Feline hypersomatotropism and acromegaly tumorigenesis: a potential role for the AIP gene

Acromegaly in humans is usually sporadic, however up to 20% of familial isolated pituitary adenomas are caused by germline sequence variants of the aryl-hydrocarbon-receptor interacting protein (AIP) gene. Feline acromegaly has similarities to human acromegalic families with AIP mutations. The aim of this study was to sequence the feline AIP gene, identify sequence variants and compare the AIP gene sequence between feline acromegalic and control cats, and in acromegalic siblings. The feline AIP gene was amplified through PCR using whole blood genomic DNA from 10 acromegalic and 10 control cats, and 3 sibling pairs affected by acromegaly. PCR products were sequenced and compared with the published predicted feline AIP gene. A single nonsynonymous SNP was identified in exon 1 (AIP:c.9T > G) of two acromegalic cats and none of the control cats, as well as both members of one sibling pair. The region of this SNP is considered essential for the interaction of the AIP protein with its receptor. This sequence variant has not previously been reported in humans. Two additional synonymous sequence variants were identified (AIP:c.481C > T and AIP:c.826C > T). This is the first molecular study to investigate a potential genetic cause of feline acromegaly and identified a nonsynonymous AIP single nucleotide polymorphism in 20% of the acromegalic cat population evaluated, as well as in one of the sibling pairs evaluated

Prospective evaluation of a protocol for transitioning porcine lente insulintreated diabetic cats to human recombinant protamine zinc insulin

Objectives The objective was to evaluate a nadir-led protocol for transitioning porcine lente insulin suspension (PLIS)-treated diabetic cats onto human recombinant protamine zinc insulin (PZIR). Methods Recently diagnosed (<5 months) diabetic cats, treated with PLIS q12h for 6 weeks, were recruited. Fructosamine, 24 h blood glucose curve (BGC), quality of life assessment (DIAQoL-pet score) and Diabetic Clinical Score (DCS) were assessed at enrolment (PLIS-treated) and 2, 4 and 12 weeks after transitioning to PZIR (starting dose 0.2-0.7 U/kg q12h). Short duration of insulin action was defined as <9 h. Linear mixed effects modelling assessed for change in fructosamine, mean blood glucose (MBG) during BGCs, DIAQoL-pet score, DCS and q12h insulin dose. McNemar's tests compared the proportion of cats with hypoglycaemia at week 0 (PLIS-treated) and week 4 (PZIR-treated). Results Twenty-two cats were recruited. Median PLIS dose at enrolment was 0.5 U/kg (interquartile range 0.3-0.7 U/kg) q12h, equalling median PZIR starting dose (0.5 U/kg; interquartile range 0.3-0.7 U/kg q12h). Transitioning was followed by significant decreases in fructosamine (P = 0.00007), insulin dose (P = 0.02), DCS (P = 8.1 x 10(-8)) and DIAQoL-pet score (P = 0.003), indicating improved quality of life. MBG did not alter significantly (P = 0.1). Five cats (22.7%) achieved remission. Hypoglycaemia was recorded in 30/190 12 h BGCs (15.8%) and five cats experienced clinical hypoglycaemia. The proportion of cats with hypoglycaemia did not differ between PLIS (week 0) and PZIR (week 4) (P = 1.0). Duration of action was analysed in 19 cats. Six cats (31.6%) showed short duration of action on PLIS, compared with two cats (10.5%) after 4 weeks on PZIR. All six cats with short PLIS duration showed duration of 9 h on PZIR. Conclusions and relevance Used alongside a low-carbohydrate diet, transitioning to PZIR was associated with significantly improved clinical signs and quality of life, with some cats achieving remission. Transition to PZIR should be considered for cats with short duration of action on PLIS

