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1.  Key roles for GRB2-associated-binding protein 1, phosphatidylinositol-3-kinase, cyclooxygenase 2, prostaglandin E2 and transforming growth factor alpha in linoleic acid-induced upregulation of lung and breast cancer cell growth 
The omega-6 polyunsaturated fatty acid linoleic acid (LA; C18:2 n-6) is prevalent in Western diets and has been shown to enhance tumorigenesis of several cancer models. However, the modes by which LA affects carcinogenesis have not been fully elucidated. In this study, a mechanism for LA-induced upregulation of cancer cell growth is defined. Cellular proliferation was enhanced with LA treatment in BT-474 human breast ductal carcinoma and A549 human lung adenocarcinoma cell lines. Enrichment of LA increased COX activity and led to increases in PGE2 production, followed by increases in MMP and TGF-α levels, which are all key elements involved in the enhancement of cancer cell growth. Further investigation revealed that LA supplementation in both BT-474 breast and A549 lung cancer cell lines greatly increased the association between the scaffolding protein Gab1 and EGFR, while at the same time dramatically decreasing Gab1 protein levels. These changes are concomitant with increases in activated Akt (pAkt), a downstream signaling component in the PI3K signaling pathway. Moreover, inhibitors of EGFR, PI3K and Gab1-specific siRNAs were capable of reversing LA-induced upregulation of pAkt, as well as observed increases in cell proliferation for these models. These data establish Gab1 as major target in LA-induced enhancement of tumorigenesis.
PMCID: PMC4138981  PMID: 24374147
2.  Identifying environmental health priorities in underserved populations: a study of rural versus urban communities 
Public health  2013;127(11):994-1004.
Understanding and effectively addressing persistent health disparities in minority communities requires a clear picture of members’ concerns and priorities. This study was intended to engage residents in urban and rural communities in order to identify environmental health priorities. Specific emphasis was placed on how the communities defined the term environment, their perceptions of environmental exposures as affecting their health, specific priorities in their communities, and differences in urban versus rural populations.
Study design
A community-engaged approach was used to develop and implement focus groups and compare environmental health priorities in urban versus rural communities.
A total of eight focus groups were conducted: four in rural and four in urban communities. Topics included defining the term environment, how the environment may affect health, and environmental priorities within their communities, using both open discussion and a predefined list. Data were analysed both qualitatively and quantitatively to identify patterns and trends.
There were important areas of overlap in priorities between urban and rural communities; both emphasized the importance of the social environment and shared a concern over air pollution from industrial sources. In contrast, for urban focus groups, abandoned houses and their social and physical sequelae were a high priority while concerns about adequate sewer and water services and road maintenance were high priorities in rural communities.
This study was able to identify environmental health priorities in urban versus rural minority communities. In contrast to some previous risk perception research, the results of this study suggest prioritization of tangible, known risks in everyday life instead of rare, disaster-related events, even in communities that have recently experienced devastating damage from tornadoes. The findings can help inform future efforts to study, understand and effectively address environmental issues, and are particularly relevant to developing effective community-based strategies in vulnerable populations.
PMCID: PMC3851598  PMID: 24239281
Community-engaged approach; Rural versus urban communities; Minority populations; Community-based interventions; Risk perception
3.  Display of consistent ictal networks in refractory mesial temporal lobe epilepsy 
Exploration of emergent ictal networks was performed in homogeneous subjects with refractory medial temporal lobe epilepsy.
Maximal Synchrony Index (SI) values were calculated for all electrode pairs for each second during 25 seizures and displayed as connectivity animations. Consistent temporal patterns of SI value and spatial connectivity were observed across seizures and subjects, and used to define a sequence of network stages.
Highest SI values were found in electrodes within the area of surgical resection. Analysis of these electrodes by network stage demonstrated lateral temporal cortex dominance at seizure initiation, giving way to hippocampal synchrony during the major portion of the seizure, with lateral temporal regions re-emerging as the seizure terminated. SI values also corresponded to behavioral severity of seizures, and lower SI values were associated with post-surgical seizure freedom.
SI based methods of network characterization consistently display the intrinsic MTLE ictal network and may be sensitive to clinical features.
Consistency of EEG-derived network patterns is an important step as network features are applied towards improvement of clinical management. These data confirm consistency of network patterns within and across subjects and support the potential for these methods to distinguish relevant clinical variables.
