Search PubMed⌕ Search

Biomedical subjects

D Hogan

Publications and source records attributed to D Hogan.

At least 19 recordsLinked to original sources
PubMed1999

Asymmetric connections, duplicate layers, and a vertically inverted map in the primary visual system.

The achiasmatic mutation is a remarkable and rare visual system mutation carried in a line of black sheepdogs. In affected animals, the optic chiasm is missing, and each retina projects entirely to the ipsilateral hemisphere. As a result of this navigational error, maps of visual space in the lateral geniculate nucleus (LGN) have a unique structure with mirror reversals of field position across the A-A1 border. Animals also have a persistent and severe congenital nystagmus. In this report we analyze a novel variant of the achiasmatic mutation, one in which retinal axons from only one eye successfully cross midline and in which the great majority of fibers from both eyes terminate in a single lateral geniculate nucleus. The dominant optic tract contains four times as many axons as the other tract. The hyperinnervated LGN has a lamination pattern consisting of duplicate and partly interwoven layers. A multiunit mapping study of visual cortex (primarily area 17 along the marginal gyrus) shows that receptive field topography and orientation selectivity are normal. The size of central binocular visual space is nearly normal and is flanked by monocular domains in the periphery. However, there is an inexplicable vertical inversion in the orientation of the cortical representation: superior fields are located rostrally, and inferior fields are located caudally. Despite a host of drastic abnormalities at all level of the visual system, from retina to cortex, this animal was behaviorally indistinguishable from normal dogs and did not have any detectable oculomotor abnormalities.

Animals↗
PubMed1999

Homologue scanning mutagenesis reveals CD66 receptor residues required for neisserial Opa protein binding.

The immunoglobulin-like family of CD66 antigens, present on human neutrophils and epithelial cells, are used as receptors for adhesins expressed by the pathogenic Neisseriae. N. gonorrhoeae strain MS11 can express 11 isoforms of these adhesins, called opacity-related (Opa) proteins. Each MS11 Opa protein recognizes a distinct spectrum of CD66 receptors. CD66-Opa binding is mediated by the NH(2)-terminal domain of the receptor and occurs through protein-protein interactions. In this report, we have investigated the molecular basis for the binding between the CD66 and Opa protein families by mapping amino acids in CD66 receptors that determine Opa protein binding. We performed homologue scanning mutagenesis between CD66e, which binds multiple Opa variants, and CD66b, which binds none, and tested both loss-of-function by CD66e and gain-of-function by CD66b in solution assays and in assays involving full-length receptors expressed by epithelial cells. We found that three residues in the CD66e N-domain are required for maximal Opa protein receptor activity. Opa proteins that recognize the same spectrum of native CD66 molecules showed differential binding of receptors with submaximal activity, indicating that the binding characteristics of these Opa proteins are actually slightly different. These data provide a first step toward resolving the structural requirements for Opa-CD66 interaction.

Amino Acid Sequence↗
PubMed1998

CD66 receptor specificity exhibited by neisserial Opa variants is controlled by protein determinants in CD66 N-domains.

Neisseria gonorrhoeae strain MS11 is able to express 11 different opacity (Opa) proteins on its outer surface. A number of these Opa proteins have been shown to function as adhesins through binding of CD66 receptors present on human cells. CD66 antigens, or carcinoembryonic antigen family members, constitute a family of glycoproteins belonging to the immunoglobulin superfamily. Opa variants recognize this class of receptors in a differential manner such that certain Opa variants recognize up to four different CD66 receptors (CD66a, -c, -d, and -e), whereas others recognize only two (CD66a and -e) or none. We explored the basis for this receptor tropism in the present study. Our data show that glycoforms of CD66e and deglycosylated CD66e are recognized by gonococci in an Opa-specific manner. Binding by Opa variants of recombinant N-terminal domains of CD66 receptors expressed in Escherichia coli reflected the adherence specificities of Opa variants to HeLa cells expressing native CD66 molecules. These data indicate that recognition of CD66 receptors by Opa variants is mediated by the protein backbone of the CD66 N-domains. Furthermore, by using chimeric constructs between different CD66 N-domains we identified distinct binding regions on the CD66e N-domain for specific groups of Opa variants, suggesting that the differential recognition of CD66 receptors by Opa variants is dictated by the presence of specific binding regions on the N-domain of the receptor.

