Suspected cerebral salt wasting syndrome secondary to traumatic brain injury in a dog.

OBJECTIVE: To describe a dog with suspected cerebral salt wasting syndrome (CSWS) secondary to traumatic brain injury (TBI). CASE SUMMARY: A 2-month-old intact male Chihuahua-American Pitbull Terrier mix weighing 1.94 kg presented to a veterinary teaching emergency room after suffering bite wound-penetrating trauma to the head. Treatment was initiated with hyperosmotic agents, fluid resuscitation, and analgesia. The dog's neurologic dysfunction warranted hospitalization and continuous monitoring. Within 24 hours, the dog developed hyponatremia (133 mmol/L compared to 143 mmol/L on presentation [reference interval 142-149 mmol/L]). As the dog had concurrent tachycardia, increase in urine sodium concentration, polyuria, and weight loss, a diagnosis of cerebral salt wasting was suspected. A 2% hypertonic saline constant rate infusion was administered for volume replacement, and the patient showed improvement in clinical signs and blood sodium concentration. The dog was discharged on Day 5. Recheck examination showed significant neurologic improvement with sodium just below the low end of the reference range (141 mmol/L [reference interval 142-149 mmol/L]). NEW OR UNIQUE INFORMATION PROVIDED: This is the first description of suspected CSWS in veterinary medicine. Hyponatremia is a common finding in critically ill neurologic people, including those with TBI, and is typically associated with either syndrome of inappropriate antidiuretic hormone or CSWS. As treatment recommendations for syndrome of inappropriate antidiuretic hormone and CSWS are diametrically opposed, identifying the presence of hyponatremia and distinguishing between these 2 clinical entities is critical for improving patient care for those with TBI. This case highlights the characteristics and clinical progression regarding the diagnosis and management of suspected CSWS.

Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement.

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.

Successful treatment of a severe 5-hydroxytrytophan intoxication using carbon hemoperfusion, hemodiafiltration, and mechanical ventilation in a dog.

OBJECTIVE: To describe the successful use of carbon hemoperfusion and hemodiafiltration in combination with mechanical ventilation (MV) to treat a severe intoxication of 5-hydroxytryptophan (5-HTP) in a dog. CASE SUMMARY: A dog ingested a minimum of 550 mg/kg of extended-release 5-HTP, resulting in serotonin syndrome that progressed to a comatose state and severe hypoventilation requiring MV. Extracorporeal carbon hemoperfusion coupled with hemodiafiltration was performed to remove 5-HTP from this patient. A carbon hemoperfusion cartridge was placed in series upstream in the extracorporeal circuit from the hemodialyzer. A total of 46.5 L of blood (4.89 L/kg) was processed during a 4.85-hour treatment. Serial plasma samples were obtained at 0, 60, 90, and 150 minutes during the session and 14 hours after the session. These samples were later analyzed for 5-HTP and serotonin concentrations. The extraction ratio of 5-HTP was 93.6%-98.9% through the carbon filter. The dog was weaned from MV within 8 hours after extracorporeal therapy and, after a full recovery, was successfully discharged. NEW OR UNIQUE INFORMATION PROVIDED: Despite an extensive review of the available literature, this appears to be the first reported case of using a carbon hemoperfusion, hemodiafiltration, and MV to treat severe serotonin syndrome secondary to 5-HTP intoxication in a dog. The combination of carbon hemoperfusion and hemodiafiltration can significantly reduce plasma 5-HTP concentrations after acute intoxication and may serve to decrease morbidity and mortality in patients with severe intoxication.

Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment.

While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n â€‹= â€‹1) or G239S variant (n â€‹= â€‹2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell patch-clamp electrophysiological experiments in Chinese Hamster Ovary cells transiently-transfected with the cDNAs encoding Kv7.2 subunits carrying the Y141N or G239S variants in homomeric or heteromeric configurations with Kv7.2 subunits, revealed that currents from channels incorporating mutant subunits displayed increased current densities and hyperpolarizing shifts of about 10 â€‹mV in activation gating; both these functional features are consistent with an in vitro GoF phenotype. The antidepressant drug amitriptyline induced a reversible and concentration-dependent inhibition of current carried by Kv7.2 Y141N and G239S mutant channels. Based on in vitro results, amitriptyline was prescribed in one patient (G239S), prompting a significant improvement in motor, verbal, social, sensory and adaptive behavior skillsduring the two-year-treatment period. Thus, our results suggest that KCNQ2 GoF variants Y141N and G239S cause a mild DD with prominent language deficits in the absence of neonatal seizures and that treatment with the Kv7 channel blocker amitriptyline might represent a potential targeted treatment for patients with KCNQ2 GoF variants.

Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy.

