Malnutrition modifies the response to multimodal prehabilitation: a pooled analysis of prehabilitation trials.

Patients with colorectal cancer are at risk of malnutrition before surgery. Multimodal prehabilitation (nutrition, exercise, stress reduction) readies patients physically and mentally for their operation. However, it is unclear whether extent of malnutrition influences prehabilitation outcomes. We conducted a pooled analysis from five 4-week multimodal prehabilitation trials in colorectal cancer surgery (prehabilitation: n = 195; control: n = 71). Each patient's nutritional status was evaluated at baseline using the Patient-Generated Subjective Global Assessment (PG-SGA; higher score, greater need for treatment of malnutrition). Functional walking capacity was measured with the 6-minute walk test distance (6MWD) at baseline and before surgery. A multivariable mixed effects logistic regression model evaluated the potential modifying effect of PG-SGA on a clinically meaningful change of ≥19 m in 6MWD before surgery. Multimodal prehabilitation increased the odds by 3.4 times that colorectal cancer patients improved their 6MWD before surgery as compared with control (95% confidence interval (CI): 1.6 to 7.3; P = 0.001, n = 220). Nutritional status significantly modified this outcome (P = 0.007): Neither those patients with PG-SGA ≥9 (adjusted odds ratio: 1.3; 95% CI: 0.23 to 7.2, P = 0.771, n = 39) nor PG-SGA <4 (adjusted odds ratio: 1.3; 95% CI: 0.5 to 3.8, P = 0.574, n = 87) improved in 6MWD with prehabilitation. In conclusion, baseline nutritional status modifies prehabilitation effectiveness before colorectal cancer surgery. Patients with a PG-SGA score 4-8 appear to benefit most (physically) from 4 weeks of multimodal prehabilitation. Novelty: Nutritional status is an effect modifier of prehabilitation physical function outcomes. Patients with a PG-SGA score 4-8 benefited physically from 4 weeks of multimodal prehabilitation.

Prenatal exposure to maternal cigarette smoking and structural properties of the human corpus callosum.

Alterations induced by prenatal exposure to nicotine have been observed in experimental (rodent) studies. While numerous developmental outcomes have been associated with prenatal exposure to maternal cigarette smoking (PEMCS) in humans, the possible relation with brain structure is less clear. Here we sought to elucidate the relation between PEMCS and structural properties of human corpus callosum in adolescence and early adulthood in a total of 1,747 youth. We deployed three community-based cohorts of 446 (age 25-27 years, 46% exposed), 934 (age 12-18 years, 47% exposed) and 367 individuals (age 18-21 years, 9% exposed). A mega-analysis revealed lower mean diffusivity in the callosal segments of exposed males. We speculate that prenatal exposure to maternal cigarette smoking disrupts the early programming of callosal structure and increases the relative portion of small-diameter fibres.

Visceral fat enhances blood pressure reactivity to physical but not mental challenges in male adolescents.

BACKGROUND: Excess visceral fat is a major risk factor for hypertension. Enhanced blood pressure (BP) reactivity and delayed BP recovery from physical and mental challenges predict future hypertension. OBJECTIVES: Determine whether visceral fat is associated with higher BP reactivity and delayed BP recovery from physical and mental challenges during adolescence. METHODS: In a community-based sample of 283 male and 308 female adolescents, we measured visceral fat with magnetic resonance imaging, total body fat with bioimpedance, and beat-by-beat BP with a Finometer at rest and during physical (10-min standing) and mental (2-min math stress) challenges. RESULTS: Males vs. females showed greater BP reactivity and no differences in BP recovery from either type of challenges. Visceral fat was positively associated with BP reactivity to standing up only and in males only (+8.4 ± 3.6 mmHg per 1 log cm(3) of visceral fat, P = 0.008), and this association was independent of total body fat. No association was seen between visceral fat and BP recovery from either type of challenge in either sex. All these associations were independent of age, puberty stage, height and initial BP. CONCLUSIONS: Adolescent males vs. females demonstrate greater BP reactivity but similar BP recovery from physical and mental challenges. Excess visceral fat enhances BP reactivity to physical but not mental challenges in males only.

Saguenay Youth Study: a multi-generational approach to studying virtual trajectories of the brain and cardio-metabolic health.

