Magnetic resonance imaging as a structural refinement to the American College of Rheumathology clinical classification criteria for knee osteoarthritis.

OBJECTIVE: To evaluate if fulfilment of the definition of osteoarthritis (OA) based on the American College of Rheumatology (ACR) clinical criteria corresponds to pathological knee findings evaluated by magnetic resonance imaging (MRI). To evaluate if any such criteria is associated with a specific MRI pattern. METHODS: Forty-six consecutive patients aged 50 years or more referred by their general practitioners (GPs) to a radiology department because of non-traumatic knee pain underwent MRI using a dedicated low field (0.2 T) machine. RESULTS: MRI results were compared against the ACR criteria for knee OA. Patients with knee pain fulfilling the ACR criteria showed more severe synovial fluid effusion (OR 6.2, 95% CI 2.02 to 19.1), cartilage lesions in the medial area (OR 2.4, 95% CI 1.2 to 5) and higher mean number of osteophytes (OR 2.3, 95% CI 1.1 to 4.5). The association between single criteria and MRI features was more difficult to establish. Nonetheless, crepitus at joint movement was associated with synovial fluid effusion (p=0.02); bone enlargement was more frequent in patients with lesions of the posterior cruciate ligament (p=0.0001); no palpable warmth was associated with cartilage lesions (p=0.02), and morning stiffness shorter than 30 minutes was associated with the surface of bone edema (p=0.02). CONCLUSIONS: The ACR clinical criteria identify patients showing the most important features of OA. The association between individual clinical ACR criteria and OA pathology depicted by MRI may be difficult to explain on the basis of anatomical changes and needs further evaluation.

Behçet's syndrome as a tool to dissect the mechanisms of thrombo-inflammation: clinical and pathogenetic aspects.

Behçet's syndrome (BS) is a complex disease with different organ involvement. The vascular one is the most intriguing, considering the existence of a specific group of patients suffering from recurrent vascular events involving the venous and, more rarely, the arterial vessels. Several clinical clues suggest the inflammatory nature of thrombosis in BS, especially of the venous involvement, thus BS is considered a model of inflammation-induced thrombosis. Unique among other inflammatory conditions, venous involvement (together with the arterial one) is currently treated with immunosuppressants, rather than with anti-coagulants. Although many in-vitro studies have suggested the different roles of the multiple players involved in clot formation, in-vivo models are crucial to study this process in a physiological context. At present, no clear mechanisms describing the pathophysiology of thrombo-inflammation in BS exist. Recently, we focused our attention on BS patients as a human in-vivo model of inflammation-induced thrombosis to investigate a new mechanism of clot formation. Indeed, fibrinogen displays a critical role not only in inflammatory processes, but also in clot formation, both in the fibrin network and in platelet aggregation. Reactive oxygen species (ROS)-derived modifications represent the main post-translational fibrinogen alterations responsible for structural and functional changes. Recent data have revealed that neutrophils (pivotal in the pathogenetic mechanisms leading to BS damage) promote fibrinogen oxidation and thrombus formation in BS. Altogether, these new findings may help understand the pathogenetic bases of inflammation-induced thrombosis and, more importantly, may suggest potential targets for innovative therapeutic approaches.

Analysis of waste management issues arising from a field study evaluating decontamination of a biological agent from a building.

