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1.  Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases 
Our goal was to develop strategies to quantify the accumulation of model therapeutics in small brain metastases using multimodal imaging, in order to enhance the potential for successful treatment. Human melanoma cells were injected into the left cardiac ventricle of immunodeficient mice. Bioluminescent, MR and PET imaging were applied to evaluate the limits of detection and potential for contrast agent extravasation in small brain metastases. A pharmacokinetic model was applied to estimate vascular permeability. Bioluminescent imaging after injecting D-Luciferin (molecular weight (MW) 320D) suggested tumor cell extravasation had already occurred at week 1, which was confirmed by histology. 7T T1w MRI at week 4 was able to detect non-leaky 100 μm sized lesions and leaky tumors with diameters down to 200 μm after contrast injection at week 5. PET imaging showed that 18F-FLT (MW 244D) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559D and 2.066kD) extravasated after 5 weeks (tumor diameter 600 μm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27×10-5 cm/s versus 1.12×10-5 cm/s). PET imaging further demonstrated tumor permeability to 64Cu-BSA (MW 65.55kD) at week 6 (tumor diameter 700 μm). In conclusion, high field T1w MRI without contrast may improve the detection limit of small brain metastases, allowing for earlier diagnosis of patients, although the smallest lesions detected with T1w MRI were permeable only to D-Luciferin and the amphipathic small molecule 18F-FLT. Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies.
PMCID: PMC3922207  PMID: 24161382
Brain metastasis; MRI; PET; bioluminescence imaging; contrast agents
2.  Quantitative assessment of microglial morphology and density reveals remarkable consistency in the distribution and morphology of cells within the healthy prefrontal cortex of the rat 
Microglial morphology within the healthy brain has been the subject of a number of observational studies. These have suggested that microglia may consist of separate classes, which possess substantially different morphological features. Critically, there have been no systematic quantitative studies of microglial morphology within the healthy brain.
We examined microglial cells within the adult rat prefrontal cortex. At high magnification, digital reconstructions of cells labelled with the microglial-specific marker ionized calcium-binding adapter molecule-1 (Iba-1) were made in each of the cortical layers. These reconstructions were subsequently analyzed to determine the convex hull area of the cells, their somal perimeter, the length of processes, the number of processes, the extent of process branching and the volume of processes. We additionally examined whether cells’ morphological features were associated with cell size or numerical density.
Our analysis indicated that while there was substantial variability in the size of cells within the prefrontal cortex, cellular morphology was extremely consistent within each of the cortical layers.
Our results provide quantitative confirmation that microglia are largely homogenous in the uninjured rodent prefrontal cortex.
PMCID: PMC4213482  PMID: 25343964
Iba-1; Microglia; Morphology; Prefrontal cortex
3.  Effects of Obesity on Bone Mass and Quality in Ovariectomized Female Zucker Rats 
Journal of Obesity  2014;2014:690123.
Obesity and osteoporosis are two chronic conditions that have been increasing in prevalence. Despite prior data supporting the positive relationship between body weight and bone mineral density (BMD), recent findings show excess body weight to be detrimental to bone mass, strength, and quality. To evaluate whether obesity would further exacerbate the effects of ovariectomy on bone, we examined the tibiae and fourth lumbar (L4) vertebrae from leptin receptor-deficient female (Leprfa/fa) Zucker rats and their heterozygous lean controls (Leprfa/+) that were either sham-operated or ovariectomized (Ovx). BMD of L4 vertebra was measured using dual-energy X-ray absorptiometry, and microcomputed tomography was used to assess the microstructural properties of the tibiae. Ovariectomy significantly (P < 0.001) decreased the BMD of L4 vertebrae in lean and obese Zucker rats. Lower trabecular number and greater trabecular separation (P < 0.001) were also observed in the tibiae of lean- and obese-Ovx rats when compared to sham rats. However, only the obese-Ovx rats had lower trabecular thickness (Tb.Th) (P < 0.005) than the other groups. These findings demonstrated that ovarian hormone deficiency adversely affected bone mass and quality in lean and obese rats while obesity only affected Tb.Th in Ovx-female Zucker rats.
PMCID: PMC4189520  PMID: 25309751
4.  The effect of expectancy and personality on cortical excitability in Parkinson’s disease 
Our previous studies in PD have shown that both levodopa and expectancy of receiving levodopa reduce cortical excitability. We designed this study to evaluate how degree of expectancy and other individual factors modulate placebo response in Parkinson’s patients.
Twenty-six Parkinson’s patients were randomized to one of three groups: 0%, 50% and 100% expectancy of receiving levodopa. All subjects received placebo regardless of expectancy group. Subjects completed the NEO-Five Factor Inventory, General Perceived Self-Efficacy Scale, and Perceived Stress Scale. Cortical excitability was measured by the amplitude of motor evoked potential (MEP) evoked by transcranial magnetic stimulation. Objective physical fatigue of Extensor carpi radialis before and after placebo levodopa was also measured. Responders were defined as subjects who responded to the placebo levodopa with a decrease in MEP.
