The aetiology behind torticollis and variable spine defects in patients with M��llerian duct/renal aplasia-cervicothoracic somite dysplasia syndrome: 3D CT scan analysis

The aim of the article is fourfold; firstly, to detect the aetiology of torticollis in patients with Müllerian duct/renal aplasia-cervicothoracic somite dysplasia syndrome; secondly, spine pathology in Müllerian duct/renal aplasia-cervicothoracic somite dysplasia syndrome varies considerably from one patient to another and there are remarkable differences in severity and localization; thirdly, mismanagement of congenital spine pathology is a frequent cause of morbid/fatal outcome; and fourthly, the application of prophylactic surgical treatment to balance the growth of the spine at an early stage is mandatory. Reformatted CT scans helped in exploring the craniocervical and the entire spine in these patients. The reason behind torticollis ranged between aplasia of the posterior arch of the atlas, assimilation of the atlas and extensive fusion of the lower cervical vertebrae (bilateral failure of segmentation) in four patients; in one patient, in addition to the hypoplastic posterior arch of the atlas, we observed ossification of the anterior and the posterior longitudinal spinal ligaments giving rise to a block vertebrae-like suggestive of early senile ankylosing vertebral hyperostosis (Forestier disease). Scoliosis at different spine levels was attributable to variable spine defects. Pelvic ultrasound showed the classical renal agenesis in four patients; whereas in one patient, the MRI showed pelvic cake kidney (renal fused ectopia) associated with ovarian, uterine and vaginal abnormalities. This is the first exploratory study on the craniocervical and the entire spine in a group of patients with MURCS association.     

A qualitative investigation into the levers and barriers to weight loss in children: opinions of obese children

Background

The alarming increase in the worldwide prevalence of childhood obesity is now recognised as a major public health concern. Failure to isolate and understand the external and internal factors contributing to successful weight loss may well be contributing to the ineffectiveness of current treatment interventions.

Aim

To identify the physical and psychological levers and barriers to weight loss experienced by obese children using qualitative techniques.

Methods

20 participants were randomly selected from a population of clinically obese children (7–15 years old) attending a weight‐loss clinic for >3 months. The children expressed their opinions in a series of interviews and focus group sessions. Data were recorded, semitranscribed and analysed using the thematic framework analysis technique and behavioural‐change models.

Results

Children described the humiliation of social torment and exclusion as the main reasons for wanting to lose weight, although initiation of behavioural change required the active intervention of a role model. The continuation of action was deemed improbable without continual emotional support offered at an individual level. Behavioural sacrifice, delayed parental recognition and previous negative experiences of weight loss were recognised as barriers to action. Participants identified shortcomings in their own physical abilities, the extended time period required to lose weight and external restrictions beyond their control as barriers to maintaining behavioural change.

Discussion

This study identifies the important levers and barriers experienced by obese children in their attempt to lose weight. Dealing with these levers and barriers while acknowledging the complex interplay of social and emotional factors unique to the individual may well promote successful weight control.Recent expansion of population‐based epidemiological evidence shows dramatic increases in both overweight and obese populations across the developed world.¹ Research suggests that the levels of childhood obesity in the UK have more than doubled within the last decade,² and increasing numbers of children are maintaining their obesity status into adulthood.³ With the National Health Service already fronting an annual sum exceeding £2.5 billion² as a direct result of the obesity epidemic, the implications for future health expenditure are obvious. Obesity should be our public health priority, as it is proving to be one of the largest threats to longevity achieved over the last century.A review of the evidence base⁴ allows weight‐reduction studies centred around overweight and obese children to be categorised into five types: family‐based physical activity and health promotion interventions; family‐based programmes using parents as the major agents of change; family‐based behaviour‐modification programmes; behaviour‐modification programmes with no parental input; and exercise treatment programmes. The results have been mixed, with tentative conclusions and little indication as to the most effective way to progress forward.So why is it that our population of obese children find it so difficult to lose weight when those lifestyle factors that contribute to the condition are so widely recognised? Perhaps one explanation lies with the social psychology of risk taking. Human nature dictates that people will not always respond in a rational and predictable manner when given information about future health risks.⁵ Simply educating a population rarely has a marked effect on behavioural change,⁶ particularly with regard to children, in whom evidence has shown that supplying the required knowledge does not necessarily lead to action.⁷ To engage the obese child, we must first gain an insight into the ideas and opinions of that child so that we can work together towards a weight‐reduction scheme that is relevant to the child as an individual. This study aimed to examine the levers and barriers to weight loss from a child''s perspective using qualitative techniques previously proved successful in exploring human perception and opinion.^8,9 A qualitative approach to this study was deemed most appropriate as it provides “a holistic perspective which preserves the complexity of human behaviour”.¹⁰     

The Constituents of Echinacea atrorubens Roots and Aerial Parts

Eleven isobutylamides have been isolated from the n -hexane extract of the dried roots of Echinacea atrorubens Nutt. Undeca-2 E, 4 E -dien-8,10-diynoic acid isobutylamide represents a new compound. The lipophilic profiles of constituents of the roots and the herb were similar as the alkamide profiles previously found in E. purpurea and E. angustifolia. The polar components of E. atrorubens roots and the aerial parts, however, seem to be very different from E. purpurea and E. angustifolia, since neither cichoric acid nor echinacoside could be found.     

Alcoholics Anonymous and Reduced Impulsivity: A Novel Mechanism of Change

ABSTRACT

Reduced impulsivity is a novel, yet plausible, mechanism of change associated with the salutary effects of Alcoholics Anonymous (AA). Here, the authors review their work on links between AA attendance and reduced impulsivity using a 16-year prospective study of men and women with alcohol use disorders (AUDs) who were initially untreated for their drinking problems. Across the study period, there were significant mean-level decreases in impulsivity, and longer AA duration was associated with reductions in impulsivity. In turn, decreases in impulsivity from baseline to Year 1 were associated with fewer legal problems and better drinking and psychosocial outcomes at Year 1, and better psychosocial functioning at Year 8. Decreases in impulsivity mediated associations between longer AA duration and improvements on several Year 1 outcomes, with the indirect effects conditional on participants’ age. Findings are discussed in terms of their potential implications for research on AA and, more broadly, interventions for individuals with AUDs.     

High-risk alcohol consumption and late-life alcohol use problems

OBJECTIVES: We used several different guidelines for appropriate alcohol use to identify patterns of high-risk alcohol consumption among older women and men and examined associations between these patterns and late-life alcohol use problems. METHODS: A sample of 1291 older adults participated in a survey of alcohol consumption and alcohol use problems and was studied again 10 years later. RESULTS: Depending on the guideline, 23% to 50% of women and 29% to 45% of men engaged in potentially unsafe alcohol use patterns. The likelihood of risky alcohol use declined over the 10 years; however, the numbers of drinks consumed per week and per day were associated with alcohol use problems at both assessment intervals. CONCLUSION: Our findings imply that guidelines for alcohol consumption should be no more liberal for older men than for older women.     

Sensory irritation as a basis for setting occupational exposure limits

There is a need of guidance on how local irritancy data should be incorporated into risk assessment procedures, particularly with respect to the derivation of occupational exposure limits (OELs). Therefore, a board of experts from German committees in charge of the derivation of OELs discussed the major challenges of this particular end point for regulatory toxicology. As a result, this overview deals with the question of integrating results of local toxicity at the eyes and the upper respiratory tract (URT). Part 1 describes the morphology and physiology of the relevant target sites, i.e., the outer eye, nasal cavity, and larynx/pharynx in humans. Special emphasis is placed on sensory innervation, species differences between humans and rodents, and possible effects of obnoxious odor in humans. Based on this physiological basis, Part 2 describes a conceptual model for the causation of adverse health effects at these targets that is composed of two pathways. The first, “sensory irritation” pathway is initiated by the interaction of local irritants with receptors of the nervous system (e.g., trigeminal nerve endings) and a downstream cascade of reflexes and defense mechanisms (e.g., eyeblinks, coughing). While the first stages of this pathway are thought to be completely reversible, high or prolonged exposure can lead to neurogenic inflammation and subsequently tissue damage. The second, “tissue irritation” pathway starts with the interaction of the local irritant with the epithelial cell layers of the eyes and the URT. Adaptive changes are the first response on that pathway followed by inflammation and irreversible damages. Regardless of these initial steps, at high concentrations and prolonged exposures, the two pathways converge to the adverse effect of morphologically and biochemically ascertainable changes. Experimental exposure studies with human volunteers provide the empirical basis for effects along the sensory irritation pathway and thus, “sensory NOAEC_human” can be derived. In contrast, inhalation studies with rodents investigate the second pathway that yields an “irritative NOAEC_animal.” Usually the data for both pathways is not available and extrapolation across species is necessary. Part 3 comprises an empirical approach for the derivation of a default factor for interspecies differences. Therefore, from those substances under discussion in German scientific and regulatory bodies, 19 substances were identified known to be human irritants with available human and animal data. The evaluation started with three substances: ethyl acrylate, formaldehyde, and methyl methacrylate. For these substances, appropriate chronic animal and a controlled human exposure studies were available. The comparison of the sensory NOAEC_human with the irritative NOAEC_animal (chronic) resulted in an interspecies extrapolation factor (iEF) of 3 for extrapolating animal data concerning local sensory irritating effects. The adequacy of this iEF was confirmed by its application to additional substances with lower data density (acetaldehyde, ammonia, n-butyl acetate, hydrogen sulfide, and 2-ethylhexanol). Thus, extrapolating from animal studies, an iEF of 3 should be applied for local sensory irritants without reliable human data, unless individual data argue for a substance-specific approach.     

