Jean P. O'Malley

Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes

Periventricular white matter injury (PWMI) is the leading cause of cerebral palsy and chronic neurological disability in survivors of prematurity. Despite the large number of affected children, the pathogenetic mechanisms related to PWMI remain controversial. Through studies of 33 human autopsy brains, we determined that early PWMI was related to oxidative damage that particularly targeted the oligodendrocyte lineage, whereas other neuronal and glial cell types were markedly more resistant. F2‐isoprostanes, an arachidinate metabolite/lipid peroxidation marker of oxidative damage, were significantly increased in early PWMI lesions but not in cerebral cortex. That deleterious lipid peroxidation accompanied early PWMI was supported by similar increases in F2‐isoprostanes levels in the cerebral cortex from term infants with hypoxic‐ischemic cortical injury. Detection of F4‐neuroprostanes, a neuronal‐specific oxidative damage marker, confirmed that neuroaxonal elements were resistant to injury in cerebral cortex and white matter. Significant protein nitration was not detected in PWMI lesions by 3‐nitrotyrosine staining. Significant cellular degeneration was confirmed in early PWMI lesions by terminal deoxynucleotidyltransferase–mediated dUTP nick end labeling and a marked depletion of oligodendrocyte progenitors of 71 ± 8%. Hence, the predilection of preterm infants for PWMI is related to selective lipid peroxidation–mediated injury of cerebral white matter and targeted death of oligodendrocyte progenitors. Ann Neurol 2005;58:108–120

Assessment of the Psychometric Properties of the Family Management Measure

OBJECTIVE This paper reports development of the Family Management Measure (FaMM) of parental perceptions of family management of chronic conditions. METHOD By telephone interview, 579 parents of children age 3 to 19 with a chronic condition (349 partnered mothers, 165 partners, 65 single mothers) completed the FaMM and measures of child functional status and behavioral problems and family functioning. Analyses addressed reliability, factor structure, and construct validity. RESULTS Exploratory factor analysis yielded six scales: Childs Daily Life, Condition Management Ability, Condition Management Effort, Family Life Difficulty, Parental Mutuality, and View of Condition Impact. Internal consistency reliability ranged from .72 to .91, and test-retest reliability from .71 to .94. Construct validity was supported by significant correlations in hypothesized directions between FaMM scales and established measures. CONCLUSION Results support FaMMs; reliability and validity, indicating it performs in a theoretically meaningful way and taps distinct aspects of family response to childhood chronic conditions.

The influence of apolipoprotein E phenotype on the response to lovastatin therapy in patients with heterozygous familial hypercholesterolemia

Apolipoprotein E (apo E) phenotypes have been previously shown to influence plasma lipoprotein concentrations in normal populations and to affect the response to some lipid lowering drugs. The purpose of the present study was to determine if variations in the apo E phenotype also affect basal lipoprotein concentrations in patients with heterozygous familial hypercholesterolemia (FH) and if the apo E phenotype influenced their subsequent response to lovastatin. Apo E phenotypes were determined on plasma from 134 FH patients. The relative frequencies of the epsilon 2, epsilon 3, and epsilon 4 alleles were .090, .772, and .138, respectively. Plasma triglycerides were found to be 34% higher in E3/2 heterozygotes relative to E3/3 patients. Baseline concentrations of low-density lipoprotein (LDL) cholesterol in untreated FH patients were not influenced by the apo E phenotype; the hypolipidemic response to lovastatin (20 or 40 mg twice daily) was also independent of the apo-E phenotype of the patients.

Sequential Immunization with a Subtype B HIV-1 Envelope Quasispecies Partially Mimics the In Vivo Development of Neutralizing Antibodies

ABSTRACT A major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is the design of Envelope (Env)-based immunogens effective at eliciting heterologous or broad neutralizing antibodies (NAbs). We hypothesized that programming the B-cell response could be achieved by sequentially exposing the host to a collection of env variants representing the viral quasispecies members isolated from an individual that developed broad NAbs over time. This ordered vaccine approach (sequential) was compared to exposure to a cocktail of env clones (mixture) and to a single env variant (clonal). The three strategies induced comparable levels of the autologous and heterologous neutralization of tier 1 pseudoviruses. Sequential and mixture exposure to quasispecies led to epitope targeting similar to that observed in the simian-human immunodeficiency virus (SHIV)-infected animal from which the env variants were cloned, while clonal and sequential exposure led to greater antibody maturation than the mixture. Therefore, the sequential vaccine approach best replicated the features of the NAb response observed in that animal. This study is the first to explore the use of a collection of HIV-1 env quasispecies variants as immunogens and to present evidence that it is possible to educate the B-cell response by sequential exposure to native HIV-1 quasispecies env variants derived from an individual with a broadened NAb response.