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

Infrared thermography is a novel tool to assess small intestinal surface temperature in dogs undergoing laparotomy for foreign body obstruction.

OBJECTIVE: To evaluate local temperature differences directly over and adjacent to small intestinal foreign body obstruction (FBO) using infrared thermography (IRT) in dogs. ANIMALS: 49 client-owned dogs were initially enrolled. METHODS: In a prospective, clinical observational study, IRT was utilized to compare median small intestinal (SI) surface temperature differences at the site of FBO and segments oral and aboral before and after surgical resolution from April 24, 2019, to July 19, 2020. These differences were evaluated for correlation with canine acute patient physiologic and laboratory evaluation fast (APPLEfast) scoring, lactate, foreign body material (hard vs soft), and blood pressure. RESULTS: There was not a significant surface temperature difference between SI segments at the site of FBO, oral or aboral. After resolution of obstruction, there was a significant decrease in median temperature directly over the FBO (2.4 °C; IQR, -2.55 to 10.6 °C; P = .0043). A decrease in surface temperature of the oral SI segment was appreciated with FBO due to hard material (-1.7 °C; IQR, -5.2 to 3.4 °C), whereas soft material had an increase in SI surface temperature oral to the FBO (+1.1 °C; IQR, 0.3 to 3.2 °C). This difference did not achieve significance (P = .08; Z = 1.75). No correlation was found between APPLEfast, lactate, or blood pressure and SI segment temperatures. CLINICAL RELEVANCE: IRT may be useful diagnostic modality to identify changes in small intestinal surface temperature relating to FBO. Further evaluation is warranted to determine if IRT may be a clinically useful to evaluate intestinal perfusion.

Possible development and resolution of dilated cardiomyopathy phenotype secondary to atypical hypoadrenocorticism in a dog.

OBJECTIVE: To report the possible occurrence of dilated cardiomyopathy phenotype associated with atypical hypoadrenocorticism and subsequent marked improvement with treatment in a mixed breed dog. CASE SUMMARY: A 4.5-year-old, neutered male mixed breed dog was evaluated for a history and clinicopathological changes consistent with atypical hypoadrenocorticism. The dog was being fed a grain-free diet. While hospitalized for supportive care and diagnostics, the patient developed and was diagnosed with biventricular congestive heart failure secondary to dilated cardiomyopathy phenotype and IV fluid administration. The left-sided congestive heart failure resolved with discontinuation of IV fluid therapy and short-term administration of diuretics. After treatment of atypical hypoadrenocorticism with glucocorticoid supplementation, and while continuing to be fed varying grain-free diets, the patient's dilated cardiomyopathy phenotype largely resolved. The patient fully recovered and did not require any long-term cardiac medications. NEW OR UNIQUE INFORMATION PROVIDED: Development of dilated cardiomyopathy phenotype has not been described in dogs as a sequela of untreated hypoadrenocorticism but has been reported in human literature. Given the fact that standard management of hypoadrenocorticism typically involves aggressive fluid resuscitation, awareness of this potential sequela is important for patients that fail to respond or develop signs consistent with volume overload.

Thromboelastographic results and hypercoagulability in dogs with surgically treated hepatocellular adenoma and carcinoma: A Veterinary Society of Surgical Oncology prospective study.

BACKGROUND: The most common haemostatic abnormality in dogs with cancer is hypercoagulability. A transient hypercoagulability has been documented in people with hepatocellular carcinoma (HCC) that resolves within weeks following hepatic tumour resection. OBJECTIVE: The objective was to compare the haemostatic status of dogs with liver tumours and healthy control dogs, by comparing coagulation and thromboelastography (TEG) measurements at three time points. METHODS: Liver tumour and healthy control dogs receiving surgery for liver lobectomy and ovariohysterectomy, respectively, were prospectively enrolled. All dogs had blood collected at three time points: pre-operative, 24 h post-operative and ~2 weeks post-operative. Haematological and haemostatic values were compared across time points in each group using repeated measures ANOVA tests. RESULTS: Ten and eight dogs were enrolled for the liver and control groups, respectively. Platelet count was significantly higher in the liver group than the control group at all time points, but within the normal range (pre-operative: 438.7 vs. 300.9 × 109 /L, p = .0078; 24 h post-operative: 416.2 vs. 283.9 × 109 /L, p = .0123; 10-14 days post-operative: 524.6 vs. 317.3 × 109 /L, p = .0072). The measure of the overall coagulant state (G-value) was significantly increased for the liver group compared to the control group at all time points (pre-operative: 15.6 vs. 8.6 d/sc, p = .0003; 24 h post-operative: 18.3 vs. 11.2 d/sc, p = .039; 10-14 days post-operative: 15.1 vs. 9.6 d/sc, p = .015). CONCLUSION: The liver group was hypercoagulable based on elevated G-values at all time points compared to the control group. This hypercoagulability was attributed to the effect of hepatic tumours alone, and not secondary to surgery and anaesthesia.

