Transglutaminases in fibrosis-overview and recent advances.

Transglutaminases (TGs) are a family of protein cross-linking enzymes that are capable of stiffening and insolubilizing proteins and creating protein networks, and thereby altering biological functions of proteins. Their role in fibrosis progression has been widely investigated with a focus on kidney, lung, liver, and heart where activity is triggered by various stimuli including hypoxia, inflammation, and hyperglycemia. TG2 has been considered one of the key enzymes in the pathogenesis of fibrosis mainly through transforming growth factor beta (TGF-beta) signaling and matrix cross-linking mechanisms. Although TG2 has been most widely studied in this context, the involvement of other TGs, TG1 and Factor XIII-A (FXIII-A), is beginning to emerge. This mini-review highlights the major steps taken in the TG and fibrosis research and summarizes the most recent advances and contributions of TG2, TG1, and FXIII-A to the progression of fibrosis in various animal models. Also, their mechanisms of action as well as therapeutic prospects are discussed.

Epidermal clearance of Candida albicans is mediated by IL-17 but independent of fungal innate immune receptors.

IL-17 plays important roles in host defense against Candida albicans at barrier surfaces and during invasive infection. However, the role of IL-17 in host defense after colonization of the epidermis, a main site of C. albicans infection, remains poorly understood. Using a murine model of epicutaneous candidiasis without skin abrasion, we found that skin inflammation triggered by epidermal C. albicans colonization was self-limiting with fungal clearance completed by day 7 after inoculation in wild-type mice or animals deficient in IL-17A or IL-17F. In contrast, marked neutrophilic inflammation in the epidermis and impaired fungal clearance were observed in mice lacking both IL-17A and IL-17F. Clearance of C. albicans was independent of Dectin-1, Dectin-2, CARD9 (caspase-recruitment domain family, member 9), TLR2 (Toll-like receptor 2) and MyD88 in the epidermal colonization model. We found that group 3 innate lymphoid cells (ILC3s) and γδT cells were the major IL-17 producers in the epicutaneous candidiasis model. Analyses of Rag2-/- mice and Rag2-/-Il2rg-/- mice revealed that production of IL-17A and IL-17F by ILC3s was sufficient for C. albicans clearance. Finally, we found that depletion of neutrophils impaired C. albicans clearance in the epidermal colonization model. Taken together, these findings indicate a critical and redundant function of IL-17A and IL-17F produced by ILC3s in host defense against C. albicans in the epidermis. The results also suggest that epidermal C. albicans clearance is independent of innate immune receptors or that these receptors act redundantly in fungal recognition and clearance.

Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy.

Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG3, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS, and SCHLAP1, we also noted a significant decrease in both KLK3 (prostate-specific antigen ) and FOLH1 (prostate-specific membrane antigen) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.

Improved chest wall trauma taxonomy: an interdisciplinary CWIS and ASER collaboration.

PURPOSE: Chest wall injury taxonomy and nomenclature are important components of chest wall injury classification and can be helpful in communicating between providers for treatment planning. Despite the common nature of these injuries, there remains a lack of consensus regarding injury description. The Chest Wall Injury Society (CWIS) developed a taxonomy among surgeons in the field; however, it lacked consensus and clarity in critical areas and collaboration with multidisciplinary partners. We believe an interdisciplinary collaboration between CWIS and American Society of Emergency Radiology (ASER) will improve existing chest wall injury nomenclature and help further research on this topic. METHODS: A collaboration between CWIS and ASER gathered feedback on the consensus recommendations. The workgroup held a series of meetings reviewing each consensus statement, refining the terminology, and contributing additional clarifications from a multidisciplinary lens. RESULTS: After identifying incomplete definitions in the CWIS survey, the workgroup expanded on and clarified the language proposed by the survey. More precise definitions related to rib and costal cartilage fracture quality and location were developed. Proposed changes include more accurate characterization of rib fracture displacement and consistent description of costal cartilage fractures. CONCLUSIONS: The 2019 consensus survey from CWIS provides a framework to discuss chest wall injuries, but several concepts remained unclear. Creating a universally accepted taxonomy and nomenclature, utilizing the CWIS survey and this article as a scaffolding, may help providers communicate the severity of chest wall injury accurately, allow for better operative planning, and provide a common language for researchers in the future.

