Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis

OBJECTIVE: To investigate the roles of CD59a in the protection of joint tissue in the context of murine antigen-induced arthritis (AIA). METHODS: AIA was triggered in CD59a-deficient (CD59a(-/-)) mice and in CD59a-sufficient (CD59a(+/+)) controls; the course and severity of disease were compared between groups. The effects on arthritis of restoring CD59 to the joint in CD59a(-/-) mice by use of a membrane-targeted recombinant CD59 were also explored. RESULTS: Disease, as assessed clinically by measurement of joint swelling on day 1 (P < 0.0001), day 2 (P < 0.01), and day 7 (P < 0.02) and histologically from indicators of joint damage on day 21 (P < 0.02), was significantly enhanced in CD59a(-/-) mice compared with CD59a(+/+) wild-type controls. Membrane attack complex (MAC) deposition in the arthritic joints of CD59a(-/-) mice was also increased compared with that in the joints of CD59a(+/+) controls. Restitution of CD59 activity in joints of CD59a(-/-) mice was attempted with soluble recombinant rat CD59 (sCD59) or with a novel membrane-targeted rat CD59 derivative (sCD59-APT542). Strong immunohistochemical staining of the synovial membrane and subsynovial tissue was apparent in sCD59-APT542-injected joints, but not in joints injected with untargeted sCD59. Intraarticular administration of sCD59-APT542 markedly ameliorated disease severity in CD59a(-/-) mice, knee swelling was significantly reduced over the time course of the disease, and joint damage, assessed histologically, was significantly milder on day 21 (P < 0.05). CONCLUSION: These data firmly implicate the MAC of complement as a major effector of joint damage in the murine AIA model of rheumatoid arthritis (RA), and they provide a rationale for the inhibition of MAC assembly as a therapeutic strategy for RA.     

How 25 years of psychosocial research has contributed to a better understanding of the links between depression and diabetes

This narrative review of the literature provides a summary and discussion of 25 years of research into the complex links between depression and diabetes. Systematic reviews have shown that depression occurs more frequently in people with type 1 or type 2 diabetes compared with people without diabetes. Currently, it remains unclear whether depression is also more common in people with impaired glucose metabolism or undiagnosed type 2 diabetes compared with people without diabetes. More prospective epidemiological research into the course of depression and an exploration of mechanisms in individuals with diabetes are needed. Depression in diabetes is associated with less optimal self-care behaviours, suboptimal glycaemic control, impaired quality of life, incident micro- and macrovascular diseases, and elevated mortality rates. Randomized controlled trails concluded that depression in diabetes can be treated with antidepressant medication, cognitive–behavioural therapy (individual, group-based or web-based), mindfulness-based cognitive therapy and stepped care. Although big strides forward have been made in the past 25 years, scientific evidence about depression in diabetes remains incomplete. Future studies should investigate mechanisms that link both conditions and test new diabetes-specific web- or app-based interventions for depression in diabetes. It is important to determine whether treatment or prevention of depression prevents future diabetes complications and lowers mortality rates.     

Translating in vitro prediction of cytotoxic T cell alloreactivity to hematopoietic stem cell transplantation outcome

IntroductionPreviously we developed a weighted amino acid (AA) mismatch score predictive for cytotoxic T cell (CTL) alloreactivity (in vitro CTLp assay) based on the structure of the HLA class I molecule. The aim of this study is to confirm the clinical relevance of the CTLp assay and to validate the AA mismatch score as an alternative and easy to use tool to predict permissible mismatches in hematopoietic stem cell transplantation (HSCT).MethodsWe selected patients transplanted with a 9/10 single HLA class I mismatched graft (n = 171) at three Dutch HSCT centers. A CTLp assay was performed in 73 donor–recipient pairs. As a control we selected 168 10/10 HLA matched pairs that were matched to the 9/10 single HLA class I mismatched pairs for HSCT year, donor type, patient age and diagnosis.ResultsWe observed that pairs with negative a CTLp assay had statistically significant decreased incidence of mortality after HSCT comparable to that of 10/10 HLA matched pairs. However, the weighted AA mismatch score did not significantly predict any HSCT end point of interest.ConclusionFurther investigation is needed to unravel the mechanisms involved in causing the beneficial effect of a negative CTLp assay, before other alternative tools to predict HSCT outcome may be developed.     

An in vitro study into the accuracy of a novel method for recording the mandibular transverse horizontal axis

Objectives

To assess the accuracy of a novel, non-invasive method for determining the axis of rotation of articulated dental study casts.

Method

A 3D structured light scanner was constructed using a projector and two CMOS cameras. Dental stone casts were arbitrarily mounted on an average value articulator. With the teeth together, sets of 10 scans were taken from three different viewpoints. Each scan captured approximately six upper teeth and six lower teeth. The teeth were then propped open, creating 10 mm of incisal separation, and the three sets of 10 scans were repeated. From each pair of scans an axis of rotation was calculated using custom software. A total of 900 axes were created this way. The locations of these axes were plotted in sagittal planes located 57.5 mm left and right of the midline to represent the position of the temporo-mandibular joints (TMJs). The accuracy of axis location was then assessed.

Results

The average radius of error of the individual axes, compared to the real axis, was 2.65 ± 1.01 mm. 61.3% of the axes lay within 3 mm of the true axis, and 99.2% of the axes lay within 5 mm of the true axis.

Conclusions

The accuracy of this method is clinically acceptable. Further studies are required to confirm the accuracy of the virtual inter-occlusal records at the level of the dentition. Clinical studies are then indicated to determine whether the transverse horizontal axis on a patient can similarly be determined.     

Evidence for multiple tumor suppressor genes on chromosome arm 8p in supraglottic laryngeal cancer

Loss of heterozygosity studies of a variety of human tumors suggest that there are several tumor suppressor genes on chromosome arm 8p. To localize these genes more precisely, we utilized polymerase chain reaction amplification of microsatellite repeat polymorphisms and examined the allelic loss patterns of 17 marker loci on 8p in a population of 59 supraglottic laryngeal squamous cell carcinomas. Twenty-three of these tumors (39%) had an allelic loss at one or more of the markers examined. The allelic loss patterns of these tumors support the presence of at least three different tumor suppressor genes on 8p: one in 8p23, one in 8p22–23, and another in 8p21. Genes Chromosom Cancer 16:164–169 (1996). © 1996 Wiley-Liss, Inc.     

Chondrosarcoma of the jaws: clinical findings, histopathology, and treatment

Three cases of chondrosarcoma involving the jaws are presented, one in the maxilla and two in the mandible. The salient points of clinical presentation elucidated by this series of cases are that a widened periodontal ligament space is present in chondrosarcomas as well as in osteosarcomas, and that a slowly increasing diastema may be the earliest clinical sign. The most important lesson to be learned from the histopathology is that one should not accept a diagnosis of a benign cartilaginous tumor of the jaws. Treatment of these lesions should consist of wide surgical excision and consideration of adjunctive or palliative radiotherapy, especially in the maxilla. It should also be noted that recurrences may develop 10 to 20 years later, and follow-up should be lifelong.