Amino Acid Sequence↗
PubMed1998

Inhibition of rabbit duodenal bicarbonate secretion by ulcerogenic agents: histamine-dependent and -independent effects.

BACKGROUND & AIMS: The gastroduodenal epithelium is protected from acid-peptic damage, in part, by its ability to secrete bicarbonate. Patients with duodenal ulcer disease have impaired proximal duodenal mucosal bicarbonate secretion. We have shown in vitro that histamine inhibits prostaglandin-stimulated bicarbonate secretion in rabbit duodenal mucosa via histamine H2 receptors and enteric nerves. In this study we examined whether the proulcerogenic compounds aspirin or ethanol regulate duodenal bicarbonate secretion and the involvement of histamine. METHODS: Bicarbonate secretion by rabbit proximal duodenal mucosa was examined in vitro in Ussing chambers. RESULTS: Aspirin and ethanol decreased basal and prostaglandin-stimulated bicarbonate secretion; the latter effect was specific for prostaglandin. The inhibitory effects of the two ulcerogenic compounds were at least additive. Ranitidine and tetrodotoxin abolished the inhibitory effects on stimulated, but not basal, secretion. Aspirin and ethanol also induced release of duodenal histamine. CONCLUSIONS: Aspirin and ethanol act by two distinct pathways to impair duodenal bicarbonate secretion. Both agents inhibit basal secretion via a histamine-independent and neurally independent pathway while they inhibit prostaglandin E2-stimulated secretion via histamine release, likely from mast cells, and actions on enteric nerves. Our findings may be of relevance to the understanding and potential treatment of nonsteroidal anti-inflammatory drug-associated mucosal injury.

Animals↗
PubMed1997

Presence and treatment of vascular risk factors in patients with vascular cognitive impairment.

OBJECTIVE: To document the presence and treatment of selected vascular risk factors in patients with vascular cognitive impairment and elements affecting undertreatment of vascular risk factors. DESIGN: Secondary analysis of the Canadian Study of Health and Aging database, which is a national, representative, cross-sectional study of the epidemiologic distribution of dementia in elderly people in Canada. SETTING: Survey. PATIENTS: Institutionalized and community-dwelling elderly people. MAIN OUTCOME MEASURES: Vascular risk factors, dementia diagnosed by standard methods, and medication use. RESULTS: Treatable vascular risk factors occurred significantly more often in patients with vascular cognitive impairment (with and without dementia) than in patients with probable Alzheimer disease or normal cognitive function. For example, 76% of patients with vascular dementia and 57% of those with vascular cognitive impairment without dementia had a history of stroke, compared with only 5% of those with probable Alzheimer disease and 7% of those with no cognitive loss. (For hypertension, the comparable figures are 55%, 48%, 24%, and 38%, respectively.) Potential undertreatment of vascular risk factors had little effect on mean control of vascular risk factors. For example, the mean (+/- SD) systolic blood pressure in those being treated was 144 +/- 26 mm Hg, compared with 142 +/- 25 mm Hg in those not receiving pharmacological treatment. In each group (treated vs untreated), the proportion of patients with a systolic blood pressure higher than 160 mm Hg was 20% and 16%, respectively. Potential undertreatment occurred most often in those with severe dementia and those living in nursing homes. CONCLUSIONS: Vascular risk factors occurred more commonly in patients with vascular cognitive impairment compared with other patients, including those with other forms of dementia. When present, such risk factors were often treated pharmacologically, except in patients with severe dementia and those in long-term care institutions. Undertreatment does not, in general, result in worsened risk factor control.

Aged↗
PubMed1997

Integration host factor is a transcriptional cofactor of pilE in Neisseria gonorrhoeae.