A role for the cleaved cytoplasmic domain of E-cadherin in the nucleus

Cell-cell contacts play a vital role in intracellular signaling, although the molecular mechanisms of these signaling pathways are not fully understood. E-cadherin, an important mediator of cell-cell adhesions, has been shown to be cleaved by γ-secretase. This cleavage releases a fragment of E-cadherin, E-cadherin C-terminal fragment 2 (E-cad/CTF2), into the cytosol. Here, we study the fate and function of this fragment. First, we show that coexpression of the cadherin-binding protein, p120 catenin (p120), enhances the nuclear translocation of E-cad/CTF2. By knocking down p120 with short interfering RNA, we also demonstrate that p120 is necessary for the nuclear localization of E-cad/CTF2. Furthermore, p120 enhances and is required for the specific binding of E-cad/CTF2 to DNA. Finally, we show that E-cad/CTF2 can regulate the p120-Kaiso-mediated signaling pathway in the nucleus. These data indicate a novel role for cleaved E-cadherin in the nucleus

Epidemiology of diabetes mellitus among 193,435 cats attending primary-care veterinary practices in England

BACKGROUND: Diabetes mellitus (DM) is a common endocrine disease of cats. The prevalence of DM in cats in England is not well‐defined. HYPOTHESIS/OBJECTIVES: To estimate the prevalence and identify risk factors for DM in a large population of cats attending primary‐care practices. ANIMALS: A cohort of 193,563 cats in the VetCompass Programme attending 118 primary‐care practices in England. METHODS: Cross‐sectional analysis of cohort clinical data. Data were extracted covering September 1st 2009 and August 31st 2014. Period prevalence of DM was calculated. Associations between risk factors and DM were assessed using logistic regression modelling. RESULTS: Of 1,128 DM cases were identified among 194,563 cats (period prevalence 0.58%; 95% confidence interval [CI] 0.54–0.61). Multivariable modelling indicated that Tonkinese (OR 4.1; 95% CI 1.8–9.6; P = .001), Norwegian Forest (odds ratio [OR] 3.5; 95% CI 1.3–9.6; P = .001) and Burmese (OR 3.0; 95% CI 2.0–4.4; P < .001) cats had increased odds of DM compared with crossbred cats. DM odds increased as bodyweight categories increased above 4 kg (P < .001), as cats aged beyond 6 years old (P < .001) and in insured cats (OR 2.0; 95% CI 1.6–2.4; P < .001) but sex was not significantly associated with DM. CONCLUSIONS AND CLINICAL IMPORTANCE: Diabetes mellitus is an important component of the primary‐care practice caseload with 1‐in‐200 cats affected. An increased risk of DM in certain cat breeds supports a genetic predisposition. These results can guide future research and preventative healthcare

Origin and evolution of the Laguna Potrok Aike maar (Patagonia, Argentina)