This paper provides an overview of the Saguenay Youth Study (SYS) and its parental arm. The overarching goal of this effort is to develop trans-generational models of developmental cascades contributing to the emergence of common chronic disorders, such as depression, addictions, dementia and cardio-metabolic diseases. Over the past 10 years, we have acquired detailed brain and cardio-metabolic phenotypes, and genome-wide genotypes, in 1029 adolescents recruited in a population with a known genetic founder effect. At present, we are extending this dataset to acquire comparable phenotypes and genotypes in the biological parents of these individuals. After providing conceptual background for this work (transactions across time, systems and organs), we describe briefly the tools employed in the adolescent arm of this cohort and highlight some of the initial accomplishments. We then outline in detail the phenotyping protocol used to acquire comparable data in the parents.

Psychological characteristics of patients with myotonic dystrophy type 1.

OBJECTIVES: Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy. It is associated with motor symptoms but patients also display non-motor symptoms such as particular personality traits. Studies have reported mixed results about personality characteristics which may be attributable to small sample sizes, different disease severity of groups studied, and use of different questionnaires or method. This study aimed to describe the psychological characteristics of a large cohort of patients with DM1, to characterize those at risk of developing a psychiatric disorder, and to compare characteristics between two DM1 phenotypes, a mild and more severe adult-onset phenotype. METHODS: Two hundred patients with DM1 (152 adult-onset; 48 mild) were asked to complete questionnaires assessing personality traits, psychological symptoms, self-esteem, and suicidal risk. Neurological and neuropsychological assessments were performed to compare personality characteristics to clinical and cognitive measures. RESULTS: Patients with DM1 globally showed personality traits and psychological symptoms in the average range compared to normative data, with normal levels of self-esteem and suicidal ideation. However, 27% of patients were found to be at high risk of developing a psychiatric disorder. Moreover, psychological traits differed across phenotypes, with the most severe phenotype tending to show more severe psychological symptoms. The presence of higher phobic anxiety and lower self-esteem was associated with lower education, a higher number of CTG repeats, more severe muscular impairment, and lower cognitive functioning (P < 0.001). CONCLUSIONS: Different phenotypes should thus be taken into account in clinical settings for individual management of patients and optimizing therapeutic success.

Unilateral Möbius syndrome: two cases and a review of the literature.

IMPORTANCE: The Möbius sequence is a rare condition defined by the combination of congenital non-progressive facial and abducens nerve palsies. The etiology of the sequence is still unknown, but likely encompasses a group of heterogeneous disorders involving genetic maldevelopment of the brainstem, a fetal vascular insult and/or teratogen exposure. The clinical phenotype reported has expanded over the years, and may be associated with more extensive cranial nerve and oropharyngeal involvement, as well as limb defects. OBSERVATIONS: We describe two cases of children presenting with unilateral Möbius syndrome associated with ipsilateral unilateral palatal weakness. Investigations failed to identified a clear underlying etiology, but both cases shared phenotypic features of other more common cranial facial disorders such as craniofacial microsomia and the velocardiofacial syndrome. CONCLUSION AND RELEVANCE: These two cases highlight the clinical heterogeneity of the Möbius sequence. Although asymmetries are not uncommon, cases with strictly unilateral features are extremely rare, and as such these may represent a distinct subgroup that may pertain to a specific etiology. Although in many cases, evidence of an intrauterine vascular insult may be identified, a contributing genetic etiology should be considered, even in cases with strictly unilateral features. As such genes expressed in the developing rhombencephalon and its vasculature represent good candidates for future investigation.

Opioid receptor mu 1 gene, fat intake and obesity in adolescence.

Dietary preference for fat may increase risk for obesity. It is a complex behavior regulated in part by the amygdala, a brain structure involved in reward processing and food behavior, and modulated by genetic factors. Here, we conducted a genome-wide association study (GWAS) to search for gene loci associated with dietary intake of fat, and we tested whether these loci are also associated with adiposity and amygdala volume. We studied 598 adolescents (12-18 years) recruited from the French-Canadian founder population and genotyped them with 530 011 single-nucleotide polymorphisms. Fat intake was assessed with a 24-hour food recall. Adiposity was examined with anthropometry and bioimpedance. Amygdala volume was measured by magnetic resonance imaging. GWAS identified a locus of fat intake in the µ-opioid receptor gene (OPRM1, rs2281617, P=5.2 × 10(-6)), which encodes a receptor expressed in the brain-reward system and shown previously to modulate fat preference in animals. The minor OPRM1 allele appeared to have a 'protective' effect: it was associated with lower fat intake (by 4%) and lower body-fat mass (by ∼2 kg, P=0.02). Consistent with the possible amygdala-mediated inhibition of fat preference, this allele was additionally associated with higher amygdala volume (by 69 mm(3), P=0.02) and, in the carriers of this allele, amygdala volume correlated inversely with fat intake (P=0.02). Finally, OPRM1 was associated with fat intake in an independent sample of 490 young adults. In summary, OPRM1 may modulate dietary intake of fat and hence risk for obesity, and this effect may be modulated by subtle variations in the amygdala volume.

