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In order to visualize restricted diffusion, the present study developed a novel method called 'apparent diffusion coefficient (ADC) subtraction method (ASM)' and compared it with diffusion kurtosis imaging (DKI). The diffusion-weighted images of physiological saline, in addtion to bio-phatoms of low cell density and the highest cell density were obtained using two sequences with different effective diffusion times. Then, the calculated ADC values were subtracted. The mean values and standard deviations (SD) of the ADC values of physiological saline, low cell density and the highest cell density phantoms were 2.95±0.08x10‑3, 1.90±0.35x10‑3 and 0.79±0.05x10‑3 mm2/sec, respectively. The mean kurtosis values and SD of DKI were 0.04±0.01, 0.44±0.13 and 1.27±0.03, respectively. The ASM and SD values were 0.25±0.20x104, 0.51±0.41x104 and 4.80±4.51x104 (sec/mm2)2, respectively. Using bio‑phantoms, the present study demonstrated that DKI exhibits restricted diffusion in the extracellular space. Similarly, ASM may reflect the extent of restricted diffusion in the extracellular space.

Avian pathogenic Escherichia coli (APEC) is the causative agent of colibacillosis in poultry, an economically important disease worldwide. In Ontario, Canada, early and late systemic bacterial infections due to APEC were the most commonly reported diseases in broiler chickens. In 2016, Ontario poultry veterinarians submitted samples from 331 cases of broiler and broiler breeder chickens with a high suspicion of colibacillosis to the Animal Health Laboratory (Guelph, Ontario, Canada) for bacterial culture. Escherichia coli isolates from those samples were tested with multiplex PCR to detect the presence of 13 virulence-associated genes. The most common genes identified were sitA (detected in 93% of isolates), iss (88%), iroN (85%), iutA (79%), ompT (77%), and etsB (67%). In 94% of isolates, at least three virulence-associated genes were detected. Antimicrobial susceptibility testing of isolates by using the disk diffusion method revealed high frequencies of resistance to tetracycline (57% of isolates), gentamicin (50%), spectinomycin (46%), and ampicillin (44%). Relatively fewer isolates were resistant to trimethoprim-sulfamethoxazole (18%), ceftiofur (15%), kanamycin (11%), and apramycin (3%). A high proportion (46%) of the isolates were multidrug resistant (≥3 antimicrobial classes). On the basis of multivariable, mixed effects logistic regression models, statistically significant associations ( P ≤ 0.05) were identified between the following: ampicillin resistance and the presence of kpsII (odds ratio [OR] = 1.88), tsh (OR = 0.46), and ireA (OR = 0.32); ceftiofur resistance and etsB (OR = 2.98) and kpsII (OR = 2.61); gentamicin resistance and ompT (OR = 3.89) and sitA (OR = 3.54); kanamycin resistance and papC (OR = 50.10); spectinomycin resistance and ireA (OR = 2.50) and iutA (OR = 3.15); trimethoprim-sulfamethoxazole resistance and ompT (OR = 0.14) and tsh (OR = 0.31); and tetracycline resistance and cvaC (OR = 2.12), eitA (OR = 2.15), and papC (OR = 8.27). On the basis of a multivariable, mixed effects Poisson regression model, the number of antimicrobials to which an isolate was resistant increased with the presence of eitA (risk ratio [RR] = 1.37), iroN (RR = 1.24), papC (RR = 1.34), and sitA (RR = 1.77) and decreased with the presence of tsh (RR = 0.79). On the basis of bivariable logistic regression models, age group and time of sample collection were not significantly associated with resistance to individual antimicrobials, the presence of multidrug resistance, or the presence of virulence-associated genes. Our results provide information on antimicrobial resistance and virulence gene patterns currently present on Ontario broiler chicken and broiler breeder farms that can be used as a benchmark from which to measure changes.

Sensory neuropathy is a relevant side effect of the antineoplastic agent cisplatin. Mitochondrial damage is assumed to play a critical role in cisplatin-induced peripheral neuropathy, but the pathomechanisms underlying cisplatin-induced mitotoxicity and neurodegeneration are incompletely understood. In an animal model of cisplatin-induced neuropathy, we determined in detail the extent and spatial distribution of mitochondrial damage during cisplatin treatment. Changes in the total number of axonal mitochondria during cisplatin treatment were assessed in intercostal nerves from transgenic mice that express cyan fluorescent protein. Further, we explored the impact of cisplatin on the expression of nuclear encoded molecules of mitochondrial fusion and fission, including mitofusin-2 (MFN2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (DRP1). Cisplatin treatment resulted in a loss of total mitochondrial mass in axons and in an abnormal mitochondrial morphology including atypical enlargement, increased vacuolization, and loss of cristae. These changes were observed in distal and proximal nerve segments and were more prominent in axons than in Schwann cells. Transcripts of fusion and fission proteins were reduced in distal nerve segments. Significant reduced expression levels of the fusion protein MFN2 was detected in nerves of cisplatin-exposed animals. In summary, we provide for the first time an evidence that cisplatin alters mitochondrial dynamics in peripheral nerves. Loss of MFN2, previously implicated in the pathogenesis of other neurodegenerative diseases, also contributes to the pathogenesis in cisplatin-induced neuropathy.

