Evaluation of haem dipstick pad, urine protein, urine pH and urine protein:creatinine ratio results as a marker of bacteriuria in dogs and cats with inactive urine sediment.

OBJECTIVES: Evaluation of haem dipstick pad, urine protein, urine pH and urine protein:creatinine ratio results as a marker of bacteriuria in dogs and cats with inactive urine sediment. MATERIALS AND METHODS: Cats and dogs with contemporaneous urine dipstick, microscopic sediment analysis and microbiological culture and sensitivity results over a four-year period (2016 to 2020) were retrospectively identified. Dogs and cats with active urine sediments (at least five erythrocytes and/or five leukocytes per high-power field) and/or spermaturia were excluded. Association between urine pH, haem dipstick result, protein dipstick result and urine protein:creatinine ratio with bacteriuria were evaluated using binary logistic regression analysis. Likelihood ratios for bacteriuria were calculated at different diagnostic thresholds. RESULTS: A total of 668 and 169 dog and cat urine samples were included. Of these, 166 dogs (25%) had a positive urine culture, whilst only 29 cats (17%) had a positive urine culture. In dogs and cats, any positive haem dipstick result was significantly associated with bacteriuria, although only a ≥4+ haem positive result in dogs was associated with a small increase in the likelihood of a positive urine culture, and positive likelihood ratios did not support the use of haem dipstick results as a screening test for bacteriuria in cats. pH, urine protein:creatinine ratio and protein dipstick results were not associated with bacteriuria. CLINICAL SIGNIFICANCE: Our findings provide proof of concept that haem dipstick pad results in dogs with inactive sediment and without spermaturia might be useful as a screening test for bacteriuria, although further studies are required to confirm these findings.

Urinary extracellular vesicles as a source of protein-based biomarkers in feline chronic kidney disease and hypertension.

OBJECTIVES: To validate a methodology for isolating feline urinary extracellular vesicles and characterise the urinary extracellular vesicle population and proteome in cats with normal renal function and cats with normotensive or hypertensive chronic kidney disease. METHODS: Feline urinary extracellular vesicles were isolated using three different methods (precipitation alone, precipitation followed by size exclusion chromatography and ultrafiltration followed by size exclusion chromatography, which were compared via transmission electron microscopy and nanoparticle tracking analysis. Cats with normal renal function (n=9), normotensive chronic kidney disease (n=10) and hypertensive chronic kidney disease (n=9) were identified and urinary extracellular vesicles isolated from patient urine samples via ultrafiltration followed by size exclusion chromatography. Extracellular vesicle size and concentration were determined using nanoparticle tracking analysis, and subsequently underwent proteomic analysis using liquid chromatography with tandem mass spectrometry to identify differences in protein expression between categories. RESULTS: Urinary extracellular vesicle preparations contained particles of the expected size and morphology, and those obtained by ultrafiltration + size exclusion chromatography had a significantly higher purity (highest particle: protein ratio). The urinary extracellular vesicle proteomes contained extracellular vesicle markers and proteins originating from all nephron segments. Urinary extracellular vesicle concentration and size were unaffected by renal disease or hypertension. There were no differentially expressed proteins detected when comparing urinary extracellular vesicles derived from cats in the healthy category with the combined chronic kidney disease category, but five differentially expressed proteins were identified between the normotensive chronic kidney disease and hypertensive chronic kidney disease categories. CLINICAL SIGNIFICANCE: Feline urinary extracellular vesicles can be successfully isolated from stored urine samples. Differentially expressed urinary extracellular vesicle proteins were discovered in cats with hypertensive chronic kidney disease, and warrant further investigation into their utility as biomarkers or therapeutic targets.

Prevalence of depression in amyotrophic lateral sclerosis/motor neuron disease: multi-attribute ascertainment and trajectories over 30 months.