Visceral fat is associated with lower executive functioning in adolescents.

BACKGROUND: Obesity, a major risk factor for cardiometabolic disease, is associated with lower cognitive performance from childhood to senescence, especially on tasks of executive function. In the cardiovascular domain, fat stored viscerally rather than elsewhere in the body carries particularly high risk. It is unknown whether this is also true in case of obesity-cognition relationships. The aim of this study was to assess the cross-sectional relationship between visceral fat (VF) and cognitive performance in a community sample of healthy adolescents. METHODS: In a community-based sample of 983 adolescents (12-18 years old, 480 males), VF was quantified using magnetic resonance imaging, total body fat was measured using a multifrequency bioimpedance, and cognitive performance was assessed using a battery of cognitive tests measuring executive function and memory. RESULTS: We found that larger volumes of VF were associated with lower performance on six measures of executive function (P=0.0001-0.02). We also found that the association of VF with executive function was moderated by sex for a subset of measures, such that relationship was present mainly in female subjects and not in male subjects (sex-by-VF interaction: P=0.001-0.04). These relationships were independent of the quantity of total body fat and a number of potential confounders, including age, puberty stage and household income. CONCLUSIONS: Our results suggest that the adverse association between obesity and executive function may be attributed to fat stored viscerally and not to fat stored elsewhere in the body. They also suggest that female subjects compared with male subjects may be more sensitive to the potentially detrimental effects of VF on cognition.

Troubleshooting the rabbit ferric chloride-induced arterial model of thrombosis to assess in vivo efficacy of antithrombotic drugs.

INTRODUCTION: The FeCl3-induced arterial model of thrombosis is one of the most widely used animal models to assess arterial efficacy of new antithrombotic drug candidates. This model is well-established in rodents but in a less extent in the rabbit. In this work, we present a methodology for a rabbit FeCl3-induced arterial model of thrombosis derived from our troubleshooting which allows the generation of reliable efficacy data for new antithrombotic drug candidates. METHODS: Rabbits were administered with heparin 4.5U/kg/min, argatroban 10µg/kg/min or saline by intravenous infusion. The blood flow was monitored using a Doppler flow probe. The time from the application of FeCl3 to the recorded zero blood flow was defined as the time to occlusion, with a maximum recording time of 60min post-FeCl3 application. After 30min of infusion, thrombosis was induced by wrapping a FeCl3-saturated filter paper around the carotid artery caudal to the flow probe. Animals were subject to exclusion criteria based on the visual aspect of the artery FeCl3-induced injury and based on changes in blood flow upon FeCl3 application. RESULTS: Following the application of FeCl3, a mean time to occlusion for saline, heparin and argatroban of 24.3±1.8, 52.5±4.8 and 53.5±4.5min was obtained, respectively. Mean time to occlusion for heparin and argatroban administered groups was significantly different when compared to the saline-treated group (p<0.05). These results for the test compounds represent approximately 80% of the maximum possible prolongation. DISCUSSION: The rabbit FeCl3-induced arterial model of thrombosis presented in this paper derived from our troubleshooting is sensitive and reproducible for the generation of accurate and reliable efficacy data in the assessment of new antithrombotic agents in preclinical drug development.

An optimized method to assess in vivo efficacy of antithrombotic drugs using optical coherence tomography and a modified Doppler flow system.

