Towards Validation of a New Computerised Test of Goal Neglect: Preliminary Evidence from Clinical and Neuroimaging Pilot Studies

Objective

Goal neglect is a significant problem following brain injury, and is a target for rehabilitation. It is not yet known how neural activation might change to reflect rehabilitation gains. We developed a computerised multiple elements test (CMET), suitable for use in neuroimaging paradigms.

Design

Pilot correlational study and event-related fMRI study.

Methods

In Study 1, 18 adults with acquired brain injury were assessed using the CMET, other tests of goal neglect (Hotel Test; Modified Six Elements Test) and tests of reasoning. In Study 2, 12 healthy adults underwent fMRI, during which the CMET was administered under two conditions: self-generated switching and experimenter-prompted switching.

Results

Among the clinical sample, CMET performance was positively correlated with both the Hotel Test (r = 0.675, p = 0.003) and the Modified Six Elements Test (r = 0.568, p = 0.014), but not with other clinical or demographic measures. In the healthy sample, fMRI demonstrated significant activation in rostro-lateral prefrontal cortex in the self-generated condition compared with the prompted condition (peak 40, 44, 4; Z_E = 4.25, p_(FWEcorr) = 0.026).

Conclusions

These pilot studies provide preliminary evidence towards the validation of the CMET as a measure of goal neglect. Future studies will aim to further establish its psychometric properties, and determine optimum pre- and post-rehabilitation fMRI paradigms.     

Estimation of the Basic Reproductive Number and Mean Serial Interval of a Novel Pathogen in a Small,Well-Observed Discrete Population

Background

Accurately assessing the transmissibility and serial interval of a novel human pathogen is public health priority so that the timing and required strength of interventions may be determined. Recent theoretical work has focused on making best use of data from the initial exponential phase of growth of incidence in large populations.

Methods

We measured generational transmissibility by the basic reproductive number R₀ and the serial interval by its mean T_g. First, we constructed a simulation algorithm for case data arising from a small population of known size with R₀ and T_g also known. We then developed an inferential model for the likelihood of these case data as a function of R₀ and T_g. The model was designed to capture a) any signal of the serial interval distribution in the initial stochastic phase b) the growth rate of the exponential phase and c) the unique combination of R₀ and T_g that generates a specific shape of peak incidence when the susceptible portion of a small population is depleted.

Findings

Extensive repeat simulation and parameter estimation revealed no bias in univariate estimates of either R₀ and T_g. We were also able to simultaneously estimate both R₀ and T_g. However, accurate final estimates could be obtained only much later in the outbreak. In particular, estimates of T_g were considerably less accurate in the bivariate case until the peak of incidence had passed.

Conclusions

The basic reproductive number and mean serial interval can be estimated simultaneously in real time during an outbreak of an emerging pathogen. Repeated application of these methods to small scale outbreaks at the start of an epidemic would permit accurate estimates of key parameters.     

Comparison of Dixon Sequences for Estimation of Percent Breast Fibroglandular Tissue

Objectives

To evaluate sources of error in the Magnetic Resonance Imaging (MRI) measurement of percent fibroglandular tissue (%FGT) using two-point Dixon sequences for fat-water separation.

Methods

Ten female volunteers (median age: 31 yrs, range: 23–50 yrs) gave informed consent following Research Ethics Committee approval. Each volunteer was scanned twice following repositioning to enable an estimation of measurement repeatability from high-resolution gradient-echo (GRE) proton-density (PD)-weighted Dixon sequences. Differences in measures of %FGT attributable to resolution, T₁ weighting and sequence type were assessed by comparison of this Dixon sequence with low-resolution GRE PD-weighted Dixon data, and against gradient-echo (GRE) or spin-echo (SE) based T₁-weighted Dixon datasets, respectively.