Peptidic Inhibitors and a Fluorescent Probe for the Selective Inhibition and Labelling of Factor XIIIa Transglutaminase.

Factor XIIIa (FXIIIa) is a transglutaminase of major therapeutic interest for the development of anticoagulants due to its essential role in the blood coagulation cascade. While numerous FXIIIa inhibitors have been reported, they failed to reach clinical evaluation due to their lack of metabolic stability and low selectivity over transglutaminase 2 (TG2). Furthermore, the chemical tools available for the study of FXIIIa activity and localization are extremely limited. To combat these shortcomings, we designed, synthesised, and evaluated a library of 21 novel FXIIIa inhibitors. Electrophilic warheads, linker lengths, and hydrophobic units were varied on small molecule and peptidic scaffolds to optimize isozyme selectivity and potency. A previously reported FXIIIa inhibitor was then adapted for the design of a probe bearing a rhodamine B moiety, producing the innovative KM93 as the first known fluorescent probe designed to selectively label active FXIIIa with high efficiency (kinact/KI = 127,300 M-1 min-1) and 6.5-fold selectivity over TG2. The probe KM93 facilitated fluorescent microscopy studies within bone marrow macrophages, labelling FXIIIa with high efficiency and selectivity in cell culture. The structure-activity trends with these novel inhibitors and probes will help in the future study of the activity, inhibition, and localization of FXIIIa.

Costal cartilage fractures in blunt polytrauma patients - a prospective clinical and radiological follow-up study.

PURPOSE: To assess the healing of costal cartilage fractures (CCFX) in patients with blunt polytrauma with follow-up imaging and clinical examination. Effect on physical performance and quality of life (QoL) was also evaluated. METHODS: The study group comprised twenty-one patients with diagnosed CCFX in trauma CT. All the patients underwent MRI, ultrasound, ultra-low-dose CT examinations, and clinical status control. The patients completed QoL questionnaires. Two radiologists evaluated the images regarding fracture union, dislocation, calcifications, and persistent edema at fracture site. An attending trauma surgeon clinically examined the patients, with emphasis on focal tenderness and ribcage mobility. Trauma registry data were accessed to evaluate injury severity and outcome. RESULTS: The patients were imaged at an average of 34.1 months (median 36, range 15.8-57.7) after the initial trauma. In 15 patients (71.4%), CCFX were considered stable on imaging. Cartilage calcifications were seen on healed fracture sites in all the patients. The fracture dislocation had increased in 5 patients (23.8%), and 1 patient (4.8%) showed signs of a non-stable union. Four patients (19.0%) reported persistent symptoms from CCFX. CONCLUSION: Non-union in CCFX is uncommon but may lead to decreased stability and discomfort. Both clinical and radiological examinations play an important part in the post-traumatic evaluation of CCFX. CT and MRI visualize the healing process, while dynamic ultrasound may reveal instability. No significant difference in QoL was detected between patients with radiologically healed and non-healed CCFX. Post-traumatic disability was mostly due to other non-thoracic injuries.

Transglutaminase regulation of cell function.

Transglutaminases (TGs) are multifunctional proteins having enzymatic and scaffolding functions that participate in regulation of cell fate in a wide range of cellular systems and are implicated to have roles in development of disease. This review highlights the mechanism of action of these proteins with respect to their structure, impact on cell differentiation and survival, role in cancer development and progression, and function in signal transduction. We also discuss the mechanisms whereby TG level is controlled and how TGs control downstream targets. The studies described herein begin to clarify the physiological roles of TGs in both normal biology and disease states.

Study of the K_{L}→π

The rare decay K_{L}→π^{0}νν[over ¯] was studied with the dataset taken at the J-PARC KOTO experiment in 2016, 2017, and 2018. With a single event sensitivity of (7.20±0.05_{stat}±0.66_{syst})×10^{-10}, three candidate events were observed in the signal region. After unveiling them, contaminations from K^{±} and scattered K_{L} decays were studied, and the total number of background events was estimated to be 1.22±0.26. We conclude that the number of observed events is statistically consistent with the background expectation. For this dataset, we set an upper limit of 4.9×10^{-9} on the branching fraction of K_{L}→π^{0}νν[over ¯] at the 90% confidence level.

Diagnostic performance of CT and the use of GI contrast material for detection of hollow viscus injury after penetrating abdominal trauma. Experience from a level 1 Nordic trauma center.