Degree of expectancy had a significant effect on MEP response (p<0.05). Subjects in the 50% and 100% expectancy groups responded with a decrease in MEP, while those in the 0% expectancy group responded with an increase in MEP (p<0.05). Responders tended to be more open to experience than non-responders. There were no significant changes in objective physical fatigue between the expectancy groups, or between responders and non-responders.
Expectancy is associated with changes in cortical excitability. Further studies are needed to examine the relationship between personality and placebo effect in Parkinson’s patients.
PMCID: PMC3735617  PMID: 23630185
Parkinson’s disease; Levodopa; Expectancy; Cortical Excitability; Transcranial Magnetic Stimulation (TMS)
5.  Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis 
Oncotarget  2014;5(12):4118-4128.
Although novel drugs have contributed immensely to improving outcomes of patients with multiple myeloma (MM), many patients develop drug resistance and ultimately succumb to MM. Here, we show that artesunate, an anti-malarial drug, reliably induces cell death in vitro in naïve as well as drug-resistant MM cells at concentrations shown to be safe in humans. Artesunate induced apoptosis predominantly through the non-caspase mediated pathway by primarily targeting mitochondria and causing outer mitochondrial membrane permeabilization that led to cytosolic and subsequent nuclear translocation of mitochondrial proteins apoptosis inducing factor (AIF) and endonuclease G (EndoG). Nuclear translocation of AIF and EndoG was accompanied by low levels of reactive oxygen species (ROS) and increased mitochondrial production of superoxide. These effects were present before apoptosis was evident and were related to intracellular levels of bivalent iron (Fe+2). Artesunate's unique mechanism probably was at least partially responsible for, its ability to act synergistically with multiple anti-myeloma agents. Our findings suggest that artesunate acts through iron to affect the mitochondria and induce low ROS and non-caspase–mediated apoptosis. Its potency, toxicity profile, and synergism with other drugs make it an intriguing new candidate for MM treatment.
PMCID: PMC4147310  PMID: 24948357
artesunate; apoptosis; caspases; myeloma; ROS
6.  Hippocampal Shape Abnormalities of Patients With Childhood-Onset Schizophrenia and Their Unaffected Siblings 
The hippocampus has been implicated in the pathogenesis of schizophrenia, and hippocampal volume deficits have been a consistently reported abnormality, but the subregional specificity of the deficits remains unknown. The authors explored the nature and developmental trajectory of subregional shape abnormalities of the hippocampus in patients with childhood-onset schizophrenia (COS), their healthy siblings, and healthy volunteers.
Two hundred twenty-five anatomic brain magnetic resonance images were obtained from 103 patients with COS, 169 from their 79 healthy siblings, and 255 from 101 age- and sex-matched healthy volunteers (age range = 9–29 years). The hippocampus was segmented using Free-Surfer automated image analysis software, and hippocampal shape was evaluated by comparing subjects at more than 6,000 vertices on the left and right hippocampal surfaces. Longitudinal data were examined using mixed model regression analysis.
Patients with COS showed significant bilateral inward deformation in the anterior hippocampus. Healthy siblings also showed a trend for anterior inward deformation. However, the trajectory of shape change did not differ significantly between the groups. Inward deformations in the anterior hippocampus were positively related to positive symptom severity, whereas outward surface displacement was positively related to overall functioning.
This is the first and largest longitudinal three-way analysis of subregional hippocampal shape abnormalities in patients with COS and their healthy siblings compared with healthy controls. The anterior hippocampal abnormalities in COS suggest the pathophysiologic importance of this subregion in schizophrenia. The trend level and overlapping shape abnormalities in the healthy siblings suggest a more subtle, subregionally specific neuroanatomic endophenotype.
PMCID: PMC3812431  PMID: 23622854
hippocampus; longitudinal; magnetic resonance imaging; neurodevelopment; schizophrenia
7.  Study to find the best extraction solvent for use with guava leaves (Psidium guajava L.) for high antioxidant efficacy 
Food Science & Nutrition  2014;2(2):174-180.
The effects of guava leaves extracted using solvents of water, ethanol, methanol, and different concentrations of hydroethanolic solvents on phenolic compounds and flavonoids, and antioxidant properties have been investigated. The antioxidant capability was assessed based on 2,2-diphenyl-1-picrylhydrazyl radical and 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radical-scavenging abilities, reducing power, and nitric oxide-and nitrate-scavenging activities. The results demonstrated that the antioxidant ability of guava leaf extracts has a strong relationship with phenolic compound content rather than flavonoid content. Phenolic compound content of water extracted guava leaves was higher compared to pure ethanol and methanol extracts. However, phenolic compound content extracted using hydroethanolic solvent was higher than water, whereas 50% hydroethanolic was observed to be the most effective solvent showing high antioxidant ability.
