Outcomes of children with constipation and autism spectrum disorder treated with antegrade continence enemas.

BACKGROUND: Treatment of functional constipation (FC) in children with autism spectrum disorder (ASD) is challenging due to sensory and behavioral issues. We aimed to understand whether antegrade continence enemas (ACEs) are successful in the treatment of FC in children with ASD. METHODS: A single-institution retrospective review was performed in children diagnosed with ASD and FC who underwent appendicostomy or cecostomy placement from 2007 to 2019. Descriptive statistics regarding soiling and complications were calculated. RESULTS: There were 33 patients included, with a median age of 9.7 years at the time of ACE initiation. The average intelligence quotient was 63.6 (SD = 18.0, n = 12), the average behavioral adaptive score was 59.9 (SD = 11.1, n = 13), and the average total Child Behavioral Checklist score was 72.5 (SD = 7.1, n = 10). Soiling rates were significantly lower following ACE initiation (42.3% vs. 14.8%, p = 0.04). Behavioral issues only prevented 1 patient (3.0%) from proper ACE use. Eleven patients (36.6%) were able to transition to laxatives. There were significant improvements in patient-reported outcomes measures and quality of life. CONCLUSION: Placement of an appendicostomy or cecostomy for management of FC in children with severe ASD was successful in treating constipation and improving quality of life.

Exploring the Effectiveness of an Integrated Physical Activity and Psychosocial Program Targeting At-Risk Adolescent Girls: Protocol for the Girls United and on the Move (GUM) Intervention Study.

BACKGROUND: Adolescents are highly susceptible to negative self-perceptions, likely due to their social cues and environment. The presence of these negative self-perceptions has been shown to adversely impact levels of physical activity (PA). Although PA has the ability to foster improved self-perceptions, the rates of PA among adolescents continue to descend, with girls appearing to be most susceptible to these declines. At-risk adolescent girls, who may experience a number of negative preceding lifestyle conditions, may be exceptionally vulnerable to declines in PA. There are a high number of adolescent girls from low-income and abusive households in British Columbia, Canada, thus indicating a need for a program to relay the importance of PA and healthy lifestyle behaviors. OBJECTIVE: This paper aims to describe the protocol of the Girls United and on the Move (GUM) pragmatic intervention, an integrated PA and psychosocial program aimed at improving self-compassion, social connectedness, and overall self-perceptions among at-risk adolescent girls. METHODS: Using a quasi-experimental mixed methods approach, the GUM intervention was conducted in 5 schools in British Columbia, Canada. Adolescent girls aged 11 to 15 years who were identified as at risk were included in the study. The 9-week intervention, co-delivered by a PA/health promotion-trained researcher and a registered social worker, involved a PA component and a psychosocial component with evidence-based topics addressing the concerns of the adolescent girls. The following outcomes were evaluated: PA, self-compassion, social support, leader supportiveness, and sport enjoyment and commitment. Program acceptability and satisfaction was also examined. Outcome measures were assessed at baseline (week 1), week 6, and postintervention (week 9), and interview data concerning program acceptability and satisfaction were collected at postintervention from a subsample of participants. RESULTS: A total of 101 participants were invited to participate in the GUM intervention. Reporting of the results is projected for the fall of 2020. CONCLUSIONS: It is anticipated that the GUM intervention will enhance PA while also improving self-compassion, social connectedness, and overall self-perceptions among at-risk adolescent girls. The findings of this research will contribute to the literature concerning PA and various psychosocial factors that impact the physical and mental health of at-risk adolescent girls. TRIAL REGISTRATION: Clinicaltrials.gov NCT03567200; https://clinicaltrials.gov/ct2/show/NCT03567200. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15302.

Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: A randomized phase II study of the Sarah Cannon Research Institute (SCRI).

PURPOSE: To evaluate the efficacy of erlotinib, continued after tumor progression, plus sorafenib versus sorafenib alone in patients with refractory metastatic non-small cell lung cancer (NSCLC) who previously benefitted from single-agent erlotinib. PATIENTS AND METHODS: Patients with progressive refractory NSCLC who had previously benefitted from erlotinib (objective response or stable disease >8weeks) were randomized to receive treatment with either erlotinib and sorafenib (400mg orally twice daily) or sorafenib alone. Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. RESULTS: Fifty-three patients were randomized (erlotinib/sorafenib, 25; sorafenib, 28) and 52 patients received study treatment. Patients in both groups received a median of 8weeks of treatment. The median PFS was 3.1months for erlotinib/sorafenib versus 1.7months for sorafenib alone; response rates were 8% and 4%, respectively. Both regimens were tolerable, but toxicity was more frequent with erlotinib/sorafenib. CONCLUSIONS: These results do not suggest any benefit in continuing erlotinib after tumor progression in patients with refractory metastatic NSCLC. Both regimens tested had limited efficacy, consistent with results from other studies. ClinicalTrials.gov ID:NCT00609804.

