Pediatric patients with Osteogenesis Imperfecta (OI), a heritable connective tissue disorder, frequently suffer from long bone deformations. Surgical correction often results in bone non-unions, ...necessitating revision surgery with autogenous bone grafting using bone-marrow-derived stem cells (BM-SC) to regenerate bone. BM-SC harvest is generally invasive and limited in supply; thus, adipose tissue's stromal vascular fraction (SVF) has been introduced as an alternative stem cell reservoir. To elucidate if OI patients' surgical site dissected adipose tissue could be used as autologous bone graft in future, we investigated whether the underlying genetic condition alters SVF's cell populations and in vitro differentiation capacity. After optimizing SVF isolation, we demonstrate successful isolation of SVF of pediatric OI patients and non-OI controls. The number of viable cells was comparable between OI and controls, with about 450,000 per gram tissue. Age, sex, type of OI, disease-causing collagen mutation, or anatomical site of harvest did not affect cell outcome. Further, SVF-containing cell populations were similar between OI and controls, and all isolated SVF's demonstrated chondrogenic, adipogenic, and osteogenic differentiation capacity in vitro. These results indicate that SVF from pediatric OI patients could be used as a source of stem cells for autologous stem cell therapy in OI.
Osteogenesis imperfecta (OI) is associated with short stature, which is mild, severe and moderate in OI types I, III and IV, respectively. Standardized OI type- and sex-specific growth charts across ...all pediatric ages do not exist.
We assessed 573 individuals with OI (type I, III or IV), each with at least one height measurement between ages 3 months and 20 years (total 6523 observations). Analogous to the Centers for Disease Control pediatric growth charts, we generated OI type- and sex-specific growth charts for infants (ages 3-36 months) as well as children and adolescents (ages 2-20 years). Growth curves were fitted to the data using the LMS method and percentiles were smoothed.
Age was associated with a decline in height z-scores (p < 0.001 for all OI types), which was more pronounced in females. Height multiplier curves were produced to predict adult height in children with OI. Among individuals with OI type I, those with COL1A1 pathogenic variants leading to haploinsufficiency were taller than those with COL1A1 or COL1A2 pathogenic variants not leading to haploinsufficiency.
Our standardized OI type- and sex-specific growth charts can be used to assess the growth of individuals with OI from infancy to adulthood.
Standardized osteogenesis imperfecta (OI) type- and sex-specific growth charts across all pediatric ages do not exist. Our study is the first to generate OI type- and sex-specific growth charts across all pediatric ages. Our height multiplier curves can be utilized to predict adult height in children with OI.
Short stature is common in osteogenesis imperfecta (OI) and is usually severe in OI types III and IV. The characteristics of pubertal growth in OI have not been studied in detail.
We assessed 82 ...individuals with OI caused by pathogenic variants in COL1A1 or COL1A2 who had annual height data between 6 and 16 years of age at a minimum. Height velocity curves were fitted to each individual's height data to describe the pubertal growth spurt.
Curve fitting was successful in 30 of the 33 individuals with OI type I (91%), in 23 of the 32 individuals with OI type IV (72%), and in 4 of the 17 participants with OI type III (24%). Pubertal growth spurt could be identified in most individuals with OI types I and IV, but rarely in OI type III. The timing of the pubertal growth spurt was similar between OI types I and IV in both sexes. However, height velocity was consistently higher in OI type I, leading to a widening height gap between OI types I and IV.
A pubertal growth spurt was present in most individuals with OI types I and IV, but rarely in OI type III.
To describe bone densitometry results using lumbar spine dual-energy X-ray absorptiometry and forearm peripheral quantitative computed tomography (pQCT) in children with arthrogryposis multiplex ...congenita (AMC).
Prospective study.
Lumbar spine areal bone mineral density (BMD) was measured in 58 participants (mean age 6.8 years, range 1 month to 19.7 years; 26 males). The diagnostic subgroup was Amyoplasia in 27 participants, distal arthrogryposis (unclassified, n = 13; type 2A, n = 1; type 2B, n = 2; type 8, n = 2) in 18 patients, an unclassified form of arthrogryposis in 6 patients, and a syndromic form of arthrogryposis in 7 patients. The mean lumbar spine areal BMD was −0.4 (SD: 1.5) which was significantly below 0 (p < 0.05, one-sample t-test). The mean lumbar spine bone mineral apparent density z-score (+0.4 SD: 1.4), a measure that is largely independent of bone size, was not significantly different from 0 (P > 0.05). A subset of 22 patients aged 6 years or older (mean age 10.9 years, 11 males) had forearm pQCT analysis. Mean z-scores for trabecular and cortical volumetric BMD at the radius were similar to healthy controls. Radius periosteal bone circumference and bone mineral content were appropriate for height. These densitometric results did not differ between patients with Amyoplasia or individuals with other diagnoses.
Low areal BMD in children and adolescents with AMC reflects their smaller bone size rather than a specific bone mass deficit. These data do not suggest that children and adolescents with AMC in general require regular monitoring by bone densitometry unless there are specific clinical concerns.
•Lumbar spine areal BMD was decreased in children and adolescents with arthrogryposis.•Results normalized after adjustment for bone size.•Trabecular and cortical volumetric BMD at the radius were normal.•Low areal BMD in this group with arthrogryposis reflected smaller bone size.
Osteogenesis imperfecta (OI) is commonly associated with short stature, but it is unclear whether this is exclusively secondary to fractures and bone deformities or whether there is a primary defect ...in longitudinal bone growth. As metacarpal and phalangeal bones are rarely affected by fractures and deformities, any length deficits in these bones should reflect a direct disease effect on longitudinal growth. This study therefore assessed the relationship of hand bone length with clinical OI type and genotype.
Prospective study.
The length of all 19 tubular hand bones were measured in 144 individuals (age 6 to 57 years; 68 female) who had OI caused by COL1A1 or COL1A2 variants. Measurements of bone length were converted to z-scores using published reference data. Bone length was mostly normal in OI type I but was significantly decreased in OI types III and IV. Mean hand bone length z-score (i.e., the average length z-score of all 19 bones of a hand) was −0.2 for OI type I, −2.9 for OI type III and −1.2 for OI type IV. Mean hand bone length z-score was positively associated with height z-score (r2 = 0.65, P < 0.001). Regarding genotype-phenotype correlations, mean hand bone length z-score was close to 0 in individuals with COL1A1 mutations leading to haploinsufficiency but were significantly lower in the presence of mutations leading to triple-helical glycine substitutions in either the alpha 1 or alpha 2 chain of collagen type I.
COL1A1 and COL1A2 mutations affect bone growth not only by inducing fractures and bone deformities, but also through longitudinal growth deficits in bones that do not fracture or deform.
•The length of metacarpal and phalangeal bones is mostly normal in OI type I.•Metacarpal and phalangeal bone length is low in OI types III and IV.•Mean hand bone length z-score is positively associated with height z-score.•OI causes longitudinal growth deficits in bones that do not fracture or deform.
Small hydro power systems (SHPSs) are increasingly installed in water distribution systems (WDSs). With only minor adaptations in a WDS, pressure surplus can be utilised. In such systems, a water ...surplus is also often available. In this work, water consumption data of a real Alpine WDS over one year are used as an input for an Epanet2 long-term simulation model to assess such a SHPS. In addition, the combinations of pressure and water surplus devices in a WDS are investigated. For such a specific investigated case, the yearly profit of 1750 € for a single SHPS could be increased to 3550 € when combining two interacting devices. Further, necessary and upcoming rehabilitation measures are investigated concerning their positive impact on the energy production potential and how additional costs (e.g., higher diameters (200 mm instead of 125 mm)) can be compensated by additional profits from energy production (maximum 5250 € per year).
