Multivariate characterization of white matter heterogeneity in autism spectrum disorder.

The complexity and heterogeneity of neuroimaging findings in individuals with autism spectrum disorder has suggested that many of the underlying alterations are subtle and involve many brain regions and networks. The ability to account for multivariate brain features and identify neuroimaging measures that can be used to characterize individual variation have thus become increasingly important for interpreting and understanding the neurobiological mechanisms of autism. In the present study, we utilize the Mahalanobis distance, a multidimensional counterpart of the Euclidean distance, as an informative index to characterize individual brain variation and deviation in autism. Longitudinal diffusion tensor imaging data from 149 participants (92 diagnosed with autism spectrum disorder and 57 typically developing controls) between 3.1 and 36.83 years of age were acquired over a roughly 10-year period and used to construct the Mahalanobis distance from regional measures of white matter microstructure. Mahalanobis distances were significantly greater and more variable in the autistic individuals as compared to control participants, demonstrating increased atypicalities and variation in the group of individuals diagnosed with autism spectrum disorder. Distributions of multivariate measures were also found to provide greater discrimination and more sensitive delineation between autistic and typically developing individuals than conventional univariate measures, while also being significantly associated with observed traits of the autism group. These results help substantiate autism as a truly heterogeneous neurodevelopmental disorder, while also suggesting that collectively considering neuroimaging measures from multiple brain regions provides improved insight into the diversity of brain measures in autism that is not observed when considering the same regions separately. Distinguishing multidimensional brain relationships may thus be informative for identifying neuroimaging-based phenotypes, as well as help elucidate underlying neural mechanisms of brain variation in autism spectrum disorders.

Awareness of Emotional Stimuli Determines the Behavioral Consequences of Amygdala Activation and Amygdala-Prefrontal Connectivity.

Conscious awareness of negative cues is thought to enhance emotion-regulatory capacity, but the neural mechanisms underlying this effect are unknown. Using continuous flash suppression (CFS) in the MRI scanner, we manipulated visual awareness of fearful faces during an affect misattribution paradigm, in which preferences for neutral objects can be biased by the valence of a previously presented stimulus. The amygdala responded to fearful faces independently of awareness. However, when awareness of fearful faces was prevented, individuals with greater amygdala responses displayed a negative bias toward unrelated novel neutral faces. In contrast, during the aware condition, inverse coupling between the amygdala and prefrontal cortex reduced this bias, particularly among individuals with higher structural connectivity in the major white matter pathway connecting the prefrontal cortex and amygdala. Collectively, these results indicate that awareness promotes the function of a critical emotion-regulatory network targeting the amygdala, providing a mechanistic account for the role of awareness in emotion regulation.

Episodic memory in normal aging and Alzheimer disease: Insights from imaging and behavioral studies.

Age-related cognitive changes often include difficulties in retrieving memories, particularly those that rely on personal experiences within their temporal and spatial contexts (i.e., episodic memories). This decline may vary depending on the studied phase (i.e., encoding, storage or retrieval), according to inter-individual differences, and whether we are talking about normal or pathological (e.g., Alzheimer disease; AD) aging. Such cognitive changes are associated with different structural and functional alterations in the human neural network that underpins episodic memory. The prefrontal cortex is the first structure to be affected by age, followed by the medial temporal lobe (MTL), the parietal cortex and the cerebellum. In AD, however, the modifications occur mainly in the MTL (hippocampus and adjacent structures) before spreading to the neocortex. In this review, we will present results that attempt to characterize normal and pathological cognitive aging at multiple levels by integrating structural, behavioral, inter-individual and neuroimaging measures of episodic memory.

Acute and Late Bowel Toxicity in Radiotherapy Patients with Inflammatory Bowel Disease: A Systematic Review.

