Genetic influences modulating the radiological severity of rheumatoid arthritis.

This review focuses on the contribution of genetic markers to the severity of radiological damage in rheumatoid arthritis (RA). Currently available biomarkers of more severe disease include elevated erythrocyte sedimentation rates or C-reactive protein levels and rheumatoid factor (RF) or anticyclic citrullinated protein antibodies positivity; however, these biomarkers explain a relatively modest proportion of the variance in radiological damage. An important role of genetic factors on RA severity has recently emerged but studies to date have generally been of low statistical power and many have not been replicated. Genetic markers have a number of advantages over conventional biomarkers; genotypes are stable, measurable at disease onset, remain unchanged by treatment and are amenable to high-throughput assays. The recent advances in genome-wide genetic analysis should lead to a more comprehensive understanding of RA severity genes. This knowledge could be used, along with existing biomarkers, to therapeutically target subjects at risk of poor radiological outcome.

Cytokine pharmacogenetics.

Genetic variation plays a significant role in the normal functioning of the immune system, and also in the interaction between many common drugs and cellular pathways. With a growing number of cytokine-based therapies now in mainstream clinical use, the prospect of targeting these agents to the individuals likely to benefit from them most is an appealing one. This review outlines the potential clinical impact of cytokine pharmacogenetics in targeting these therapies to individuals with favourable genetic profiles. The use of such approaches may have important pharmacoeconomic benefits and lead to improved therapeutic profiles for these treatments.

OX40 ligation enhances cell cycle turnover of Ag-activated CD4 T cells in vivo.

OX40 costimulates T cells, increases activated T cell longevity, and promotes memory acquisition. T cells activated in vivo with agonist anti-OX40 and ovalbumin have a unique pattern of survival and cell division compared to control cells, but are able to respond to recall Ag equally well. BrdU incorporation shows that early cellular division rates of the anti-OX40-treated and the control groups are similar. Nevertheless, more BrdU(+) Ag-specific T cells accumulate in lymphoid tissue upon anti-OX40 administration. Thus, OX40 ligation does not necessarily lead to increased cell cycle entry, but promotes the accumulation of dividing cells. However, CFSE staining shows that OX40 ligation allows cells to progress through more cellular division cycles, while control cells stall or die. Moreover, OX40 ligation leads to a proportional decrease in apoptotic Ag-specific T cells. Thus, OX40 ligation boosts immunity by promoting an increase in the number cell cycles completed, thereby increasing the life span of Ag-activated CD4 T cells.

Danger and OX40 receptor signaling synergize to enhance memory T cell survival by inhibiting peripheral deletion.

This report defines a cell surface receptor (OX40) expressed on effector CD4 T cells, which when engaged in conjunction with a danger signal, rescues Ag-stimulated effector cells from activation-induced cell death in vivo. Specifically, three signals were necessary to promote optimal generation of long-lived CD4 T cell memory in vivo: Ag, a danger signal (LPS), and OX40 engagement. Mice treated with Ag or superantigen (SAg) alone produced very few SAg-specific T cells. OX40 ligation or LPS stimulation, enhanced SAg-driven clonal expansion and the survival of responding T cells. However, when SAg was administered with a danger signal at the time of OX40 ligation, a synergistic effect was observed which led to a 60-fold increase in the number of long-lived, Ag-specific CD4 memory T cells. These data lay the foundation for the provision of increased numbers of memory T cells which should enhance the efficacy of vaccine strategies for infectious diseases, or cancer, while also providing a potential target (OX40) to limit the number of auto-Ag-specific memory T cells in autoimmune disease.

Use of the Maxwell-Brancheau arthroereisis implant for the correction of posterior tibial tendon dysfunction.

Successful management of the flexible flatfoot deformity relies not only on correcting causal factors, but also on addressing the adaptive changes that have occurred and any coexisting deformities present. The three primary goals of any therapy--relief of pain, biomechanical control of excessive pronation, and prevention of the progression of the deformity--should be considered. With thorough assessment of causal factors and planal dominance of the deforming and compensative forces, one can expect to increase the predictability and success of the surgical management of PTTD in the flexible adult flatfoot deformity.

CD40 activation boosts T cell immunity in vivo by enhancing T cell clonal expansion and delaying peripheral T cell deletion.

In this report we show that activation of APC with an agonist anti-CD40 mAb profoundly alters the behavior of CD4 T cells in vivo. Stimulation of mice with anti-CD40 2 days before, but not 1 day after, administration of superantigen (SAg) enhanced CD4 and CD8 T cell clonal expansion by approximately threefold. Further, CD40 activation also delayed peripheral T cell deletion after activation. Dying, activated T cells were quantitated by detecting extracellular phosphatidylserine with concomitant staining for SAg-reactive T cells using a TCR Vbeta-specific mAb. Upon close examination, it was shown that CD40 activation delayed the death of the activated T cells. Additionally, it was found that enhanced survival of CD4 T cells was equally dependent on APC expression of B7-1 and B7-2. This is in contrast to CD8 T cells, which did not depend as much on B7-1 as B7-2. Thus, CD40 activation indirectly promotes T cell growth and delays the death of SAg-stimulated CD4 T cells in vivo. These data suggest that one way CD40 activation promotes a more robust immune response is by indirectly increasing the production of effector T cells and by keeping them alive for longer periods of time.