BACKGROUND: Use of gastrointestinal (GI) contrast material for computed tomography (CT) diagnosis of hollow viscus injury (HVI) after penetrating abdominal trauma is still controversial. PURPOSE: To assess the sensitivity of CT and GI contrast material use in detecting HVI after penetrating abdominal trauma. MATERIAL AND METHODS: Retrospective analysis (2013-2016) of patients with penetrating abdominal trauma. Data from the local trauma registry, medical records, and imaging from PACS were reviewed. CT and surgical findings were compared. RESULTS: Of 636 patients with penetrating trauma, 177 (163 men, 14 women) had abdominal trauma (mean age 34 years, age range 16-88 years): 155/177 (85%) were imaged with CT on arrival; 128/155 (83%) were stab wounds and 21/155 (14%) were gunshot wounds; 47/155 (30%) had emergent surgery after CT. Two patients were imaged using oral, rectal and i.v. contrast; 23 with rectal and i.v. contrast; and 22 with i.v. contrast only. Surgery revealed HVI in 26 patients. CT had an overall sensitivity 69.2%, specificity 90.5%, PPV 90.0%, and NPV 70.4%. CT with oral and/or rectal contrast (n = 25) had sensitivity 66.7%, specificity 71.4%, PPV 85.7%, and NPV 45.5%. CT with i.v. contrast only (n = 22) had 75% sensitivity, 100% specificity, PPV 100%, and NPV 87.5%. No statistically significant difference was found between sensitivity of CT with GI contrast material and i.v. contrast only (P = 1). CONCLUSION: Stab wounds were the most common cause of penetrating abdominal trauma. CT had 69.2% sensitivity and 90.5% specificity in detecting HVI. CT with GI contrast had similar sensitivity as CT with i.v. contrast only.

Transglutaminases and Obesity in Humans: Association of F13A1 to Adipocyte Hypertrophy and Adipose Tissue Immune Response.

Transglutaminases TG2 and FXIII-A have recently been linked to adipose tissue biology and obesity, however, human studies for TG family members in adipocytes have not been conducted. In this study, we investigated the association of TGM family members to acquired weight gain in a rare set of monozygotic (MZ) twins discordant for body weight, i.e., heavy-lean twin pairs. We report that F13A1 is the only TGM family member showing significantly altered, higher expression in adipose tissue of the heavier twin. Our previous work linked adipocyte F13A1 to increased weight, body fat mass, adipocyte size, and pro-inflammatory pathways. Here, we explored further the link of F13A1 to adipocyte size in the MZ twins via a previously conducted TWA study that was further mined for genes that specifically associate to hypertrophic adipocytes. We report that differential expression of F13A1 (ΔHeavy-Lean) associated with 47 genes which were linked via gene enrichment analysis to immune response, leucocyte and neutrophil activation, as well as cytokine response and signaling. Our work brings further support to the role of F13A1 in the human adipose tissue pathology, suggesting a role in the cascade that links hypertrophic adipocytes with inflammation.

Search for K_{L}→π

A search for the rare decay K_{L}→π^{0}νν[over ¯] was performed. With the data collected in 2015, corresponding to 2.2×10^{19} protons on target, a single event sensitivity of (1.30±0.01_{stat}±0.14_{syst})×10^{-9} was achieved and no candidate events were observed. We set an upper limit of 3.0×10^{-9} for the branching fraction of K_{L}→π^{0}νν[over ¯] at the 90% confidence level (C.L.), which improved the previous limit by almost an order of magnitude. An upper limit for K_{L}→π^{0}X^{0} was also set as 2.4×10^{-9} at the 90% C.L., where X^{0} is an invisible boson with a mass of 135 MeV/c^{2}.

Transglutaminase activity regulates differentiation, migration and fusion of osteoclasts via affecting actin dynamics.

Osteoclasts, bone resorbing cells, derive from monocyte/macrophage cell lineage. Increased osteoclast activity is responsible for bone destruction in diseases such as osteoporosis, periodontitis and rheumatoid arthritis. Transglutaminases (TGs), protein crosslinking enzymes, were recently found involved in osteoclastogenesis in vivo, however their mechanisms of action have remained unknown. In this study, we have investigated the role of TG activity in osteoclastogenesis in vitro using four TG inhibitors, NC9, Z006, T101, and monodansyl cadaverine. Our results showed that all TG inhibitors were capable of blocking the entire osteoclastogenesis process. The most potent of the inhibitors, NC9 when added to cultures at different phases of osteoclastogenesis, inhibited differentiation, migration, and fusion of pre-osteoclasts as well as resorption activity of mature osteoclasts. Further investigation into the mechanisms revealed that NC9 increased RhoA levels and blocked podosome belt formation suggesting that TG activity regulates actin dynamics in pre-osteoclasts. The inhibitory effect of NC9 on osteoclastogenesis as well as podosome belt formation was completely reversed with a Rho-family inhibitor Exoenzyme C3. Microtubule architecture, acetylation, and detyrosination of α-tubulin were not affected. Finally, we demonstrated that macrophages and osteoclasts expressed mRNA of three TGs:TG1, TG2, and Factor XIII-A which were all differentially regulated in these cells during differentiation. Immunofluoresence microscopic analysis showed that all three enzymes co-localized to podosomes in osteoclasts. Taken together, our data suggests that TG activity regulates differentiation, migration and fusion of osteoclasts via affecting actin dynamics and that this may involve contribution from all three TG enzymes.

Incidence and Imaging Findings of Costal Cartilage Fractures in Patients with Blunt Chest Trauma: A Retrospective Review of 1461 Consecutive Whole-Body CT Examinations for Trauma.

Purpose To assess the incidence of costal cartilage (CC) fractures in whole-body computed tomographic (CT) examinations for blunt trauma and to evaluate distribution of CC fractures, concomitant injuries, mechanism of injury, accuracy of reporting, and the effect on 30-day mortality. Materials and Methods Institutional review board approval was obtained for this retrospective study. All whole-body CT examinations for blunt trauma over 36 months were reviewed retrospectively and chest trauma CT studies were evaluated by a second reader. Of 1461 patients who underwent a whole-body CT examination, 39% (574 of 1461) had signs of thoracic injuries (men, 74.0% [425 of 574]; mean age, 46.6 years; women, 26.0% [149 of 574]; mean age, 48.9 years). χ2 and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Interobserver agreement was calculated by using Cohen kappa values. Results A total of 114 patients (men, 86.8% [99 of 114]; mean age, 48.6 years; women, 13.2% [15 of 114]; mean age, 45.1 years) had 221 CC fractures. The incidence was 7.8% (114 of 1461) in all whole-body CT examinations and 19.9% (114 of 574) in patients with thoracic trauma. Cartilage of rib 7 (21.3%, 47 of 221) was most commonly injured. Bilateral multiple consecutive rib fractures occurred in 36% (41 of 114) versus 14% (64 of 460) in other patients with chest trauma (OR, 3.48; 95% CI: 2.18, 5.53; P < .0001). Hepatic injuries were more common in patients with chest trauma with CC fractures (13%, 15 of 114) versus patients with chest trauma without CC fractures (4%, 18 of 460) (OR, 3.72; 95% CI: 1.81, 7.64; P = .0001), as well as aortic injuries (n = 4 vs n = 0; P = .0015; OR, unavailable). Kappa value for interobserver agreement in detecting CC fractures was 0.65 (substantial agreement). CC fractures were documented in 39.5% (45 of 114) of primary reports. The 30-day mortality of patients with CC fractures was 7.02% (eight of 114) versus 4.78% (22 of 460) of other patients with chest trauma (OR, 1.50; 95% CI: 0.65, 3.47; P = .3371). Conclusion CC fractures are common in high-energy blunt chest trauma and often occur with multiple consecutive rib fractures. Aortic and hepatic injuries were more common in patients with CC fractures than in patients without CC fractures. © RSNA, 2017.

Control of the heat stress-induced alternative splicing of a subset of genes by hnRNP K.

Pre-mRNA splicing is widely repressed upon heat shock in eukaryotic cells. However, it has been shown that HSP105 pre-mRNA is alternatively spliced in response to heat stress. Using RNAi screening in HeLa cells, we found that RNA-binding proteins hnRNP K and PSF/SFPQ are necessary for the exon 12 exclusion of HSP105 during heat stress. Moreover, exon array analyses showed that a group of genes is alternatively spliced during heat stress in an hnRNP K-dependent manner, whereas hnRNP K is not necessary for the stress-induced alternative splicing of the remaining genes. Among the latter group, we found that SRp38/SRSF10 and SC35/SRSF2 are necessary for the inclusion of exon 13 of TNRC6A during heat stress. Thus, our study clearly showed that several RNA-binding proteins are involved in the splicing regulation in response to heat stress in mammalian cells.

