Brendan J. McCullough

Haplo-insufficiency revealed in deafwaddler mice when tested for hearing loss and ataxia

The auditory and vestibular systems rely on the plasma membrane calcium ATPase, isoform 2 (PMCA2) to extrude calcium that enters the stereocilia during transduction. Mutations in the gene encoding this protein result in recessive sensorineural deafness and ataxia in the deafwaddler mouse. In this study, we report the identification of a new allele of deafwaddler, dfw(3j). This allele contains a 4-nucleotide deletion resulting in a frame-shift and predicted truncation of PMCA2. No protein is detected in dfw(3j) homozygotes. To examine the dependence of auditory and vestibular function on PMCA2 activity, we compared dfw(3j) with another functional null allele, dfw(2j), and the partial loss-of-function allele, dfw. All mice studied were in the good-hearing CBA/CaJ background. Heterozygotes of either functional null allele displayed highly significant hearing loss by auditory-evoked brainstem responses relative to controls (P < 0.0001), particularly at high frequencies (> 24 kHz). Ataxia was also apparent in these mice on an accelerating rotarod (P < 0.05). In contrast, +/dfw mice were not measurably different from controls in either behavioral test. dfw/dfw mice were deaf, but showed less ataxia than dfw(2j)/dfw(2j) or dfw(3j)/dfw(3j) mice. These results demonstrate that hearing loss and ataxia are dependent on gene dosage and PMCA2 dysfunction.

Ferumoxytol in clinical practice: Implications for MRI

Ferumoxytol is an iron‐containing parenteral treatment for iron deficiency anemia that was recently approved by the Food and Drug Administration. The iron is in the form of a superparamagnetic iron oxide that causes T1, T2, and T2* shortening on magnetic resonance imaging (MRI). Furthermore, the drug has a long intravascular half‐life of 14–15 hours; a standard dose can affect MRI for days to months. We describe a case in which a patient underwent contrast‐enhanced MRI of the liver 2 days after receiving a dose of ferumoxytol, which was unknown to the radiology team. The blood pool and soft tissues were hyperintense on T1‐weighted images, concealing enhancement from the gadolinium‐based contrast agent that was administered during the exam and rendering the exam nondiagnostic. Radiologists must be aware of this potential effect in screening patients for MRI and interpreting exams. J. Magn. Reson. Imaging 2013;37:1476–1479.

Major Medical Outcomes With Spinal Augmentation vs Conservative Therapy

IMPORTANCE The symptomatic benefits of spinal augmentation (vertebroplasty or kyphoplasty) for the treatment of osteoporotic vertebral compression fractures are controversial. Recent population-based studies using medical billing claims have reported significant reductions in mortality with spinal augmentation compared with conservative therapy, but in nonrandomized settings such as these, there is the potential for selection bias to influence results. OBJECTIVE To compare major medical outcomes following treatment of osteoporotic vertebral fractures with spinal augmentation or conservative therapy. Additionally, we evaluate the role of selection bias using preprocedure outcomes and propensity score analysis. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort analysis of Medicare claims for the 2002-2006 period. We compared 30-day and 1-year outcomes in patients with newly diagnosed vertebral fractures treated with spinal augmentation (n = 10,541) or conservative therapy (control group, n = 115,851). Outcomes were compared using traditional multivariate analyses adjusted for patient demographics and comorbid conditions. We also used propensity score matching to select 9017 pairs from the initial groups to compare the same outcomes. EXPOSURES Spinal augmentation (vertebroplasty or kyphoplasty) or conservative therapy. MAIN OUTCOMES AND MEASURES Mortality, major complications, and health care utilization. RESULTS Using traditional covariate adjustments, mortality was significantly lower in the augmented group than among controls (5.2% vs 6.7% at 1 year; hazard ratio, 0.83; 95% CI, 0.75-0.92). However, patients in the augmented group who had not yet undergone augmentation (preprocedure subgroup) had lower rates of medical complications 30 days post fracture than did controls (6.5% vs 9.5%; odds ratio, 0.66; 95% CI, 0.57-0.78), suggesting that the augmented group was less medically ill. After propensity score matching to better account for selection bias, 1-year mortality was not significantly different between the groups. Furthermore, 1-year major medical complications were also similar between the groups, and the augmented group had higher rates of health care utilization, including hospital and intensive care unit admissions and discharges to skilled nursing facilities. CONCLUSIONS AND RELEVANCE After accounting for selection bias, spinal augmentation did not improve mortality or major medical outcomes and was associated with greater health care utilization than conservative therapy. Our results also highlight how analyses of claims-based data that do not adequately account for unrecognized confounding can arrive at misleading conclusions.

Lumbar MR Imaging and Reporting Epidemiology: Do Epidemiologic Data in Reports Affect Clinical Management?