PMCID: PMC4215559  PMID: 23639378
Epilepsy; Hippocampus; Synchrony; Temporal lobectomy; Seizure; EEG; Quantitative EEG
4.  Effects of traumatic brain injury on intestinal contractility 
Patients with traumatic brain injury (TBI) often suffer from gastrointestinal dysfunction including intolerance to enteral feedings. However, it is unclear how TBI affects small intestinal contractile activity. The purpose of this study was to determine if TBI affects intestinal smooth muscle function.
Sprague–Dawley rats were subjected to controlled cortical impact injury (TBI). Sham animals underwent a similar surgery but no injury (SHAM). Animals were sacrificed 1, 3, and 7 days after TBI and intestinal smooth muscle tissue was collected for measurement of contractile activity and transit, NF-kB activity, and cytokine levels. Brains were collected after sacrifice to determine volume loss due to injury.
Key Results
Contractile activity decreased significantly in ileum, but not jejunum, in the TBI group 7 days after injury compared with SHAM. Brain volume loss increased significantly 7 days after injury compared with 3 days and correlated significantly with the contractile activity 1 day after injury. In the intestinal smooth muscle, NF-kB activity increased significantly in the TBI group 3 and 7 days after injury vs SHAM. Wet to dry weight ratio, indicating edema, also increased significantly in the TBI group. Interleukin- 1α, -1β, and -17 increased significantly in the TBI group compared with SHAM.
Conclusions & Inferences
Traumatic brain injury causes a delayed but significant decrease in intestinal contractile activity in the ileum leading to delayed transit. The decreased intestinal contractile activity is attributed to secondary inflammatory injury as evidenced by increased NF-kB activity, increased edema, and increased inflammatory cytokines in the intestinal smooth muscle.
PMCID: PMC3982791  PMID: 23551971
brain injury; inflammation; intestinal contractility
One advantage of using cartilage to replace/repair bone is that the implant disappears as bone is formed by endochondral ossification. Previously, we showed that cartilage spheroids, grown in a rotating bioreactor (Synthecon, Inc.) and implanted into a 2 mm skull defect, contributed to healing of the defect. Skulls with or without implants were subjected to microCT scans. Mineralized regions from microCT sections correlated with regions of bone in histological sections of the defect region of demineralized skulls. Recently, sections from microCT scans of live mice were compared to histological sections from the same mice. The area of the defect staining for bone in histological sections of demineralized skulls was the same region shown as mineralized in microCT sections. Defects without implants were not healed. This study demonstrates that microCT scans are an important corollary to histological studies evaluating the use of implants in healing of bony defects.
PMCID: PMC3902829  PMID: 24478573
6.  Literature Search Strategies for Conducting Knowledge-building and Theory-generating Qualitative Systematic Reviews: Discussion Paper 
Journal of advanced nursing  2012;69(1):194-204.
This paper is a report of literature search strategies for the purpose of conducting knowledge-building and theory-generating qualitative systematic reviews.
Qualitative systematic reviews lie on a continuum from knowledge-building and theory-generating to aggregating and summarizing. Different types of literature searches are needed to optimally support these dissimilar reviews.
Data Sources
Articles published between 1989 - Autumn 2011. These documents were identified using a hermeneutic approach and multiple literature search strategies.
Redundancy is not the sole measure of validity when conducting knowledge-building and theory-generating systematic reviews. When conducting these types of reviews, literature searches should be consistent with the goal of fully explicating concepts and the interrelationships among them. To accomplish this objective, a berry picking approach is recommended along with strategies for overcoming barriers to finding qualitative research reports.
To enhance integrity of knowledge-building and theory-generating systematic reviews, reviewers are urged to make literature search processes as transparent as possible, despite their complexity. This includes fully explaining and rationalizing what databases were used and how they were searched. It also means describing how literature tracking was conducted and grey literature was searched. In the end, the decision to cease searching also needs to be fully explained and rationalized.
Predetermined linear search strategies are unlikely to generate search results that are adequate for purposes of conducting knowledge-building and theory-generating qualitative systematic reviews. Instead, it is recommended that iterative search strategies take shape as reviews evolve.
