Risk factors for development of internal neoplasms in koi carp (Cyprinus carpio koi)

Fish, like mammals, can be affected by neoplastic proliferations. As yet, there are only a very small number of studies reporting on the occurrence of tumours in koi carp Cyprinus carpio koi and only sporadic reports on the nature of the tumours or on risk factors associated with their development. Between 2008 and 2012, koi with abdominal swelling were examined pathologically: neoplastic lesions were diagnosed and classified histologically. We evaluated possible risk factors for the development of these internal neoplasms in koi carp in Switzerland, using an online 2-part questionnaire sent to fish keepers with koi affected by internal tumours and to fish keepers who had not previously reported any affected koi. Part 1 addressed all participants and focused on general information about koi husbandry and pond technical data; Part 2 addressed participants that had one or several case(s) of koi with internal tumour(s) between 2008 and 2012, and consisted of specific questions about affected koi. A total of 112 internal tumours were reported by the 353 koi keepers participating in the survey. Analysis of the obtained data revealed that tumour occurrence was significantly associated with the location (indoors vs. outdoors) and volume of the pond, frequency of water changes, origin of the koi, number of koi kept in a Pond and the use of certain pond disinfectant/medication products. Our results contribute to the identification of possible risk factors, which in turn could help to establish prophylactic measures in order to reduce the occurrence of internal neoplasms in koi.

NOX3-Targeted Therapies for Inner Ear Pathologies

Inner ear pathologies are associated with major morbidity and loss of life quality in affected patients. In many of these conditions, production of reactive oxygen-species (ROS) is thought to be a key pathological mechanism. While the sources of ROS are complex (including for example mitochondria), there is increasing evidence that activation of NOX enzymes, in particular NOX3, plays a key role. NOX3 is a multi-subunit NADPH oxidase, functionally and structurally closely related to NOX1 and NOX2. In both the vestibular and the cochlear compartments of the inner ear, high levels of NOX3 mRNA are expressed. In NOX3 mutant mice, the vestibular function is perturbed due to a lack of otoconia, while only minor alterations of hearing have been documented. However, there is increasing evidence that activation of NOX3 through drugs, noise and probably also aging, leads to hearing loss. Thus, NOX3 is an interesting target to treat and prevent inner ear pathologies and a few first animal models based on drug - or molecular therapy have been reported. So far however, there are no specific NOX3 inhibitors with a documented penetration into the inner ear. Nevertheless, certain antioxidants and non-specific NOX inhibitors diminish hearing loss in animal models. Development of small molecules inhibitors or molecular strategies against NOX3 could improve specificity and efficiency of redox-targeted treatments. In this review, we will discuss arguments for the involvement of NOX3 in inner ear pathologies and therapeutic approaches to target NOX3 activity.

Effect of tympanic cavity evacuation and flushing on microbial isolates during total ear canal ablation with lateral bulla osteotomy in dogs.

OBJECTIVE To evaluate differences in bacterial numbers, identity, and susceptibility in samples obtained from the tympanic cavity on entry (preflush) and after evacuation and lavage (postflush) and assess perioperative and empiric antimicrobial selection in dogs that underwent total ear canal ablation (TECA) with lateral bulla osteotomy (LBO) or reoperation LBO. DESIGN Prospective clinical study. ANIMALS 34 dogs. PROCEDURE TECA with LBO or reoperation LBO was performed on 47 ears. Pre- and postflush aerobic and anaerobic samples were obtained from the tympanic cavity. Isolates and antimicrobial susceptibility patterns were compared. RESULTS Different isolates (31/44 [70%] ears) and susceptibility patterns of isolate pairs (6/44 [14%] ears) were detected in pre- and postflush samples from 84% of ears. Evacuation and lavage of the tympanic cavity decreased the number of bacterial isolates by 33%. In 26% of ears, bacteria were isolated from post-flush samples but not preflush samples. Only 26% of isolates tested were susceptible to cefazolin. At least 1 isolate from 53% of dogs that received empirically chosen antimicrobials postoperatively was resistant to the selected drugs. Anaerobic bacteria were recovered from 6 ears. CONCLUSIONS AND CLINICAL RELEVANCE Accurate microbiologic assessment of the tympanic cavity should be the basis for selection of antimicrobials in dogs undergoing TECA with LBO. Bacteria remain in the tympanic cavity after evacuation and lavage. Cefazolin was a poor choice for dogs that underwent TECA with LBO, as judged on the basis of culture and susceptibility testing results.

