentrations as low as 0.1 microM. Inhibition appears to be selective and results from competitive binding of the drug to a discrete region within the Rev binding site. Interestingly, the molecular basis for the AK.A-RNA interaction, as well as the mode of RNA binding differs from previously described aminoglycoside Rev inhibitors. Analysis of a variety of aromatic heterocyclic compounds and their derivatives reveals stereo-specific features required for the inhibition. Our results further demonstrate the feasibility of identifying and designing small molecules that selectively block viral RNA-protein interactions.

Aminoglycosides↗
PubMed1997

Parasites of mammals on the Sevilleta National Wildlife Refuge, Socorro, New Mexico: Cuterebra austeni and C. neomexicana (Diptera:Oestridae) from Neotoma and Peromyscus (Rodentia:Muridae), 1991-1994.

In total, 6,486 rodents representing 3 families (Muridae, Heteromyidae, and Sciuridae) and 24 species were trapped May through August of 1991 through 1994. Of these, only the white-throated woodrat. Neotoma albigula Hartley; piñon mouse, Peromyscus truei Shufeldt; and white-footed mouse, P. leucopus Rafinesque, were infested with Cuterebra Clark larvae. Of the 594 N. albigula that were captured 103 (17.3%) were infested with 139 Cuterebra larvae with all infestations occurring in the throat region. N. albigula infestations were observed in 4 of 5 habitats sampled. The highest prevalence of infestation occurred during May-June (27.2%) versus July-August (9.1%) and in males (25.2%) versus females (18.3%). Prevalence of infestation was not significantly different between animals from the mark-release webs versus removal webs or adults versus juveniles. Also, there was no correlation between relative density of N. albigula and prevalence of infestation. Fifteen adults were reared from puparia and identified as C. austeni Sabrosky. Of 716 P. truei captured, 22 (3.1%) were infested with a total of 25 Cuterebra larvae with all infestations occurring in the scapular region. Although P. truei were captured in all 5 habitats, they were only infested in the piñon-juniper habitat: the highest prevalence of infestation occurred during July-August (10.9%) versus May-June (3.3%). Prevalence of infestation was not significantly different between animals from mark-release webs versus removal webs, males versus females, or adults versus juveniles. As in the N. albigula, there was no correlation between relative density of P. truei and prevalence of infestation. The adult reared from a puparium was identified as C. neomexicana Sabrosky. Of the 310 P. leucopus captured, only 3 (1%) were infested with Cuterebra larvae.

Animals↗
PubMed1997

Phenotypic characterization of lymphocyte subpopulations in horses affected with chronic obstructive pulmonary disease and in normal controls.

The alterations in lymphocyte subsets in chronic obstructive pulmonary disease (COPD) in the horse were investigated by using monoclonal antibodies to identify CD3+, CD4+, CD8+, and surface immunoglobulin positive (sIg+) lymphocytes in peripheral blood, bronchoalveolar lavage fluid (BALF), and pulmonary biopsy frozen tissue sections. COPD-affected horses (n = 5) and normal controls (n = 5) were sampled prestabling and 14 days poststabling, at which time the COPD-affected horses wee exhibiting clinical signs of COPD. The peripheral blood absolute CD4+ lymphocyte count was significantly elevated in the COPD-affected horses pre- and poststabling. The CD4:CD8 ratio in peripheral blood of COPD-affect horses was unaffected by stabling, but the same ratio in the control horses was significantly decreased. These findings support a hypothesis of deficient regulation of a systemic immune response to indoor air in the COPD-affected horses. A large population of leukocytes in pulmonary biopsy immunohistochemical sections from both groups of horses appeared to be CD3+ CD4- CD8-, an uncommon phenotype in both the peripheral blood and BALF.

Animals↗
PubMed1997

Effect of treatment with erythromycin on bronchoalveolar lavage fluid cell populations in foals.

OBJECTIVE: To determine whether oral administration of erythromycin alters the inflammatory response to bronchoalveolar lavage (BAL) in young horses. ANIMALS: 12 healthy, unweaned, mixed-breed foals of either sex, between 2 and 4 months old. PROCEDURE: BAL was performed; 250 ml of phosphate-buffered saline solution (300 mOsm, pH 7.4) was administered in 50-ml aliquots. Foals were carefully monitored for 4 days, then erythromycin base (25 mg/kg of body weight, PO, q 12 h) was given to foals of the treated group. After 4 days, foals were reanesthetized, and the same lung was relavaged. Cytologic examination was performed on BAL fluid (BALF) samples from both groups of foals. At 12 hours after administration of the final dose, erythromycin A and anhydroerythromycin A concentrations were determined in plasma of treated foals. RESULTS: In the second BALF sample from the same lung of control foals, percentage of neutrophils was significantly increased (53 +/- 38.0%) [corrected], compared with that from erythromycin-treated foals (4.88 +/- 3.66%, P < 0.05), and was associated with apparent decrease in the ability of BALF cells from erythromycin-treated foals to migrate toward a chemoattractant source. Significantly fewer BALF cells adhered to a cell culture substratum after erythromycin treatment of foals. Erythromycin A was not detected in plasma of any treated foal at the time of the second BAL; anhydroerythromycin A, a degradation product of erythromycin, was detected in plasma of 5 of 6 foals (mean concentration, 0.2 +/- 0.06 micrograms/ml). CONCLUSION AND CLINICAL RELEVANCE: Bal induces neutrophilic inflammation, which persists for at least 4 days in the lungs of young horses. Erythromycin [corrected] (25 mg/kg, PO q 12 h) diminishes this inflammatory response through a mechanism that may involve alteration of BALF cell function. Degradation of erythromycin to biologically active products or presence of parent drug in pulmonary secretions may be responsible for alterations in pulmonary lavage cell chemotaxis and adherence. Erythromycin administered orally to foals at clinically relevant doses appears to have nonantimicrobial effects that may interfere with host cell metabolism and decrease inflammatory responses in airways.

Administration, Oral↗
PubMed1997

Analysis of the structure and folding of the 3' genomic RNA of flaviviruses.

The structure of the 3' genomic RNA of flaviviruses has been analyzed by thermal melting, and by chemical and enzymatic probing of model RNAs. The 3' RNA had more transitions than could be assigned to individual stem-loops and a transition in the 40-45 degrees C range was assigned to tertiary structure unfolding. In support of this assignment, mutants designed to destabilize the proposed pseudoknot tertiary structure lose the 40-45 degrees C transition. Enzyme cleavage of the RNA and chemical probing as a function of temperature also support a pseudoknot tertiary structure for the 3' flavivirus RNA.

Base Sequence↗
PubMed1996

Targeting the minor groove of DNA: crystal structures of two complexes between furan derivatives of berenil and the DNA dodecamer d(CGCGAATTCGCG)2.

Crystal structures are reported of complexes of two novel furan derivatives of berenil with alkyl benzamidine groups bound to the DNA sequence d(CGCGAATTCGCG)2. They have both been determined to 2.2 A resolution and refined to R factors of 16.9% and 18.6%. In both structures the alkyl substituents, cyclopropyl and isopropyl, are found to be orientated away from the floor of the minor groove. The drugs are located in the minor groove by two strong amidinium hydrogen bonds, to the O2 of the thymines situated at the 5' and 3' ends of the AT-rich region. The isopropyl-substituted derivative has a tight hydrogen-bonded water network in the minor groove at one amidine site, which alters the orientation of the isopropyl substituent. This compound has superior DNA-binding properties and activity against Pneumocystis carinii and Cryptosporidium parvum infections in vivo compared to the cyclopropyl derivative, which in turn is superior to the parent furan compound. We suggest that the nature and extent of the interactions of these compounds in the DNA minor groove play an important role in these activities, possibly in conjunction with a DNA-binding protein. The overall effect of these alkyl benzamidine substitutions is to increase the binding of the drugs to the minor groove.

Crystallography, X-Ray↗
PubMed1996

Inhibition of HIV-1 Rev-RRE interaction by diphenylfuran derivatives.

The interactions between RNA structures, such as RRE in the HIV-1 genome, and proteins, such as Rev of HIV-1, are essential for efficient viral replication. Compounds that bind specifically to such RNAs and disrupt their protein complexes offer a novel mechanism for inhibition of replication of the virus. As a step in this approach, we have designed and characterized a series of synthetic diphenylfuran cations that selectively inhibit Rev binding to RRE. Fluorescence titrations and gel band-shift results indicate that the diphenylfurans bind to RRE and inhibit Rev complex formation in a structure-dependent manner. The derivative with the greatest affinity for RRE has an association constant of greater than 10(7) M-1 and inhibits formation of the Rev--RRE complex at concentrations below 1 microM. It binds to RRE considerably more strongly than it binds to simple RNA duplexes. Spectral changes and energy transfer results on complex formation suggest that the compound has a nonclassical intercalation binding mode. CD studies with modified RRE hairpins indicate that the active diphenylfurans bind at the structured internal loop of RRE and cause a conformational change. The most active diphenylfurans are tetracations that appear to bind to RRE by a threading intercalation mode and cause a conformational change in the RNA that is essential for inhibition of Rev complex formation with RRE.

