Signalling pathways in succinate dehydrogenase B-associated renal carcinoma.

AIMS: Renal tumours have recently been described in association with mutations in the gene encoding the B subunit of succinate dehydrogenase, a mitochondrial Krebs cycle and electron transport chain enzyme (SDHB-associated renal cell carcinomas). The aim of this study was to investigate the roles of different signalling pathways in the pathogenesis of these tumours. METHODS AND RESULTS: We used immunohistochemistry and antibodies against phospho-specific epitopes to examine the activity of three potential signalling pathways in tumour cells of three genetically confirmed cases of SDHB-associated renal cell carcinomas. We found no evidence supporting a role for either the mTOR [p-mTOR (Ser2448), p-S6 riboprotein (Ser235/236)] or hypoxia-inducible (carbonic anhydrase 9 and EGFR) pathways. However, there was immunohistochemical reactivity for phosphorylated AMP-dependent kinase (p-AMPK Thr172) and glycogen synthase kinase 3 (GSK3) phosphorylation (p-GSK3 Ser12), and nuclear expression of cyclin D1. CONCLUSIONS: We suggest that these tumours may arise through a mechanism involving ATP depletion, activation of AMPK, and induction of cyclin D1, and that this may be a unique pathway of tumour development that has the potential for therapeutic intervention in these rare tumours.

Improvements in Awareness and Testing Have Led to a Threefold Increase Over 10 Years in the Identification of Monogenic Diabetes in the U.K.

OBJECTIVE: Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes. In 2009, >80% of U.K. cases were estimated to be misdiagnosed. Since then, there have been a number of initiatives to improve the awareness and detection of MODY, including education initiatives (Genetic Diabetes Nurse [GDN] project), the MODY probability calculator, and targeted next-generation sequencing (tNGS). We examined how the estimated prevalence of MODY and other forms of monogenic diabetes diagnosed outside the neonatal period has changed over time and how the initiatives have impacted case finding. RESEARCH DESIGN AND METHODS: U.K. referrals for genetic testing for monogenic diabetes diagnosed >1 year of age from 1 January 1996 to 31 December 2019 were examined. Positive test rates were compared for referrals reporting GDN involvement/MODY calculator use with those that did not. RESULTS: A diagnosis of monogenic diabetes was confirmed in 3,860 individuals, more than threefold higher than 2009 (1 January 1996 to 28 February 2009, n = 1,177). Median age at diagnosis in probands was 21 years. GDN involvement was reported in 21% of referrals; these referrals had a higher positive test rate than those without GDN involvement (32% vs. 23%, P < 0.001). MODY calculator usage was indicated in 74% of eligible referrals since 2014; these referrals had a higher positive test rate than those not using the calculator (33% vs. 25%, P = 0.001). Four hundred ten (10.6%) cases were identified through tNGS. Monogenic diabetes prevalence was estimated to be 248 cases/million (double that estimated in 2009 because of increased case finding). CONCLUSIONS: Since 2009, referral rates and case diagnosis have increased threefold. This is likely to be the consequence of tNGS, GDN education, and use of the MODY calculator.

Prevalence of and risk factors for feline hyperthyroidism in South Africa.

Objectives Hyperthyroidism is a disorder of older cats that may have a geographical variation in prevalence. Prevalence studies have not yet been performed in South Africa, a geographical area where hyperthyroidism in cats has recently been observed and where, reportedly, the incidence appears to be increasing. The purpose of this study was to determine the prevalence of feline hyperthyroidism in South Africa and to identify any potential risk factors. Further information on the worldwide prevalence and possible causative factors would increase our understanding of the aetiology of this disease and help identify any preventive measures. Methods Serum total thyroxine (tT4) and canine thyroid-stimulating hormone (cTSH) were measured in 302 cats aged 9 years and older that were presented at various veterinary clinics throughout South Africa. In cats with equivocal tT4 and undetectable cTSH values, serum free thyroxine (fT4) was also measured. At the time of blood sampling a questionnaire was completed regarding vaccination history, internal and external parasite control, diet and environment. Results Prevalence of hyperthyroidism (tT4 >50 nmol/l or tT4 between 30 and 50 nmol/l with TSH <0.03 ng/ml and fT4 >50 pmol/l) was 7% (95% confidence interval 4.4-10.4), with no significant difference between healthy (5%) and sick (8%) cats. Cats ⩾12 years of age (odds ratio [OR] 4.3, P = 0.02) and cats eating canned food (OR 2.1, P = 0.1) were more likely to be diagnosed with hyperthyroidism. No significant relationship between vaccinations, parasite control or indoor environment and hyperthyroidism was observed. Hyperthyroid cats were more likely to present with weight loss (OR 3.2, P = 0.01) and with a heart rate ⩾200 beats per min (OR 5, P = 0.01) than cats without the disease. Conclusions and relevance Hyperthyroidism does not appear to be uncommon in the South African cat population. Risk factors for hyperthyroidism, specifically older age and eating canned food, were present in this as in other reported populations.

Use of the melanoma vaccine in 38 dogs: The South African experience.

The commercially available vaccine Oncept is indicated for the management of dogs with stage II or III oral melanoma after local control has been achieved. Survival times in dogs with both oral and digit melanoma have been shown to be significantly increased following vaccination. This retrospective study was designed to document the investigators' experiences with Oncept vaccine when used as an adjunct therapy for treatment of stage II-IV oral, digit and malignant melanoma of other sites after local control had been achieved in dogs presented to a South African specialist referral veterinary practice. Thirty-eight dogs diagnosed with melanoma (25 oral, 6 digit and 7 infiltrative at various other sites) underwent a combination of surgical excision and Oncept vaccination. At the end of the study period there were 16 live and 22 dead dogs; median survival time of the live dogs was 29 months (range 2-46 months) versus 8 months (range 2-16 months) for those that died from progressive disease. This study showed that by using a combination of surgical excision and vaccination with Oncept survival times in dogs with malignant melanoma of the oral cavity, digit and other sites can be increased significantly.

Worldwide prevalence and risk factors for feline hyperthyroidism: A review.

Since first reported in the late 1970s, there has been a steady but dramatic increase in the worldwide prevalence of hyperthyroidism in cats. It is now regarded as the most common feline endocrine disorder, with diabetes mellitus coming a close second. Not only is there evidence for an increased worldwide prevalence of feline hyperthyroidism, but also for geographical variation in the prevalence of the disease. Despite its frequency, the underlying cause(s) of this common disease is or are not known, and therefore prevention of the disease is not possible. Due to the multiple risk factors that have been described for feline hyperthyroidism, however, it is likely that more than one factor is involved in its pathogenesis. Continuous, lifelong exposure to environmental thyroid-disruptor chemicals or goitrogens in food or water, acting together or in an additive fashion, may lead to euthyroid goitre and ultimately to autonomous adenomatous hyperplasia, thyroid adenoma and hyperthyroidism. This review aims to summarise the available published evidence for the changes observed in the worldwide prevalence of the disease, as well as risk factors that may contribute to development of hyperthyroidism in susceptible cats.