Laguna Potrok Aike, a maar lake in southern-most Patagonia, is located at about 110 m a.s.l. in the Pliocene to late Quaternary Pali Aike Volcanic Field (Santa Cruz, southern Patagonia, Argentina) at about 52°S and 70°W, some 20 km north of the Strait of Magellan and approximately 90 km west of the city of Rio Gallegos. The lake is almost circular and bowl-shaped with a 100 m deep, flat plain in its central part and an approximate diameter of 3.5 km.Steep slopes separate the central plain from the lake shoulder at about 35 m water depth. At present, strong winds permanently mix the entire water column. The closed lake basin contains a sub saline water body and has only episodic inflows with the most important episodic tributary situated on the western shore. Discharge is restricted to major snowmelt events.Laguna Potrok Aike is presently located at the boundary between the Southern Hemispheric Westerlies and the Antarctic Polar Front. The sedimentary regime is thus influenced by climatic and hydrologic conditions related to the Antarctic Circumpolar Current, the Southern HemisphericWesterlies and sporadic outbreaks of Antarctic polar air masses. Previous studies demonstrated that closed lakes in southern South America are sensitive to variations in the evaporation/precipitation ratio and have experienced drastic lake level changes in the past causing for example the desiccation of the 75 m deep Lago Cardiel during the Late Glacial. Multiproxy environmental reconstruction of the last 16 ka documents that Laguna Potrok Aike is highly sensitive to climate change. Based on an Ar/Ar age determination, the phreatomagmatic tephra that is assumed to relate to the Potrok Aike maar eruption was formed around 770 ka. Thus Laguna Potrok Aike sediments contain almost 0.8 million years of climate history spanning several past glacial-interglacial cycles making it a unique archive for non-tropical and non-polar regions of the Southern Hemisphere. In particular, variations of the hydrological cycle, changes in eolian dust deposition, frequencies and consequences of volcanic activities and other natural forces controlling climatic and environmental responses can be tracked throughout time. Laguna Potrok Aike has thus become a major focus of the International Continental Scientific Drilling Program. Drilling operations were carried out within PASADO (Potrok Aike Maar Lake Sediment Archive Drilling Project) in late 2008 and penetrated ~100 m into the lacustrine sediment.Laguna Potrok Aike is surrounded by a series of subaerial paleo-shorelines of modern to Holocene age that reach up to 21 m above the 2003 AD lake level. An erosional unconformity which can be observed basin-wide along the lake shoulder at about 33 m below the 2003 AD lake level marks the lowest lake level reached during Late Glacial to Holocene times. A high- resolution seismic survey revealed a series of buried, subaquatic paleo-shorelines that hold a record of the complex transgressional history of the past approximately 6800 years, which was temporarily interrupted by two regressional phases from approximately 5800 to 5400 and 4700 to 4000 cal BP. Seismic reflection and refraction data provide insights into the sedimentary infill and the underlying volcanic structure of Laguna Potrok Aike. Reflection data show undisturbed, stratified lacustrine sediments at least in the upper ~100 m of the sedimentary infill. Two stratigraphic boundaries were identified in the seismic profiles (separating subunits I-ab, I-c and I-d) that are likely related to changes in lake level. Subunits I-ab and I-d are quite similar even though velocities are enhanced in subunit I-d. This might point at cementation in subunit I-d. Subunit I-c is restricted to the central parts of the lake and thins out laterally.A velocity-depth model calculated from seismic refraction data reveals a funnel-shaped structure embedded in the sandstone rocks of the surrounding Santa Cruz Formation. This funnel struc

A biomechanical mathematical model for the collagen bundle distribution-dependent contraction and subsequent retraction of healing dermal wounds

A continuum hypothesis-based, biomechanical model is presented for the simulation of the collagen bundle distribution-dependent contraction and subsequent retraction of healing dermal wounds that cover a large surface area. Since wound contraction mainly takes place in the dermal layer of the skin, solely a portion of this layer is included explicitly into the model. This portion of dermal layer is modeled as a heterogeneous, orthotropic continuous solid with bulk mechanical properties that are locally dependent on both the local concentration and the local geometrical arrangement of the collagen bundles. With respect to the dynamic regulation of the geometrical arrangement of the collagen bundles, it is assumed that a portion of the collagen molecules are deposited and reoriented in the direction of movement of (myo)fibroblasts. The remainder of the newly secreted collagen molecules are deposited by ratio in the direction of the present collagen bundles. Simulation results show that the distribution of the collagen bundles influences the evolution over time of both the shape of the wounded area and the degree of overall contraction of the wounded area. Interestingly, these effects are solely a consequence of alterations in the initial overall distribution of the collagen bundles, and not a consequence of alterations in the evolution over time of the different cell densities and concentrations of the modeled constituents. In accordance with experimental observations, simulation results show furthermore that ultimately the majority of the collagen molecules ends up permanently oriented toward the center of the wound and in the plane that runs parallel to the surface of the skin

Pilot study assessing the use of cabergoline for the treatment of cats with hypersomatotropism and diabetes mellitus

