Subsequent ipsi- and contralateral femoral fractures after intramedullary nailing of a trochanteric or subtrochanteric fracture: a cohort study on 2012 patients

Background: The literature is inconclusive as to whether an intramedullary nail changes the distribution of a subsequent ipsi- or contralateral fracture of the femur. We have compared the incidence, localisation, and fracture pattern of subsequent femoral fractures after intramedullary nailing of trochanteric or subtrochanteric fractures in patients without previous implants in either femur at the time of surgery. Methods: Retrospective analysis was performed of a two-centre cohort of 2012 patients treated with a short or long intramedullary nail for the management of trochanteric or subtrochanteric fracture between January 2005 and December 2018. Subsequent presentations with ipsi- and contralateral femoral fractures were documented. Only patients with no previous femoral surgery performed, other than the index nailing were followed. Odds ratios (ORs) for subsequent femoral fracture were calculated using robust variance estimates in logistic regression. Results: The mean age of the cohort was 82.4 years and 72.1% were female. The total number of patients presenting with subsequent femoral fractures was 299 (14.9%). The number of patients presenting with subsequent ipsilateral and contralateral femoral fractures was 51 (2.5%) and 248 (12.3%) respectively (OR 5.0; CI 3.7–6.9). Twenty-six (8.7%) of all subsequent femoral fractures occured in the ipsilateral shaft, 14 (4.7%) in the ipsilateral metaphyseal area, one (0.33%) in the contralateral shaft, and three (1.0%) in the contralateral metaphysis (OR 10; CI 3.6–29). Conclusion: An intramedullary nail significantly changes the fracture pattern in the event of a second low-energy trauma, reducing the risk of subsequent proximal ipsilateral femoral fractures and increasing the risk of subsequent ipsilateral femoral fractures in the shaft and distal metaphyseal area compared with the native contralateral femur.publishedVersio

Phase I study evaluating the safety, tolerability and pharmacokinetics of a novel oral dissolvable film containing dexamethasone versus Fortecortin dexamethasone tablets

Introduction: Systemic corticosteroids are anti-inflammatory agents with dexamethasone among the most potent in the class. Within (respiratory) allergy, systemic corticosteroids are usually applied in medical emergencies. In these situations, patients may experience physical or logistic problems taking tablets. To fulfil a practical unmet need for outpatients, Dexa ODF, an oral dissolvable film containing dexamethasone, was developed. Objectives: We compared the safety, tolerability and pharmacokinetics (PK) of Dexa ODF with Fortecortin tablets in healthy subjects. Methods: Thirty subjects participated in this open label, two-way, cross-over study, consisting of two treatment visits separated by 5-10 days. On both treatment visits, subjects randomly received one single dose of Dexa ODF (one strip; 8 mg dexamethasone) or one single dose of Fortecortin (two 4 mg tablets). Safety evaluations and blood sampling for PK were conducted until 48 h post-dose and bioequivalence analysis was performed on AUC(0-t), AUC(0-8) and Cmax. Results: All subjects were dosed. Forty-five adverse events (AEs) were reported by 17 subjects and approximately 50% were deemed ` possibly treatment related' (14 on Dexa ODF; 12 on Fortecortin) with no significant difference between treatments. For all three bioequivalence parameters the 90% CIs were within the acceptance limits of bioequivalence (0.8; 1.25). Conclusion: We demonstrated good tolerability and bioequivalence of Dexa ODF (8 mg dexamethasone) compared to Fortecortin tablets (2 x 4 mg dexamethasone). Dexa ODF is currently under development as an innovative treatment for use within respiratory and allergic conditions, including emergencies