Long-chain alkenes of the haptophytes Isochrysis galbana and Emiliania huxleyi.

The major alkenes of the haptophytes Isochrysis galbana (strain CCAP 927/14) and Emiliania huxleyi (strains CCAP 920/2 and VAN 556) have been identified by nuclear magnetic resonance spectroscopy and by mass spectrometric analysis of their dimethyl disulfide adducts. The dominant alkene in I. galbana is (22Z)-1 ,22-hentriacontadiene, with 1,24-hentriacontadiene and 1,24-tritriacontadiene present in much lower abundance; (22Z)-1,22-hentriacontadiene also occurs in E. huxleyi (strain CCAP 920/2), together with (2Z,22Z)-2,22-hentriacontadliene (the major hydrocarbon) and (3Z,22Z)-3,22-hentriacontadiene. Minor abundances of 2,24-hentriacontadiene and 2,24-tritriacontadiene are also present in this strain. In contrast, the dominant alkene in E. huxleyi (strain VAN 556) is (15 E,22E)-1,16,23-heptatriacontatriene with the related alkatriene 1,15,22-octatriacontatriene also present and (22Z)-1,22-hentriacontadiene occurring as a minor component. From structural relationships (15E,22E)-1,15,22-heptatriacontatriene is proposed to derive from the same biosynthetic pathway as that of the characteristic C37 alkenones which occur in both E. huxleyi and I. galbana. The C31 and C33 dienes likely derive from chain extension and decarboxylation of (Z)-9-octadecenoic acid or (Z)-7-hexadecenoic acid, using a pathway analogous to that elucidated previously in the chlorophyte Botryococcus braunii. Therefore, long-chain dienes and trienes, which can co-occur in haptophytes, may have distinct biosynthetic pathways.

High-performance liquid chromatography-mass spectrometry of porphyrins by using an atmospheric pressure interface.

A method is described for the high-performance liquid chromatography (HPLC) mass spectrometry analysis of porphyrin mixtures by using an atmospheric pressure interface, which can operate in two modes: pneumatically assisted elecrrospray and atmospheric pressure chemical ionization (APCI). Optimization of the conditions and evaluation of spectral information has been carried out by using direct injection of free-base and metallo porphyrin standards. The most effective results were obtained using APCI. HPLC-APCI mass spectrometry analysis of the demetallated vanadyl porphyrin fraction from the Triassic Serpiano oil shale has allowed rapid characterization of the distribution; more than 50 significant components are present. The presence of trace amounts of high molecular weight (>C33) cycloalkano porphyrins indicates the occurrence of photic zone anoxia in the ancient water column. This example illustrates the potential of the approach for studies of porphyrin mixtures of environmental or biological significance, which should be applicable to other types of metallo and free-base components that can be separated by HPLC under normal or reversed-phase conditions.

Case report 878: Densely calcifying synovial sarcoma of the hip metastatic to the lungs.

We discuss a patient with an occult, densely calcified synovial sarcoma of the hip who came to clinical attention because of pulmonary metastases. When synovial sarcomas present with dense and conglomerate calcification, they may be confused with benign processes such as myositis ossificans or tumoral calcinosis. Malignancies such as extraskeletal osteogenic sarcoma, extraskeletal chondrosarcoma, and mesenchymal chondrosarcoma must also be considered in the differential diagnosis.

Porphyrin and chlorin distributions in a Late Pliocene lacustrine sediment.

The tetrapyrroles in a highly immature Late Pliocene lacustrine sediment (Willershausen, Germany) show a simple distribution of both chlorin and porphyrin components as the free bases. The major components are C32 desoxophylloerythroaetioporphyrin (DPEP), a C33 bicycloalkano porphyrin, the chlorin analogue of the latter, and desoxophylloerythrin and its chlorin counterpart. The structure of the novel bicycloalkano chlorin was determined using a combination of two-dimensional phase-sensitive COSY NMR and nOe studies. Measurements of delta 13C and other data indicate that DPEP and the bicycloalkano porphyrin were derived from the chlorophyll(s) of photosynthetic organisms utilising a common source of CO2, probably diatoms. The occurrence of DPEP and other minor alkyl porphyrins indicates that the chlorophyll defunctionalisation pathway leading to these components can occur at low temperature and was probably biologically mediated, as was the condensation leading to the fused ring components.

Carbon and nitrogen isotopic compositions of alkyl porphyrins from the Triassic Serpiano oil shale.