Objective: Evidence is equivocal about the prevalence of depression in amyotrophic lateral sclerosis (ALS). This study uses a multi-attribute ascertainment of the prevalence of depression and examines this prevalence over time. Methods: Patients with ALS were recruited into the Trajectories of Outcome in Neurological Conditions (TONiC-ALS) study. Caseness was identified by the Modified-Hospital Anxiety and Depression Scale (M-HADS). In addition, participants provided data on co-morbidities and medication use. A combination of the three was used to derive the estimate for the prevalence of depression, treated or untreated. Longitudinal data were analyzed by trajectory analysis of interval level M-HADS-Depression data. Results: Among 1120 participants, the mean age was 65.0 years (SD 10.7), 60.4% male, and the median duration since diagnosis was 9 months (IQR 4-24). Caseness of probable depression at baseline, defined by M-HADS-Depression, was 6.45% (95%CI: 5.1-8.0). Taken together with antidepressant medication and co-morbidity data, the prevalence of depression was 23.1% (95%CI: 20.7-25.6). Of those with depression, 17.8% were untreated. Trajectory analysis identified three groups, one of which contained the most cases; the level of depression for each group remained almost constant over time. Conclusion: Depression affects almost a quarter of those with ALS, largely confined to a single trajectory group. Prevalence estimates based on screening for current depressive symptoms substantially under-estimate the population experiencing depression. Future prevalence studies should differentiate data based on current symptoms from those including treated patients. Both have their place in assessing depression and the response by the health care system, including medication, depending upon the hypothesis under test.

Epidemiological Survey on Gastrointestinal and Pulmonary Parasites in Cats Around Toulouse (France).

Various feline parasites are potentially zoonotic thus establishing factors associated with parasitism is of animal and public health interest. The aim of this study was to determine the prevalence of endoparasites in client-owned cats, living in the area of Toulouse, France, over the period 2015 - 2017, and to investigate possible risk factors. A total of 498 faecal samples from cats of the University Animal Hospital of Ecole Nationale Vétérinaire de Toulouse were analysed, 448 from cats presented for consultation and 50 at post-mortem. Analysis was performed using a commercial flotation enrichment method with a hypersaturated sodium chloride solution and Baermann technique. Further examination of the gastrointestinal tract contents was conducted on necropsied cats. Overall, 11.6 % of cats were positive for endoparasites; 50 (11.2 %) consultation cases and 8 (16 %) post-mortem cases, with no significant difference in prevalence between the groups. Amongst infected cats, most were infected by a single species of parasite and 10.3 % (n=6) were infected with two or more. The most common parasite was Toxocara cati with a prevalence of 9.4 % (n=47). Other endoparasites encountered were: Cystoisospora sp 1.0 % (n=5), Aelurostrongylus abstrusus 1.0 % (n=5), Strongyloides sp 0.6 % (n=3), Dipylidium caninum 0.4 % (n=2), Aonchotheca putorii 0.2 % (n=1), Ancylostomatidae 0.2 % (n=1) and Toxascaris leonina 0.2 % (n=1). The examination of the gastronintestinal tract contents of the necropsied cats revealed Mesocestoides sp 0.4 % (n=2) and Tænia (Hydatigera) tæniaeformis sensu lato 0.2 % (n=1) which are seldomly diagnosed by flotation methods. In this study, increasing age and neutered status were statistically associated with reduced odds of infection by endoparasites (helminth and coccidian). Predictors of significantly increased risk included being male, intact, and not receiving regular anthelmintic treatment. The same risk factors were highlighted specifically for Toxocara cati infections, with rural location being an additional risk factor for infection.

Histopathological frequency of canine hepatobiliary disease in the United Kingdom.

OBJECTIVES: Canine hepatobiliary disease is common; however, data determining disease frequency and breed predispositions are lacking. The primary objective was to identify the frequency of different hepatobiliary disease in a United Kingdom population of dogs and consequently determine breeds at both an increased and decreased risk of hepatobiliary disease. MATERIALS AND METHODS: Anonymised histopathology reports from a commercial veterinary diagnostic laboratory, which were submitted between August 2013 and February 2018, were analysed. Data were retrospectively categorised into hepatobiliary diseases according to World Small Animal Veterinary Association Standards and the breed, age and genders recorded. Cases with incomplete data or no definitive diagnosis were excluded. Breed predisposition was calculated using odds ratios and 95% confidence intervals against a United Kingdom-based control population of micro-chipped dogs. RESULTS: Histopathology results from 4584 cases met inclusion criteria. The most frequent histological diagnoses were reactive hepatitis (n=770); chronic hepatitis (n=735) and reversible hepatocellular injury (n=589). A number of breeds were shown to be at an increased or decreased risk of individual liver diseases. CLINICAL SIGNIFICANCE: This is the first study to document the histopathological frequency of hepatobiliary diseases in a large cohort of dogs in the United Kingdom, as well as novel possible breed and age predispositions. Despite multivariable analysis not being performed to account for confounding factors, this information hopes to inform and support future investigations for hepatic disease in particular breeds and potential predispositions.

Clinical findings and outcome following medical treatment in dogs with idiopathic renal haematuria: 41 cases (2001-2018).

OBJECTIVES: To characterise and document the progression of idiopathic renal haematuria in a large cohort of medically managed UK dogs. MATERIALS AND METHODS: Retrospective study of 41 client-owned dogs with confirmed (n=14), or suspected (n=27) idiopathic renal haematuria from 4 UK-based referral centres. Clinical findings and outcomes of dogs (2001 to 2018) were determined from the review of medical records and telephone follow-up. RESULTS: Median survival time from diagnosis was long [1482 (152 to 1825) days] irrespective of treatment and clinical response. Only 1 case was euthanased due to idiopathic renal haematuria, and anaemia or azotaemia occurred infrequently. In total, 25 dogs received angiotensin-converting enzyme-inhibitor or angiotensin receptor blocker therapy, of which 23 received benazepril [0.44 (0.19 to 0.82) mg/kg/24 hours], two received enalapril (0.40 and 0.78 mg/kg/24 hours) and one received telmisartan (1 mg/kg/24 hours). In cases with follow-up urinalyses, complete resolution of haematuria was documented in eight of 19 (42%) dogs following angiotensin-converting enzyme-inhibitor/angiotensin receptor blocker treatment, with partial improvement in five of 19 (26%) and no improvement in six of 19 (31%). Conversely, of the two untreated dogs where outcome was available, one had partial improvement and the other had no improvement. CLINICAL SIGNIFICANCE: In this study, idiopathic renal haematuria was associated with a good prognosis and low complication rate. Resolution or improvement in haematuria occurred in both angiotensin-converting enzyme-inhibitor/angiotensin receptor blocker-treated and untreated dogs, indicating that further studies are required to evaluate the effectiveness and safety of these interventions.

Measuring coping in people with amyotrophic lateral sclerosis using the Coping Index-ALS: A patient derived, Rasch compliant scale.

OBJECTIVE: The progressively disabling and terminal nature of ALS/MND imposes major coping demands on patients. We wished to improve the psychometric properties of our previously published MND-Coping Scale, so that parametric analyses were valid, and to make it simpler for patients to complete and clinicians to score. METHODS: After a new qualitative analysis of 26 patients with ALS/MND, the draft Coping Index-ALS (CI-ALS) was administered to 465 additional patients, alongside COPE-60, General Perceived Self Efficacy scale, and WHOQOL-BREF. Validity of the CI-ALS was assessed using the Rasch model. External validity was checked against comparator measures. RESULTS: Thirteen centres contributed 465 patients, mean age 64.9 years (SD 10.8), mean disease duration 28.4 months (SD 37.5). The CI-ALS-Self and CI-ALS-Others both satisfied Rasch model expectations and showed invariance across age, gender, marital status and type of onset. Expected correlations were observed with comparator scales. A nomogram is available to convert the raw scores to interval level measures suitable for parametric analysis. CONCLUSIONS: Coping abilities in ALS/MND can now be measured using a simple 21 item self-report measure, offering two subscales with a focus of 'coping by self ' and 'coping with others'. This allows clinicians to identify individuals with poor coping and facilitates research on interventions that may improve coping skills.

Evaluation of the Idexx ProCyte Dx® for analysis of canine cerebrospinal fluid.

OBJECTIVES: To assess the utility of the Idexx ProCyte Dx® haematology analyser for assessing total nucleated cell count and differential cell counts in canine cerebrospinal fluid. MATERIALS AND METHODS: Seventy-three client-owned dogs undergoing investigations for pyrexia and/or neurological signs were prospectively included. Cerebrospinal fluid samples were assessed using an Idexx ProCyte Dx® analyser and the results were compared to those obtained with the external laboratory reference standard. RESULTS: The Idexx ProCyte Dx® performed with good sensitivity (92.6%) and moderate specificity (67.4%) for total nucleated cell count when compared to the reference standard. Qualitative assessment of the Idexx ProCyte Dx® scatter plots, and quantitative assessment of differential cell counts where available, appeared to correlate well with the external laboratory manual differential cell counts, with a good-to-high agreement in 25 of 26 samples (96.2%). CLINICAL SIGNIFICANCE: The Idexx ProCyte Dx® analyser performed well in determining the total nucleated cell count and differential cell counts in canine cerebrospinal fluid when compared to a reference standard of external laboratory analysis, except for cell counts higher than ~1000/µL. As the Idexx ProCyte Dx® currently only provides a cell count in 10 cells/µL increments, software modification may improve agreement between the two methods. As in human medicine, automated methods may prove useful in the future for cerebrospinal fluid analysis in addition to manual assessment, particularly in an emergency setting.

Calcitonin Response to Naturally Occurring Ionized Hypercalcemia in Cats with Chronic Kidney Disease.

BACKGROUND: Hypercalcemia is commonly associated with chronic kidney disease (CKD) in cats. OBJECTIVES: To explore the calcitonin response to naturally occurring ionized hypercalcemia in cats with azotemic CKD, and to assess the relationship of plasma calcitonin with ionized calcium, alkaline phosphatase (ALP), and urinary calcium excretion. ANIMALS: Thirty-three client-owned cats with azotemic CKD and ionized hypercalcemia from first opinion practice. METHODS: Cohort study. Calcitonin was measured with an immunoradiometric assay in heparinized plasma. Simple correlations were assessed with Kendall's rank correlation, and the within-subject correlations of calcitonin with ionized calcium and other clinicopathological variables were calculated with a bivariate linear mixed effects model. RESULTS: Calcitonin concentrations above the lower limit of detection (>1.2 pg/mL; range, 1.7-87.2 pg/mL) were observed in 11 of 33 hypercalcemic cats (responders). Blood ionized calcium concentration did not differ significantly between responders (median, 1.59 [1.46, 1.66] mmol/L) and nonresponders (median, 1.48 [1.43, 1.65] mmol/L; P = 0.22). No evidence was found for calcitonin and ionized calcium to correlate between cats (τb = 0.14; P = 0.31; n = 33), but significant positive correlation was evident within individual responders over time (within-subject correlation coefficient [rwithin ], 0.83; 95% confidence interval [CI], 0.63-0.92). Calcitonin correlated negatively over time with plasma ALP (rwithin , -0.55; 95% CI, -0.79 to -0.16). CONCLUSIONS AND CLINICAL IMPORTANCE: Calcitonin does not appear to have an important role in calcium metabolism in cats with CKD.

Serum Cystatin C Concentrations in Cats with Hyperthyroidism and Chronic Kidney Disease.

BACKGROUND: Currently, no test can accurately predict the development of azotemia after treatment of hyperthyroidism. Serum cystatin C concentrations (sCysC) might be less influenced by changes in body muscle mass and so better indicate the presence of concurrent chronic kidney disease (CKD) in hyperthyroidism. HYPOTHESES: sCysC will be higher in hyperthyroid cats that develop azotemia compared with hyperthyroid cats that remain nonazotemic after treatment; sCysC will be higher in nonhyperthyroid cats with azotemic CKD than healthy older cats and, sCysC will decrease after treatment of hyperthyroidism. ANIMALS: Ninety-one cats treated in first opinion practice. METHODS: Case-control study. sCysC were compared between hyperthyroid cats which developed azotemia within 4 months of successful treatment of hyperthyroidism (pre-azotemic group) and hyperthyroid cats which remained nonazotemic after treatment (nonazotemic group), and between nonhyperthyroid cats with azotemic CKD and healthy older cats. sCysC were also compared between hyperthyroid cats before treatment and at time of establishment of euthyroidism. Data are presented as median [25th, 75th percentile]. RESULTS: Baseline sCysC were not different between the pre-azotemic and nonazotemic groups (1.9 [1.4, 2.3] mg/L versus 1.5 [1.1, 2.2] mg/L, respectively; P = .22). sCysC in nonhyperthyroid cats with azotemic CKD and healthy older cats were not significantly different (1.5 [1.0, 1.9] mg/L versus 1.2 [0.8, 1.4] mg/L, respectively; P = .16). sCysC did not change significantly after treatment of hyperthyroidism (pretreatment 1.8 [1.2, 2.3] mg/L, after treatment 1.6 [1.1, 2.4] mg/L; P = .82). CONCLUSIONS AND CLINICAL IMPORTANCE: sCysC do not appear to be a reliable marker of renal function in hyperthyroid cats.

Evaluation of urinary biomarkers for azotaemic chronic kidney disease in cats.

OBJECTIVES: Evaluation of urine albumin:creatinine ratio, urine cystatin C:creatinine ratio, urine protein:creatinine ratio and urine specific gravity as screening tests for azotaemic chronic kidney disease in cats. METHODS: A group of cats over eight years old were defined as either (i) healthy non-azotaemic (n=40) if they had serum creatinine concentration <153 µmol/L and no history of apparent disease or (2) having azotaemic chronic kidney disease (n=12) if they had serum creatinine concentration >153 µmol/L with urine specific gravity <1·035. Urine albumin:creatinine ratio, urine cystatin C:creatinine ratio, urine protein:creatinine ratio and urine specific gravity were compared between the two groups. RESULTS: Urine cystatin C:creatinine ratio was significantly lower in cats with azotaemic chronic kidney disease than that in healthy cats [3·7 (1·4, 4·3)×10(-6) versus 13·9 (6·3, 24·7)×10(-6) ; P=0·011]. Urine specific gravity was also significantly lower in the azotaemic chronic kidney disease group than that in the healthy group [1·022 (1·017, 1·028) versus 1·043 (1·034, >1·050); P<0·001]. Urine albumin:creatinine ratio and urine protein:creatinine ratio were not significantly different between the groups (P=0·075 and P=0·965, respectively). CLINICAL SIGNIFICANCE: Urine cystatin C:creatinine ratio and urine specific gravity were significantly lower in cats with azotaemic chronic kidney disease than that in healthy cats; however, neither biomarker was an adequate sole screening test for azotaemic chronic kidney disease.

Association between the findings on magnetic resonance imaging screening for syringomyelia in asymptomatic Cavalier King Charles spaniels and observation of clinical signs consistent with syringomyelia in later life.

A questionnaire-based study was used to investigate the association between the findings on magnetic resonance imaging (MRI) screening for syringomyelia (SM) in 79 asymptomatic Cavalier King Charles spaniels (CKCS) and the subsequent development of clinical signs consistent with SM in later life. Owners reported clinical signs consistent with SM in 13/79 (16%) dogs at the time of the questionnaire. A significantly greater proportion of CKCS with a syrinx visible on MRI screening showed clinical signs in later life (9/25, 36%) than dogs without a visible syrinx (4/54, 7%; odds ratio 6.9). Whether the findings of MRI screening can be used to indicate the likelihood of an asymptomatic CKCS developing clinical signs consistent with SM in later life warrants further prospective study in a larger cohort of dogs.

Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism.

BACKGROUND: Iatrogenic hypothyroidism is associated with an increased incidence of azotemia after treatment of hyperthyroidism, and decreased survival time in azotemic hyperthyroid cats. HYPOTHESIS: Restoration of euthyroidism will decrease plasma creatinine concentrations. ANIMALS: Nineteen client-owned, methimazole- or carbimazole-treated, hyperthyroid cats with documented iatrogenic hypothyroidism (based on subnormal plasma total thyroxine concentrations [TT4] and increased plasma thyroid-stimulating hormone concentrations). METHODS: Prospective interventional study. Doses of antithyroid medication were reduced until euthyroidism was restored (TT4 10-40 nmol/L). Plasma creatinine concentration and selected other clinicopathologic variables were evaluated before and after restoration of euthyroidism and compared by nonparametric statistics. Data are presented as median [25th, 75th percentile]. RESULTS: Restoration of euthyroidism was associated with a significant decrease in plasma creatinine concentrations (2.61 [1.90, 3.26] mg/dL versus 2.07 [1.42, 2.82] mg/dL; P < .001) and body weight (4.03 [3.59, 4.53] kg versus 3.89 [3.34, 4.18] kg; P = .019), and a significant increase in packed cell volume (30 [28, 39]% versus 34 [29, 39]%; P = .038), heart rate (174 [163, 201] bpm versus 190 [164, 202] bpm; P = .009), and plasma alkaline phosphatase activity (26.6 [17.0, 33.0] IU/L versus 38.0 [23.5, 46.5] IU/L; P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Restoration of euthyroidism in medically treated hyperthyroid cats with iatrogenic hypothyroidism causes a reduction in plasma creatinine concentrations, and thus might improve renal function; however, this could be influenced by concurrent changes in body weight.

Association between urinary vascular endothelial growth factor excretion and chronic kidney disease in hyperthyroid cats.

Many hyperthyroid cats develop azotaemic chronic kidney disease (aCKD) following treatment, which has led to the hypothesis that hyperthyroidism might be detrimental to renal function. Renin-angiotensin-aldosterone system (RAAS) activation occurs in hyperthyroidism, which could cause peri-tubular hypoxia, tubular damage and the development of aCKD. Urinary vascular endothelial growth factor:creatinine ratio (VEGFCR) is postulated to be a marker of tubular hypoxia. VEGFCR was correlated with plasma renin activity (PRA) and compared between hyperthyroid cats that did and did not develop aCKD following treatment (pre-azotaemic and non-azotaemic groups respectively). PRA was positively correlated with VEGFCR (rs = 0.382; P = 0.028); however, pre-azotaemic hyperthyroid cats had significantly lower VEGFCR than non-azotaemic cats at baseline (median 122.3 fg/g versus 167.0 fg/g; P < 0.001). RAAS activation in hyperthyroidism is associated with increased VEGFCR; however, increased VEGFCR was not correlated with the development of aCKD. Therefore, tubular hypoxia may not be a mechanism for renal damage in hyperthyroid cats.

Investigation of the pathophysiological mechanism for altered calcium homeostasis in hyperthyroid cats.

OBJECTIVE: To investigate possible pathophysiological mechanisms (reduced plasma calcitriol concentrations and/or presence of concurrent or masked chronic kidney disease) for hypocalcaemiain hyperthyroid cats. METHODS: Prospective cohort study. Routine plasma biochemical parameters, plasma parathyroid hormone and calcitriol concentrations, ionized calcium concentrations, and venous pH, were measured at diagnosis and following treatment of hyperthyroidism. Linear regression analysis was used to determine predictors of ionized calcium concentration. RESULTS: Hyperthyroid cats (n=45) had lower ionized calcium concentrations than healthy geriatric cats (n=52), however, ionized calcium concentrations were higher in hyperthyroid cats with concurrent or masked chronic kidney disease than non-azotaemic hyperthyroid cats. Plasma calcitriol concentrations were higher in hyperthyroid cats than control cats. Plasma total thyroxine concentration and venous pH were independent predictors of ionized calcium concentration. Plasma total thyroxine concentration was also a predictor of ionized calcium concentration after adjustment for plasma parathyroid hormone and calcitriol concentrations. CLINICAL SIGNIFICANCE: Hypocalcaemia in hyperthyroid cats is not associated with the presence of concurrent or masked chronic kidney disease or reduced plasma calcitriol concentrations. Increased thyroid hormone concentrations might influence ionized calcium concentrations through a mechanism, yet to be determined, that is independent of control by parathyroid hormone and calcitriol.

Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS. METHODS: The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31. FINDINGS: Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ(2) on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40-1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event. INTERPRETATION: We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments. FUNDING: The Motor Neurone Disease Association of Great Britain and Northern Ireland.

Renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without concurrent hypertension.

BACKGROUND: Hypertension is present in some hyperthyroid cats at diagnosis or can develop after treatment for hyperthyroidism. Activation of the renin-angiotensin-aldosterone system (RAAS) could be involved in the pathogenesis of hypertension. HYPOTHESIS: Hyperthyroid cats that develop hypertension before or after treatment for hyperthyroidism will have greater RAAS activation than normotensive cats. ANIMALS: Ninety-nine hyperthyroid cats. METHODS: Retrospective case-control study. Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in untreated hyperthyroid hypertensive cats (HT-Pre group), initially normotensive hyperthyroid cats that develop hypertension after treatment (HT-Post group), and hyperthyroid cats that are normotensive (NT group). Data are presented as median [25th, 75th percentile]. RESULTS: Baseline PRA was not significantly different among the 3 groups (HT-Pre group 1.50 [0.05, 2.37] ng/mL/h, HT-Post group 0.66 [0.17, 2.31] ng/mL/h, NT group 1.11 [0.57, 2.18] ng/mL/h; P = .44). PRA decreased significantly after treatment in the NT group (1.09 [0.53, 2.47] versus 0.22 [0.05, 0.76] ng/mL/h; P < .001) and the HT-Post group (0.71 [0.17, 2.33] versus 0.28 [0.07, 0.57] ng/mL/h; P = .006). Baseline PAC was not significantly different among the 3 groups (HT-Pre group 72.2 [40.0, 145.6] pg/mL, HT-Post group 69.7 [43.3, 142.6] pg/mL, NT group 109.0 [68.2, 184.6] pg/mL; P = .10). PAC decreased significantly after treatment in the NT group (114.4 [56.6, 204.1] versus 59.5 [32.4, 98.2] pg/mL; P < .001) but did not change significantly in the HT-Post group (61.2 [44.9, 124.0] versus 58.4 [42.0, 97.7] pg/mL; P = .59). CONCLUSIONS AND CLINICAL IMPORTANCE: RAAS activation occurs in hyperthyroid cats, but is not associated with the development of hypertension. PAC is not influenced by changes in PRA in hyperthyroid cats that develop hypertension after treatment, perhaps indicating RAAS dysfunction in these cats.

Current status of adult spinal deformity.

