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Microfluidic platforms to study host-microbiome interactions

Fri, 05/20/2016 - 3:30pm

About three-quarters of human body surface is exposed to dense microbial population along the gastro-intestinal tract (GIT) that accommodates around 80% of immune cells. The GIT is one of the most critical sites for metabolic and immunologic homeostasis in the body. While large-scale genomic analysis and germ-free mice have been widely used, they are limited to capture the dynamic functional interaction between host-microbiome in a humanized setting. in-vitro recapitulation of GIT physiology can be a powerful alternative for hypothesis testing in diseases like IBD and cancer.

As a first step, we developed a simple transwell assembly to closely emulate GIT anatomy and the barrier function in a quantitative and analytical manner. The system enables us to sequentially house bacterial cells, a mucus layer, human intestinal epithelial cells and human peripheral blood mononuclear cells (hPBMCs) in a single co-culture platform. Porcine intestine-derived mucin formed a biophysically relevant barrier and also provided in-vivo like biochemical milieu to bacterial cells. Addition of human epithelial cell monolayer on a collagen coated semi-permeable membrane added another level of cellular and biophysical complexity. Finally, by introducing human peripheral blood mononuclear cells (hPBMCs), we simulated host-microbiome interactions and successfully captured responses relevant to gut inflammation. Initial data indicate that bacterial products successfully stimulate hPBMCs. Whereas, mucus and epithelial barriers demonstrated strong immunomodulatory functions. Further investigations are being carried out in order to create models that will incorporate differentiated epithelial cells (villi), physiologically relevant flow and stress conditions along with co-culture of aerobic (mucosal) and anaerobic (luminal) components of the human GIT. Hopefully, these models will enable us to study mechanistic interactions of the microbiome with the host and reveal novel therapeutic targets for diseases associated with the dysregulation of host-microbiome homeostasis in human GIT.

Structural and Molecular Analysis of a Protective Epitope of Lyme Disease Antigen OspA and Antibody Interactions

Fri, 05/20/2016 - 3:30pm

The murine monoclonal antibody LA-2 recognizes a clinically protective epitope on outer surface protein (OspA) of Borrelia burgdorferi, the causative agent of Lyme disease in North America. Human antibody equivalence to LA-2 is the best serologic correlate of protective antibody responses following OspA vaccination. Understanding the structural and functional basis of the LA-2 protective epitope is important for developing OspA-based vaccines and discovering prophylactic antibodies against Lyme disease.

Here, we present a detailed structure-based analysis of the LA-2/OspA interaction interface and identification of residues mediating antibody recognition. Mutations were introduced into both OspA and LA-2 based on computational predictions on the crystal structure of the complex, and experimentally tested for in-vitro binding and borreliacidal activity. We find that Y32 and H49 on the LA-2 light chain, N52 on the LA-2 heavy chain and residues A208, N228 and N251 on OspA were the key constituents of OspA/LA-2 interface. These results reveal specific residues that may be exploited to modulate recognition of the protective epitope of OspA and have implications for design of vaccines against Lyme disease.

Association between First Trimester Pregnancy Associated Plasma Protein–A and the Development of Gestational Diabetes Mellitus

Fri, 05/20/2016 - 3:30pm

Background: Gestational diabetes (GDM) is a common pregnancy complication with significant cardiometabolic consequences for mothers and offspring. Previous research from our group suggests that adipose tissue IGFBP-5 and its unique metalloprotease PAPP-A (Pregnancy Associated Plasma Protein-A) may play mechanistic roles in GDM development by regulating functional IGF-1 levels and lipid storage and metabolism.

Aim: To examine the relationship between circulating PAPP-A levels and GDM development. We hypothesized that high first trimester PAPP-A levels would be associated with decreased GDM risk.

Methods: A retrospective cohort of women delivering singleton gestations at UMass Memorial Healthcare (2009, 2010, 2014, 2015) was assembled by abstracting electronic medical records. PAPP-A was measured in first trimester (11-14 weeks), and reported as quartiles of multiples of the mean (MoM) based on gestational age and adjusted for maternal weight and race/ethnicity. GDM diagnosis based on standard 2-step protocol (~24-28 weeks; failed 50g 1hr glucola screen then ≥2 abnormal values per Carpenter-Coustan criteria on 100g 3hr glucose tolerance test). Crude and multivariable-adjusted logistic regression models estimated the association between PAPP-A MoM quartiles and GDM.