PMCID: PMC3959964  PMID: 24804076
Antioxidant; flavonoid; guava; hydroethanolic solvent; phenolic compound
8.  Absence of anatomic corpus callosal abnormalities in childhood onset schizophrenia patients and healthy siblings 
Psychiatry research  2012;211(1):11-16.
The corpus callosum (CC) has been implicated in the pathogenesis of schizophrenia, and CC deficits have been reported in adults with schizophrenia. We explored the developmental trajectory of the corpus callosum in Childhood-onset schizophrenia (COS) patients, their healthy siblings and healthy volunteers. We obtained 235 anatomic brain MRI scans from 98 COS patients, 153 scans from 71 of their healthy siblings, and 253 scans from 100 age and gender matched healthy volunteers, across ages 9–30 years. The volumes of 5 sub-regions of the CC were calculated using FreeSurfer, and summed to give the total volume. Longitudinal data were examined using mixed model regression analysis. There were no significant differences for the total or sub-regional CC volumes between the three groups. There were also no significant differences between the groups for developmental trajectory (slope) of the CC. This is the largest longitudinal study of CC development in schizophrenia and the first COS study of the CC to include healthy siblings. Overall, CC volume and growth trajectory did not differ between COS patients, healthy siblings, or healthy volunteers. These results suggest that CC development, at least at a macroscopic level, may not be a salient feature of schizophrenia.
PMCID: PMC3557544  PMID: 23154096
Corpus Callosum; MRI; Neuroimaging; Development
9.  DNA Damage Enhancement from Gold Nanoparticles for Clinical MV Photon Beams 
Radiation research  2012;178(6):604-608.
In this study, we quantify the relative damage enhancement due to the presence of gold nanoparticles (GNP) in vitro in a clinical 6 MV beam for various delivery parameters and depths. It is expected that depths and delivery modes that produce a larger proportions of low-energy photons will have a larger effect on the cell samples containing GNP. HeLa cells with and without 50 nm GNP were irradiated at depths of 1.5, 5, 10, 15 and 20 cm. Conventional beams with square aperture sizes 5, 10 and 15 cm at isocenter, and flattening filter free (FFF) beams were used. Relative DNA damage enhancement with GNP was evaluated by γ-H2AX staining. Statistically significant increases in DNA damage with GNP, compared to the absence of GNP, were observed for all depths and delivery modes. Relative to the shallowest depth, damage enhancement was observed to increase as a function of increasing depth for all deliveries. For the conventional (open field) delivery, DNA damage enhancement with GNP was seen to increase as a function of field size. For FFF delivery, a substantial increase in enhancement was found relative to the conventional field delivery. The measured relative DNA damage enhancement validates the theoretically predicted trends as a function of depth and delivery mode for clinical MV photon beams. The results of this study open new possibilities for the clinical development of gold nanoparticle-aided radiation therapy.
PMCID: PMC3525114  PMID: 23148509
10.  Interactions between Parents and Parents and Pups in the Monogamous California Mouse (Peromyscus californicus) 
PLoS ONE  2013;8(9):e75725.
The California mouse (Peromyscuscalifornicus) may be a valuable animal model to study parenting as it is one of the few monogamous and biparental rodent species. By using automated infra-red imaging and video documentation of established pairs spanning two days prior to birth of the litter until d 5 of post natal development (PND), it was possible to follow interactions between parents and between parents and pups. The paired males were attentive to their partners in the form of grooming and sniffing throughout the time period studied. Both these and other activities of the partners, such as eating and drinking, peaked during late light/ mid-dark period. Beginning the day before birth, and most significantly on PND 0, the female made aggressive attempts to exclude the male from nest-attending, acts that were not reciprocated by the male, although he made repeated attempts to mate his partner during that period. By PND 1, males were permitted to return to the nest, where they initiated grooming, licking, and huddling over the litter, although time spent by the male on parental care was still less than that of the female. Male and female pups were of similar size and grew at the same rate. Pups, which are believed to be exothermic for at least the first two weeks post-natally, maintained a body temperature higher than that of their parents until PND 16. Data are consistent with the inference that the male California mouse parent is important in helping retain pup body heat and permit dams increased time to procure food to accommodate her increased energy needs for lactation. These assessments provide indices that may be used to assess the effects of extrinsic factors, such as endocrine disrupting chemicals, on biparental behaviors and offspring development.
PMCID: PMC3777941  PMID: 24069441
11.  Effects of Vitamin E on Bone Biomechanical and Histomorphometric Parameters in Ovariectomized Rats 
Journal of Osteoporosis  2013;2013:825985.
The present study examined the dose-dependent effect of vitamin E in reversing bone loss in ovariectomized (Ovx) rats. Sprague-Dawley rats were either Sham-operated (Sham) or Ovx and fed control diet for 120 days to lose bone. Subsequently, rats were divided into 5 groups (n = 12/group): Sham, Ovx-control, low dose (Ovx + 300 mg/kg diet; LD), medium dose (Ovx + 525 mg/kg diet; MD), and high dose (Ovx + 750 mg/kg diet; HD) of vitamin E and sacrificed after 100 days. Animals receiving MD and HD of vitamin E had increased serum alkaline phosphatase compared to the Ovx-control group. Bone histomorphometry analysis indicated a decrease in bone resorption as well as increased bone formation and mineralization in the Ovx groups supplemented with MD and HD of vitamin E. Microcomputed tomography findings indicated no effects of vitamin E on trabecular bone of fifth lumbar vertebrae. Animals receiving HD of vitamin E had enhanced fourth lumbar vertebra quality as evidenced by improved ultimate and yield load and stress when compared to Ovx-control group. These findings demonstrate that vitamin E improves bone quality, attenuates bone resorption, and enhances the rate of bone formation while being unable to restore bone density and trabecular bone structure.
PMCID: PMC3780659  PMID: 24089643
12.  Characterization of a Mouse-Adapted Staphylococcus aureus Strain 
PLoS ONE  2013;8(9):e71142.
More effective antibiotics and a protective vaccine are desperately needed to combat the ‘superbug’ Staphylococcus aureus. While in vivo pathogenicity studies routinely involve infection of mice with human S. aureus isolates, recent genetic studies have demonstrated that S. aureus lineages are largely host-specific. The use of such animal-adapted S. aureus strains may therefore be a promising approach for developing more clinically relevant animal infection models. We have isolated a mouse-adapted S. aureus strain (JSNZ) which caused a severe outbreak of preputial gland abscesses among male C57BL/6J mice. We aimed to extensively characterize this strain on a genomic level and determine its virulence potential in murine colonization and infection models. JSNZ belongs to the MLST type ST88, rare among human isolates, and lacks an hlb-converting phage encoding human-specific immune evasion factors. Naive mice were found to be more susceptible to nasal and gastrointestinal colonization with JSNZ than with the human-derived Newman strain. Furthermore, naïve mice required antibiotic pre-treatment to become colonized with Newman. In contrast, JSNZ was able to colonize mice in the absence of antibiotic treatment suggesting that this strain can compete with the natural flora for space and nutrients. In a renal abscess model, JSNZ caused more severe disease than Newman with greater weight loss and bacterial burden. In contrast to most other clinical isolates, JSNZ can also be readily genetically modified by phage transduction and electroporation. In conclusion, the mouse-adapted strain JSNZ may represent a valuable tool for studying aspects of mucosal colonization and for screening novel vaccines and therapies directed at preventing colonization.
PMCID: PMC3759423  PMID: 24023720
13.  Examining Racial and Ethnic Minority Differences among YMSM during Recruitment for an Online HIV Prevention Intervention Study 
AIDS and Behavior  2012;16(6):1430-1435.
HIV disproportionately affects racial and ethnic minority young men who have sex with men (YMSM). HIV prevention research does not include these YMSM commensurate to their HIV burden. We examined racial and ethnic differences during a unique three-step recruitment process for an online, YMSM HIV prevention intervention study (N=660). Step one was completed in-person; steps two and three online. Fewer Black and Latino YMSM completed step two – initiating online participation – than White YMSM. Internet use frequency accounted for the Latino vs. White difference in initiating online participation, but not the Black vs. White difference. Future online HIV prevention interventions recruiting diverse YMSM should focus on initiating online engagement among Black participants.
PMCID: PMC3288566  PMID: 21986869
YMSM; HIV prevention; online intervention; research engagement; Keep it Up!
14.  Spatial and temporal estimation of air pollutants in New York City: exposure assignment for use in a birth outcomes study 
Environmental Health  2013;12:51.
Recent epidemiological studies have examined the associations between air pollution and birth outcomes. Regulatory air quality monitors often used in these studies, however, were spatially sparse and unable to capture relevant within-city variation in exposure during pregnancy.
This study developed two-week average exposure estimates for fine particles (PM2.5) and nitrogen dioxide (NO2) during pregnancy for 274,996 New York City births in 2008–2010. The two-week average exposures were constructed by first developing land use regression (LUR) models of spatial variation in annual average PM2.5 and NO2 data from 150 locations in the New York City Community Air Survey and emissions source data near monitors. The annual average concentrations from the spatial models were adjusted to account for city-wide temporal trends using time series derived from regulatory monitors. Models were developed using Year 1 data and validated using Year 2 data. Two-week average exposures were then estimated for three buffers of maternal address and were averaged into the last six weeks, the trimesters, and the entire period of gestation. We characterized temporal variation of exposure estimates, correlation between PM2.5 and NO2, and correlation of exposures across trimesters.
The LUR models of average annual concentrations explained a substantial amount of the spatial variation (R2 = 0.79 for PM2.5 and 0.80 for NO2). In the validation, predictions of Year 2 two-week average concentrations showed strong agreement with measured concentrations (R2 = 0.83 for PM2.5 and 0.79 for NO2). PM2.5 exhibited greater temporal variation than NO2. The relative contribution of temporal vs. spatial variation in the estimated exposures varied by time window. The differing seasonal cycle of these pollutants (bi-annual for PM2.5 and annual for NO2) resulted in different patterns of correlations in the estimated exposures across trimesters. The three levels of spatial buffer did not make a substantive difference in estimated exposures.
The combination of spatially resolved monitoring data, LUR models and temporal adjustment using regulatory monitoring data yielded exposure estimates for PM2.5 and NO2 that performed well in validation tests. The interaction between seasonality of air pollution and exposure intervals during pregnancy needs to be considered in future studies.
PMCID: PMC3704849  PMID: 23802774
Air pollution; Birth outcomes; Particulate matter; Nitrogen dioxide; Land use regression; NYCCAS; Temporal adjustment
15.  Preadult Parental Diet Affects Offspring Development and Metabolism in Drosophila melanogaster 
PLoS ONE  2013;8(3):e59530.
When Drosophila melanogaster larvae are reared on isocaloric diets differing in their amounts of protein relative to sugar, emerging adults exhibit significantly different development times and metabolic pools of protein, glycogen and trigylcerides. In the current study, we show that the influence of larval diet experienced during just one generation extends into the next generation, even when that subsequent generation had been shifted to a standard diet during development. Offspring of flies that were reared on high protein relative to sugar underwent metamorphosis significantly faster, had higher reproductive outputs, and different metabolic pool contents compared to the offspring of adults from low protein relative to sugar diets. In addition, isofemale lines differed in the degree to which parental effects were observed, suggesting a genetic component to the observed transgenerational influences.
PMCID: PMC3608729  PMID: 23555695
16.  Cytotoxic Capacity of SIV-Specific CD8+ T Cells against Primary Autologous Targets Correlates with Immune Control in SIV-Infected Rhesus Macaques 
PLoS Pathogens  2013;9(2):e1003195.
Although the study of non-human primates has resulted in important advances for understanding HIV-specific immunity, a clear correlate of immune control over simian immunodeficiency virus (SIV) replication has not been found to date. In this study, CD8+ T-cell cytotoxic capacity was examined to determine whether this function is a correlate of immune control in the rhesus macaque (RM) SIV infection model as has been suggested in chronic HIV infection. SIVmac251-infected human reverse transcriptase (hTERT)-transduced CD4+ T-cell clone targets were co-incubated with autologous macaque effector cells to measure infected CD4+ T-cell elimination (ICE). Twenty-three SIV-infected rhesus macaques with widely varying plasma viral RNA levels were evaluated in a blinded fashion. Nineteen of 23 subjects (83%) were correctly classified as long-term nonprogressor/elite controller (LTNP/EC), slow progressor, progressor or SIV-negative rhesus macaques based on measurements of ICE (weighted Kappa 0.75). LTNP/EC had higher median ICE than progressors (67.3% [22.0–91.7%] vs. 23.7% [0.0–58.0%], p = 0.002). In addition, significant correlations between ICE and viral load (r = −0.57, p = 0.01), and between granzyme B delivery and ICE (r = 0.89, p<0.001) were observed. Furthermore, the CD8+ T cells of LTNP/EC exhibited higher per-cell cytotoxic capacity than those of progressors (p = 0.004). These findings support that greater lytic granule loading of virus-specific CD8+ T cells and efficient delivery of active granzyme B to SIV-infected targets are associated with superior control of SIV infection in rhesus macaques, consistent with observations of HIV infection in humans. Therefore, such measurements appear to represent a correlate of control of viral replication in chronic SIV infection and their role as predictors of immunologic control in the vaccine setting should be evaluated.
Author Summary
Clues regarding the features of effective immunity against lentiviruses have come from the study of non-human primates. We evaluated rhesus macaques infected with Simian Immunodeficiency Virus (SIV), a lentivirus closely related to Human Immunodeficiency Virus (HIV). In contrast to most SIV-infected rhesus macaques that develop progressive disease, a small proportion are able to control SIV replication and remain healthy for prolonged durations. In this study, we found that these long-term nonprogressor/elite controller (LTNP/EC) macaques have CD8+ T cells that are extremely effective at killing SIV-infected cells. It seems that this control is mediated by the efficient delivery of active granzyme B, a key molecule involved in the elimination of virus-infected cells. Furthermore, we correctly predicted the presence or absence of control of SIV infection in the majority of animals through measurements of the killing capacity of their CD8+ T cells. These findings indicate that measuring these functions could be used in the evaluation of vaccines against SIV in non-human primates.
PMCID: PMC3585127  PMID: 23468632
17.  Current methods and attitudes of women towards contraception in Europe and America 
Reproductive Health  2013;10:7.
The choice of available contraceptive methods has increased in recent years; however, recent data on women’s awareness of methods and reasons for their method choice, or reasons for changing methods, is limited. The aim of this study was to examine the use and awareness of contraceptive methods in the USA, UK, Germany, Italy and Spain.