The carbon and nitrogen isotopic compositions of seven of the most abundant alkylporphyrins from the Serpiano oil shale (marine, Triassic) were determined. For the C31 and C32 butanoporphyrins, values of delta 13CPDB and delta 15NAIR averaged -24.0% and -3.1%. In contrast, the C31 and C32 methylpropanoporphyrins, DPEP, and a C30 13-nor etioporphyrin had delta 13C and delta 15N values averaging -27.5 and -3.3%, respectively. Carbon and nitrogen isotopic values for kerogen averaged -30.8 and -0.9, whereas those for total extract averaged -31.6, and -4.0%. The butanoporphyrins apparently derive from a biological source different from that giving rise to the other porphyrins, their 13C enrichment not being related to carbon isotopic fractionation accompanying diagenetic reactions. The delta 15N values for all the porphyrins indicate that the depletion of 15N observed in the kerogen is of primary origin. Consistent with the very high abundance of hopanoids and methyl hopanoids in the aliphatic hydrocarbon fraction, it is suggested that cyanobacterial fixation of N2 may have been the main cause of 15N depletion.

Synthesis of 5-aryl-2H-tetrazoles, 5-aryl-2H-tetrazole-2-acetic acids, and [(4-phenyl-5-aryl-4H-1,2,4-triazol-3-yl)thio]acetic acids as possible superoxide scavengers and antiinflammatory agents.

A series of 5-aryl-2H-tetrazoles, 5-aryl-2H-tetrazole-2-acetic acids, and [(4-phenyl-5-aryl-4H-1,2,4-triazol-3-yl)thio]acetic acids were synthesized and tested in vitro for superoxide scavenging activity, in vivo in the carrageenan-induced rat paw edema assay, and in the reverse passive Arthus reaction. The hydroxy-substituted compounds were effective as in vitro scavengers of superoxide but were not effective as in vivo antiinflammatory agents.

Extended hopanoids in peat environments.

Detailed results are presented for the distributions of triterpenoid alkanes, acids and alcohols of the hopane family in ten samples of peat from three environments, and of contributing organisms in the case of Lyne of Skene, Scotland. Extended hopanoids of the beta alpha and alpha beta configuration appear at the very earliest stage of diagenesis. Such environments appear to be characterised by particular distributions of C32 hopanoid acids and alcohols, and a high preponderance of the C31 alpha beta hopane.

Achilles tendon rupture: a case report and discussion of conservative versus surgical repair.

The authors review the literature on Achilles tendon ruptures and discuss the conservative and surgical approaches to treatment of acute ruptures. A case history of acute Achilles tendon rupture is presented, including clinical signs not previously described. The primary complication of Achilles tendon rupture is the high incidence of rerupture after conservative therapy. The authors note that complications after surgical repair of an Achilles tendon rupture may be avoided by a surgeon skilled in the performance of this procedure and by the use of an appropriate surgical drain. The authors conclude that primary surgical repair is the treatment of choice for acute Achilles tendon ruptures.

Chemical fossils: the geological fate of steroids.

Steroids are used to illustrate some of the significant advances that have been made in recent years in understanding the biological origin and geological fate of the organic compounds in sediments. The precursor sterols are transformed, initially by microbial activity and later by physicochemical constraints, into thermodynamically more stable saturated and aromatic hydrocarbons in mature sediments and petroleums. The steps in this transformation result in a complex web linking biogenesis, diagenesis, and catagenesis. Indeed, the complexity and variety of biological lipids such as the steroids are evidently matched in the corresponding geolipids. The extent of preservation of the biochemical imprint in the structures and stereochemistry of these geolipids, even over hundreds of millions of years, is startling, as is the systematic and sequential nature of the geochemical changes they evidently undergo. This new understanding of molecular organic geochemistry has applications in petroleum geochemistry, where biological marker compounds are valuable in the assessment of sediment maturity and in correlation work.

Specific acyclic isoprenoids as biological markers of methanogenic bacteria in marine sediments.

The widespread occurrence of extended hopanoids in sediments and petroleums illustrates the importance of bacterial lipid contributions to geological materials. In archaebacteria, however, hopanoids are absent; their role as structural components of biomembranes is fulfilled by acyclic isoprenoids. Recent studies of the lipid constituents of archaebacteria have greatly extended the range of acyclic isoprenoid skeletons known in organisms (Fig. 1). In particularly, isoprenoids with head-to-head linkages have been identified, and such compounds (for example, 3,7,11,15,18,22,26,30-octamethyldotriacontane, I) have been recognized in petroleum and as degradation products of Messel shale kerogen. Here we report the first recognition of 2,6,10,15,19-pentamethyleicosane (II), a known component of methanogens, in marine sediments of Recent to Cretaceous age (Table 1) and suggest that it and certain other acyclic isoprenoids may be used as biological markers for methanogens.