Results: Women (N=1,251) were 29.7 (SD:5.7) years old and 12.5 (SD:0.6) weeks gestation at PAPP-A measurement. 7.6% (n=95) developed GDM. Median PAPP-A MoM were 0.7 (inter-quartile range [IQR]=0.5-1.0) among women with GDM and 0.9 (IQR=0.6-1.3) among controls; 39% versus 23% were in the 1st quartile, respectively. After adjusting for pre-pregnancy body mass index, nuchal translucency, crown rump length, smoking status, and parity, women with PAPP-A MoM in 2nd, 3rd, and 4th quartiles had 52% (OR=0.48, 95%CI=0.26-0.88), 45% (OR=0.55, 95%CI=0.30-0.99) and 73% (OR=0.27, 95%CI=0.13-0.53) lower odds of GDM compared to women in the 1st quartile.

Conclusion: Higher PAPP-A MoM levels were associated with lower GDM risk. Future studies will assess whether higher PAPP-A levels are associated with enhanced IGF-1 signaling and improved pregnancy metabolic homeostasis.

5-Hyroxymethylcytosine Immunohistochemical Staining Correlates with Overall Survival in Patients with Chronic Myelomonocytic Leukemia

Fri, 05/20/2016 - 3:30pm

Introduction Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm that has been associated with a number of genetic mutations, most commonly TET2 mutations in up to 50-60% of cases. Mutations in epigenetic genes such as TET2 are known to disrupt the conversion of 5-methycytosine to 5-hydroxymethylcytosine (5hmC), contributing to oncogenesis. We hypothesized that CMML cases would exhibit decreased 5hmC expression, reflecting the propensity for TET2 mutations in CMML. We also sought to determine whether 5hmC IHC status reflected disease severity in terms of progression to AML and overall patient survival.

Methods Thirty-five cases of CMML from between 1/2006 and 12/2014 were identified from the pathology archives at UMass, under an IRB-approved protocol. IHC was performed on FFPE bone marrow biopsy specimens with an anti-5hmC antibody. Staining was scored based on intensity of nuclear staining: 0 (neg) to 3+ (strong); and proportion of cells staining: 0 ( < 1%), 1 (1-25%), 2 (26-50%), 3 (51-75%), 4 ( > 76%). A combined product score was calculated yielding scores of 0-12. Correlation to clinical parameters (age, blast count, progression to AML, and overall patient survival) was investigated.

Results 60% (21/35) of CMML cases showed low expression of 5hmc (combined score < =4). This loss of 5hmC expression correlated significantly with poorer overall survival in Kaplan-Meier curves (p=0.0287). There was no significant correlation between 5hmC score and patient age, blast count, or AML progression.

Conclusion IHC detection of 5hmC in CMML is significantly correlated with patient overall survival and could potentially be utilized as a prognostic biomarker. Loss of 5hmC expression likely reflects mutations to epigenetic pathways and could be useful in guiding treatment with hypomethylating agents.

Identification of fully human monoclonal antibodies against the adhesin domain of colonizing factor antigen I of Escherichia coli

Fri, 05/20/2016 - 3:30pm

Enterotoxigenic Escherichia coli (ETEC) causes significant diarrheal illness in infants in the developing world and travelers to endemic countries including military personnel. Infection of the host involves bacterial colonization of the small intestinal epithelium and toxin secretion leading to watery diarrhea. CFA/I is the most common colonizing factor antigens expressed on the surface of ETEC isolates. The CFA/I adhesin, CfaE, appears to be required for ETEC binding to human intestinal cells for colonization. Human antibodies against the binding domain of CfaE have potential to block colonization of ETEC and serve as a potent immunoprophylactic therapeutic for ETEC-related diarrhea.

In the current study, we generated a panel of fully human monoclonal antibodies (HuMabs) against the adhesin domain of CfaE using mice transgenic for human immunoglobulin genes and identified lead antibodies utilizing a series of in vitro assays. Mice were immunized with the N-terminal binding domain of CfaE fused to maltose binding protein. Over thirty unique IgG1 HuMabs were identified with binding activity to recombinant CfaE. These antibodies were tested for inhibition of hemagglutination of type A human erythrocytes by ETEC. Two lead HuMabs, 837-6 and 840-53, inhibited hemagglutination at low concentrations (< 1 nM). Both antibodies also blocked the binding of ETEC with intestinal epithelial cells. Biacore analysis revealed an affinity of less than 2 nM with distinct epitopes of CfaE. Our analysis suggests that CfaE specific HuMabs 837-6 and 840-53, as the first isolated fully human monoclonal antibodies against CfaE adhesion domain, could potentially be used in combination with heat labile toxin neutralizing antibodies to prevent traveler’s diarrhea.