Assessment and comparison of microcirculation and macrocirculation in horses undergoing emergency exploratory celiotomy versus elective surgical procedures.

OBJECTIVE: To assess oral buccal microcirculation by hand-held videomicroscopy in horses during colic surgery, comparing microcirculation values with macrocirculatory parameters and with those of healthy elective surgical horses. STUDY DESIGN: Clinical prospective study. ANIMALS: Client-owned horses (nine in the colic group; 11 in the elective group). METHODS: In the colic group, buccal mucosal side stream dark-field microscopy (DFM) videos, cardiac output (CO), mean arterial pressure (MAP), and lactate were obtained at three timepoints under general anesthesia (30, 90, and 150 min after induction). Video analysis was used to determine total vessel density, proportion of perfused vessels, perfused vessel density, and heterogeneity index. Dark-field microscopy videos, MAP, and lactate were obtained at a single timepoint under general anesthesia (45 min after induction) in the elective group. RESULTS: There were no differences in microcirculatory parameters between colic and elective horses, nor was there a difference across timepoints in the colic group. There was a weak negative correlation between microvascular parameters and CO (rho = -0.23). CONCLUSION: The colic group did not have decreased microcirculation in comparison with the healthy elective group. Dark-field microscopy did not correlate well with macrocirculatory parameters in the colic group. IMPACT: Dark-field microscopy may not be a sensitive enough indicator to detect differences in microcirculation between colic and elective groups. The lack of difference in microcirculation may be due to sample size, probe location, or variation in disease severity.

KCNA1 gain-of-function epileptic encephalopathy treated with 4-aminopyridine.

Precision medicine for Mendelian epilepsy is rapidly developing. We describe an early infant with severely pharmacoresistant multifocal epilepsy. Exome sequencing revealed the de novo variant p.(Leu296Phe) in the gene KCNA1, encoding the voltage-gated K+ channel subunit KV 1.1. So far, loss-of-function variants in KCNA1 have been associated with episodic ataxia type 1 or epilepsy. Functional studies of the mutated subunit in oocytes revealed a gain-of-function caused by a hyperpolarizing shift of voltage dependence. Leu296Phe channels are sensitive to block by 4-aminopyridine. Clinical use of 4-aminopyridine was associated with reduced seizure burden, enabled simplification of co-medication and prevented rehospitalization.

Association between the COVID-19 global pandemic and the prevalence of cats presenting with urethral obstruction at two university veterinary emergency rooms.

OBJECTIVES: The aim of this study was to investigate a potential association between the COVID-19 pandemic stay-at-home orders and the prevalence of emergency room presentations for urethral obstruction (UO) in feline patients. METHODS: Medical records and hospital census were retrospectively searched to identify the total number of cats and total number of male cats with UO presenting to two academic veterinary medical centers from 22 March to 10 August in the years 2018 (123), 2019 (137) and 2020 (175). Cats were grouped based on the year of presentation and the proportions of UO cases relative to all cats presenting to the emergency rooms during the same time frame. Absolute (year of interest - reference year) and relative ([year of interest - reference year]/[reference year]) change in prevalence was determined. These were compared for each year using a two-sample z-test. RESULTS: The absolute and relative prevalence of UO presentations across the combined population increased significantly during the COVID-19 pandemic in comparison with 2018 (2.2% and 59%, respectively; P = 0.0003) and 2019 (1.9% and 48%, respectively; P = 0.0021). For the individual institutions, a significant increase in UO presentations was found for institution A when comparing 2020 with both 2018 (P = 0.0072) and 2019 (P = 0.0073), but not for institution B (P = 0.057 and P = 0.18, respectively). No significant differences were found when 2018 and 2019 were compared across the combined population or within institutions. CONCLUSIONS AND RELEVANCE: The results of this study demonstrate an increased prevalence of UO during the initial months of the COVID-19 pandemic, which may be related to environmental change and stress imposed by stay-at-home orders.

Preliminary study evaluating the assessment of changes in pulmonary function associated with body positioning in dogs with suspected aspiration pneumonia.

OBJECTIVE: To evaluate the variability in arterial blood gas (ABG) assessment of pulmonary function with different body positioning in dogs with suspected aspiration pneumonia. KEY FINDINGS: The median differences in alveolar-arterial gradient, Pao2 , and Paco2 values in different recumbencies were not statistically significantly different, both within patients and across the study population. No difference was noted in ABG values in the subgroups with unilateral or bilateral disease or that were more affected on the right side versus the left side. SIGNIFICANCE: This preliminary study provides data that can be used to calculate appropriate sample sizes for subsequent studies investigating the impact of recumbency on pulmonary function in patients with aspiration pneumonia.

