Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield.

Intellectual disability (ID) is a measurable phenotypic consequence of genetic and environmental factors. In this study, we prospectively assessed the diagnostic yield of genomic tools (molecular karyotyping, multi-gene panel and exome sequencing) in a cohort of 337 ID subjects as a first-tier test and compared it with a standard clinical evaluation performed in parallel. Standard clinical evaluation suggested a diagnosis in 16% of cases (54/337) but only 70% of these (38/54) were subsequently confirmed. On the other hand, the genomic approach revealed a likely diagnosis in 58% (n=196). These included copy number variants in 14% (n=54, 15% are novel), and point mutations revealed by multi-gene panel and exome sequencing in the remaining 43% (1% were found to have Fragile-X). The identified point mutations were mostly recessive (n=117, 81%), consistent with the high consanguinity of the study cohort, but also X-linked (n=8, 6%) and de novo dominant (n=19, 13%). When applied directly on all cases with negative molecular karyotyping, the diagnostic yield of exome sequencing was 60% (77/129). Exome sequencing also identified likely pathogenic variants in three novel candidate genes (DENND5A, NEMF and DNHD1) each of which harbored independent homozygous mutations in patients with overlapping phenotypes. In addition, exome sequencing revealed de novo and recessive variants in 32 genes (MAMDC2, TUBAL3, CPNE6, KLHL24, USP2, PIP5K1A, UBE4A, TP53TG5, ATOH1, C16ORF90, SLC39A14, TRERF1, RGL1, CDH11, SYDE2, HIRA, FEZF2, PROCA1, PIANP, PLK2, QRFPR, AP3B2, NUDT2, UFC1, BTN3A2, TADA1, ARFGEF3, FAM160B1, ZMYM5, SLC45A1, ARHGAP33 and CAPS2), which we highlight as potential candidates on the basis of several lines of evidence, and one of these genes (SLC39A14) was biallelically inactivated in a potentially treatable form of hypermanganesemia and neurodegeneration. Finally, likely causal variants in previously published candidate genes were identified (ASTN1, HELZ, THOC6, WDR45B, ADRA2B and CLIP1), thus supporting their involvement in ID pathogenesis. Our results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.

Efficacy of selected treadmill training programme on oxidative stress in adolescents with Down syndrome.

The aim of this study was to assess the efficacy of an electronic treadmill exercise training programme on malondialdehyde (MDA) as a marker for lipid peroxidation and the antioxidant enzyme glutathione peroxidase (GPx) in adolescents with Down syndrome. The study was carried out on 30 adolescent males with Down syndrome, ranging in age from 15 to 18 years, with 30 healthy subjects as a control group. Clinical examination, anthropometric measurements and determination of GPx activity and MDA before and after exercise were done. A treadmill training programme was performed for 12 weeks. Our data showed a significant increase in GPx activity and decrease in serum level of MDA in Down syndrome individuals after treadmill exercise for 3 months. Exercise promotion for adolescents with Down syndrome requires attention to motivators and facilitators of exercise adherence as it may limit risk of increased neurological consequences associated with oxidative stress and improve quality of life.

Assessment of biological changes of continuous whole body exposure to static magnetic field and extremely low frequency electromagnetic fields in mice.

The question whether static magnetic fields (SMFs) and extremely low frequency electromagnetic fields (ELF-EMF) cause biological effects is of special interest. We investigated the effects of continuous whole body exposure to both fields for 30 days on some liver and blood parameters in mice. Two exposure systems were designed; the first produced a gradient SMF while the second generated uniform 50 Hz ELF-EMF. The results showed a gradual body weight loss when mice were exposed to either field. This is coupled with a significant decrease (P<0.05) in the levels of glucose, total protein and the activity of alkaline phosphatase in serum. A significant increase in lactate dehydrogenase activity was demonstrated in serum and liver paralleled with a significant elevation in hepatic γ-glutamyl transferase activity. The glutathione-S-transferase activity and lipid peroxidation level in the liver were significantly increased while a significant decrease in hepatic gluthathione content was recorded. A significant decrease in the counts of monocytes, platelets, peripheral lymphocytes as well as splenic total, T and B lymphocytes levels was observed for SMF and ELF-EMF exposed groups. The granulocytes percentage was significantly increased. The results indicate that there is a relation between the exposure to SMF or ELF-EMF and the oxidative stress through distressing redox balance leading to physiological disturbances.

On modelling the immune system as a complex system.

We argued that immune system is an adaptive complex system. It is shown that it has emergent properties. Its network structure is of the small world network type. The network is of the threshold type, which helps in avoiding autoimmunity. It has the property that every antigen (e.g. virus or bacteria) is typically attacked by more than one effector. This stabilizes the equilibrium state. Modelling complex systems is discussed. Cellular automata (CA)-type models are successful, but there are much less analytic results about CA than about other less successful models e.g. partial differential equations (PDE). A compromise is proposed.

Three-dimensional description of pulmonary deposition of inhaled aerosol using data from multimodality imaging.

