Effects of reduced crude protein diets while maintaining essential amino acid concentrations on growth performance, nitrogen output, ammonia production, and meat yield.

An experiment was conducted to determine the effect of feeding reduced crude protein (CP) diets to Ross × Ross 708 male broilers while providing adequate essential amino acid (AA) concentrations on growth performance, nitrogen (N) and ammonia output, and carcass characteristics from d 1 to 33 post hatch. Birds received 1 of 6 dietary treatments (10 replicate pens per treatment) varying in CP content. Diet 1 (control) was formulated with DL-Met, L-Lys, and L-Thr (23.2, 20.7, and 19.1% CP) in the starter (1-14 d of age), grower (15-25 d of age), and finisher (26-33 d of age) periods, respectively. Dietary L-Val, Gly (only in starter period), L-Ile, L-Arg, and L-Trp were sequentially supplemented in the order of limitation in Diets 2 through 6. Dietary CP was reduced gradually across the dietary treatments resulting in a CP reduction in Diets 1 to 6 by 3.4, 3.4, and 2.3% points in the starter, grower, and finisher periods, respectively. At d 14, 25, and 33 posthatch, feed conversion decreased (P < 0.05) with L-Val addition (Diet 2) and increased (P < 0.01) with L-Val to L-Trp addition (Diet 6) to the control. Dietary treatments did not alter weights and yields of carcass, breast, drum, or thighs. Dietary CP reduction with added L-Val (Diet 2), L-Val to L-Arg (Diet 5), or L-Val to L-Trp (Diet 6) increased abdominal fat (P < 0.01) compared with control. Nitrogen excretion (g/bird; P = 0.003) and equilibrium ammonia concentration (mg/kg; P = 0.041) at day 33 reduced by 16% and 48% respectively in birds fed reduced-CP diets with L-Val to L-Trp (Diet 6) compared with control-fed birds. This study indicated that sequential addition of supplemental AA in the order of limitation from DL-Met to L-Arg allowed reduction of dietary CP beyond 2%-point without depressing growth performance and meat yield of broilers from day 1 to 33 while reducing nitrogen excretion and ammonia emissions.

A phase 2, open-label study of single-dose dupilumab in children aged 6 months to <6 years with severe uncontrolled atopic dermatitis: pharmacokinetics, safety and efficacy.

BACKGROUND: Dupilumab has demonstrated efficacy and acceptable safety in adults and children (aged 6-17 years) with moderate-to-severe atopic dermatitis (AD), but effective systemic therapy with a favorable risk-benefit profile in younger children remains a significant unmet need. OBJECTIVES: To determine the pharmacokinetics, safety and efficacy of single-dose dupilumab in children with severe AD aged ≥6 months to <6 years. METHODS: This open-label, multicenter, phase 2, sequential, two-age cohort, two-dose level study (LIBERTY AD PRE-SCHOOL; NCT03346434) included an initial cohort of older children aged ≥2 to <6 years, followed by a younger cohort aged ≥6 months to <2 years. Pharmacokinetic sampling, safety monitoring and efficacy assessments were performed during the 4-week period after a single subcutaneous injection of dupilumab, in two sequential dosing groups (3 mg/kg, then 6 mg/kg). The use of standardized, low-to-medium potency topical corticosteroids was allowed. RESULTS: Forty patients were enrolled (20/age cohort, 10/dose level within a cohort) between December 20, 2017 and July 22, 2019. Within each age cohort, pharmacokinetic exposures after a single injection of dupilumab increased in a greater than dose-proportional manner. At week 3, treatment with 3 and 6 mg/kg dupilumab reduced scores of mean Eczema Area and Severity Index by -44.6% and -49.7% (older cohort) and -42.7% and -38.8% (younger cohort), and mean Peak Pruritus NRS scores by -22.9% and -44.7% (older cohort) and -11.1% and -18.2% (younger cohort), respectively. At week 4, improvements in most efficacy outcomes diminished in both age groups, particularly with the lower dose. The safety profile was comparable to that seen in adults, adolescents and children. CONCLUSIONS: Single-dose dupilumab was generally well tolerated and substantially reduced clinical signs/symptoms of AD. Slightly better responses were seen in older than younger children. The pharmacokinetics of dupilumab were non-linear, consistent with previous studies in adults and adolescents.

Dupilumab in adolescents with uncontrolled moderate-to-severe atopic dermatitis: results from a phase IIa open-label trial and subsequent phase III open-label extension.

BACKGROUND: Dupilumab (monoclonal antibody inhibiting IL-4/IL-13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate-to-severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16-week, randomised, placebo-controlled phase III trial in adolescents (NCT03054428). OBJECTIVES: To characterize the pharmacokinetics of dupilumab, and long-term safety and efficacy in adolescents. METHODS: This was a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study with a phase III open-label extension (OLE) in adolescents with moderate-to-severe AD. In the phase IIa study, patients received one dupilumab dose (2 mg kg-1 or 4 mg kg-1 ) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8-week safety follow-up. Patients then enrolled in the OLE, continuing 2 mg kg-1 or 4 mg kg-1 dupilumab weekly. Primary end points were dupilumab concentration-time profile and incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI). RESULTS: Forty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target-mediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L-1 and 161 ± 60 mg L-1 for 2 mg kg-1 and 4 mg kg-1 , respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg-1 ], 47% [4 mg kg-1 ]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction -34% ± 20% (2 mg kg-1 ) and -51% ± 29% (4 mg kg-1 )]. With continuing treatment, EASI scores improved further [week 52: -85% ± 12% (2 mg kg-1 ) and -84% ± 20% (4 mg kg-1 )]. CONCLUSIONS: In adolescents with moderate-to-severe AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52-week safety and efficacy data support long-term use of dupilumab in this patient population. What's already known about this topic? Adolescents with moderate-to-severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options. Dupilumab (monoclonal antibody against interleukin-4 receptor α) is approved for the treatment of adolescents with moderate-to-severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union). A 16-week, randomized, placebo-controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile. What does this study add? These studies demonstrate the long-term safety and efficacy of dupilumab in adolescents with moderate-to-severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16-week dupilumab phase III trial. The data from these studies also support the use of dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16-week phase III monotherapy trial.

Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Physiological responses of feedlot heifers provided access to different levels of shade.

Heat stress has a significant impact on all livestock and poultry species causing economic losses and animal well-being concerns. Providing shade is one heat-abatement strategy that has been studied for years. Material selected to provide shade for animals greatly influences the overall stress reduction provided by shade. A study was conducted to quantify both the environment and animal response, when cattle had no shade access during summertime exposure or were given access to shade provided by three different materials. A total of 32 Black Angus heifers were assigned to one of the four treatment pens according to weight (eight animals per pen). Each pen was assigned a shade treatment: No Shade, Snow Fence, 60% Aluminet Shade Cloth and 100% Shade Cloth. In the shaded treatment pens, the shade structure covered ~40% of the pen (7.5 m2/animal). Animals were moved to a different treatment every 2 weeks in a 4×4 Latin square design to ensure each treatment was applied to each group of animals. Both environmental parameters and physiological responses were measured during the experiment. Environmental parameters included dry-bulb temperature, relative humidity, wind speed, black globe temperature (BGT), solar radiation (SR) and feedlot surface temperature. Animal response measurements included manual respiration rate (RRm), electronic respiration rate (RRe), vaginal temperature (body temperature (BT)), complete blood count (CBC) and plasma cortisol. The environmental data demonstrated changes proportional to the quality of shade offered. However, the animal responses did not follow this same trend. Some of the data suggest that any amount of shade was beneficial to the animals. However, Snow Fence may not offer adequate protection to reduce BT. For some of the parameters (BT, CBC and cortisol), 60% Aluminet and 100% Shade Cloth offers similar protection. The 60% Aluminet lowered RRe the most during extreme conditions. When considering all parameters, environmental and physiological, 60% Aluminet Shade Cloth offered reductions of BGT, SR, feedlot surface temperature and the best (or equal to the best) overall protection for the animals (RRe, RRm, BT, blood parameters).

Exploratory Population PK Analysis of Dupilumab, a Fully Human Monoclonal Antibody Against IL-4Rα, in Atopic Dermatitis Patients and Normal Volunteers.

An exploratory population pharmacokinetic model for functional dupilumab was developed. Data from healthy volunteers and patients with atopic dermatitis (AD) receiving intravenous or subcutaneous doses were integrated. The data included 197 participants (2,518 measurements of dupilumab in serum) from six phase I and II studies. The data were analyzed using stochastic approximation expectation-maximization and importance sampling methods. The best structural model was a two-compartment model with parallel linear and Michaelis-Menten elimination from the central compartment. Estimated parameters were: central volume 2.74 L, elimination rate 0.0459 d-1 , central-to-peripheral rate 0.0652 d-1 , peripheral-to-central rate 0.129 d-1 , bioavailability 60.7%, maximal target-mediated elimination rate 0.968 mg/L/d, and Michaelis-Menten constant 0.01 mg/L. Body weight was a significant covariate of the central volume. No gender effect was observed when controlling for weight. No differences between healthy volunteers and patients with AD were found. The model adequately described dupilumab pharmacokinetics for intravenous and subcutaneous routes of administration.

Challenges and Opportunities for Quantitative Clinical Pharmacology in Cancer Immunotherapy: Something Old, Something New, Something Borrowed, and Something Blue.

Cancer immunotherapy (CIT) initiates or enhances the host immune response against cancer. Following decades of development, patients with previously few therapeutic options may now benefit from CIT. Although the quantitative clinical pharmacology (qCP) of previous classes of anticancer drugs has matured during this time, application to CIT may not be straightforward since CIT acts via the immune system. Here we discuss where qCP approaches might best borrow or start anew for CIT.

A Mechanistic Systems Pharmacology Model for Prediction of LDL Cholesterol Lowering by PCSK9 Antagonism in Human Dyslipidemic Populations.

PCSK9 is a promising target for the treatment of hyperlipidemia and cardiovascular disease. A Quantitative Systems Pharmacology model of the mechanisms of action of statin and anti-PCSK9 therapies was developed to predict low density lipoprotein (LDL) changes in response to anti-PCSK9 mAb for different treatment protocols and patient subpopulations. Mechanistic interactions and cross-regulation of LDL, LDL receptor, and PCSK9 were modeled, and numerous virtual subjects were developed and validated against clinical data. Simulations predict a slightly greater maximum percent reduction in LDL cholesterol (LDLc) when anti-PCSK9 is administered on statin background therapy compared to as a monotherapy. The difference results primarily from higher PCSK9 levels in patients on statin background. However, higher PCSK9 levels are also predicted to increase clearance of anti-PCSK9, resulting in a faster rebound of LDLc. Simulations of subjects with impaired LDL receptor (LDLR) function predict compromised anti-PCSK9 responses in patients such as homozygous familial hypercholesterolemics, whose functional LDLR is below 10% of normal.

Live production and carcass characteristics of broilers fed a blend of poultry fat and corn oil derived from distillers dried grains with solubles.

Corn distillers dried grains with solubles (DDGS) are now being further processed to remove corn oil, which may be used as a dietary energy source for poultry. The objectives of this study were to compare the effects of a poultry fat (PF) and a new DDGS-derived corn oil blend (CO) on live performance and carcass characteristics of 49-d-old broilers. Four corn-soybean meal based diets were formulated with differing blends of PF and CO. All diets contained the same percentage of total fat, but differed in the fat source. One diet had the sole source of fat as PF (100:0% PF:CO) and was then replaced with 25% CO, 75% CO, and a 100% replacement of CO. Each of the diets was fed in a 3-phase feeding program to 6 replicate pens. At day of hatch, Ross × Ross 708 broilers were randomly allocated to 24 pens composed of 42 birds of equal sex. On d 49, 10 birds from each pen were processed, and carcass, abdominal fat pad, and breast muscle components were determined. There were no significant differences in live performance for the starter phase (0-18 d). For the grower phase (19-35 d), birds fed 75:25% PF:CO significantly (P ≤ 0.05) increased BW, BW gain, and decreased feed conversion compared with the control (100:0% PF:CO). Birds fed 0:100% PF:CO also observed similar improvements in BW, BW gain, and feed conversion during the grower phase. There were no significant differences for the finisher phase (36-48 d). On d 49, live weights for birds fed the 0:100% PF:CO diets were significantly lower compared with other treatments. A trend for lower carcass and breast weights and increased abdominal fat was also observed for birds fed the 0:100% PF:CO. The addition of CO led to significant improvements in pellet durability for grower and finisher pellets. The results of this study indicate that DDGS-derived CO can be used to partially replace PF in broiler diets without any detrimental effects.

The use of beat-to-beat electrocardiogram analysis to distinguish QT/QTc interval changes caused by moxifloxacin from those caused by vardenafil.

QT correction factors (QTc) can cause errors in the interpretation of drug effects on cardiac repolarization because they do not adequately differentiate changes when heart rate or autonomic state deviates from the baseline QT/RR interval relationship. The purpose of our study was to determine whether the new method of QT interval dynamic beat-to-beat (QTbtb) analysis could better discriminate between impaired repolarization caused by moxifloxacin and normal autonomic changes induced by subtle reflex tachycardia after vardenafil. Moxifloxacin produced maximum mean increases of 13-14 ms in QTbtb, QTcF, and QTcI after 4 h. After vardenafil administration, a 10-ms effect could be excluded at all time points with QTbtb but not with QTcF or QTcI. Subset analysis of the vardenafil upper pharmacokinetic quartile showed that the upper bound of QTcF and QTcI was >10 ms, whereas that of QTbtb was <8 ms. This study demonstrated that newer methods of electrocardiogram (ECG) analysis can differentiate changes in the QT interval to improve identification of proarrhythmia risk.

