Three challenges for connecting model to mechanism in decision-making.

Recent years have seen a growing interest in understanding the neural mechanisms that support decision-making. The advent of new tools for measuring and manipulating neurons, alongside the inclusion of multiple new animal models and sensory systems has led to the generation of many novel datasets. The potential for these new approaches to constrain decision-making models is unprecedented. Here, we argue that to fully leverage these new approaches, three challenges must be met. First, experimenters must design well-controlled behavioral experiments that make it possible to distinguish competing behavioral strategies. Second, analyses of neural responses should think beyond single neurons, taking into account tradeoffs of single-trial versus trial-averaged approaches. Finally, quantitative model comparisons should be used, but must consider common obstacles.

Mortality from sudden unexpected death in epilepsy (SUDEP) in a cohort of adults with intellectual disability.

BACKGROUND: People with intellectual disability (ID) and epilepsy are more likely to die prematurely than the general population. A significant number of deaths in people with epilepsy may be potentially preventable through better seizure control, regular monitoring and raising awareness among patients and carers. The aim of this project was to study mortality from sudden unexpected death in epilepsy (SUDEP) in adults with ID. METHODS: All adults (≥20 years old) living in Leicester city, Leicestershire and Rutland, UK, with ID between 1993 and 2010 were identified using the Leicestershire Intellectual Disability Register database. People with and without ID who died during the same period were identified using death certificate data from the Office for National Statistics (ONS). Deaths from probable and definite SUDEP were identified. Additional information on adults with ID who had died from probable or definite SUDEP was obtained from case notes and post-mortem reports, where available. Cases of probable and definite SUDEP in adults with ID were compared with the general population using standardised mortality ratios (SMRs). RESULTS: A total of 898 adults with ID had died over the 18-year study period. Of these, 244 deaths (27%) occurred in people with ID who had a diagnosis of epilepsy. Twenty-six people with ID died from probable or definite SUDEP, which was the second most common cause of death among adults with ID and epilepsy. All-cause specific SMRs were 2.2 [95% confidence interval (CI): 2.0-2.4] and 2.8 (95% CI: 2.5-3.1) for men and women with ID respectively. SMRs were 3.2 (95% CI: 2.7-3.8) and 5.6 (95% CI: 4.6-6.7) for men and women with epilepsy and ID respectively. During the same study period, 83 adults without ID had died of probable or definite SUDEP. The SMRs for SUDEP in patients with ID were 37.6 for men (95% CI: 21.9-60.2) and 52.0 for women (95% CI: 23.8-98.8). We found that in the majority of ID cases there was little detailed documentation on the circumstances surrounding deaths, no communication with patients/carers about risk of SUDEP and an absence of post-mortem reports or carers' referral for bereavement counselling. CONCLUSION: The authors believe that a comprehensive risk management under a multiagency/multidisciplinary framework should be undertaken for all adults with ID and epilepsy in day-to-day clinical practice to reduce mortality in people with ID.

Urban-rural differences in the nature and prevalence of mental ill-health in adults with intellectual disabilities.

BACKGROUND: In the general population there are statistically significant urban-rural differences in the rate of common mental disorders. In people with intellectual disability (ID) no study has attempted to address this issue. AIMS: To compare the prevalence of mental illness, autism spectrum disorder (ASD) and behaviour disorder in people with ID living in urban areas with those living in rural areas. METHODS: Cross-sectional study of 2713 individuals registered with an ID service. Participants were assigned to urban or rural groups using the Department for Environment Food and Rural Affairs rural/urban local authority classification for their district. The main outcome variable was a clinical diagnosis of mental illness, ASD and behaviour disorder. Differences between diagnoses of mental illness in urban and rural areas were evaluated using the chi-squared test for the difference in two independent proportions. RESULTS: No differences were observed between gender, age and level of ID of service users based on their place of residence. But more people from an ethnic minority background were living in urban areas than rural areas. No differences were observed in the overall prevalence of mental illness by place of residence. However, the results showed that ASD was more common in people living in rural areas. CONCLUSIONS: We found these results surprising and at odds with the majority of studies carried out in the general population and propose several reasons for the differences found. We believe that the results and further studies in this area will help inform health service provision for those with ID who live in different geographical areas.

