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.

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.

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.

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.

Electron spin resonance and biochemical studies of the interaction of the polyamine, spermine, with the skeletal network of proteins in human erythrocyte membranes.

Spermine (N, N'-bis(aminopropyl)-1,4-butanediamine) is a polyamine thought to be important in several cell regulatory processes. Previous studies had shown that spermine prevented the lateral diffusion of transmembrane proteins in human erythrocyte ghosts (Schindler et al. (1980) Proc. Natl. Acad. Sci. USA 77, 1457-1461). In this paper, we present results of studies on the effect of spermine on erythrocyte membranes by employing electron spin resonance spin-labeling techniques in conjunction with spin labels specific for skeletal proteins, bilayer lipids or cell-surface sialic acid of the membrane and by employing SDS-polyacrylamide gel electrophoresis analysis of extracted spectrin and Triton shells. The major findings are: (1) spermine significantly decreases the segmental motion of protein spin-label binding sites (P less than 0.0001), which are predominantly on cytoskeletal proteins; (2) addition of spermine leads to a significant increase in the rotational motion of spin-labeled terminal sialic acid residues (P less than 0.001), most of which are located on glycophorin A, a result which may be secondarily caused by spermine-induced aggregation of cytoskeletal proteins and the cytoplasmic pole of this transmembrane sialoglycoprotein; (3) spermine completely inhibits the low-ionic strength extraction of spectrin, the major protein of the skeletal network which is attached to the bilayer proteins by two or more connecting proteins; (4) pretreatment of ghosts with spermine followed by Triton extraction resulted in the retention of significantly increased amounts of Band 3 and other skeletal and bilayer proteins including Bands 4.2, 6 and 7 in Triton X-100 shells relative to that of control-treated ghosts. These results suggest that spermine acts both to increase protein-protein interactions in the cytoskeletal protein network and to bridge skeletal and bilayer proteins and are discussed with reference to possible molecular mechanisms by which spermine may influence cell functions.

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.

Electron spin resonance investigation of the interaction of the anion and glucose transport inhibitor, p-azidobenzylphlorizin, with the human red cell membrane.

The membrane perturbations caused by the interaction of p-azidobenzylphlorizin (p-AzBPhz), a potential photoaffinity labeling agent of the anion and D-glucose transporters in the human erythrocyte, have been studied using electron spin resonance (ESR) spectrometry. Two lipid-specific spin labels have been employed; one of these agents, a hexadecyl-quarternary amine with the nitroxide reporter group covalently attached to the cationic nitrogen, (CAT-16), has been used to monitor changes in the physical state of the membrane's extracellular phospholipid/water interface. The other spin label, 5-doxylstearic acid (5-NS), is designed to examine the order and motion of the lipid bilayer near the cell surface. In separate experiments, intact human red cells labeled with these lipid-specific spin labels were exposed to small amounts of the phlorizin azide. A dose-dependent alteration in CAT-16 motion was observed, but the p-AzBPhz interaction with the membrane had no effect on the spectrum of 5-NS. The half-maximal effect of the phlorizin derivative on the CAT-16 spectrum occurred when about 2 million molecules were bound to each cell. This is also the combined amount of band 3 and band 4.5 present in the red cell membrane and represents the concentration necessary to inhibit both anion and glucose transport. Our results suggest that the first p-AzBPhz molecules binding to the red cell membrane interact with the anion and sugar transporters, and not with the bulk lipid bilayer.

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.

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.

Effects of alteration in the light cycle on outer segment shedding in the fetal retina.

Shedding of outer segment discs and their phagocytosis by retinal pigment epithelial cells (RPE) in the guinea pig starts to occur during in utero development. The number of phagosomes in the fetal RPE varies in a cyclical manner somewhat analogous to that observed in mature animals. The present study addresses the question of whether the cycles in fetus and mother are independent or linked. Pregnant guinea pigs were subjected to 10 days of alteration of their lighting schedules beginning on the 46th day of gestation. Dams and fetuses were sacrificed on day 56, and large phagosomes in the RPE of each were counted. A 10-hour phase advance was employed, ie, from 0800 (lights on): 2000 (light off) in controls, to 2200 (on): 1000 (off) in experimental animals. Counts of large phagosomes in the posterior retina were compared in both control and experimental nulliparous, gravid, and fetal animals. A significant burst of shedding occurred within one hour after light onset in the experimental groups comprised of either nulliparous or pregnant animals. The latter also showed a smaller rise in phagosome numbers at the original time of onset of illumination. In contrast, no shift in the time of maximum shedding activity was observed in fetuses in the experimental regime. Their activity was similar to that present in the original 0800:2000 cycle. Whereas maternal RPE shedding cycles can be reentrained in a 10-day period, those in the 46- to 56-day fetal retina are refractory to significant change. Based on this finding, it is likely that the shedding cycles in the mother and fetus at this age are under independent control, and, therefore, that shedding in the fetus is not mediated by maternal borne factors.