Application of 3D scanned imaging methodology for volume, surface area, and envelope density evaluation of densified biomass.

Measurement of volume, surface area, and density is an essential for quantifying, evaluating, and designing the biomass densification, storage, and transport operations. Acquiring accurate and repeated measurements of these parameters for hygroscopic densified biomass are not straightforward and only a few methods are available. A 3D laser scanner was used as a measurement device and the 3D images were analyzed using image processing software. The validity of the method was verified using reference objects of known geometry and the accuracy obtained was in excess of 98%. Cotton gin trash briquettes, switchgrass pellets, switchgrass cubes, hardwood pellets, and softwood chips were tested. Most accurate results of the volume and surface area required the highest possible resolution of the scanner, which increased the total scan-process times, and image file size. Physical property determination using the 3D scanning and image analysis is highly repeatable (coefficient of variation <0.3%), non-invasive, accurate, and alternative methodology. The various limitations and merits of the developed method were also enumerated.

Eye surface area and dosage rates for spray vaccination.

Spray application of Mycoplasma gallisepticum (MG) vaccines is a labor- and time-saving means of mass vaccination of layer chickens. Recent assessment of spray characteristics of nozzles commonly used to apply MG vaccine in layer chicken operations has shown that the amount of respirable droplets (< 5 microm) is negligible. Topical application of vaccine onto the eye surface has been suggested as a route of vaccination, but no estimates of vaccine load delivered via spray application were found in the literature. Estimates of eye surface area were developed using digital imaging; 24 layer pullets were used for analysis, and the mean eye surface area, corrected for corneal curvature, was found to be 0.609 cm2. This surface area was then used to estimate vaccine load for commercially available live MG vaccine sprayed through popular nozzles. Less than 3000 colony-forming units can be expected for direct deposition onto the surface of an eye.

A bio-inspired apposition compound eye machine vision sensor system.

The Wyoming Information, Signal Processing, and Robotics Laboratory is developing a wide variety of bio-inspired vision sensors. We are interested in exploring the vision system of various insects and adapting some of their features toward the development of specialized vision sensors. We do not attempt to supplant traditional digital imaging techniques but rather develop sensor systems tailor made for the application at hand. We envision that many applications may require a hybrid approach using conventional digital imaging techniques enhanced with bio-inspired analogue sensors. In this specific project, we investigated the apposition compound eye and its characteristics commonly found in diurnal insects and certain species of arthropods. We developed and characterized an array of apposition compound eye-type sensors and tested them on an autonomous robotic vehicle. The robot exhibits the ability to follow a pre-defined target and avoid specified obstacles using a simple control algorithm.

A longitudinal study of drivers with Alzheimer disease.

OBJECTIVE: The goal of this study was to define the natural progression of driving impairment in persons who initially have very mild to mild dementia. METHODS: We studied 128 older drivers, including 84 with early Alzheimer disease (AD) and 44 age-matched control subjects without cognitive impairment. Subjects underwent repeated assessments of their cognitive, neurologic, visual, and physical function over 3 years. Self-reports of driving accidents and traffic violations were supplemented by reports from family informants and state records. Within 2 weeks of the office evaluation, subjects were examined by a professional driving instructor on a standardized road test. RESULTS: At baseline, subjects with AD had experienced more accidents and performed more poorly on the road test, compared to controls. Over time, both groups declined in driving performance on the road test, with subjects with AD declining more than controls. Survival analysis indicated that while the majority of subjects with AD passed the examination at baseline, greater severity of dementia, increased age, and lower education were associated with higher rates of failure and marginal performance. CONCLUSIONS: This study confirms previous reports of potentially hazardous driving in persons with early Alzheimer disease, but also indicates that some individuals with very mild dementia can continue to drive safely for extended periods of time. Regular follow-up assessments, however, are warranted in those individuals.

Neuropsychiatric aspects of hypothyroidism and treatment reversibility. .