AIMS: Inflammatory bowel disease has traditionally been considered a relative contraindication for radiotherapy due to a perceived increased risk of disease exacerbation and bowel toxicity. The aim of this review was to evaluate the current literature regarding rates of radiotherapy-induced acute and late bowel toxicity in patients with inflammatory bowel disease and to compare these data with those of patients without the disease. MATERIALS AND METHODS: An Ovid Medline search was conducted to identify original articles pertaining to the review question. Using the PRISMA convention a total of 442 articles screened, resulting 8 articles which were suitable for inclusion in the review. RESULTS: In general, the grading of toxicity was scored using either the Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events scoring systems. It was found that acute bowel toxicity of ≥ grade 3 occurred in 20% of patients receiving external beam radiotherapy (EBRT) and in 7% of patients receiving brachytherapy. Late bowel toxicity ≥ grade 3 occurred in 15% of EBRT patients and in 5% of patients receiving brachytherapy. Brachytherapy was shown to have similar rates of toxicity and EBRT produced a moderate increase in both acute and late toxicity when compared with individuals without inflammatory bowel disease. CONCLUSION: In view of these results, we suggest that brachytherapy should be considered as a suitable treatment option for treating pelvic malignancy in patients with inflammatory bowel disease, whereas EBRT should be used with caution.

Transitive inference in two lemur species (Eulemur macaco and Eulemur fulvus).

When confronted with tasks involving reasoning instead of simple learning through trial and error, lemurs appeared to be less competent than simians. Our study aims to investigate lemurs' capability for transitive inference, a form of deductive reasoning in which the subject deduces logical conclusions from preliminary information. Transitive inference may have an adaptative function, especially in species living in large, complex social groups and is proposed to play a major role in rank estimation and establishment of dominance hierarchies. We proposed to test the capacities of reasoning using transitive inference in two species of lemurs, the brown lemur (Eulemur fulvus) and the black lemur (Eulemur macaco), both living in multimale-multifemale societies. For that purpose, we designed an original setup providing, for the first time in this kind of cognitive task, pictures of conspecifics' faces as stimuli. Subjects were trained to differentiate six photographs of unknown conspecifics named randomly from A to F to establish the order A > B > C > D > E > F and select consistently the highest-ranking photograph in five adjacent pairs AB, BC, CD, DE, and EF. Then lemurs were presented with the same adjacent pairs and three new and non-adjacent pairs BD, BE, CE. The results showed that all subjects correctly selected the highest-ranking photograph in every non-adjacent pair, reflecting lemurs' capacity for transitive inference. Our results are discussed in the context of the still debated current theories about the mechanisms underlying this specific capacity.

Professional delay in head and neck cancer patients: analysis of the diagnostic pathway.

The aim of this study was to identify which factors are related to specialist delay and to determine the length of the diagnostic pathway in head and neck cancer patients. Three hundred and six patients with a carcinoma of the larynx, pharynx or oral cavity were included in the study. Logistic regression analysis was used to identify risk factors for specialist delay. Large (T3-T4) tumors showed significantly less specialist delay than small (T1-T2) tumors (p=0.045, odds ratio [OR]=0.6). Pharyngeal (p=0.00, OR=0.2) and oral carcinomas (p=0.00, OR=0.2) had less specialist delay than glottic carcinomas. Hoarseness was associated with prolonged specialist delay (p=0.00, OR=5.9). Heavy drinking in combination with smoking (p=0.005, OR=0.3), a sore throat (p=0.02, OR=0.4) or having a lesion (p=0.03, OR=0.2) showed a shorter diagnostic period. The duration of the diagnostic process in a general hospital ranged from 0 to 570 days, with a median of 14 days. Only a small group of patients met the ideal management standards in our head and neck clinic. Although prolonged delay was associated with small (glottic) tumors, the diagnostic process takes a fairly long time. The results indicate that continued educational programs for professionals are warranted.

Medical care-seeking and health-risk behavior in patients with head and neck cancer: the role of health value, control beliefs and psychological distress.