PMCID: PMC3424349  PMID: 22591030
Qualitative systematic review; literature search; sample; theory development; knowledge development; validity; nurse
7.  Long-term outcomes of urinary tract reconstruction in patients with neurogenic urinary tract dysfunction 
The advent of specialized spinal units and better understanding of the pathophysiology of neurogenic urinary tract dysfunction has made long-term survival of these patients a reality. This has, in turn, led to an increase in quality and choice of management modalities offered to these patients including complex anatomic urinary tract reconstructive procedures tailored to the unique needs of each individual with variable outcomes. We performed a literature review evaluating the long-term outcomes of these reconstructive procedures. To achieve this, we conducted a world-wide electronic literature search of long-term outcomes published in English. As the premise of this review is long-term outcomes, we have focused on pathologies where evidence of long-term outcome is available such as patients with spinal injuries and spina bifida. Therapeutic success following urinary tract reconstruction is usually measured by preservation of renal function, improvement in quality-of-life, the satisfactory achievement of agreed outcomes and the prevention of serious complications. Prognostic factors include neuropathic detrusor overactivity; sphincter dyssynergia; bladder over distension; high pressure storage and high leak point pressures; vesicoureteric reflex, stone formation and urinary tract infections. Although, the past decade has witnessed a reduction in the total number of bladder reconstructive surgeries in the UK, these procedures are essentially safe and effective; but require long-term clinical and functional follow-up/monitoring. Until tissue engineering and gene therapy becomes more mainstream, we feel there is still a place for urinary tract reconstruction in patients with neurogenic lower urinary tract dysfunction.
PMCID: PMC3822350  PMID: 24235796
Botulinum toxin; clam augmentation; clam cystoplasty; conduit urinary diversion; continent diversion; detrusor myomectomy; enterocystoplasy; ileocystoplasty; long-term outcome; neobladder; neurogenic; reconstruction; review; sphincterotomy; spinal cord injury; urethral stent; urinary tract dysfunction
9.  Examining new phylogenetic markers to uncover the evolutionary history of early-diverging fungi: comparing MCM7, TSR1 and rRNA genes for single- and multi-gene analyses of the Kickxellomycotina 
The recently recognised protein-coding genes MCM7 and TSR1 have shown significant promise for phylogenetic resolution within the Ascomycota and Basidiomycota, but have remained unexamined within other fungal groups (except for Mucorales). We designed and tested primers to amplify these genes across early-diverging fungal clades, with emphasis on the Kickxellomycotina, zygomycetous fungi with characteristic flared septal walls forming pores with lenticular plugs. Phylogenetic tree resolution and congruence with MCM7 and TSR1 were compared against those inferred with nuclear small (SSU) and large subunit (LSU) rRNA genes. We also combined MCM7 and TSR1 data with the rDNA data to create 3- and 4-gene trees of the Kickxellomycotina that help to resolve evolutionary relationships among and within the core clades of this subphylum. Phylogenetic inference suggests that Barbatospora, Orphella, Ramicandelaber and Spiromyces may represent unique lineages. It is suggested that these markers may be more broadly useful for phylogenetic studies among other groups of early-diverging fungi.
PMCID: PMC3734964  PMID: 24027350
DNA replication licensing factor; Harpellales; Kickxellomycotina; MCM7; MS277; MS456; ribosomal biogenesis protein; Trichomycetes; TSR1; Zygomycota
10.  Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole, Itraconazole, Posaconazole, and Voriconazole 
Antimicrobial Agents and Chemotherapy  2012;56(11):5898-5906.
Epidemiological cutoff values (ECVs) for the Cryptococcus neoformans-Cryptococcus gattii species complex versus fluconazole, itraconazole, posaconazole, and voriconazole are not available. We established ECVs for these species and agents based on wild-type (WT) MIC distributions. A total of 2,985 to 5,733 CLSI MICs for C. neoformans (including isolates of molecular type VNI [MICs for 759 to 1,137 isolates] and VNII, VNIII, and VNIV [MICs for 24 to 57 isolates]) and 705 to 975 MICs for C. gattii (including 42 to 260 for VGI, VGII, VGIII, and VGIV isolates) were gathered in 15 to 24 laboratories (Europe, United States, Argentina, Australia, Brazil, Canada, Cuba, India, Mexico, and South Africa) and were aggregated for analysis. Additionally, 220 to 359 MICs measured using CLSI yeast nitrogen base (YNB) medium instead of CLSI RPMI medium for C. neoformans were evaluated. CLSI RPMI medium ECVs for distributions originating from at least three laboratories, which included ≥95% of the modeled WT population, were as follows: fluconazole, 8 μg/ml (VNI, C. gattii nontyped, VGI, VGIIa, and VGIII), 16 μg/ml (C. neoformans nontyped, VNIII, and VGIV), and 32 μg/ml (VGII); itraconazole, 0.25 μg/ml (VNI), 0.5 μg/ml (C. neoformans and C. gattii nontyped and VGI to VGIII), and 1 μg/ml (VGIV); posaconazole, 0.25 μg/ml (C. neoformans nontyped and VNI) and 0.5 μg/ml (C. gattii nontyped and VGI); and voriconazole, 0.12 μg/ml (VNIV), 0.25 μg/ml (C. neoformans and C. gattii nontyped, VNI, VNIII, VGII, and VGIIa,), and 0.5 μg/ml (VGI). The number of laboratories contributing data for other molecular types was too low to ascertain that the differences were due to factors other than assay variation. In the absence of clinical breakpoints, our ECVs may aid in the detection of isolates with acquired resistance mechanisms and should be listed in the revised CLSI M27-A3 and CLSI M27-S3 documents.