Referrals to integrative medicine in a tertiary hospital: findings from electronic health record data and qualitative interviews.

OBJECTIVE: To examine patterns of, and decision-making processes, informing referrals for inpatient access to integrative medicine (IM) services at a large, acute care hospital. DESIGN: Retrospective electronic health record review and structured qualitative interviews. SETTING: A 630-bed tertiary care hospital with an IM service available to inpatients. PARTICIPANTS: IM referrals of all inpatients aged ≥18 years between July 2012 and December 2014 were identified using the hospital's electronic health record. Fifteen physicians, 15 nurses and 7 administrators were interviewed to better understand roles and perspectives in referring patients for IM services. RESULTS: In the study hospital, primary sources of referrals for IM services were the orthopaedic and neuroscience/spine service lines. While the largest absolute number of IM referrals was made for patients with lengths of stay of 3 days or fewer, a disproportionate number of total IM referrals was made for patients with long lengths of stay (≥10 days), compared with a smaller percentage of patients in the hospital with lengths of stay ≥10 days. Physicians and nurses were more likely to refer patients who displayed strong symptoms (eg, pain and anxiety) and/or did not respond to conventional therapies. IM referrals were predominantly nurse-initiated. A built-in delay in the time from referral initiation to service delivery discouraged referrals of some patients. CONCLUSIONS: Conventional providers refer patients for IM services when these services are available in a tertiary hospital. Referral patterns are influenced by patient characteristics, operational features and provider perspectives. Nurses play a key role in the referral process. Overcoming cultural and knowledge differences between conventional and IM providers is likely to be a continuing challenge to providing IM in inpatient settings.

Practitioner Perspectives on Delivering Integrative Medicine in a Large, Acute Care Hospital.

Background. We describe the process and challenges of delivering integrative medicine (IM) at a large, acute care hospital, from the perspectives of IM practitioners. To date, minimal literature that addresses the delivery of IM care in an inpatient setting from this perspective exists. Methods. Fifteen IM practitioners were interviewed about their experience delivering IM services at Abbott Northwestern Hospital (ANW), a 630-bed tertiary care hospital. Themes were drawn from codes developed through analysis of the data. Results. Analysis of interview transcripts highlighted challenges of ensuring efficient use of IM practitioner resources across a large hospital, the IM practitioner role in affecting patient experiences, and the ways practitioners navigated differences in IM and conventional medicine cultures in an inpatient setting. Conclusions. IM practitioners favorably viewed their role in patient care, but this work existed within the context of challenges related to balancing supply and demand for services and to integrating an IM program into the established culture of a large hospital. Hospitals planning IM programs should carefully assess the supply and demand dynamics of offering IM in a hospital, advocate for the unique IM practitioner role in patient care, and actively support integration of conventional and complementary approaches.

Calcium supplementation and parathyroid hormone response to vigorous walking in postmenopausal women.

INTRODUCTION: Disruptions in calcium (Ca) homeostasis during exercise may influence skeletal adaptations to exercise training. In young men, vigorous cycling causes increases in parathyroid hormone (PTH) and bone resorption (C-terminal telopeptides of type I collagen [CTX]); responses are attenuated by Ca supplementation. The study aimed to determine whether vigorous walking causes similar increases in PTH and CTX in older women and how the timing of Ca supplementation before and during exercise influences these responses. METHODS: In experiment 1, 10 women (61 ± 4 yr) consumed 125 mL of either a Ca-fortified (1 g·L) or control beverage every 15 min during exercise starting 60 min before and continuing during 60 min of exercise. In experiment 2, 23 women (61 ± 4 yr) consumed 200 mL of a Ca-fortified (1 g·L) or control beverage every 15 min starting 15 min before and continuing during 60 min of exercise. The exercise was treadmill walking at 75%-80% V˙O2peak. RESULTS: In experiment 1, serum ionized Ca decreased in the control condition (P < 0.001), but not with Ca supplementation. PTH increased after exercise on both days (Ca, P = 0.05; control, P = 0.009) but was attenuated by Ca supplementation (8.3 vs 26.1 pg·mL; P = 0.03). CTX increased only on the control day (P = 0.02). In experiment 2, serum ionized Ca decreased on Ca and control days (Ca and control, P < 0.001), but less so on the Ca day (P = 0.04). PTH (Ca and control, P < 0.001) and CTX (Ca, P = 0.02; control P = 0.007) increased on the Ca and control day, and there were no differences in the changes. CONCLUSION: The timing of Ca supplementation may be a key mediator of Ca homeostasis during acute exercise. Further research is necessary to determine how this influences skeletal adaptations to training.

