Assessing adherence to objective disease monitoring and outcomes with adalimumab in a real-world IBD cohort.

BACKGROUND: Data suggests that tight objective monitoring may improve clinical outcomes in IBD. AIM: To assess the adherence to serial tight objective monitoring(clinical and biomarkers) and its effect on clinical outcomes. METHODS: We retrospectively reviewed the chart of 428 consecutive IBD patients started on adalimumab between January 1,2015-January 1,2019 [338 Crohn's disease(CD), 90 ulcerative colitis(UC)]. Clinical symptoms(assessed by Harvey-Bradshaw-Index,partial Mayo),C-Reactive Protein(CRP), and fecal calprotectin(FCAL) assessments were captured at treatment initiation and at 3,6,9, and12 months. Dose optimization and drug sustainability curves were plotted by Kaplan-Meier method. RESULTS: Clinical evaluation was available in nearly all patients at 3(CD-UC:95-94%), 6(90-83%), 9(86-85%) and 12(96-89%) months. CRP testing frequency decreased in CD patients over time. Compliance to serial FCAL testing was low. Clinical remission at one-year was higher in patients adherent to early assessment visit at 3 months(p = 0.001 for CD and UC). Adherence to early follow-up resulted in earlier dose optimization in CD and UC patients(pLogrank=0.026 for UC & p = 0.09 for CD). Overall drug sustainability did not differ. CONCLUSION: Clinical & CRP, but not FCAL, were frequently assessed in patients starting adalimumab. Adherence to early objective combined follow-up visits resulted in earlier dose optimization, improved one-year clinical outcomes but did not change drug sustainability.

Automated syndrome diagnosis by three-dimensional facial imaging.

PURPOSE: Deep phenotyping is an emerging trend in precision medicine for genetic disease. The shape of the face is affected in 30-40% of known genetic syndromes. Here, we determine whether syndromes can be diagnosed from 3D images of human faces. METHODS: We analyzed variation in three-dimensional (3D) facial images of 7057 subjects: 3327 with 396 different syndromes, 727 of their relatives, and 3003 unrelated, unaffected subjects. We developed and tested machine learning and parametric approaches to automated syndrome diagnosis using 3D facial images. RESULTS: Unrelated, unaffected subjects were correctly classified with 96% accuracy. Considering both syndromic and unrelated, unaffected subjects together, balanced accuracy was 73% and mean sensitivity 49%. Excluding unrelated, unaffected subjects substantially improved both balanced accuracy (78.1%) and sensitivity (56.9%) of syndrome diagnosis. The best predictors of classification accuracy were phenotypic severity and facial distinctiveness of syndromes. Surprisingly, unaffected relatives of syndromic subjects were frequently classified as syndromic, often to the syndrome of their affected relative. CONCLUSION: Deep phenotyping by quantitative 3D facial imaging has considerable potential to facilitate syndrome diagnosis. Furthermore, 3D facial imaging of "unaffected" relatives may identify unrecognized cases or may reveal novel examples of semidominant inheritance.

The impact of competition on elephant musth strategies: A game-theoretic model.

Mature male African Savannah elephants are known to periodically enter a temporary state of heightened aggression called "musth", often linked with increased androgens, particularly testosterone. Sexually mature males are capable of entering musth at any time of year, and will often travel long distances to find estrous females. When two musth bulls or two non-musth bulls encounter one another, the agonistic interaction is usually won by the larger male. However, when a smaller musth bull encounters a larger non-musth bull, the smaller musth male can win. The relative mating success of musth males is due partly to this fighting advantage, and partly to estrous females' general preference for musth males. Though musth behavior has long been observed and documented, the evolutionary advantages of musth remain poorly understood. Here we develop a game-theoretic model of male musth behavior which assumes musth duration as a parameter, and distributions of small, medium and large musth males are predicted in both time and space. The predicted results are similar to the musth timing behavior observed in the Amboseli National Park elephant population, and further results are generated with relevance to Samburu National Park. We discuss small male musth behavior, the effects of estrous female spatial heterogeneity on musth timing, conservation applications, and the assumptions underpinning the model.