Variance as a signature of neural computations during decision making.

Traditionally, insights into neural computation have been furnished by averaged firing rates from many stimulus repetitions or trials. We pursue an analysis of neural response variance to unveil neural computations that cannot be discerned from measures of average firing rate. We analyzed single-neuron recordings from the lateral intraparietal area (LIP), during a perceptual decision-making task. Spike count variance was divided into two components using the law of total variance for doubly stochastic processes: (1) variance of counts that would be produced by a stochastic point process with a given rate, and loosely (2) the variance of the rates that would produce those counts (i.e., "conditional expectation"). The variance and correlation of the conditional expectation exposed several neural mechanisms: mixtures of firing rate states preceding the decision, accumulation of stochastic "evidence" during decision formation, and a stereotyped response at decision end. These analyses help to differentiate among several alternative decision-making models.

Brief report: Aggressive challenging behaviour in adults with intellectual disability following community resettlement.

BACKGROUND: Aggressive challenging behaviour is common in adults with intellectual disability (ID) in long-term care facilities. The government's commitment to the closure of all facilities in England has led to concerns over how to manage this behaviour in the community. The aim of this study was to assess changes in aggressive challenging behaviour and psychotropic drug use in adults with ID following resettlement using a person-centred approach. METHOD: The Modified Overt Aggression Scale was administered to carers of 49 adults with ID prior to discharge from a long-stay hospital and 6 months and 1 year after community resettlement. RESULTS: All areas of aggressive challenging behaviour reduced significantly between baseline and 6 months following resettlement (P < 0.001). This reduction remained (but did not decrease further) at 1-year follow-up. CONCLUSIONS: Further work is needed to evaluate the role of environmental setting on aggressive challenging behaviour in adults with ID.

Effects of neonatal C-fiber depletion on the integration of paired-whisker inputs in rat barrel cortex.

In the present study we used computer-controlled mechanical displacement of paired whiskers in normal and C-fiber-depleted rats to quantitatively examine the role of C-fibers in the receptive field properties of barrel cortical cells. In rodents when adjacent whiskers are stimulated prior to the main whisker responses to the main whisker are inhibited, the degree of inhibition being a function of the inter-deflection intervals. The adjacent-whisker-evoked inhibition of barrel cells in normal and C-fiber-depleted rats using neonatal capsaicin treatment were examined by stimulation of the adjacent whisker zero, 10, 20, 30, 50 and 100 ms prior to the main whisker deflection. C-fiber depletion reduced the suppressive effect of paired whisker stimulation at all of the tested inter-stimulus intervals without changing response latencies. The main effect was observed during the later phase of response (about 13-17 ms from stimulus onset) and not during the initial responses (7-12 ms). These results suggest that the inhibitory receptive field properties of low-threshold mechanical somatosensory cells are influenced by C-fibers.

Double-blind, double-dummy comparison of azithromycin and cephalexin in the treatment of skin and skin structure infections.

In this double-blind, randomised trial conducted in 22 centres in the USA, azithromycin given over five days, as a once-a-day regimen, (500 mg on day 1, 250 mg on days 2-5) was compared with cephalexin (500 mg b.i.d.) given for ten days in the treatment of patients with skin and skin structure infections. A total of 366 patients entered the study and 179 of these were eligible for the efficacy analysis. The overall clinical response to azithromycin was 94.0%, compared with 95.8% for cephalexin. The clinical cure rates were 53.0% for azithromycin and 59.4% for cephalexin; the respective improvement rates were 41.0% and 36.5%. Distribution of response (cured, improved, failed) was similar in each group (p = 0.37). The bacteriological eradication rate for azithromycin-treated patients was 94.2% and for cephalexin-treated patients was 90.3% (p = 0.34). Clinical and bacteriological response was similar in each group for all primary diagnoses. The two antibiotics were well tolerated, the overall incidence of side effects being 13.7% with approximately 60% due to gastrointestinal disturbances. In all but one case (cephalexin) the severity of the reported side effects was mild or moderate. Six patients withdrew from the study due to treatment-related events; five had been treated with azithromycin and one with cephalexin. In summary, a five-day, once-daily regimen of azithromycin was as effective as a ten-day, twice-daily regimen of cephalexin in the treatment of patients with skin and skin structure infections.

