Fractionated oral dosing and its effect on cyclophosphamide pharmacokinetics in dogs with high-grade multicentric lymphoma

Cyclophosphamide (CP) is an alkylating agent commonly included in multi-drug treatment protocols for canine cancer. As a prodrug, CP requires hepatic metabolism for activation to the intermediate compound 4-hydroxycyclophosphamide (4-OHCP) which then spontaneously forms alkylating phosphoramide mustard. CP is frequently administered in a fractionated manner, with the total dose given over multiple days. CP is reported to cause auto-induction of metabolism in humans, with faster CP clearance and relatively increased 4-OHCP formation following fractionated versus bolus dosing, however canine pharmacokinetic studies of CP dose fractionation are lacking. The study objective was to evaluate the pharmacokinetics of fractionated oral CP dosing at a dose of 200–250 mg/m² over 3 to 4 days in a prospectively identified population of cancer-bearing dogs. Plasma concentrations of CP and 4-OHCP were measured by ultra-high performance liquid chromatography tandem-mass spectrometry in eight dogs following the first and last doses to assess for auto-induction of CP metabolism. No significant difference in the rate of CP elimination between first and last doses were detected (0.73 ± 0.46 vs. 1.22 ± 0.5 h⁻¹; p = .125). Additionally, no significant difference in dose-normalized 4-OHCP exposure was identified between first and last doses (5.9 ± 2.1 vs. 7.9 ± 6.4 h × ng/ml; p = .936). These results suggest that fractionated dosing may not increase exposure to the active metabolite of CP in dogs as it does in humans. As such, standard bolus dosing and fractionated dosing may be equivalent in terms of bio-activation of CP in dogs administered a dose of 200–250 mg/m².     

Evaluation of mechlorethamine,vinblastine, procarbazine,and prednisone for the treatment of resistant multicentric canine lymphoma

Multi-agent chemotherapy successfully induces remission in most naïve, high-grade canine lymphoma patients; however, disease recurrence is common. MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) is an effective rescue protocol used to re-induce remission, but is associated with gastrointestinal toxicity and can be a less desirable option for patients that previously failed vincristine-containing protocols. Therefore, alternative members of the vinca alkaloid family, such as vinblastine, could be potentially advantageous as substitutes for vincristine to reduce gastrointestinal toxicity and chemoresistance. The objective of this study was to report the clinical outcomes and toxicity of 36 dogs with relapsed or refractory multicentric lymphoma treated with a modified MOPP protocol whereby vincristine was replaced with vinblastine (MVPP). The overall response rate to MVPP was 25% with a median progression free survival of 15 days and a median overall survival of 45 days. MVPP at the prescribed doses resulted in modest and transient clinical benefit, but was well tolerated with no treatment delays or hospitalizations secondary to side effects. Given the minimal toxicity, dose intensification could be considered to improve clinical responses.     

Highly recurrent BRAF p.V595E mutation in canine papillary oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is the most common oral epithelial malignancy in dogs. It exhibits locally aggressive biological behaviour with the potential to metastasize, and a reported 1-year survival rate of 0% when left untreated. Expression studies suggest that aberrant MAPK signalling plays a key role in canine OSCC tumorigenesis, which is consistent with BRAF and HRAS MAPK-activating mutations reported in some tumours. Several morphological subtypes of canine OSCC have been described, with papillary, conventional, and basaloid as the most common patterns. We hypothesized that mutational differences may underlie these phenotypic variations. In this study, targeted Sanger sequencing and restriction fragment length polymorphism assays demonstrate that up to 85.7% of canine papillary OSCC (n = 14) harbour a BRAF p.V595E mutation. Assessment of neoplastic epithelial cell proliferation using Ki67 immunolabelling (n = 10) confirmed a relatively high proliferation activity, consistent with their known aggressive clinical behaviour. These findings underscore a consistent genetic feature of canine papillary OSCC and provide a basis for the development of novel diagnostic and targeted therapeutic approaches that can improve the quality of veterinary care.     

