High-resolution photoacoustic tomography of resting-state functional connectivity in the mouse brain

The increasing use of mouse models for human brain disease studies presents an emerging need for a new functional imaging modality. Using optical excitation and acoustic detection, we developed a functional connectivity photoacoustic tomography system, which allows noninvasive imaging of resting-state functional connectivity in the mouse brain, with a large field of view and a high spatial resolution. Bilateral correlations were observed in eight functional regions, including the olfactory bulb, limbic, parietal, somatosensory, retrosplenial, visual, motor, and temporal regions, as well as in several subregions. The borders and locations of these regions agreed well with the Paxinos mouse brain atlas. By subjecting the mouse to alternating hyperoxic and hypoxic conditions, strong and weak functional connectivities were observed, respectively. In addition to connectivity images, vascular images were simultaneously acquired. These studies show that functional connectivity photoacoustic tomography is a promising, noninvasive technique for functional imaging of the mouse brain.Resting-state functional connectivity (RSFC) is an emerging neuroimaging approach that aims to identify low-frequency, spontaneous cerebral hemodynamic fluctuations and their associated functional connections (1, 2). Recent research suggests that these fluctuations are highly correlated with local neuronal activity (3, 4). The spontaneous fluctuations relate to activity that is intrinsically generated by the brain, instead of activity attributable to specific tasks or stimuli (2). A hallmark of functional organization in the cortex is the striking bilateral symmetry of corresponding functional regions in the left and right hemispheres (5). This symmetry also exists in spontaneous resting-state hemodynamics, where strong correlations are found interhemispherically between bilaterally homologous regions as well as intrahemispherically within the same functional regions (3). Clinical studies have demonstrated that RSFC is altered in brain disorders such as stroke, Alzheimer’s disease, schizophrenia, multiple sclerosis, autism, and epilepsy (6–12). These diseases disrupt the healthy functional network patterns, most often reducing correlations between functional regions. Due to its task-free nature, RSFC imaging requires neither stimulation of the subject nor performance of a task during imaging (13). Thus, it can be performed on patients under anesthesia (14), on patients unable to perform cognitive tasks (15, 16), and even on patients with brain injury (17, 18).RSFC imaging is also an appealing technique for studying brain diseases in animal models, in particular the mouse, a species that holds the largest variety of neurological disease models (3, 13, 19, 20). Compared with clinical studies, imaging genetically modified mice allows exploration of molecular pathways underlying the pathogenesis of neurological disorders (21). The connection between RSFC maps and neurological disorders permits testing and validation of new therapeutic approaches. However, conventional neuroimaging modalities cannot easily be applied to mice. For instance, in functional connectivity magnetic resonance imaging (fcMRI) (22), the resting-state brain activity is determined via the blood-oxygen-level–dependent (BOLD) signal contrast, which originates mainly from deoxy-hemoglobin (23). The correlation analysis central to functional connectivity requires a high signal-to-noise ratio (SNR). However, achieving a sufficient SNR is made challenging by the high magnetic fields and small voxel size needed for imaging the mouse brain, as well as the complexity of compensating for field inhomogeneities caused by tissue–bone or tissue–air boundaries (24). Functional connectivity mapping with optical intrinsic signal imaging (fcOIS) was recently introduced as an alternative method to image functional connectivity in mice (3, 20). In fcOIS, changes in hemoglobin concentrations are determined based on changes in the reflected light intensity from the surface of the brain (3, 25). Therefore, neuronal activity can be measured through the neurovascular response, similar to the method used in fcMRI. However, due to the diffusion of light in tissue, the spatial resolution of fcOIS is limited, and experiments have thus far been performed using an exposed skull preparation, which increases the complexity for longitudinal imaging.Photoacoustic imaging of the brain is based on the acoustic detection of optical absorption from tissue chromophores, such as oxy-hemoglobin (HbO₂) and deoxy-hemoglobin (Hb) (26, 27). This imaging modality can simultaneously provide high-resolution images of the brain vasculature and hemodynamics with intact scalp (28, 29). In this article, we perform functional connectivity photoacoustic tomography (fcPAT) to study RSFC in live mice under either hyperoxic or hypoxic conditions, as well as in dead mice. Our experiments show that fcPAT is able to detect connectivities between different functional regions and even between subregions, promising a powerful functional imaging modality for future brain research.     