CT-based adaptive high-dose-rate endorectal brachytherapy in the preoperative treatment of locally advanced rectal cancer: Technical and practical aspects.

PURPOSE: During the last decade due to the availability of a CT scan in the brachytherapy suite, high-dose-rate endorectal brachytherapy (HDREBT) has evolved as a CT-based daily adaptive treatment. An update of the technical and practical aspects of HDREBT is provided. METHODS AND MATERIALS: Description of technical and practical aspects of HDREBT focused on the preoperative treatment of locally advanced rectal cancer. During preoperative HDREBT, 26 Gy is delivered in four daily applications of 6.5 Gy prescribed to the 100% isodose, covering the clinical target volume. Daily CT scans are obtained and used for plan optimization, leaving patient positioning unchanged between CT scan and treatment delivery. RESULTS: All steps of HDREBT treatment procedure are discussed in detail: flexible proctosigmoidoscopy and clipping; patient setup; applicator placement; target delineation; treatment planning and delivery; and patient care. Afterward, treatment results are reviewed. CONCLUSIONS: CT-based adaptive preoperative HDREBT is a practical and feasible therapy for locally advanced rectal cancer, offering excellent local control with a favorable toxicity profile.

Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease--the McGill experience.

BACKGROUND: Ustekinumab is a fully human IgG1κ monoclonal antibody that blocks the biologic activity of interleukin-12/23. Ustekinumab is approved for treatment of plaque psoriasis and has been shown to be effective for induction and maintenance of clinical response in anti-TNF resistant Crohn's disease (CD). The aim of the study was to describe the real-life experience with open-label use of ustekinumab in anti-TNF resistant CD patients. METHODS: A retrospective observational open-label study. Clinical response was defined by physician's global assessment combined with decision to continue therapy. The clinical response was evaluated at 3, 6, 12months and last follow-up. RESULTS: Thirty-eight patients were included in the study. Initial clinical response was achieved in 28/38 (73.7%) of the patients. Among the initial responders, 80% with follow-up data maintained their response for 6months. At 12months of follow-up, 88.9% of patients responding at 6months maintained their response. At the last follow-up (7.9±5.2 mo) 27/38 (71%) of the patients were responding, and 73.3% were able to discontinue corticosteroids. Dose escalation was required in 47.7% of the patients and was successful in 61.1% of them. SUMMARY: In this real-life cohort of severe anti-TNF resistant CD, an initial clinical response to subcutaneous ustekinumab was observed in 73.7% of the patients. The initial response was successfully maintained in the majority of patients for up to 12months. Subcutaneous ustekinumab is an effective therapeutic option in this challenging patient cohort. The optimal dosing and injection schedule remain to be established in future studies.

Interstitial deletions at 6q14.1q15 associated with developmental delay and a marfanoid phenotype.

There are a number of reports of interstitial deletions of the long arm of chromosome 6 that have developmental delay and obesity suggesting that this is a distinct phenotype almost like Prader-Willi syndrome. Here we report a patient with a similar deletion but a strikingly different phenotype, one more in keeping with Marfan syndrome, although he does not fulfil the criteria for that syndrome. Array comparative genomic hybridization was performed to investigate a patient with a striking phenotype. This revealed an interstitial deletion of 6q14.1q15. Parental FISH studies were normal, indicating that this is a de novo deletion. Our patient has a completely different phenotype compared to other patients reported to have similar deletions. The common feature is developmental delay, but the body features are quite different in that our patient is tall, strikingly thin with pectus excavatum, scoliosis, skin striae, arachnodactyly, pes planus, cataracts, and a high-arched palate. This contrasts with other patients who have a similar deletion but have short stature and obesity. 6q14.1q15 interstitial deletions can have a very variable phenotype and do not necessarily conform to a clinical recognizable microdeletion syndrome caused by haploinsufficiency of dosage-sensitive genes in that region as proposed by others.

Occult dysplasia in a localized giant pseudopolyp in Crohn's colitis: a case report.