Integration host factor (IHF) is a small, heterodimeric DNA-binding protein with pleiotropic function. IHF was purified to apparent homogeneity from Neisseria gonorrhoeae. Gel-retardation assays demonstrated binding of IHF to the pilE promoter region. The IHF-binding site was identified by DNase I protection assays and mapped proximal to three previously defined pilE promoters. Removal of the putative IHF-binding domain from pilE promoter DNA negated retardation of the DNA fragment when assessed by gel-shift analysis. Kleinschmidt electron microscopy showed pronounced kinking of pilE promoter DNA following incubation with IHF. Isogenic N. gonorrhoeae strains were constructed that contained either a wild-type pilE locus or a deleted pilE locus where the IHF-binding domain was removed. Primer-extension analysis and Northern blotting of total gonococcal RNA showed that in the absence of IHF binding at the pilE promoter, transcription was reduced 10-fold. Together, these data indicate that IHF is a transcriptional co-activator of pilE.

Bacterial Proteins↗
PubMed1997

The Borrelia burgdorferi circular plasmid cp26: conservation of plasmid structure and targeted inactivation of the ospC gene.

The 26 to 28kb circular plasmid of B. burgdorferi sensu lato (cp26) is ubiquitous among bacteria of this group and contains loci implicated in the mouse-tick transmission cycle. Restriction mapping and Southern hybridization indicated that the structure of cp26 is conserved among isolates from different origins and culture passage histories. The cp26 ospC gene encodes an outer surface protein whose synthesis within infected ticks increases when the ticks feed, and whose synthesis in culture increases after a temperature upshift. Previous studies of ospC coding sequences showed them to have stretches of sequence apparently derived from the ospC genes of distantly related isolates by homologous recombination after DNA transfer. We found conservation of the promoter regions of the ospC and guaA genes, which are divergently transcribed. We also demonstrated that the increase in OspC protein after a temperature upshift parallels increases in mRNA levels, as expected if regulatory regions adjoin the conserved sequences in the promoter regions. Finally, we used directed insertion to inactivate the ospC gene of a non-infectious isolate. This first example of directed gene inactivation in B. burgdorferi shows that the OspC protein is not required for stable maintenance of cp26 or growth in culture.

Antigens, Bacterial↗
PubMed1997

Selection of Opa+ Neisseria gonorrhoeae by limited availability of normal human serum.

Experimental infections of human male volunteers with Neisseria gonorrhoeae have provided valuable insights into the early stages of gonorrheal disease. Bacterial variants expressing outer membrane opacity (Opa) proteins appear to be selected from the inoculum during a period in which total recoverable numbers of bacteria decrease rapidly. This apparent survival advantage occurs simultaneously with the onset of an inflammatory response, characterized by local production of interleukin 6 (IL-6) and IL-8 and the appearance of leukocytes in urine. Since the inflammatory response may also result in the presence of serum factors on the mucosal surface, we investigated the possibility that killing in normal human serum (NHS) leads to the selection of Opa+ variants. We therefore studied killing of separate populations and mixtures of Opa- and Opa+ N. gonorrhoeae MS11mk in NHS. Expression of an Opa protein conferred a survival advantage upon the organism; i.e., the Opa+ variants were more serum resistant than their isogenic Opa- counterparts, resulting in a selection for Opa+ phenotypes when a mixture of Opa+ and Opa- gonococci (GC) was exposed to submaximal doses of NHS. This selection was observed in three different lipooligosaccharide (LOS) backgrounds, indicating that it was not due to a difference in LOS expression between Opa- and Opa+ phenotypes. Incubation in NHS of sialylated GC resulted in a similar selection for Opa+ variants. The presence of normal human urine during the serum killing assay had no effect on the selection phenomenon but drastically depleted NHS of bactericidal activity, which was found to be at least partly due to complement inhibition. The results suggest that serum killing may contribute to the transition from Opa- to Opa+ phenotypes during the early stages of infection of the male urethra.

Antigens, Bacterial↗
PubMed1996

Physical injuries and fatalities resulting from the Oklahoma City bombing.