Health behavior plays an important role in the development, detection and course of cancer of the head and neck. Relevant health behavior includes prompt medical care seeking, and smoking and drinking cessation after diagnosis. This study examines the relationship between these health behaviors and health value and control beliefs, as well as psychological distress. Two hundred and sixty-four recently diagnosed head and neck cancer patients were interviewed about their health behavior, and they filled in a questionnaire on health beliefs and psychological distress. The results showed that one-quarter (25%) of the patients had waited more than 3 months before seeking medical care, 50% had continued to smoke and 80% had continued to drink after the diagnosis. The patients, particularly those who smoked and drank before diagnosis, reported lower levels of health value and perceived health competence than a general population sample with which they were compared. Patients who engaged in patient delay reported a lack of perceived health competence. Psychological distress and lack of perceived health competence were found to be more common among patients who continued to smoke. The implications of these findings are discussed with regard to interventions aimed at promoting these specific health behaviors.

Psychological factors and patient delay in patients with head and neck cancer.

There is a rising incidence of patients presenting with advanced cancer in the head and neck region. Late presentation may be due to a delay in seeking medical attention, which is sometimes surprisingly long. The aim of the present prospective study was to investigate the association between patient delay and the psychological factors of optimism, health hardiness, overall defensive functioning, coping styles and psychological distress in 277 patients with cancer of the head and neck. Significant correlations were found between patient delay and the psychological factors. Twenty-six percent of the patients waited more than three months before seeking medical attention and they reported less optimism (P = 0.0001), less health hardiness (P = 0.008), less active coping (P = 0.019) and less seeking support as a coping style (P = 0.017) than patients presenting within three months. Excessive drinkers (5+ alcoholic drinks/day) tended to show more delay than patients who did not drink or were moderate drinkers (0-2 drinks/day) or moderate-heavy drinkers (3-4 drinks/day). Together, the psychological factors could explain 25% of the variance of patient delay in excessive drinkers compared with 21% and 6% in moderate-heavy drinkers and non-drinkers to moderate drinkers, respectively. These results suggest that psychological factors affect health-care seeking behaviour. Health education aimed at the risk group of excessive drinkers should take psychological factors into account that influence their health behaviour.

Increasing incidence of advanced stage head and neck tumours.

The aim of this study was to determine whether the incidence of advanced stage (T4) head and neck tumours has increased. We analysed retrospectively 3178 patients diagnosed with oral, pharyngeal or laryngeal cancer in the period 1980-2000 at the University Medical Center Utrecht (UMCU), The Netherlands. There was a statistically significant increase in the proportion of T4 head and neck tumours compared with non-T4 tumours over the period 1980-2000. Linear regression analysis estimated an increase of 0.9% every year. The observed increase in T4 tumours at UMCU shows up in figures from the Netherlands Regional Cancer Registry (IKMN) and the National Cancer Registration (NCR). Although these bodies report for fewer years, this finding refutes the possibility of selected referral to the University Medical Center Utrecht. In conclusion, the number of head and neck cancer patients presenting with an advanced stage carcinoma (T4) has increased over a period of 21 years.

[Rising incidence of invasive (T4) head-neck carcinoma at the Utrecht University Medical Center, 1980-1998]. / Stijgende incidentie van invasieve (T4)-hoofd-halscarcinomen in het Universitair Medisch Centrum Utrecht, 1980-1998.

OBJECTIVE: To determine whether there is an increase in the incidence of diagnosed head and neck tumours at an advanced stage (T4). DESIGN: Secondary data-analysis. METHOD: Data of patients registered in 1980-1998 at the Utrecht University Medical Centre, the Netherlands, were analysed for the relative prevalence of T4 tumours in the oral cavity, pharynx and larynx on the basis of sex, age and tobacco and alcohol usage. The results were compared with figures from the Dutch national cancer registry (1989-1997). RESULTS: Data were collected for 2993 patents (2256 men and 737 women; average age 63 years (SD 12)). Of these 35 had a carcinoma situated on the lips, 1091 in the oral cavity, 1321 in the larynx and 546 in the pharynx. There was an increase in T4 tumours of 12.2% (43/353) of all tumours in 1980-1984 to 27.2% (252/1033) in 1995-1998. Linear regression analysis estimated an increase of 0.9% every year. Selected referral to the Utrecht University Medical Centre was unlikely because the increased incidence of T4 tumours could be recognised in the national cancer registry. There was no change in the sex distribution over the study period. The increase in the 40 to 50-year-old age group was greater than that of the patients aged 80 years and over. T4 tumours were more prevalent than T1 tumours in patients who had smoked 20 or more cigarettes per day or drank more than 4 units of alcohol per day. CONCLUSION: The percentage of cancer patients presenting with an advanced stage (T4) of head-neck tumours increased during the study period.