UNLABELLED: The Bio-response Operational Testing and Evaluation (BOTE) Project was a cross-government effort designed to operationally test and evaluate a response to a biological incident (release of Bacillus anthracis [Ba] spores, the causative agent for anthrax) from initial public health and law enforcement response through environmental remediation. The BOTE Project was designed to address site remediation after the release of a Ba simulant, Bacillus atrophaeus spp. globigii (Bg), within a facility, drawing upon recent advances in the biological sampling and decontamination areas. A key component of response to a biological contamination incident is the proper management of wastes and residues, which is woven throughout all response activities. Waste is generated throughout the response and includes items like sampling media packaging materials, discarded personal protective equipment, items removed from the facility either prior to or following decontamination, aqueous waste streams, and materials generated through the application of decontamination technologies. The amount of residual contaminating agent will impact the available disposal pathways and waste management costs. Waste management is an integral part of the decontamination process and should be included through "Pre-Incident" response planning. Overall, the pH-adjusted bleach decontamination process generated the most waste from the decontamination efforts, and fumigation with chlorine dioxide generated the least waste. A majority of the solid waste generated during pH-adjusted bleach decontamination was the nonporous surfaces that were removed, bagged, decontaminated ex situ, and treated as waste. The waste during the two fumigation rounds of the BOTE Project was associated mainly with sampling activities. Waste management activities may represent a significant contribution to the overall cost of the response/recovery operation. This paper addresses the waste management activities for the BOTE field test. IMPLICATIONS: Management of waste is a critical element of activities dealing with remediation of buildings and outdoor areas following a biological contamination incident. Waste management must be integrated into the overall remediation process, along with sampling, decontamination, resource management, and other important response elements, rather than being a stand-alone activity. The results presented in this paper will provide decision makers and emergency planners at the federal/state/tribal/local level information that can be used to integrate waste management into an overall systems approach to planning and response activities.

Medical treatment of joint prosthesis: indication, opportunities and liability profiles.

Orthopaedic specialists should completely and sequentially manage osteoarthritis, from the onset to the prosthesis, with no attitude of resignation, complying with national and international Guidelines (GLs) and abiding by the criteria of appropriateness of drugs, rehabilitation and orthopaedic device prescription, in line with the ethics of the medical profession. The GLs are a paper that rationalises the quantity of existing information for a disease, without abusing the decision of the doctor; a large volume of scientific knowledge is concentrated in a format that is easily accessible to doctors when carrying out their work. The use of drugs has taken on a connotation of a rational and multifactorial choice, rather than an accidental and incremental choice - inspired only by safety, rather than efficacy criteria. The Notes compiled by the Italian Medicines Agency - a legal instrument to define the reimbursability of medicines and, therefore, an instrument for managing pharmaceutical expenditure – are, in reality, a means to guarantee the appropriateness of the use of medicines, orienting the therapeutic choices according to established Guidelines. In the specific case of osteoarthritis, the knowledge of the GLs is the most appropriate and complete approach towards the disease, in the context of its pathogenetic complexity in its natural history. Moreover, pharmacological treatment of the subchondral osteometabolic damage becomes necessary when documented by magnetic resonance or a scintigraphy; the bone-related pain cannot be challenged through symptomatic analgesic treatment alone.

METABOLIC BONE CHANGES IN OSTEOARTHRITIS: THE ROLE OF IMAGING AND PATHOGENETIC INTERPRETATION.

Osteoarthritis (OA) is the most prevalent chronic joint disease and one of the major causes of disability in the adult population. Although OA is considered a progressive degenerative process which involves the whole joint, articular cartilage and subchondral bone play a determinant role in its pathogenesis. In particular, metabolic-triggered subchondral bone damage, together with biochemical markers, are referred as important indicators of the disease. Magnetic resonance (MR) is the best imaging technique to detect and characterize such bone abnormalities. It represents an effective method through which to not only diagnose, describe and follow the course of OA but also to deepen our understanding of the natural history of the disease, with the ultimate purpose of attaining improved outcome in terms of therapy and prognosis. Even though MR has enormous potential, some diagnostic pitfalls may occur in clinical practice, hence an accurate clinical assessment of the patient is mandatory in combination with optimal imaging evaluation.

Systemic lupus erythematosus: immunopathogenesis and novel therapeutic targets.

Systemic lupus erythematosus (SLE) is the prototype of autoimmune diseases with multiorgan involvement. SLE presents many genetic and epigenetic associations and the pathogenesis is characterized by a complex network of alterations affecting both adaptative and innate immunity. The disclosure of novel mechanisms of SLE pathogenesis suggested new therapeutic targets, based on interference with the cytokine pathways or on depletion of the immune cells.

The Simpson-Golabi-Behmel syndrome: A clinical case and a detective story.

The Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth condition comprising "coarseness" of facial traits, supernumerary nipples, congenital heart defects, polydactyly and fingernail hypoplasia, and an increased risk of neonatal death and later neoplasia. Psychomotor development is usually normal. The syndrome is caused by mutation/deletion of the X-linked gene GPC3. We describe a new case of SGBS, that led to the discovery of an extended family segregating a GPC3 mutation and, ultimately, of an affected relative forgotten, but not lost, in an anatomical museum, where he was classified as a macrosomic newborn, who was born probably around 1940 and died neonatally of unknown cause. This baby boy becomes the oldest case of SGBS on record.

[Dynamic contrast-enhanced magnetic resonance imaging of the wrist in early arthritis]. / La risonanza magnetica dinamica del polso nella valutazione delle artriti precoci.

OBJECTIVES: MRI has been proposed as the imaging method of choice to evaluate the long-term outcome in patients with early arthritis. The role of dynamic MRI, performed at presentation, in predicting the outcome of patients with early arthritis has been addressed in the present study. METHODS: 39 patients with early arthritis, involving at least one wrist, were studied with clinical visits and laboratory investigations, every 3 months. Dynamic MRI was performed with a low-field (0.2T), extremity-dedicated machine (Artoscan, Esaote, Genova, Italy) equipped with a permanent magnet and with a dedicated hand and wrist coil. During the intravenous injection of Gd-DTPA, twenty consecutive fast images of 3 slices of the wrist were acquired. The synovial contrast enhancement ratio was calculated both as rate of early enhancement (REE) per second during the first 55" and as relative enhancement (RE) at t seconds. RESULTS: In our cohort of patients, REE and RE were significantly lower than those observed in a historical cohort of 36 patients with active rheumatoid arthritis. In univariate analysis, low RE predicted complete remission of arthritis. In multivariate analysis, fulfillment of RA criteria during follow-up was predicted by high RE. The need for immunosoppressive treatment at the end of follow-up was predicted by both low RE and high REE. CONCLUSIONS: Dynamic MRI may be used to predict several outcomes of early arthritis involving the wrist.

[Magnetic resonance imaging of the peripheral joints in psoriatic arthritis]. / La risonanza magnetica delle articolazioni periferiche nell'artrite psoriasica.

OBJECTIVE: Magnetic resonance imaging (MRI) has been widely used for the evaluation of rheumatoid arthritis (RA), with only a minority of studies considering other types of arthritis. This review is concerned with an evaluation of the MRI appearance of peripheral joints in psoriatic arthritis (PsA). METHODS: A Medline search was performed to identify all publications from the years 1985 to 2006 concerning MRI of the peripheral joints and PsA. Additional papers were retrieved by scanning the references to the Medline-listed articles. Articles written in English, French, German, and Italian were included. RESULTS: Most papers studied the hand and wrist, and only few of them were concerned with the knee, foot, temporomandibular joint, and elbow. Patients with PsA showed often, but not always, a pattern of joint inflammation which extended beyond the capsule into the extraarticular tissue. Bone oedema and erosions were less frequent than in RA. In particular, bone oedema at the entheseal junction was seen, especially in the knee. The degree of synovitis, assessed by dynamic MRI, was similar in PsA and RA. DISCUSSION: Data on MRI of the peripheral joints in PsA are scanty. Only few studies were specifically designed to evaluate the pattern of arthritis in PsA, with most information deriving from papers where different types of arthritis were considered together. An enthesis-related origin of PsA has been proposed in contrast to the primarily synovial inflammation of RA. This pathogenic interpretation is likely to be true, but does not explain all cases of PsA, and needs to be confirmed by further studies.