Effect of Left Atrial Function Index on Late Atrial Fibrillation Recurrence after Pulmonary Vein Isolation

Fri, 05/20/2016 - 3:30pm

Background: Although the rates of catheter ablation (CA) for atrial fibrillation (AF) are rapidly increasing, there are few predictors of outcome to help inform appropriate patient selection for this procedure. Traditional echocardiographic measures of atrial structure do not significantly reclassify risk of AF recurrence over and above the clinical risk factors. Left Atrial Function Index (LAFI) is a rhythm-independent measure of atrial function. We hypothesized that baseline LAFI would relate to AF recurrence after CA.

Methods: Pre-procedural echocardiograms from 170 participants, who underwent CA for AF and were enrolled in the UMMC AF Treatment Registry, were analyzed. LAFI was calculated by a previously validated formula. Primary outcome was late or clinically significant AF recurrence 3-12 months after CA. Baseline clinical, laboratory and echocardiographic variables were compared between the recurrence and non-recurrence groups.

Results: Study participants were middle aged (60+/10 years) and had a moderate-to-severe burden of cardiovascular comorbidities. 78 participants (46%) experienced late AF recurrence. Mean LAFI was 0.26+/-0.18. In multivariate analysis, lower LAFI was independently associated with the risk of recurrence (0.23 in recurrence group vs 0.29 in non-recurrence group, p < 0.01). Predictive value of LAFI for AF recurrence was similar to CHADS2 score (c-statistic 0.60 vs 0.58, p 0.76). In subgroup of patients with persistent AF, LAFI predicted AF recurrence more strongly than CHADS2 score (c-statistic: 0.79 vs 0.58, p 0.02).

Conclusions: In our cohort of 170 participants with AF undergoing index CA ablation, we observed that LAFI related to late AF recurrence after CA, independent of the traditional risk factors. Since LAFI can be calculated from almost any traditional echocardiographic recording, our findings suggest that LAFI may help guide therapeutic decision-making regarding application of CA, particularly among challenging patients with symptomatic persistent AF.

Show Back: Evaluation of Scoresheet for Identifying Self-Management Medication Problems of Older Adults

Fri, 05/20/2016 - 3:30pm

Purpose The study purpose was to test the feasibility of a scoresheet to screen for problems older adults may have managing medications after discharge from a hospital or nursing home facility.

Background Adverse drug events (ADE) prevention is an important patient safety priority, with ADEs accounting for an estimated one-third of hospital adverse events and approximately 280,000 hospital admissions annually. Home healthcare nurses work with older adults to avoid ADEs and promote self-management of medications. Few, if any, studies have described older adults’ cognitive and psychomotor abilities to manage their medications after being discharged home.

Methods We enrolled patients if they were aged 65 and older, recently discharged from a hospital, rehabilitation center, or nursing facility, and were prescribed at least one antidiabetic, anticoagulant, or opioid medication. A physician and homecare nurse observed and scored patients’ proficiency managing across five domains: identification, explanation of purpose, organization, administration, and timing. Based on the experiences in the first 20 visits, we created a protocol and a detailed manual for determining proficiency in each domain. Through the subsequent home visits, we determined inter-rater reliability using Cohen’s Kappa (κ).

Results Thirty older adults participated. During the ten visits completed after we developed the protocol and scoring guide, we scored a total of 90 medications with an average of 8 (SD±2.04) medications per patient. The physician and nurse scored the explanation domain most reliably, with an inter-rater reliability Kappa of 0.872 (p < 0.0001), followed by timing (κ=0.707, p < 0.0001), organization (κ=0.624, p < 0.0001), and identification (0.376, p < 0.0001). The physician and nurse scorers were least reliable in scoring the administration domain (κ=0.133, p=0.4454).

Conclusions & Implication: The Show Back scoresheet shows promise to identify domain-specific problems faced by older adults’ managing their medications at home. We plan to hone our protocol and recalculate agreement in subsequent cohort of patients.