Molecular diagnostics of myeloproliferative neoplasms

Since the discovery of the JAK2 V617F mutation in the majority of the myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia and primary myelofibrosis ten years ago, further MPN-specific mutational events, notably in JAK2 exon 12, MPL exon 10 and CALR exon 9 have been identified. These discoveries have been rapidly incorporated into evolving molecular diagnostic algorithms. Whilst many of these mutations appear to have prognostic implications, establishing MPN diagnosis is of immediate clinical importance with selection, implementation and the continual evaluation of the appropriate laboratory methodology to achieve this diagnosis similarly vital. The advantages and limitations of these approaches in identifying and quantitating the common MPN-associated mutations are considered herein with particular regard to their clinical utility. The evolution of molecular diagnostic applications and platforms has occurred in parallel with the discovery of MPN-associated mutations, and it therefore appears likely that emerging technologies such as next-generation sequencing and digital PCR will in the future play an increasing role in the molecular diagnosis of MPN. Accepted for publication 30 April 2015 doi:10.1111/ejh.12578

Bone conduction responses of middle ear structures in Thiel embalmed heads

Thiel-embalmed human whole-head specimens offer a promising alternative model for bone conduction (BC) studies of middle ear structures. In this work we present the Thiel model’s linearity and stability over time as well as its possible use in the study of a fixed ossicle chain. Using laser Doppler vibrometry (LDV), the motion of the retroauricular skull, the promontory, the stapes footplate and the round window (RW) were measured. A bone-anchored hearing aid stimulated the ears with step sinus tones logarithmically spread between 0.1 and 10 kHz. Linearity of the model was verified using input levels in steps of 10 dBV. The stability of the Thiel model over time was examined with measurements repeated after hours and weeks. The influence of a cement-fixed stapes was assessed. The middle ear elements measured responded linearly in amplitude for the applied input levels (100, 32.6, and 10 mV). The variability of measurements for both short- (2 h) and long-term (4-16 weeks) repetitions in the same ear was lower than the interindividual difference. The fixation of the stapes induced a lowered RW displacement for frequencies near 750 Hz (-4 dB) and an increased displacement for frequencies above 1 kHz (max. +3.7 dB at 4 kHz). LDV assessment of BC-induced middle ear motion in Thiel heads can be performed with stable results. The vibratory RW response is affected by the fixation of the stapes, indicating a measurable effect of ossicle chain inertia on BC response in Thiel embalmed heads.

"An attentive Ear, a watchful Eye, and a Calm judicious Pen": William Samuel Johnson, the Colonial Agents, and the Transformation of the British Atlantic World

By looking at Great Britain and the American colonies in conjunction with the larger British Atlantic Empire, historians can better understand the political, social, and cultural transformations that occurred when transatlantic actors met. William Samuel Johnson is an example of an "ordinary" agent who nonetheless had extensive contacts with numerous British and American thinkers. While acting on Connecticut's behalf in London between 1767 and 1771, he sent reports back to Connecticut governors Jonathan Trumbull and William Pitkin on parliamentary proceedings while corresponding with the people who traveled around the Atlantic world during this critical period-merchants, seafarers, emigrants, soldiers, missionaries, radicals and conservatives, reformers, and politicians. He is also representative of the late eighteenth-century empire writ large. Agents, who had once been a source of stability in the far-flung colonies, became a destabilizing force as confusion and conflict grew over conceptual ideas of what constituted "the empire" and who was included in it. Johnson was a sane observer in the midst of the ideological and administrative upheaval of the 1760's and 1770's. His subsequent loyalism and political obscurity during the war years was in many ways a result of his attempts to reconcile various factional interests during his tenure as an agent. Although he did his best to resolve these divisions and provide an accurate account of the powerful nationalistic forces gathering on both sides of the Atlantic on the eve of the American Revolution, the agents' collective failures as transatlantic mediators helped bring about the collapse of an imperial community. This disintegration had dramatic effects on the whole of the Atlantic world.

The nature and treatment of diseases of the ear

by William Kramer. Transl. from the German, with the latest improvements of the author since the last German ed. by James Risdon Bennett

A cohort study of occupational asbestos-exposure related neoplasms in Texas Gulf Coast area

A cohort study was conducted in Texas and Louisiana Gulf Coast area on individual workers who have been exposed to asbestos for 15 years or more. Most of these workers were employed in petrochemical industries. Of the 15,742 subjects initially selected for the cohort study, 3,258 had positive chest X-ray findings believed to be related to prolonged asbestos exposure. These subjects were further investigated. Their work out included detailed medical and occupational history, laboratory tests and spirometry. One thousand eight-hundred and three cases with positive chest X-ray findings whose data files were considered complete at the end of May 1986 were analyzed and their findings included in this report.^ The prevalence of lung cancer and cancer of the following sights: skin, stomach, oropharyngeal, pancreas and kidneys were significantly increased when compared to data from Connecticut Tumor Registry. The prevalence of other chronic conditions such as hypertension, emphysema, heart disease and peptic ulcer was also significantly high when compared to data for the U.S. and general population furnished by the National Center for Health Statistics (NCHS). In most instances the occurrence of cancer and the chronic ailment previously mentioned appeared to follow 15-25 years of exposure to asbestos. ^

Expression of p53, {\it * ras\/} and PCNA in human colonic neoplasms: Possible biomarkers of malignant potential

