Syngeneic bone marrow transplantation reduces the hearing loss associated with murine mucopolysaccharidosis type VII

MPS VII mice are deficient in beta-glucuronidase and share many clinical, biochemical, and pathologic characteristics with human mucopolysaccharidosis type VII (MPS VII). We have shown that syngeneic bone marrow transplantation (BMT) prolongs survival and reduces lysosomal storage in many organs of the MPS VII mouse. In this report, we quantify the hearing loss and determine the impact of syngeneic BMT on the development of deafness and the associated pathology in the MPS VII mouse. Eleven weeks after syngeneic BMT performed at birth, treated MPS VII mice had normal auditory-evoked brainstem responses (ABR), whereas untreated MPS VII mice had ABR thresholds 43 dB higher than normal. Treated MPS VII mice had beta-glucuronidase-positive cells in the temporal bone and in the subepithelial connective tissue of the external auditory canal. There was less thickening of the tympanic membrane and middle ear mucosa and decreased distortion of the ossicles and the cochlear bone. Although transplanted MPS VII mice had increased ABR thresholds by 33 weeks of age, four of the six had thresholds 12 to 32 dB lower than untreated mutants. These data indicate that syngeneic BMT in newborn MPS VII mice prevents early hearing loss and, in some animals, results in long-term improved auditory function.     

Large-scale isolation of Eastern spiny mouse Acomys dimidiatus microsatellite loci through GS-FLX 454 titanium sequencing

We isolated and characterized Eastern spiny mouse, Acomys dimidiatus microsatellite loci. A microsatellite-enriched library was created and A. dimidiatus fragments sequenced using 454 sequencing. In total, 1,221 primer-designable microsatellite sequences were identified. We designed primer sets for 20 loci. Loci were characterized in A. dimidiatus individuals from a semi-isolated desert wadi (valley) in St. Katherine Protectorate, Egypt. After initial trails, 18 microsatellite loci were genotyped in 67 mice. The number of alleles displayed in the 18 markers ranged from three to nine (mean = 6) with mean expected and observed heterozygosities of 0.63 and 0.65, respectively. All 18 selected loci were in Hardy–Weinberg equilibrium (P > 0.01). These markers will be used to investigate the fine-scale spatial patterns of genetic diversity and divergence of A. dimidiatus populations. The isolated loci are of potential utility in other murines, including 260 threatened species.     

Emotional demands at work and risk of hospital-treated depressive disorder in up to 1.6 million Danish employees: a prospective nationwide register-based cohort study

ObjectivePrevious studies on effects of emotional demands on depression have relied on self-reported exposure data and lacked control for potential confounding by pre-employment risk factors for depression. This study used a register-based design to examine the risk of hospital-treated depressive disorder in relation to occupational levels of emotional demands at work, furthermore addressing the role of risk factors for depression before workforce entry.MethodsWe analyzed data from two Danish register-based cohorts – Job Exposure Matrix Analyses of Psychosocial Factors and Healthy Ageing in Denmark (JEMPAD, N= 1 665 798) (17) and Danish Work Life Course Cohort (DaWCo, N=939 411), which link assessments of emotional demands by job exposure matrices to records of hospital-treated depressive disorder among employees aged 15–59 years at baseline (average follow up: 9.7 years in JEMPAD, 7.3 years in DaWCo). Potential confounders comprised sociodemographics, job control, work-related violence and physical demands at work. In DaWCo, we followed individuals from their entry into the workforce, and also included data on risk factors for depression before workforce entry (eg, parental income, education, and psychiatric diagnoses).ResultsEmployees in occupations with high emotional demands had an increased risk of hospital-treated depressive disorder with confounder-adjusted hazard ratios of 1.32 [95% confidence interval (CI) 1.24‒1.41] and 1.19 (95% CI 1.09‒1.30) in JEMPAD and DaWCO, respectively. This association remained after controlling for risk factors before workforce entry.ConclusionsThis study suggests that employees in occupations with high emotional demands are at increased risk of hospital-treated depressive disorder. This increased risk was neither attributable to reporting bias nor explained by the included risk factors for depression recorded before workforce entry.     