Localized giant pseudopolyposis of the colon (pseudopolyp larger than 1.5 cm in size) is a rare complication of inflammatory bowel disease. There is one report of an occult carcinoma within such a lesion, and no reports of sole dysplasia. A case of a 42-year-old man with longstanding Crohn's colitis who underwent a colonoscopy revealing a large, multilobulated mass at the splenic flexure that was not amenable to endoscopic removal, is described. Multiple biopsies showed no dysplasia and histology was consistent with an inflammatory pseudopolyp. Computed tomographic colonography demonstrated a mass resembling a large villous tumour. A decision for surgery was made. The surgical specimen was a complex anastomosing inflammatory pseudopolyp 5 cm x 4 cm x 3 cm in size, with a focus of low-grade dysplasia in an area free of inflammation. The present case is the first reported occult dysplasia in a giant pseudopolyp. Occult dysplasia without superficial dysplasia may exist in these lesions and further studies are needed to examine risk factors that make a giant pseudopolyp more likely to harbour dysplasia and/or carcinoma.

Evidence for the validity and utility of the Stages of Exercise Behaviour Change scale in young adults.

This study examined the validity and utility of the Stages of Exercise Behaviour Change (SEBC) scale in 244 young British adults. One-way ANOVA revealed significant differences (F > 7.34, P < 0.01) between the Exercise Behaviour Change Categories of Precontemplation/Contemplation (n = 49), Preparation (n = 87) and Action/Maintenance (n = 108) in self-report levels of exercise behaviour. Significant differences (F > 3.14, P < 0.05) were also revealed in exercise self-efficacy, physical self-perception sub-domains and global self-esteem scores. Subsequent step-wise discriminant analyses revealed that discrimination between the Categories of Exercise Behaviour Change was possible on the basis of selected behavioural and psychological parameters (Canonical r = 0.76-0.82, Wilks' lambda = 0.30-0.33, chi 2 = 60.3-94.6, d.f. = 14, P < 0.0001). In both males and females, the most dominant discriminatory variables in the first Function were revealed to be perceived physical conditioning and 'strenuous' exercise behaviour. For males, the second Function comprised exercise self-efficacy and perceived bodily attractiveness, whilst for females it comprised perceived bodily attractiveness, perceived sports competence and perceived physical strength. Subsequent cross-validation analysis, using a randomly selected 40% sub-sample, revealed that 67.8-70.7% of subjects were assigned to the correct Category. These results appear to confirm the concurrent validity of the SEBC scale in terms of self-report of exercise behaviour. Furthermore, the utility of the SEBC scale was demonstrated via the ability to predict membership of specific Categories of Exercise Behaviour Change using a selection of behavioural and psychological parameters.

Time-of-day dependence of isokinetic leg strength and associated interday variability.

The purpose of this study was to assess the interday variability and time-of-day effects on selected isokinetic leg strength indices. Nine adult collegiate sportsmen (mean(s.e.) age 19.6(0.5) years; mean(s.e.) height 1.81(0.02) m; mean(s.e.) body mass 76.5(3.1) kg) completed a series of nine test sessions, organized so that each subject was tested three times within a day (08.00-09.00 hours; 13.00-14.00 hours; 18.00-19.30 hours), on three occasions, each separated by a minimum of 7 days. Gravity-corrected indices of extension peak torque (EPT), flexion peak torque (FPT), and the peak torque ratio (PTR), at contraction velocities of 1.05 rad s-1 and 3.14 rad s-1, were calculated for each subject using an isokinetic dynamometer. Two-way repeated measures analysis of variance of coefficient of variation (V%) scores revealed no significant differences in performance variability across within-subject factors of time-of-day and performance index (P > 0.05). Overall mean(s.e.) V% for scores across experimental conditions were 3.97(0.72)% at 1.05 rad s-1 and 5.98(1.23)% at 3.14 rad s-1, suggesting that similar levels of measurement error occur between 08.00-19.30 hours. One-way repeated measures analysis of variance of absolute strength indices (EPT, FPT and PTR) revealed that significantly higher scores were achieved during session 3 (18.00-19.30 hours), with mean(s.e.) values of 249.1(40.0) N m, 149.0(32.3) N m, 59.5(5.0)% at 1.05 rad s-1, and 172.1(38.7) N m, 121.3(27.7) N m, 71.1(6.2)% at 3.14 rad s-1, respectively (P < 0.05). This finding appears to be consistent with current knowledge about time-of-day effects on the assessment of muscular strength. Thus for stable and maximal values to be obtained during isokinetic leg testing, the use of multiple-trial protocols is recommended, with testing occurring as close to 18.00-19.30 hours as possible. In addition, the observed significant time-of-day effect suggests that appropriate comparison of maximal isokinetic leg strength can only be achieved based on data obtained within 30 min of the same time of day.