The hypolipidemic effects of lovastatin and clofibrate alone and in combination in patients with type III hyperlipoproteinemia

The hypolipidemic effects of lovastatin and clofibrate have been evaluated in 12 patients with type III hyperlipoproteinemia. In these patients plasma concentrations of total cholesterol decreased from 500 +/- 56 mg/dL (mean +/- SEM) at baseline to 278 +/- 23 mg/dL on lovastatin (20 mg twice daily), and were 299 +/- 15 mg/dL during treatment with clofibrate (1 g twice daily). Nine patients were treated sequentially with lovastatin at doses of 20 and 40 mg twice daily and clofibrate; in these patients total plasma cholesterol concentrations decreased from 549 +/- 67 mg/dL at baseline to 291 +/- 24 mg/dL on lovastatin (20 mg twice daily), 247 +/- 20 mg/dL (40 mg twice daily) and were 297 +/- 18 mg/dL on monotherapy with clofibrate. Concentrations of very-low-density lipoprotein (VLDL) cholesterol were similar on clofibrate and the higher dose of lovastatin, whereas concentrations of low-density lipoprotein (LDL) cholesterol were significantly lower on lovastatin. In six patients who remained hyperlipidemic on monotherapy with either drug, combination drug therapy with lovastatin (20 mg twice daily) plus clofibrate reduced plasma concentrations of total cholesterol from 635 +/- 79 mg/dL to 205 +/- 11 mg/dL. No patients were discontinued from single or combined drug therapy and no significant biochemical abnormalities were observed. The results of this study demonstrate the potential usefulness of lovastatin in the therapy of type III hyperlipoproteinemia and indicate that, in selected patients who remain hypercholesterolemic on monotherapy with either clofibrate or lovastatin, combination drug therapy with both of these drugs is effective in further reducing plasma concentrations of total, VLDL, and LDL cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlates of Utilization of PTSD Specialty Treatment Among Recently Diagnosed Veterans at the VA

OBJECTIVES This study described utilization of specialty treatment for posttraumatic stress disorder (PTSD) at U.S. Department of Veterans Affairs (VA) facilities among veterans of Operation Enduring Freedom (OEF), in Afghanistan, or of Operation Iraqi Freedom (OIF), in Iraq, and non-OEF-OIF veterans recently diagnosed as having PTSD. It also identified predictors of receiving minimally adequate specialty treatment, defined as attending at least nine clinic visits within 365 days of screening positive for PTSD. METHODS VA administrative data were obtained for 869 veterans who screened positive for PTSD between November 7, 2006, and September 30, 2008, received a diagnosis of PTSD, and visited a PTSD specialty clinic operated by the VA in the Pacific Northwest at least once within a year of screening positive. RESULTS A total of 286 (33%) of the 852 veterans for whom complete data were available received minimally adequate specialty treatment; OEF-OIF veterans were less likely than non-OEF-OIF veterans to receive minimally adequate specialty treatment (29% versus 36%, p=.021) and attended fewer mean±SD visits to a PTSD clinic (8.2±11.4 versus 9.9±13.5, p=.045). Predictors of receiving minimally adequate specialty treatment included attending a PTSD clinic visit within 30 days of a positive screen, living in an urban location, and having psychiatric comorbidities. CONCLUSIONS Most veterans with new PTSD diagnoses who initiated VA PTSD specialty care did not receive minimally adequate specialty treatment. Future studies should examine factors that lead to premature discontinuation of PTSD treatment and to what extent specialty treatment for PTSD is necessary.

