Postoperative pain as a risk factor for stiff knee following total knee arthroplasty and excellent patient-reported outcomes after manipulation under anesthesia

Background and purpose - Manipulation under anesthesia (MUA) is the first-choice treatment for stiffness following total knee arthroplasty (TKA) unresponsive to pain management and physiotherapy. Some of the predisposing factors and patient-reported outcome measures (PROMs) following MUA remain poorly studied. We retrospectively investigated the etiological risk factors and the outcomes of MUA. Patients and methods - 391 TKA patients from a randomized trial comparing the use of a tourniquet and anesthesia (spinal or general) were analyzed, and patients needing MUA were identified (MUA group). We evaluated in-hospital opioid consumption, Oxford Knee Score (OKS), range of motion (ROM), and pain assessed by the Brief Pain Inventory-short form with a 1-year follow-up. Results - 39 (10%) MUA patients were identified. The MUA patients were younger (60 years vs. 64 years, difference -4, 95% CI -6 to -1) and had higher postoperative oxycodone consumption (66 mg vs. 51 mg, median difference 11, CI 1-22) than the no-MUA patients. The proportion of MUA patients who contacted the emergency department within 3 months because of pain was larger than that of non-MUA patients (41% vs. 12%, OR 5, CI 3-10). At the 1-year follow-up, the ROM was improved by 39 degrees following MUA, but the total ROM was worse in the MUA group (115 degrees vs. 124 degrees, p < 0.001). No difference was found in the OKS between the MUA and no-MUA patients. Interpretation - Higher postoperative pain seems to predict MUA risk. MUA performed 3 months postoperatively offers substantial ROM improvement and comparable PROMs to no-MUA patients 1 year after TKA.Peer reviewe

Regulation of Early Adipose Commitment by Zfp521

While there has been significant progress in determining the transcriptional cascade involved in terminal adipocyte differentiation, less is known about early events leading to lineage commitment and cell fate choice. It has been recently discovered that zinc finger protein 423 (Zfp423) is an early actor in adipose determination. Here, we show that a close paralog of Zfp423, Zfp521, acts as a key regulator of adipose commitment and differentiation in vitro and in vivo. Zfp521 exerts its actions by binding to early B cell factor 1 (Ebf1), a transcription factor required for the generation of adipocyte progenitors, and inhibiting the expression of Zfp423. Overexpression of Zfp521 in cells greatly inhibits adipogenic potential, whereas RNAi-mediated knock-down or genetic ablation of Zfp521 enhances differentiation. In addition, $Zfp521^{−/−}$ embryos exhibit increased mass of interscapular brown adipose tissue and subcutaneous white adipocytes, a cell autonomous effect. Finally, Ebf1 participates in a negative feedback loop to repress Zfp521 as differentiation proceeds. Because Zfp521 is known to promote bone development, our results suggest that it acts as a critical switch in the commitment decision between the adipogenic and osteogenic lineages

Exome sequencing reveals candidate mutations implicated in sinonasal carcinoma and malignant transformation of sinonasal inverted papilloma

We explored somatic mutations in dysplastic sinonasal inverted papilloma (SNIP), SNIP with concomitant sinonasal squamous cell carcinoma (SNSCC), and SNSCC without preceding SNIP. Ten SNIP and SNSCC samples were analyzed with exome sequencing and tested for human papillomavirus. The identified mutations were compared to the most frequently mutated genes in head and neck squamous cell carcinoma (HNSCC) in the COSMIC database. Exome sequencing data were also analyzed for mutations not previously linked to SNSCC. Seven of the most commonly mutated genes in HNSCC and SNSCC in COSMIC harbored mutations in our data. In addition, we identified mutations in 23 genes that are likely to contribute to SNIP and SNSCC oncogenesis.Peer reviewe

PASI: A novel pathway method to identify delicate group effects

Pathway analysis is a common approach in diverse biomedical studies, yet the currently-available pathway tools do not typically support the increasingly popular personalized analyses. Another weakness of the currently-available pathway methods is their inability to handle challenging data with only modest group-based effects compared to natural individual variation. In an effort to address these issues, this study presents a novel pathway method PASI (Pathway Analysis for Sample-level Information) and demonstrates its performance on complex diseases with different levels of group-based differences in gene expression. PASI is freely available as an R package