PMCID: PMC3486550  PMID: 22948877
11.  Perceived Competency and Resolution of Homelessness Among Women with Substance Abuse Problems 
Qualitative Health Research  2011;22(3):416-427.
Using a metasynthesis approach, our aim was to articulate new insights relating to the most efficient and effective means of helping homeless women with substance abuse problems to enhance their well-being and become more stably housed. Distorted perceptions of competency, which are shaped by dysfunctional relationships and mental health problems, make it challenging for women with substance abuse problems to resolve homelessness. Women with particularly low or high levels of perceived competency tend to grapple with challenges related to structure and control, trust, and hopelessness. Therapeutic strategies for approaching these women include careful assessment, caring, personalized structure and control, development of interpersonal trust, instillation of hope, and the targeted use of psychotherapeutic agents and counseling. Framing care for homeless women within the context of perceived competency offers a new way of understanding their plight and shaping interventions to more expeditiously move them toward healthy and stable lives.
PMCID: PMC3260396  PMID: 21890717
addiction/substance use; homelessness; metasynthesis; poverty; women’s health
12.  Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Amphotericin B and Flucytosine 
Clinical breakpoints (CBPs) are not available for the Cryptococcus neoformans-Cryptococcus gattii species complex. MIC distributions were constructed for the wild type (WT) to establish epidemiologic cutoff values (ECVs) for C. neoformans and C. gattii versus amphotericin B and flucytosine. A total of 3,590 amphotericin B and 3,045 flucytosine CLSI MICs for C. neoformans (including 1,002 VNI isolates and 8 to 39 VNII, VNIII, and VNIV isolates) and 985 and 853 MICs for C. gattii, respectively (including 42 to 259 VGI, VGII, VGIII, and VGIV isolates), were gathered in 9 to 16 (amphotericin B) and 8 to 13 (flucytosine) laboratories (Europe, United States, Australia, Brazil, Canada, India, and South Africa) and aggregated for the analyses. Additionally, 442 amphotericin B and 313 flucytosine MICs measured by using CLSI-YNB medium instead of CLSI-RPMI medium and 237 Etest amphotericin B MICs for C. neoformans were evaluated. CLSI-RPMI ECVs for distributions originating in ≥3 laboratories (with the percentages of isolates for which MICs were less than or equal to ECVs given in parentheses) were as follows: for amphotericin B, 0.5 μg/ml for C. neoformans VNI (97.2%) and C. gattii VGI and VGIIa (99.2 and 97.5%, respectively) and 1 μg/ml for C. neoformans (98.5%) and C. gattii nontyped (100%) and VGII (99.2%) isolates; for flucytosine, 4 μg/ml for C. gattii nontyped (96.4%) and VGI (95.7%) isolates, 8 μg/ml for VNI (96.6%) isolates, and 16 μg/ml for C. neoformans nontyped (98.6%) and C. gattii VGII (97.1%) isolates. Other molecular types had apparent variations in MIC distributions, but the number of laboratories contributing data was too low to allow us to ascertain that the differences were due to factors other than assay variation. ECVs may aid in the detection of isolates with acquired resistance mechanisms.
PMCID: PMC3370763  PMID: 22391546
13.  Catastrophizing: a predictor of persistent pain among women with endometriosis at 1 year 
Human Reproduction (Oxford, England)  2011;26(11):3078-3084.