Randomized controlled trial demonstrates nutritional management is superior to metronidazole for treatment of acute colitis in dogs.

OBJECTIVE: To describe the outcome of dietary management of canine noninfectious acute colitis with or without concurrent oral administration of metronidazole using a randomized controlled clinical trial. ANIMALS: 59 client-owned dogs with noninfectious acute colitis. PROCEDURES: Dogs with acute noninfectious colitis were enrolled in a 30-day diet trial after exclusion of parasitic infectious etiologies (fecal centrifugation floatation, Giardia/Cryptosporidium antigen testing) and systemic disease (CBC, biochemistry, urinalysis). Dogs were randomized into 3 placebo-controlled groups: group 1, easily digestible diet + placebo tablet; group 2, easily digestible diet + metronidazole tablet; and group 3, psyllium-enhanced easily digestible diet + placebo tablet. Dogs were evaluated serially using fecal scoring for time to remission, average fecal score, relapse after remission, and dysbiosis index. RESULTS: Median remission time was significantly different among the 3 groups (P < .01) with median times of 5 days (range, 4 to 10) for group 1, 8.5 days (range, 7 to 12) for group 2, and 5 days (range, 3 to 6) for group 3. Metronidazole addition affected the fecal dysbiosis index negatively at days 7 to 10. No adverse effects or complications were noted throughout the study. CLINICAL RELEVANCE: For canine noninfectious acute colitis, dietary management with an easily digestible diet with or without psyllium enhancement proved a superior management strategy compared to metronidazole. The omission of metronidazole reduced the adverse impact significantly on intestinal microbiota. Longitudinal clinical trials are necessary to compare the long-term response, stability, and complications associated with dietary management alone versus combined dietary and antimicrobial therapy for canine acute colitis.

Genetic Variant in Nicotinic Receptor α4-Subunit Causes Sleep-Related Hyperkinetic Epilepsy via Increased Channel Opening.

We describe genetic and molecular-level functional alterations in the α4ß2 neuronal nicotinic acetylcholine receptor (nAChR) from a patient with sleep-related hyperkinetic epilepsy and a family history of epilepsy. Genetic sequencing revealed a heterozygous variant c.851C>G in the CHRNA4 gene encoding the α4 subunit, resulting in the missense mutation p.Ser284Trp. Patch clamp recordings from genetically engineered nAChRs incorporating the α4-Ser284Trp subunit revealed aberrant channel openings in the absence of agonist and markedly prolonged openings in its presence. Measurements of single channel current amplitude distinguished two pentameric stoichiometries of the variant nAChR containing either two or three copies of the α4-Ser284Trp subunit, each exhibiting aberrant spontaneous and prolonged agonist-elicited channel openings. The α4-Ser284 residue is highly conserved and located within the M2 transmembrane α-helix that lines the ion channel. When mapped onto the receptor's three-dimensional structure, the larger Trp substitution sterically clashes with the M2 α-helix from the neighboring subunit, promoting expansion of the pore and stabilizing the open relative to the closed conformation of the channel. Together, the clinical, genetic, functional, and structural observations demonstrate that α4-Ser284Trp enhances channel opening, predicting increased membrane excitability and a pathogenic seizure phenotype.

Cost analysis of a watch-and-wait approach in patients with a complete clinical response to chemoradiotherapy for rectal cancer.

BACKGROUND: There is increasing interest in the watch-and-wait approach for patients with rectal cancer who have had a complete clinical response following neoadjuvant long course chemoradiotherapy. This study is a cost analysis of expenditure on patients in the watch-and-wait program versus patients who underwent standard rectal resection followed by routine surveillance. METHODS: Data were prospectively collated and retrospectively analysed in all patients who presented with rectal cancer from January 2016 to January 2018 at Sir Charles Gairdner Hospital, Perth, Western Australia. Software developed by the North Metropolitan Health Service was used to capture comprehensive data to calculate the in-hospital expenditure for an individual patient throughout their treatment journey. RESULTS: For a patient enrolled in the watch-and-wait pathway, the total cost of surveillance over a 5-year period was $45 246. This was compared with the cost of an ultra-low anterior resection/loop ileostomy/closure of loop and routine postoperative surveillance which came to a total of $87 473. While a patient who had an abdominoperineal resection followed by routine 5-year surveillance had an expenditure of $82 290. CONCLUSION: There is growing evidence that the watch-and-wait strategy is a valid management option. In the cost-conscious environment of the current health care system, the watch-and-wait pathway is a cost-effective and economically advantage treatment.