Making predictions about future rewards is an important ability for primates, and its neurophysiological mechanisms have been studied extensively. One important approach is to identify neural systems ...that process errors related to reward prediction (i.e., areas that register the occurrence of unpredicted rewards and the failure of expected rewards). In monkeys that have learned to predict appetitive rewards during reward-directed behaviors, dopamine neurons reliably signal both types of prediction error. The mechanisms in the human brain involved in processing prediction error for monetary rewards are not well understood. Furthermore, nothing is known of how such systems operate when rewards are not contingent on behavior. We used event-related fMRI to localize responses to both classes of prediction error. Subjects were able to predict a monetary reward or a nonreward on the basis of a prior visual cue. On occasional trials, cue–outcome contingencies were reversed (unpredicted rewards and failure of expected rewards). Subjects were not required to make decisions or actions. We compared each type of prediction error trial with its corresponding control trial in which the same prediction did not fail. Each type of prediction error evoked activity in a distinct frontotemporal circuit. Unexpected reward failure evoked activity in the temporal cortex and frontal pole (area 10). Unpredicted rewards evoked activity in the orbitofrontal cortex, the frontal pole, parahippocampal cortex, and cerebellum. Activity time-locked to prediction errors in frontotemporal circuits suggests that they are involved in encoding the associations between visual cues and monetary rewards in the human brain.
BACKGROUND: Role of renin‐angiotensin aldosterone system (RAAS) in feline systemic hypertension is poorly understood. OBJECTIVES: Examine plasma renin activity (PRA) and plasma aldosterone ...concentrations (PAC) in normotensive and hypertensive cats with variable renal function and in response to antihypertensive therapy. ANIMALS: One hundred and ninety‐six cats >9 years from first opinion practice. METHODS: PRA, PAC, and aldosterone‐to‐renin ratio (ARR) were evaluated in cats recruited prospectively and grouped according to systolic blood pressure (SBP) and renal function (nonazotemic normotensive Non‐Azo‐NT, nonazotemic hypertensive Non‐Azo‐HT, azotemic normotensive Azo‐NT, azotemic hypertensive Azo‐HT). Changes in PRA and PAC were evaluated with antihypertensive therapy (amlodipine besylate). RESULTS: Plasma renin activity (ng/mL/h; P = .0013), PAC (pg/mL; P < .001), and ARR (P = 0.0062) differed significantly among groups. PRA (ng/mL/h) was significantly lower in hypertensive (Non‐Azo‐HT; n = 25, median 0.22 25th percentile 0.09, 75th percentile 0.39, Azo‐HT; n = 44, 0.33 0.15, 0.48) compared with Non‐Azo‐NT cats (n = 57, 0.52 0.28, 1.02). Azo‐HT cats had significantly higher PAC (n = 22, 149.8 103.1, 228.7) than normotensive cats (Non‐Azo‐NT; n = 26, 45.4 19.6, 65.0, Azo‐NT; n = 18, 84.1 38.6, 137.8). ARR was significantly higher in Azo‐HT (n = 20, 503.8 298.8, 1511) than Azo‐NT cats (n = 16, 97.8 77.0, 496.4). Significant increase in PRA was documented with antihypertensive therapy (pretreatment n = 20 0.32 0.15–0.46, posttreatment 0.54 0.28, 1.51), but PAC did not change. CONCLUSIONS AND CLINICAL IMPORTANCE: Hypertensive cats demonstrate significantly increased PAC with decreased PRA. PRA significantly increases with antihypertensive therapy. Additional work is required to determine the role of plasma aldosterone concentration in the pathogenesis of hypertension and whether this relates to autonomous production or activation of RAAS without demonstrable increase in PRA.
Background
Numerous validated psychometric tools are available to assess impact of disease on a human's quality of life (QoL). To date, no psychometrically validated general health‐related QoL tool ...exists for cats.
Hypothesis/Objectives
To develop and validate a tool for assessment of owner‐perceived QoL in cats (CatQoL) and to use this tool to compare QoL between healthy cats and those with chronic kidney disease (CKD).
Animals/Subjects
Total of 204 owners of young healthy cats (YH, n = 99; <9 years), older healthy cats (OH, n = 35), and cats diagnosed with CKD (CKD, n = 70) completed the CatQoL.
Methods
Discussions with a focus group and 2 pilot surveys informed design of 16 QoL questions grouped into 4 domains. Each item scored according to frequency and importance, and item‐weighted‐impact‐scores were calculated. The validity of the tool was assessed using principal components analysis and Cronbach's α. The average item‐weighted‐impact‐score (AWIS) was compared among groups and domains.