PURPOSE To retrospectively examine the association between the inclusion of epidemiologic information in lumbar spine magnetic resonance (MR) imaging reports regarding findings in asymptomatic individuals and the rates of subsequent cross-sectional imaging and treatments in patients with low back pain or radiculopathy referred for imaging by primary care providers. MATERIALS AND METHODS Institutional review board approval was received for a retrospective chart review, with waiver of informed consent and HIPAA authorization. During 3 years, an epidemiologic statement was routinely but arbitrarily included in lumbar spine MR imaging reports. Two hundred thirty-seven reports documenting uncomplicated degenerative changes on initial lumbar spine MR images were identified, 71 (30%) of which included the statement (statement group) and 166 (70%) did not (nonstatement group). The rates of repeat cross-sectional imaging and treatments within 1 year were compared between groups by using logistic regression controlling for severity of MR imaging findings. RESULTS Patients in the statement group were significantly less likely to receive a prescription for narcotics for their symptoms than patients in the nonstatement group (odds ratio = 0.29, P = .01). Repeat cross-sectional imaging and physical therapy referrals were also less common in the statement group than in the nonstatement group (odds ratio = 0.22 and 0.55, respectively), but these differences were not statistically significant (P = .14 and .06, respectively). Rates of steroid injections, surgical consultations, and surgeries were similar between groups. CONCLUSION Patients were less likely to receive narcotics prescriptions from primary care providers when epidemiologic information was included in their lumbar spine MR imaging reports.

3p- syndrome defines a hearing loss locus in 3p25.3

Deletions affecting the terminal end of chromosome 3p result in a characteristic set of clinical features termed 3p-- syndrome. Bilateral, sensorineural hearing loss (SNHL) has been found in some but not all cases, suggesting the possibility that it is due to loss of a critical gene in band 3p25. To date, no genetic locus in this region has been shown to cause human hearing loss. However, the ATP2B2 gene is located in 3p25.3, and haploinsufficiency of the mouse homolog results in SNHL with similar severity. We compared auditory test results with fine deletion mapping in seven previously unreported 3p-- syndrome patients and identified a 1.38Mb region in 3p25.3 in which deletions were associated with moderate to severe, bilateral SNHL. This novel hearing loss locus contains 18 genes, including ATP2B2. ATP2B2 encodes the plasma membrane calcium pump PMCA2. We used immunohistochemistry in human cochlear sections to show that PMCA2 is located in the stereocilia of hair cells, suggesting its function in the auditory system is conserved between humans and mice. Although other genes in this region remain candidates, we conclude that haploinsufficiency of ATP2B2 is the most likely cause of SNHL in 3p-- syndrome.

Diagnosis of Concussion: The Role of Imaging Now and in the Future

The primary role of neuroimaging in the clinical context of sports-related concussion is the exclusion of a more severe, unsuspected intracranial injury. Computed tomography remains the test of choice for this purpose. Magnetic resonance imaging is more commonly used as a secondary test for the investigation of persistent symptoms. New imaging techniques are currently being developed to detect the molecular and cellular changes underlying concussion that are invisible with standard structural imaging. In the future, these techniques may be used as tools for directing rehabilitation after concussion and aiding in the decision of when it is safe for an athlete to return to play.

Issues in Response Assessment of Brain Tumor Chemotherapy

Abstract Clinical management of brain tumors and investigations into new therapies requires the ability to assess repeatedly the response of disease to treatment. Magnetic resonance imaging (MRI) is the primary means of non-invasive tumor monitoring in neuro-oncology, but it is an indirect measure of the underlying pathophysiology. In this chapter, we will first discuss the methods and limitations of measurements in neuroimaging. Next, we will examine the evolving criteria meant to standardize and interpret changes in disease on MRI. Finally, we will review the imprecise relationship between imaging and disease.

Preoperative relative cerebral blood volume analysis in gliomas predicts survival and mitigates risk of biopsy sampling error

Appropriate management of adult gliomas requires an accurate histopathological diagnosis. However, the heterogeneity of gliomas can lead to misdiagnosis and undergrading, especially with biopsy. We evaluated the role of preoperative relative cerebral blood volume (rCBV) analysis in conjunction with histopathological analysis as a predictor of overall survival and risk of undergrading. We retrospectively identified 146 patients with newly diagnosed gliomas (WHO grade II–IV) that had undergone preoperative MRI with rCBV analysis. We compared overall survival by histopathologically determined WHO tumor grade and by rCBV using Kaplan–Meier survival curves and the Cox proportional hazards model. We also compared preoperative imaging findings and initial histopathological diagnosis in 13 patients who underwent biopsy followed by subsequent resection. Survival curves by WHO grade and rCBV tier similarly separated patients into low, intermediate, and high-risk groups with shorter survival corresponding to higher grade or rCBV tier. The hazard ratio for WHO grade III versus II was 3.91 (p = 0.018) and for grade IV versus II was 11.26 (p < 0.0001) and the hazard ratio for each increase in 1.0 rCBV units was 1.12 (p < 0.002). Additionally, 3 of 13 (23%) patients initially diagnosed by biopsy were upgraded on subsequent resection. Preoperative rCBV was elevated at least one standard deviation above the mean in the 3 upgraded patients, suggestive of undergrading, but not in the ten concordant diagnoses. In conclusion, rCBV can predict overall survival similarly to pathologically determined WHO grade in patients with gliomas. Discordant rCBV analysis and histopathology may help identify patients at higher risk for undergrading.

Chapter 54 – Neuroimaging Issues in Assessing Response to Brain Tumor Therapy

Magnetic resonance imaging is an indispensable tool for both day-to-day management of brain tumor patients and neuro-oncology clinical trails. While recognizing the value of neuroimaging, there are a number of technical difficulties in the serial measurement of brain tumors, as well as uncertainties about the meaning of the information obtained. In this chapter, we first discuss the imaging appearance and behavior of common adult primary brain tumors. We then review various methods in practice used for the measurement and classification of response to treatment or progression of disease. Finally, we explore the challenges of using imaging as a surrogate measure of pathology.