Modulation of experimental autoimmunity: treatment of adjuvant arthritis by immunization with a recombinant vaccinia virus.

Live recombinant vaccinia viruses, expressing antigens from pathogenic microorganisms, are studied for their use as vaccines designed for the protection against infectious diseases. Infections with these vaccinia virus recombinants, expressing proteins or epitopes from viruses, parasites, or bacteria, have resulted in the development of specific neutralizing antibodies or cytotoxic T lymphocytes. Here, we describe the generation of a recombinant vaccinia virus expressing the mycobacterial 65-kDa heat shock protein (HSP65). A vaccinia recombinant virus was constructed by placing the gene for the Mycobacterium bovis BCG HSP65 under control of a vaccinia virus promoter and inserting this mycobacterial gene in the thymidine kinase locus of the vaccinia virus genome. Mycobacterial HSP65 is a critical antigen in the autoimmune model of adjuvant arthritis induced in Lewis rats by the immunization with Mycobacterium tuberculosis. We report the induction of immunity directed to this mycobacterial HSP65 by testing for the presence of specific antibodies and T-cell proliferation. Furthermore, induction of such immunity resulted in a reduction of arthritis severity when given to rats before or, even more interestingly, during development of arthritis. Disease reduction was not found after administration of HSP65 in the absence of vaccinia virus as a vector when given during arthritis development. Therefore, recombinant vaccinia virus may offer new prospectives for specific intervention in autoimmunity.     

Genotoxicity and physicochemical characteristics of traffic-related ambient particulate matter

Exposure to ambient particulate matter (PM) has been linked to several adverse health effects. Since vehicular traffic is a PM source of growing importance, we sampled total suspended particulate (TSP), PM(10), and PM(2.5) at six urban locations with pronounced differences in traffic intensity. The mutagenicity, DNA-adduct formation, and induction of oxidative DNA damage by the samples were studied as genotoxicological parameters, in relation to polycyclic aromatic hydrocarbon (PAH) levels, elemental composition, and radical-generating capacity (RGC) as chemical characteristics. We found pronounced differences in the genotoxicity and chemical characteristics of PM from the various locations, although we could not establish a correlation between traffic intensity and any of these characteristics for any of the PM size fractions. Therefore, the differences between locations may be due to local sources of PM, other than traffic. The concentration of total (carcinogenic) PAHs correlated positively with RGC, direct and S9-mediated mutagenicity, as well as the induction of DNA adducts and oxidative DNA damage. The interaction between total PAHs and transition metals correlated positively with DNA-adduct formation, particularly from the PM(2.5) fraction. RGC was not associated with one specific PM size fraction, but mutagenicity and DNA reactivity after metabolic activation were relatively high in PM(10) and PM(2.5), when compared with TSP. We conclude that the toxicological characteristics of urban PM samples show pronounced differences, even when PM concentrations at the sample sites are comparable. This implies that emission reduction strategies that take chemical and toxicological characteristics of PM into account may be useful for reducing the health risks associated with PM exposure.     

Initiation of the extrinsic pathway of coagulation by human and rabbit alveolar macrophages: a kinetic study

We examined assembly and expression of the factor X activating complex on human and rabbit alveolar macrophages. Kinetic parameters of the factor X activating reaction were determined by functional titrations of factors VII and X with macrophage tissue factor (TF) added. We found rapid activation of factor X to Xa on alveolar macrophage surfaces. Detection of rapid factor Xa formation on macrophages required addition of exogenous factors VII and X. At plasma concentrations of the purified factors, factor Xa was formed on freshly isolated macrophages at approximately 5.4 pmol/min/10(6) cells. After macrophage maturation in culture for 20 hours with LPS (endotoxin) added, the factor X activation rate was increased two- to sixfold. The km' (apparent km) of TF-factor VII enzymatic complexes assembled on alveolar macrophages for factor X were (258 +/- 55 and 475 +/- 264 nmol/L for human and rabbit cells, respectively). The km' did not change during macrophage maturation in culture, but V'max (apparent Vmax) was consistently increased. The K1/2 of human factor VII (concentrations giving half maximal rates of factor X activation) for the interaction with human and rabbit alveolar macrophage TF were 0.191 +/- 0.096 and 1.7 +/- 0.7 etamol/L, respectively. The K1/2 were not significantly changed after maturation, whereas rates of Xa formation at saturation with factor VII were increased. The fast rates of factor X activation observed at physiologic concentrations of plasma-derived factors VII and X indicate that TF on alveolar macrophages is likely to provide sites for binding of factor VII and activation of factor X in vivo during clotting reactions associated with alveolar edema and inflammation.     