Results
Sixteen‐item CatQoL showed good internal consistency reliability (Cronbach's α, 0.77) and unidimensionality with significant loadings (0.2–0.7) and communalities (>0.3). Young healthy cats had significantly higher AWIS (median IQR, 1.25 0.63, 1.88) than OH (0.56 −0.06, 1.00) and CKD cats (−0.06 −0.81, 0.88), P < .001). CKD cats had significantly lower AWIS for eating domain (YH: 2.00 1.00, 3.00; OH: 2.00 0.67, 3.00; CKD : 1.00 0.00, 2.67) when compared with the YH group and OH group, and all groups differed significantly in their management domain (YH: −0.50 −1.00, 0.00; OH: −1.00 −1.88, −0.50; CKD : −1.50 −2.50, −1.00, P < .001).
Conclusions and Clinical Importance
The CatQoL was validated for use in cats, and can be used as additional assessment parameter in clinical and research settings.
Background
In the absence of ocular target organ damage (ocular‐TOD), diagnosis of hypertension is challenging in cats. Biomarkers would provide additional support for the diagnosis of hypertension.
...Hypothesis
Vascular endothelial growth factor (VEGF), N‐terminal probrain natriuretic peptide (NT‐proBNP), cardiac troponin I (cTnI), and urine protein‐to‐creatinine ratio (UPC) are predictors of systemic hypertension, will be increased in cats with hypertension with or without ocular‐TOD, and will decrease with antihypertensive treatment.
Methods
Plasma VEGF, NT‐proBNP, and cTnI concentrations and UPC were determined in healthy geriatric cats, normotensive cats with chronic kidney disease (CKD), hypertensive cats with evidence of hypertensive retinopathy (HT‐ocular‐TOD), and hypertensive cats without hypertensive ocular‐TOD (HT‐noTOD). Comparisons among groups were performed. Multivariable binary logistic regression models were built to identify independent biomarkers of hypertension and ocular‐TOD. Receiver operator characteristic (ROC) curves were drawn to assess clinical use.
Results
Cats with HT‐ocular‐TOD had significantly higher VEGF than all other groups (P < .05) and significantly higher NT‐proBNP than healthy cats (P < .001). Healthy cats had significantly lower cTnI than all other groups (P < .05). No differences were found among groups for UPC (P = .08). Cardiac troponin I and VEGF were independent predictors of hypertension (P < .05), but none of the biomarkers were independent predictors of ocular‐TOD. N‐terminal probrain natriuretic peptide concentrations decreased with antihypertensive treatment (P < .001). The ROC curves indicated that none of the biomarkers met the criteria to function as diagnostic tests for the diagnosis of hypertension or associated ocular‐TOD.
Conclusions and Clinical Significance
Despite statistical significance and changes with ocular‐TOD, antihypertensive treatment, or both, VEGF, NT‐proBNP, and cTnI did not function as useful diagnostic tests for hypertension. Persistently increased systolic blood pressure (SBP) measurements in combination with fundoscopy remains the preferred method for diagnosis of feline hypertension.
To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib ...pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa).
Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m(2)/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m(2)).
A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m(2) (diarrhea, hypotension) occurring at an average 1-hour post-dose of >/= 75% 20S PI. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at >/= 50% 20S PI. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes.
The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.
Schizophrenia is a severe mental illness that may significantly affect maternal sensitive behaviour. Neural correlates of maternal behaviour represent a potentially valuable means of differentiating ...objectively between healthy mothers expressing variations in maternal sensitivity. As mothers with schizophrenia (MWS) show deficits in behavioural responses to infants compared to healthy mothers, we explored whether maternal brain responses to infant stimuli would be significantly reduced in MWS. We also examined whether differences in maternal behaviour between healthy and ill mothers (during play interactions with own infant) were associated with differences in brain activation to infant stimuli.
We found no evidence of differential ‘maternal brain’ responses or ‘maternal behavioural’ responses in 11 new MWS compared to 20 healthy new mums; neither were neural responses to infants linked to behavioural or cognitive aspects of the mother's relationship with her infant in MWS. These preliminary findings suggest maternal sensitivity differences between MWS and healthy mothers, suggested in previous studies, may be reversible in stable treated MWS.
•Twelve polymorphisms have now been identified in the feline calcium sensing receptor.•One polymorphism was associated with parathyroid hormone concentration at diagnosis of CKD in non-pedigree ...cats.•No associations yet identified between identified polymorphisms and ionised calcium or phosphate in non-pedigree cats.