Colorectal cancer is a leading cause of cancer mortality and early detection can significantly improve the clinical outcome. Most colorectal cancers arise from benign neoplastic lesions recognized as adenomas. Only a small percentage of all adenomas will become malignant. Thus, there is a need to identify specific markers of malignant potential. Studies at the molecular level have demonstrated an accumulation of genetic alterations, some hereditary but for the most occurring in somatic cells. The most common are the activation of ras, an oncogene involved in signal transduction, and the inactivation of p53, a tumor suppressor gene implicated in cell cycle regulation. In this study, 38 carcinomas, 95 adenomas and 20 benign polyps were analyzed by immunohistochemistry for the abnormal expression of p53 and ras proteins. An index of cellular proliferation was also measured by labeling with PCNA. A general overexpression of p53 was immunodetected in 66% of the carcinomas, while 26% of adenomas displayed scattered individual positive cells or a focal high concentration of positive cells. This later was more associated with severe dysplasia. Ras protein was detected in 37% of carcinomas and 32% of adenomas mostly throughout the tissue. p53 immunodetection was more frequent in adenomas originating in colons with synchronous carcinomas, particularly in patients with familial adenomatous polyposis and it may be a useful marker in these cases. Difference in the frequency of p53 and ras alterationbs was related to the location of the neoplasm. Immunodetection of p53 protein was correlated to the presence of a mutation in p53 gene at exon 7 and 5 in 4/6 carcinomas studied and 2 villous adenomas. Thus, we characterized in adenomas the abnormal expression of two proteins encoded by the most commonly altered genes in colorectal cancer. p53 alteration appears to be more specifically associated with transition to malignancy than ras. By using immunohistochemistry, a technique that keeps the architecture of the tissue intact, it was possible to correlate these alterations to histopathological characteristics that were associated with higher risks for transformation: villous content, dysplasia and size of adenoma. ^

The mouse pale ear (ep) mutation is the homologue of human Hermansky–Pudlak syndrome

The recessive mutation at the pale ear (ep) locus on mouse chromosome 19 was found to be the homologue of human Hermansky–Pudlak syndrome (HPS). A positional cloning strategy using yeast artificial chromosomes spanning the HPS locus was used to identify the HPS gene and its murine counterpart. These genes and their predicted proteins are highly conserved at the nucleotide and amino acid levels. Sequence analysis of the mutant ep gene revealed the insertion of an intracisternal A particle element in a protein-coding 3′ exon. Here we demonstrate that mice with the ep mutation exhibit abnormalities similar to human HPS patients in melanosomes and platelet-dense granules. These results establish an animal model of HPS and will facilitate biochemical and molecular analyses of the functions of this protein in the membranes of specialized intracellular organelles.

Otogelin: A glycoprotein specific to the acellular membranes of the inner ear

Efforts to identify the specific components of the mammalian inner ear have been hampered by the small number of neuroepithelial cells and the variety of supporting cells. To circumvent these difficulties, we used a PCR-based subtractive method on cDNA from 2-day-old mouse cochlea. A cDNA encoding a predicted 2910-amino acid protein related to mucin has been isolated. Several lines of evidence indicate, however, that this protein does not undergo the O-glycosylation characteristic to mucins. As confirmed by immunocytochemistry and biochemical experiments, this protein is specific to the inner ear. Immunohistofluorescence labeling showed that this protein is a component of all the acellular membranes of the inner ear: i.e., the tectorial membrane of the cochlea, the otoconial and accessory membranes of the utricule and saccule, the cupula of the semicircular canals, and a previously undescribed acellular material covering the otoconia of the saccule. The protein has been named otogelin with reference to its localization. A variety of nonsensory cells located underneath these membranes could be identified as synthesizing otogelin. Finally, this study revealed a maturation process of the tectorial membrane, as evidenced by the progressive organization of otogelin labeling into thick and spaced radial fiber-like structures.

Expression of the Recessive Glomerulosclerosis Gene Mpv17 Regulates MMP-2 Expression in Fibroblasts, the Kidney, and the Inner Ear of Mice

The recessive mouse mutant Mpv17 is characterized by the development of early-onset glomerulosclerosis, concomitant hypertension, and structural alterations of the inner ear. The primary cause of the disease is the loss of function of the Mpv17 protein, a peroxisomal gene product involved in reactive oxygen metabolism. In our search of a common mediator exerting effects on several aspects of the phenotype, we discovered that the absence of the Mpv17 gene product causes a strong increase in matrix metalloproteinase 2 (MMP-2) expression. This was seen in the kidney and cochlea of Mpv17-negative mice as well as in tissue culture cells derived from these animals. When these cells were transfected with the human Mpv17 homolog, an inverse causal relationship between Mpv17 and MMP-2 expression was established. These results indicate that the Mpv17 protein plays a crucial role in the regulation of MMP-2 and suggest that enhanced MMP-2 expression might mediate the mechanisms leading to glomerulosclerosis, inner ear disease, and hypertension in this model.