OBJECTIVE: To provide an epidemiologic description of physical injuries and fatalities resulting from the April 19, 1995, bombing of the Alfred P. Murrah Federal Building in Oklahoma City. DESIGN AND SETTING: Descriptive epidemiologic study of all persons injured by the bombing and of all at-risk occupants of the federal building and 4 adjacent buildings. Data were gathered from hospital emergency and medical records departments, medical examiner records, and surveys of area physicians, building occupants, and survivors. STUDY POPULATION: All persons known to have been exposed to the blast. MAIN OUTCOME MEASURES: Characteristics of fatalities and injuries, injury maps, and injury rates by building location. RESULTS: A total of 759 persons sustained injuries, 167 persons died, 83 survivors were hospitalized, and 509 persons were treated as outpatients. Of the 361 persons who were in the federal building, 319 (88%) were injured, of whom 163 (45%) died, including 19 children. Persons in the collapsed part of the federal building were significantly more likely to die (153/175, 87%) than those in other parts of the building (10/186, 5%) (risk ratio [RR], 16.3; 95% confidence interval [CI], 8.9-29.8). In 4 adjacent buildings, injury rates varied from 38% to 100%; 3 persons in these buildings and 1 person in an outdoor location died. The most frequent cause of death was multiple injuries. Among survivors, soft tissue injuries, fractures, sprains, strains, and head injuries were most common; these injuries were most often caused by flying glass and other debris and collapsed ceilings. CONCLUSIONS: The Oklahoma City bombing resulted in the largest number of fatalities of any terrorist act in the United States, and there were 4 times as many nonfatal injuries as fatalities. Disaster management plans should include the possibility of terrorist bombing, and medical preparedness should anticipate that most injuries will be nonfatal. The role of building collapse in fatal injuries should be considered in the design of buildings at high risk of being bombed so as to reduce injuries.

Cause of Death↗
PubMed1996

Evaluation of a self-medication program.

OBJECTIVE: To determine the effect of an inpatient self-medication program (SMP) on the ability to self-medicate, patient medication knowledge, compliance, and patient morale. DESIGN: Randomized controlled clinical trial. POPULATION: One hundred seven consecutive patients admitted to a geriatric assessment and rehabilitation program were randomized to either participate in the SMP or to receive standard care. INTERVENTION: The SMP was a three-stage program in which patients were given increasing responsibility for the administration of their own medications. MEASUREMENTS: Ability to self-medicate on discharge from hospital; medication compliance at 1 month; patient medication knowledge; Philadelphia Morale Scale. MAIN RESULTS: Participation in the self-medication program did not increase the proportion of patients who were able to self-medicate on discharge from hospital. Compliance was improved by the program. On a proportional basis, the self-medication group made significantly fewer medication errors than the control group at 1-month follow-up (0.045 vs 0.086, P < .001). There were no significant differences in morale or medication knowledge between the SMP and control groups, although both groups made significant gains in knowledge about the names, administration times, and purposes of their medications from admission to follow-up (P < .001). CONCLUSIONS: A SMP can improve compliance in geriatric patients who are discharged to the community. Participation in a SMP does not improve patients' morale nor does it improve their medication knowledge more than pharmacy counselling alone. Participation in a SMP is unlikely to increase the probability that patients will be able to self-medicate on discharge. Cognitive factors limit patients' ability to self-medicate.

Aged↗
PubMed1996

Directed insertion of a selectable marker into a circular plasmid of Borrelia burgdorferi.

Studies of the biology of Borrelia burgdorferi and the pathogenesis of Lyme disease are severely limited by the current lack of genetic tools. As an initial step toward facile genetic manipulation of this pathogenic spirochete, we have investigated gene inactivation by allelic exchange using a mutated borrelial gyrB gene that confers resistance to the antibiotic coumermycin A1 as a selectable marker. We have transformed B. burgdorferi by electroporation with a linear fragment of DNA in which this selectable marker was flanked by sequences from a native borrelial 26-kb circular plasmid. We have identified coumermycin A1-resistant transformants in which gyrB had interrupted the targeted site on the 26-kb plasmid via homologous recombination with the flanking sequences. Antibiotic resistance conferred by the mutated gyrB gene on the plasmid is dominant, and transformed spirochetes carrying this plasmid do not contain any unaltered copies of the plasmid. Coumermycin A1 resistance can be transferred to naive B. burgdorferi by transformation with borrelial plasmid DNA from the initial transformants. This work represents the first example of a directed mutation in B. burgdorferi whereby a large segment of heterologous DNA (gyrB) has been inserted via homologous recombination with flanking sequences, thus demonstrating the feasibility of specific gene inactivation by allelic exchange.