The tourism businesses faces the challenge to reduce significantly their costs in the future and to structure internal processes more efficient. The hotel and tourism industry, which showed ...continuous growth in recent years, now looks ahead to economic turbulences and general difficult times. Given these developments, hotel companies will earn in the future less than before. This phenomenon has not been considered in tourism, while it exists since decades of years in the industrial sector. The industry applies successfully for many years modern methods and instruments to optimize productivity and efficiency and to increase the quality of services even further. These existing experiences to increase productivity in the industrial environment were taught for years as “Lean Management”. This research aims to show practical experiences of the application of Lean Management methods in the hospitality sector and to make a statement about their suitability and the possible potential for optimization. The work refers to a case study in a hotel company, where several Lean methods have been implemented successfully.
AIDS-associated morbidity has diminished due to excellent viral control. Multimorbidity are more prevalent and incident in Swiss HIV-positive persons compared to HIV-negative controls. However, ...smoking, but not HIV status, had a strong impact on cardiovascular risk and multimorbidity.
Background.
Although acquired immune deficiency syndrome-associated morbidity has diminished due to excellent viral control, multimorbidity may be increasing among human immunodeficiency virus (HIV)-infected persons compared with the general population.
Methods.
We assessed the prevalence of comorbidities and multimorbidity in participants of the Swiss HIV Cohort Study (SHCS) compared with the population-based CoLaus study and the primary care-based FIRE (Family Medicine ICPC-Research using Electronic Medical Records) records. The incidence of the respective endpoints were assessed among SHCS and CoLaus participants. Poisson regression models were adjusted for age, sex, body mass index, and smoking.
Results.
Overall, 74 291 participants contributed data to prevalence analyses (3230 HIV-infected; 71 061 controls). In CoLaus, FIRE, and SHCS, multimorbidity was present among 26%, 13%, and 27% of participants. Compared with nonsmoking individuals from CoLaus, the incidence of cardiovascular disease was elevated among smoking individuals but independent of HIV status (HIV-negative smoking: incidence rate ratio IRR = 1.7, 95% confidence interval CI = 1.2–2.5; HIV-positive smoking: IRR = 1.7, 95% CI = 1.1–2.6; HIV-positive nonsmoking: IRR = 0.79, 95% CI = 0.44–1.4). Compared with nonsmoking HIV-negative persons, multivariable Poisson regression identified associations of HIV infection with hypertension (nonsmoking: IRR = 1.9, 95% CI = 1.5–2.4; smoking: IRR = 2.0, 95% CI = 1.6–2.4), kidney (nonsmoking: IRR = 2.7, 95% CI = 1.9–3.8; smoking: IRR = 2.6, 95% CI = 1.9–3.6), and liver disease (nonsmoking: IRR = 1.8, 95% CI = 1.4–2.4; smoking: IRR = 1.7, 95% CI = 1.4–2.2). No evidence was found for an association of HIV-infection or smoking with diabetes mellitus.
Conclusions.
Multimorbidity is more prevalent and incident in HIV-positive compared with HIV-negative individuals. Smoking, but not HIV status, has a strong impact on cardiovascular risk and multimorbidity.
There is a growing recognition of the importance of protein kinases in the control of alternative splicing. To define the underlying regulatory mechanisms, highly selective inhibitors are needed. ...Here, we report the discovery and characterization of the dichloroindolyl enaminonitrile KH-CB19, a potent and highly specific inhibitor of the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4). Cocrystal structures of KH-CB19 with CLK1 and CLK3 revealed a non-ATP mimetic binding mode, conformational changes in helix αC and the phosphate binding loop and halogen bonding to the kinase hinge region. KH-CB19 effectively suppressed phosphorylation of SR (serine/arginine) proteins in cells, consistent with its expected mechanism of action. Chemical inhibition of CLK1/CLK4 generated a unique pattern of splicing factor dephosphorylation and had at low nM concentration a profound effect on splicing of the two tissue factor isoforms flTF (full-length TF) and asHTF (alternatively spliced human TF).
► We report a highly selective nanomolar inhibitor KH-CB19 for the kinases CLK1/4 and DYRK1 ► KH-CB19 cocrystal structures revealed an ATP competitive but not ATP mimetic binding mode ► KH-CB19 formed halogen bonds with the kinase hinge region ► KH-CB19 led to dephosphorylation of SR proteins and effected splicing of TF isoforms in cells
PDF