Results

%FGT measurement from high-resolution PD-weighted Dixon sequences had a coefficient of repeatability of ±4.3%. There was no significant difference in %FGT between high-resolution and low-resolution PD-weighted data. Values of %FGT from GRE and SE T₁-weighted data were strongly correlated with that derived from PD-weighted data (r = 0.995 and 0.96, respectively). However, both sequences exhibited higher mean %FGT by 2.9% (p < 0.0001) and 12.6% (p < 0.0001), respectively, in comparison with PD-weighted data; the increase in %FGT from the SE T₁-weighted sequence was significantly larger at lower breast densities.

Conclusion

Although measurement of %FGT at low resolution is feasible, T₁ weighting and sequence type impact on the accuracy of Dixon-based %FGT measurements; Dixon MRI protocols for %FGT measurement should be carefully considered, particularly for longitudinal or multi-centre studies.     

Association of Lung Inflammatory Cells with Small Airways Function and Exhaled Breath Markers in Smokers – Is There a Specific Role for Mast Cells?

Background

Smoking is associated with a mixed inflammatory infiltrate in the airways. We evaluated whether airway inflammation in smokers is related to lung function parameters and inflammatory markers in exhaled breath.

Methods

Thirty-seven smokers undergoing lung resection for primary lung cancer were assessed pre-operatively by lung function testing including single-breath-nitrogen washout test (sb-N2-test), measurement of fractional exhaled nitric oxide (FeNO) and pH/8-isoprostane in exhaled breath condensate (EBC). Lung tissue sections containing cancer-free large (LA) and small airways (SA) were stained for inflammatory cells. Mucosal (MC_T) respectively connective tissue mast cells (MC_TC) and interleukin-17A (IL-17A) expression by mast cells was analysed using a double-staining protocol.

Results

The median number of neutrophils, macrophages and mast cells infiltrating the lamina propria and adventitia of SA was higher than in LA. Both MCTC and MC_T were higher in the lamina propria of SA compared to LA (MC_TC: 49 vs. 27.4 cells/mm²; MC_T: 162.5 vs. 35.4 cells/mm²; P<0.005 for both instances). IL-17A expression was predominantly detected in MC_TC of LA. Significant correlations were found for the slope of phase III % pred. of the sb-N2-test (r_s= -0.39), for the FEV₁% pred. (r_s= 0.37) and for FEV₁/FVC ratio (r_s=0.38) with MC_T in SA (P<0.05 for all instances). 8-isoprostane concentration correlated with the mast cells in the SA (r_s=0.44), there was no correlation for pH or FeNO with cellular distribution in SA.

Conclusions

Neutrophils, macrophages and mast cells are more prominent in the SA indicating that these cells are involved in the development of small airway dysfunction in smokers. Among these cell types, the best correlation was found for mast cells with lung function parameters and inflammatory markers in exhaled breath. Furthermore, the observed predominant expression of IL-17A in mast cells warrants further investigation to elucidate their role in smoking-induced lung injury, despite the lack of correlation with lung function and exhaled breath parameters.     

Multiparametric MRI of Epiphyseal Cartilage Necrosis (Osteochondrosis) with Histological Validation in a Goat Model

Purpose

To evaluate multiple MRI parameters in a surgical model of osteochondrosis (OC) in goats.

Methods

Focal ischemic lesions of two different sizes were induced in the epiphyseal cartilage of the medial femoral condyles of goats at 4 days of age by surgical transection of cartilage canal blood vessels. Goats were euthanized and specimens harvested 3, 4, 5, 6, 9 and 10 weeks post-op. Ex vivo MRI scans were conducted at 9.4 Tesla for mapping the T₁, T₂, T_1ρ, adiabatic T_1ρ and T_RAFF relaxation times of articular cartilage, unaffected epiphyseal cartilage, and epiphyseal cartilage within the area of the induced lesion. After MRI scans, safranin O staining was conducted to validate areas of ischemic necrosis induced in the medial femoral condyles of six goats, and to allow comparison of MRI findings with the semi-quantitative proteoglycan assessment in corresponding safranin O-stained histological sections.

Results

All relaxation time constants differentiated normal epiphyseal cartilage from lesions of ischemic cartilage necrosis, and the histological staining results confirmed the proteoglycan (PG) loss in the areas of ischemia. In the scanned specimens, all of the measured relaxation time constants were higher in the articular than in the normal epiphyseal cartilage, consistently allowing differentiation between these two tissues.

