Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium,cartilage, and bone in the LITHE study

Objective

We investigated the effects of tocilizumab (TCZ) on joint tissue remodeling in patients with moderate to severely active RA by measuring tissue-specific biomarker.

Methods

The LITHE biomarker study (n = 740) was a phase III study of 4- and 8-mg/kg TCZ in combination with MTX. Early response was evaluated at week 16 as ±20% improvement in swollen/tender joint counts; and ACR50 was evaluated at week 52. Biomarkers (tissue inflammation: C3M, CRPM, and VICM; cartilage degradation: C2M; and bone turnover: CTx and osteocalcin) were tested in serum from baseline, week 4, 16, 24, and 52, and dose-dependent effect was investigated. Patients were divided into the following three groups: early non-responders (ENR), ACR50 responders, and non-responders; their biomarker profiles were compared.

Results

At week 52, CRP was inhibited to 4% and 40% of baseline by TCZ8 and TCZ4, respectively. CRPM (63%), C2M (84%), C3M (69%), and VICM (42%) were significantly (p < 0.05) reduced by TCZ8, but not by TCZ4. MMP3 and osteocalcin changed to <58% and >111%, respectively, in response to TCZ. CTx was not changed significantly. ENRs had significantly less inhibition of CRPM (p < 0.05), C2M (p < 0.01), and C3M (p < 0.01) compared to early responders. There was a significant difference in the C2M, C3M, and CRPM profiles of the ENRs, non-responders, and responders. ACR50 responders had significantly inhibited levels (p < 0.001), irrespective of dose.

Conclusions

TCZ8 strongly inhibited the biomarkers of joint tissue remodeling suggesting that TCZ actively suppresses key pathobiological processes at the site of inflammation in RA patients. The differences in biomarkers' profiles of responders and non-responders indicate that specific responder profiles exist.     

Effects of fibrinogen and platelet supplementation on clot formation and platelet aggregation in blood samples from cardiac surgery patients

Introduction

Bleeding after cardiac surgery may be caused by surgical factors, impaired haemostasis, or a combination of both. Transfusion of blood products is used to improve haemostasis, but little is known about what combination is optimal. We hypothesized that addition of both fibrinogen and platelets to blood samples from cardiac surgery patients would improve clot formation and platelet aggregation to a greater extent than if the components were added separately.

Materials and Methods

Increasing doses of fibrinogen concentrate (+ 0.5, 1.0, and 1.5 g · l^- 1) and/or platelet concentrate (+ 46, 92, and 138 × 10⁹ platelets l^- 1) were added to postoperative blood samples from 15 cardiac surgery patients. Clot formation was assessed with rotational thromboelastometry and platelet aggregation was assessed with multiple-electrode aggregometry before and after addition of the blood products. The effects of the different additives were compared.

Results and Conclusions

Ex vivo supplementation with fibrinogen or platelet concentrate resulted in significantly shortened clotting time and improved clot strength in a dose-dependent manner. Combination of fibrinogen and platelets further improved the clotting time and strength. Platelet supplementation enhanced platelet aggregation in a dose-dependent manner while fibrinogen had no or reducing effect. Combining fibrinogen and platelets improved platelet aggregation less than the use of platelets alone. In conclusion, combined platelet and fibrinogen supplementation of blood samples from cardiac surgery patients had an additive effect on clot formation compared to the individual components, but it resulted in less platelet aggregation than with platelet supplementation alone. These results may have implications for clinical transfusion protocols.     

Brain circuit imprints of developmental 17α-Ethinylestradiol exposure in guppies (Poecilia reticulata): Persistent effects on anxiety but not on reproductive behaviour

The effects of endocrine disruptors may vary with the timing of exposure. The physiological implications of adult exposure are present during and shortly after exposure while embryonic exposure can imprint changes manifested in adulthood. In this study, guppy (Poecilia reticulata) embryos were exposed to 2 and 20ng/L of 17α-ethinylestradiol during development via the mother and reared in clean water from gestation until 6months of age. As adults, fish exposed to 20ng/L during development showed significantly altered behaviour in the Novel Tank test, where anxiety is determined as the tendency to remain at the bottom upon introduction into an unfamiliar tank. 17α-ethinylestradiol treatment increased the latency time before swimming to the upper half of the tank and decreased the number of transitions to the upper half. In control females the basal stress behaviour responses were significantly higher than in males, as indicated by longer latency period and fewer and shorter visits to the upper half, supporting the importance of gonadal hormones for the behaviour. The anxiety increased, however, with treatment in both sexes, suggesting that the observed response is not entirely due to feminisation of the males. Shoaling behaviour, analysed as tendency to leave a shoal of littermates, was neither sex-differentiated nor changed by treatment. Also male reproductive behaviour, brain aromatase activity and testes histology, previously shown to respond to oestrogen exposure in adult guppy, were unaffected by the developmental treatment. This suggests that the stress system in the guppy is very sensitive to 17α-ethinylestradiol, which possibly causes an early organisational imprint on the brain circuit that regulates stress reactions.     

New diagnostics of the dentition on panoramic radiographs—Focusing on the peripheral nervous system as an important aetiological factor behind dental anomalies

The present review article is a summary of several previously published articles focusing on the aetiology behind deviations in the dental development such as malformation, agenesis, eruption deviations and abnormal resorption. The previous findings have not been compiled before and are documented in a series of new cases in this article. The evaluation of aetiology is based on histological knowledge about early dental development and new knowledge about the periodontal membrane. The article describes the different deviations in the dentition based on an analysis of ectodermal mucosa, innervation and ectomesenchyme. Focus is on the developmental fields in the jaws, determined by the course of the peripheral nerves.The article documents that the innervation of the jaws and teeth is an important aetiological factor behind deviations in dental development and dental eruption. The association of deviations in teeth with deviations in skin is also documented and demonstrated in agenesis, dental malformations and eruption deviations. Furthermore, the interrelationship between findings in the primary and permanent dentitions is described, specifically in resorption.The analysis distinguishes between deviations in a limited field and deviations occurring generally in the dentition. Furthermore, the bilateral occurrence of deviations in contralateral fields is described.Conclusively, the article presents advice regarding conditions that should be included in aetiology-based diagnostics.     

Development of sarcoidosis following etanercept treatment: a report of three cases

After over 10 years of use of tumor necrosis factor-alpha (TNF-α) inhibitors, their side effects and complications are reasonably well documented. Recently, however, granulomatous reactions and cases of complete sarcoidosis have been reported, especially in patients treated with the TNF-α receptor protein, etanercept. This is intriguing because the TNF-α antibody drugs infliximab and adalimumab are reportedly used to treat sarcoidosis. We present three patients who developed sarcoidosis while on etanercept treatment, and discuss if possible differences in cytokine profiles and T regulatory cell function in patients taking different TNF-α inhibitors may explain this paradox.     

Predictors of signs and symptoms of temporomandibular disorders: a 20-year follow-up study from childhood to adulthood

The aim of this study was to find possible predictors of signs and symptoms of temporomandibular disorders (TMD) in a long-term perspective. Baseline questionnaire and clinical examinations focusing on function and dysfunction of the masticatory system were performed in a sample of 402 subjects 7, 11, and 15 years old. After 20 years, 320 subjects (80% of the original sample) completed a similar questionnaire as at baseline. From the oldest age group, now aged 35 years, 100 subjects (74% of the original sample) also attended a clinical examination. Three variables from the 20-year follow-up were chosen as dependent variables in logistic regression analyses, with independent variables selected from the baseline examinations. Three variables at baseline were significant predictors for reported TMJ clicking at the 20-year follow-up, tooth wear index being the strongest (odds ratio = 4.3). Reported TMJ clicking at the start was the only significant predictor for TMD symptoms without clicking 20 years later (odds ratio = 2.3). The third logistic regression model, using the Helkimo Clinical Dysfunction Score as dependent variable, resulted in four significant predictors from the baseline examinations (bruxism, oral parafunctions, TMJ clicking, and deep bite). The results indicated that some signs and symptoms might predict TMD signs and symptoms in a long-term perspective. However, it cannot be concluded from this study whether these symptoms recorded in childhood - oral parafunction, tooth wear, TMJ clicking, and deep bite - can be used for predicting manifest TMD in adult age.     

Eruption of the central incisor,the intermaxillary suture,and maxillary growth in patients with a single median maxillary central incisor

The occurrence of a single median maxillary central incisor (SMMCI) is a very rare condition and might be a sign of a more severe midline defect, which could be a mild degree of holoprosencephaly. Absence of the internasal and partial absence of the intermaxillary suture has been observed in a fetus with holoprosencephaly. The purpose of this study was to evaluate the intermaxillary suture, the eruption pattern of the single central incisor in the SMMCI condition, and the growth of the maxilla in a group of patients with SMMCI. A similar study was not found in the scientific literature. The material included orthopantomographs, dental radiographs, and lateral cephalometric radiographs from 11 patients with an SMMCI. The orthopantomographs and dental radiographs showed that the intermaxillary suture was abnormal anterior to the incisive foramen; however, the SMMCI erupted within the expected time interval. Superimposition on stable structures on lateral cephalometric radiographs from two untreated patients, in which growth analysis was possible, showed that the horizontal and vertical growth of the maxilla was normal. Due to the sutural midline defect it is suggested that a transversal growth analysis is included in all treatment planning of SMMCI patients.     

Dental auscultation for nursing personnel as a model of oral health care education: development,baseline, and 6-month follow-up assessments

Oral health care has been shown to have low priority in nursing and has been only partly successful. To create more positive effects than those achieved through traditional oral health care education, this project tested an educational model for nursing staff personnel. In addition to traditional oral health care education, some of the nursing staff members passed an additional dental auscultation period and served as oral care aides. The aides were responsible for the oral health care of the residents at their nursing facilities (intervention group). The intervention nursing facilities were compared with facilities where nursing personnel only received a traditional oral health care education program. Assessments were made at baseline and at a 6-month follow-up. At follow-up it was shown that the nursing staff in the intervention group gave higher priority to the oral health care work than the nursing staff in the control group.     

A premaxilla with a supernumerary tooth indicating a developmental region with a variety of dental abnormalities: a report of nine cases

The aim of this study was to elucidate whether a premaxilla with a supernumerary tooth has additional dental abnormalities. The study does not include premaxillas with a mesiodens, only premaxillas with parasagittally located supernumerary teeth. Radiographs from eight children, followed from 1 year and 5 months to 11 years and 5 months in the municipal dental health service in Denmark, were analyzed. One patient was seen only once. Dental abnormalities recorded included: invaginations on permanent incisors, resorption of roots of incisors, curved roots of incisors, delayed eruption, and delayed formation of roots. The study shows that there are dental abnormalities within the premaxillary region where the supernumerary tooth is located. This indicates that, apart from the supernumerary tooth, a more widespread deviation from normal conditions including tooth malformation, arrested eruption, and root resorption occur within the premaxillary region. The most important outcome of this study is that in the region with a supernumerary tooth the adjacent incisor shows delayed eruption after surgical removal of the supernumerary tooth. The deviations in root morphology, including root resorption, are not limited to patients who have had orthodontic treatment, but patients who did not receive orthodontic treatment also revealed deviations in root morphology. Therefore the treatment outcome can be different from the expected outcome.