Where is the neck?: Alpha angle measurement revisited

Background and purpose

The alpha angle is the most used measurement to classify concavity of the femoral head-neck junction. It is not only used for treatment decisions for hip impingement, but also in cohort studies relating hip morphology and osteoarthritis. Alpha angle measurement requires identification of the femoral neck axis, the definition of which may vary between studies. The original “3-point method” uses 1 single point to construct the femoral neck axis, whereas the “anatomic method” uses multiple points and attempts to define the true anatomic neck axis. Depending on the method used, the alpha angle may or may not account for other morphological characteristics such as head-neck offset.

Methods

We compared 2 methods of alpha angle measurement (termed “anatomic” and “3-point”) in 59 cadaver femora and 83 cross-table lateral radiographs of asymptomatic subjects. Results were compared using Bland-Altman plots.

Results

Discrepancies of up to 13 degrees were seen between the methods. The 3-point method had an “equalizing effect” by disregarding femoral head position relative to the neck: in femora with high alpha angle, it resulted in lower values than anatomic measurement, and vice versa in femora with low alpha angles. Using the anatomic method, we derived a reference interval for the alpha angle in normal hips in the general population of 30–66 degrees.

Interpretation

We recommend the anatomic method because it also reflects the position of the femoral head on the neck. Consensus and standardization of technique of alpha angle measurement is warranted, not only for planar measurements but also for CT or MRI-based measurements.Hip morphology variants may influence the development of osteoarthritis (OA) (Ganz et al. 2008). Femoral morphology variants may be best characterized by concavity, a compound measure determined by the sphericity and offset of the femoral head (determined from relative neck width and femoral head position on the neck). The most used concavity measure is the alpha angle, described initially by Nötzli et al. (2002) to diagnose cam deformity and increasingly used in cohort studies examining the risk of OA development (Johnston et al. 2008, Nicholls et al. 2011, Agricola et al. 2013). Nötzli et al. (2002) measured the alpha angle between 2 lines drawn between 3 points (“3-point method”). One line is called the femoral neck axis based on a single point at the center of the narrowest part of the femoral neck (Figure 1), but it is important to recognize that this line will only correspond to the anatomic femoral neck axis if the femoral head is positioned centrally on the neck.Open in a separate windowFigure 1.3-point and anatomic method compared in high alpha angle (A) and low alpha angle (B). 3-point method (A.1 and B.1) uses the midpoint of the femoral neck at its narrowest point. The anatomic method (B.2 and B.2) defines the femoral neck axis by connecting the centers of 3 circles projected over the neck contour. The axis is translated to the center of the femoral head if necessary, to measure the alpha angle. In this example, alpha angle A.1 = 64˚, A.2 = 73˚. Angle B.1 and B.2 are both 30˚, while the femoral head is positioned central on the femoral neck.However, in many human femora the position of the femoral head on the neck may not be central, but shifted or tilted posteriorly (Murray and Duncan 1971, Hogervorst et al. 2009). In such femora, use of a femoral neck axis line connecting the center of the femoral head and neck will decrease the alpha angle (Figure 1). Use of the anatomic center line (the “anatomic method”) rather than a single point for the femoral neck axis (the “3-point method”) probably more accurately represents femoral head-neck morphology, as it may also account for femoral head translation as measured by the anterior offset ratio (Eijer et al. 2001, Pollard et al. 2010). Furthermore, the increasing number of cohort studies using the alpha angle mandates consensus on measurement technique.Measurements in 155 cross-table radiographs

Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer's disease in men

OBJECTIVES: To assess the association between testosterone levels and APOEepsilon4 in cases with AD and controls. METHOD: We included 61 men with definite or probable Alzheimer's disease (AD) and 55 elderly male controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA). Testosterone was measured using a competitive enzyme immunoassay (Bayer). RESULTS: We found that both low serum testosterone and the interaction between testosterone and APOEepsilon4 were associated with AD. Furthermore, testosterone levels were lower in APOEepsilon4-positive controls (mean: 11.3 nmol/L) than in controls without the allele (19.1 nmol/L). CONCLUSIONS: Low testosterone is potentially a modifiable risk factor, which may prove relevant to APOEepsilon4 carriers who are at risk of AD.     

Nasal dermoids: the significance of a midline punctum

Nasal dermoids are rare and their diagnosis is often delayed until complications occur. Signs such as a midline nasal punctum may be noted at birth but the significance of this finding frequently passes unrecognised. The cases are reported of two patients which illustrate the typical presentation of these lesions and their subsequent management is discussed.     

Telephone word-list recall tested in the rural aging and memory study: two parallel versions for the TICS-M

BACKGROUND: Parallel versions of memory tasks are useful in clinical and research settings to reduce practice effects engendered by multiple administrations. We aimed to investigate the usefulness of three parallel versions of ten-item word list recall tasks administered by telephone. METHODS: A population based telephone survey of middle-aged and elderly residents of Bradley County, Arkansas was carried out as part of the Rural Aging and Memory Study (RAMS). Participants in the study were 1845 persons aged 40 to 95 years. Word lists included that used in the telephone interview of cognitive status (TICS) as a criterion standard and two newly developed lists. RESULTS: The mean age of participants was 61.05 (SD 12.44) years; 39.5% were over age 65. 78% of the participants had completed high school, 66% were women and 21% were African-American. There was no difference in demographic characteristics between groups receiving different word list versions, and performances on the three versions were equivalent for both immediate (mean 4.22, SD 1.53) and delayed (mean 2.35 SD 1.75) recall trials. The total memory score (immediate+delayed recall) was negatively associated with older age (beta = -0.41, 95%CI=-0.11 to -0.04), lower education (beta = 0.24, 95%CI = 0.36 to 0.51), male gender (beta = -0.18, 95%CI = -1.39 to -0.90) and African-American race (beta = -0.15, 95%CI = -1.41 to -0.82). CONCLUSIONS: The two RAMS word recall lists and the TICS word recall list can be used interchangeably in telephone assessment of memory of middle-aged and elderly persons. This finding is important for future studies where parallel versions of a word-list memory task are needed. (250 words).     

Recognition of facial expressions of emotion by patients with dementia of the Alzheimer type

Bilateral amygdala damage has been linked with an inability to recognise facial expressions of emotion, particularly the expression of fear. Patients with Alzheimer's disease (AD) suffer from atrophy of the amygdala at an early stage of the disease. It was therefore predicted that AD patients would have more difficulty in two tasks of processing facial expressions of emotion. Thirteen patients diagnosed with probable AD referred to the Oxford Project to Investigate Memory and Ageing (OPTIMA) and 13 age-matched controls enrolled in the programme participated in the study. Participants were shown two tasks, one involved recognising and labelling a target expression, the other matching a target expression with one of four others. The results showed that compared with the controls, the patients were not impaired in recognising any facial expressions of emotion in the labelling task, but were impaired in matching three facial expressions of emotion in the second task. It was speculated that the impairment in the matching task could have been a result of visuospatial dysfunction rather than one of processing emotions.