Contributions of Philip Teitelbaum to affective neuroscience.

As part of a festschrift issue for Philip Teitelbaum, I offer here the thesis that Teitelbaum deserves to be viewed as an important forefather to the contemporary field of affective neuroscience (which studies motivation, emotion and affect in the brain). Teitelbaum's groundbreaking analyses of motivation deficits induced by lateral hypothalamic damage, of roles of food palatability in revealing residual function, and of recovery of 'lost' functions helped shape modern understanding of how motivation circuits operate within the brain. His redefinition of the minimum requirement for identifying motivation raised the conceptual bar for thinking about the topic among behavioral neuroscientists. His meticulous analyses of patterned stages induced by brain manipulations, life development and clinical disorders added new dimensions to our appreciation of how brain systems work. His steadfast highlighting of integrative functions and behavioral complexity helped provide a healthy functionalist counterbalance to reductionist trends in science of the late 20th century. In short, Philip Teitelbaum can be seen to have made remarkable contributions to several domains of psychology and neuroscience, including affective neuroscience.

Acute calcium ingestion attenuates exercise-induced disruption of calcium homeostasis.

PURPOSE: Exercise is associated with a decrease in bone mineral density under certain conditions. One potential mechanism is increased bone resorption due to an exercise-induced increase in parathyroid hormone (PTH), possibly triggered by dermal calcium loss. The purpose of this investigation was to determine whether calcium supplementation either before or during exercise attenuates exercise-induced increases in PTH and C-terminal telopeptide of Type I collagen (CTX; a marker of bone resorption). METHODS: Male endurance athletes (n = 20) completed three 35-km cycling time trials under differing calcium supplementation conditions: 1) 1000 mg of calcium 20 min before exercise and placebo during, 2) placebo before and 250 mg of calcium every 15 min during exercise (1000 mg total), or 3) placebo before and during exercise. Calcium was delivered in a 1000-mg·L(-1) solution. Supplementation was double-blinded, and trials were performed in random order. PTH, CTX, bone-specific alkaline phosphatase (BAP; a marker of bone formation), and ionized calcium (iCa) were measured before and immediately after exercise. RESULTS: CTX increased and iCa decreased similarly in response to exercise under all test conditions. When compared with placebo, calcium supplementation before exercise attenuated the increase in PTH (mean ± SE: 55.8 ± 15.0 vs 74.0 ± 14.2 pg·mL(-1), P = 0.04); there was a similar trend (58.0 ± 17.4, P = 0.07) for calcium supplementation during exercise. There were no effects of calcium on changes in CTX, BAP, and iCa. CONCLUSIONS: Calcium supplementation before exercise attenuated the disruption of PTH. Further research is needed to determine the effects of repeated increases in PTH and CTX on bone (i.e., exercise training) and whether calcium supplementation can diminish any exercise-induced demineralization.

Prolonged maternal amino acid infusion in late-gestation pregnant sheep increases fetal amino acid oxidation.