Phagocytosis in the fetal pigment epithelium: evidence for cyclic activity.

Photoreceptor cells in guinea pig retinas begin to shed their outer segments while developing in utero. To ascertain whether phagocytosis of outer segments in the fetus is a cyclical event like that of mature animals, large phagosomes in fetal retinal pigment epithelial cells were counted at representative times during a 24 hr period. These data were then compared with similar data obtained from the pregnant dams. Gravid animals and fetuses both showed a burst of shedding after the onset of illumination. Shedding was well initiated in the pregnant animals 30 min after the onset of illumination but was delayed for 2 to 3 hr in their fetuses. Thereafter the two patterns of phagocytosis showed substantial differences. Congruent cyclical patterns could be discerned, however, by graphing fetal counts with an advance of 10 hr on the time scale relative to that of the gravid animals. The results presented here represent the first indication of a cyclical pattern of phagocytosis in a population of fetuses during retinal development.

The ontogenesis of the dopaminergic cell in the pre- and postnatal guinea pig retina.

We have examined the development of the dopaminergic system of the guinea pig retina, a species in which retinal neuronal and synaptic differentiation occurs largely in utero. Fetal animals aged 42-69 days (full term), neonates, postnatal (pn) animals to 12 weeks, and mature animals were studied to determine retinal dopamine (DA) storage, metabolism (DOPAC), in vitro tyrosine hydroxylase (TH) activity, postsynaptic target activation (cAMP stimulation) and localization (formaldehyde-induced histofluorescence). DA-stimulated adenylate cyclase at 42 days of gestation was threefold over basal activity, preceding the onset of the accumulation of DA and DOPAC at 45 days, and the initial localization of DA in cell perikarya at 47 days and in processes at 50 days. At birth DA and DOPAC levels were 45 and 37%, respectively, of adult levels. DA levels remained stable during the first few days pn, although in vitro TH activity was capable of stimulation by light in the neonate as in the mature animal. DA and TH activity increased from 1 week pn to reach adult levels by 10 weeks pn. Although a significant degree of development of the dopaminergic neurotransmitter system in the guinea pig occurs before birth the attainment of a fully mature system postnatally may require normal photic stimulation of physiologic activity.

Assay of serum thyroxine by competitive protein binding: reuse of disposable sephadex columns.

A method for the assay of total serum thyroxine on reusable Sephadex G-25 fine columns, obtained from the Ames Tetralute kit, and competitive protein binding with TBG is described. The columns are regenerated with diluted plasma and may be used for at least 3 months. The procedure is rapid and simple and requires no extraction, centrifugation or evaporation. Recovery of added thyroxine from serum is essentially complete. The between-assay and within-assay coefficients of variation are about 5.5%. Correlation with values obtained using the Tetralute kit was good (r = 0.988). Values in 75 euthyroid subjects were normally distributed and therefore the normal range was taken as the mean +/- 2 SD or 4.6-10.4 mug/100 ml.

On the mechanism of polychlorinated biphenyl-induced hypobilirubinaemia.

Treatment of normal rats with a polychlorinated biphenyl mixture of DDT increased liver microsomal protein concentration. Hepatic microsomal bilirubin UDP-glucuronyltransferase activity was elevated in the DDT-treated, but not in the polychlorinated biphenyl-treated rats. In contrast polychlorinated biphenyl, but not DDT, reduced serum bilirubin concentrations in jaundiced Gunn rats, as did sulphadiazine; sulphonamides compete with bilirubin for binding sites on plasma albumin. Polychlorinated biphenyls appear to lower serum bilirubin concentration by reducing the binding of bilirubin to plasma protein.

Renewal of rod outer segments following light-induced damage of the retina.

Fluorescent lighting was used to induce severe but reversible damage of the rod outer segments of the retinas of albino rats. The animals were then kept in continuous darkness for up to 12 days. Pairs of animals were killed after 1, 3, 5, 7, 9 and 12 days of continuous darkness. Light microscopic examination of the retinas demonstrated a sharp demarcation between the light-damaged distal ends of the rod outer segments and the newly formed proximal ends. Measurement of the proximal ends demonstrated proximo-distal renewal of the rod outer segments during the first 9 days of continuous darkness. Parametric statistical analysis of the data revealed that the renewal occurred linearly, at an average rate of 2.66 micron/d, which is similar to the rate of renewal of the rod outer segments in the undamaged retina of the rat.

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.