Farmers' perception on self created water management rules in a pioneer scheme: The mula irrigation scheme, India

During the past two decades with farmer participation in irrigation management moving to center stage, the traditional view of having a centralized control over the water resources for better management has changed. Nevertheless, success of irrigation management transfer depend on a whole set of institutional arrangements or the rules-in-use and the willingness of the users to comply and enforce and/or change the rules in the light of changing circumstances. There are many institutional analyses of water sector, much of them touch on law, policy and administration, and characteristics of the users. The present paper is based on the study carried out to examine the institutional arrangements in one of the water users association that was first in the Maharashtra state. It focuses on the institutional arrangements governing water use and distribution and attempts to elicit the perceptions of the members regarding the rules-in-use. The findings reveal that the WUA has been successful in devising and enforcing the rules for water distribution, fee collection and conflict resolution for over a decade. However, current socio-economic developments such as political heterogeneity have required explicit conflict resolution mechanisms. These issues have now become issues demanding immediate attention and may be use of existing courts or legal institutions to help the WUA sustain in future.     

Habitat suitability and connectivity modeling reveal priority areas for Indiana bat (Myotis sodalis) conservation in a complex habitat mosaic

Context

Conservation for the Indiana bat (Myotis sodalis), a federally endangered species in the United States of America, is typically focused on local maternity sites; however, the species is a regional migrant, interacting with the environment at multiple spatial scales. Hierarchical levels of management may be necessary, but we have limited knowledge of landscape-level ecology, distribution, and connectivity of suitable areas in complex landscapes.

Objectives

We sought to (1) identify factors influencing M. sodalis maternity colony distribution in a mosaic landscape, (2) map suitable maternity habitat, and (3) quantify connectivity importance of patches to direct conservation action.

Methods

Using 3 decades of occurrence data, we tested a priori, hypothesis-driven habitat suitability models. We mapped suitable areas and quantified connectivity importance of habitat patches with probabilistic habitat availability metrics.

Results

Factors improving landscape-scale suitability included limited agriculture, more forest cover, forest edge, proximity to medium-sized water bodies, lower elevations, and limited urban development. Areas closer to hibernacula and rivers were suitable. Binary maps showed that 30% of the study area was suitable for M. sodalis and 29% was important for connectivity. Most suitable patches were important for intra-patch connectivity and far fewer contributed to inter-patch connectivity.

Conclusions

While simple models may be effective for small, homogenous landscapes, complex models are needed to explain habitat suitability in large, mixed landscapes. Suitability modeling identified factors that made sites attractive as maternity areas. Connectivity analysis improved our understanding of important areas for bats and prioritized areas to target for restoration.

     

控制猪球虫病的亚临床感染

近20年来,商品化养猪场的猪群健康状况有了相当大的提高。虽然许多重要的疾病已被消灭,但仍然存在着若干较温和的地方病(如球虫病),它们会显著提高养猪生产成本。     

Obstructive struvite ureterolithiasis in 4-month-old intact male Bernese mountain dog

A 4-month-old, 7 kg, intact male, Bernese mountain dog was presented for obstructive struvite ureterolithiasis. Multiple urethroliths, ureteroliths, and urocystoliths were present. Based on an abdominal ultrasound, there was severe left hydronephrosis and hydroureter from distal ureterolith obstruction, just proximal to the vesicoureteral junction. The dog was not azotemic. Successful treatment was accomplished via ventral cystotomy. Bladder wall culture revealed a methicillin-resistant Staphylococcus spp. No predisposing cause was identified. There are no known genetic predispositions in Bernese mountain dogs for struvite urolithiasis. The urinary tract infection resolved with surgical retrieval of the uroliths and antibiotic treatment. The dog remained clinically normal after the cystotomy but developed a subclinical urinary tract infection 4 mo post-operatively.Key clinical message:Urolithiasis is rare in pediatric veterinary patients. To the authors’ knowledge, this is the first report of obstructive ureterolithiasis in a puppy. There is no known genetic predisposition for urolithiasis in Bernese mountain dogs.