Amidines↗
PubMed1996

Synthesis and structure-DNA binding relationship analysis of DNA triple-helix specific intercalators.

4-[N-(Aminoalkyl)amino]-2-arylquinolines with conformational freedom around positions 2 and 4 of the quinoline stabilize strongly poly(dT.dA.dT) (triplex DNA) and bind weakly to poly-(dA.dT) (duplex DNA). Basicity of N1 of the quinoline parallels the interaction strength of these compounds with the triple-helical DNA structure suggesting that N1 of the quinoline is protonated in the complex with the DNA triplex. The experimental results support the interaction model suggested previously.

DNA↗
PubMed1996

Corynebacterium pseudotuberculosis infection in horses: 538 cases (1982-1993).

OBJECTIVE: To describe clinical manifestations of Corynebacterium pseudotuberculosis infection in horses and to evaluate diagnostic methods for identification of this disease. DESIGN: Retrospective case series. ANIMALS: 538 horses with a diagnosis of C pseudotuberculosis infection. RESULTS: Median age of horses with external abscesses was similar to that in horses with internal abscesses. Breed and sex did not appear to be associated with infection. Cases were detected during all 12 months; however, the disease was most common in the fall and early winter, with the highest incidence in September, October, and November in every year. Most horses (492/538, 91.4%) had a single episode of infection, without recurrence in subsequent years. Of 538 horses, 308 had pectoral abscesses, although infection was documented in many other anatomic locations. Forty-two horses had internal abscesses involving the abdomen or thoracic cavity. Corynebacterium pseudotuberculosis infection was readily identified by bacterial culture of aspirate samples from abscesses. The synergistic hemolysis inhibition test was useful for diagnosis of internal abscesses; however, it was unreliable for the diagnosis of external abscesses. Horses with external abscesses responded well to conventional treatment, in contrast to those with internal abscesses. The overall case fatality was low (3.9%), and was considerably lower for horses with external abscesses (0.8%) than for horses with internal abscesses (40.5%). CLINICAL IMPLICATIONS: Serology (synergistic hemolysis inhibition titers > or = 512) is useful for diagnosis of internal abscesses, but not reliable for diagnosis in horses with external abscesses. Prognosis for horses with internal abscesses is considerably poorer than for those with external abscesses.

Abscess↗
PubMed1996

A crystallographic and spectroscopic study of the complex between d(CGCGAATTCGCG)2 and 2,5-bis(4-guanylphenyl)furan, an analogue of berenil. Structural origins of enhanced DNA-binding affinity.

2,5-Bis(4-guanylphenyl)furan ("furamidine") is a dicationic minor groove binding drug that has been shown to be more effective than pentamidine against the Pneumocystis carinii pathogen in an immunosuppressed rat model. It has a close structural similarity to the antitrypanosomal drug berenil, differing only on the replacement of the central triazene unit with a furan moiety. we have determined the crystal structure of the complex between furamidine and the DNA dodecamer d(CGCGAATTCGCG)2 and compared it with the same DNA sequence by UV-visible, fluorescence, and CD spectroscopy. Furamidine shows tighter binding to this sequence (Keq = 6.7 x 10(6)) than berenil (Keq = 6.6 x 10(5)). The crystal structure reveals that, unlike berenil, furamidine makes direct hydrogen bond interactions with this DNA sequence through both amidinium groups to O2 atoms of thymine bases and is more isohelical with the minor groove. Molecular mechanics calculations support the hypothesis that these differences result in the improved interaction energy between the ligand and the DNA.

Amidines↗
PubMed1996

Evidence for the existence of a pseudoknot structure at the 3' terminus of the flavivirus genomic RNA.

The 3'-terminal nucleotides of the flavivirus genomic RNA form conserved secondary structures that may function as cis-acting signals for RNA replication. Here we provide evidence for the existence of a conserved pseudoknot structure at the 3' terminus of the flavivirus genomic RNA. A truncated version of the West Nile virus (WNV) 3'-terminal RNA sequence was used as the model for these studies. Circular dichroism spectra indicated the presence of a highly structured RNA conformation with a significant amount of A-form helix. Ribonuclease probing not only confirmed the presence of the predicted secondary structure, which consists of a long stem-loop (SL1) and a shorter stem-loop (SL2), but also suggested that base pairing occurs between nucleotides in the loop of SL2 and those in an internal loop strand located on the 5' side of SL1. Analysis of three mutant RNAs further supported the existence of pseudoknot interactions. UV-melting analysis of the WNV 3' model RNA showed three transitions with significant hyperchromicity at approximately 46, 62, and 79 degrees C. UV-melting analysis with either SL1 or SL2 RNA alone suggested that the 62 and 79 degree C transitions represent the unfolding of SL2 and SL1, respectively. The 46 degree C transition is most likely due to the opening of the proposed tertiary structure. A similar melting curve was obtained for another flavivirus (dengue-3 virus) 3'-terminal RNA, providing further support for the conservation of the structure among flaviviruses. Molecular modeling of the RNA indicated that a pseudoknot structure is a stereochemically and energetically reasonable model for the 3' terminus of flavivirus genomic RNA.