INTRODUCTION: Animal models of venous and arterial thrombosis are extremely useful to study the efficacy of antithrombotic agents. Variability in efficacy data is often observed in those preclinical studies. The goal of this study was to optimize the methodology for assessing antithrombotic drug efficacy by the use of optical coherence tomography (OCT) and a modified Doppler flow system in rat models of thrombosis. METHODS: Thrombus formation was assessed in both the rat venous and arterial ferric chloride (FeCl(3)) models of thrombosis. In the venous model, thrombus volume post-treatment was measured using OCT, and data were correlated against the thrombus weight. In the arterial model, the time to occlusion was measured using a Doppler flow probe connected to a perivascular flow module which allowed the reporting of dynamic blood flow data every 30s. Heparin (130 or 165U/kg), argatroban (4.5mg/kg), bivalirudin (1.3mg/kg) or saline were administered intravenously. RESULTS: In the venous model, for all treatment groups a strong linear correlation (R(2)=0.998) was observed between thrombus volume measured by OCT and thrombus weight. In the arterial model, using a high sampling rate of a dynamic blood flow using a modified Doppler flow system provided data accuracy and precision of the time to occlusion measurement. DISCUSSION: This study demonstrates that OCT is a powerful tool for the assessment of antithrombotic drug efficacy. Furthermore, it shows that a high Doppler sampling rates of dynamic blood flow leads to data accuracy and precision.

Autonomic nervous system dysfunction in obesity and Prader-Willi syndrome: current evidence and implications for future obesity therapies.

The autonomic nervous system (ANS) controls essential functions like breathing, heart rate, digestion, body temperature and hormone levels. Evidence suggests that ANS dysfunction is associated with adult and childhood obesity and plays a role in the distribution of total body fat and the development of obesity-related complications in humans. This review summarizes our current understanding of ANS involvement in the pathogenesis of obesity and Prader-Willi syndrome. Available evidence of ANS dysfunction in the control of energy balance is limited and, in some cases, contradictory. Further investigation in this area is warranted in order to better understand the important contributions of the ANS to regulation of body fat, development of obesity and its comorbidities. Results from these studies will guide the development of novel obesity therapeutics targeting specific ANS dysfunction.

Clinical and genetic knowledge and attitudes of patients with myotonic dystrophy type 1.

AIMS: The goal was to assess clinical and genetic knowledge and attitudes in patients affected by myotonic dystrophy type 1 (DM1). METHODS: Two hundred patients with molecular confirmation of the diagnosis of DM1 completed a multi-choice questionnaire. DM1 patients' knowledge and views were compared to clinically normal DM1 noncarriers (n = 264) and controls (n = 1,474). RESULTS: Knowledge of the DM1 mode of inheritance was better in noncarriers than in patients (p < 0.001). Noncarriers were more aware than DM1 patients of the common clinical characteristics of DM1 such as limitations in physical activities and problems related to employment, schooling, activities of daily living, parenthood, peer relationships, and personality (p < 0.001). Compared to controls, DM1 patients felt less informed about the availability of clinical genetic services (p < 0.05) and new genetic technologies (p < 0.001). Among patients, logistic regression revealed that each additional year of education (p < 0.05) and each additional 100 CTG repeats (p < 0.01), respectively, increased and decreased the odds of knowing the DM1 mode of inheritance by about 23% and 18% respectively, independently of age, age at onset of symptoms, gender, severity of muscular impairment, and intellectual quotient. CONCLUSIONS: DM1 patients' genetic knowledge is significantly dependent of the level of education and the number of CTG repeats. Healthcare providers should be aware of this situation in order to adjust counselling and education accordingly.

Sexual dimorphism in the adolescent brain: Role of testosterone and androgen receptor in global and local volumes of grey and white matter.

Here we examined sex differences in the volumes of grey and white matter, and in grey-matter "density," in a group of typically developing adolescents participating in the Saguenay Youth Study (n=419; 12-18 years). In male adolescents, we also investigated the role of a functional polymorphism in androgen-receptor gene (AR) in moderating the effect of testosterone on volumes of grey and white matter and grey-matter density. Overall, both absolute and relative volumes of white matter were larger in male vs. females adolescents. The relative grey-matter volumes were slightly larger in female than male adolescents and so was the grey-matter density in a large number of cortical regions. In male adolescents, functional polymorphism of AR moderated the effect of testosterone on relative white- and grey-matter volumes. Following a discussion of several methodological and interpretational issues, we outline future directions in investigating brain-behavior relationships vis-à-vis psychopathology.

Sex differences in the growth of white matter during adolescence.

The purpose of this study was to examine sex differences in the maturation of white matter during adolescence (12 to 18 years of age). We measured lobular volumes of white matter and white-matter "density" throughout the brain using T1-weighted images, and estimated the myelination index using magnetisation-transfer ratio (MTR). In male adolescents, we observed age-related increases in white-matter lobular volumes accompanied by decreases in the lobular values of white-matter MTR. White-matter density in the putative cortico-spinal tract (pCST) decreased with age. In female adolescents, on the other hand, we found only small age-related increase in white-matter volumes and no age-related changes in white-matter MTR, with the exception of the frontal lobe where MTR increased. White-matter density in the pCST also increased with age. These results suggest that sex-specific mechanisms may underlie the growth of white matter during adolescence. We speculate that these mechanisms involve primarily age-related increases in axonal calibre in males and increased myelination in females.