Heterogeneity of Cortical Lesion Susceptibility Mapping in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping has been used to characterize iron and myelin content in the deep gray matter of patients with multiple sclerosis. Our aim was to characterize the susceptibility mapping of cortical lesions in patients with MS and compare it with neuropathologic observations. MATERIALS AND METHODS: The pattern of microglial activation was studied in postmortem brain tissues from 16 patients with secondary-progressive MS and 5 age-matched controls. Thirty-six patients with MS underwent 3T MR imaging, including 3D double inversion recovery and 3D-echo-planar SWI. RESULTS: Neuropathologic analysis revealed the presence of an intense band of microglia activation close to the pial membrane in subpial cortical lesions or to the WM border of leukocortical cortical lesions. The quantitative susceptibility mapping analysis revealed 131 cortical lesions classified as hyperintense; 33, as isointense; and 84, as hypointense. Quantitative susceptibility mapping hyperintensity edge found in the proximity of the pial surface or at the white matter/gray matter interface in some of the quantitative susceptibility mapping-hyperintense cortical lesions accurately mirrors the microglia activation observed in the neuropathology analysis. CONCLUSIONS: Cortical lesion susceptibility maps are highly heterogeneous, even at individual levels. Quantitative susceptibility mapping hyperintensity edge found in proximity to the pial surface might be due to the subpial gradient of microglial activation.

How normal are the hands of normal controls? A study with dedicated magnetic resonance imaging.

OBJECTIVE: To investigate bone and soft tissue changes in the hands of normal subjects by MRI. METHODS: Twenty-three normal volunteers (16 women) agreed to be examined. MRI of the hand was performed with a dedicated-extremity 0.2 Tesla device using gradient echo, spin echo and STIR sequences. Joint space width was measured in 16 different locations of the hand. Bone lesions, including bone oedema, ankylosis, and erosions, as well as the presence of tenosynovitis were investigated. RESULTS: Reproducibility of measures of joint space width was relatively good with an intraclass correlation coefficient of 0.82 and 0.71 in the intra-observer and inter-observer evaluations, respectively. No age- or sex-related differences of joint space were observed. Reproducibility of the readings of bone oedema and tenosynovitis were optimal. Bone oedema and erosions were observed in 2/23 (8.7%) and in 6/23 (26.1%) subjects, respectively. Tenosynovitis of the extensor tendons was present in 1/23 subjects (4.3%), whereas tenosynovitis of the flexor tendons was seen in 4/23 (17.4%). CONCLUSION: This study demonstrates that joint changes considered to be peculiar of arthritis can be found by MRI in a relevant percentage of healthy subjects. Our data suggest that a control group of healthy subjects should be included in MRI studies on the appearance of the wrist in disease.

c-FLIP efficiently rescues TRAF-2-/- cells from TNF-induced apoptosis.

For the past 20 years, it has been known that preparations of Tumor Necrosis Factor alpha (TNF) fail to induce apoptosis due to cytoprotective responses that render cells resistant to its cytotoxic activity. Here we show that TRAF-2-/- embryonic fibroblasts express reduced levels of the anti-apoptotic molecule c-FLIP due to extensive degradation of the protein. Reconstitution of TRAF-2-/- EF with c-FLIP is sufficient for resistance to TNF toxicity. Our results strengthen the role of c-FLIP in protecting cells from the cytotoxic effect of TNF and have implication for the treatment of inflammatory and proliferative disorders.

Thyroid-hormone effects on putative biochemical pathways involved in UCP3 activation in rat skeletal muscle mitochondria.

In vitro, uncoupling protein 3 (UCP3)-mediated uncoupling requires cofactors [e.g., superoxides, coenzyme Q (CoQ) and fatty acids (FA)] or their derivatives, but it is not yet clear whether or how such activators interact with each other under given physiological or pathophysiological conditions. Since triiodothyronine (T3) stimulates lipid metabolism, UCP3 expression and mitochondrial uncoupling, we examined its effects on some biochemical pathways that may underlie UCP3-mediated uncoupling. T3-treated rats (Hyper) showed increased mitochondrial lipid-oxidation rates, increased expression and activity of enzymes involved in lipid handling and increased mitochondrial superoxide production and CoQ levels. Despite the higher mitochondrial superoxide production in Hyper, euthyroid and hyperthyroid mitochondria showed no differences in proton-conductance when FA were chelated by bovine serum albumin. However, mitochondria from Hyper showed a palmitoyl-carnitine-induced and GDP-inhibited increased proton-conductance in the presence of carboxyatractylate. We suggest that T3 stimulates the UCP3 activity in vivo by affecting the complex network of biochemical pathways underlying the UCP3 activation.