Acute hormonal findings after aneurysmal subarachnoid hemorrhage - report from a single center

Purpose: The aim was to assess anterior pituitary hormone levels during the acute phase of aneurysmal subarachnoid hemorrhage (aSAH) and analyze the possible association with the clinical condition and outcome. Material and methods: Forty patients with aSAH whose aneurysm was secured by endovascular coiling were enrolled. Basal secretions of cortisol, testosterone, luteinizing hormone (LH), prolactin (PRL), and sex hormone binding globulin (SHBG) levels were measured up to 14 days after the incident. Results: The main finding was that hypocortisolism was rare whereas testosterone deficiency was common in male patients. Furthermore, various other hormone deviations were frequent and there was wide interindividual variability. We found no association between delayed cerebral ischemia (DCI), outcome of the patients or aneurysm location, and hormone abnormalities, while both Hunt & Hess and Fisher grade were associated with low PRL levels. Hunt & Hess 5 was associated with low PRL concentration when compared to grades 1 (OR = 4.81, 95% CI 1.15-20.14, p = 0.03), 3 (OR 7.73, 95% CI 1.33-45.01, p = 0.02), and 4 (OR = 6.86 95% CI 1.28-26.83, p = 0.02). Fisher grade 4 was associated with low PRL concentration when compared to grades 3 (OR 3.37, 95% CI 1.06-10.73, p = 0.03) and 2 (OR 9.71, 95% CI 1.22-77.10, p = 0.04). Conclusion: Deviations from normal and huge interindividual differences are common in hormone levels during the acute phase of aSAH. Routine assessment of anterior pituitary function in the acute phase of aSAH is not warranted. During the follow-up in the outpatient clinic, hormone concentrations were not measured, which would have brought a more long-term perspective into our findings.Peer reviewe

Recombinant Antibodies with Unique Specificities Allow for Sensitive and Specific Detection of Uncarboxylated Osteocalcin in Human Circulation

Osteocalcin is a bone-specific protein which contains three glutamic acid residues (Glu) that undergo post-translational gamma-carboxylation. Uncarboxylated osteocalcin (ucOC) may participate in the regulation of glucose metabolism, thus measurement of ucOC could be useful in evaluating interactions between bone and glucose metabolism. We developed recombinant antibodies and immunoassay to specifically detect ucOC in human blood samples. ucOC-specific recombinant antibodies were selected from an antibody library by phage display. Four candidates were characterized, and one (Fab-AP13) was used to set up an immunoassay with a pre-existing MAb. Plasma ucOC levels were measured in subjects with normal fasting blood glucose (= 7 mmol/l,N = 29). Further, we analyzed ucOC in age- and gender-matched patients with diagnosed type 2 diabetes (T2D,N = 49). Antibodies recognized ucOC without cross-reaction to carboxylated osteocalcin. Antibodies had unique binding sites at the carboxylation region, with Glu17 included in all epitopes. Immunoassay was set up and characterized. Immunoassay detected ucOC in serum and plasma, with on average 1.6-fold higher levels in plasma. ucOC concentrations were significantly lower in subjects with hyperglycemia (median 0.58 ng/ml,p = 0.008) or with T2D diagnosis (0.68 ng/ml,p = 0.015) than in subjects with normal blood glucose (1.01 ng/ml). ucOC negatively correlated with fasting plasma glucose in subjects without T2D (r = - 0.24,p = 0.035) but not in T2D patients (p = 0.41). Our immunoassay, based on the novel recombinant antibody, allows for specific and sensitive detection of ucOC in human circulation. Correlation between ucOC and plasma glucose suggests interactions between osteocalcin and glucose metabolism in humans

Age-Progressive and Gender-Dependent Bone Phenotype in Mice Lacking Both Ebf1 and Ebf2 in Prrx1-Expressing Mesenchymal Cells

Ebfs are a family of transcription factors regulating the differentiation of multiple cell types of mesenchymal origin, including osteoblasts. Global deletion of Ebf1 results in increased bone formation and bone mass, while global loss of Ebf2 leads to enhanced bone resorption and decreased bone mass. Targeted deletion of Ebf1 in early committed osteoblasts leads to increased bone formation, whereas deletion in mature osteoblasts has no effect. To study the effects of Ebf2 specifically on long bone development, we created a limb bud mesenchyme targeted Ebf2 knockout mouse model by using paired related homeobox gene 1 (Prrx1) Cre. To investigate the possible interplay between Ebf1 and Ebf2, we deleted both Ebf1 and Ebf2 in the cells expressing Prrx1. Mice with Prrx1-targeted deletion of Ebf2 had a very mild bone phenotype. However, deletion of both Ebf1 and Ebf2 in mesenchymal lineage cells lead to significant, age progressive increase in bone volume. The phenotype was to some extent gender dependent, leading to an increase in both trabecular and cortical bone in females, while in males a mild cortical bone phenotype and a growth plate defect was observed. The phenotype was observed at both 6 and 12 weeks of age, but it was more pronounced in older female mice. Our data suggest that Ebfs modulate bone homeostasis and they are likely able to compensate for the lack of each other. The roles of Ebfs in bone formation appear to be complex and affected by multiple factors, such as age and gender

Novel effects of the gastrointestinal hormone secretin on cardiac metabolism and renal function

The cardiac benefits of gastrointestinal hormones have been of interest in recent years. The aim of this study was to explore the myocardial and renal effects of the gastrointestinal hormone secretin in the GUTBAT trial (NCT03290846). A placebo-controlled crossover study was conducted on 15 healthy males in fasting conditions, where subjects were blinded to the intervention. Myocardial glucose uptake was measured with [F-18]2-fluoro-2-deoxy-o-glucose ([F-18]FDG) positron emission tomography. Kidney function was measured with [F-18]FDG renal clearance and estimated glomerular filtration rate (eGFR). Secretin increased myocardial glucose uptake compared with placebo (secretin vs. placebo, means +/- SD, 15.5 +/- 7.4 vs. 9.7 +/- 4.9 gmol/100 g/min, 95% confidence interval (CI) [2.2, 9.4], P = 0.004). Secretin also increased [F-18]FDG renal clearance (44.5 +/- 5.4 vs. 39.5 8.5 mL/min, 95%CI [1.9, 8.1], P = 0.004), and eGFR was significantly increased from baseline after secretin, compared with placebo (17.8 +/- 9.8 vs. 6.0 +/- 5.2 Delta mL/min/1.73 m(2),( ) 95%CI [6.0, 17.6], P = 0.001). Our results implicate that secretin increases heart work and renal filtration, making it an interesting drug candidate for future studies in heart and kidney failure. NEW & NOTEWORTHY Secretin increases myocardial glucose uptake compared with placebo, supporting a previously proposed inotropic effect. Secretin also increased renal filtration rate.Peer reviewe

Coordinated transcriptional regulation of bone homeostasis by Ebf1 and Zfp521 in both mesenchymal and hematopoietic lineages

Bone homeostasis is maintained by the coupled actions of hematopoietic bone-resorbing osteoclasts (OCs) and mesenchymal bone-forming osteoblasts (OBs). Here we identify early B cell factor 1 (Ebf1) and the transcriptional coregulator Zfp521 as components of the machinery that regulates bone homeostasis through coordinated effects in both lineages. Deletion of Zfp521 in OBs led to impaired bone formation and increased OB-dependent osteoclastogenesis (OC-genesis), and deletion in hematopoietic cells revealed a strong cell-autonomous role for Zfp521 in OC progenitors. In adult mice, the effects of Zfp521 were largely caused by repression of Ebf1, and the bone phenotype of Zfp521+/− mice was rescued in Zfp521+/−:Ebf1+/− mice. Zfp521 interacted with Ebf1 and repressed its transcriptional activity. Accordingly, deletion of Zfp521 led to increased Ebf1 activity in OBs and OCs. In vivo, Ebf1 overexpression in OBs resulted in suppressed bone formation, similar to the phenotype seen after OB-targeted deletion of Zfp521. Conversely, Ebf1 deletion led to cell-autonomous defects in both OB-dependent and cell-intrinsic OC-genesis, a phenotype opposite to that of the Zfp521 knockout. Thus, we have identified the interplay between Zfp521 and Ebf1 as a novel rheostat for bone homeostasis