Endometriosis is the most common gynecological diagnosis among women with chronic pelvic pain, but the underlying mechanisms of endometriosis-associated chronic pelvic pain remain unclear. Therefore, the objective of this study was to determine the biopsychosocial predictors of pain improvement among women with endometriosis.
One hundred and fifteen women who presented for treatment of endometriosis-associated chronic pelvic pain at a tertiary referral center at a university-based hospital participated in this prospective observational study of clinical practice. Participants completed questionnaires assessing pain, mental health and catastrophizing at entry and 1 year follow-up. The main outcome measure assessed was the interval change in pain report using the McGill pain 1uestionnaire.
On average, participants experienced a 37.4% reduction in interval pain (P < 0.001). Adjusted for baseline pain, nulliparity (P = 0.002) and catastrophizing (P = 0.04) were associated with decreased probability of interval improvement in pain. Those referred for physical therapy had less interval pain improvement (P = 0.04). However, undergoing hysterectomy was a strong predictor of improvement in pain (P = 0.008).
Our study suggests that chronic pain in endometriosis may be more akin to other idiopathic pain disorders. Specifically, biopsychosocial variables, such as catastrophizing, play an important role in reported severity. Further research on biopsychosocial correlates of chronic pelvic pain in endometriosis is warranted.
PMCID: PMC3196877  PMID: 21900393
chronic pelvic pain; endometriosis; catastrophizing; pain-related outcomes; psychological factors
14.  Therapeutic Substance Abuse Treatment for Incarcerated Women 
Clinical nursing research  2011;20(4):462-481.
The purpose of this qualitative systematic review was to explicate attributes of optimal therapeutic strategies for treating incarcerated women who have a history of substance abuse. An expansive search of electronic databases for qualitative research reports relating to substance abuse treatment for incarcerated women was conducted. Nine qualitative research reports comprised the sample for this review. Findings from these reports were extracted, placed into a data analysis matrix, coded, and categorized. Memos were written, and strategies for treating incarcerated women with alcohol problems were identified. Therapeutic effects of treatment programs for incarcerated women with substance-abuse problems appear to be enhanced when trust-based relationships are established, individualized and just care is provided, and treatment facilities are separate from the general prison environment.
PMCID: PMC3201785  PMID: 21771929
Incarceration; substance abuse treatment; systematic review; therapeutic communities; women
15.  Expanded dog leukocyte antigen (DLA) single nucleotide polymorphism (SNP) genotyping reveals spurious class II associations 
The dog leukocyte antigen (DLA) system contains many of the functional genes of the immune system, thereby making it a candidate region for involvement in immune-mediated disorders. A number of studies have identified associations between specific DLA class II haplotypes and canine immune hemolytic anemia, thyroiditis, immune polyarthritis, type I diabetes mellitus, hypoadrenocorticism, systemic lupus erythematosus-related disease complex, necrotizing meningoencephalitis (NME) and anal furunculosis. These studies have relied on sequencing approximately 300 bases of exon 2 of each of the DLA class II genes: DLA-DRB1, DLA-DQA1 and DLA-DQB1. An association (odds ratio = 4.29) was identified by this method between Weimaraner dogs with hypertrophic osteodystrophy (HOD) and DLA-DRB1*01501.
In the present study, a genotyping assay of 126 coding single nucleotide polymorphisms (SNPs) from across the entire DLA, spanning a region of 2.5 Mb (3,320,000–5,830,000) on CFA12, was developed and tested on Weimaraners with HOD, as well as two additional breeds with diseases associated with DLA class II: Nova Scotia duck tolling retrievers with hypoadrenocorticism and Pug dogs with NME. No significant associations were found between Weimaraners with HOD or Nova Scotia duck tolling retrievers with hypoadrenocorticism and SNPs spanning the DLA region. In contrast, significant associations were found with NME in Pug dogs, although the associated region extended beyond the class II genes. By including a larger number of genes from a larger genomic region a SNP genotyping assay was generated that provides coverage of the extended DLA region and may be useful in identifying and fine mapping DLA associations in dogs.
PMCID: PMC3152640  PMID: 21741283
Canine; Inherited disorders; Major histocompatibility complex (MHC); Dog leukocyte antigen (DLA); Disease associations
16.  Viral Life Cycles Captured in Three-Dimensions with Electron Microscopy Tomography 
Current opinion in virology  2011;1(2):125-133.