Purpose To review the current literature for the nonoperative and operative treatment for adult spinal deformity. Recent Findings With more than 11 million baby boomers joining the population of over 60 years of age in the United States, the incidence of lumbar deformity is greatly increasing. Recent literature suggests that a lack of evidence exists to support the effectiveness of nonoperative treatment for adult scoliosis. In regards to operative treatment, current literature reports a varying range of improved clinical outcomes, curve correction, and complication rates. The extension of fusion to S1 compared with L5 and lower thoracic levels compared with L1 remains a highly controversial topic among literature. Summary Most adult deformity patients never seek nonoperative or operative treatment. Of the few that seek treatment, many can benefit from nonoperative treatment. However, in selected patients who have failed nonoperative treatment and who are candidates for surgical intervention, the literature reflects positive outcomes related to surgical intervention as compared with nonoperative treatment despite varying associated ranges in morbidity and mortality rates. If nonoperative therapy fails in addressing a patient's complaints, then an appropriate surgical procedure that relieves neural compression, corrects excessive sagittal or coronal imbalance, and results in a solidly fused, pain-free spine is warranted.

Calcium and phosphate homeostasis in hyperthyroid cats: associations with development of azotaemia and survival time.

OBJECTIVES: To evaluate calcium and phosphate homeostasis in hyperthyroid cats and determine if plasma parathyroid hormone and fibroblast growth factor-23 are associated with the presence of -azotaemic chronic kidney disease and/or have prognostic significance. METHODS: Retrospective cohort study. Logistic regression analysis and Cox regression analysis were performed to identify if parathyroid hormone and fibroblast growth factor-23 were predictors of development of azotaemia following treatment and survival time, respectively. RESULTS: Two hundred and seven hyperthyroid cats were included. Elevated plasma parathyroid hormone concentrations, hyperphosphataemia, decreased plasma fibroblast growth factor-23 concentrations and hypocalcaemia were documented; however, all parameters returned to reference intervals following treatment of hyperthyroid cats without azotaemic chronic kidney disease. After adjustment for plasma creatinine concentration, baseline plasma parathyroid hormone and fibroblast growth factor-23 concentrations were not predictors of the development of azotaemia following treatment. Baseline plasma fibroblast growth factor-23 concentrations were associated with all-cause mortality; however, this association was not maintained after adjustment for packed cell volume. CLINICAL SIGNIFICANCE: Changes in plasma parathyroid hormone and fibroblast growth factor-23 concentrations which occur in hyperthyroid cats are not mediators of progression of chronic kidney disease; however, fibroblast growth factor-23 would appear to have some prognostic significance in hyperthyroidism.

Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism.

BACKGROUND: Iatrogenic hypothyroidism can occur after treatment of hyperthyroidism, and is correlated with a reduced glomerular filtration rate in humans and dogs. HYPOTHESIS: Cats with iatrogenic hypothyroidism after treatment for hyperthyroidism will have a greater incidence of azotemia than euthyroid cats. ANIMALS: Eighty client owned cats with hyperthyroidism. METHODS: Two retrospective studies. (1) Longitudinal study of 12 hyperthyroid cats treated with radioiodine (documented as euthyroid after treatment), to assess changes in plasma thyroid stimulating hormone (TSH) concentration over a 6-month follow-up period, (2) Cross-sectional study of 75 hyperthyroid cats (documented as euthyroid) 6 months after commencement of treatment for hyperthyroidism to identify the relationship between thyroid status and the development of azotemia. Kaplan-Meier survival analysis was performed to identify relationships between thyroid and renal status and survival. RESULTS: Plasma TSH concentrations were not suppressed in 7 of 8 cats with hypothyroidism 3 months after radioiodine treatment. The proportion of cats with azotemia was significantly (P= .028) greater in the hypothyroid (16 of 28) than the euthyroid group (14 of 47). Twenty-eight of 41 cats (68%) with plasma TT4 concentration below the laboratory reference range had an increased plasma TSH concentration. Hypothyroid cats that developed azotemia within the follow-up period had significantly (P= .018) shorter survival times (median survival time 456 days, range 231-1589 days) than those that remained nonazotemic (median survival time 905 days, range 316-1869 days). CONCLUSIONS AND CLINICAL IMPORTANCE: Iatrogenic hypothyroidism appears to contribute to the development of azotemia after treatment of hyperthyroidism, and reduced survival time in azotemic cats.