Quantitative survey of heterosexual women aged 25–44 years (n=2544), with no known infertility. Questions related to knowledge and use of contraceptive methods, reasons for choice and for changing methods, and sources of advice.
There was generally good awareness of most forms of contraception in all five countries. Awareness and current usage was greatest for the contraceptive pill (awareness >98%, usage varied from 35% [Spain] to 63% [Germany]); and male condom (awareness >95%, usage varied from 20% [Germany] to 47% [Spain]); awareness of other methods varied between countries. Doctors have the greatest influence on women’s choice of contraceptive method (>50% for all countries), and are most likely to suggest the contraceptive pill or male condom.
Women’s contraceptive needs change; 4–36% of contraceptive pill users were likely to change their method within 12 months. For previous contraceptive pill users (n=377), most common reason for change was concern about side effects (from 26% [Italy] to 10% [UK]); however, awareness of many non-hormonal contraceptive methods was low.
Women aged 25–44 are aware of a wide variety of contraceptive methods, but knowledge and usage of the contraceptive pill and condoms predominates. Changing contraception method is frequent, occurring for a variety of reasons, including change in life circumstances and, for pill users, concerns about side effects.
PMCID: PMC3599328  PMID: 23384291
Contraception; Contraceptive pill; Condoms; Natural family planning; Persona®
18.  The effect of incision choice on outcomes of nipple-sparing mastectomy reconstruction 
The indications for nipple-sparing mastectomy (NSM) are broadening as more breast surgeons appreciate the utility of preserving the nipple-areolar complex. A number of incision locations are available to the mastectomy surgeon, including inframammary, lateral and periareolar approaches. The present study investigated the effect of these three incisions on reconstructive outcomes; specifically, nipple necrosis.
A single-centre, retrospective review of 37 breast NSM reconstructions treated with immediate tissue expander reconstruction with acellular dermis between 2007 and 2008 was performed. The primary outcome was the incidence of nipple necrosis associated with periareolar, lateral and inframammary incisions. Secondary outcomes were the effects of radiation, chemotherapy and breast size on nipple necrosis.
Thirty-seven breast procedures performed on 20 patients were included in the present study. Periareolar incisions were used in 21 cases, lateral incisions in 14 and inframammary incisions in two. The periareolar incision was associated with a significantly higher incidence of nipple necrosis compared with lateral or inframammary incisions (38.1% versus 6.3%, P=0.028). Patients receiving breast radiation (45.5% versus 15.4%, P=0.066) and those with larger breast size (540.4 g versus 425.7 g, P=0.130) also demonstrated a modest trend toward an increased rate of nipple necrosis.
The periareolar incision results in a higher rate of nipple necrosis following NSM and immediate tissue expander breast reconstruction. Using the lateral or inframammary incision reduces the incidence of nipple necrosis and may help improve overall reconstructive and cosmetic outcomes.
PMCID: PMC3269196  PMID: 23204883
Acellular dermis; Breast reconstruction; Nipple-areola complex; Nipple-sparing mastectomy; Nipple necrosis; Tissue expansion
19.  Mate Pair Sequencing of Whole-Genome-Amplified DNA Following Laser Capture Microdissection of Prostate Cancer 
High-throughput next-generation sequencing provides a revolutionary platform to unravel the precise DNA aberrations concealed within subgroups of tumour cells. However, in many instances, the limited number of cells makes the application of this technology in tumour heterogeneity studies a challenge. In order to address these limitations, we present a novel methodology to partner laser capture microdissection (LCM) with sequencing platforms, through a whole-genome amplification (WGA) protocol performed in situ directly on LCM engrafted cells. We further adapted current Illumina mate pair (MP) sequencing protocols to the input of WGA DNA and used this technology to investigate large genomic rearrangements in adjacent Gleason Pattern 3 and 4 prostate tumours separately collected by LCM. Sequencing data predicted genome coverage and depths similar to unamplified genomic DNA, with limited repetition and bias predicted in WGA protocols. Mapping algorithms developed in our laboratory predicted high-confidence rearrangements and selected events each demonstrated the predicted fusion junctions upon validation. Rearrangements were additionally confirmed in unamplified tissue and evaluated in adjacent benign-appearing tissues. A detailed understanding of gene fusions that characterize cancer will be critical in the development of biomarkers to predict the clinical outcome. The described methodology provides a mechanism of efficiently defining these events in limited pure populations of tumour tissue, aiding in the derivation of genomic aberrations that initiate cancer and drive cancer progression.
PMCID: PMC3473372  PMID: 22991452
mate pair sequencing; whole-genome amplified, laser capture microdissection; prostrate cancer
20.  The effect of three different toe props on plantar pressure and patient comfort 
Arthritic toe pathologies frequently lead to the development of painful apical pressure skin lesions that can compromise gait and affect quality of life. Historically conservative treatments involve the use of a toe prop with the intended aim of reducing plantar pressure from the apex of the digit. However, the effect of toe prop treatment on plantar digital pressure has not been investigated.