Interaction and colocalization of HERMES/RBPMS with NonO, PSF, and G3BP1 in neuronal cytoplasmic RNP granules in mouse retinal line cells.

HERMES, also called RBPMS, is a conserved RNA binding protein with a single RNA recognition motif (RRM) that is abundantly expressed in retinal ganglion cells (RGCs) and in the heart in vertebrates. Here, we identified NonO and PSF as the interacting proteins of HERMES only when the neuronal differentiation of the retinal cell line RGC-5 was induced. Although NonO and PSF are nuclear paraspeckle components, these proteins formed cytoplasmic granules with HERMES in the neurites. G3BP1, a component of stress granules, was also colocalized to the granules, interacting with NonO and HERMES even in the absence of cellular stress. Consistent with a previous report that KIF5 interacts with neuronal granules, the localization of KIF5A overlapped with the cytoplasmic granules in differentiated RGC-5 cells. Thus, our study strongly suggests that the cytoplasmic granule containing HERMES, NonO, PSF, and G3BP1 is a neuronal RNA-protein granule that is transported in neurites during retinal differentiation.

Factor XIII-A transglutaminase acts as a switch between preadipocyte proliferation and differentiation.

Factor XIII-A (FXIII-A) transglutaminase (TG) was recently identified as a potential causative obesity gene in human white adipose tissue (WAT). Here, we have examined the role of TG activity and the role of protein crosslinking in adipogenesis. Mouse WAT and preadipocytes showed abundant TG activity arising from FXIII-A. FXIII-A was localized to the cell surface and acted as a negative regulator of adipogenesis by promoting assembly of fibronectin (FN) from plasma into preadipocyte extracellular matrix. This modulated cytoskeletal dynamics and maintained the preadipocyte state. FXIII-A-assembled plasma FN (pFN) matrix promoted preadipocyte proliferation and potentiated the proproliferative effects of insulin (INS) while suppressing the prodifferentiating INS signaling. FXIII-A-deficient mouse embryonic fibroblasts showed increased lipid accumulation and decreased proliferation as well as decreased pFN assembly into extracellular matrix. Thus, FXIII-A serves as a preadipocyte-bound proliferation/differentiation switch that mediates effects of hepatocyte-produced circulating pFN.

Immuno-based detection of extracellular vesicles in urine as diagnostic marker for prostate cancer.

Extracellular vesicles (including the subclass exosomes) secreted by cells contain specific proteins and RNA that could be of interest in determining new markers. Isolation/characterization of PCa-derived exosomes from bodily fluids enables us to discover new markers for this disease. Unfortunately, isolation with current techniques (ultracentrifugation) is labor intensive and other techniques are still under development. The goal of our study was to develop a highly sensitive time-resolved fluorescence immunoassay (TR-FIA) for capture/detection of PCa-derived exosomes. In our assay, biotinylated capture antibodies against human CD9 or CD63 were incubated on streptavidin-coated wells. After application of exosomes, Europium-labeled detection antibodies (CD9 or CD63) were added. Cell medium from 37 cell lines was taken to validate this TR-FIA. Urine was collected (after digital rectal exam) from patients with PCa (n = 67), men without PCa (n = 76). As a control, urine was collected from men after radical prostatectomy (n = 13), women (n = 16) and patients with prostate cancer without digital rectal exam (n = 16). Signal intensities were corrected for urinary PSA and creatinine. This TR-FIA can measure purified exosomes with high sensitivity and minimal background signals. Exosomes can be measured in medium from 37 cell lines and in urine. DRE resulted in a pronounced increase in CD63 signals. After DRE and correction for urinary PSA, CD9 and CD63 were significantly higher in men with PCa. This TR-FIA enabled us to measure exosomes with high sensitivity directly from urine and cell medium. This TR-FIA forms the basis for testing different antibodies directed against exosome membrane markers to generate disease-specific detection assays.

Detyrosinated Glu-tubulin is a substrate for cellular Factor XIIIA transglutaminase in differentiating osteoblasts.