Improving the well-being of elderly patients via community pharmacy-based provision of pharmaceutical care: a multicentre study in seven European countries.

OBJECTIVE: This study aimed to measure the outcomes of a harmonised, structured pharmaceutical care programme provided to elderly patients (> or =65 years of age) by community pharmacists in a multicentre international study performed in 7 European countries. DESIGN AND SETTING: The study was a randomised, controlled, longitudinal, clinical trial with repeated measures performed over an 18-month period. A total of 104 intervention and 86 control pharmacy sites participated in the research and 1290 intervention patients and 1164 control patients were recruited into the study. MAIN OUTCOME MEASURES AND RESULTS: A general decline in health-related quality of life over time was observed in the pooled data; however, significant improvements were achieved in patients involved in the pharmaceutical care programme in some countries. Intervention patients reported better control of their medical conditions as a result of the study and cost savings associated with pharmaceutical care provision were observed in most countries. The new structured service was well accepted by intervention patients and patient satisfaction with the services improved during the study. The pharmacists involved in providing pharmaceutical care had a positive opinion on the new approach, as did the majority of general practitioners surveyed. The positive effects appear to have been achieved via social and psychosocial aspects of the intervention, such as the increased support provided by community pharmacists, rather than via biomedical mechanisms. CONCLUSIONS: This study is the first large-scale, multicentre study to investigate the effects of pharmaceutical care provision by community pharmacists to elderly patients. Future research methodology and implementation will be informed by the experience gained from this challenging trial.

Development of pharmaceutical care in The Netherlands: pharmacy's contemporary focus on the patient.

OBJECTIVE: To describe how developments in the pharmacy profession in The Netherlands converged into the current movement toward pharmaceutical care. SETTING: Dutch community pharmacy. DESCRIPTION: Literature was reviewed for key elements of pharmacists' professional development over the last 40 years--the pharmacist-physician relationship, the pharmacist-patient relationship, the education of the pharmacist, provision of information to patients, medication surveillance, clinical pharmacy, and social pharmacy. Consideration was given to how, when and if these elements interacted and contributed to the movement toward pharmaceutical care. RESULTS: During the early years of the 20th century the professional role of the pharmacist, based on preparing medications, declined because of the increased industrial production of drugs. In The Netherlands, a number of developments, starting around 1995, led to a "reprofessionalization" movement in pharmacy, characterized by pharmacists' increased awareness of social and ethical responsibilities with respect to drugs and patients. These developments included an improved relationship between pharmacists and physicians, the implementation of clinical pharmacy and medical surveillance in daily community pharmacy practice in the 1970s and 1980s, and the increased awareness of the rights of patients to quality drug information and counseling in the 1980s and 1990s. By the end of 1980 these trends had coalesced into a professional movement supporting the need for a pharmaceutical care model of practice. CONCLUSION: Dutch pharmacy is gradually implementing pharmaceutical care in daily community practice. However, a proactive attitude, not only from the "front runners," but from all pharmacists, is desirable if pharmaceutical care is to be incorporated into routine community practice.

Comparison of gastrointestinal blood loss induced by cloximate in two formulations and by naproxen.

In a double-blind baseline controlled crossover trial gastrointestinal blood loss induced by cloximate in two different formulations (enteric-coated and non-enteric coated) was compared with naproxen. Gastrointestinal blood loss increased more in the naproxen group (0.41 ml/24 h) than in the group treated with non-enteric coated cloximate. The group treated with coated cloximate had a higher mean increase in gastrointestinal blood loss (0.36 ml/24 h) compared with placebo than those treated with non-coated cloximate.