Collecting Histories of Education and Employment Activities from Young Adults with Serious Mental Health Conditions

Fri, 05/20/2016 - 3:30pm

Young adulthood is a critical time for establishing the foundation of an adult working life. As adolescents mature and explore career interests, they also begin to focus in on particular career pathways. However, lower levels of employment and educational attainment, as well as the demands of parenting, prevent and delay Youth and Young adults (Y&YAs) with serious mental health conditions (SMHCs) from participating in settings where career development and exploration activities typically occur. Of Y&YA parents who do work, the majority will work part-time, at low-level service jobs, and at low salaries (Osgood, et al., 2005). Y&YA parents with SMHCs are particularly vulnerable as they are more likely than their normative peers to experience unemployment, poverty, and dependence on government assistance (Luciano, et al., 2013). Through a one-time, semi-structured interview, this study seeks to describe the education and employment activities of Y&YAs between the ages of 25-30 with SMHCs, explore barriers and facilitators to these activities, and understand how parenting affects these experiences. Preliminary findings will be presented as they relate to themes of career exploration/development, the barriers and facilitators to education and employment activities this population encounters, including the impact that parenthood can have on these activities in young adulthood. We will also describe the education and employment activities and trajectories that were obtained as part of these interviews.

Contemporary Analysis of Malignancies in Women of Child-Bearing Age: An NSQIP Analysis

Fri, 05/20/2016 - 3:30pm

Background: Recent evidence suggests that cancer incidence among pregnant women is increasing. The pattern of malignancies in pregnant women and how these compare to their nonpregnant counterparts has not been explored. Here we describe the differences in the proportion of resected malignancies in this population. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify women aged 18-49 who underwent an operation for malignancy from 2007-2012. Age-adjusted distribution of specific surgical interventions for malignancy based on ICD-9 codes were compared among pregnant and non-pregnant women using logistic regression analysis. Results: 42,732 subjects with malignancies surgically treated during child-bearing age were identified. 0.33% (n=143) were pregnant. The most common tumors requiring resection were breast (51%), thyroid (17%), and colorectal (9%). The distribution for most cancers was similar between groups. The age-adjusted proportion was significantly increased in breast, major salivary gland and oropharyngeal malignancies (p<0.05). The proportion of resected colorectal cancers was significantly lower in pregnant women (p<0.05; Table 1). Conclusion: This study serves as the first comprehensive and contemporary overview of malignancies resected in women of childbearing age. This study demonstrates that the proportion of resections among pregnant women was significantly greater in breast, major salivary gland and oropharyngeal cancers and lower for colorectal cancers. While these data might represent true differences in cancer incidence, further work is necessary to demonstrate if these are true differences in incidence versus differences in detection and treatment of the pregnant patient.

Immune features that afford protection from clinical disease versus sterilizing immunity to Bordetella pertussis infection in a nonhuman primate model of whooping cough

Fri, 05/20/2016 - 3:30pm

The respiratory bacterial infection caused by Bordetella pertussis (whooping cough) is the only vaccine-preventable disease whose incidence has been increasing over the last 3 decades. To better understand the resurgence of this infection, a baboon animal model of pertussis infection has been developed. Naïve baboons that recover from experimental pertussis infection are resistant both to clinical disease and to airway colonization when re-challenged. In contrast, animals vaccinated with acellular pertussis vaccine and experimentally challenged do not develop disease, but airways remain colonized for 4-6 weeks. We explored the possibility that the IgG antibody response to pertussis infection is qualitatively different from antibodies induced by acellular pertussis vaccination.

IgG was purified from pertussis-convalescent baboons shown to be resistant to pertussis disease and airway colonization. Purified IgG contained high titers to pertussis toxin, pertactin, and filamentous hemagglutinin. This pertussis-immune IgG or control IgG was passively transferred to naïve, juvenile baboons before experimental airway pertussis inoculation. The control animal that received normal IgG developed a typical symptomatic infection including leukocytosis, cough and airway colonization for 4 weeks. In contrast, baboons that received convalescent IgG maintained normal WBC counts and were asymptomatic. However, despite remaining asymptomatic, their airways were colonized for 4-6 weeks with B. pertussis. All animals developed IgG and IgA anti-pertussis antibody responses. Interestingly, the clearance of B. pertussis from airways coincided with the emergence of a serum anti-pertussis IgA response.