Maternal cigarette smoking during pregnancy and cognitive performance in adolescence.

BACKGROUND: The incidence of cigarette smoking during pregnancy remains high. Maternal smoking during pregnancy is known to be associated with cognitive and behavioural sequelae in childhood and adolescence. We assessed the relationship between maternal cigarette smoking during pregnancy and cognitive abilities in adolescent offspring (n = 503, 12- to 18-years old) using an extensive 6-h battery of tests. METHODS: Non-exposed adolescents (controls) were matched to exposed adolescents (cases) by maternal education and school attended. Cognitive abilities were evaluated using a neuropsychological battery consisting of 33 tasks measuring verbal abilities, visuo-spatial skills, verbal and visual memory, processing speed, resistance to interference and motor dexterity. RESULTS: We found no differences between cases and controls in any of the cognitive domains whether potential confounders were included in the model or not. In addition to maternal smoking during pregnancy, we also evaluated the effect of sex and age on the various cognitive abilities in this large adolescent sample and found that most of the abilities continue to improve during adolescence to the same extent in girls and boys, with several age-independent sex differences. CONCLUSIONS: We found no effect of maternal cigarette smoking during pregnancy on cognitive abilities of the adolescent offspring when matching cases and controls by maternal education, the most common confounder of maternal cigarette smoking during pregnancy.

Corpus callosum in adolescent offspring exposed prenatally to maternal cigarette smoking.

Teratogens, such as alcohol or anti-epileptic drugs, affect the size of the corpus callosum. Here we report findings obtained in a case-control study that investigated possible effects of teratogens contained in cigarette smoke on the size and structural properties of this structure. We recruited and scanned with magnetic resonance imaging a total of 408 adolescents (12 to 18 years of age); a subsample of 300 adolescents is considered in this report. Cases (n=146) were exposed to maternal cigarette smoking during pregnancy; non-exposed controls (n=154) were matched to cases by maternal education. We measured the size of corpus callosum (CC) and its sections (corrected for brain size), as well as mean values of magnetization-transfer ratio (MTR) in each CC section. Corpus callosum, and especially its posterior part, was smaller in the exposed vs. non-exposed female adolescents; no significant effects were found in males. Exposed and non-exposed subjects did not differ in the MTR-based index of myelination in either gender in any CC section. Given the lack of exposure effect on the myelination index, this finding might reflect a lower number of inter-hemispheric connections in female offspring of mothers who smoked during pregnancy.

Development of a multi-channel system for intrinsic cardiac neural recording.

Recent clinical evidence suggests that abnormal neural input can contribute to the onset perpetuation of atrial arrhythmias, such that neural elements have become potential targets for ablation. A better understanding of the influence of the cardiac autonomous nervous system is required to improve therapy. We have developed a multi-channel system to record neural activity simultaneously at different intra and pericardiac locations. The paper presents the specific requirements to be met for recording neuronal extracellular potentials in these repertoires of neurons and the solutions that were adopted.

Diagnostic profile of neonatal hypotonia: an 11-year study.

The profile of disorders presenting with neonatal hypotonia to the neonatal intensive care unit has not been studied previously. An 11-year retrospective cohort study of neonates, who were identified through computer database records and were admitted to the Neonatal Intensive Care Unit from January 1989 to December 1999 at the Montreal Children's Hospital (Montreal, Québec), is presented. The final diagnoses, tests obtained, and outcome were determined from a structured review of the subject's hospital record. The database search generated 95 records, of which 50 neonates met the inclusion criteria. The hypotonia was classified as central in 33 patients (66%) and peripheral in 17 (34%). Hypoxic-ischemic encephalopathy (n = 13), Prader-Willi syndrome (n = 6), myotonic dystrophy (n = 6), other muscle disorders (n = 6), chromosomal disorders (n = 4), and peripheral nerve disorders (n = 3) were the most common diagnoses. The genetic tests of highest yield were fluorescent in situ hybridization for Prader-Willi syndrome, DNA methylation studies for Prader-Willi syndrome, trinucleotide repeat testing for myotonic dystrophy, and karyotype analysis. A diagnostic approach is proposed based on the results.