UNLABELLED: Three-dimensional assessment of pulmonary deposition of inhaled aerosol may be performed using SPECT. The use of aligned anatomical images enables improved accuracy of quantification and anatomical localization of deposition. METHODS: Techniques of analyzing these data and their application to deposition studies of two nebulizer-generated aerosols (mass median diameter 1.5 and 6.5 microM respectively) in 12 normal subjects are described. The deposition data were transformed to a standard hemispherical shape and the mean distribution pattern for each aerosol evaluated. Deposition by airway generation was then calculated using a spatial model of airway morphology. The results were compared to those from planar image analysis. RESULTS: The hemispherical transform yielded considerably more qualitative information on deposition pattern. The central-to-peripheral concentration ratio between conducting and alveolated airways was 5.27 for the coarser aerosol and 2.43 for the fine. The two-dimensional spatial estimates of the ratio were 2.61 and 2.03 respectively. CONCLUSION: Analysis of multimodality imaging data considerably enhanced information on deposition compared to planar imaging. It provides new data on aerosol deposition which will be of value to physicians involved in drug inhalation therapy.

Modelling the effect of charge on selective deposition of particles in a diseased lung using aerosol boli.

The technique of using a charged bolus of aerosol to deliver a drug or other agent is advantageous since sites of interest within the lung can be selectively targeted. Ideally, the volume of the bolus should match that of the targeted region allowing the aerosol bolus particles to be confined to the selected area during the pause period after inhalation. Our existing computer model for predicting the deposition of charged aerosol particles has been developed to encompass aerosol boli, some diseased lung morphologies and drug dose administered per breathing cycle. Aerosol deposition in the targeted region is found to be enhanced by increasing particle charge, pause period and particle size. For particles in the size range 1-2.5 microm, aerosol deposition in the region affected by bronchoconstriction does not alter significantly with flow rate variation (range 250-1000 ml s(-1)) for a targeted charged bolus of matched volume. The technique may enable the optimal delivery of therapeutic or other agents to diseased or normal lungs.

Evaluation of the accuracy and precision of lung aerosol deposition measurements from planar radionuclide imaging using simulation.

Planar images of known, theoretical distributions of radioaerosol in the lung have been simulated using lung models derived from magnetic resonance studies on human subjects. Total lung activity was evaluated from the simulated images together with the absolute penetration index (PI) and a relative value expressed as a fraction of that in a simulated ventilation image. The accuracy and precision of these measurements were calculated by comparison with the true values used in the simulation. Total activity was assessed with systematic errors within 5% and precision within 6.5%. Measured PIs varied only slowly with true PI and inter-model variation masked changes between measurements on the different distributions. The relative PI reduced inter-model variation and provided significant differences between all the distributions. PI was significantly affected by misalignment of the lung region of interest. The conducting airways deposition fraction (CADF) used in the simulation correlated linearly with the fractional activity in a central lung region, allowing CADF to be estimated with a precision of 21%.

Double half-cone flap umbilicoplasty: a new technique for the proboscoid umbilical hernia in children.

OBJECTIVE: Although many techniques have been described for reconstruction of the protruding umbilicus in children with umbilical hernia, we present a simple new technique for umbilicoplasty. METHODS: Ten children (six males and four females) with umbilical hernias and protruding skin were operated upon. Operative description consists of amputation of the protruding umbilical skin, leaving two unequal half-cones, a short cephalic half-cone (0.5 cm) and a long caudal half-cone (1 cm). These two half-cones are fashioned, closed, and inverted to constitute the new umbilicus following a classic hernia repair. RESULTS: The early results were excellent in all cases with no infection and no ischaemic changes encountered in the skin of the reconstructed umbilicus. Follow-up periods between 6 and 18 months revealed a cosmetically pleasing shape of the umbilicus. Only one case developed hypertrophy of the resulting scar. CONCLUSION: We present our initial experience with the new technique. This new technique provides a good solution for reconstruction of the protruding umbilical skin. Our double half-cone flap umbilicoplasty technique is easy to learn and to perform.

Assessment of deposition of inhaled aerosol in the respiratory tract of man using three-dimensional multimodality imaging and mathematical modeling.

Multimodality medical imaging enables measurement of the three-dimensional spatial distribution of a radiolabeled aerosol within the lung. Using a conceptual spatial morphological model these data may be transformed to provide information on deposition per airway generation. This methodology has been used to study the intrapulmonary deposition patterns of two formulations of a metered dose inhaler and two nebulizers in control subjects. The nebulizer study has also been stimulated using a computer model of deposition. The comparison between derived experimental results and those from computer modeling shows areas of agreement, although there are also areas of discrepancy. The new methodology has considerable potential value in the fields of inhalation therapy and deposition modeling, although more detailed validation is still required.

Early prenatal diagnosis of genetic abnormality by chorion villus sampling.

We describe a series of 100 cases of prenatal genetic diagnosis using the technique of chorion villus sampling. The advantage of chorion villus sampling in terms of earlier diagnosis, and its disadvantage of a higher incidence of false results, compared with amniocentesis, are noted. The comparative risks for pregnancy loss are discussed.

Towards understanding the immune system.