Phosphoglycerate kinase deficiency: biochemical and molecular genetic studies in a new myopathic variant (PGK Alberta)

Biochemical analysis of muscle in a 37-year-old man with exercise intolerance, myalgia, recurrent myoglobinuria, and retinitis pigmentosa showed phosphoglycerate kinase (PGK) deficiency. Kinetic and physical characteristics of the mutant enzyme differed from those of two previously reported cases, suggesting a distinct mutation. Southern blot analysis showed similar bands in patient and control, but Northern blot analysis of muscle mRNA showed an abnormally large message. These data demonstrate that PGK deficiency is clinically, biochemically, and genetically heterogeneous.

Regrowth of PNS axons through grafts of the optic nerve of the Browman-Wyse (BW) mutant rat.

We have examined the behaviour in vivo of regenerating PNS axons in the presence of grafts of optic nerve taken from the Browman-Wyse mutant rat. Browman-Wyse optic nerves are unusual because a 2-4 mm length of the proximal (retinal) end of the nerve lacks oligodendrocytes and CNS myelin and therefore retinal ganglion cell axons lying within the proximal segment are unmyelinated and ensheathed by processes of astrocyte cytoplasm. Schwann cells may also be present within some proximal segments. Distally, Browman-Wyse optic nerves are morphologically and immunohistochemically indistinguishable from control optic nerves. When we grafted intact Browman-Wyse optic nerves or 'triplets' consisting of proximal, junctional and distal segments of Browman-Wyse optic nerve between the stumps of freshly transected sciatic nerves, we found that regenerating axons avoided all the grafts which did not contain Schwann cells, i.e., proximal segments which contained only astrocytes; regions of Schwann cell-bearing proximal segments which did not contain Schwann cells; junctional and distal segments (which contained astrocytes, oligodendrocytes and CNS myelin debris). However, axons did enter and grow through proximal segments which contained Schwann cells in addition to astrocytes. Schwann cells were seen within grafts even after mitomycin C pretreatment of sciatic proximal nerve stumps had delayed outgrowth of Schwann cells from the host nerves; we therefore conclude that the Schwann cells which became associated with regenerating axons within the grafts of Browman-Wyse optic nerve were derived from an endogenous population. Our findings indicate that astrocytes may be capable of supporting axonal regeneration in the presence of Schwann cells.

Regeneration of axons in the optic nerve of the adult Browman-Wyse (BW) mutant rat.

We have studied the regeneration of axons in the optic nerves of the BW rat in which both oligodendrocytes and CNS myelin are absent from a variable length of the proximal (retinal) end of the nerve. In the optic nerves of some of these animals, Schwann cells are present. Axons failed to regenerate in the exclusively astrocytic environment of the unmyelinated segment of BW optic nerves but readily regrew in the presence of Schwann cells even across the junctional zone and into the myelin debris filled distal segment. In the latter animals, the essential condition for regeneration was that the lesion was sited in a region of the nerve in which Schwann cells were resident. Regenerating fibres appeared to be sequestered within Schwann cell tubes although fibres traversed the neuropil intervening between the ends of discontinuous bundles of Schwann cell tubes, in both the proximal unmyelinated and myelin debris laden distal segments of the BW optic nerve. Regenerating axons never grew beyond the distal point of termination of the tubes. These observations demonstrate that central myelin is not an absolute requirement for regenerative failure, and that important contributing factors might include inhibition of astrocytes and/or absence of trophic factors. Regeneration presumably occurs in the BW optic nerve because trophic molecules are provided by resident Schwann cells, even in the presence of central myelin, oligodendrocytes and astrocytes. All the above experimental BW animals also have Schwann cells in their retinae which myelinate retinal ganglion cell axons in the fibre layer. Control animals comprised normal Long Evans Hooded rats, BW rats in which both retina and optic nerve were normal, and BW rats with Schwann cells in the retina but with normal, i.e. CNS myelinated, optic nerves. Regeneration was not observed in any of the control groups, demonstrating that, although the presence of Schwann cells in the retina may enhance the survival of retinal ganglion cells after crush, concomitant regrowth of axons cut in the optic nerve does not take place.