Feline chronic kidney disease (CKD) is associated with high variability in severity of CKD-mineral and bone disorder (CKD-MBD). The calcium sensing receptor (CaSR) regulates circulating parathyroid hormone (PTH) and calcium concentrations. Single nucleotide polymorphisms (SNPs) in the CaSR are associated with severity of secondary renal hyperparathyroidism and total calcium concentrations in human patients receiving haemodialysis. The objective of this study was to explore associations between polymorphisms in the feline CaSR (fCaSR) and biochemical changes observed in CKD-MBD.
Client owned cats (≥9years) were retrospectively included. SNP discovery was performed in 20 cats with azotaemic CKD and normal or dysregulated calcium concentrations. Non-pedigree cats (n=192) (125 with azotaemic CKD and 66 healthy), Persians (n=40) and Burmese (n=25) were genotyped for all identified SNPs using KASP. Biochemical parameters from the date of CKD diagnosis or from first visit to the clinic (healthy cats) were used. Associations between genotype and ionized calcium, total calcium, phosphate, PTH and FGF-23 were performed for non-pedigree cats using logistic regression.
Sequence alignment against the fCaSR sequence revealed eight novel exonic SNPs. KASP genotyping had high accuracy (99.6%) and a low failure rate (<6%) for all SNPs. Allele frequencies varied between breeds. In non-pedigree cats, one synonymous SNP CaSR:c.1269G>A was associated with logPTH concentration (adjusted for plasma creatinine concentration), with a recessive model having the best fit (G/G vs A/A-G/A, P=0.031).
Genetic variation in the fCaSR is unlikely to explain the majority of the variability in presence and severity of CKD-MBD in cats.
This paper deals with a relatively new area of radio-frequency (RF) technology based on microelectro-mechanical systems (MEMS). RF MEMS provides a class of new devices and components which display ...superior high-frequency performance relative to conventional (usually semiconductor) devices, and which enable new system capabilities. In addition, MEMS devices are designed and fabricated by techniques similar to those of very large-scale integration, and can be manufactured by traditional batch-processing methods. In this paper, the only device addressed is the electrostatic microswitch - perhaps the paradigm RF-MEMS device. Through its superior performance characteristics, the microswitch is being developed in a number of existing circuits and systems, including radio front-ends, capacitor banks, and time-delay networks. The superior performance combined with ultra-low-power dissipation and large-scale integration should enable new system functionality as well. Two possibilities addressed here are quasi-optical beam steering and electrically reconfigurable antennas.
Background: Chronic kidney disease (CKD) is a common condition in geriatric cats. Diagnosis is based on the development of persistent azotemia with inadequate urine concentrating ability. Biomarkers ...are sought for early identification.
Hypothesis: Clinical variables, urine concentrating ability, proteinuria, and N‐acetyl‐β‐d‐glucosaminidase (NAG) index will be predictive of cats at risk of developing azotemia within 12 months.
Animals: Client‐owned nonazotemic geriatric (≥9 years) cats.
Methods: Prospective longitudinal cohort study monitoring a population of healthy nonazotemic geriatric cats every 6 months until development of azotemia, death, or the study end point (September 30, 2007). Multivariable logistic regression analysis was used to assess baseline clinical, biochemical, and urinalysis variables, urine protein to creatinine ratio (UP/C), urine albumin to creatinine (UA/C) ratio, and urinary NAG index as predictors of development of azotemia.
Results: One hundred and eighteen cats were recruited with a median age of 13 years. Ninety‐five cats (80.5%) had been followed or reached the study end point by 12 months of which 30.5% (29/95) developed azotemia. Age, systolic blood pressure, plasma creatinine concentration, urine specific gravity, UP/C, UA/C, and NAG index were significantly associated with development of azotemia in the univariable analysis (P≤ .05). However, in the multivariable analysis, only plasma creatinine concentration with either UP/C (Model 1) or UA/C (Model 2) remained significant.
Conclusions and Clinical Importance: This study demonstrates a high incidence of azotemia in a population of previously healthy geriatric cats. Proteinuria at presentation was significantly associated with development of azotemia although causal association cannot be inferred. Evaluation of NAG index offered no additional benefit.
Benzodiazepines treat anxiety, but can also produce euphoric effects, contributing to abuse. Using perfusion magnetic resonance imaging, we provide the first direct evidence in humans that alprazolam ...(
Xanax)
acutely increases perfusion in the nucleus accumbens, a key reward-processing region linked to addiction.
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