Predictive ability of C-reactive protein for early mortality after ischemic stroke: comparison with NIHSS score

We aimed to compare the association of high-sensitivity C-reactive protein (CRP) and National Institutes of Health Stroke Scale (NIHSS) score with mortality risk and to determine the optimal threshold of CRP for prediction of mortality in ischemic-stroke patients. A series of 162 patients with first-ever ischemic-stroke admitted within 24 h after onset of symptoms was enrolled. CRP and NIHSS score were estimated on admission and their predictive abilities for mortality at 7 days were determined by logistic-regression analyses. Receiver-Operating Characteristic (ROC) curves were depicted to identify the optimal cut-off of CRP, using the maximum Youden-index and the shortest-distance methods. Deceased patients had higher levels of CRP and NIHSS on admission (8.87 ± 7.11 vs. 2.20 ± 4.71 mg/l for CRP, and 17.31 ± 6.36 vs. 8.70 ± 4.85 U for NIHSS, respectively, P < 0.01). CRP and NIHSS were correlated with each other (r ² = 0.39, P < 0.001) and were also independently associated with increased risk of mortality [odds ratios (95 % confidence interval) of 1.16 (1.05–1.28) and 1.20 (1.07–1.35) for CRP and NIHSS, respectively, P < 0.01]. The areas under the ROC curves of CRP and NIHSS for mortality were 0.82 and 0.84, respectively. The CRP value of 2.2 mg/l was identified as the optimal cut-off value for prediction of mortality within 7 days (sensitivity: 0.81, specificity: 0.80). Thus, CRP as an independent predictor of mortality following ischemic-stroke is comparable with NIHSS and the value of 2.2 mg/l yields the optimum sensitivity and specificity for mortality prediction.     

Acid and Microhardness of Mineral Trioxide Aggregate and Mineral Trioxide Aggregate–like Materials

Introduction

The aim of this study was to compare the surface microhardness of BioAggregate, ProRoot MTA, and CEM Cement when exposed to an acidic environment or phosphate-buffered saline (PBS) as a synthetic tissue fluid.

Methods

Ninety cylindrical molds made of polymethyl methacrylate with an internal diameter of 6 mm and height of 4 mm (according to ASTM E384 standard for microhardness tests) were fabricated and filled with BioAggregate (n = 30), tooth-colored ProRoot MTA (n = 30), or CEM Cement (n = 30). Each group was then divided into 3 subgroups of 10 specimens consisting of those exposed to distilled water, exposed to PBS (pH = 7.4), or exposed to butyric acid (pH = 5.4). After 1 week the Vickers surface microhardness test was performed. Statistical analysis included 2-way analysis of variance, followed by post hoc Dunnett T3 in cases with lack of homoscedasticity and Tukey honestly significant difference in cases with homoscedasticity.

Results

The indentations obtained from the CEM Cement specimens exposed to an acidic pH were not readable because of incomplete setting. There was a significant difference between the microhardness of the materials regardless of the environmental conditions (P < .001). In all the environmental conditions, MTA had significantly higher and CEM Cement had significantly lower microhardness values (P < .001). All experimental cements had significantly higher microhardness values when exposed to PBS (P < .001) and had significantly lower microhardness values when exposed to butyric acid (P < .001).

Conclusions

The surface microhardness of BioAggregate, ProRoot MTA, and CEM Cement was reduced significantly by exposure to butyric acid and increased significantly by exposure to PBS. In all environmental conditions, MTA had significantly higher microhardness values.     