Protein supplementation during human pregnancy does not improve fetal growth and may increase small-for-gestational-age birth rates and mortality. To define possible mechanisms, sheep with twin pregnancies were infused with amino acids (AA group, n = 7) or saline (C group, n = 4) for 4 days during late gestation. In the AA group, fetal plasma leucine, isoleucine, valine, and lysine concentrations were increased (P < 0.05), and threonine was decreased (P < 0.05). In the AA group, fetal arterial pH (7.365 +/- 0.007 day 0 vs. 7.336 +/- 0.012 day 4, P < 0.005), hemoglobin-oxygen saturation (46.2 +/- 2.6 vs. 37.8 +/- 3.6%, P < 0.005), and total oxygen content (3.17 +/- 0.17 vs. 2.49 +/- 0.20 mmol/l, P < 0.0001) were decreased on day 4 compared with day 0. Fetal leucine disposal did not change (9.22 +/- 0.73 vs. 8.09 +/- 0.63 micromol x min(-1) x kg(-1), AA vs. C), but the rate of leucine oxidation increased 43% in the AA group (2.63 +/- 0.16 vs. 1.84 +/- 0.24 micromol x min(-1) x kg(-1), P < 0.05). Fetal oxygen utilization tended to be increased in the AA group (327 +/- 23 vs. 250 +/- 29 micromol x min(-1) x kg(-1), P = 0.06). Rates of leucine incorporation into fetal protein (5.19 +/- 0.97 vs. 5.47 +/- 0.89 micromol x min(-1) x kg(-1), AA vs. C), release from protein breakdown (4.20 +/- 0.95 vs. 4.62 +/- 0.74 micromol x min(-1) x kg(-1)), and protein accretion (1.00 +/- 0.30 vs. 0.85 +/- 0.25 micromol x min(-1) x kg(-1)) did not change. Consistent with these data, there was no change in the fetal skeletal muscle ubiquitin ligases MaFBx1 or MuRF1 or in the protein synthesis regulators 4E-BP1, eEF2, eIF2alpha, and p70(S6K). Decreased concentrations of certain essential amino acids, increased amino acid oxidation, fetal acidosis, and fetal hypoxia are possible mechanisms to explain fetal toxicity during maternal amino acid supplementation.

Clinical NOE 13C MRS for neuropsychiatric disorders of the frontal lobe.

In this communication, a scheme is described whereby in vivo (13)C MRS can safely be performed in the frontal lobe, a human brain region hitherto precluded on grounds of SAR, but important in being the seat of impaired cognitive function in many neuropsychiatric and developmental disorders. By combining two well known features of (13)C NMR-the use of low power NOE and the focus on (13)C carbon atoms which are only minimally coupled to protons, we are able to overcome the obstacle of SAR and develop means of monitoring the (13)C fluxes of critically important metabolic pathways in frontal brain structures of normal volunteers and patients. Using a combination of low-power WALTZ decoupling, variants of random noise for nuclear overhauser effect enhancement it was possible to reduce power deposition to 20% of the advised maximum specific absorption rate (SAR). In model solutions (13)C signal enhancement achieved with this scheme were comparable to that obtained with WALTZ-4. In human brain, the low power procedure effectively determined glutamine, glutamate and bicarbonate in the posterior parietal brain after [1-(13)C] glucose infusion. The same (13)C enriched metabolites were defined in frontal brain of human volunteers after administration of [1-(13)C] acetate, a recognized probe of glial metabolism. Time courses of incorporation of (13)C into cerebral glutamate, glutamine and bicarbonate were constructed. The results suggest efficacy for measurement of in vivo cerebral metabolic rates of the glutamate-glutamine and tricarboxylic acid cycles in 20 min MR scans in previously inaccessible brain regions in humans at 1.5 T. We predict these will be clinically useful biomarkers in many human neuropsychiatric and genetic conditions.

Cloning and characterization of a lipid-activated CTP:phosphocholine cytidylyltransferase from Caenorhabditis elegans: identification of a 21-residue segment critical for lipid activation.

The genome of the nematode Caenorhabditis elegans contains several genes that appear to encode proteins similar to CTP:phosphocholine cytidylyltransferase (CCT). We have isolated a 1044-nucleotide cDNA clone from a C. elegans cDNA library that encodes the 347-amino acid version of CCT that is most similar to previously-identified CCTs. Native and His-tagged forms were expressed and purified using a baculovirus expression system. The enzyme was maximally activated by 5 microM phosphatidylcholine:oleate (50:50) vesicles with a k(cat) value in the presence of lipid 37-fold greater than the k(cat) value in the absence of lipid. To localize the region of C. elegans CCT critical for lipid activation, a series of C-terminal truncation mutants was analyzed. CCT truncated after amino acids 225 or 245 was quite active in the absence of lipids and not further activated in the presence of lipids, supporting the concept that the lipid-activation segment is inhibitory to catalysis in the absence of lipids. CCT truncated after amino acids 266, 281, or 319 was activated by lipid similar to wild-type enzyme. Kinetic analysis in the absence of lipid revealed the lipid-independent CCT truncated after amino acid 245 to have a k(cat) value 15-fold greater than either full-length CCT or CCT truncated after amino acid 266. We conclude that elements critical for activation of C. elegans CCT by lipids are contained within amino acids 246-266, that this region is inhibitory in the absence of lipids, and that the inhibition is relieved by the association of the enzyme with lipid.

Enzymatic and cellular characterization of a catalytic fragment of CTP:phosphocholine cytidylyltransferase alpha.

To probe the mechanism of lipid activation of CTP:phosphocholine cytidylyltransferase (CCTalpha), we have characterized a catalytic fragment of the enzyme that lacks the membrane-binding segment. The kinetic properties of the purified fragment, CCTalpha236, were characterized, as well as the effects of expressing the fragment in cultured cells. CCTalpha236 was truncated after residue 236, which corresponds to the end of the highly conserved catalytic domain. The activity of purified CCTalpha236 was independent of lipids and about 50-fold higher than the activity of wild-type CCTalpha assayed in the absence of lipids, supporting a model in which the membrane-binding segment functions as an inhibitor of the catalytic domain. The kcat/Km values for CCTalpha236 were only slightly lower than those for lipid-activated CCTalpha. The importance of the membrane-binding segment in vivo was tested by expression of CCTalpha236 in CHO58 cells, a cell line that is temperature-sensitive for growth and CCTalpha activity. Expression of wild-type CCTalpha in these cells complemented the defective growth phenotype when the cells were cultured in complete or delipidated fetal bovine serum. Expression of CCTalpha236, however, did not complement the growth phenotype in the absence of serum lipids. These cells were capable of making phosphatidylcholine in the delipidated medium, so the inability of the cells to grow was not due to defective phosphatidylcholine synthesis. Supplementation of the delipidated medium with an unsaturated fatty acid allowed growth of CHO58 cells expressing CCTalpha236. These results indicate that the membrane-binding segment of CCTalpha has an important role in cellular lipid metabolism.

Expression of wild-type and mutant rat liver CTP: phosphocholine cytidylyltransferase in a cytidylyltransferase-deficient Chinese hamster ovary cell line.

The strain 58 Chinese hamster ovary (CHO) mutant defective in CTP:phosphocholine cytidylyltransferase was characterized as an expression system for exogenous cytidylyltransferase. Strain 58 cells express less than 5% of the wild-type level of cytidylyltransferase protein at the permissive temperature even though the steady-state messenger RNA levels were found to be similar to those in the parental CHO-K1 cell line. A point mutation from arginine to histidine at amino acid 140 was identified in the strain 58 protein. Rat liver cytidylyltransferase was stably expressed in strain 58 cells and shown to be active, targeted to the nucleus, phosphorylated, and activated by methylethanolamine supplementation or phospholipase C treatment. Thus, the mechanisms by which cytidylyltransferase is processed and regulated in CHO-K1 cells are intact in strain 58 cells. The heterologously expressed protein complemented the strain 58 defects in both temperature-sensitive growth and phosphatidylcholine biosynthesis, consistent with a single lesion in the structural gene for cytidylyltransferase being responsible for both phenomena. Overexpression of cytidylyltransferase activity at levels up to eightfold higher than those in CHO-K1 cells did not appreciably affect phosphatidylcholine metabolism. A putative casein kinase II phosphorylation site was altered by site-directed mutagenesis and expressed in the strain 58 cells. Alteration of this site did not affect expression and regulation of cytidylyltransferase activity.

Immunolocalization of membrane-associated CTP:phosphocholine cytidylyltransferase in phosphatidylcholine-deficient Chinese hamster ovary cells.

The location of CTP:phosphocholine cytidylyltransferase in Chinese hamster ovary (CHO) cells made deficient in phosphatidylcholine was determined by immunofluorescence techniques. A rabbit polyclonal antibody was raised against a synthetic peptide corresponding to the amino-terminal 17 amino acid residues of rat liver cytidylyltransferase. The antibody recognized both native and denatured cytidylyltransferase from both rat liver and CHO cells. CHO cells were treated with phospholipase C to alter the lipid composition of the plasma membrane and to elicit translocation of cytidylyltransferase from the less active soluble pool to an activated membrane fraction. Visualization of cytidylyltransferase by indirect immunofluorescence revealed staining of the nuclear envelope in phospholipase C-treated cells but not in untreated cells. CHO cells were also starved for choline and supplemented with a choline analogue to provide an alternative technique of rendering the cells phosphatidylcholine-deficient. Although this treatment should affect different cellular membranes than those affected by phospholipase C treatment, cytidylyltransferase still translocated to the nuclear envelope, as shown by indirect immunofluorescence. These results indicate that activated, membrane-bound cytidylyltransferase is associated with the nuclear membrane and suggest that the nuclear membrane may be a site of de novo phosphatidylcholine synthesis.