Alleles↗
PubMed1996

The relationship between capsid protein (VP2) sequence and pathogenicity of Aleutian mink disease parvovirus (ADV): a possible role for raccoons in the transmission of ADV infections.

Aleutian mink disease parvovirus (ADV) DNA was identified by PCR in samples from mink and raccoons on commercial ranches during an outbreak of Aleutian disease (AD). Comparison of DNA sequences of the hypervariable portion of VP2, the major capsid protein of ADV, indicated that both mink and raccoons were infected by a new isolate of ADV, designated ADV-TR. Because the capsid proteins of other parvoviruses play a prominent role in the determination of viral pathogenicity and host range, we decided to examine the relationship between the capsid protein sequences and pathogenicity of ADV. Comparison of the ADV-TR hypervariable region sequence with sequences of other isolates of ADV revealed that ADV-TR was 94 to 100% related to the nonpathogenic type 1 ADV-G at both the DNA and amino acid levels but less than 90% related to other pathogenic ADVs like the type 2 ADV-Utah, the type 3 ADV-ZK8, or ADV-Pullman. This finding indicated that a virus with a type 1 hypervariable region could be pathogenic. To perform a more comprehensive analysis, the complete VP2 sequence of ADV-TR was obtained and compared with that of the 647-amino-acid VP2 of ADV-G and the corresponding VP2 sequences of the pathogenic ADV-Utah, ADV-Pullman, and ADV-ZK8. Although the hypervariable region amino acid sequence of ADV-TR was identical to that of ADV-G, there were 12 amino acid differences between ADV-G and ADV-TR. Each of these differences was at a position where other pathogenic isolates also differed from ADV-G. Thus, although ADV-TR had the hypervariable sequence of the nonpathogenic type 1 ADV-G, the remainder of the VP2 sequence resembled sequences of other pathogenic ADVs. Under experimental conditions, ADV-TR and ADV-Utah were highly pathogenic and induced typical AD in trios of both Aleutian and non-Aleutian mink, whereas ADV-Pullman was pathogenic only for Aleutian mink and ADV-G was noninfectious. Trios of raccoons experimentally inoculated with ADV-TR and ADV-Utah all became infected with ADV, but only a single ADV-Pullman-inoculated raccoon showed evidence of infection. Furthermore, none of the ADV isolates induced pathological findings of AD in raccoons. Finally, when a preparation of ADV-TR prepared from infected raccoon lymph nodes was inoculated into mink and raccoons, typical AD was induced in Aleutian and non-Aleutian mink, but raccoons failed to show serological or pathological evidence of infection. These results indicated that raccoons can become infected with ADV and may have a role in the transmission of virus to mink but that raccoon-to-raccoon transmission of ADV is unlikely.

Aleutian Mink Disease↗
PubMed1995

Analysis of the retinas and optic nerves of achiasmatic Belgian sheepdogs.

An autosomal recessive mutation carried in a family of black Belgian sheepdogs eliminates the optic chiasm--all retinal ganglion cell axons extend directly into the ipsilateral optic tract. One key issue we are trying to resolve is whether the retina or the chiasm is the principal site of mutant gene action. In this study, we have examined retinas of mutants to discover any associated changes in retinal structure. Retinas of mutant animals are relatively normal. Inner and outer nuclear layers are qualitatively indistinguishable from those of normal dogs. The principal difference is that the area centralis of mutants is smaller and had a lower peak ganglion cell density than that of normal dogs (8,100 vs 10,500/mm2, P < 0.05). This mutant phenotype is similar to that seen in retinas of Siamese cats and albino ferrets. Beyond area centralis, the central-to-peripheral gradient in ganglion cell density is normal in mutants. The size of the optic nerves, density of axons, and total number of axons do not differ between mutant and normal dogs. One of three mutant dogs had a small abnormal optic chiasm. Retrograde labeling of ganglion cells demonstrated that the residual crossed projection originated from cells in a widespread region in nasal retina and not solely from the peripheral nasal region, as might be expected of an anti-albino. Although our analysis does not rule out the retina as a site of mutant gene action, the modest differences between mutant and normal retinas suggest that the mutation either acts outside the retina or exerts a highly specific effect on ganglion cell trajectories alone.

Animals↗
PubMed1995

A comparison of diagnosis, evaluation, and treatment of patients with dermatologic disorders.

BACKGROUND: Managed care in the American health care system may limit access to health care specialists. OBJECTIVE: We assessed primary care providers' abilities at diagnosing and treating patients with a previously undiagnosed skin disorder. METHODS: Patients with previously undiagnosed skin disorders were seen and examined sequentially by three groups of physicians: (1) internal medicine residents, (2) board-certified internal medicine attending physicians and (3) dermatology faculty. The internal medicine residents and attending physicians' diagnoses were compared with the dermatologists'. Appropriateness of therapy ordered by the internal medicine residents and attending physicians was assessed. RESULTS: Medical residents' diagnoses were correct in 43% of the patients whereas the attending physicians diagnosed 52% of cases correctly. Attending physicians and residents frequently ordered therapy inappropriate for the patient's diagnosis. Internal medicine residents and attending physicians were more likely to order skin biopsies than dermatologists. CONCLUSIONS: Our results confirm earlier studies that nondermatologists perform poorly in the diagnosis and treatment of skin disease. Primary care providers should receive more training in dermatology, or dermatologists should be permitted to act as primary caregivers to patients with skin disease.

Adult↗
PubMed1994

Homology between Borrelia burgdorferi OspC and members of the family of Borrelia hermsii variable major proteins.

Synthesis of the Borrelia burgdorferi outer surface protein C (OspC) is quite variable. We have cloned and sequenced the ospC gene from B. burgdorferi isolate CA-11.2A, a clone in which ospC expression varies. The 5' flanking region of the gene contains at least two consensus promoter regions, as well as two large overlapping inverted repeats. Sequence comparison to other OspC proteins indicated that the CA-11.2A OspC is as closely related to OspC from two different genospecies of Lyme disease spirochetes as it is to OspC from the prototype B. burgdorferi strain, B31. Comparisons of the OspC amino acid (aa) sequence with those in aa sequence databases revealed partial identity with the variable major proteins Vmp3 and Vmp24 of B. hermsii, a causative agent of tick-borne relapsing fever. An ospC probe hybridized to B. hermsii restriction fragments and linear plasmids that also were recognized by the vmp3 and vmp24 probes. OspC and these Vmp appear to be related, but their synthesis is regulated differently in the two species of spirochetes. This represents a fascinating example of the evolution of the number, position, regulation and perhaps function of homologous genes in two related pathogens. These parameters may relate to characteristic properties of the pathogens and their separate tick vectors.

Amino Acid Sequence↗
PubMed1994

Target recognition and visual maps in the thalamus of achiasmatic dogs.

Vision is dependent on ordered neuronal representations or maps of visual space. These maps depend on precise connections between retinal axons and their targets cells. In mammals, nerve fibres from right and left eyes produce congruent maps of contralateral visual space in adjacent layers of the lateral geniculate nucleus (LGN). We have identified an autosomal recessive mutation in Belgian sheepdogs that eliminates the optic chiasm. In these mutants, all retinal axons project into the ipsilateral optic tract, including those originating in the nasal hemiretina that normally cross midline. These animals exhibit a pronounced horizontal nystagmus. The abnormal ipsilaterally directed nasal fibres innervate the LGN as if they had successfully crossed the midline, terminating in the appropriate layer of the nucleus. As a consequence, the LGN contains non-congruent, mirror-image maps of visual space in adjacent layers. These results show that there is a robust affinity between nasal and temporal retinal axons and specific LGN layers even when all retinal axons originate from a single eye.

Animals↗