Modulation of microRNA processing by 5‐lipoxygenase

The miRNA biogenesis is tightly regulated to avoid dysfunction and consequent disease development. Here, we describe modulation of miRNA processing as a novel noncanonical function of the 5‐lipoxygenase (5‐LO) enzyme in monocytic cells. In differentiated Mono Mac 6 (MM6) cells, we found an in situ interaction of 5‐LO with Dicer, a key enzyme in miRNA biogenesis. RNA sequencing of small noncoding RNAs revealed a functional impact, knockout of 5‐LO altered the expression profile of several miRNAs. Effects of 5‐LO could be observed at two levels. qPCR analyses thus indicated that (a) 5‐LO promotes the transcription of the evolutionarily conserved miR‐99b/let‐7e/miR‐125a cluster and (b) the 5‐LO‐Dicer interaction downregulates the processing of pre‐let‐7e, resulting in an increase in miR‐125a and miR‐99b levels by 5‐LO without concomitant changes in let‐7e levels in differentiated MM6 cells. Our observations suggest that 5‐LO regulates the miRNA profile by modulating the Dicer‐mediated processing of distinct pre‐miRNAs. 5‐LO inhibits the formation of let‐7e which is a well‐known inducer of cell differentiation, but promotes the generation of miR‐99b and miR‐125a known to induce cell proliferation and the maintenance of leukemic stem cell functions

Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGF beta expression

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial fatal progressive degenerative disorder. One of the pathological hallmarks of CADASIL is a dramatic reduction of vascular smooth muscle cells (VSMCs) in cerebral arteries. Using VSMCs from the vasculature of the human umbilical cord, placenta and cerebrum of CADASIL patients, we found that CADASIL VSMCs had a lower proliferation rate compared to control VSMCs. Exposure of control VSMCs and endothelial cells (ECs) to media derived from CADASIL VSMCs lowered the proliferation rate of all cells examined. By quantitative RT-PCR analysis, we observed increased Transforming growth factor-beta (TGF beta) gene expression in CADASIL VSMCs. Adding TGF beta-neutralizing antibody restored the proliferation rate of CADASIL VSMCs. We assessed proliferation differences in the presence or absence of TGF beta-neutralizing antibody in ECs co-cultured with VSMCs. ECs co-cultured with CADASIL VSMCs exhibited a lower proliferation rate than those co-cultured with control VSMCs, and neutralization of TGF beta normalized the proliferation rate of ECs co-cultured with CADASIL VSMCs. We suggest that increased TGF beta expression in CADASIL VSMCs is involved in the reduced VSMC proliferation in CADASIL and may play a role in situ in altered proliferation of neighbouring cells in the vasculature.Peer reviewe

Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression

Cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial fatal progressive degenerative disorder. One of the pathological hallmarks of CADASIL is a dramatic reduction of vascular smooth muscle cells (VSMCs) in cerebral arteries. Using VSMCs from the vasculature of the human umbilical cord, placenta and cerebrum of CADASIL patients, we found that CADASIL VSMCs had a lower proliferation rate compared to control VSMCs. Exposure of control VSMCs and endothelial cells (ECs) to media derived from CADASIL VSMCs lowered the proliferation rate of all cells examined. By quantitative RT‐PCR analysis, we observed increased Transforming growth factor‐β (TGFβ) gene expression in CADASIL VSMCs. Adding TGFβ‐neutralizing antibody restored the proliferation rate of CADASIL VSMCs. We assessed proliferation differences in the presence or absence of TGFβ‐neutralizing antibody in ECs co‐cultured with VSMCs. ECs co‐cultured with CADASIL VSMCs exhibited a lower proliferation rate than those co‐cultured with control VSMCs, and neutralization of TGFβ normalized the proliferation rate of ECs co‐cultured with CADASIL VSMCs. We suggest that increased TGFβ expression in CADASIL VSMCs is involved in the reduced VSMC proliferation in CADASIL and may play a role in situ in altered proliferation of neighbouring cells in the vasculature. </p

Spectrum of Perforin Gene Mutations in Familial Hemophagocytic Lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease of early childhood characterized by nonmalignant accumulation and multivisceral infiltration of activated T lymphocytes and histiocytes (macrophages). Cytotoxic T and natural killer (NK) cell activity is markedly reduced or absent in these patients, and mutations in a lytic granule constituent, perforin, were recently identified in a number of FHL individuals. Here, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutations, and one patient was a compound heterozygote. Four novel mutations were detected: one nonsense, two missense, and one deletion of one amino acid. In four families, a previously reported mutation at codon 374, causing a premature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mutations in 20% of all FHL patients investigated (7/34), with a somewhat higher prevalence, ∼30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phenotype of the patients was evident from the present study. Our combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%–40% of the FHL cases and the FHL 1 locus on chromosome 9 for ∼10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes