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.

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.

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.

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.

Body weight: reduction by long-term glycerol treatment.

Elevation of body glycerol concentration by multiple daily injections of glycerol was shown to lead to hypophagia and body weight loss followed by normal food intake and normal rate of body weight increase in rats. Termination of injections was followed by hyperphagia and an accelerated rate of growth. These findings suggest that the blood glycerol concentration plays an important role in the control of body weight and may be one signal by which the central nervous system monitors body lipid content.

Food intake controlled by a blood factor.

Intake of food by hungry rats was reduced 50 percent below normal after their blood had been mixed with that of satiated rats. Intake of food by deprived rats was not reduced when the donor rat was deprived of food for 24 hours prior to mixing of the blood or when a deprived donor was fed to satiety immediately before such transfusion.

Sustained intracerebroventricular infusion of brain fuels reduces body weight and food intake in rats.

Long-term infusion of glucose, beta-hydroxybutyrate, and glycerol into the third ventricle of the rat brain caused a stabilization of body weight at a lower than normal level. Among the glucose- and glycerol-treated animals this weight loss was caused in part by temporary hypophagia. Among the animals treated with beta-hydroxybutyrate the weight loss was unaccompanied by a reduction in food intake. The results are consistent with the view that the systems controlling food intake and body weight are sensitive to the availability of brain fuels. They are not consistent however, with the view that these control systems monitor calories independently of their source.

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.

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).

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.

Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbs embryonic vasculature.

The novel aminosterol, squalamine, inhibits angiogenesis and tumor growth in multiple animal models. This effect is mediated, at least in part, by blocking mitogen-induced proliferation and migration of endothelial cells, thus preventing neovascularization of the tumor. Squalamine has no observable effect on unstimulated endothelial cells, is not directly cytotoxic to tumor cells, does not alter mitogen production by tumor cells, and has no obvious effects on the growth of newborn vertebrates. Squalamine was also found to have remarkable effects on the primitive vascular bed of the chick chorioallantoic membrane, which has striking similarities to tumor capillaries. Squalamine may thus be well suited for treatment of tumors and other diseases characterized by neovascularization in humans.

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.

Pirprofen and aspirin in the treatment of rheumatoid arthritis.

Pirprofen (800 mg/day) or aspirin (3,600 mg/day) was administered in double-blind fashion for up to one year to 40 adult outpatients with rheumatoid arthritis, after a short, single-blind placebo period. There were no statistically significant differences in efficacy between pirprofen and aspirin, as evidenced by patient opinion, observer opinion, grip strength, walking time, number of tender joints, number of swollen joints, or erythrocyte sedimentation rate. Clinically significant pain of gastrointestinal origin occurred in an equal number of patients from each group. Audiologic evaluation revealed 3 pirprofen-treated patients and 5 aspirin-treated patients in whom sensorineural hearing loss progressed during therapy and required either discontinuation or reduction of drug dosage. Ophthalmologic evaluation disclosed a high prevalence of lesions, the most common being decreased visual acuity and cataracts not explained by previous antiarthritic therapy. The high prevalence of audiologic and ophthalmologic pathology reported in the literature in patients with rheumatoid arthritis makes it difficult to establish in our study whether pirprofen or aspirin affected these organ systems.

Fenoprofen, aspirin, and gold induction in rheumatoid arthritis.

Fenoprofen calcium (2,400 mg/day) or aspirin (3,900 mg/day) was administered in double-blind fashion to 20 rheumatoid patients during 6 months of gold induction therapy, and to 20 rheumatoid patients not receiving gold. Among both the gold-treated and nongold-treated patients, the fenoprofen and aspirin groups improved equally in all but one parameter of disease activity. Fenoprofen and aspirin did not differ significantly in the observed prevalences of abdominal discomfort, guaiac-positive stools, or peptic ulcers. Aspirin was associated with significantly higher mean serum glutamic oxaloacetic transaminase (SGOT) levels than fenoprofen, but only among patients undergoing gold induction. Comparison of efficacy parameters between patients treated with gold and patients treated with oral drugs alone revealed significant differences favoring gold.

Distention of the small intestine, satiety, and the control of food intake.

The studies reported here investigated the role that filling of the small intestine plays in the control of ingestion. Adding mannitol, a nonabsorbable carbohydrate, to a palatable solution reduced meal size in rats in proportion to its concentration. Intake is suppressed for the duration of time that the small intestine remains full. If dietary fiber, which sequesters water and swells, fills the small intestine sufficiently, it may act to suppress meal size and prolong the length of intermeal intervals.

Health status of Persian Gulf War veterans: self-reported symptoms, environmental exposures and the effect of stress.

BACKGROUND: Most US troops returned home from the Persian Gulf War (PGW) by Spring 1991 and many began reporting increased health symptoms and medical problems soon after. This investigation examines the relationships between several Gulf-service environmental exposures and health symptom reporting, and the role of traumatic psychological stress on the exposure-health symptom relationships. METHODS: Stratified, random samples of two cohorts of PGW veterans, from the New England area (n = 220) and from the New Orleans area (n = 71), were selected from larger cohorts being followed longitudinally since arrival home from the Gulf. A group of PGW-era veterans deployed to Germany (n = 50) served as a comparison group. The study protocol included questionnaires, a neuropsychological test battery, an environmental interview, and psychological diagnostic interviews. This report focuses on self-reported health symptoms and exposures of participants who completed a 52-item health symptom checklist and a checklist of environmental exposures. RESULTS: The prevalence of reported symptoms was greater in both Persian Gulf-deployed cohorts compared to the Germany cohort. Analyses of the body-system symptom scores (BSS), weighted to account for sampling design, and adjusted by age, sex, and education, indicated that Persian Gulf-deployed veterans were more likely to report neurological, pulmonary, gastrointestinal, cardiac, dermatological, musculoskeletal, psychological and neuropsychological system symptoms than Germany veterans. Using a priori hypotheses about the toxicant effects of exposure to specific toxicants, the relationships between self-reported exposures and body-system symptom groupings were examined through multiple regression analyses, controlling for war-zone exposure and post-traumatic stress disorder (PTSD). Self-reported exposures to pesticides, debris from Scuds, chemical and biological warfare (CBW) agents, and smoke from tent heaters each were significantly related to increased reporting of specific predicted BSS groupings. CONCLUSIONS: Veterans deployed to the Persian Gulf have higher self-reported prevalence of health symptoms compared to PGW veterans who were deployed only as far as Germany. Several Gulf-service environmental exposures are associated with increased health symptom reporting involving predicted body-systems, after adjusting for war-zone stressor exposures and PTSD.

Analysis of the microstructure of the rhythmic tongue movements of rats ingesting maltose and sucrose solutions.

The interlick interval distribution of rats while ingesting maltose under real and sham feeding conditions and while ingesting seven concentrations of sucrose under real feeding conditions was analyzed. The analysis revealed that the licking behavior of rats is organized into bursts of licking at a high rate. These bursts occurred in clusters that were separated by brief (250-500 ms) interruptions. The clusters were separated by intervals that ranged from 500 ms to many hundreds of seconds. Sham feeding increased the length of the meal by increasing the number but not the size of the clusters. Increasing the concentration of sucrose increased monotonically the size of the clusters but varied the number of clusters as an inverted-V-shaped function. This analysis revealed the details of the central nervous system's control over ingestive behavior.