Bringing Molecular Biology to Bear on Adhesion Prevention: Postsurgical Adhesion Reduction Using Intraperitoneal Inoculation of Hyaluronic Acid–Inducing Adenoviral Vector in a Murine Model

Objective: Seprafilm (Genzyme, Cambridge, MA) an absorbable adhesion barrier incorporating hyaluronic acid (HA), a high molecular mass glycosaminoglycan and important component of the extracellular matrix, has been shown to prevent adhesions in both experimental models and human subjects. Yet, the application of HA as a sheet at the time of surgery has several important logistic limitations. Recently, our laboratory has identified and cloned the genes encoding murine hyaluronic acid synthase 2 (mHAS2) and 3 (mHAS3) and engineered adenoviruses incorporating these genes, which, on intraperitoneal injection, significantly increases HA in peritoneal fluid. We hypothesized that intraperitoneal gene therapy with mHAS2 or mHAS3 via an adenoviral vector prior to a standardized cecal abrasion surgery would lead to a reduction in postoperative adhesion severity. Methods: Mice were assigned to one of four groups: (1) intraperitoneal inoculation with adenovirus encoding mHAS2; (2) mHAS3; (3) a control reporter adenovirus (RV) encoding GFP; or (4) intraoperative placement of a commercially available and murine-validated hyaluronic acid adhesion barrier (Seprafilm, SF). An a priori sample size calculation was performed. Mice in groups 1, 2, and 3 underwent injection of 2 x 107 viral particles in 1 ml of fluid on day -1. Sham injection was performed on group 4 SF mice. On day 0, laparotomy was performed in random sequence by surgeon blinded to the experimental group. On day 7, adhesion scores (0-3) were assigned independently by two blinded investigators. Results: Mean adhesion scores (n = 247) were 0.68 (mHAS2), 0.91 (mHAS3), 1.28 (RV), and 0.47 (SF). Pairwise comparisons using Wilcoxon rank-sum test revealed significant reduction in severity of adhesions between mHAS2, mHAS3, and SF compared to RV (p = 0.0004, 0.039, and 0.0001, respectively). Significance persisted despite correction for multiple comparisons (p = 0.0002, Kruskal-Wallis). There was a direct relationship between intraperitoneal HA concentration and adhesion reduction. Only one death (RV) was secondary to adhesive disease; differential risk of death between groups was statistically significant (p = 0.008) (highest in mHAS2 group). Conclusions: In a dose-response relationship, an intraperitoneal gene therapy approach to adhesion prevention in a murine model was successful, with adenoviruses most productive of HA resulting in the most significant reduction in adhesion scores compared to empty virus (RV). Although SF best reduced postoperative adhesions, the adenoviral gene delivery approach may prove to be more effective in clinical use when peritoneal injury is less localized or at laparoscopy where the application of SF is not possible. Further studies to elucidate the reason for the differential death rates (time bias may have played a role) and to validate results are in progress

The MUC1 Cytoplasmic Tail and Tandem Repeat Domains Contribute to Mammary Oncogenesis in FVB Mice

Background: Though the importance of the transmembrane mucin MUC1 in mammary oncogenesis has long been recognized, the relative contributions of the cytoplasmic tail and tandem repeat domains are poorly understood.Methods: To address this, mouse models of mammary carcinogenesis were created expressing full-length, cytoplasmic tail-deleted, or tandem repeat-deleted MUC1 constructs.Results: Overexpression of full-length MUC1 resulted in tumor formation in young mice (12 months); however, loss of either the cytoplasmic tail or the tandem repeat domain abrogated this oncogenic capacity. Aged mice in all strains developed late-onset mammary tumors similar to those previously described for the FVB background.Conclusions: This study is the fi rst spontaneous cancer model to address the relative importance of the cytoplasmic tail and tandem repeat domains to MUC1-driven mammary oncogenesis, and suggests that both of these domains are essential for tumor formation

Impact of Zumba on Cognition and Quality of Life is Independent of APOE4 Carrier Status in Cognitively Unimpaired Older Women: A 6-Month Randomized Controlled Pilot Study

Objective: To investigate the association of a 6-month Zumba intervention with cognition and quality of life among older cognitively unimpaired apolipoprotein SMALL ELEMENT OF4 (APOE4) carrier and noncarrier women. Methods: Fifty-three women were randomly assigned to either twice-weekly Zumba group classes or maintenance of habitual exercise (control group) for 6 months. At baseline, 3, and 6 months, all participants underwent neuropsychological, physical activity, and quality-of-life assessments. Results: Overall, neuropsychological test scores and level of physical activity did not differ between intervention and control groups at any time. However, compared to the control group, quality of life was higher at 3 months, and visuospatial working memory and response inhibition improved more in the intervention group by 6 months. Apolipoprotein SMALL ELEMENT OF4 status did not affect the results. Discussion: Zumba may strengthen performance on visuospatial working memory among cognitively unimpaired older women but this needs to be tested in a larger clinical trial

Essential Tremor in the Elderly and Risk for Dementia

The objective is to examine the risk of dementia in subjects with essential tremor (ET) involved in the Arizona Study of Aging and Neurodegenerative Disorders. All subjects were free of a neurodegenerative diagnosis at baseline and had annual motor, general neurological, and neuropsychological assessments. Subjects with ET were compared with controls for the risk of dementia. There were 83 subjects with ET and 424 subjects without tremor. Mean age at study entry was 80±5.9 for ET and 76±8.5 for controls. Median tremor duration was 5.2 years at study entry. Followup was a median of 5.4 years (range 0.9 to 12.1). The hazard ratio for the association between ET and dementia was 0.79 (95% CI 0.33 to 1.85). The hazard ratio for the association between tremor onset at age 65 or over, versus onset before age 65, was 2.1 (95% CI 0.24 to 18) and the hazard ratio for the association between tremor duration greater than 5 years, versus less than 5 years, was 0.46 (95% CI 0.08 to 2.6). We conclude that all elderly ET was not associated with an increased risk of dementia but that a subset of subjects with older age onset/shorter duration tremor may be at higher risk

Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts

Serologic studies are an important diagnostic tool in the clinical evaluation and follow-up of persons with coccidioidomycosis. Numerous types of serologic tests are available, including immunodiffusion, enzyme immunoassay, and complement fixation. We conducted a retrospective review of the results of 1,797 serologic tests spanning 12 months from the onset of coccidioidomycosis in 298 immunocompetent and 62 immunosuppressed persons with symptomatic infection. Using the onset of symptoms as a reference point, we plotted the positive or negative serologic results over time for both groups. Compared with the immunocompetent group, immunosuppressed persons had lower rates of seropositivity for every type of test during the first year after onset of symptoms for coccidioidomycosis, although many results did not achieve statistical significance. Combining the results of these tests increased the sensitivity of the serologic evaluation in immunocompromised patients. Immunosuppressed persons have the ability to mount a serologic response to coccidioidomycosis, but in some circumstances, multiple methods may be required to improve detection

Determinants of pain interference and headache impact in patients who have chronic migraine with medication overuse: Results from the MOTS trial

OBJECTIVE: Pain interference and headache impact refer to negative consequences that pain and headache have on one\u27s life. This study investigated determinants of these negative impacts in a large patient cohort who have chronic migraine with medication overuse. METHODS: Six hundred and eleven adults were enrolled from 34 headache, neurology, and primary care clinics. Negative consequences of chronic migraine with medication overuse were determined using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference 6b questionnaire and the Headache Impact Test 6. Relationships between PROMIS-6b and Headache Impact Test 6 scores with demographics, headache characteristics, medication use, anxiety symptoms, and depression symptoms were assessed with linear regression. Elastic Net regression was used to develop a multiple regression model. RESULTS: PROMIS-6b T-Scores averaged 65.2 (SD 5.4) and Headache Impact Test 6 scores averaged 65.0 (SD 5.3), indicating severe negative consequences of chronic migraine with medication overuse. Chronic migraine with medication overuse interfered with enjoyment of life, concentration, daily activities, doing tasks away from home, and socializing. Depression symptom severity had the strongest relationship with pain interference and headache impact. Moderate-to-severe headache frequency, headache intensity, and anxiety symptoms were also associated with pain interference and headache impact. CONCLUSIONS: Chronic migraine with medication overuse is associated with substantial negative consequences, the extent of which is most strongly related to depression symptoms

Major flaws in conflict prevention policies towards Africa : the conceptual deficits of international actors’ approaches and how to overcome them

Current thinking on African conflicts suffers from misinterpretations oversimplification, lack of focus, lack of conceptual clarity, state-centrism and lack of vision). The paper analyses a variety of the dominant explanations of major international actors and donors, showing how these frequently do not distinguish with sufficient clarity between the ‘root causes’ of a conflict, its aggravating factors and its triggers. Specifically, a correct assessment of conflict prolonging (or sustaining) factors is of vital importance in Africa’s lingering confrontations. Broader approaches (e.g. “structural stability”) offer a better analytical framework than familiar one-dimensional explanations. Moreover, for explaining and dealing with violent conflicts a shift of attention from the nation-state towards the local and sub-regional level is needed.Aktuelle Analysen afrikanischer Gewaltkonflikte sind häufig voller Fehlinterpretationen (Mangel an Differenzierung, Genauigkeit und konzeptioneller Klarheit, Staatszentriertheit, fehlende mittelfristige Zielvorstellungen). Breitere Ansätze (z. B. das Modell der Strukturellen Stabilität) könnten die Grundlage für bessere Analyseraster und Politiken sein als eindimensionale Erklärungen. häufig differenzieren Erklärungsansätze nicht mit ausreichender Klarheit zwischen Ursachen, verschärfenden und auslösenden Faktoren. Insbesondere die richtige Einordnung konfliktverlängernder Faktoren ist in den jahrzehntelangen gewaltsamen Auseinandersetzungen in Afrika von zentraler Bedeutung. Das Diskussionspapier stellt die große Variationsbreite dominanter Erklärungsmuster der wichtigsten internationalen Geber und Akteure gegenüber und fordert einen Perspektivenwechsel zum Einbezug der lokalen und der subregionalen Ebene für die Erklärung und Bearbeitung gewaltsamer Konflikte

Restoration of Femoral Anatomy in TKA With Unisex and Gender-specific Components

Recent modifications in total knee prosthesis design theoretically better accommodate the anatomy of the female femur and thereby have the theoretical potential to improve clinical results in TKA by more accurately restoring femoral posterior condylar offset, reducing femoral notching, reducing femoral component flexion, and reducing component overhang. First, we radiographically evaluated whether a contemporary unisex prosthesis would accommodate female anatomy equally as well as male anatomy. Next, we radiographically evaluated female knees in which a gender-specific prosthesis was used. Pre- and postoperative radiographs of 122 knees (42 female unisex, 41 male unisex, 39 female gender-specific) were reviewed. In the unisex groups, there were no differences in femoral notching or femoral component flexion. Posterior femoral offset increased in both groups. However, femoral component overhang was worse in female knees (17%) than in male knees (0%). In the gender-specific female group, the incidence of component overhang was similar to that in the unisex female group. Unisex femoral components of this specific design do not equally match the native anatomy male and female knees. In some women, a compromise was required in sizing