These studies demonstrate that passive administration of pertussis-specific IgG from previously infected animals can prevent clinical disease but does not affect prolonged airway colonization with B. pertussis. This outcome is similar to that observed following acellular pertussis vaccination. Understanding immune mechanisms—other than IgG—that are capable of preventing airway colonization with B. pertussis will be critical for developing more effective vaccines to prevent whooping cough.

The Therapeutic Effects of per os Artemisinin Delivered as Dried Leaf Artemisia annuavs. Artesunate in Non-small Cell Lung Cancer

Fri, 05/20/2016 - 3:30pm

Artemisinin, the active component of Artemisia annua L. used to treat malaria, also has therapeutic efficacy against many types of cancer. Solubility issues led to development of more soluble semi-synthetic derivatives. Artesunate (ART), in particular, is a more soluble derivative of artemisinin and has profound cytotoxicity toward many types of tumor cells, but healthy cells are less sensitive. Artemisinin delivered per os as dried leaves, referred to as dried leaf artemisinin (DLA), was shown in rodent studies to improve bioavailability by more than 40-fold. ART has been widely studied for its anti-cancer properties, but it has yet to be shown if DLA also improves therapeutic efficacy. As A. annua produces a wide array of phytochemicals with anti-cancer activity other than artemisinin, it is reasonable to expect DLA may provide a more potent therapeutic. Using two non-small cell lung cancer cell lines, PC-9 and H1299, artemisinin delivered as DLA effectively reduced viability with 24h IC50 values of 56.3 and 77.5 µM for PC-9 and H1299, respectively, as determined by MTT assay. For PC-9 cells, this was a 2.5-fold improvement in the 24h IC50 value for ART at 142.9 µM. However, for the H1299 cells, ART at 60.6 µM was better than DLA by about 25%. Ongoing studies are comparing the mechanism of action of DLA and ART on these two cell lines and will analyze markers for apoptosis, proliferation and metastatic migration and invasion. Xenograft models also will be used to compare in vivo efficacy of DLA and ART on tumor reduction. These studies will help us further understand the anti-cancer effects of artemisinin when delivered per os as dried plant leaves.

The Effect of Oral Antibiotics on the Development of Community Acquired Clostridium Difficile Colitis in Medicare Beneficiaries

Fri, 05/20/2016 - 3:30pm

Clostridium difficile infection (CDI) is increasingly prevalent among community dwelling Americans. Older Americans are particularly vulnerable to community-acquired Clostridium difficile (CACD), in part to increasing use of antibiotics. We studied the association between outpatient antibiotics and CACD among Medicare beneficiaries.

Case-control study utilizing a 5% sample of Medicare beneficiaries (2009-2011). Patients with CACD severe enough to warrant hospitalization were identified by a primary diagnosis code for CDI and no exposure to a healthcare environment within 90-days of admission. 1,514 CACD cases were matched to ten controls each on birth year and sex. Potential controls with exposure to healthcare environment were excluded. Outpatient oral antibiotic exposure was classified into three groups: ≤30 days, 31-60 days, or 61-90 days prior to case subject’s index admission. Metronidazole and Vancomycin were excluded because they are used to treat CDI. Multivariable models were utilized to determine the independent effect of antibiotics on the development of CACD while controlling for several patient associated characteristics.

Cases of CACD had more outpatient antibiotic exposure in each time period examined: ≤30 days = 40.0% vs 8.4%; 31-60 = 10.7% vs 5.0%; and 61-90 = 5.5% vs 4.4% (all p-values < 0.05). Subjects exposed to antibiotics ≤30 days prior to admission had a markedly higher risk of being admitted with CACD compared with those not exposed (OR 8.09, 95% CI 7.13, 9.19). Similarly, subjects taking antibiotics 31-60 days and 61-90 days prior to admission had increased risk of CDI admission (OR 3.65, 95% CI 3.02, 4.41) and (OR 2.06, 95% CI 1.61, 2.63) respectively.

Recent exposure to outpatient oral antibiotics increases the risk of CACD among community dwelling elderly with the risk persisting as long as 90 days after exposure. Inappropriate antibiotic usage must be minimized and older Americans who require outpatient antibiotic treatment may warrant close observation for signs of CDI.