Neurotoxicity is a relevant side effect of bortezomib treatment. Previous reports have shown that the development of peripheral neuropathy caused by anti-neoplastic agents may be a result of reduced axonal transport. Based on evidence from prior studies that the kinesin-5 inhibitor monastrol enhances axonal transport and improves neuronal regeneration, we focused on the neuroprotective role of monastrol during the chemotherapeutic treatment with bortezomib. Prolonged treatment of C57BL/6 mice with bortezomib induced a length-dependent small-fiber neuropathy with axonal atrophy and loss of sensory nerve fibers. The administration of monastrol substantially alleviated morphological features of axonal injury and functional measures of sensory neuropathy. Cytotoxicity studies in leukemia and multiple myeloma cell lines showed no interference of monastrol with the cytostatic effects of bortezomib. Our data indicate that the novel approach of targeting microtubule turnover by monastrol provides protection against bortezomib-induced neurotoxicity. The favorable cytotoxic profile of monastrol makes it an interesting candidate as neuroprotective agent in combined chemotherapy regimens that warrants further consideration.

Paclitaxel is an integral component of solid tumor treatment. This chemotherapeutic agent provokes an often irreversible peripheral sensory neuropathy with pathological features of distal axonal degeneration. Current pathological concepts assume that polymerization of axonal microtubules and mitochondrial dysfunction contributes to the development of paclitaxel-induced peripheral neuropathy. The relationship, however, between microtubule stabilization, mitotoxicity and axonal degeneration is still not completely understood. To explore the function of axonal mitochondria we treated transgenic mice that harbor cyan fluorescent protein (CFP)-labeled neuronal mitochondria with repeated doses of paclitaxel and assessed neuropathic changes by nerve conduction and histological studies. In addition, mitochondrial content and morphology was determined by ex vivo imaging of axons containing CFP-labeled mitochondria. Using quantitative RT-PCR and fluorescence-labeled mRNA we determined axonal mRNA transport of nuclear encoded mitochondrial proteins. Prolonged treatment with high doses of paclitaxel-induced a predominant sensory neuropathy in mice. Although mitochondrial velocity in axons per se was not altered, we observed significant changes in mitochondrial morphology, suggesting that paclitaxel treatment impairs the dynamics of axonal mitochondria. These changes were caused by decreased levels of nuclear encoded mRNA, including the mitochondrial fusion/fission machinery. Moreover, impaired axonal mRNA transport in vitro resulted in mitochondrial dysfunction and subsequent axonal degeneration. Taken together, our experiments provide evidence that disrupted axonal transport of nuclear derived mRNA plays a crucial role in the pathogenesis of paclitaxel-induced sensory neuropathy., (Copyright © 2015. Published by Elsevier Inc.)

Peripheral nerve injury triggers the activation of the small GTPase RhoA in spinal motor and peripheral sensory neurons. C3 transferase, an exoenzyme produced by Clostridium botulinum that inactivates RhoA by ADP-ribosylation, has been successfully applied in central nervous system (CNS) lesion models to facilitate regeneration functionally and morphologically. Until now it has not been demonstrated if C3bot exerts positive effects on peripheral axon regeneration as well. In organotypic spinal cord preparations, C3bot reduced axonal growth of motoneurons, while no effect on sensory axon outgrowth from dorsal root ganglia (DRG) explants was observed. Enzymatically inactive C3E174Q was ineffective in both culture models. Spinal cord slices exhibited a significant increase in microglia/macrophages after treatment with C3bot suggesting an inflammatory component in the inhibition of axon growth. C3bot or C3E174Q were then applied into conduits implanted after transection of the sciatic nerve in rats. Functional evaluation by electrophysiology, nociception, and walking track tests did not show any significant difference between groups with active or mutant C3E174Q . Transmission electron microscopy of the regenerated nerves revealed no significant differences in the number of myelinated and unmyelinated axons 6 weeks after surgery. Compared to the CNS, the functional significance of RhoA may be limited during nerve regeneration in a growth-promoting environment., (© 2013 Peripheral Nerve Society.)

Very few reports on the phenotype of short fifth metacarpals have been published in the medical literature. We report a Jordanian family in which three sisters aged 15, 13 and 8 years revealed bilateral shortening of the fifth fingers and radiological shortening of the fifth metacarpals. The father had unilateral short fifth metacarpal. The elder two sisters, their father as well as their brother and another sister manifested insulin resistance. Spherocytosis was diagnosed in one of the girls and her father. The parents are non-consanguineous. This constellation of findings has not been previously reported and could point to the presence of two disorders segregating in the family or to a novel syndrome with autosomal dominant inheritance and variable expressivity.

Two morbilliviruses were isolated from Mediterranean monk seals (Monachus monachus), one from a stranded animal in Greece and the other one from carcasses washed ashore during a mass die-off in Mauritania. From both viruses N and P gene fragments were sequenced and compared to those of other known morbilliviruses. The monk seal morbilliviruses most closely resembled previously identified cetacean morbilliviruses, indicating that interspecies transmission from cetaceans to pinnipeds has occurred.

During the past few months, more than half of the total population of about 300 highly endangered Mediterranean monk seals (Monachus monachus) on the western Saharan coast of Africa, died in a mysterious disease outbreak. Epizootiological and postmortem findings were reminiscent of similar outbreaks amongst pinniped and cetacean species in recent years, which were caused by an infection with newly discovered morbilliviruses (for review see osterhaus et al.). Virological, as well as toxicological, analysis performed on tissue samples collected from relatively fresh carcasses during the outbreak indicate that infection with a virus closely related to dolphin morbillivirus (DMV), possibly originating from affected dolphins in the same area, was the primary cause of the outbreak. Therefore it is concluded that vaccination with a safe and effective non-replicating vaccine should be considered as a management tool in the conservation of Mediterranean monk seals.