Conclusions

Multiparametric MRI provided a sensitive approach to discriminate between necrotic and viable epiphyseal cartilage and between articular and epiphyseal cartilage, which may be useful for diagnosing and monitoring OC lesions and, potentially, for assessing effectiveness of treatment interventions.     

Ebola Response: Modeling the Risk of Heat Stress from Personal Protective Clothing

Introduction

A significant number of healthcare workers have responded to aid in the relief and containment of the 2013 Ebola virus disease (EVD) outbreak in West Africa. Healthcare workers are required to wear personal protective clothing (PPC) to impede the transmission of the virus; however, the impermeable design and the hot humid environment lead to risk of heat stress.

Objective

Provide healthcare workers quantitative modeling and analysis to aid in the prevention of heat stress while wearing PPC in West Africa.

Methods

A sweating thermal manikin was used to measure the thermal (R_ct) and evaporative resistance (R_et) of the five currently used levels of PPC for healthcare workers in the West Africa EVD response. Mathematical methods of predicting the rise in core body temperature (T_c) in response to clothing, activity, and environment was used to simulate different responses to PPC levels, individual body sizes, and two hot humid conditions: morning/evening (air temperature: 25°C, relative humidity: 40%, mean radiant temperature: 35°C, wind velocity: 1 m/s) and mid-day (30°C, 60%, 70°C, 1 m/s).

Results

Nearly still air (0.4 m/s) measures of R_ct ranged from 0.18 to 0.26 m² K/W and R_et ranged from 25.53 to 340.26 m² Pa/W.

Conclusion

Biophysical assessments and modeling in this study provide quantitative guidance for prevention of heat stress of healthcare workers wearing PPC responding to the EVD outbreak in West Africa.     

Magnetic Resonance Imaging Is Sensitive to Pathological Amelioration in a Model for Laminin-Deficient Congenital Muscular Dystrophy (MDC1A)

Purpose

To elucidate the reliability of MRI as a non-invasive tool for assessing in vivo muscle health and pathological amelioration in response to Losartan (Angiotensin II Type 1 receptor blocker) in DyW mice (mouse model for Laminin-deficient Congenital Muscular Dystrophy Type 1A).

Methods

Multiparametric MR quantifications along with histological/biochemical analyses were utilized to measure muscle volume and composition in untreated and Losartan-treated 7-week old DyW mice.

Results

MRI shows that DyW mice have significantly less hind limb muscle volume and areas of hyperintensity that are absent in WT muscle. DyW mice also have significantly elevated muscle levels (suggestive of inflammation and edema). Muscle T₂ returned to WT levels in response to Losartan treatment. When considering only muscle pixels without T₂ elevation, DyW T₂ levels are significantly lower than WT (suggestive of fibrosis) whereas Losartan-treated animals do not demonstrate this decrease in muscle T₂. MRI measurements suggestive of elevated inflammation and fibrosis corroborate with increased Mac-1 positive cells as well as increased Picrosirius red staining/COL1a gene expression that is returned to WT levels in response to Losartan.

Conclusions

MRI is sensitive to and tightly corresponds with pathological changes in DyW mice and thus is a viable and effective non-invasive tool for assessing pathological changes.     

The Role of Principal and Secondary Diagnoses of Hospitalized Eye Trauma: A Nationwide Cohort in Taiwan, 1996-2010

Purpose

To estimate the rate of hospitalized eye trauma in Taiwan and investigate the role between principal and secondary diagnoses of such trauma.

Methods

Nationwide fixed cohort study of 1,000,000 beneficiaries from the Taiwan Longitudinal Health Database was used and 4819 patients who were hospitalized for eye trauma during 1996-2010 were analyzed.