Correlation between creatinine clearance and Helicobacter pylori infection eradication with sequential and triple therapeutic regimens: A randomised clinical trial

Background and study aimsUraemic patients show susceptibility to gastrointestinal mucosal lesions and colonisation by Helicobacter pylori (HP). Antibiotic resistance constitutes a problem in treatment and bismuth preparations are toxic in uraemic patients. This study aimed to assess the correlation between creatinine clearance (CrCl) and eradication of HP infection with new sequential and standard triple therapeutic regimens.Patients and methodsA total of 120 HP-positive patients with renal function impairment and 60 control patients with HP infection were enrolled in this study. Patients were divided into four groups on the basis of CrCl and were randomly assigned to one of the two different regimens: A 14-day standard triple therapy with 20 mg omeprazole bid, 1000 mg amoxicillin bid and 500 mg clarithromycin bid and a new sequential regimen with 20 mg omeprazole bid and 1000 mg amoxicillin bid both for 14 days, 500 mg ciprofloxacin bid for the first 7 days and 200 mg furazolidone bid for the last 7 days. Doses of amoxicillin, clarithromycin and ciprofloxacin were reduced to 50% in the cases of CrCl <30 mg dl^?1.ResultsOne hundred and sixty two out of 180 HP-positive patients (54.3% male, 51.6 ± 12.1 years) completed treatment in the four groups and were studied. According to renal function they were classified into group A (n = 39), haemodialysis (HD) patients; group B (n = 37), CrCl <30 mg dl^?1 without HD; group C (n = 36), CrCl between 30 and 60 mg dl^?1; and group D (n = 50), control subjects with CrCl >90 mg dl^?1. HP was successfully eradicated in 77.7% of patients with standard triple therapy and in 81.4% of patients with the sequential therapy. There was no significant difference among the study groups in the rate of HP-infection eradication with both regimens.ConclusionHP eradication rates did not differ with both sequential and standard therapeutic regimens in uraemic and non-uraemic patients. We, therefore, prefer the standard triple therapy due to its simplicity and reported.     

Physician empathy: definition,components, measurement,and relationship to gender and specialty

OBJECTIVE: There is a dearth of empirical research on physician empathy despite its mediating role in patient-physician relationships and clinical outcomes. This study was designed to investigate the components of physician empathy, its measurement properties, and group differences in empathy scores. METHOD: A revised version of the Jefferson Scale of Physician Empathy (with 20 Likert-type items) was mailed to 1,007 physicians affiliated with the Jefferson Health System in the greater Philadelphia region; 704 (70%) responded. Construct validity, reliability of the empathy scale, and the differences on mean empathy scores by physicians' gender and specialty were examined. RESULTS: Three meaningful factors emerged (perspective taking, compassionate care, and standing in the patient's shoes) to provide support for the construct validity of the empathy scale that was also found to be internally consistent with relatively stable scores over time. Women scored higher than men to a degree that was nearly significant. With control for gender, psychiatrists scored a mean empathy rating that was significantly higher than that of physicians specializing in anesthesiology, orthopedic surgery, neurosurgery, radiology, cardiovascular surgery, obstetrics and gynecology, and general surgery. No significant difference was observed on empathy scores among physicians specializing in psychiatry, internal medicine, pediatrics, emergency medicine, and family medicine. CONCLUSIONS: Empathy is a multidimensional concept that varies among physicians and can be measured with a psychometrically sound tool. Implications for specialty selection and career counseling are discussed.     

Physicians' Perceptions of the Changing Health Care System: Comparisons by Gender and Specialties

This study was designed to investigate physicians' perceptions of changes in the United States health care system impacting academic medicine, quality of care, patient referrals, cost, ethical and sociopolitical aspects of medicine. A survey was mailed in 1998 to 1,272 physicians (graduates of Jefferson Medical College between 1987 and 1992); 835 physicians (66%) responded. Results showed that a substantial majority (92%) believed that learning to work in a managed care environment should become an essential component of medical education. Physicians perceived that current changes impair physicians' autonomy (94%), and restrain physicians' freedom to provide optimal care (84%). A sizable majority (76%) endorsed patients' freedom to seek specialist care, and 55% believed that capitation reduces physicians' motivation for long-term monitoring of patients. The majority endorsed universal health coverage (80%), and agreed to support rather than resist the changes (62%). Only 18% hold a positive view of the changes in the future. The majority believed that medical education should prepare physicians to provide end-of-life care (92%), and that organized medicine should take a stand on social issues that can influence the well-being of society (79%). Only 34% endorsed the legalization of physician-assisted suicide. No gender differences were observed, but a few differences were found between generalists and specialists. Results can help in understanding physicians' perceptions of current changes in the United States health care system, and in providing guidelines for the development of educational programs to prepare physicians to face new challenges.