Uncoupling protein-3 is a molecular determinant for the regulation of resting metabolic rate by thyroid hormone.

Thyroid hormones increase energy expenditure, partly by reducing metabolic efficiency. The control of specific genes at the transcriptional level is thought to be the major molecular mechanism. However, both the number and the identity of the thyroid hormone-controlled genes remain unknown, as do their relative contributions. Uncoupling protein-3, a recently identified member of the mitochondrial transporter superfamily and one that is predominantly expressed in skeletal muscle, has the potential to be a molecular determinant for thyroid thermogenesis. However, changes in mitochondrial proton conductance and resting metabolic rate after physiologically mediated changes in uncoupling protein-3 levels have not been described. Here, in a study on hypothyroid rats given a single injection of T(3), we describe a strict correlation in terms of time course between the induced increase in uncoupling protein-3 expression (at mRNA and protein levels) and decrease in mitochondrial respiratory efficiency, on the one hand, and the increase in resting metabolic rate, on the other. First, we describe our finding that uncoupling protein-3 is present and regulated by T(3) only in metabolically relevant tissues (such as skeletal muscle and heart). Second, we follow the time course (at 0, 6, 12, 24, 48, 65, 96, and 144 h) of both uncoupling protein-3 mRNA levels and mitochondrial uncoupling protein-3 density in gastrocnemius muscle and heart. In both tissues, the maximal (12-fold) increase in uncoupling protein-3 density was reached at 65 h. The resting metabolic rate [lO(2)(kg(0.75))(-1)h(-1)] showed the same time course, and at 65 h the increase vs. time zero was 45% (1.316 +/- 0.026 vs. 0.940 +/- 0.007; P < 0.001). At the same time point, gastrocnemius muscle mitochondria showed a significantly higher nonphosphorylating respiration rate (nanoatoms of oxygen per min/mg protein; increase vs. time zero, 40%; 118 +/- 4 vs. 85 +/- 9; P < 0.05), whereas the membrane potential decreased by 8% (168 +/- 2 vs. 182 +/- 4; P < 0.05). These data are diagnostic of mitochondrial uncoupling. The results reported here provide the first direct in vivo evidence that uncoupling protein-3 has the potential to act as a molecular determinant in the regulation of resting metabolic rate by T(3).

Skeletal muscle mitochondrial free-fatty-acid content and membrane potential sensitivity in different thyroid states: involvement of uncoupling protein-3 and adenine nucleotide translocase.

The effect of triiodothyronine (T3) on mitochondrial efficiency could be related to an increase in the concentrations of some proteins, such as uncoupling proteins (UCPs). Free fatty acids (FFA) seem to be a cofactor essential for the uncoupling activity of UCP3. In this paper, we report that the hypothyroidism-hyperthyroidism transition is accompanied by increases: (i) in the endogenous levels of mitochondrial FFA and (ii) in the sensitivity to FFA shown by the mitochondrial respiration rate and membrane potential, which correlated with the level of UCP3 protein. The level of the mRNA for adenine-nucleotide translocase-1 (ANT) was not affected by the thyroid state, while the ANT contribution to FFA-induced changes in mitochondrial uncoupling was low in the hypothyroid and euthyroid states but became more relevant in the hyperthyroid state at the highest concentration of FFA.

Split hand/split foot, syndactyly, urinary tract obstruction, radial, diaphragmatic, and neural tube defects: Czeizel-Losonci syndrome?

We report on a baby girl with absence of the left hemidiaphragm, lumbosacral myelomeningocele, syndactyly with limb deficiencies, and bilateral hydronephrosis. A similar array of malformations was described previously by Czeizel and Losonci [Hum Genet 77:203-204, 1987] in a single family which showed a transmission pattern suggesting autosomal dominant inheritance with variable expressivity. The presence of limb abnormalities and the location of the neural tube defects in these cases suggest that the underlying pathogenesis probably does not involve the same disturbances of midline field development which have been postulated to occur in the schisis association.