It is proposed that using both self-non-self and danger theories give a better understanding of how the immune system works. It is proposed that comparing the immune system to the police force is useful in this case since the police respond both to danger or damage signals and foreign or suspicious behavior even if no danger signals existed. We also propose that due to low zone tolerance, immunotherapy needs to be combined with another treatment method for cancer, e.g., chemotherapy or/and radiotherapy, to get sufficient eradication of tumors. Finally, we propose that fractional order differential equations are more suitable than the familiar integer order differential equations. A fractional order example of two immune effectors attacking an antigen is given.

Human bronchiolar deposition and retention of 6-, 8- and 10-micrograms particles.

Three groups, each consisting of 6 healthy subjects, inhaled, respectively, 6-micrograms (aerodynamic diameter), 8-micrograms, and 10-micrograms Teflon particles, labeled with indium-111. The particles were inhaled at an extremely low flow rate, 0.05 L/s. Lung retention was measured after 0, 24, 48, and 72 h. Two models were used to calculate particle deposition in the lungs in the various generations: the Karolinska Institute model (KI model) and the University of Southampton model (US model). From the experimental clearance data and the theoretical deposition data, it was calculated that the average retention after 24 h was around 100% for particles deposited in generations 13-16 (ciliated bronchioles) and around 20% in generations 0-12 (both large and small ciliated airways). In these calculations, it was assumed that the retained fractions were independent of particle size. The depositions in the bronchial region (generations 0-8), bronchiolar region (generations 9-15 or 9-16), and the alveolar region were calculated using the two models and compared with the recent ICRP model. On the whole, the three models agreed fairly well.

Trisomy 16 detected at chorion villus sampling.

Trisomy 16 detected at chorion villus sampling (CVS) may reflect the placental but not the fetal karyotype. We describe a case in which the pregnancy continued until intrauterine death at 37 weeks. Cytogenetic study of two placental samples showed 47, + 16 and 46,XX; the fetus was morphologically grossly normal, but fetal tissue culture was unsuccessful. Conservative management may be appropriate when trisomy 16 is detected at CVS and the pregnancy is normal ultrasonographically.

Transanal one-stage endorectal pull-through for Hirschsprung's disease: a multicenter study.

BACKGROUND/PURPOSE: Transanal endorectal pull-through (TEPT) is the latest development in treatment of Hirschsprung's disease (HD). This prospective study was designed to evaluate the safety and efficacy of 1 stage TEPT technique in the management of patients with HD. METHODS: One hundred forty-nine children (116 boys and 33 girls) aged 8 days to 14 years underwent 1 stage TEPT procedure over an 18-month period at 5 Egyptian academic pediatric surgical centers and affiliated hospitals. Median follow-up was 12 months (range, 3 to 21 months). These patients were evaluated with regard to age, sex, length of the aganglionic segment, intraoperative details, and postoperative functional results or complications. An electromyogram (EMG), endorectal ultrasound scan, and lower gastrointestinal (GI) motility studies were reserved for patients with postoperative problems with bowel control. RESULTS: Mean operating time was 120.2 +/- 27.8 minutes (range, 60 to 210 minutes). The average length of resected bowel was 26.8 +/- 12.4 cm (range, 15 to 45 cm). Thirteen patients required laparotomy because of extension of aganglionic segment beyond the sigmoid colon in 9, tear in the mesenteric vessels in 2, and difficulties in getting to the submucosal plane in 2. Three deaths (2%) occurred 3 days, 4 days, and 4 weeks postoperatively, respectively. Postoperative complications included transient perianal excoriation in 48 patients (30 were <3 months of age), enterocolitis (n = 26), anastomotic stricture (n = 7), recurrent constipation (n = 6), hypoganglionosis at distal end of pulled through segment (n = 2), cuff abscess (n = 3), anastomotic leak (n = 1), adhesive bowel obstruction (n = 1), and rectal prolapse (n = 1). Complete anorectal continence was noted in 35 of 42 (83.3%) children older than 3 years, whereas soiling and frequent accidents still occur in 7, who showed a steady improvement in their continence status. CONCLUSIONS: One-stage TEPT technique is both feasible and safe technique in properly selected children with rectosigmoid HD in all ages. The technique is easily learned and is associated with excellent clinical results.

Efficacy of selected treadmill training programme on oxidative stress in adolescents with Down syndrome

The aim of this study was to assess the efficacy of an electronic treadmill exercise training programme on malondialdehyde [MDA] as a marker for lipid peroxidation and the antioxidant enzyme glutathione peroxidase [GPx] in adolescents with Down syndrome. The study was carried out on 30 adolescent males with Down syndrome, ranging in age from 15 to 18 years, with 30 healthy subjects as a control group. Clinical examination, anthropometric measurements and determination of GPx activity and MDA before and after exercise were done. A treadmill training programme was performed for 12 weeks. Our data showed a significant increase in GPx activity and decrease in serum level of MDA in Down syndrome individuals after treadmill exercise for 3 months. Exercise promotion for adolescents with Down syndrome requires attention to motivators and facilitators of exercise adherence as it may limit risk of increased neurological consequences associated with oxidative stress and improve quality of life