Results

During 1996-2010, the incidence rates of hospitalized eye trauma (per 100 000 person-years) were 35.0 (95% confidence interval (CI), 34.0 to 36.0) for total diagnosis, 9.8 (95% CI, 9.3 to 10.3) for a principal diagnosis, and 25.3 (95% CI, 24.4 to 26.1) for a secondary diagnosis. The sex risk ratio was 3.1 for a principal diagnosis and 2.1 for a secondary diagnosis. The main causes of eye trauma were traffic accident, work accident, assault (among males <60 years of age), and falls (among elderly men and women). The proportion admitted to an ophthalmic department among those with a principal diagnosis of eye trauma (64.8%) was significantly higher than among those with a secondary diagnosis (2.3%) (p<.0001). Patients with a principal diagnosis of eye trauma had shorter hospital stays (7.1±10.2 days) and lower fatality (0.07%) than those with a secondary diagnosis of eye trauma (10.0±31.6 days and 0.3%, respectively).

Conclusion

Data only from ophthalmic admissions tends to underestimate the true incidence rate of hospitalized eye trauma. Patients with a principal diagnosis of eye trauma had less severe injuries than did those with a secondary diagnosis.     

Impact of Endoscopic Lung Volume Reduction on Right Ventricular Myocardial Function

Introduction

Endoscopic lung volume reduction (ELVR) provides a minimally invasive therapy for patients with severe lung emphysema. As its impact on right ventricular (R_tV) function is undefined, we examined the extent of R_tV functional changes following ELVR, as assessed by use of speckle tracking-based R_tV deformation analysis.

Methods

We enrolled 32 patients with severe emphysematous COPD scheduled for bronchoscopic LVR using endobronchial valves (Zephyr, PulmonX, Inc.), comprising 16 matched clinical responders and 16 non-responders. Echocardiography was conducted one day prior to ELVR and at an eight-week postprocedural interval.

Results

Patients were predominantly of late middle-age (65.8±8.7yrs), male (62.5%) and presented advanced COPD emphysema (means FEV1 and RV: 32.6% and 239.1% of predicted, respectively). After ELVR, R_tV apical longitudinal strain improved significantly in the total study cohort (-7.96±7.02% vs. -13.35±11.48%, p=0.04), whereas there were no significant changes in other parameters of R_tV function such as R_tV global longitudinal strain, TAPSE or pulmonary arterial systolic pressure. In responding patients, 6MWT-improvement correlated with a decrease in NT-proBNP (Pearson´s r: -0.53, p=0.03). However, clinical non-responders did not exhibit any R_tV functional improvement.

Discussion

ELVR beneficially impacts R_tV functional parameters. Speckle tracking-based R_tV apical longitudinal strain analysis allows early determination of R_tV contractile gain and identification of clinical responsiveness.     

Measuring energy expenditure in sub-adult and hatchling sea turtles via accelerometry

Measuring the metabolic of sea turtles is fundamental to understanding their ecology yet the presently available methods are limited. Accelerometry is a relatively new technique for estimating metabolic rate that has shown promise with a number of species but its utility with air-breathing divers is not yet established. The present study undertakes laboratory experiments to investigate whether rate of oxygen uptake ( o ₂) at the surface in active sub-adult green turtles Chelonia mydas and hatchling loggerhead turtles Caretta caretta correlates with overall dynamic body acceleration (ODBA), a derivative of acceleration used as a proxy for metabolic rate. Six green turtles (25–44 kg) and two loggerhead turtles (20 g) were instrumented with tri-axial acceleration logging devices and placed singly into a respirometry chamber. The green turtles were able to submerge freely within a 1.5 m deep tank and the loggerhead turtles were tethered in water 16 cm deep so that they swam at the surface. A significant prediction equation for mean o ₂ over an hour in a green turtle from measures of ODBA and mean flipper length (R² = 0.56) returned a mean estimate error across turtles of 8.0%. The range of temperatures used in the green turtle experiments (22–30°C) had only a small effect on o ₂. A o ₂-ODBA equation for the loggerhead hatchling data was also significant (R² = 0.67). Together these data indicate the potential of the accelerometry technique for estimating energy expenditure in sea turtles, which may have important applications in sea turtle diving ecology, and also in conservation such as assessing turtle survival times when trapped underwater in fishing nets.     

