An adult-based insulin resistance genetic risk score associates with insulin resistance,metabolic traits and altered fat distribution in Danish children and adolescents who are overweight or obese

Aims/hypothesis

A genetic risk score (GRS) consisting of 53 insulin resistance variants (GRS₅₃) was recently demonstrated to associate with insulin resistance in adults. We speculated that the GRS₅₃ might already associate with insulin resistance during childhood, and we therefore aimed to investigate this in populations of Danish children and adolescents. Furthermore, we aimed to address whether the GRS associates with components of the metabolic syndrome and altered body composition in children and adolescents.

Methods

We examined a total of 689 children and adolescents who were overweight or obese and 675 children and adolescents from a population-based study. Anthropometric data, dual-energy x-ray absorptiometry scans, BP, fasting plasma glucose, fasting serum insulin and fasting plasma lipid measurements were obtained, and HOMA-IR was calculated. The GRS₅₃ was examined for association with metabolic traits in children by linear regressions using an additive genetic model.

Results

In overweight/obese children and adolescents, the GRS₅₃ associated with higher HOMA-IR (β?=?0.109?±?0.050 (SE); p?=?2.73?×?10^?2), fasting plasma glucose (β?=?0.010?±?0.005 mmol/l; p?=?2.51?×?10^?2) and systolic BP SD score (β?=?0.026?±?0.012; p?=?3.32?×?10^?2) as well as lower HDL-cholesterol (β?=??0.008?±?0.003 mmol/l; p?=?1.23?×?10^?3), total fat-mass percentage (β?=??0.143?±?0.054%; p?=?9.15?×?10^?3) and fat-mass percentage in the legs (β?=??0.197?±?0.055%; p?=?4.09?×?10^?4). In the population-based sample of children, the GRS₅₃ only associated with lower HDL-cholesterol concentrations (β?=??0.007?±?0.003 mmol/l; p?=?1.79?×?10^?2).

Conclusions/interpretation

An adult-based GRS comprising 53 insulin resistance susceptibility SNPs associates with insulin resistance, markers of the metabolic syndrome and altered fat distribution in a sample of Danish children and adolescents who were overweight or obese.

     

Increase in expression of receptor activator of nuclear factor kappaB at sites of bone erosion correlates with progression of inflammation in evolving collagen-induced arthritis

OBJECTIVE: The receptor activator of nuclear factor kappaB (RANK)/RANK ligand (RANKL) pathway is critical in osteoclastogenesis and bone resorption and has been implicated in the process of focal bone erosion in arthritis. This study was undertaken to identify in vivo the hitherto-unknown origin and localization of RANK-expressing osteoclast precursor cells at sites of bone erosion in arthritis. METHODS: DBA-1 mice were immunized with bovine type II collagen/Freund's complete adjuvant and were given an intraperitoneal booster injection of type II collagen on day 21. Arthritis was monitored visually, and joint pathology was examined histologically. RANK and RANKL expression were analyzed using specific immunohistochemistry, and tartrate-resistant acid phosphatase (TRAP) staining was performed. In addition, TRAP and cathepsin K messenger RNA expression were analyzed by in situ hybridization. RESULTS: A marked increase in the number of cells expressing RANK correlated with the progression of synovial inflammation and clinical disease severity in evolving collagen-induced arthritis (CIA). Interestingly, RANK expression demonstrated a gradient pattern with increased numbers of RANK-positive cells within the synovial infiltrate in areas closer to periosteum and cortical bone. Cells expressing RANK included cells in synovial tissue, bone lining cells on the surface of trabecular bone at sites of erosion, and cells in periosteal areas adjacent to synovial inflammation. In areas where RANK-positive cells were abundant, TRAP-positive, multinucleated osteoclast-like cells were also present at sites of focal bone erosion, suggesting differentiation of synovially derived RANK-positive osteoclast precursor cells into osteoclasts. In addition, TRAP- and cathepsin K-double-positive osteoclast-like cells were detected on the synovial side of cortical bone at sites of early and advanced cortical bone erosion. Sites of RANK expression also correlated well with sites of RANKL expression, and there was a close correlation of the temporal expression of the receptor-ligand pair. CONCLUSION: Cells expressing RANK increased in abundance with the progression of arthritis in evolving CIA, and sites of RANK-expressing cells correlated with sites of TRAP-positive, multinucleated osteoclast-like cells as well as with sites of RANKL expression. These data support the hypothesis that the RANK/RANKL pathway plays an important role in the process of bone erosion in CIA.     

Defecographic findings in patients with anal incontinence and constipation and their relation to rectal emptying

PURPOSE: The aim of this study was to examine defecographic findings in patients with anal incontinence and constipation and to compare these findings with rectal emptying. METHODS: One hundred seventy-five preoperative defecographies documented on videotape in patients with either anal incontinence or constipation were retrospectively reviewed. The examinations were evaluated with respect to anatomic abnormalities of the rectum or anal canal. The results were compared with a semiquantitative assessment of rectal emptying as it appeared on the video sequence after one minute of strain. RESULTS: Anatomic abnormalities were found equally in incontinent and constipated patients, except for failure to open the anal canal, which was found only in constipated patients. Rectal intussusception was the most frequent finding. Abnormal defecograms were found in both sexes. Enteroceles, sigmoidoceles, and large rectoceles were found only in women. The presence of intussusception, lacking relaxation of the puborectalis muscle, and rectocele did not correlate with poor rectal emptying. Poor rectal emptying was also found in 19 of 58 patients with normal defecograms. CONCLUSIONS: Anatomic abnormalities of the rectum may be demonstrated independently of the clinical symptoms and are not always correlated to impaired rectal emptying. Since they may also be found in healthy controls, surgical correction of these abnormalities should be considered only with great caution.     

Transoral robotic surgery for the management of head and neck squamous cell carcinoma of unknown primary

Conclusion: The addition of transoral robotic surgery (TORS) in the diagnostic management of patients classified with head and neck squamous cell carcinoma of unknown primary (SCCUP) is promising and appears to improve detection rates of the primary tumour. The approach presented in this first Scandinavian study could potentially minimize the radiation field to the pharyngeal axis in patients with identified primary tumours. Objectives: The aim of the study was to investigate whether bilateral lingual tonsillectomy performed with TORS is feasible, and whether it could improve the detection rates of primary tumours in patients diagnosed and classified as having SCCUP. Methods: The study was retrospective and included 13 patients with SCCUP who were referred to TORS between October 2013 and January 2015. All 13 patients had previously undergone a full investigation programme following the national guidelines including whole-body PET/CT, examination in general anaesthesia, including random biopsies of the base of the tongue and bilateral palatine tonsillectomy without identification of the primary tumour. Results: The primary tumour was identified by TORS in seven of the 13 patients (54%) at the lingual tonsils. Human papillomavirus DNA and p16 were positive in all identified primary tumour specimens and in the corresponding lymph node metastases.     

Structures of thymidine kinase 1 of human and mycoplasmic origin

Cytosolic thymidine kinase 1, TK1, is a well known cell-cycle-regulated enzyme of importance in nucleotide metabolism as well as an activator of antiviral and anticancer drugs such as 3'-azido-3'-deoxythymidine (AZT). We have now determined the structures of the TK1 family, the human and Ureaplasma urealyticum enzymes, in complex with the feedback inhibitor dTTP. The TK1s have a tetrameric structure in which each subunit contains an alpha/beta-domain that is similar to ATPase domains of members of the RecA structural family and a domain containing a structural zinc. The zinc ion connects beta-structures at the root of a beta-ribbon that forms a stem that widens to a lasso-type loop. The thymidine of dTTP is hydrogen-bonded to main-chain atoms predominantly coming from the lasso loop. This binding is in contrast to other deoxyribonucleoside kinases where specific interactions occur with side chains. The TK1 structure differs fundamentally from the structures of the other deoxyribonucleoside kinases, indicating a different evolutionary origin.     

Assessment of Schistosoma mansoni induced intestinal inflammation by means of eosinophil cationic protein, eosinophil protein X and myeloperoxidase before and after treatment with praziquantel

Faecal concentrations of eosinophil cationic protein (ECP), eosinophil protein X (EPX) and myeloperoxidase (MPO) were measured in extracts of stool samples obtained from a cohort of people (n=182) living in Bugoigo, a fishing community on the Eastern shore of Lake Albert, Buliisa District, in North Western Uganda where Schistosoma mansoni is endemic. Samples were collected before treatment and 5, 15, 20 and 52 weeks after treatment with praziquantel. Significantly increased levels of faecal ECP and EPX were found in S. mansoni infected individuals (n=155) compared to the levels found in stools from non-infected (n=27) (median values ECP: 11.3 microg/g vs. 5.9 microg/g, P=0.005, and EPX: 413.5 ng/g vs. 232.2 ng/g, P=0.045). An increased level of MPO was also found among the infected individuals compared to the non-infected 11.6 mu/g vs. 5.3 mu/g, P=0.07). Significant but weak correlations were found between faecal egg counts and faecal concentrations of ECP and EPX. Treatment with praziquantel induced a significant decline in both ECP and EPX, but only a non-significant reduction in faecal MPO. Following reinfection and despite of very low infection intensities, the protein levels increased significantly reaching the pre-treatment level (ECP and EPX) or levels significantly higher than the pre-treatment levels (MPO). This response pattern may imply a rebound effect during reinfection following treatment and resolution of immune regulatory immunosuppressive mechanisms in function during the chronic infection.     

Case report: vitamin D‐dependent rickets type 1 caused by a novel CYP27B1 mutation

Vitamin D‐dependent rickets type 1 VDDR‐1 is a recessive inherited disorder with impaired activation of vitamin D, caused by mutations in CYP27B1. We present long‐time follow‐up of a case with a novel mutation including high‐resolution peripheral quantitative computed tomography of the bone. Adequate treatment resulted in a normalized phenotype.     

Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 2004

There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m(2) and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of veno-occlusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541).