Rosa Bellmann-Weiler

Real-Time Sonoelastography of Lateral Epicondylitis: Comparison of Findings Between Patients and Healthy Volunteers

OBJECTIVE The purpose of this study was to evaluate real-time sonoelastography in the assessment of the origins the common extensor tendon in healthy volunteers and in patients with symptoms of lateral epicondylitis. The findings were compared with those obtained at clinical examination, ultrasonography, and power Doppler sonography. SUBJECTS AND METHODS Thirty-eight elbows of 32 consecutively registered patients with symptoms of lateral epicondylitis and 44 asymptomatic elbows of 28 healthy volunteers were assessed with ultrasound and real-time sonoelastography. A clinical examination was performed, and pain was classified with a visual analog scale. RESULTS In healthy volunteers, real-time sonoelastographic images showed hard tendon structures in 96% of tendon thirds and mild alterations in 4%. Real-time sonoelastography of patients showed hard structures in 33% of tendon thirds but softening of different grades in 67%, a statistically significant difference in relation to the findings in healthy volunteers (p < 0.001). Lateral collateral ligament involvement and overlying fascial involvement were more commonly detected with real-time sonoelastography. The sensitivity of real-time sonoelastography was 100%, the specificity 89%, and the accuracy 94% with clinical examination as the reference standard. Good correlation with ultrasound findings was found (r > or = 0.900). No correlation was observed between ultrasound or real-time sonoelastographic findings and power Doppler sonographic findings, but power Doppler sonographic findings had a strong correlation with the visual analog scale score. CONCLUSION Real-time sonoelastography is valuable in the detection of the intratendinous and peritendinous alterations of lateral epicondylitis and facilitates differentiation between healthy and symptomatic extensor tendon origins with excellent sensitivity and excellent correlation with ultrasound findings.

Pathways for the regulation of interferon-γ-inducible genes by iron in human monocytic cells

To elucidate iron‐regulated interferon‐γ (IFN‐γ) effector functions, we investigated three IFN‐γ‐inducible genes [intercellular adhesion molecule‐1 (ICAM‐1), human leukocyte antigen (HLA)‐DR, guanosine 5′‐triphosphate‐cyclohydrolase I (GTP‐CH)] in primary human monocytes and the cell line THP‐1. IFN‐γ increased the surface expression of ICAM‐1 and HLA‐DR and stimulated GTP‐CH activity. Addition of iron before cytokine stimulation resulted in a dose‐dependent reduction of these pathways, and iron restriction by desferrioxamine (DFO) enhanced ICAM‐1, HLA‐DR, and GTP‐CH expression. Iron neither affected IFN‐γ binding to its receptor nor IFN‐γ receptor surface expression. IFN‐γ‐inducible mRNA expression of ICAM‐1, HLA‐DR, and GTP‐CH was reduced by iron and increased by DFO by a transcriptional mechanism. Moreover, ICAM‐1 and to a lesser extent, GTP‐CH and HLA‐DR mRNA expression were regulated post‐transcriptionally, as iron pretreatment resulted in shortening the mRNA half‐life compared with cells treated with IFN‐γ alone. Thus, iron perturbations regulate IFN‐γ effector pathways by transcriptional and post‐transcriptional mechanisms, indicating that iron rather interferes with IFN‐γ signal‐transduction processes.

The Macrophage: A Cellular Factory at the Interphase Between Iron and Immunity for the Control of Infections

Likewise the macrophage is the most important cellular player at the interface between iron and immunity. This is due to the facts that macrophages need iron to produce highly toxic hydroxyl radicals, while at the same time macrophages are major storage sites of iron under inflammatory conditions. Cytokines and radicals produced by macrophages as well as acute phase proteins originating from the liver affect macrophage iron homeostasis by modulating iron uptake and iron release by these cells leading to increased iron retention within macrophages under inflammatory conditions. At the same time iron modulates macrophage effector pathways by regulating cytokine activities, the induction of anti-microbial effector pathways of macrophages and indirectly via regulating lymphocyte proliferation and activities which then affect macrophage differentiation and activation. Since iron is an essential compound for microbial growth and proliferation the control over iron homeostasis is a central battlefield deciding about the fate of an infection. Thus, it is not surprising that phagolysosomal proteins which are associated with resistance towards infections with intracellular pathogens also act as iron transporters. Thus, alterations in immune function affect iron homeostasis and vice versa (Porto et al. 1994; Roy & Andrews 2001; Meyer et al. 2002; Weiss 2002b). This minireview should provide an overview of our current knowledge of the iron immunity network and how this interplay may be favorably affected in order to obtain a better control over certain infectious agents.

Sonoelastography: Musculoskeletal Applications

All participants for image samplings provided written informed consent. Conventional B-mode ultrasonography (US) has been widely utilized for musculoskeletal problems as a first-line approach because of the advantages of real-time access and the relatively low cost. The biomechanical properties of soft tissues reflect to some degree the pathophysiology of the musculoskeletal disorder. Sonoelastography is an in situ method that can be used to assess the mechanical properties of soft tissue qualitatively and quantitatively through US imaging techniques. Sonoelastography has demonstrated feasibility in the diagnosis of cancers of the breast and liver, and in some preliminary work, in several musculoskeletal disorders. The main types of sonoelastography are compression elastography, shear-wave elastography, and transient elastography. In this article, the current knowledge of sonoelastographic techniques and their use in musculoskeletal imaging will be reviewed.

Indoleamine-2, 3-Dioxygenase and Other Interferon-γ-Mediated Pathways in Patients with Human Immunodeficiency Virus Infection

Human immunodeficiency virus type 1 (HIV) infection is characterized by progressive immunodeficiency despite of an overwhelming cellular immune activation. Patients show highly elevated serum/plasma concentrations of the proinflammatory cytokine interferon-γ (IFN-γ ), which induces human monocytes to form neopterin, to produce reactive oxygen species (ROS) and in parallel, to degrade tryptophan. Enhanced tryptophan degradation by the enzyme indoleamine-2, 3-dioxygenase (IDO) contributes importantly to disease progression and “complications” of HIV infection: By a subsequent impairment of protein metabolism and serotonin formation, the development of neuropsychiatric disorders and weight loss in HIV infected patients can be enforced. Furthermore, increased IDO-activation efficiently suppresses the growth and proliferation of pathogens as well as host T-cells. IDO and other IFN-γ-mediated pathways are strongly induced in patients with HIV infection and are also linked with disease progression: Neopterin formation by GTPcyclohydrolase I sensitively reflects the stage of the disease, and determination of the pteridine in body fluids is useful to monitor the efficacy of antiretroviral therapy. Neopterin is an independent prognostic factor for the outcome of disease, and well suited to estimate the degree of immune activation in vivo and the responsiveness of immunocompetent cells to stimulation in vitro. ROS formation may contribute to the development of oxidative stress in HIV infection, resulting in depletion of antioxidants. The cause-effective role of an overwhelming Th1-type immune response together with the activation of IDO and other IFN-γ-mediated biochemical pathways for the course of HIV infection, the development of immunodeficiency, anemia and weight loss in HIV patients is discussed.

Carpal Tunnel Syndrome: Diagnosis by Means of Median Nerve Elasticity—Improved Diagnostic Accuracy of US with Sonoelastography

PURPOSE To compare the elasticity of the median nerve (MN) between healthy volunteers and patients with carpal tunnel syndrome (CTS) and to evaluate the diagnostic utility of sonoelastographic measurements of the elasticity of the MN. MATERIALS AND METHODS This study was performed with institutional review board approval and written informed consent from all participants. Hands in 22 healthy volunteers and in 31 patients with symptomatic CTS were studied. The cross-sectional area (CSA) and the elasticity of the MN, which was measured as the acoustic coupler (AC)/MN strain ratio, were evaluated. RESULTS Both hands in 22 healthy volunteers (three men [mean age, 52.7 years; age range, 41-65 years]; 19 women [mean age, 62.2 years; age range, 40-88 years]) and 43 hands in 31 patients with symptomatic CTS (three men [mean age, 69.0 years; age range, 46-88 years]; 28 women [mean age, 61.2 years; age range, 39-92 years]) were studied. Both the AC/MN strain ratio and the CSA in the patients with CTS were significantly higher than those in the healthy volunteers (P < .001). The presence of CTS was predicted by means of AC/MN strain ratio and CSA cutoff values, respectively, of 4.3 and 11 mm(2), with areas under the receiver operating characteristic curves (AUCs) of 0.78 (95% confidence interval [CI]: 0.69, 0.88) and 0.85 (95% CI: 0.78, 0.93). A logistic model that combined the AC/MN strain ratio and the CSA improved diagnostic accuracy for CTS, with an AUC of 0.91 (95% CI: 0.85, 0.97; P < .001). CONCLUSION Sonoelastography provides significant improvement in the diagnostic accuracy of the ultrasonographic assessment of CTS.

Growth differentiation factor 15 in anaemia of chronic disease, iron deficiency anaemia and mixed type anaemia.

Recently, the iron and erythropoiesis‐controlled growth differentiation factor 15 (GDF15) has been shown to inhibit the expression of hepcidin in β‐thalassaemia patients, thereby increasing iron absorption despite iron overload. To access the diagnostic and pathogenic impact of GDF15 in inflammatory anaemia the association of GDF15 expression with serum iron parameters and hepcidin was studied in patients suffering from iron deficiency anaemia (IDA), anaemia of chronic disease (ACD) and ACD subjects with true iron deficiency (ACD/IDA). GDF15 was significantly increased in both ACD and ACD/IDA, but not in IDA subjects as compared to controls. In contrast, hepcidin levels were significantly lower in IDA and ACD/IDA subjects than in ACD patients. IDA and ACD/IDA, but not ACD, showed an association between GDF15 and soluble transferrin receptor, an indicator of iron requirement for erythropoiesis. However, GDF15 did not correlate to hepcidin in either patient group. While GDF15 levels were linked to the needs for erythropoiesis and iron homeostasis in IDA, the immunity‐driven increase of GDF15 may not primarily affect iron homeostasis and hepcidin expression. This indicates that other ACD‐related factors may overcome the regulatory effects of GDF15 on hepcidin expression during inflammation.

Altered Pharmacokinetics of Voriconazole in a Patient with Liver Cirrhosis

Voriconazole (VRC; Vfend [Pfizer, United Kingdom]) is a broad-spectrum triazole with activity against fungi including non-albicans Candida, Aspergillus, Fusarium, and Scedosporium species. Favorable therapeutic responses in patients with plasma VRC levels above 2.05 μg/ml were found previously (9). The main adverse effects of VRC are hepatotoxicity and blurred vision (1, 2, 4, 6, 11). Prolonged exposure to high plasma VRC concentrations (trough blood VRC levels of >5.5 μg/ml for more than 7 days) was found to be associated with an enhanced risk of serious neurological adverse events (5). A 45-year-old male (body weight, 100 kg) with fatty-liver cirrhosis (Child-Pugh class C; model of end-stage liver disease score, 20) who was listed for liver transplantation and showed signs of portal hypertension (esophageal varices and ascites) and cholestasis (plasma bilirubin level, 20.26 mg/dl, or 346 μmol/liter) received 2 mg of VRC/kg of body weight orally twice a day because of suspected pulmonary aspergillosis. At day 30 of clinical treatment with VRC, he was transferred to the intensive care unit because of unconsciousness (Glasgow Coma Scale score, 5 of 15) and hyperventilation. Plasma VRC concentrations were determined by high-performance liquid chromatography and UV detection (3). Pharmacokinetic parameters were calculated using a noncompartmental model. Upon admission to the intensive care unit (15 h after the last intake of VRC), the plasma VRC level amounted to 13.9 μg/ml (Fig. ​(Fig.1).1). Therefore, VRC therapy was discontinued. The patients condition, particularly the central nervous system symptoms, gradually improved as VRC levels slowly declined, and he could be transferred to the ward after 2 days (VRC concentration, 10.0 μg/ml). A half-life of 53.1 h (half-life in healthy volunteers, 4.7 h [7]), an apparent volume of distribution at steady state of 0.13 liters/kg (volume of distribution in healthy volunteers, 2.04 liters/kg [7]), and a VRC clearance rate as low as 1.4 ml/h/kg (clearance rate in healthy volunteers, 253.9 ml/h/kg [7]) were calculated. Even after 11 days, VRC was detectable in the plasma (0.66 μg/ml). Since diagnostic reevaluation did not reveal any signs of fungal infection, there was no need to continue antimycotic treatment at that time. The patient underwent a successful liver transplantation 1 month later. FIG. 1. Voriconazole elimination after discontinuation of voriconazole. The dashed line indicates the concentration limit for favorable responses (9). The elimination of VRC appears to be markedly prolonged in patients with decompensated liver cirrhosis, and this delay leads to potentially toxic levels of VRC in the plasma. After cytochrome P450 (2C9, 2C19, and 3A4)-dependent hepatic metabolism, about 80% of VRC is eliminated via the kidneys. Biliary elimination accounts for 20%. VRC displays nonlinear pharmacokinetics, with a prolonged half-life at higher concentrations (8). In patients with moderate liver cirrhosis (Child-Pugh class B), the VRC clearance rate is approximately half that in patients with normal hepatic function after oral intake. A reduction of the maintenance dose by 50% is recommended for patients with mild to moderate hepatic insufficiency (10). For patients with severely impaired liver function, a dose reduction of more than 50% appears to be required, and therapeutic drug monitoring will greatly improve therapeutic safety. Pharmacokinetic studies in patients with severe hepatic impairment should be performed in order to establish reliable dose recommendations for this group of patients, who are at high risk of developing invasive fungal infections.

Greater Trochanteric Pain Syndrome

Pain around the greater trochanter is still a common clinical problem that may be secondary to a variety of either intra-articular or periarticular pathologies. Gluteal tendon pathologies are one of the primary causes of greater trochanteric pain, with attrition of the fasciae latae against the gluteus medius and minimus tendons, and the trochanteric bursa being possible causes. Key sonographic findings of gluteal tendinopathy, bursitis, and differential diagnosis are described in this overview. Clinical diagnosis and treatment of greater trochanteric pain syndrome is still challenging; therefore ultrasound is helpful to localize the origin of pain, determine underlying pathology, and, based on these findings, to guide local aspiration and/or injection in cases of tendinopathy and/or bursitis.

Feasibility of second‐generation ultrasound contrast media in the detection of active sacroiliitis

OBJECTIVE To determine whether a recently available contrast-enhanced ultrasound (CEUS) technique using second-generation microbubbles allows for the detection of active sacroiliitis, and to measure CEUS enhancement depth at the dorsocaudal part of the sacroiliac (SI) joints in healthy volunteers compared with patients with sacroiliitis. METHODS Forty-two consecutive patients (84 SI joints) presenting with a clinical diagnosis of sacroiliitis in 50 SI joints and 21 controls (42 SI joints) were investigated by CEUS using a standardized low mechanical index ultrasound protocol. Detected vascularity was used to retrospectively measure the enhancement depth in the dorsocaudal part of the SI joints. RESULTS CEUS detected enhancement in all clinically active SI joints, showing an enhancement depth into the dorsal SI joint cleft of 18.5 mm (range 16-22.1), which was significantly higher compared with both inactive joints of patients (3.6 mm, range 0-12; P < 0.001) and healthy controls (3.1 mm, range 0-7.8; P < 0.001). All inactive joints were correctly classified based on a lack of deep enhancement in patients with sacroiliitis and controls (42 of 42, 100% sensitivity, 100% specificity; Cohens kappa = 1). CONCLUSION CEUS allowed the differentiation of active sacroiliitis from inactive SI joints, and proved to be a feasible method for the detection of vascularity in clinically active sacroiliitis by showing deep contrast enhancement into the SI joints not detectable in inactive joints of patients or controls. If this technique might add information to the earlier detection of sacroiliitis, it should be addressed in further studies.