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Biomedical subjects

Jennifer Kim

Publications and source records attributed to Jennifer Kim.

15 recordsLinked to original sources
PubMed2006

Deducing the transmembrane domain organization of presenilin-1 in gamma-secretase by cysteine disulfide cross-linking.

Gamma-secretase is a founding member of membrane-embedded aspartyl proteases that cleave substrates within transmembrane domains, and this enzyme is an important target for the development of therapeutics for Alzheimer's disease. The structure of gamma-secretase and its precise catalytic mechanism still remain largely unknown. Gamma-secretase is a complex of four integral membrane proteins, with presenilin (PS) as the catalytic component. To gain structural and functional information about the nine-transmembrane domain (TMD) presenilin, we employed a cysteine mutagenesis/disulfide cross-linking approach. Here we report that native Cys92 is close to both Cys410 and Cys419, strongly implying that TMD1 and TMD8 are adjacent to each other. This structural arrangement also suggests that TMD8 is distorted from an ideal helix. Importantly, binding of an active site directed inhibitor, but not a docking site directed inhibitor, reduces the ability of the native cysteine pairs of PS1 to cross-link upon oxidation. These findings suggest that the conserved cysteines of TMD1 and TMD8 contribute to or allosterically interact with the active site of gamma-secretase.

Amino Acid Sequence↗
PubMed2005

Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls.

BACKGROUND AND PURPOSE: Apolipoprotein E genotype (APOE) is associated with cholesterol metabolism, ischemic heart disease, and cerebral amyloid angiopathy, and so may affect risk of both ischemic and hemorrhagic stroke. METHODS: We comprehensively sought and identified studies of the association of apoE with ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). We did meta-analyses to assess the evidence for an association between APOE and the various pathological types and subtypes of stroke, and assessed the effects of several methodological criteria. RESULTS: We analyzed data from 31 eligible studies (26 IS, 8 ICH, and 3 SAH) in 5961 cases and 17 965 controls. epsilon4 allele-containing (epsilon4+) genotypes were significantly associated with IS (odds ratio [OR], 1.11; 95% CI, 1.01 to 1.22) and SAH (OR, 1.42; 95% CI, 1.01 to 1.99) and nonsignificantly with ICH (OR, 1.16; 95% CI, 0.93 to 1.44), whereas epsilon2+ genotypes were associated with ICH (OR, 1.32; 95% CI, 1.01 to 1.74). Associations appeared stronger with epsilon4+ genotypes for large artery compared with other IS subtypes and for Asian compared with white populations, and with epsilon2+ genotypes for lobar compared with deep hemorrhages. However, we found no association between epsilon4+ genotypes and IS when we analyzed only larger studies (>200 cases; OR, 0.99; 95% CI, 0.88 to 1.11) or studies without control selection bias (OR, 0.99; 95% CI, 0.85 to 1.17). CONCLUSIONS: Publication and selection biases make existing studies of APOE and stroke unreliable. Further, very large, methodologically rigorous studies are needed.

Adult↗
PubMed2005

Simultaneous development of the Pediatric GERD Caregiver Impact Questionnaire (PGCIQ) in American English and American Spanish.

BACKGROUND: The objective of this study was to develop simultaneously a new questionnaire, the Pediatric GERD Caregiver Impact Questionnaire (PGCIQ), in American English and American Spanish in order to elucidate the impact of caring for a child with GERD. METHODS: Two focus group discussions were conducted in American English and American Spanish to develop a relevant conceptual model. Focus group participants were the primary caregivers of children with GERD (newborn through 12 years of age). Participant responses were qualitatively analyzed to identify potential differences in caregiver perspectives by the caregiver's language, socio-economic status and demographic profile as well as the child's age and disease severity level. Items in the PGCIQ were generated simultaneously in English and Spanish by reviewing results of qualitative analysis from focus groups in each language. The PGCIQ was finalized in both languages after testing content validity and conducting an in-depth translatability assessment. RESULTS: Analysis of focus group comments resulted in the development of a first draft questionnaire consisting of 58 items in 10 domains. Content validity testing and an in-depth translatability assessment resulted in wording modification of 37 items, deletion of 14 items and the addition of a domain with five items. Feedback from the content validity testing interviews indicated that the instrument is conceptually relevant in both American English and American Spanish, clear, comprehensive and easy to complete within 10 minutes. The final version of the PGCIQ contains 49 items assessing ten domains. An optional module with nine items is available for investigative research purposes and for use only at baseline. CONCLUSION: The PGCIQ was developed using simultaneous item generation, a process that allows for consideration of concept relevance in all stages of development and in all languages being developed. The PGCIQ is the first questionnaire to document the multidimensional impact of caring for an infant or young child with GERD. Linguistic adaptation of the PGCIQ in multiple languages is ongoing. A validation study of the PGCIQ is needed to examine its psychometric properties, further refine the items and develop an appropriate scoring model.