Validation of a Care and Comfort Hypertonicity Questionnaire

The lack of evidence regarding functional and quality of life benefits resulting from tone reduction with intrathecal baclofen (ITB) infusion treatment relates to the lack of validated and responsive measures. We integrated our scale/questionnaire, developed from chart review, with the non‐validated Caregiver Questionnaire (CQ) to yield a final document, the Care and Comfort Hypertonicity Questionnaire (CCHQ). Convergent validity was achieved by administering the CCHQ to 47 patients with spastic/dystonic cerebral palsy (CP) who were being evaluated for tone management. The population studied included 18 females and 29 males (mean age 10y [SD 4y 10mo]; range 3y 1mo–21y 1mo). Twenty‐five patients were subsequently referred for botulinum toxin (BTX‐A) injections (mean Gross Motor Function Classification System [GMFCS] 3.2); 11 patients were referred for ITB (mean GMFCS 4.4); four were referred for orthopedic surgery (mean GMFCS 3.3); 3 were referred for selective dorsal rhizotomy (mean GMFCS 2.7); one was recommended for oral baclofen (GMFCS 5); and three were recommended for no treatment (mean GMFCS 3.7). Blinded to the score, those with the highest scores (severe hypertonicity) were recommended for ITB; those with the lowest scores were recommended for BTX‐A injections. Responsiveness of the CCHQ was established by administering the questionnaire to patients who already had an implanted ITB pump. The children with the largest dose increase demonstrated a statistically significant improvement in the CCHQ score. This scale can be used to document the efficacy or treating severe hypertonicity both in clinical and research protocols.

Influence of health insurance coverage on breast, cervical, and colorectal cancer screening in rural primary care settings.

The current study was performed to determine, in rural settings, the relation between the type and status of insurance coverage and being up‐to‐date for breast, cervical, and colorectal cancer screening.

GABAergic System Gene Expression Predicts Clinical Outcome in Patients With Neuroblastoma

PURPOSE Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinical behavior. The purpose of this study was to identify potential NB biomarkers that may improve outcome prediction. PATIENTS AND METHODS The suppression subtractive hybridization (SSH) technique was used to identify the genes differentially expressed between NB and control tissue. RNA isolated from 235 primary NB tumor samples obtained from the Childrens Cancer Group was evaluated for expression of the candidate markers using quantitative reverse transcriptase polymerase chain reaction (Taqman assays). The association between the mRNA expression levels in the identified candidate genes and clinical outcome was evaluated. RESULTS SSH analysis identified differential expression of members of the GABAergic gene family in NB. Lower levels of gamma-aminobutyric acid (GABA) receptor-associated protein (GABARAP) gene expression predict decreased survival among all patients. GABA(A) delta receptor subunit gene expression was predictive of a poor outcome among Evans stage IV-S patients. An index of five coexpressed GABA(A) receptor subunits was identified (GABA(A) profile [GAP score]). Patients with a higher GAP score (> -1) had a survival advantage. Multivariate analysis showed that GABARAP and GABA(A) alpha2 receptor subunit gene expression levels and GAP score remained predictors of clinical outcome after accounting for current prognostic indicators. CONCLUSION Dysregulation of the GABAergic system may constitute a fundamental event in the development of NB, and assessment of GABAergic system gene expression could provide improved patient stratification and potential new therapies.

Agreement of Medicaid claims and electronic health records for assessing preventive care quality among adults.

To compare the agreement of electronic health record (EHR) data versus Medicaid claims data in documenting adult preventive care. Insurance claims are commonly used to measure care quality. EHR data could serve this purpose, but little information exists about how this source compares in service documentation. For 13 101 Medicaid-insured adult patients attending 43 Oregon community health centers, we compared documentation of 11 preventive services, based on EHR versus Medicaid claims data. Documentation was comparable for most services. Agreement was highest for influenza vaccination (κ =  0.77; 95% CI 0.75 to 0.79), cholesterol screening (κ = 0.80; 95% CI 0.79 to 0.81), and cervical cancer screening (κ = 0.71; 95% CI 0.70 to 0.73), and lowest on services commonly referred out of primary care clinics and those that usually do not generate claims. EHRs show promise for use in quality reporting. Strategies to maximize data capture in EHRs are needed to optimize the use of EHR data for service documentation.