A Monte Carlo brachytherapy study for dose distribution prediction in an inhomogeneous medium

The purpose of this study was to present a theoretical analysis of how the presence of bone in interstitial brachytherapy affects dose rate distributions. This study was carried out using a Monte Carlo simulation of the dose distribution in homogeneous medium for 3 commonly used brachytherapy seeds. The 3 seeds investigated in this study are iridium-192 (¹⁹²Ir) iodine-125 (¹²⁵I), and palladium-103 (¹⁰³Pd). The computer code was validated by comparing the specific dose rate (Λ), the radial dose function g(r), and anisotropy function F(r,θ) for all 3 seeds with the AAPM TG-43 dosimetry formalism and current literature. The ¹⁹²Ir seed resulted in a dose rate of 1.115 ± 0.001 cGy-hr⁻¹-U⁻¹, the ¹²⁵I seed resulted in a dose rate of 0.965 ± 0.006 cGy/h⁻¹/U⁻¹, and the ¹⁰³Pd seed resulted in a dose rate of 0.671 ± 0.002 cGy/h⁻¹/U⁻¹. The results for all 3 seeds are in good agreement with the AAPM TG-43 and current literature. The validated computer code was then applied to a simple inhomogeneous model to determine the effect bone has on dose distribution from an interstitial implant. The inhomogeneous model showed a decrease in dose rate of 2% for the ¹⁹²Ir, an increase in dose rate of 84% for ¹²⁵I, and an increase in dose rate of 83% for the ¹⁰³Pd at the surface of the bone nearest to the source.     

Effect of exposure to calcium entry blockers on doxorubicin accumulation and cytotoxicity in multidrug-resistant cells

Flow cytometry has been used to measure doxorubicin (DOX) retention in several pairs of drug-sensitive and multidrug-resistant (MDR) cell lines and in unselected human tumor cell lines. Co-exposure to several agents that have been reported to reverse multidrug resistance, particularly calcium entry blockers (CEBs), produced a dose-dependent increase in DOX accumulation in MDR cell lines. In MDR Chinese hamster ovary cells (CHRC5), DOX levels declined rapidly following removal of CEBs, reaching a plateau value above that found in cells treated with DOX alone; this small increase probably represents DOX that is not accessible to the p170 efflux pump overexpressed in these cells. Increased DOX retention could be observed even after brief exposure to CEBs and washout and correlates with a decrease in cell proliferation over a 3-day growth assay. These results suggest that only a brief inhibition of drug efflux is sufficient to produce a meaningful reversal of drug resistance.     

Development of a GIS-based, real-time Internet mapping tool for rabies surveillance

Background  

Oral rabies vaccination programs have been implemented to control the spread of wildlife rabies in the United States. However, current surveillance systems are inadequate for the efficient management and evaluation of these large scale vaccine baiting programs. With this in mind, a GIS-based rabies surveillance database and Internet mapping application was created. This surveillance system, RabID, provides a new resource for the rapid mapping and dissemination of data on animal rabies cases in relation to unaffected, enzootic, and baited areas where current interventions are underway.     

Bony inlet stenosis as a cause of nasal airway obstruction

Two cases of congenital bony stenosis of the nasal piriform aperture (anterior nares) are presented. Both patients experienced episodes of respiratory distress and clinical symptoms similar to those seen in patients with posterior choanal atresia. The underlying anatomic abnormalities in congenital bony inlet stenosis are quite different from those in choanal atresia and require different surgical approaches for correction. Computed tomography demonstrates in detail the underlying anatomic abnormality and allows differentiation of bony inlet stenosis from choanal atresia.     

Clinicians' appraisal of sonography

The perceived efficacy of sonography in making diagnostic and management decisions in clinical practice was determined through a questionnaire survey of physicians who had recently referred patients to a university radiology department. Of 2,178 questionnaires sent, 1,611 were returned (74%). Sensitivity and specificity of sonography, corrected for verification bias, were 72% and 84%. Referring physicians considered the studies to be of value in arriving at the final diagnosis and in the clinical management of patients in approximately two-thirds of the cases. Results were considered of no value and misleading in 4% of the cases. Sonography was more accurate and was reported to be valuable by approximately 10% more physicians when a specific indication for an examination could be identified rather than when indications were vague and when sonographic findings were abnormal rather than normal (P less than .005). In general, sonography was of equal value to both specialists and nonspecialists. The results of this study suggest that sonography is, and is perceived by clinicians to be, an accurate and valuable clinical diagnostic modality.