Microtubule components α- and ß-tubulin undergo a number of posttranslational modifications that modulate their dynamics and cellular functions. These modifications include polyamination and covalent crosslinking by transglutaminase enzymes. We have demonstrated previously that the less dynamic and more stable tubulin form-detyrosinated Glu-tubulin-is found in high molecular weight, oligomeric complexes in bone-forming osteoblasts during differentiation and along with deposition of collagenous extracellular matrix. In this study, we report that oligomeric Glu-tubulin has high nocodazole tolerance, indicating further increased stability. We show that α-tubulin, which gives rise to Glu-tubulin, is a transglutaminase substrate in in vitro assays and that it is crosslinked into oligomers (dimers, trimers and tetramers) by transglutaminase 2 and Factor XIIIA; ß-tubulin was not crosslinked by transglutaminase activity. The oligomeric Glu-tubulin was specifically localized to the plasma membrane of osteoblasts as analyzed by subcellular fractionation, cell surface biotinylation experiments and total internal reflection fluorescence (TIRF) microscopy. Glu- and α-tubulin co-localized with cellular Factor XIIIA as analyzed by conventional and TIRF microscopy. The Factor XIIIA-specific substrate peptide bF11 co-localized with α-tubulin and acted as a competitive inhibitor to oligomerization of Glu-tubulin, attenuating its formation in cells. This was associated with significantly decreased type I collagen deposition and decreased secretory activity as measured by synaptotagmin VII levels on the osteoblast plasma membrane. Our results suggest that Glu-tubulin may exist as covalently stabilized form which may be linked to the secretion and elaboration of collagenous extracellular matrix.

Circulating undercarboxylated osteocalcin and gingival crevicular fluid tumour necrosis factor-α in children.

BACKGROUND: Osteocalcin, a protein secreted by osteoblasts during bone formation, is negatively associated with adult periodontal disease. Little is known about this association in children. AIM: To examine the extent to which plasma undercarboxylated osteocalcin (ucOC) is associated with gingival crevicular fluid tumour necrosis factor-alpha (GCF TNF-α) - a potential marker of gingival inflammation - in children. METHODS: We used data from the Quebec Adipose and Lifestyle InvesTigation in Youth cohort, an ongoing longitudinal study on the natural history of obesity among Caucasian children with a family history of obesity in Quebec, Canada. This cross-sectional analysis from the baseline visit includes 120 children aged 8-10 years. Plasma ucOC and GCF TNF-α levels were determined by enzyme-linked immunosorbent assay. Linear regression analyses, adjusting for age, gender, family income, sexual maturity stage, daily physical activity, obesity, and fasting glucose were conducted, with TNF-α level as the dependent variable. RESULTS: A 1-ng/ml increase in ucOC was associated with a 0.96% decrease (95% confidence interval (CI): -1.69, -0.23) in GCF TNF-α level. CONCLUSION: A negative association between a marker of bone formation and a marker of gingival inflammation was observed as early as childhood among Caucasian children with a family history of obesity.

Change characteristics of health-related quality of life and its association with post-stroke fatigue at four-year follow-up.

OBJECTIVE: To explore trajectories that describe change in post-stroke health-related quality of life with fatigue as outcome. DESIGN: Observational and prospective study. SUBJECTS: Stroke survivors (N = 144) with predominantly mild or moderate strokes. METHODS: The multidimensional Stroke-Specific Quality of Life scale was used at 1 and 4 years, and the Fatigue Severity Scale at 4 years post-stroke. Latent class growth analyses were used as person-oriented analyses to identify meaningful trajectories. Socio-demographic and stroke-related covariables provided customary adjustment of the outcome, as well as prediction of class membership. RESULTS: The latent class growth analysis models were estimated for "physical health", "visual-language", and "cognitive-social-mental" components of the Stroke-Specific Quality of Life scale, which extracted trajectories describing a variation in stable, deteriorating and improving functional patterns. The stable, well-functioning trajectory was most frequent across all components. More pronounced fatigue was associated with trajectories describing worse functioning, which was more prominent among females compared with males. Living alone implied more fatigue in the "cognitive-social-mental" component. Within the "visual-language" components' trajectories, younger and older participants reported more fatigue compared with middle-aged participants. CONCLUSION: Most participants belonged to the stable, well-functioning trajectories, which showed a consistently lower level of fatigue compared with the other trajectories.