Immunocytochemical analysis of glial cells in the hypomyelinated optic nerve of the BW mutant rat.

The Browman-Wyse (BW) rat is a mutant with structural defects of the visual system, including a failure of the proximal (retinal) end of the optic nerve to myelinate. This latter abnormality is correlated with an absence of CAII+ oligodendrocytes, but we have previously shown that astrocytes are normally distributed, as judged by morphological characteristics of GFAP+ cells in vivo. We have further examined in vitro the immunohistochemical characteristics of macroglia isolated from the BW optic nerve, either as cell suspensions or after 4 days in culture. Cell cultures derived from the hypomyelinated proximal segment of BW optic nerves contained very few 0-2A progenitor cells (from which oligodendrocytes and cells with the GFAP+/A2B5+ phenotype develop), whereas over 90% of the glia were Schwann cells. A proportion of these few 0-2A progenitor cells differentiated normally after 4 days in vitro into both progeny phenotypes in appropriate media. Accordingly, we conclude that the myelination deficiency in the BW optic nerve could be explained as a failure of 0-2A progenitor cells to populate fully the proximal extremity of the nerve during development. Since most glia isolated from adult optic nerves did not adhere to the culture substrate, we analysed the phenotypes of freshly isolated cells in suspension. Comparing optic nerves of normal adult rats with those of BW mutants, a significantly higher fraction of the GFAP+ cells reacted with A2B5 in cell suspensions of the latter. The double-labelled cells which are present in abnormally high numbers may be the differentiated progeny of 0-2A progenitors in the hypomyelinated segment of nerve. One explanation for these findings is that Schwann cells within the BW nerve induce the differentiation of 0-2A progenitor cells to the GFAP+/A2B5+ phenotype. We investigated this possibility using conditioned medium from cultured Schwann cells which increased tenfold the frequency of GFAP+/A2B5+ cells in normal neonatal rat optic nerve cultures. Oligodendrocyte numbers showed a concomitant decline with increasing concentration of Schwann cell conditioned medium. Hypomyelination in the BW rat optic nerve may therefore arise because Schwann cells, present in the proximal segment of the nerve, not only impede the migration of 0-2A progenitor cells but also release a factor which induces those 0-2A progenitor cells which arrive in the proximal segment of the nerve to differentiate into GFAP+ cells at a critical stage in oligodendrocyte development.

Membrane processes associated with the osmotic-pulse incorporation of inositol hexaphosphate.

In previous studies (Biochem. Biophys. Res. Commun. 144, 779-786 (1987); Prog. Clin. Biol. Res. 292, 65-75 (1989)), we showed that inositol hexaphosphate (IHP), when added to erythrocyte membrane ghosts in the range 0.6-2.5 mM, caused a large disruption of skeletal protein-protein interactions as monitored by electron paramagnetic resonance techniques. IHP incorporated into intact cells by an osmotic-pulse method (J. Cell. Physiol. 129, 221-229 (1986)) leads to cells with markedly decreased oxygen affinity. Exposure of the red cells to higher levels of IHP during the osmotic pulse leads to less lysis and more normal cellular indices after healing of the transiently-disrupted membrane (J. Lab. Clin. Med. 113, 58-66 (1989)). In order to determine what effect higher levels of IHP had on skeletal proteins and bilayer lipids of membrane ghosts, spin labeling studies were performed. The main findings were: (a) There was a concentration-dependent alteration in skeletal protein interactions. At concentrations greater than 25 mM IHP, the effectiveness of IHP to disrupt skeletal protein interactions was diminished. (b) No apparent alteration of the motion or order of phospholipids or the lipid water interface of intact cells into which IHP was incorporated occurred, suggesting that higher levels of IHP do not alter the physical state of the lipid bilayer.

Ontogenesis of the electroretinogram in a precocial mammal, the guinea pig (Cavia porcellus).

1. Ontogenesis of the electroretinogram, the mass electrical response of the retina to flash light stimuli, was studied in the guinea pig (Cavia porcellus), a precocial species with visual function at birth. 2. a-Wave components, b-wave, oscillatory potentials, slow PIII, and c-wave responses to flash stimuli developed between 55 and 64 days of gestation (full term is 68-69 days). 3. a-Waves attributable to photoreceptor functions were fully mature at 60 days. 4. ERG development lagged behind the reported critical milestones in retinal development; its prenatal onset indicates that no history of light entrainment is required for initiation of a mature ERG response.

Defective myelination in the optic nerve of the Browman-Wyse (BW) mutant rat.

The Browman-Wyse (BW) rat displays a spectrum of ocular abnormalities which include myelination by Schwann cells of retinal ganglion cell (RGC) axons within the retina. Immunohistochemical and ultrastructural studies of the optic nerves of adult BW rats (30-60 days of age) with myelinated intraretinal axons were performed. Although individual nerves displayed considerable morphological variability, all were characterized by an initial dysmyelinated proximal segment which was separated from a normally myelinated distal segment by a transitional junctional zone. The proximal segment contained axons which were predominantly unmyelinated: where myelination occurred, almost all sheaths were Po-positive, proteolipid protein-negative, and the myelinating cell was a Schwann cell. In the distal segment the distribution of myelinated axons appeared to be normal, sheaths were PLP+, and the myelinating cell was an oligodendrocyte. Within the proximal segment, axons that were myelinated by Schwann cells were isolated by a basal lamina and expanded extracellular spaces from the bulk of other RGC axons within the optic nerve. Few carbonic anhydrase (CAII)+ or GalC+ oligodendrocytes were seen in proximal segments that contained Schwann cells: anti-CAII antibody stained atypical cells within the proximal segments which did not resemble CAII+ oligodendrocytes in the distal segment, and which were probably GalC-. Astrocytes appeared normal throughout the length of the nerve, and there was no morphological specialization at the junctional zone similar to that at the lamina cribrosa. The possible source(s) of the intraneural Schwann cells, and the pathogenetic mechanisms underlying the aberrant myelination of RGC axons within the BW optic nerve are discussed.

Interaction of hemin with erythrocyte membranes: alterations in the physical state of the major sialoglycoprotein.

Hemin has been shown to disrupt erythrocyte membrane skeletal protein-protein interactions, initially those involving band 4.1 (Shaklai et. al. (1986) Biochem. Int. 13, 467-477). We have used electron spin resonance (ESR) spin labels specific for cell-surface carbohydrates, skeletal membrane proteins, or bilayer lipids to find: (1) simultaneous reaction of the protein-specific spin label, MAL-6, which binds to skeletal protein SH residues, and 10 microM hemin suggested that hemin decreased skeletal protein-protein interactions; (2) 10 microM hemin markedly decreased (greater than 60%, P less than 0.001) the rotational motion of spin-labeled erythrocyte membrane cell-surface sialic acid residues, 70% of which are located on the major transmembrane sialoglycoprotein, glycophorin A; and (3) 10 microM hemin caused a small, but significant (P less than 0.02), decrease in the motion of a lipid bilayer specific spin label (5-NS) in the erythrocyte membrane. Since glycophorin A is reportedly linked to the erythrocyte membrane skeletal protein network by band 4.1, it is conceivable that hemin-induced disruption of skeletal protein interactions, particularly those of band 4.1, could subsequently lead to the alterations in the motion of cell-surface sialic acid presented in this report.