Magnetic Resonance Assessment of Hypertrophic and Pseudo-Hypertrophic Changes in Lower Leg Muscles of Boys with Duchenne Muscular Dystrophy and Their Relationship to Functional Measurements

Introduction

The primary objectives of this study were to evaluate contractile and non-contractile content of lower leg muscles of boys with Duchenne muscular dystrophy (DMD) and determine the relationships between non-contractile content and functional abilities.

Methods

Lower leg muscles of thirty-two boys with DMD and sixteen age matched unaffected controls were imaged. Non-contractile content, contractile cross sectional area and non-contractile cross sectional area of lower leg muscles (tibialis anterior, extensor digitorum longus, peroneal, medial gastrocnemius and soleus) were assessed by magnetic resonance imaging (MRI). Muscle strength, timed functional tests and the Brooke lower extremity score were also assessed.

Results

Non-contractile content of lower leg muscles (peroneal, medial gastrocnemius, and soleus) was significantly greater than control group (p<0.05). Non-contractile content of lower leg muscles correlated with Brooke score (r_s = 0.64-0.84) and 30 feet walk (r_s = 0.66-0.80). Dorsiflexor (DF) and plantarflexor (PF) specific torque was significantly different between the groups.

Discussion

Overall, non-contractile content of the lower leg muscles was greater in DMD than controls. Furthermore, there was an age dependent increase in contractile content in the medial gastrocnemius of boys with DMD. The findings of this study suggest that T₁ weighted MR images can be used to monitor disease progression and provide a quantitative estimate of contractile and non-contractile content of tissue in children with DMD.     

The Head and Neck Anatomy of Sea Turtles (Cryptodira: Chelonioidea) and Skull Shape in Testudines

Background

Sea turtles (Chelonoidea) are a charismatic group of marine reptiles that occupy a range of important ecological roles. However, the diversity and evolution of their feeding anatomy remain incompletely known.

Methodology/Principal Findings

Using computed tomography and classical comparative anatomy we describe the cranial anatomy in two sea turtles, the loggerhead (Caretta caretta) and Kemp’s ridley (Lepidochelys kempii), for a better understanding of sea turtle functional anatomy and morphological variation. In both taxa the temporal region of the skull is enclosed by bone and the jaw joint structure and muscle arrangement indicate that palinal jaw movement is possible. The tongue is relatively small, and the hyoid apparatus is not as conspicuous as in some freshwater aquatic turtles. We find several similarities between the muscles of C. caretta and L. kempii, but comparison with other turtles suggests only one of these characters may be derived: connection of the m. adductor mandibulae internus into the Pars intramandibularis via the Zwischensehne. The large fleshy origin of the m. adductor mandibulae externus Pars superficialis from the jugal seems to be a characteristic feature of sea turtles.

Conclusions/Significance

In C. caretta and L. kempii the ability to suction feed does not seem to be as well developed as that found in some freshwater aquatic turtles. Instead both have skulls suited to forceful biting. This is consistent with the observation that both taxa tend to feed on relatively slow moving but sometimes armoured prey. The broad fleshy origin of the m. adductor mandibulae externus Pars superficialis may be linked to thecheek region being almost fully enclosed in bone but the relationship is complex.     

Reliability and Validity of the Self- and Interviewer-Administered Versions of the Global Physical Activity Questionnaire (GPAQ)

Objective

The Global Physical Activity Questionnaire (GPAQ) was originally designed to be interviewer-administered by the World Health Organization in assessing physical activity. The main aim of this study was to compare the psychometric properties of a self-administered GPAQ with the original interviewer-administered approach. Additionally, this study explored whether using different accelerometry-based physical activity bout definitions might affect the questionnaire’s validity.

Methods

A total of 110 participants were recruited and randomly allocated to an interviewer- (n = 56) or a self-administered (n = 54) group for test-retest reliability, of which 108 participants who met the wear time criteria were included in the validity study. Reliability was assessed by administration of questionnaires twice with a one-week interval. Criterion validity was assessed by comparing against seven-day accelerometer measures. Two definitions for accelerometry-data scoring were employed: (1) total-min of activity, and (2) 10-min bout.

Results

Participants had similar baseline characteristics in both administration groups and no significant difference was found between the two formats in terms of validity (correlations between the GPAQ and accelerometer). For validity, the GPAQ demonstrated fair-to-moderate correlations for moderate-to-vigorous physical activity (MVPA) for self-administration (r _s = 0.30) and interviewer-administration (r _s = 0.46). Findings were similar when considering 10-min activity bouts in the accelerometer analysis for MVPA (r _s = 0.29 vs. 0.42 for self vs. interviewer). Within each mode of administration, the strongest correlations were observed for vigorous-intensity activity. However, Bland-Altman plots illustrated bias toward overestimation for higher levels of MVPA, vigorous- and moderate-intensity activities, and underestimation for lower levels of these measures. Reliability for MVPA revealed moderate correlations (r _s = 0.61 vs. 0.63 for self vs. interviewer).

Conclusions

Our findings showed comparability between both self- and interviewer-administration modes of the GPAQ. The GPAQ in general but especially the self-administered version may offer a relatively inexpensive method for measuring physical activity of various types and at different domains. However, there may be bias in the GPAQ measurements depending on the overall physical activity. It is advisable to incorporate accelerometers in future studies, particularly when measuring different intensities of physical activity.     

Structural Pathways between Child Abuse,Poor Mental Health Outcomes and Male-Perpetrated Intimate Partner Violence (IPV)

Background

Violent trauma exposures, including child abuse, are risk factors for PTSD and comorbid mental health disorders. Child abuse experiences of men exacerbate adult male-perpetrated intimate partner violence (IPV). The relationship between child abuse, poor mental health and IPV perpetration is complex but research among the general population is lacking. This study describes the relationship and pathways between history of child abuse exposure and male-perpetrated IPV while exploring the potentially mediating effect of poor mental health.

Methods

We analysed data from a randomly selected, two-stage clustered, cross-sectional household survey conducted with 416 adult men in Gauteng Province of South Africa. We used multinomial regression modelling to identify associated factors and Structural Equation Modelling (SEM) to test the primary hypothesis that poor mental health (defined as abusing alcohol or having PTSD or depressive symptoms) mediates the relationship between child abuse and IPV perpetration.

Results

Eighty eight percent of men were physically abused, 55% were neglected, 63% were emotionally abused and 20% were sexually abused at least once in their childhood. Twenty four percent of men had PTSD symptoms, 24% had depressive symptoms and 36% binge drank. Fifty six percent of men physically abused and 31% sexually abused partners at least once in their lifetime. Twenty two percent of men had one episode and 40% had repeat episodes of IPV perpetration. PTSD symptomatology risk increased with severity of child trauma and other trauma. PTSD severity increased the risk for binge drinking. Child trauma, other trauma and PTSD symptomatology increased the severity of depressive symptoms. PTSD symptomatology was comorbid with alcohol abuse and depressive symptoms. Child trauma, having worked in the year before the survey, other trauma and PTSD increased the risk of repeat episodes of IPV perpetration. Highly equitable gender attitudes were protective against single and repeat episodes of IPV perpetration. There was a direct path between the history of child trauma and IPV perpetration and three other indirect paths showing the mediating effects of PTSD, other trauma and gender attitudes.

Conclusions

Child trauma is a risk factor for both poor mental health and male-perpetrated IPV among men in Gauteng. Male-perpetrated IPV in these settings should be explained through a combination of the Trauma, Feminist, and Intergenerational Transmission of Family Violence theories. Prevention interventions for male- perpetrated IPV in South Africa need to incorporate strategies and therapies to address poor mental health conditions.     

Alginate Microspheres Containing Temperature Sensitive Liposomes (TSL) for MR-Guided Embolization and Triggered Release of Doxorubicin

Objective

The objective of this study was to develop and characterize alginate microspheres suitable for embolization with on-demand triggered doxorubicin (DOX) release and whereby the microspheres as well as the drug releasing process can be visualized in vivo using MRI.

Methods and Findings

For this purpose, barium crosslinked alginate microspheres were loaded with temperature sensitive liposomes (TSL/TSL-Ba-ms), which release their payload upon mild hyperthermia. These TSL contained DOX and [Gd(HPDO3A)(H₂O)], a T₁ MRI contrast agent, for real time visualization of the release. Empty alginate microspheres crosslinked with holmium ions (T₂* MRI contrast agent, Ho-ms) were mixed with TSL-Ba-ms to allow microsphere visualization. TSL-Ba-ms and Ho-ms were prepared with a homemade spray device and sized by sieving. Encapsulation of TSL in barium crosslinked microspheres changed the triggered release properties only slightly: 95% of the loaded DOX was released from free TSL vs. 86% release for TSL-Ba-ms within 30 seconds in 50% FBS at 42°C. TSL-Ba-ms (76 ± 41 μm) and Ho-ms (64 ± 29 μm) had a comparable size, which most likely will result in a similar in vivo tissue distribution after an i.v. co-injection and therefore Ho-ms can be used as tracer for the TSL-Ba-ms. MR imaging of a TSL-Ba-ms and Ho-ms mixture (ratio 95:5) before and after hyperthermia allowed in vitro and in vivo visualization of microsphere deposition (T₂*-weighted images) as well as temperature-triggered release (T₁-weighted images). The [Gd(HPDO3A)(H₂O)] release and clusters of microspheres containing holmium ions were visualized in a VX₂ tumor model in a rabbit using MRI.

Conclusions

In conclusion, these TSL-Ba-ms and Ho-ms are promising systems for real-time, MR-guided embolization and triggered release of drugs in vivo.     

Interactions of the Gasotransmitters Contribute to Microvascular Tone (Dys)regulation in the Preterm Neonate

Background & Aims

Hydrogen sulphide (H₂S), nitric oxide (NO), and carbon monoxide (CO) are involved in transitional microvascular tone dysregulation in the preterm infant; however there is conflicting evidence on the interaction of these gasotransmitters, and their overall contribution to the microcirculation in newborns is not known. The aim of this study was to measure the levels of all 3 gasotransmitters, characterise their interrelationships and elucidate their combined effects on microvascular blood flow.

Methods

90 preterm neonates were studied at 24h postnatal age. Microvascular studies were performed by laser Doppler. Arterial COHb levels (a measure of CO) were determined through co-oximetry. NO was measured as nitrate and nitrite in urine. H₂S was measured as thiosulphate by liquid chromatography. Relationships between levels of the gasotransmitters and microvascular blood flow were assessed through partial correlation controlling for the influence of gestational age. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow and derive a theoretical model of their interactions.

Results

No relationship was observed between NO and CO (p = 0.18, r = 0.18). A positive relationship between NO and H₂S (p = 0.008, r = 0.28) and an inverse relationship between CO and H₂S (p = 0.01, r = -0.33) exists. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow. The model with the best fit is presented.

Conclusions

The relationships between NO and H₂S, and CO and H₂S may be of importance in the preterm newborn, particularly as NO levels in males are associated with higher H₂S levels and higher microvascular blood flow and CO in females appears to convey protection against vascular dysregulation. Here we present a theoretical model of these interactions and their overall effects on microvascular flow in the preterm newborn, upon which future mechanistic studies may be based.     

Tumor T1 Relaxation Time for Assessing Response to Bevacizumab Anti-Angiogenic Therapy in a Mouse Ovarian Cancer Model

Purpose

To assess whether T₁ relaxation time of tumors may be used to assess response to bevacizumab anti-angiogenic therapy. Procedures: 12 female nude mice bearing subcutaneous SKOV3ip1-LC ovarian tumors were administered bevacizumab (6.25ug/g, n=6) or PBS (control, n=6) therapy twice a week for two weeks. T₁ maps of tumors were generated before, two days, and 2 weeks after initiating therapy. Tumor weight was assessed by MR and at necropsy. Histology for microvessel density, proliferation, and apoptosis was performed.