Twenty two subjects were recruited with lesser digital deformities and associated apical skin lesions. Individual pressure sensors were placed on the apices of the lesser toes and pressure was recorded under three toe prop conditions (leather, gel and silicone mould). A modified comfort index was utilised to assess the comfort of each condition.
Significant difference (p < 0.05) in mean peak pressure was observed at the apex of the 2nd toe when using the gel (p < 0.001) and silicone (p < 0.001) toe prop compared to no toe prop. There was also a significant difference in the mean pressure time integral at the apex of the 2nd toe when using gel (p < 0.001) and silicone (p < 0.004) toe props. There was no significant correlation between comfort and the recorded peak pressures. However, there was an indication that the silicone toe prop was more comfortable.
As compared to the leather and silicone mould toe props, gel toe props were found to be the most effective for reducing peak pressure and pressure time integral on the apex of the second digit in patients with claw or hammer toe deformity.
PMCID: PMC3503803  PMID: 22932230
Apical peak pressure; Digital deformities; Toe prop therapy; Comfort
21.  Spatial variability in levels of benzene, formaldehyde, and total benzene, toluene, ethylbenzene and xylenes in New York City: a land-use regression study 
Environmental Health  2012;11:51.
Hazardous air pollutant exposures are common in urban areas contributing to increased risk of cancer and other adverse health outcomes. While recent analyses indicate that New York City residents experience significantly higher cancer risks attributable to hazardous air pollutant exposures than the United States as a whole, limited data exist to assess intra-urban variability in air toxics exposures.
To assess intra-urban spatial variability in exposures to common hazardous air pollutants, street-level air sampling for volatile organic compounds and aldehydes was conducted at 70 sites throughout New York City during the spring of 2011. Land-use regression models were developed using a subset of 59 sites and validated against the remaining 11 sites to describe the relationship between concentrations of benzene, total BTEX (benzene, toluene, ethylbenzene, xylenes) and formaldehyde to indicators of local sources, adjusting for temporal variation.
Total BTEX levels exhibited the most spatial variability, followed by benzene and formaldehyde (coefficient of variation of temporally adjusted measurements of 0.57, 0.35, 0.22, respectively). Total roadway length within 100 m, traffic signal density within 400 m of monitoring sites, and an indicator of temporal variation explained 65% of the total variability in benzene while 70% of the total variability in BTEX was accounted for by traffic signal density within 450 m, density of permitted solvent-use industries within 500 m, and an indicator of temporal variation. Measures of temporal variation, traffic signal density within 400 m, road length within 100 m, and interior building area within 100 m (indicator of heating fuel combustion) predicted 83% of the total variability of formaldehyde. The models built with the modeling subset were found to predict concentrations well, predicting 62% to 68% of monitored values at validation sites.
Traffic and point source emissions cause substantial variation in street-level exposures to common toxic volatile organic compounds in New York City. Land-use regression models were successfully developed for benzene, formaldehyde, and total BTEX using spatial indicators of on-road vehicle emissions and emissions from stationary sources. These estimates will improve the understanding of health effects of individual pollutants in complex urban pollutant mixtures and inform local air quality improvement efforts that reduce disparities in exposure.
PMCID: PMC3420325  PMID: 22849853
Benzene; Formaldehyde; BTEX; Land use regression (LUR); Air toxics; Traffic; Hazardous air pollutants (HAP)
22.  Examining the Link between Neighborhood Context and Parental Messages to their Adolescent Children About Violence 
Living in violent neighborhoods has been shown to alter adolescent’s social-cognitions and increase aggressive behavior. A similar process may also occur for parents and result in parental support of aggressive behavior. This research examines the influence of perceived neighborhood violence and neighborhood collective efficacy on parents’ attitudes toward violence and the messages they give their adolescent children about how to resolve interpersonal conflict.
These data come from 143 African-American parents and their adolescent children recruited from 3 inner-city middle schools to participate in a parenting intervention. Models were fit using structural equation modeling in Mplus.
Contrary to expectations, exposure to neighborhood violence was not predictive of either aggressive attitudes or conflict solutions for parents or adolescents. Rather, a mixed effect was found for neighborhood collective efficacy, with higher perceived neighborhood collective efficacy related to less violent attitudes for adolescents but not parents. Collective efficacy also predicted the messages that parents gave their adolescents about interpersonal conflict, with higher collective efficacy related to messages that were less supportive of violence.
Parent and adolescent perception of neighborhood collective efficacy influences the messages that adolescents receive about interpersonal conflict resolution. This suggests that for parents living in violent neighborhoods their appraisal of the neighborhood is more important in shaping conflict resolution messages than parents’ own experiences with violence. Parent and family-based programs to prevent youth violence need to address neighborhood factors that influence the messages adolescents receive about how to resolve conflict.