Serum time curve characteristics of a fixed dose of beta-carotene in young and old men.

The present study was designed to evaluate age-related differences in serum beta-carotene time curve response characteristics when a beta-carotene dose was given in conjunction with 1500 kcal over the course of a day. On two consecutive days, seven old (73 +/- 4 years) and six young (24 +/- 1 years) men were each fed three 500-kcal meals of an isotonic liquid formula diet containing only trace amounts of beta-carotene. On the first day of testing, no supplemental beta-carotene was given (baseline day). A 15 mg dose of beta-carotene was fed with the morning meal on the second day (test dose day). Fasting blood and hourly blood samples were obtained for 8 consecutive hours on both days. Additional blood was drawn 24 and 48 hours after the test beta-carotene dose. There were no statistical differences in baseline beta-carotene concentrations between the two age groups tested, but, because of high individual variability, serum time curve characteristics were adjusted for fasting beta-carotene levels. After adjustment, the postdose serum beta-carotene response was two to three times greater (p less than or equal to 0.04) in young subjects, as evaluated by peak concentration, area under the curve, or ascending slope of the serum response curve. Examination of factors besides age group that may have accounted for these results suggests that the serum response of the elderly may be more a function of body composition and/or serum lipid patterns than of age per se. However, in the present US population, it may not be valid to control for these factors, which are both closely related to aging.

Normal serum response to oral beta-carotene in humans.

This study was performed to determine (1) the normal serum response to a single oral dose of beta-carotene (BC), (2) the effect of meal timing and serum response to meal lipids on serum BC, (3) the effect of administered BC on other serum carotenoids and retinoids, and (4) the relationship of body composition to serum BC response. Subjects consumed one BC dose with a liquid 500 kcal BC-free diet; fasting and hourly venous blood was collected for 8 hours and again at 24 hours. A second liquid BC-free meal was consumed 4 hours post-dosing; this midday meal was omitted in some subjects. Serum BC levels rose and peaked initially at 5 hours, but continued to be absorbed in most subjects, remaining significantly elevated at 24 hours as compared to baseline values (p less than 0.001), independent of BC dose. The area under the BC absorption curve (8-hr AUC) increased linearly with BC dose and correlated positively with peak serum triglycerides (TG) after a meal (n = 26 tests, r = 0.56, p less than 0.003). Omission of the midday meal significantly delayed the initial BC peak to 7 hours (p less than 0.0004). Serum levels of retinol, alpha-carotene, cryptoxanthin, lycopene, and lutein remained unchanged. Serum retinyl esters did not rise in all subjects following BC intake; when it did, retinyl esters rose and peaked concomitantly with BC, but declined within 8 hours. There was no correlation between the initial serum BC, peak BC, 24-hr BC, 8-hr AUC, or peak serum TG and the percentage of body fat. We conclude that: (1) the timing of the serum response to oral BC is independent of dose, (2) the serum BC response is greater in those with a greater serum triglyceride response to meal lipids, (3) BC at the doses given does not alter the levels of other serum carotenoids, and (4) there is no correlation between the serum BC parameters measured and adiposity.

Comparative, multicenter studies of cefixime and amoxicillin in the treatment of respiratory tract infections.