Advanced MRI Center: a 3 Tesla Magnetic Resonance system for preclinical, translational and clinical imaging studies

Fri, 05/20/2016 - 3:30pm

The Advanced MRI Center, located in the UMass Medical School building, is a research core facility providing the latest magnetic resonance imaging and spectroscopy capabilities to UMass scientists. It is equipped with a Philips Achieva 3.0T X-series whole-body scanner and radiofrequency coils for studying all organs of the human body, and small and large animals, such as mice, rats, rabbits, dogs, sheep and non-human primates. The center also includes a radiofrequency coil lab, a nurses’ station, two patient holding rooms and two patient changing rooms.

The Center’s specialized techniques are able to elucidate functional, physiological and biochemical information from all organs of the body.

The 3.0 Tesla system features the Quasar Dual gradient system with industry leading performance specifications, that allow high-level diffusion tensor imaging and functional MRI (fMRI) applications in humans, and high resolution imaging studies in small animal studies. A fMRI stimulus delivery system, a MRI compatible goggle set with eye tracking system, microphone and earphones are available for facilitating fMRI studies.

Small animal monitoring and gating system and an MR compatible Anesthesia system with heater and ventilator option are also available.

The 3.0T MR system is also equipped with a Multi-nuclear spectroscopy system, which provide the ability to perform 13C, 31P, 7Li, 23Na and other nuclei spectroscopy and imaging. Technical and clinical expertise for collaborative research is also provided.

Rational Design of an Epitope-Based Hepatitis C Virus Vaccine

Fri, 05/20/2016 - 3:30pm

Despite improving treatment methods and therapeutic options, hepatitis C virus (HCV) remains a major global disease burden, and a vaccine would help greatly in reducing its incidence. Due to its extremely high sequence variability, HCV can readily escape the immune response, thus a vaccine must elicit an immune response toward conserved, functionally important epitopes.

Using structural data of the broadly neutralizing antibody HCV1 in complex with a conserved linear epitope from the HCV E2 protein (aa 412-423, referred to as epitope I or domain E), we performed structure-based design to generate vaccine immunogens to induce antibody responses to this epitope. Designs selected for immunological characterization included a stabilized minimal epitope structure based on a defensin protein, as well as a bivalent vaccine featuring two copies of epitope I on the E2 surface. In vivo studies confirmed that these designs successfully generated robust antibody responses to this epitope, and sera from vaccinated mice neutralized HCV. In addition to presenting several effective HCV vaccine immunogens, this study demonstrates that induction of neutralizing anti-HCV antibodies is possible using an epitope-based vaccine, providing the basis for further efforts in structure-based vaccine design to target this and other critical epitopes of HCV.

Advancing Medical Device and Biotech Innovations

Fri, 05/20/2016 - 3:30pm

M2D2 is a UMass Lowell – UMass Medical School Worcester initiative that helps entrepreneurs move new medical device and biotech ideas from patent to production and offers early-stage inventors and established companies easy, affordable and coordinated access to world-class researchers and resources at both the Lowell and Worcester campuses.

UMass Lowell and UMass Worcester extend use of engineering and scientific resources to M2D2 companies. These core resources are available to researchers by using the research services agreement. The use of UMass Lowell and UMass Worcester interns and faculty is an enormous benefit to an emerging medical device or biotech company.

UMass Worcester’s campus offers access to core research supports and highly trained personnel to efficiently conduct animal or clinical studies across the life cycle of projects.

UMass Lowell has two M2D2 facilities with private and shared wet lab space, equipment, office space and conference rooms. It offers business and medical feasibility assessments, product development, medical and clinical pathway assistance, SBIR and STTR research partnerships and access to capital.

M2D2 was established with seed funding from the UMass President’s Office, the Mass Life Sciences Center and the Commonwealth of Massachusetts.

Predisposed Health Conditions of Children Exposed to Methamphetamine In Utero

Fri, 05/20/2016 - 3:30pm

Methamphetamine (MA) use and abuse is a growing problem worldwide [United Nations World Drug Report]. It is common knowledge that MA use affects not only the user, but also friends, family, and the communities close to them [NIDA]. One area of impact that is lacking sufficient study is the effects of MA use by expectant mothers on her child later in life. That is to say, a child who was exposed to MA in utero may be more likely than an unexposed fetus to have predispositions to a variety of health conditions. After an extensive PubMed database search, it is apparent that research is limited on the childhood illnesses and health conditions related to fetal exposure to MA. Some research, suggests a potential link between a fetus exposed to MA and the development of attention deficit hyperactivity disorder (ADHD) later in childhood. [Kiblawi, et. al.; Legasse, et. al.] The lack of available research warrants an exhaustive database search and a retrospective epidemiological study to better understand the health risk of children exposed to MA. The knowledge gained from this work can inform healthcare providers and public health officials when intervening to reduce MA use and addiction.