Thyroid hormone has important actions in the adult brain, and it is well accepted that hypothyroidism is associated with neuropsychiatric complaints and symptoms. Neuropsychiatric symptoms refer to a spectrum of emotional and cognitive problems that are directly related to changes in the brain secondary to multiple factors, including the direct effects of thyroid disease, as well as hormone deprivation in brain tissue. Hypothyroidism impacts aspects of cognitive functioning and mood. More severe hypothyroidism can mimic melancholic de-pression and dementia. Neuropsychiatric symptoms tend to improve with treatment and normalization to a euthyroid state, though the pattern is inconsistent and complete recovery is uncertain. The degree to which mild hypothyroidism, or subclinical hypothyroidism (SCH), impacts mood and cognitive functions and whether these symptoms respond to treatment, remains controversial. Most studies support a relationship between thyroid state and cognition, particularly slowed information processing speed, reduced efficiency in executive functions, and poor learning. Furthermore, hypo-thyroidism is associated with an increased susceptibility to depression and reductions in health-related quality of life. Controlled studies suggest that cognitive and mood symptoms improve with treatment, though the data are equivocal and limited by diverse methodologies. Functional neuroimaging data provide support for the mood and cognitive findings and treatment reversibility for both overt and SCH. These findings are not, however, without controversy. Recent investigations into the impact of SCH on cognition and mood, coupled epidemiological studies investigating the normal spectrum of thyroid stimulating hormone, have fueled significant debate regarding the appropriate, healthy range for TSH levels. This has led to concern over whether patients with overt hypothyroidism may be undertreated and whether SCH patients are truly out of the range of normal thyroid functioning and should be treated. The following is a review of the extant literature on the impact of hypothyroidism on cognition and mood, reversibility of symptoms, and treatment approaches. The spectrum of thyroid disease is reviewed, but mild, or subclinical, hypothyroidism is emphasized. The potential role of autoimmunity in neuropsychiatric symptoms and treatment resistance is addressed. Limitations of the current literature and future directions are discussed.

Orosensory stimulation is sufficient and postingestive negative feedback is not necessary for neuropeptide Y to increase sucrose intake.

Although central administration of neuropeptide Y (NPY) has a potent orexic effect, it is not clear how NPY changes the potency of peripheral feedbacks from the gut to prolong eating and increase meal size. It has been suggested that NPY increases the stimulating effect of orosensory sweet stimuli or that it decreases the inhibitory effect of postingestive stimuli. To clarify this issue, we compared the orexic effect of NPY (2 microg) injected into the third ventricle of the brain on the volume and microstructure of intake of 0.8M sucrose during sham feeding (SF) and real feeding (RF) in male Sprague Dawley rats. The rationale for this comparison is that orosensory stimulation occurs in SF and RF, but postingestive negative feedback is present only in RF. NPY increased the volume ingested and the rate and number of clusters of licking significantly more in SF than in RF. This demonstrates that orosensory sucrose stimulation is sufficient and postingestive negative feedback is not necessary for the orexic effect of NPY under these experimental conditions.

Gastric negative feedback produced by volume and nutrient during a meal in rats.

To investigate the gastric negative-feedback control of eating during a meal, we implanted male rats with pyloric cuffs and gastric catheters and gave them access to sweet milk for 30 min after overnight deprivation. Ingested milk and infused milk or saline were confined to the stomach because the pyloric cuffs were closed in all tests. Rats received five consecutive tests with no gastric infusion or with infusions of 3, 6, or 12 ml of milk or saline during the first 6 min of the test meal. Only 12-ml infusions decreased intake significantly compared with no infusion. Because 12 ml of saline inhibited intake as much as 12 ml of milk, the decreased intake was due to volume or rate of infusion, not nutrient. Although infusions of 3 and 6 ml of milk did not decrease intake, they decreased the number of licks after the infusions significantly more than equal volumes of saline. Thus a large volume or rapid rate of gastric infusion decreases intake, and some other aspect of small milk infusions decreases the rate of licking.

A possible role of the striatum in linear and nonlinear category learning: evidence from patients with Huntington's disease.

Linear and nonlinear categorization rule learning was examined in patients with Huntington's disease (HD) and a group of controls using the perceptual categorization task. Participants learned to categorize simple line stimuli into 1 of 2 categories over 600 trials. In addition to traditional measures of accuracy, quantitative model-based analyses were applied to each participant's data to characterize better the nature of any observed deficits. In the linear rule condition, HD patients displayed an early-training deficit relative to controls, whereas later in training the HD patients were not statistically different from controls. In the nonlinear rule condition, HD patients displayed both an early- and late-training deficit. The quantitative model-based analyses revealed that the HD patients' deficits in the linear condition were due to an impairment in learning the experimenter-defined rule and not in applying a learned rule inconsistently. In the nonlinear condition, in contrast, the HD patients' deficits were due to an impairment in learning the experimenter-defined rule and in applying a learned rule inconsistently. Overall, these results suggest that HD can result in a deficit in learning both linear and nonlinear categorization rules.