Adult↗
PubMed2005

Economic implications of extended-release metoprolol succinate for heart failure in the MERIT-HF trial: a US perspective of the MERIT-HF trial.

BACKGROUND: The MERIT-HF trial demonstrated improved survival and fewer hospitalizations for worsening heart failure with extended-release (ER) metoprolol succinate in patients with heart failure. This study sought to estimate the economic implications of this trial from a US perspective. METHODS AND RESULTS: A discrete event simulation was developed to examine the course of patients with heart failure. Characteristics of the population modeled, probabilities of hospitalization and death with standard therapy, and risk reductions with ER metoprolol succinate were obtained from Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) and evaluated in weekly cycles. Direct medical costs were estimated from US databases in 2001 US dollars. Uncertainty in inputs was incorporated and analyses were carried out to estimate events prevented total and net costs. The model predicts that ER metoprolol succinate will prevent approximately 7 deaths and 15 hospitalizations from heart failure per 100 patients over 2 years. Compared with standard therapy alone, this translates to a cost reduction between $395 and $1112 per patient, depending on whether the costs of hospitalizations for other causes are included. Savings were maintained in 90% of the simulations. CONCLUSION: This analysis predicts that the positive effect of ER metoprolol succinate on mortality and morbidity demonstrated in MERIT-HF leads to substantial savings.

Adrenergic beta-Antagonists↗
PubMed2005

Treatment patterns and real-world effectiveness of warfarin in nonvalvular atrial fibrillation within a managed care system.

OBJECTIVE: To examine warfarin utilization and clinical effectiveness among patients with nonvalvular atrial fibrillation within usual clinical care in a managed care system. RESEARCH DESIGN AND METHODS: A retrospective analysis of health care claims for an approximately four million member managed care organization was performed. Health plan members with a diagnosis of nonvalvular atrial fibrillation in calendar year 2000 were identified and stratified into two cohorts: Warfarin Therapy (newly initiating warfarin) or Warfarin Candidates (eligible for warfarin therapy according to the ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation, but did not receive warfarin). MEASUREMENTS: The occurrence of thromboembolism, ischemic stroke, and hemorrhage during a maximum 720-day follow-up were compared between cohorts, adjusting for age, gender, and other risk factors, using Cox regression. RESULTS: Among 12 539 subjects (mean age 78.0 +/- 8.8 years) with nonvalvular atrial fibrillation, 4895 (39.0%) initiated Warfarin Therapy and 7644 (61.0%) were Warfarin Candidates. Event occurrences among Warfarin Therapy vs. Warfarin Candidates were: ischemic stroke, 3.7% vs. 4.5%; any thromboembolism, 7.8% vs. 10.8%; and hemorrhage, 4.4% vs. 4.9%, respectively. Warfarin therapy was not associated with an increased risk for hemorrhage (hazard ratio [HR] = 0.97, 95% confidence interval [CI] = 0.82-1.15), while risks for ischemic stroke and any thromboembolism were significantly reduced, by 22% (HR = 0.78, 95% CI = 0.65-0.93) and 34% (HR = 0.66, 95% CI = 0.59-0.75), respectively. CONCLUSIONS: Within usual clinical care for the managed care population examined, warfarin remains underused despite current guidelines recommending its use in nearly all patients with nonvalvular atrial fibrillation. Although utilization of anticoagulation clinics and INR values attained were unknown in this study, the observed risk reductions for ischemic stroke and thromboembolism were lower than those achieved in clinical trials, while no increased risk for hemorrhage was observed. These findings suggest that warfarin is used conservatively, and dosed cautiously, diminishing the full potential benefit of anticoagulant therapy in patients with nonvalvular atrial fibrillation.

Aged↗
PubMed2005

Treatment of agitation following traumatic brain injury: a review of the literature.

Agitation, restlessness, and aggression are frequent neurobehavioural sequelae in the early stages of recovery from traumatic brain injury (TBI). These behavioural symptoms disrupt patient care and impede rehabilitation efforts. We review the current literature (1985 onwards) examining the pharmacological management of post-TBI agitation in both acute and post-acute conditions. This article will assess the evidence for the use of selected alkylphenols, benzodiazepines, estrogens, antiandrogens, neuroleptics/antipsychotics, antidepressants, anti-Parkinsonian agents, antipsychotics, anticonvulsants, lithium carbonate, buspirone, beta-blockers, and psychostimulants in agitated TBI survivors. Review of the literature suggests that there is limited evidence to accurately guide clinicians in the management of this patient population.

Adrenergic beta-Antagonists↗
PubMed2003

Positive influence of AP-2alpha transcription factor on cadherin gene expression and differentiation of the ocular surface.