Lipoaspirate and Adipose Stem Cells as Potential Therapeutics for Chronic Scars

Fri, 05/20/2016 - 3:30pm

Introduction: Burn injuries can lead to hypertrophic or keloid scars, causing pain and long lasting mobility issues. Current therapies are often unsatisfactory, costly, or morbid. Prior studies suggest adipose derived stem cells (ADSCs) and lipoaspirate can improve scar outcomes of acute thermal wounds. Clinical reports suggest lipoaspirate and ADSCs can improve chronic burn scar remodeling. However, this has not been extensively studied in animal models. We sought to determine if adipose tissue can improve chronic scar remodeling and to compare the effects of ADSCs and processed lipoaspirate.

Methods: 50 CD1 nu/nu athymic mice received a standardized deep partial-thickness thermal burn. Scars matured for 6 weeks. Photographs and perfusion measurements by hyperspectral imaging (HSI) were taken over the entire study. Lipoaspirate and ADSCs (SVF and ex-vivo culture with flow cytometry confirmation) were obtained from a discarded human pannus specimen. After 6 weeks, animals received a 0.6cc subcutaneous graft beneath the scar of either: human lipoaspirate processed with the Coleman technique, high-dose (106) hADSCs in Matrigel, low-dose (104) hADSCs in Matrigel, Matrigel only, or not injected (n=10 per group). At 10 weeks, animals were sacrificed and scar tissue was harvested for histological and molecular analysis.

Results: HSI oxygenated hemoglobin values in lipoaspirate treated scars increased significantly more compared to 6-week pre-treatment baseline than all other groups (p < 0.05). Planimetry analysis showed reduction in wound area in lipoaspirate treated mice compared to control groups (p < 0.01). Blood vessel density quantification on Masson’s trichrome stains suggests increased density in lipoaspirate treated scars versus controls (p < 0.01).

Conclusion: HSI, blood vessel density, and scar analysis suggest improvement in lipoaspirate treated scars compared to controls. Preliminary molecular data offers some insight to this trend. No effect was seen with ADSCs at either concentration at the analyzed timepoints. Molecular analyses are ongoing to investigate cellular mechanisms in regulating scar remodeling.

Angina Characteristics as Predictors of Trajectories of Quality of Life Following Acute Coronary Syndrome in the Transitions, Risks and Actions in Coronary Events-Center for Outcomes Research and Education cohort (TRACE-CORE)

Fri, 05/20/2016 - 3:30pm

BACKGROUND: To describe longitudinal trajectories of health-related quality of life (HRQoL) after hospitalization with an acute coronary syndrome (ACS), their associations with baseline angina characteristics, and associations with anxiety, depression, and cognitive impairment.

METHODS: TRACE-CORE participants (N=1,613) completed the SF-36 during hospitalization for ACS and 1, 3, & 6 months post-discharge. Latent growth curves identified trajectories of physical and mental components of HRQOL (MCS and PCS) and sequential multiple logistic regression estimated associations between trajectories and angina characteristics.

RESULTS: Participants (N=1613) had mean age 63.3 (SD 11.4) years, 33.0% female, and 78.2% non-Hispanic white. We identified 2 MCS trajectories: AVERAGE and IMPAIRED HRQoL. The majority of participants (81.0%) had AVERAGE MCS at baseline (mean MCS 53.6) and slight improvement in scores over time. A minority (19.0%) had IMPAIRED HRQoL at baseline (mean MCS 36.7) and slight improvement in scores over time. We identified 2 similar PCS trajectories with similar patterns of scores over time: AVERAGE (71.1%) and IMPAIRED (28.9%) HRQoL at baseline. Adjusting for demographics & comorbidities, patients with less severe baseline angina were more likely to have AVERAGE MCS (odds ratio [OR]/10 unit change in severity 1.1) and PCS (OR 1.1) trajectories, and similarly for less frequent angina (MCS OR 1.2; PCS OR 1.3). The associations of MCS trajectory with severity and frequency lost significance after adjusting for psychosocial factors, whereas the PCS associations remained significant [All p < 0.05 unless noted].