Viruses hijack host cell functions and optimize them for viral replication causing a severe threat to human health. However, viruses are also tools to understand cell biology and they may be effective reagents in nano-medicine. Studies from the molecular to cellular levels are aimed at understanding the details of viral life cycles and the underlying virus-host interactions. Recent developments in electron microscopy tomography allow viral and cellular events to be observed in fine structural detail in three-dimension. By combining high-resolution structures of individual proteins and macro-complexes obtained by crystallography and electron cryo-microscopy and image reconstruction with reconstructions performed on sub-tomographic volumes, electron tomography has advanced the structural and mechanistic understanding of virus infections both in vitro and in host cells.
PMCID: PMC3163493  PMID: 21887207
Electron tomography; Virus
17.  Wild-Type MIC Distributions and Epidemiological Cutoff Values for Amphotericin B and Aspergillus spp. for the CLSI Broth Microdilution Method (M38-A2 Document)▿ 
Antimicrobial Agents and Chemotherapy  2011;55(11):5150-5154.
Although clinical breakpoints have not been established for mold testing, epidemiological cutoff values (ECVs) are available for Aspergillus spp. versus the triazoles and caspofungin. Wild-type (WT) MIC distributions (organisms in a species-drug combination with no acquired resistance mechanisms) were defined in order to establish ECVs for six Aspergillus spp. and amphotericin B. Two sets (CLSI/EUCAST broth microdilution) of available MICs were evaluated: those for A. fumigatus (3,988/833), A. flavus (793/194), A. nidulans (184/69), A. niger (673/140), A. terreus (545/266), and A. versicolor (135/22). Three sets of data were analyzed: (i) CLSI data gathered in eight independent laboratories in Canada, Europe, and the United States; (ii) EUCAST data from a single laboratory; and (iii) the combined CLSI and EUCAST data. ECVs, expressed in μg/ml, that captured 95%, 97.5%, and 99% of the modeled wild-type population (CLSI and combined data) were as follows: for A. fumigatus, 2, 2, and 4; for A. flavus, 2, 4, and 4; for A. nidulans, 4, 4, and 4; for A. niger, 2, 2, and 2; for A. terreus, 4, 4, and 8; and for A. versicolor, 2, 2, and 2. Similar to the case for the triazoles and caspofungin, amphotericin B ECVs may aid in the detection of strains with acquired mechanisms of resistance to this agent.
PMCID: PMC3195003  PMID: 21876047
19.  Fulminant encephalopathy with basal ganglia hyperintensities in HIV-infected drug users 
Neurology  2011;76(9):787-794.
To define a clinical syndrome associated with active drug abuse in HIV-infected individuals.
We performed a retrospective review to identify individuals treated at the Johns Hopkins Hospital from 1993 to 2008 who were HIV-infected and were actively abusing drugs and had bilateral basal ganglia lesions on MRI. They were identified using a key word search in the radiology database, autopsy database, and the Moore HIV clinic database. Clinical, laboratory, and radiographic findings were correlated to define the syndrome.
Ten individuals were identified who presented with a change in mental status or seizures, used cocaine or cocaine with heroin, had uncontrolled HIV infection (>190,000 copies/mL of plasma), elevated CSF protein (63–313 mg/dL), and diffuse hyperintense bilateral basal ganglia lesions on imaging. The majority of patients (8/10) had renal failure and despite supportive therapy most (7/9) ultimately died (median survival 21 days). Postmortem examination in one individual showed the presence of overwhelming microglial activation in the basal ganglia. The 2 surviving individuals were started on combined antiretroviral therapy (CART) during hospitalization.
We describe a unique clinical syndrome of a fulminant encephalopathy associated with primarily basal ganglia involvement in HIV-infected drug abusers. This syndrome is a rare but serious condition that is associated with a high mortality rate. Early CART institution may be useful and neuroprotective in this disorder, although this requires further investigation.