The family of transcription factors Activating protein-2 (AP-2) are known to play important roles in numerous developmental events, including those associated with differentiation of stratified epithelia. However, to date, the influence of the AP-2 genes on endogenous gene expression in the stratified epithelia and how this affects differentiation has not been well defined. The following study examines the detailed expression of the AP-2alpha and AP-2beta proteins in the stratified epithelia of the ocular surface, including that in the cornea and developing eyelids. The effect of altered levels of the AP-2alpha gene on ocular surface differentiation was also examined using a corneal epithelial cell line and AP-2alpha chimeric mice. Immunolocalization studies revealed that, while AP-2beta was broadly expressed throughout all cell layers of the stratified corneal epithelium, AP-2alpha expression was confined to cell compartments more basally located. AP-2alpha was also highly expressed in the less differentiated cell layers of the eyelid epidermis. Overexpression of the AP-2alpha gene in the corneal cell line, SIRC, resulted in a dramatic change in cell phenotype including a clumping growth behavior that was distinct from the smooth monolayer of the parent cell line. Accompanying this change was an up-regulation in levels of the cell adhesion molecule, N-cadherin. Examination of the ocular surface of AP-2alpha chimeric mice, derived from a mixed population of AP-2alpha-/- and AP-2alpha+/+, revealed that a down-regulation in E-cadherin expression is correlated with location of the AP-2alpha-/- null cells. Together, these findings demonstrate that AP-2alpha participates in regulating differentiation of the ocular surface through induction in cadherin expression.

Animals↗
PubMed2002

ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum.

The ability of killer T cells carrying the CD8 antigen to detect tumours or intracellular pathogens requires an extensive display of antigenic peptides by major histocompatibility complex (MHC) class I molecules on the surface of potential target cells. These peptides are derived from almost all intracellular proteins and reveal the presence of foreign pathogens and mutations. How cells produce thousands of distinct peptides cleaved to the precise lengths required for binding different MHC class I molecules remains unknown. The peptides are cleaved from endogenously synthesized proteins by the proteasome in the cytoplasm and then trimmed by an unknown aminopeptidase in the endoplasmic reticulum (ER). Here we identify ERAAP, the aminopeptidase associated with antigen processing in the ER. ERAAP has a broad substrate specificity, and its expression is strongly upregulated by interferon-gamma. Reducing the expression of ERAAP through RNA interference prevents the trimming of peptides for MHC class I molecules in the ER and greatly reduces the expression of MHC class I molecules on the cell surface. Thus, ERAAP is the missing link between the products of cytosolic processing and the final peptides presented by MHC class I molecules on the cell surface.

Amino Acid Sequence↗
PubMed2002

The role of abdominal computed tomography scanning in patients with non-traumatic abdominal symptoms.

OBJECTIVES: To describe the non-traumatic clinical settings in which abdominal computed tomography (CT) is used and to determine its diagnostic utility. METHODS: A retrospective descriptive study of consecutive non-traumatic adult patients who underwent abdominal CT in a university hospital emergency department (ED). Radiology reports and patient charts were reviewed. The indication for each CT was determined by two reviewers. Indications were described as specific (e.g. "rule-out" appendicitis) or non-specific (e.g. abdominal pain). CT results were classified as positive, negative (normal or no new information) or indeterminate (technical limitations). For those with specific indications, positive results were further subdivided into supportive (of the clinical suspicion) or non-supportive (abnormal but suggesting an alternative diagnosis). The clinical course and results of subsequent diagnostic procedures were used to confirm CT results for admitted patients. Incidental CT findings were recorded. RESULTS: 177 patients were entered; mean age was 58 years; 48% were men. The most frequent indications ("rule-outs") were aortic disorders (23%), abscess (16%), and diverticulitis (14%). In patients with specific indications (n=160), 44% of the CT results supported the indication, 13% suggested an alternative diagnosis (non-supportive), 41% were negative, and 3% were indeterminate. In admitted patients (n=129), CT findings were contradicted in 6%. CONCLUSIONS: Adult ED patients undergo abdominal CT for a variety of non-traumatic indications. Findings in less than half support the pre-test clinical suspicion and an alternative previously unsuspected diagnosis is suggested in 13%. Follow-up is inconsistent with CT results in a small but significant number of cases.

Abdominal Pain↗
PubMedDate not supplied

The effect of subcutaneously administered low-molecular-weight heparin on microarterial thrombosis in the rat.