CONCLUSIONS: About 1/3 of patients exhibited impaired 6-month HRQoL trajectories, which can be predicted by angina characteristics. Psychosocial factors may explain the prediction of mental, not physical, trajectories. Interventions to improve HRQoL after ACS should consider psychosocial factors and angina.

6-Month Change in Pain and Function by Pre-Operative Pain and Function among Patients Selected for Total Knee Replacement in the United States

Fri, 05/20/2016 - 3:30pm

Background/Purpose: The increase in total knee replacements (TKRs) between 1979 and 2006 is staggering. Debate is growing regarding the appropriate utilization of TKRs. We examined pain, function, quality of life (QOL), and satisfaction at 6-month post-surgery by pain and function at time of surgery.

Methods: Data came from the nationally representative FORCE-TJR cohort of patients from 150 surgeons. Participants had primary, unilateral TKRs due to osteoarthritis between 2011 and 2014. Their knee pain (KOOS), physical functions (SF36), and QOL were measured at pre- and 6 months post-surgery. We classified patients as having high or low pre-operative pain (KOOS Pain < 70 vs. ≥70), low or high pre-operative physical function (SF-36 PCS < 40 vs. ≥40), and grouped as: 1) Low pain-High function (LP-HF), 2) Low pain-Low function (LP-LF), 3) High pain-High function (HP-HF), and 4) High pain-Low function (HP-LF). We compared pre- and post-operative changes in pain and function scores among the four groups.

Results: Of 4,563 participants, 5% had pre-operative LP-HF and 75% HP-LF. By 6-month post-surgery, 85% of LP-HF patients reported no change and 4% reported worse symptoms; the HP-LF group had 18% no change and 52% with large improvement. For function in the LP-HF group, mean 6-month change (SD) was 2.6 (7.8), with post-operative mean of 50.0 (7.4). Mean change for the HP-LF group was 11.9 (9.0), with post-operative mean of 42.0 (9.5). For pain score in the LP-HF group, mean 6-month change was 8.3 (14.6), with post-operative mean (SD) of 88.9 (13.0). The HP-LF group had average improvement of 37.2 (19.7), and post-operative mean of 79.9 (17.3). QOL was better among the LP-HF than HP-LF groups; satisfaction was similar.

Conclusion: The majority of patients had appropriate TKR utilization and achieved large improvement in pain and function. Patients with pre-operative LP-HF achieved the smaller mean change, but better absolute outcomes.

Total hip arthroplasty and mental health status

Fri, 05/20/2016 - 3:30pm

Purpose. Total hip arthroplasty (THA) effectively restores function and alleviates pain in patients with end-stage hip osteoarthritis. Pain affects mood through its effect on disability and fatigue. Few studies have examined mental health as a consequence of pain or function after THA. We assessed change in mental health 1-year post-surgery, and examined whether change in pain and function predict change in mental health.

Methods. We used data from a prospective THA registry that began in 1996 at a large public Geneva University hospital. We included surgeries performed 2010 and 2012-2014, with demographic information, body mass index (BMI), co-morbidities, baseline and 1-year post-surgery WOMAC pain and function scores, and the SF-12 mental health component score (MCS). The pain, function, and MCS scores were normalized and ranged from 0-100; increasing score indicating better outcome. We calculated descriptive statistics, and used multivariable linear regression to predict 1-year change in MCS.

Results. Of 610 participants, mean (SD) age was 68.5 (11.8) years and BMI of 26.9 (4.9), 53% were women. Mean MCS was 44.7 (11.2) at baseline and 47.5 (10.5) at 1-year post surgery; average 1-year change was 2.8 (95% CI 1.9-3.6). WOMAC pain score was 39.6 (18.3) at baseline and 83.8 (20.4) at 1-year post surgery; 1-year change was 44.2 (95% CI 42.4-46.0). Corresponding WOMAC function was 40.2 (18.8) and 78.3 (22.1); 1-year change was 38.1 (95% CIs 36.2-40.0). On average, a 10-point increase in 1-year change in pain score was associated with a 0.7 point increase in the adjusted 1-year change in MCS (95% CI 0.2-1.1). The change in function was associated with a 0.9 point increase in 1-year change in MCS (95% CI 0.5-1.4).

Conclusion. Mental health significantly improved from baseline to 1-year post-surgery. Patients whose pain and function scores improved the most had also the greatest improvement in mental health.