PMCID: PMC3053334  PMID: 21357830
20.  Neutralizing human monoclonal antibodies binding multiple serotypes of botulinum neurotoxin 
Botulism, a disease of humans characterized by prolonged paralysis, is caused by botulinum neurotoxins (BoNTs), the most poisonous substances known. There are seven serotypes of BoNT (A–G) which differ from each other by 34–64% at the amino acid level. Each serotype is uniquely recognized by polyclonal antibodies, which originally were used to classify serotypes. To determine if there existed monoclonal antibodies (mAbs) capable of binding two or more serotypes, we evaluated the ability of 35 yeast-displayed single-chain variable fragment antibodies generated from vaccinated humans or mice for their ability to bind multiple BoNT serotypes. Two such clonally related human mAbs (1B18 and 4E17) were identified that bound BoNT serotype A (BoNT/A) and B or BoNT/A, B, E and F, respectively, with high affinity. Using molecular evolution techniques, it proved possible to both increase affinity and maintain cross-serotype reactivity for the 4E17 mAb. Both 1B18 and 4E17 bound to a relatively conserved epitope at the tip of the BoNT translocation domain. Immunoglobulin G constructed from affinity matured variants of 1B18 and 4E17 were evaluated for their ability to neutralize BoNT/B and E, respectively, in vivo. Both antibodies potently neutralized BoNT in vivo demonstrating that this epitope is functionally important in the intoxication pathway. Such cross-serotype binding and neutralizing mAbs should simplify the development of antibody-based BoNT diagnostics and therapeutics.
PMCID: PMC3038462  PMID: 21149386
botulism; botulinum neurotoxin; molecular evolution; single-chain Fv; yeast display
21.  Quality Control Guidelines for Amphotericin B, Itraconazole, Posaconazole, and Voriconazole Disk Diffusion Susceptibility Tests with Nonsupplemented Mueller-Hinton Agar (CLSI M51-A Document) for Nondermatophyte Filamentous Fungi▿ 
Journal of Clinical Microbiology  2011;49(7):2568-2571.
Although Clinical and Laboratory Standards Institute (CLSI) disk diffusion assay standard conditions are available for susceptibility testing of filamentous fungi (molds) to antifungal agents, quality control (QC) disk diffusion zone diameter ranges have not been established. This multicenter study documented the reproducibility of tests for one isolate each of five molds (Paecilomyces variotii ATCC MYA-3630, Aspergillus fumigatus ATCC MYA-3626, A. flavus ATCC MYA-3631, A. terreus ATCC MYA-3633, and Fusarium verticillioides [moniliforme] ATCC MYA-3629) and Candida krusei ATCC 6258 by the CLSI disk diffusion method (M51-A document). The zone diameter ranges for selected QC isolates were as follows: P. variotii ATCC MYA-3630, amphotericin B (15 to 24 mm), itraconazole (20 to 31 mm), and posaconazole (33 to 43 mm); A. fumigatus ATCC MYA-3626, amphotericin B (18 to 25 mm), itraconazole (11 to 21 mm), posaconazole (28 to 35 mm), and voriconazole (25 to 33 mm); and C. krusei, amphotericin B (18 to 27 mm), itraconazole (18 to 26 mm), posaconazole (28 to 38 mm), and voriconazole (29 to 39 mm). Due to low testing reproducibility, zone diameter ranges were not proposed for the other three molds.
PMCID: PMC3147863  PMID: 21543581
22.  Substance Abuse Treatment for Women who are Under Correctional Supervision in the Community: A Systematic Review of Qualitative Findings 
Issues in mental health nursing  2011;32(10):640-648.
This systematic review was conducted to more fully analyze qualitative research findings relating to community-based court-supervised substance abuse treatment for women and to make recommendations regarding treatment enhancement. Five reports of qualitative research met the inclusion criteria. Findings from these reports were extracted and analyzed using constant comparative methods. Women who are referred to court-sanctioned substance abuse treatment programs may initially be reluctant to participate. Once engaged, however, they advocate for a full complement of well-financed comprehensive services. To optimize treatment effectiveness, women recommend gender-specific programs in which ambivalence is diminished, hope is instilled, and care is individualized.