A total of 560 patients were treated in two double-blind, randomized multicenter studies to compare the safety and efficacy of cefixime (400 mg administered once daily) and amoxicillin (250 or 500 mg administered three times daily) for the treatment of bacterial respiratory tract infections. Eighty percent of the 244 patients treated in the lower respiratory tract infections (LRTI) study had acute bronchitis. Streptococcus pneumoniae (13 percent), Haemophilus influenzae (28 percent), and Escherichia coli (10 percent) were the pathogens most frequently isolated from sputum in these patients. Among evaluable patients with positive bacterial culture results at baseline, a favorable clinical response (cured or improved) was obtained in 100 percent of the cefixime-treated patients (22 of 22) and in 96 percent of the amoxicillin-treated patients (23 of 24). Bacteriologic eradication rates were 100 percent and 83 percent for cefixime and amoxicillin, respectively. In the upper respiratory tract infections (URTI) study, 316 patients with pharyngitis (80 percent) or tonsillitis (14 percent) were treated. Group A, beta-hemolytic Streptococcus (69 percent) and H. influenzae (8 percent) were the pathogens most frequently isolated from the throat culture specimens of these patients. Favorable clinical results were obtained in 99 percent of the evaluable cefixime-treated group (n = 73) and in 98 percent of the amoxicillin-treated group (n = 66). The bacteriologic eradication rates were 93 percent and 100 percent, respectively. The adverse experiences reported during both studies were similar in nature and frequency to those reported for other beta-lactam antibiotics with the exception of a higher incidence of altered bowel movement (diarrhea and stool changes) with both drugs. These episodes usually resolved without remedial medication when the treatment was withdrawn. No significant adverse laboratory findings were observed. Results of these trials demonstrate that cefixime at a dosage of 400 mg once daily is an effective and safe oral antibiotic for the treatment of acute respiratory tract infections.

The role of recent life events and social support in the control of diabetes mellitus. A pilot study.

This study evaluated objectively the relationship between recent life events, social support systems, and blood glucose control in diabetic patients using both short-term [fasting blood sugar (FBS)] and long-term [glycosylated hemoglobin (Hgb A-1C)] measures of control. We found that a higher number of life events was associated with a higher percentage of abnormal FBS and Hgb A-1C results, and that improved social support was associated with a smaller percentage of abnormal Hgb A-1C scores. These pilot findings are discussed in connection with a biopsychosocial approach to the understanding and management of diabetes mellitus.

Zomepirac-induced serum sickness. A report of two cases.

Two patients, after several weeks of zomepirac sodium use, experienced acute toxic eruption, fever, lymphadenopathy, arthralgias, angioedema of the hands, and eosinophilia. We believe that these cases represent type 3 allergic reactions to zomepirac.

Kinetic vitreous fluorophotometry in normals and noninsulin-dependent diabetics.

Kinetic vitreous fluorophotometry was performed up to five hours after intravenous injection of fluorescein in seven normal subjects and seven noninsulin-dependent diabetic patients without retinopathy. The leakage of fluorescein into the vitreous was measured, and fluorescein dynamics were assessed after correction for the most important artifacts. A detailed description of the movements of fluorescein between the blood and the chambers of the eye across the blood-ocular barriers was obtained in normal and diabetic eyes. The diabetic population could be differentiated best from the normal one with vitreous fluorophotometry measurements performed close to the retina-choroid one hour after injection.

Hypoglycemic coma associated with benign pleural mesothelioma.

A case of hypoglycemic coma and benign pleural mesothelioma is described. Serum insulin levels, as measured by insulin radioimmunoassay, were appropriately suppressed and consistent with hypoglycemia. Assay of the tumor showed insulin to be undectable. The mechanisms for hypoglycemia probably included increased glucose consumption by the tumor and, more important, the inhibition of lipolysis and hepatic gluconegenesis caused by tumor release of L-tryptophan and its metabolites and/or possibly nonsuppressible insulin-like activity, soluble in acid-ethanol(NSILA-s).