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Biomedical subjects

E Hill

Publications and source records attributed to E Hill.

At least 19 recordsLinked to original sources
PubMed2001

Cadherin superfamily proteins in Caenorhabditis elegans and Drosophila melanogaster.

The ability to form selective cell-cell adhesions is an essential property of metazoan cells. Members of the cadherin superfamily are important regulators of this process in both vertebrates and invertebrates. With the advent of genome sequencing projects, determination of the full repertoire of cadherins available to an organism is possible and here we present the identification and analysis of the cadherin repertoires in the genomes of Caenorhabditis elegans and Drosophila melanogaster. Hidden Markov models of cadherin domains were matched to the protein sequences obtained from the translation of the predicted gene sequences. Matches were made to 21 C. elegans and 18 D. melanogaster sequences. Experimental and theoretical work on C. elegans sequences, and data from ESTs, show that three pairs of genes, and two triplets, should be merged to form five single genes. It also produced sequence changes at one or both of the 5' and 3' termini of half the sequences. In D. melanogaster it is probable that two of the cadherin genes should also be merged together and that three cadherin genes should be merged with other neighbouring genes. Of the 15 cadherin proteins found in C. elegans, 13 have the features of cell surface proteins, signal sequences and transmembrane helices; the other two have only signal sequences. Of the 17 in D. melanogaster, 11 at present have both features and another five have transmembrane helices. The evidence currently available suggests about one-third of the cadherins in the two organisms can be grouped into subfamilies in which all, or parts of, the molecules are conserved. Each organism also has a approximately 980 residue protein (CDH-11 and CG11059) with two cadherin domains and whose sequences match well over their entire length two proteins from human brain. Two proteins in C. elegans, HMR-1A and HMR-1B, and three in D. melanogaster, CadN, Shg and CG7527, have cytoplasmic domains homologous to those of the classical cadherin genes of chordates but their extracellular regions have different domain structures. Other common subclasses include the seven-helix membrane cadherins, Fat-like protocadherins and the Ret-like cadherins. At present, the remaining cadherins have no obvious similarities in their extracellular domain architecture or homologies to their cytoplasmic domains and may, therefore, represent species-specific or phylum-specific molecules.

Amino Acid Sequence↗
PubMed2001

The role of dynamin and its binding partners in coated pit invagination and scission.

Plasma membrane clathrin-coated vesicles form after the directed assembly of clathrin and the adaptor complex, AP2, from the cytosol onto the membrane. In addition to these structural components, several other proteins have been implicated in clathrin-coated vesicle formation. These include the large molecular weight GTPase, dynamin, and several Src homology 3 (SH3) domain-containing proteins which bind to dynamin via interactions with its COOH-terminal proline/arginine-rich domain (PRD). To understand the mechanism of coated vesicle formation, it is essential to determine the hierarchy by which individual components are targeted to and act in coated pit assembly, invagination, and scission. To address the role of dynamin and its binding partners in the early stages of endocytosis, we have used well-established in vitro assays for the late stages of coated pit invagination and coated vesicle scission. Dynamin has previously been shown to have a role in scission of coated vesicles. We show that dynamin is also required for the late stages of invagination of clathrin-coated pits. Furthermore, dynamin must bind and hydrolyze GTP for its role in sequestering ligand into deeply invaginated coated pits. We also demonstrate that the SH3 domain of endophilin, which binds both synaptojanin and dynamin, inhibits both late stages of invagination and also scission in vitro. This inhibition results from a reduction in phosphoinositide 4,5-bisphosphate levels which causes dissociation of AP2, clathrin, and dynamin from the plasma membrane. The dramatic effects of the SH3 domain of endophilin led us to propose a model for the temporal order of addition of endophilin and its binding partner synaptojanin in the coated vesicle cycle.

Adaptor Protein Complex 2↗
PubMed2001

Mechanism of action of 1-beta-D-2,6-diaminopurine dioxolane, a prodrug of the human immunodeficiency virus type 1 inhibitor 1-beta-D-dioxolane guanosine.

(-)-beta-D-2,6-Diaminopurine dioxolane (DAPD), is a nucleoside reverse transcriptase (RT) inhibitor with activity against human immunodeficiency virus type 1 (HIV-1). DAPD, which was designed as a water-soluble prodrug, is deaminated by adenosine deaminase to give (-)-beta-D-dioxolane guanine (DXG). By using calf adenosine deaminase a K(m) value of 15 +/- 0.7 microM was determined for DAPD, which was similar to the K(m) value for adenosine. However, the k(cat) for DAPD was 540-fold slower than the k(cat) for adenosine. In CEM cells and peripheral blood mononuclear cells exposed to DAPD or DXG, only the 5'-triphosphate of DXG (DXG-TP) was detected. DXG-TP is a potent alternative substrate inhibitor of HIV-1 RT. Rapid transient kinetic studies show the efficiency of incorporation for DXG-TP to be lower than that measured for the natural substrate, 2'-deoxyguanosine 5'-triphosphate. DXG-TP is a weak inhibitor of human DNA polymerases alpha and beta. Against the large subunit of human DNA polymerase gamma a K(i) value of 4.3 +/- 0.4 microM was determined for DXG-TP. DXG showed little or no cytotoxicity and no mitochondrial toxicity at the concentrations tested.

Adenosine Deaminase Inhibitors↗
PubMed2000

The Rab6-binding kinesin, Rab6-KIFL, is required for cytokinesis.

The Rab6-binding kinesin, Rab6-KIFL, was identified in a two-hybrid screen for proteins that interact with Rab6, a small GTPase involved in membrane traffic through the Golgi apparatus. We find that Rab6-KIFL accumulates in mitotic cells where it localizes to the midzone of the spindle during anaphase, and to the cleavage furrow and midbody during telophase. Overexpression of Rab6-KIFL causes a cell division defect resulting in cell death. Microinjection of antibodies to Rab6-KIFL results in the cells becoming binucleate after one cell cycle, and time-lapse microscopy reveals that this is due to a defect in cleavage furrow formation and thus cytokinesis. These data show that endogenous Rab6-KIFL functions in cell division during cleavage furrow formation and cytokinesis, in addition to its previously described role in membrane traffic.

Base Sequence↗
PubMed2000

Tracing European founder lineages in the Near Eastern mtDNA pool.

Founder analysis is a method for analysis of nonrecombining DNA sequence data, with the aim of identification and dating of migrations into new territory. The method picks out founder sequence types in potential source populations and dates lineage clusters deriving from them in the settlement zone of interest. Here, using mtDNA, we apply the approach to the colonization of Europe, to estimate the proportion of modern lineages whose ancestors arrived during each major phase of settlement. To estimate the Palaeolithic and Neolithic contributions to European mtDNA diversity more accurately than was previously achievable, we have now extended the Near Eastern, European, and northern-Caucasus databases to 1,234, 2, 804, and 208 samples, respectively. Both back-migration into the source population and recurrent mutation in the source and derived populations represent major obstacles to this approach. We have developed phylogenetic criteria to take account of both these factors, and we suggest a way to account for multiple dispersals of common sequence types. We conclude that (i) there has been substantial back-migration into the Near East, (ii) the majority of extant mtDNA lineages entered Europe in several waves during the Upper Palaeolithic, (iii) there was a founder effect or bottleneck associated with the Last Glacial Maximum, 20,000 years ago, from which derives the largest fraction of surviving lineages, and (iv) the immigrant Neolithic component is likely to comprise less than one-quarter of the mtDNA pool of modern Europeans.

DNA, Mitochondrial↗
PubMed2000

Parathyroid hormone-related protein analog RS-66271 is an effective therapy for impaired bone healing in rabbits on corticosteroid therapy.

A new class of parathyroid hormone-related protein (PTHrP) analogs has been developed that causes a rapid gain in both trabecular and cortical bone in models of osteopenia. This study investigates the efficacy of the PTHrP analog, RS-66271 ([MAP(1-10)]22-31 hPTHrP(1-34)-NH(2)), as systemic therapy for impaired bone healing in corticosteroid-treated rabbits. A 1 mm defect was created bilaterally in the ulnae of 30 rabbits. Delayed healing was induced by daily injections of prednisone (0.15 mg/kg) beginning 2 months prior to surgery and continuing until killing. Rabbits in the experimental group received daily subcutaneous injections of PTHrP analog RS-66271 (0.01 mg/kg) starting 1 day after surgery. Control animals received subcutaneous normal saline. At the 6 week timepoint, nine of ten ulnae from PTHrP-treated rabbits achieved radiographic union, whereas only two of ten limbs achieved union in control rabbits (p < 0.01). In a separate part of the study, 20 animals (10 control, 10 RS-66271-treated) were killed when radiographic union was achieved bilaterally. In this portion of the study, all limbs in animals treated with PTHrP achieved union by 6 weeks. In the control animals that were allowed to heal for 10 weeks, only 20% of the limbs achieved radiographic union. In addition, ulnae in the PTHrP-analog-treated rabbits showed greater radiographic intensity (20%-40%), larger callus area (209% anteroposterior view, 417% lateral view) (mean area on AP radiographs: control, = 387 +/- 276 mm(2); PTHrP analog, 1195 +/- 408 mm(2)), and greater stiffness (64%) and torque (87%) when compared with controls. RS-66271 was shown to be an effective therapy for preventing impaired bone healing caused by prednisone in a rabbit model.

Animals↗
PubMed2000

Systemic corticosteroids inhibit bone healing in a rabbit ulnar osteotomy model.

Prolonged systemic administration of corticosteroids causes osteoporosis and increased risk of fracture. Despite this well documented side effect of systemic corticosteroids, the effect of these compounds on fracture healing is not well defined. The goal of this study was to test the hypothesis that systemic corticosteroid therapy adversely affects fracture healing in a rabbit ulnar osteotomy model. Non-critical sized (1 mm) defects were created bilaterally in 18 adult female New Zealand White rabbits. Starting 2 months before operative intervention and continuing for 6 weeks during healing of the osteotomies, a subcutaneous dose of either sterile saline or prednisone (0.15 mg/kg) was administered daily. Serial radiographs of the forelimb were taken immediately postoperatively and weekly beginning the second week postoperatively. After killing at 6 weeks, only 3 of 20 limbs from animals treated with prednisone achieved radiographic union while 13 of 16 control limbs achieved union. The radiographic density of bone in the defect as well as callus size were greater in the control limbs than in the limbs from prednisone-treated animals. DEXA confirmed that the bone mineral content was lower in the ulnae of prednisone-treated rabbits both within the defect and in adjacent ulnar bone. Mechanical data indicated that osteotomies from rabbits chronically treated with prednisone were weaker than in controls. In this rabbit ulnar osteotomy model, chronic prednisone treatment clearly inhibited bone healing.

Animals↗
PubMed2000

Glutamate, GABA and precursor amino acids in adult mouse neocortex: cellular diversity revealed by quantitative immunocytochemistry.

Glutamate is an important amino acid in the neocortex for metabolic and neurotransmitter functions. The objective of this study was to detect variations in cellular glutamate content using quantitative immunocytochemistry. We show that glutamate is present in almost all cortical cells and coexists with other amino acids such as aspartate, glutamine or gamma-aminobutyric acid (GABA). The patterns of aspartate and glutamine content suggests that there are no purely aspartatergic or glutaminergic neurons. GABAergic neurons showed variable levels of the precursors such as glutamate, glutamine and aspartate. Comparison of immunoreactive patterns between two cortical areas did not detect any statistically significant differences. The mean cellular intensity for GABA and glutamate was constant across different layers. Surprisingly, we found that GABAergic neurons could coexist with either low or high levels of glutamate, suggesting that metabolic levels of glutamate in these neurons could be variable. Alternatively, some GABA neurons may utilize both GABA and glutamate for neurotransmission. We show that when variations in amino acid content are separately mapped onto individual cells, co-registration is a useful technique for reporting heterogeneity among cortical cells.

Amino Acids↗
PubMed2000

Reliability of a measure of post-stroke shoulder pain in patients with and without aphasia and/or unilateral spatial neglect.

OBJECTIVE: To determine the inter/intra-rater reliability of expert physiotherapists (PTs) measuring post-stroke shoulder pain with 100 mm vertical visual analogue scales (VAS; intensity, frequency and affective response) and a categorical site-of-pain scale. DESIGN: Three PTs independently rated subjects (normal clinical procedure but with a standardized starting position) on three days, at the same time of day, during one week in a randomized order determined by a nested latin square. Reliability for VAS scores was determined with the intraclass correlation coefficient (ICC) and for site-of-pain with the kappa statistic (kappa). Acceptable reliability was set at 0.75. The limits of agreement were also calculated. SETTING: Community. SUBJECTS: Thirty-three patients, mean time post stroke 42 months (range 7-360). RESULTS: Mean inter-rater reliability was 0.79 for intensity, 0.75 for frequency and 0.62 for affective response (ICC). The limits of agreement were wide and rater bias was significant for 6/27 ratings. Mean intra-rater reliability was 0.70 for intensity, 0.77 for frequency and 0.69 for affective response (ICC). For site-of-pain inter-rater reliability ranged from 0.156 (kappa) to 0.385 (kappa) and intrarater reliability ranged from 0.300 (kappa) to 0.559 (kappa). CONCLUSIONS: Although inter-rater reliability was acceptable for intensity and frequency there was a consistently large systematic bias between pairs of raters. Agreement might be improved if a standardized assessment procedure was used and/or if training in pain behaviour interpretation was provided.

Aged↗
PubMed2000

Targeting quality improvement activities for depression. Implications of using administrative data.

BACKGROUND: Large health care organizations may use administrative data to target primary care patients with depression for quality improvement (QI) activities. However, little is known about the patients who would be identified by these data or the types of QI activities they might need. We describe the clinical characteristics and outcomes of patients identified through administrative data in 2 family practice clinics. METHODS: Patients with depression aged 18 to 65 years were identified through review of encounter/administrative data during a 16-month period. Patients agreeing to participate (N=103) were interviewed with the Primary Care Evaluation of Mental Disorders questionnaire and completed the Depression Outcomes Modules (with an embedded Medical Outcomes Short Form-36 [SF-36]), Symptom Check List-25 (SCL-25), and Alcohol use Disorders Identification Test. Follow-up assessments were completed by 83 patients at a median of 7 months. RESULTS: A large majority of identified patients (85%) met full criteria for a Diagnostic and Statistical Manual of Mental Disorders depressive disorder; those not meeting criteria usually had high levels of symptoms on the SCL-25. Seventy-seven percent of the patients reported recurrent episodes of depressed mood, and 60% reported chronic depression. Although most improved at follow-up, they continued to have substantial functional deficits on the SF-36, and 60% still had high levels of depressive symptoms. CONCLUSIONS: QI programs that use administrative data to identify primary care patients with depression will select a cohort with relatively severe, recurrent depressive disorders. Most of these patients will receive standard treatments without QI interventions and will continue to be symptomatic. QI programs targeting this population may need to offer intensive alternatives rather than monitor standard care.

Adult↗
PubMed2000

The penetrance of head injury management guidelines into the practice patterns of michigan emergency physicians

OBJECTIVE: The Brain Trauma Foundation published "Guidelines for the Management of Severe Head Injury" in 1996. These evidence based clinical guidelines (CGs) recommended against prophylactic hyperventilation and glucocorticoid use, and advocated for blood pressure (BP) resuscitation, and the careful use of mannitol in the event of elevated intracranial pressure (ICP). We sought to measure the penetrance of these guidelines into the practice patterns of Michigan emergency physicians (MEPs). METHODS: An anonymous mail survey was sent to all 566 MEPs who are members of the American College of Emergency Physicians. Three patients with severe head injury were presented, all with Glasgow Coma Scores (GCSs) of 8 or less. The physicians were asked to choose from 15 diagnostic and treatment options, which included: intubation and hyperventilation, BP resuscitation, IV mannitol administration, and IV glucocorticoid administration. RESULTS: 319 (56%) surveys were returned. 46% (95% CI = 40% to 51%) of MEPs elected to inappropriately use prophylactic hyperventilation, 78% (95% CI = 75% to 81%) did correct hypotension with systolic BP < 90 mm Hg. 83% (95% CI = 80% to 86%) administered mannitol appropriately. Very few MEPs administered IV glucocorticoids. CONCLUSIONS: Despite being published nearly 4 year ago, the "Guidelines for the Management of Severe Head Injury" have not been uniformly incorporated into the practice patterns of MEPs. Specifically, many physicians continue to rely on prophylactic hyperventilation despite strong recommendations against its use.

Journal Article↗
PubMed1999

IP3-induced Ca2+ release in A7r5 vascular smooth-muscle cells represents a partial emptying of the stores and not an all-or-none Ca2+ release of separate quanta.

There is still no agreement on the mechanism of the intracellular action of low concentrations of inositol 1,4,5-trisphosphate (IP3). Intracellular Ca2+ stores may transiently release some Ca2+ before they become insensitive to IP3. Alternatively, stores with a low IP3 threshold may lose all their Ca2+ and the others none. We now report that the IP3 threshold was not correlated with the extent of Ca2+ release in permeabilized A7r5 smooth-muscle cells. In contrast, the maximum rate of release, which was changed either by varying the level of IP3 receptor (IP3R) activation, or by changing the concentration of IP3R at a constant level of IP3R activation, was directly related to the extent of Ca2+ release. We conclude that IP3-induced Ca2+ release reflects partial emptying of the stores and not all-or-none Ca2+ release of separate quanta.

Adenosine Triphosphate↗
PubMed1999

Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia.

The prevalence of smoking is markedly elevated in schizophrenia. Low smoking cessation rates and reports that some smokers with schizophrenia experience an acute increase in symptoms during attempts to quit smoking, suggest a self-medication model. Alternatively, smoking may modulate medication side effects. The effects of treated and untreated smoking abstinence on psychotic symptoms and medication side effects were examined in this study. Nineteen outpatients with schizophrenia or schizoaffective disorder participated in a randomized, double-blind, balanced crossover study: 1 day of ad libitum smoking followed by 3 days of acute smoking abstinence while wearing 22 mg/day active or placebo transdermal nicotine patches, with a return to 3 days of smoking between patch conditions. Daily symptom and side-effect ratings, nicotine and cotinine blood levels were collected. Twelve subjects completed the study. Neither positive symptoms nor mood symptoms changed. An increase in negative symptoms during the first abstinent day occurred in both placebo and active patch conditions, but was not sustained over subsequent abstinent days. Despite physiological signs of withdrawal, completers did not endorse increased nicotine withdrawal symptoms. Dropouts reported higher withdrawal symptoms, but also had no increase in psychiatric symptoms in either phase of the study. Of note, dyskinesias decreased during abstinence and placebo patch treatment, but increased during abstinence and the active patch conditions. Acute exacerbation of psychiatric symptoms is an unlikely explanation for any difficulty smokers with schizophrenia have in early abstinence.

Administration, Cutaneous↗
PubMed1999

Concurrent treatment of patients with depression in the community: provider practices, attitudes, and barriers to collaboration.

BACKGROUND: In randomized controlled trials, patients with major depression who receive broad-based collaborative treatment by both primary care physicians (PCPs) and mental health providers (MHPs) have better outcomes than patients who receive usual care. However, little is known about the concurrent treatment of patients with depression in the community. This study describes the perceptions of PCPs of the frequency of concurrent treatment in community settings, the degree of collaboration between co-treating providers, and factors associated with greater interaction and collaboration. METHODS: A survey was distributed to a stratified, random sample of 276 eligible family physicians in Michigan. Primary analyses were descriptive statistics (point estimation) of PCP practice patterns. Secondary analyses explored predictors of collaboration with multivariable regression. RESULTS: A total of 162 eligible PCPs (59%) returned the survey. PCPs reported that they co-treated approximately 30% of their depressed patients with MHPs. They made contact with co-treating MHPs in approximately 50% of shared cases; however, provider contact seldom included joint treatment planning. PCPs perceived collaborative treatments to be more problematic when patients were enrolled in managed care programs. In multivariable regression, co-location of MHP and PCP practices (in the same building) was strongly associated with increased interaction and collaboration (P <.001). CONCLUSIONS: Concurrent treatment of depressed patients is common in the community, but these treatments are less interactive and collaborative than the treatment models proven effective in randomized controlled trails. If concurrent treatments are to become more collaborative-with regular contact and effective communication-co-location of practices appears important.

Community Mental Health Services↗
PubMed1999

What do executive factors contribute to the failure on false belief tasks by children with autism?

As children with autism have pervasive executive difficulties it is necessary to determine whether these contribute to their often-reported failure on the false belief task. Failure on this task is frequently taken to diagnose the lack of a "theory of mind". We report two studies using two tasks that make similar executive demands to the false belief task. The first experiment showed that children with autism are significantly challenged by a "conflicting desire" task, which suggests that their difficulty with the false belief task is not rooted in difficulty with grasping the representational nature of belief. In the second study children with autism were also found to be impaired on a novel version of the "false photograph task". A parsimonious reading of these data is that their difficulty with all three tasks is due to commonalities in the tasks' executive structure.

Autistic Disorder↗
PubMed1998

Frequency of symptomatic and asymptomatic herpes simplex virus type 2 reactivations among human immunodeficiency virus-infected men.

Herpes simplex virus (HSV) infection is common in persons coinfected with human immunodeficiency virus (HIV). In a prospective study, daily viral cultures of the mouth, genitals, and rectum were collected from 68 HIV-positive and 13 HIV-negative men who have sex with men. Subjects completed a median of 57 days of follow-up. Anogenital HSV-2 cultures were positive on 405 (9.7%) of 4167 days for HIV-positive men and on 24 (3.1%) of 766 days for HIV-negative men. Most reactivations were perirectal and subclinical. Risk factors for increased HSV-2 shedding among HIV-positive men were low CD4 cell count (odds ratio, 2.5; 95% confidence interval, 1.2-5.4) and antibodies to both HSV-1 and HSV-2 versus HSV-2 only (odds ratio, 1.9; 95% confidence interval, 1.0-3.7). Three isolates obtained from 3 separate subjects were resistant to acyclovir. Thus, subclinical HSV-2 reactivation is an important opportunistic infection in persons with HIV infection. Further studies are necessaryto determine the impact of subclinical HSV-2 reactivation on the natural history of HIV infection.

Acyclovir↗
PubMed1998

Phenotypic and genotypic characterization of acyclovir-resistant herpes simplex viruses from immunocompromised patients.

Phenotypic and genotypic analyses were done on 30 acyclovir-resistant and 5 acyclovir-susceptible herpes simplex virus (HSV) isolates (22 HSV type 1 and 13 HSV type 2) recovered from 24 subjects. All isolates were susceptible to foscarnet. The phenotypes of the acyclovir-resistant HSV isolates were as follows: 17 were thymidine kinase (TK) deficient, 12 had decreased TK activity (produced low amounts of viral TK) or TK with altered substrate specificity, and 1 was undetermined. Sequencing analysis of the HSV TK gene revealed that 14 (46.7%) of 30 acyclovir-resistant isolates had an insertion or deletion of 1 or 2 nucleotides, especially in homopolymer runs of Gs, Cs, and rarely in As. On the other hand, 16 (53.3%) of 30 acyclovir-resistant isolates had point mutations in conserved or nonconserved regions of the TK gene. In conclusion, HSV can develop multiple strategies to exhibit acyclovir resistance, including, in about half of the cases, frameshift mutations in homopolymer nucleotide stretches of the TK gene.

AIDS-Related Opportunistic Infections↗