PMCID: PMC3190982  PMID: 21932926
Court-mandated; criminal justice; substance abuse treatment; rehabilitation; women
23.  Wild-Type MIC Distributions and Epidemiological Cutoff Values for Caspofungin and Aspergillus spp. for the CLSI Broth Microdilution Method (M38-A2 Document)▿ 
Clinical breakpoints have not been established for mold testing. Epidemiologic cutoff values (ECVs) are available for six Aspergillus spp. and the triazoles, but not for caspofungin. Wild-type (WT) minimal effective concentration (MEC) distributions (organisms in a species-drug combination with no acquired resistance mechanisms) were defined in order to establish ECVs for six Aspergillus spp. and caspofungin. The number of available isolates was as follows: 1,691 A. fumigatus, 432 A. flavus, 192 A. nidulans, 440 A. niger, 385 A. terreus, and 75 A. versicolor isolates. CLSI broth microdilution MEC data gathered in five independent laboratories in Canada, Europe, and the United States were aggregated for the analyses. ECVs expressed in μg/ml that captured 95% and 99% of the modeled wild-type population were for A. fumigatus 0.5 and 1, A. flavus 0.25 and 0.5, A. nidulans 0.5 and 0.5, A. niger 0.25 and 0.25, A. terreus 0.25 and 0.5, and A. versicolor 0.25 and 0.5. Although caspofungin ECVs are not designed to predict the outcome of therapy, they may aid in the detection of strains with reduced antifungal susceptibility to this agent and acquired resistance mechanisms.
PMCID: PMC3101428  PMID: 21422219
24.  Healthy Lifestyles Related to Subsequent Prevalence of Age-Related Macular Degeneration 
Archives of ophthalmology  2010;129(4):470-480.
The relationships between lifestyle behaviors of diet, smoking and physical activity and the subsequent prevalence of age-related macular degeneration (AMD) were investigated.
The population included 1,313 participants (55 to 74 years) in the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women's Health Initiative Observational Study (WHIOS). Scores on a modified 2005 Healthy Eating Index (mHEI) were assigned using responses to a food frequency questionnaire administered at WHIOS baseline (1994-1998). Physical activity and lifetime smoking history were queried. An average of six years later, stereoscopic fundus photographs were taken to assess presence and severity of AMD; present in 202 women, 94% of whom had early AMD, the primary outcome.
In multivariate models, women whose diets scored in the highest compared with the lowest quintile on the mHEI had a 46% lower odds for early AMD. Women in the highest vs. lowest quintile for physical activity (MET- Hrs/Wk) had 54% lower odds for early AMD. Although smoking, alone was not independently associated with AMD, having a combination of three healthy lifestyles (healthy diet, physical activity and not smoking) was associated with a 71% lower odds for AMD compared with having high risk scores (P=0.0004).
Modifying lifestyles might reduce risk for early AMD as much as 3-fold, lowering the risk for advanced AMD in a person's lifetime and the social and economic costs of AMD to society.
PMCID: PMC3075357  PMID: 21149749
25.  A pre- post-evaluation of implementing an inpatient warfarin monitoring and education program 
Pharmacy Practice  2011;9(2):101-105.
The purpose of this study was to evaluate whether a new anticoagulation management program resulted in better monitoring of warfarin, increased warfarin patient education prior to discharge, and fewer bleeding complications associated with warfarin.
A retrospective chart review was conducted of patients who were inpatients and received warfarin from April 1, 2008 to July 31, 2008 (control group) and from April 1, 2009 to July 31, 2009 (after implementation of the new anticoagulation program). The frequency of warfarin-related laboratory orders that included international normalized ratios (INRs), complete blood counts (CBCs), and documented patient education by pharmacy, nursing, and dietary services were determined before and after program implementation. Also, data was collected to determine frequencies of bleeding complications associated with warfarin.
There were 112 patients in the pre- and 115 patients in the post-program group. After implementation of the inpatient warfarin management program, obtaining baseline INRs increased from 74% to 90% (p=0.001). Orders for baseline CBCs increased from 85% to 94% (p=0.026). Obtaining CBCs every 3 days increased from 54% to 74%, (p<0.001). However, there was no significant change in orders for daily INRs (p=0.055). Education by nursing increased from 54% to 80%, (p<0.001), by pharmacy increased from 8% to 76%, (p<0.001), and by dietary increased from 11% to 79%, (p<0.001). Documentation by all three disciplines in each patient increased from 3.6% to 59%, (p<0.001). Significantly fewer patients received vitamin K and/ or fresh frozen plasma for supratherapeutic INRs with bleeding complications after the program was initiated compared to baseline (p=0.009).
The implementation of an inpatient warfarin management program led to better monitoring of patients receiving warfarin, and increased patient education. However, a larger and longer assessment is necessary to determine if these changes are maintained and how these changes affect long-term clinical outcomes.
PMCID: PMC3969833  PMID: 24688616
Warfarin; Inpatients; Pharmacy Service, Hospital; United States

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