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Biomedical subjects

C A Hughes

Publications and source records attributed to C A Hughes.

At least 19 recordsLinked to original sources
PubMed1996

Adducin regulation. Definition of the calmodulin-binding domain and sites of phosphorylation by protein kinases A and C.

Adducin promotes association of spectrin with actin and caps the fast growing end of actin filaments. Adducin contains N-terminal core, neck, and C-terminal tail domains, is a substrate for protein kinases A (PKA) and C (PKC), and binds to Ca2+/calmodulin. Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. PKA, in addition, phosphorylated alpha-adducin at Ser-408, -436, and -481 in the neck domain. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin. The myristoylated alanine-rich protein kinase C substrate-related domain of beta-adducin was identified as the dominant Ca2+-dependent calmodulin-binding site. Calmodulin-binding was inhibited by phosphorylation of beta-adducin and of a MARCKS-related domain peptide by PKA and PKC. Calmodulin in turn inhibited the rate, but not the extent, of phosphorylation of beta-adducin, but not alpha-adducin, by PKA and that of each subunit by PKC. These findings suggest a complex reciprocal relationship between regulation of adducin function by calmodulin binding and phosphorylation by PKA and PKC.

Amino Acid Sequence↗
PubMed1996

A new function for adducin. Calcium/calmodulin-regulated capping of the barbed ends of actin filaments.

Adducin is a membrane skeleton protein originally described in human erythrocytes that promotes the binding of spectrin to actin and also binds directly to actin and bundles actin filaments. Adducin is associated with regions of cell-cell contact in nonerythroid cells, where it is believed to play a role in regulating the assembly of the spectrin-actin membrane skeleton. In this study we demonstrate a novel function for adducin; it completely blocks elongation and depolymerization at the barbed (fast growing) ends of actin filaments, thus functioning as a barbed end capping protein (Kcap approximately 100 nM). This barbed end capping activity requires the intact adducin molecule and is not provided by the NH2-terminal globular head domains alone nor by the COOH-terminal extended tail domains, which were previously shown to contain the spectrin-actin binding, calmodulin binding, and phosphorylation sites. A novel difference between adducin and other previously described capping proteins is that it is down-regulated by calmodulin in the presence of calcium. The association of stoichiometric amounts of adducin with the short erythrocyte actin filaments in the membrane skeleton indicates that adducin could be the functional barbed end capper in erythrocytes and play a role in restricting actin filament length. Our experiments also suggest novel possibilities for calcium regulation of actin filament assembly by adducin in erythrocytes and at cell-cell contact sites in nonerythroid cells.

Actin Cytoskeleton↗
PubMed1996

Ganglioside-induced adherence of botulinum and tetanus neurotoxins to adducin.

Preincubation of botulinum neurotoxin serotype A, B, or E with ganglioside GT1b was previously found to enhance adherence of botulinum neurotoxin to synapsin I and an approximately 116-kDa bovine brain synaptosomal protein; in contrast, adherence to these two proteins by tetanus neurotoxin required preincubation with GT1b. We have now found that preincubation of the neurotoxins with ganglioside GD3 enhances their adherence to the approximately 116-kDa protein more than that with GT1b. A purified preparation of the water-soluble approximately 116-kDa protein was obtained from bovine brain synaptosomes by preparative column sodium dodecyl sulfate-polyacrylamide gel electrophoresis and two-dimensional gel electrophoresis. N-Terminal amino acid sequences were obtained for two tryptic fragments of the approximately 116-kDa protein. These sequences matched with the data bank sequences for beta-adducin, a cytoskeletal protein. The carboxy-terminal tail region of adducin, but not the head region, was adhered to by the neurotoxins. Adherence of the neurotoxin to adducin and synapsin I may facilitate presentation of the neurotoxin to its specific substrate(s).

Amino Acid Sequence↗
PubMed1996

Pediatric neurotologic skull base surgery.

The objectives of neurotologic skull base surgery are complete resection of the lesion and high-grade function following surgery. There is a perception that these goals are more difficult to achieve in children than in adults. Skull base disease in children and adolescents is rare. Of the 292 skull base tumors treated from 1970 to 1995 by The Otology Group in Nashville, 15 were in patients 21 years of age or younger, with only 5 patients under 10 years old. In this retrospective study, the authors review these 15 cases and compare them to their adult series. The pathology encountered in the 15 young patients with skull base tumors included 8 glomus lesions and 4 schwannomas. In these patients, 13 tumors occurred sporadically, and 2 tumors were related to neurofibromatosis type 2. Advanced-stage disease and malignancy were prevalent in this younger patient group. All patients underwent excision of their skull base tumor, with one procedure considered a subtotal resection. As compared with an adult glomus tumor series, postoperative cranial nerve function and complication rates were generally worse in the young glomus patients. However, postoperative function and complications were consistent with the extensive procedures required for the treatment of advanced disease. Despite the advances that have been made in imaging and treatment modalities, this study illustrates the need for more timely diagnosis in younger patients with skull base tumors.

Adolescent↗
PubMed1996

Molecular and evolutionary analyses of a variable series of genes in Borrelia burgdorferi that are related to ospE and ospF, constitute a gene family, and share a common upstream homology box.

In this study we report on the molecular characterization of a series of genes that constitute a gene family related to ospE and ospF. Some members of this family appear to represent recombined or variant forms of ospE and ospF. Variant ospE and ospF genes were found in several Borrelia burgdorferi isolates, demonstrating that their occurrence is not a phenomenon relevant to only a single isolate. Hybridization analyses revealed that the upstream sequence originally identified 5' of the full-length ospEF operon exists in multiple copies ranging in number from two to six depending on the isolate. This repeated sequence, which we refer to as the upstream homology box (UHB), carries a putative promoter element. In some isolates, UHB elements were found to flank copies of ospE and ospF that exist independently of each other. We refer to this group of UHB-flanked genes collectively as the UHB gene family. The evolutionary relationships among UHB gene family members were assessed through DNA sequence analysis and gene tree construction. These analyses suggest that some UHB-flanked genes might actually represent divergent forms of other previously described genes. Analysis of the restriction fragment length polymorphism patterns of the UHB-flanked genes among B. burgdorferi isolates demonstrated that these patterns are highly variable among isolates, suggesting that these genes are not phylogenetically conserved. The variable restriction fragment length polymorphism patterns could indicate recombinational activity in these sequences. The presence of numerous copies of the UHB elements and the high degree of homology among UHB-flanked genes could provide the necessary elements to allow for homologous recombination, leading to the generation of recombination variants of UHB gene family members.

Amino Acid Sequence↗
PubMed1996

Pediatric tracheobronchial foreign bodies: historical review from the Johns Hopkins Hospital.

We investigated changing trends in pediatric tracheobronchial foreign body removal and resident experience from 1939 to 1991. We retrieved the records of 234 cases of tracheobronchial foreign body removal at Johns Hopkins. The mean number of cases per year was 5.9. The most common foreign bodies removed were peanuts, accounting for 38.9%. The average yearly incidence of pediatric tracheobronchial foreign bodies remained relatively constant during the period studied. Our data suggested little change in outcome or complications with the advent of optical telescopes in the mid-1970s, despite their great value in improved visualization. Resident experience and training were evaluated by the number of cases attended by each resident during his or her training. The number varied from 1 to 8 cases, not including experience acquired at our sister institutions. Although complete data could not be obtained in many of the older medical records, our review suggests that despite the advantage offered by the optical forceps technology, proper training and experience in traditional rigid endoscopic techniques is still crucial to optimize outcome and minimize the risk of complications in pediatric tracheobronchial foreign body removal. Chevalier Jackson's recommendation that residency training include an animal laboratory course in foreign body removal still applies.

Adolescent↗
PubMed1995

Adducin: a physical model with implications for function in assembly of spectrin-actin complexes.

Adducin binds to spectrin-actin complexes, promotes association of spectrin with actin, and is subject to regulation by calmodulin as well as protein kinases A and C. Adducin is a heteromer comprised of homologous alpha and beta-subunits with an NH2-terminal protease-resistant head domain, connected by a neck region to a COOH-terminal hydrophilic, protease-sensitive region. This study provides evidence that adducin in solution is a mixture of heterodimers and tetramers. CD spectroscopy of COOH-terminal domains of alpha- and beta-adducin bacterial recombinants provides direct evidence for an unstructured random coil configuration. Cross-linking, proteolysis, and blot-binding experiments suggest a model for the adducin tetramer in which four head domains contact one another to form a globular core with extended interacting alpha- and beta-adducin tails. The site for binding to spectrin-actin complexes on adducin was identified as the COOH-terminal tail of both the alpha- and beta-adducin subunits. The capacity of native adducin to recruit spectrin to actin filaments is similar to that of adducin tail domains. Thus, adducin tail domains alone are sufficient to interact with F-actin and a single spectrin and to recruit additional spectrin molecules to the ternary complex.

Actins↗
PubMed1995

Eosinophilia in chronic childhood sinusitis.

OBJECTIVES: To quantify eosinophilia in sinus tissues obtained from children with chronic sinusitis and to correlate the degree of eosinophilia with history of asthma, allergy, cystic fibrosis, and preoperative computed tomographic (CT) scans. DESIGN: Examination of surgical specimens from children who underwent functional endoscopic sinus surgery and controls. SETTING: Tertiary care medical center. PATIENTS: Thirty-four children who underwent functional endoscopic sinus surgery for chronic sinusitis refractory to medical treatment were divided into three groups: 13 with asthma, 11 without asthma, and 10 with cystic fibrosis. Normal sphenoid sinus mucosa was also obtained from six adults undergoing transsphenoidal hypophysectomies. MAIN OUTCOME MEASURES: Number of lamina propria and intraepithelial eosinophils in surgical specimens, allergic status, presence or absence of asthma, and CT scans obtained preoperatively. RESULTS: There were significantly more lamina propria and intraepithelial eosinophils in the tissue of children with chronic sinusitis compared with normal sphenoid sinus mucosa. More eosinophils were counted in the tissues of patients with asthma and cystic fibrosis compared with patients without concomitant disease, but this did not reach statistical significance. Allergy status did not affect the degree of tissue eosinophilia. Eosinophilia did not correlate with severity of mucosal disease as assessed by CT scans. CONCLUSIONS: Tissue eosinophilia is a characteristic histologic feature of chronic sinusitis in children, especially those with asthma. The presence of allergy does not predict tissue eosinophilia. Furthermore, the degree of tissue eosinophilia does not correlate with the severity of mucosal thickening seen on CT scans.

Adolescent↗
PubMed1994

Note-taking skills of university students with and without learning disabilities.

The notes of 30 university students with learning disabilities (LD) and 30 nondisabled university students were compared on the number of cued and noncued information units recorded and the number and type of abbreviations used. Results showed that the university students with LD performed significantly lower on all variables. Implications for practitioners are provided and future research discussed.

Adult↗
PubMed1993

Protective immunity is induced by a Borrelia burgdorferi mutant that lacks OspA and OspB.

A mutant of virulent Borrelia burgdorferi 297 was apparently selected for by long-term storage at 5 degrees C. This mutant was found to lack the plasmid which encodes outer surface protein A (OspA) and OspB. In addition to the loss of the OspA and OspB proteins, the mutant lacked two lipoproteins, of 20 and 7.5 kDa, that were observed in the wild type. Since the mutant was not recovered from the tissues or blood of hamsters injected with the mutant, the mutant was determined to be noninfectious. Hamsters vaccinated with noninfectious mutant 297 were protected completely from challenge with virulent wild-type 297 spirochetes. Prechallenge sera from hamsters vaccinated with mutant 297 lacked antibodies to OspA and OspB, while those from hamsters vaccinated with virulent wild-type 297 or avirulent 297 exhibited antibodies to these proteins. Hamsters vaccinated with virulent wild-type 297 or mutant 297 elicited antibodies to OspC and a 39-kDa protein (P39), whereas hamsters vaccinated with avirulent 297 lacked these antibodies. These results suggest that OspC and/or P39 are important for the development of a protective immune response. Study of this mutant may elucidate factors important to the development of a Lyme disease vaccine.