Pharmacokinetic interactions of almorexant with midazolam and simvastatin, two CYP3A4 model substrates, in healthy male subjects

Purpose

Pre-clinical experiments have shown that almorexant, a dual orexin receptor antagonist, is able to inhibit cytochrome P450 3A4 (CYP3A4). Therefore, a study was conducted to investigate the effects of multiple-dose almorexant on the pharmacokinetics of midazolam and simvastatin, two CYP3A4 model substrates.

Methods

Fourteen healthy male subjects were enrolled in an open-label, randomized, two-way crossover study. Treatment period A consisted of a single oral dose of 2 mg midazolam on day 1 and 40 mg simvastatin on day 3. In treatment period B, subjects received 200 mg almorexant once daily for 9 days together with a single oral dose of midazolam on day 7 and simvastatin on day 9.

Results

Concomitant administration of midazolam with almorexant at steady-state levels, achieved within 4–5 days, resulted in an increase of 1.2-fold [90 % confidence interval (CI) 1.0–1.4], 1.4-fold (90 % CI 1.2–1.6), and 1.3-fold (90 % CI 1.2–1.4) in the maximum plasma concentration (C_max), area under the concentration–time curve from time 0 to infinity (AUC_0-∞), and terminal half-life (t_1/2), respectively, of midazolam; the time to peak plasma concentration (t_max) was unchanged. Whereas C_max and t_max were not influenced by almorexant, the AUC_0-∞ of hydroxy-midazolam increased by 1.2-fold (90 % CI 1.1–1.4) and the t_1/2 by 1.3-fold (90 % CI 1.0–1.5). Concomitant administration of simvastatin with almorexant at steady-state resulted in an increase of 2.7-fold (90 % CI 2.0–3.7) and 3.4-fold (90 % CI 2.6–4.4) in C_max and AUC_0-∞, respectively, for simvastatin; the t_1/2 and t_max were unchanged. The C_max and AUC_0-∞ of hydroxyacid simvastatin both increased by 2.8-fold, with 90 % CIs of 2.3–3.5 and 2.2–3.5, respectively; the t_max increased by 2 h and the t_1/2 was unchanged. The urinary 6-β-hydroxycortisol/cortisol ratio was unaffected by almorexant.

Conclusions

Our results suggest that the observed interaction was caused by the inhibition of CYP3A4 activity, most probably at the gut level.     

Effects of experimental diabetes on endothelin-induced ventricular arrhythmias in dogs

Endothelin-1 (ET-1) is known to have a direct arrhythmogenic effect in the mammalian heart. Diabetes mellitus is accompanied by a series of endothelial and cardiac disfunctions; however, little is known about ET-1-induced direct arrhythmias in diabetes mellitus. Therefore, we infused ET-1 (33 pmol/min) into the left anterior descending coronary artery of 28 mongrel dogs, and measured basic hemodynamic parameters, coronary flow and an electrocardiogram. Diabetes mellitus was induced by alloxan (Group 4) and experiments were carried out 8 weeks later. Metabolically healthy dogs served as controls (Group 2). In a further control group, local hyperglycemia was induced by intracoronary glucose infusion (Group 3). ET-1 infusion induced prolongation of the QT-time and frequency-adjusted QT-time in all groups. Other electrophysiological parameters were comparable between the groups. This was followed by the occurence of ventricular premature beats, coupled extra-beats and later sustained ventricular tachycardia. Most of the experiments were terminated by ventricular fibrillation. The onset of arrhythmias was shorter in diabetic dogs as compared with control and locally hyperglycemic animals (18 +/- 8 minutes versus 24 +/- 8 minutes and 30 +/- 28 minutes, P < 0.05). However, there was no difference in the number of ventricular fibrillations, and the total elapsed time until the termination of the experiments. Therefore, the diabetic heart seems to be more prone to ET-1-induced arrhythmias and this is probably not a result of locally high glucose concentrations.     

Inhibition of leukotriene biosynthesis by quinolone alkaloids from the fruits of Evodia rutaecarpa

The n-hexane extract of the fruits of Evodia rutaecarpa showed a considerable inhibiting effect on leukotriene biosynthesis in human granulocytes. Bioassay-guided fractionation of the extract led to the isolation of the 5 quinolone alkaloids: 1-methyl-2-nonyl-4(1H)-quinolinone, 1-methyl-2-(6Z)-6-undecenyl-4(1H)-quinolinone, 1-methyl-2-(4Z,7Z)-4,7-tridecadienyl-4(1H)-quinolinone, evocarpine and 1-methyl-2-(6Z,9Z)-6,9-pentadecadienyl-4(1H)-quinolinone. The compounds exhibited inhibitory activity on leukotriene biosynthesis in a bioassay using human polymorphonuclear granulocytes, with IC50 values of 12.1, 10.0, 10.1, 14,6 and 12.3 microM, respectively. Structure elucidation of the compounds was achieved by 1D and 2D NMR experiments and comparison of spectral data with literature data.