OBJECTIVE: To examine the effect of administration of a low-molecular-weight heparin derivative, enoxaparin, on the rate of arterial thrombosis in a rat model. STUDY DESIGN: Prospective, randomized, blinded study. METHODS: A standard microarterial anastomosis tuck injury was created in both femoral arteries of 25 Long Evans retired breeder rats. Thirteen animals received a subcutaneous injection of 50 IU/kg of enoxaparin 2 hours before the procedure, while 12 control animals received vehicle (isotonic sodium chloride solution) alone. Sites of injury/repair were assessed 2 hours after the procedure for anastomotic patency or thrombosis. RESULTS: Six (23%) of 26 vessels in the drug-treated group developed an arterial thrombosis at the site of repair, while 6 (25%) of 24 vessels in the control group developed thrombosis. There was no statistically significant difference at the 95% confidence limit between the 2 groups based on a comparison-of-proportions test. CONCLUSION: The preoperative subcutaneous administration of 50 IU/kg of enoxaparin did not alter the rate of arterial thrombosis following the creation of a thrombogenic tuck injury/repair of the rat femoral artery.

Animals↗
PubMedDate not supplied

Muscle tissue engineering for partial glossectomy defects.

BACKGROUND: Tongue reconstruction represents a difficult reconstructive problem, based on the tongue's complex multimodality function. Existing methods of tongue reconstruction often result in significant deficits in speech and deglutition. A functional neotongue requires adequate soft tissue bulk and restoration of coordinated muscle function. Tissue engineering, a scientific approach that allows introduction of isolated cell populations of interest within 3-dimensional polymer scaffolds to create new tissue, may allow the generation of more highly functional tissue in tongue reconstruction. OBJECTIVES: To apply muscle-tissue engineering techniques in the reconstruction of partial glossectomy defects in rats, and to compare the gross and histological nature of tissue found after reconstruction of the hemiglossectomy defect with acellular vs tissue-engineered composite material. MATERIALS AND METHODS: Thirty mature Lewis rats underwent a left-sided mucosa-sparing partial glossectomy. The defects were then filled with 1 of the following 3 substances: isotonic sodium chloride solution, a collagen-rich hydrogel, or hydrogel containing a suspension of neonatal myoblasts from syngeneic rats. The animals were killed after 6 weeks and the tongues were harvested. The control and operated-on tongue halves were evaluated for weight differences and histological features. RESULTS: The group receiving the hydrogel-myoblast composite injections demonstrated a statistically significant increase in tongue weight of the operated-on side compared with the control side. In contrast, the isotonic sodium chloride solution and hydrogel groups demonstrated loss of tongue weight. These findings correlated with the results of the histological evaluation. Hemitongues from the composite group demonstrated formation of new tissue with areas of musclelike tissue extending from islands of residual hydrogel, and we found evidence of neovascularization and possible neurotization. In contrast, the isotonic sodium chloride solution group exhibited dense fibrous scar with loss of muscle architecture and dramatic loss of tongue volume. The hydrogel group demonstrated preservation of tongue volume with persistent islands of gel, but no clear evidence of new tissue formation. CONCLUSIONS: The introduction of a hydrogel into the rat hemiglossectomy pocket appears to promote volume preservation and/or muscle regeneration. The addition of myoblasts suspended in collagen gel supports the development of new tissue that preserves weight and volume after hemiglossectomy and may possess muscle properties similar to the tissue desired. This tissue-engineering approach represents a promising new strategy in tongue reconstruction and merits further investigation into the possible functional advantages it offers compared with current techniques.

Animals↗
PubMedDate not supplied

Delirium in the postoperative cardiac patient: a review.

UNLABELLED: BACKGROUND AND AIM OF REVIEW: Cardiac surgery is increasingly common and relatively safe, but there are frequent reports of neuropsychiatric sequelae occurring in the postoperative period. One of the most common neuropsychiatric presentations of cardiac surgery is delirium, also called postcardiotomy delirium (PCD). Despite the vast numbers of cardiac surgeries performed today, there is a paucity of data on risk factors and management options of PCD available to the clinician. This review aims to summarize available information, increase clinicians' awareness of PCD and suggest effective management of this illness. METHODS: Our literature search was completed using the databases Medline and CINAHL; it was limited to human and English language studies from 1964 to the present. Search terms included "delirium," "agitation," "postoperative," "cardiac," "neuropsychiatric," "neuroleptics," "psychosis," "surgery," "treatment," "postcardiotomy," and "pharmacotherapy." RESULTS: Our review of the literature revealed several risk factors for PCD, as well as various options for its pharmacological management. CONCLUSIONS: A multifactorial model should be applied when considering risk stratification for and prevention of delirium postoperatively. Pharmacologically, conventional antipsychotic agents, such as haloperidol, have long been used to manage delirium. In light of haloperidol's side effects, particularly those applicable to the cardiac patient, further research is required into the role of second generation antipsychotics. These agents are common in clinical use, and may be the preferred medications.

Cardiac Surgical Procedures↗