PMCID: PMC3124663  PMID: 21700158
Adolescents; Violence; Parenting; Collective Efficacy; Parent/child communications
23.  A geometric analysis of mastectomy incisions: Optimizing intraoperative breast volume 
The advent of acellular dermis-based tissue expander breast reconstruction has placed an increased emphasis on optimizing intraoperative volume. Because skin preservation is a critical determinant of intraoperative volume expansion, a mathematical model was developed to capture the influence of incision dimension on subsequent tissue expander volumes.
A mathematical equation was developed to calculate breast volume via integration of a geometrically modelled breast cross-section. The equation calculates volume changes associated with excised skin during the mastectomy incision by reducing the arc length of the cross-section. The degree of volume loss is subsequently calculated based on excision dimensions ranging from 35 mm to 60 mm.
A quadratic relationship between breast volume and the vertical dimension of the mastectomy incision exists, such that incrementally larger incisions lead to a disproportionally greater amount of volume loss. The vertical dimension of the mastectomy incision – more so than the horizontal dimension – is of critical importance to maintain breast volume. Moreover, the predicted volume loss is more profound in smaller breasts and primarily occurs in areas that affect breast projection on ptosis.
The present study is the first to model the relationship between the vertical dimensions of the mastectomy incision and subsequent volume loss. These geometric principles will aid in optimizing intra-operative volume expansion during expander-based breast reconstruction.
PMCID: PMC3328110  PMID: 22654531
Mastectomy incision; Mathematical model; Tissue expander; Volume
24.  Daptomycin exposure precedes infection and/or colonization with daptomycin non-susceptible enterococcus 
Daptomycin non-susceptible enterococci (DNSE) are emerging as an important cause of healthcare-associated infection, however little is known about the epidemiology of DNSE. At the University of Iowa Hospitals and Clinics (UIHC) an increase in the frequency of patients infected and/or colonized with DNSE has occurred. The goals of this study were to evaluate potential factors associated with the development of DNSE colonization and/or infection and to compare the characteristics of patients with prior daptomycin exposure to those without prior daptomycin exposure.
The study is a retrospective case-series involving all patients with DNSE infection and/or colonization at UIHC, a 734-bed academic referral center, from June 1, 2005 to June 1, 2011.
The majority of patients with DNSE colonization and/or infection had prior daptomycin exposure (15 of 25; 60%), a concomitant gastrointestinal process (19 of 25; 76%), or were immunosuppressed (21 of 25; 84%). DNSE infection was confirmed in 17 of 25 (68%) patients, including 9 patients with bacteremia. Twelve of 17 (71%) patients with DNSE infection had prior daptomycin exposure, including 7 of 9 (78%) patients with bacteremia. Compared to patients without prior daptomycin exposure, patients with prior daptomycin exposure were less likely to harbor E. faecalis (0% vs. 33%; p = 0.019). A high proportion of patients (10 of 25; 40%) died during their hospitalizations. Most enterococcal isolates were E. faecium (86%), and were vancomycin-resistant (72%). Molecular typing revealed a diverse population of DNSE.
Prior daptomycin exposure, immunosuppression, and/or a concomitant gastrointestinal process, may be associated with the development of DNSE. PFGE revealed a diverse population of DNSE, which along with both increasing numbers of DNSE detected yearly and increasing annual rates of daptomycin usage, suggests the emergence of DNSE under antimicrobial pressure.
PMCID: PMC3436660  PMID: 22958379
Enterococcus; Daptomycin; Resistance; Non-Susceptible; DNSE
25.  Evolution of reproductive morphology among recently diverged taxa in the Drosophila mojavensis species cluster 
Ecology and Evolution  2012;2(2):397-408.
The morphological evolution of sexual traits informs studies of speciation due to the potential role of these characters in reproductive isolation. In the current study, we quantified and compared genitalic variation within the Drosophila mojavensis species cluster to infer the mode of evolution of the male aedeagus. This system is ideal for such studies due to the opportunity to test and compare levels of variation along a divergence continuum at various taxonomic levels within the group. Shape variation was quantified using elliptic Fourier descriptors and compared among the four D. mojavensis host races, and between D. mojavensis and its sister species Drosophila arizonae. Aedeagus shape was diagnostic for D. arizonae, and among three of the four D. mojavensis subspecies. In each of these cases, there was less variation within subspecies than among subspecies, which is consistent with the pattern predicted if genitalia are evolving according to a punctuated change model, and are involved with mate recognition. However, aedeagus shape in Drosophila mojavensis sonorensis was highly variable and broadly overlapping with the other three subspecies, suggesting aedeagus evolution in this subspecies is more complex and subject to additional evolutionary factors. These results are interpreted and discussed in the context of selection on mate recognition systems and the potential for failed copulation.
PMCID: PMC3298951  PMID: 22423332
Genitalia; morphological evolution; morphometrics; Sonoran Desert

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