Abstract Objectives An affordable and effective treatment is needed to manage feline hypersomatotropism. The aim of this study was to assess whether treatment with oral cabergoline for 90 days in cats with hypersomatotropism and diabetes mellitus improved diabetic and insulin-like growth factor 1 (IGF-1) control. Methods This was a prospective cohort non-blinded pilot study enrolling client-owned cats with spontaneously occurring diabetes mellitus and hypersomatotropism. Cats received oral cabergoline (5–10 µg/kg q24h) for 90 consecutive days. Serum IGF-1 and fructosamine concentrations were measured on days 1, 30 and 90. Quality of life was determined using the DIAQoL-pet questionnaire on days 1 and 90. Results Nine cats were enrolled and eight completed the study. There was no significant change in the following: IGF-1 (day 1 median 2001 ng/ml [range 890–2001 ng/ml]; day 30 median 2001 ng/ml [range 929–2001 ng/ml]; day 90 median 1828 ng/ml [range 1035–2001 ng/ml]; χ2(2) = 0.667, P = 0.805); fructosamine (day 1 median 499 µmol/l [range 330–887 µmol/l], day 30 median 551 µmol/l [range 288–722 µmol/l], day 90 median 503 [range 315–851 µmol/l]; χ2(2) = 0.581, P = 0.764); or DIAQoL-pet score (median on day 1 –2.79 (range –4.62 to –0.28], median on day 90 –3.24 [range –4.41 to –0.28]; P = 0.715). There was a significant change of insulin dose (χ2(2) = 8.667, P = 0.008) with cats receiving higher insulin doses at day 90 compared with day 1 (median on day 1 was 0.98 [range 0.63–1.49] and median on day 90 was 1.56 [range 0.49–2.55] units/kg q12h; P = 0.026). Conclusions and relevance Cabergoline did not improve diabetic control or normalise insulin-like growth factor concentration, or improve patient quality of life

Time spent with cats is never wasted: Lessons learned from feline acromegalic cardiomyopathy, a naturally occurring animal model of the human disease

<div><p>Background</p><p>In humans, acromegaly due to a pituitary somatotrophic adenoma is a recognized cause of increased left ventricular (LV) mass. Acromegalic cardiomyopathy is incompletely understood, and represents a major cause of morbidity and mortality. We describe the clinical, echocardiographic and histopathologic features of naturally occurring feline acromegalic cardiomyopathy, an emerging disease among domestic cats.</p><p>Methods</p><p>Cats with confirmed hypersomatotropism (IGF-1>1000ng/ml and pituitary mass; n = 67) were prospectively recruited, as were two control groups: diabetics (IGF-1<800ng/ml; n = 24) and healthy cats without known endocrinopathy or cardiovascular disease (n = 16). Echocardiography was performed in all cases, including after hypersomatotropism treatment where applicable. Additionally, tissue samples from deceased cats with hypersomatotropism, hypertrophic cardiomyopathy and age-matched controls (n = 21 each) were collected and systematically histopathologically reviewed and compared.</p><p>Results</p><p>By echocardiography, cats with hypersomatotropism had a greater maximum LV wall thickness (6.5mm, 4.1–10.1mm) than diabetic (5.9mm, 4.2–9.1mm; Mann Whitney, p<0.001) or control cats (5.2mm, 4.1–6.5mm; Mann Whitney, p<0.001). Left atrial diameter was also greater in cats with hypersomatotropism (16.6mm, 13.0–29.5mm) than in diabetic (15.4mm, 11.2–20.3mm; Mann Whitney, p<0.001) and control cats (14.0mm, 12.6–17.4mm; Mann Whitney, p<0.001). After hypophysectomy and normalization of IGF-1 concentration (n = 20), echocardiographic changes proved mostly reversible. As in humans, histopathology of the feline acromegalic heart was dominated by myocyte hypertrophy with interstitial fibrosis and minimal myofiber disarray.</p><p>Conclusions</p><p>These results demonstrate cats could be considered a naturally occurring model of acromegalic cardiomyopathy, and as such help elucidate mechanisms driving cardiovascular remodeling in this disease.</p></div

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Contains research objectives and reports on three research projects.National Science Foundation (Grant G-16526)National Institutes of Health (Grant MH-04737-03)National Aeronautics and Space Administration (Grant NsG-496)Lincoln Laboratory, Purchase Order DDL BB-107U.S. Air Force under Contract AF 19(628)-50

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Contains research objectives and reports on two research projects.National Aeronautics and Space Administration under Grant NsG-334Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DA 36-039-AMC-03200(E)National Science Foundation (Grant GP-2495)National Aeronautics and Space Administration (Grant NsG-496