Results

Bevacizumab treatment resulted in tumor growth inhibition (p<0.04, n=6), confirming therapeutic efficacy. Tumor T₁ relaxation times increased in bevacizumab treated mice 2 days and 2 weeks after initiating therapy (p<.05, n=6). Microvessel density decreased 59% and cell proliferation (Ki67+) decreased 50% in the bevacizumab treatment group (p<.001, n=6), but not apoptosis.

Conclusions

Findings suggest that increased tumor T₁ relaxation time is associated with response to bevacizumab therapy in ovarian cancer model and might serve as an early indicator of response.     

Using an Adenosine Triphosphate Bioluminescent Assay to Determine Effective Antibiotic Combinations against Carbapenem-Resistant Gram Negative Bacteria within 24 Hours

Background

Current in vitro combination testing methods involve enumeration by bacterial plating, which is labor-intensive and time-consuming. Measurement of bioluminescence, released when bacterial adenosine triphosphate binds to firefly luciferin-luciferase, has been proposed as a surrogate for bacterial counts. We developed an ATP bioluminescent combination testing assay with a rapid turnaround time of 24h to determine effective antibiotic combinations.

Methods

100 strains of carbapenem-resistant (CR) GNB [30 Acinetobacter baumannii (AB), 30 Pseudomonas aeruginosa (PA) and 40 Klebsiella pneumoniae (KP)] were used. Bacterial suspensions (10⁵ CFU/ml) were added to 96-well plates containing clinically achievable concentrations of multiple single and two-antibiotic combinations. At 24h, the luminescence intensity of each well was measured. Receiver operator characteristic curves were plotted to determine optimal luminescence threshold (T_RLU) to discriminate between inhibitory/non-inhibitory combinations when compared to viable plating. The unweighted accuracy (UA) [(sensitivity + specificity)/2] of T_RLU values was determined. External validation was further done using 50 additional CR-GNB.

Results

Predictive accuracies of T_RLU were high for when all antibiotic combinations and species were collectively analyzed (T_RLU = 0.81, UA = 89%). When individual thresholds for each species were determined, UA remained high. Predictive accuracy was highest for KP (T_RLU = 0.81, UA = 91%), and lowest for AB (T_RLU = 0.83, UA = 87%). Upon external validation, high overall accuracy (91%) was observed. The assay distinguished inhibitory/non-inhibitory combinations with UA of 80%, 94% and 93% for AB, PA and KP respectively.

Conclusion

We developed an assay that is robust at identifying useful combinations with a rapid turn-around time of 24h, and may be employed to guide the timely selection of effective antibiotic combinations.     

Assessment of Regional Ventilation Distribution: Comparison of Vibration Response Imaging (VRI) with Electrical Impedance Tomography (EIT)

Background

Vibration response imaging (VRI) is a bedside technology to monitor ventilation by detecting lung sound vibrations. It is currently unknown whether VRI is able to accurately monitor the local distribution of ventilation within the lungs. We therefore compared VRI to electrical impedance tomography (EIT), an established technique used for the assessment of regional ventilation.

Methodology/Principal Findings

Simultaneous EIT and VRI measurements were performed in the healthy and injured lungs (ALI; induced by saline lavage) at different PEEP levels (0, 5, 10, 15 mbar) in nine piglets. Vibration energy amplitude (VEA) by VRI, and amplitudes of relative impedance changes (rel.ΔZ) by EIT, were evaluated in seven regions of interest (ROIs). To assess the distribution of tidal volume (V_T) by VRI and EIT, absolute values were normalized to the V_T obtained by simultaneous spirometry measurements. Redistribution of ventilation by ALI and PEEP was detected by VRI and EIT. The linear correlation between pooled V_T by VEA and rel.ΔZ was R² = 0.96. Bland-Altman analysis showed a bias of −1.07±24.71 ml and limits of agreement of −49.05 to +47.36 ml. Within the different ROIs, correlations of V_T-distribution by EIT and VRI ranged between R² values of 0.29 and 0.96. ALI and PEEP did not alter the agreement of V_T between VRI and EIT.

Conclusions/Significance

Measurements of regional ventilation distribution by VRI are comparable to those obtained by EIT.