Animals↗
PubMed1993

Isolation and characterization of Borrelia burgdorferi from blood of a bird captured in the Saint Croix River Valley.

Field investigations were conducted to further evaluate the role of birds in the maintenance and dissemination of Borrelia burgdorferi. Blood specimens were taken from 39 passerine birds of 17 species captured during June 1991 at the Saint Croix National Riverway in Wisconsin, and one isolate, WI91-23, was cultured from an adult song sparrow (Melospiza melodia). This isolate was shown to be infectious for Peromyscus leucopus and Mesocricetus auratus (golden hamster). Isolate WI91-23 was confirmed as B. burgdorferi by immunofluorescence assay by using species-specific anti-OspA monoclonal antibodies H3TS and H5332 and anti-OspB antibody H5TS. Isolate WI91-23 was compared with Borrelia anserina Es, Borrelia hermsii MAN-1, and other B. burgdorferi strains (ATCC 53210, CT-1, and Catharus fuscescens [veery] liver 10293). Pulsed-field gel electrophoresis of in situ-lysed spirochetes revealed that the DNA plasmid profile of WI91-23 was most similar to those of plasmids from B. burgdorferi and most different from those of plasmids from B. anserina and B. hermsii. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis indicated that the protein profile of WI91-23 was like that of other B. burgdorferi strains studied, with dominant proteins corresponding to OspA and OspB, and that it differed from the protein profiles of B. anserina and B. hermsii. These findings indicate that passerine birds may serve as reservoirs for B. burgdorferi.

Animals↗
PubMed1992

DNA analysis of Borrelia burgdorferi NCH-1, the first northcentral U.S. human Lyme disease isolate.

The DNA of the first northcentral United States human Lyme disease isolate, Borrellia burgdorferi NCH-1, was characterized and compared with the DNAs of nine other B. burgdorferi isolates. Strain NCH-1 was isolated in August 1989 from a human skin biopsy specimen. DNA was analyzed by pulsed-field gel electrophoresis and restriction endonuclease analysis. Contour-clamped homogeneous electric field pulsed-field gel electrophoresis of in situ-lysed cells was performed to compare the plasmid profiles of the various isolates. The plasmid profile of isolate NCH-1, which included five plasmids of approximately 69, 42, 38, 32, and 23 kb, could be distinguished from those of the other isolates examined. The DNA profile of NCH-1 was most similar to those of strain 297 (human cerebrospinal fluid isolate, Connecticut) and strain PAL (human erythema migrans isolate, New York) and most dissimilar from those of strain P/Gau (human erythema migrans isolate, Germany) and strain IPF (Ixodes persulcatus tick isolate, Japan). These results indicate that genetic diversity exists among B. burgdorferi strains isolated from different geographical areas.

Base Composition↗
PubMed1991

Electro-clinical correlations of positive and negative sharp waves on the temporal and central areas in premature infants.

The goal of this study on 199 premature infants (24-41 weeks CA) was to investigate the electro-clinical correlations of positive and negative sharp waves, comparing those from the temporal and central areas. Positive discharges were seen more often less than 30 weeks CA and the negative type greater than 30 weeks. Patients without sharp waves rarely have seizures and those with paroxysms often do, dependent in part on the number of these discharges. When negative sharp waves are found on the frontal or occipital areas, where they uncommonly occur, the incidence of seizure almost doubles, compared to those on the central or temporal areas. Periventricular leukomalacia (PVL) was seen in less than one fourth of all patients, increasing to 32% with negative sharp waves, but nearly doubling the latter incidence with positive paroxysms, seen especially on the temporal, rather than central areas. Positive discharges were seen much more frequently with stage III-IV hemorrhage (Hg) than in stage I-II and these were mainly temporal, not central in location. Seizures and Hg were related only with grade III-IV, not with grade I-II Hg. Based on these data, positive sharp waves would predict in 69% of these infants the presence of at least one of the triad of seizures, intracerebral Hg or PVL, similar for the temporal and central locations. Follow-up studies showed that normal records at 30 weeks often changed to abnormal ones around 36 weeks. Finally, sensitivity data showed that for the positive sharp wave the highest values were for PVL, the lowest for seizures and midway for Hg, while the negative sharp waves show exactly the opposite, highest for seizures and lowest for PVL.

Cerebral Hemorrhage↗
PubMed1990

Overcoming deficiencies of the rule-based medical expert system.

One of the current deficiencies of the rule-based expert system is its static nature. As these systems are applied to medicine, this shortcoming becomes accentuated by: the rapid speed at which new knowledge is generated, the regional differences associated with the expression of many diseases, and the rate at which patient demographics and disease incidence change over time. This research presents a solution to the static nature of the rule-based expert system by proposing a hybrid system. This system consists of an expert system and a statistical analysis system linked to a patient database. The additional feature of a rule base manager which initiates automatic database analysis to refresh the statistical correlation of each rule ensures a dynamic, current, statistically accurate rule base. The philosophical differences between data and knowledge are also addressed as they apply to this type of hybrid system. The system is then used to generate four rule bases from different knowledge sources. These rule bases are then compared.

Artificial Intelligence↗
PubMed1990

Methylated DNA in Borrelia species.

The DNA of Borrelia species was examined for the presence of methylated GATC sequences. The relapsing-fever Borrelia sp., B. coriaceae, and only 3 of 22 strains of B. burgdorferi contained adenine methylation systems. B. anserina lacked an adenine methylation system. Fundamental differences in DNA methylation exist among members of the genus Borrelia.

Base Sequence↗
PubMed1990

A word identification strategy for adolescents with learning disabilities.

Students with learning disabilities frequently experience difficulty on reading tasks. This difficulty is heightened for adolescents with learning disabilities who are responsible for reading and understanding materials written at several grade levels above their reading ability. Word identification becomes an increasingly important skill for these students, especially when confronted with unfamiliar, polysyllabic words. The present study investigated the effects of training 12 adolescents with learning disabilities in a word identification strategy, DISSECT. The results indicated that the strategy was effective in reducing reading errors for all subjects. However, it was found that increases in word identification differentially affected reading comprehension and indicate the need for separate and/or simultaneous attention to comprehension processes.

Adolescent↗
PubMed1990

The sharp theta rhythm on the occipital areas of prematures (STOP): a newly described waveform.

This study on 500 prematures and neonates with conceptional ages (CA) of 23-49 wks describes the STOP pattern (sharp theta on the occipitals of prematures). STOP is similar to PT theta (premature temporal theta) in configuration, but is faster in frequency, lower in amplitude, more often unilateral, aside from the obvious difference in location. The incidence (%) was highest at the youngest age, decreasing to zero near term, and the amount (number of bursts) was greatest at 25 wks (CA). Three different parts appear in the incidence and amplitude curves, and these three parts may be related to changes in the laterality of the pattern. In the youngest age these rhythms are mainly bilateral, in the older neonates they are unilateral and are either for the ages between those extremes. STOP is seen more often in active sleep, but is reduced in incidence in patients with abnormal slow waves, ictal or immature patterns. Right-sided STOP was more frequently associated with abnormal EEGs, especially in males with right-sided sharp waves, often noted in the patients with seizures and intraventricular hemorrhages.

Electroencephalography↗