Base Sequence↗
PubMed1996

Synthesis and DNA interactions of benzimidazole dications which have activity against opportunistic infections.

Considerable evidence now indicates that DNA is the receptor site for dicationic benzimidazole anti-opportunistic infections agents (Bell, C.A.; Dykstra, C.C.; Naiman N.A.I.; Cory, M.; Fairley, T.A.; Tidwell, R.R. Antimicrob. Agents Chemother. 1993, 37, 2668-2673. Tidwell R.R.; Jones, S.K.; Naiman, N.A.; Berger, I.C.; Brake, W.R.; Dykstra, C.C.; Hall, J.E. Antimicrob. Agents Chemother. 1993, 37, 1713-1716). To obtain additional information on benzimidazole-receptor complexes, the syntheses and DNA interactions of series of symmetric benzimidazole cations, linked by alkyl or alkenyl groups, have been evaluated. Biophysical techniques, thermal denaturation measurement (deltaTm), kinetics, and circular dichroism (CD) have been used in conjunction with NMR and molecular modeling to evaluate the affinities, binding mode, and structure of complexes formed between these compounds and DNA. All the compounds bind strongly to DNA samples with four or more consecutive AT base pairs, and they bind negligibly to GC rich DNA or to RNA. Spectral and kinetics characteristics of the benzimidazole complexes indicate that the compounds bind in the DNA minor groove at AT sequences. NMR and molecular modeling of the complex formed between an ethylene-linked benzimidazole derivative, 5, and the self-complementary oligomer d(GCGAATTCGC) have been used to establish structural details for the minor groove complex. These results have been used as a starting point for molecular mechanics calculations to refine the model of the minor groove-benzimidazole complex and to draw conclusions regarding the molecular basis for the effects of substituent changes on benzimidazole-DNA affinities.

AIDS-Related Opportunistic Infections↗
PubMed1996

An oligodeoxyribonucleotide N3'--> P5' phosphoramidate duplex forms an A-type helix in solution.

The solution conformations of the dinucleotide d(TT) and the modified duplex d(CGCGAATTCGCG)2 with N3'--> P5' phosphoramidate internucleoside linkages have been studied using circular dichroism (CD) and NMR spectroscopy. The CD spectra indicate that the duplex conformation is similar to that of isosequential phosphodiester RNA, a A-type helix, and is different from that of DNA, a B-type helix, NMR studies of model dimers d(TpT) and N3'--> P5' phosphoramidate d(TnpT) show that the sugar ring conformation changes from predominantly C2'-endo to C3'-endo when the 3'-phosphoester is replaced by a phosphoramidate group. Two-dimensional NMR (NOESY, DQF-COSY and TOCSY spectra) studies of the duplex provide additional details about the A-type duplex conformation of the oligonucleotide phosphoramidate and confirm that all furanose rings of 3'-aminonucleotides adopt predominantly N-type sugar puckering.

Base Sequence↗
PubMed1996

Surgical treatment for colic in the foal (67 cases): 1980-1992.

Sixty-seven foals age < 150 days underwent a ventral celiotomy for colic. Of the 67 foals, 51 foals (82%) recovered from anaesthesia and 42 (63%) were subsequently released from the hospital. Three (6%) of the 51 foals were subjected to a repeat celiotomy. Long term follow-up was available on 36 foals. Twenty-nine (57%) of the 51 foals recovered from anaesthesia, were alive at least 2 years following surgery. Adhesions were identified in 8 (17%) of the foals which recovered from general anaesthesia but were subsequently subjected to euthanasia due to recurrent colic. Strangulating lesions were associated with a lower survival rate. Nineteen per cent of foals with strangulating intestinal lesions survived > 2 years following surgery, compared to 69% of foals with nonstrangulating lesions. The age of foals on admission had a significant effect on survival. Only 10% of foals less than 14 days of age survived, compared to 45.8% of foals between age 15 and 150 days.

Aging↗