Monoamine oxidase A down-regulation contributes to high metanephrine concentration in pheochromocytoma.

CONTEXT: The high diagnostic performance of plasma-free metanephrines (metanephrine and normetanephrine) (MN) for pheochromocytoma (PHEO) results from the tumoral expression of catechol-O-methyltransferase (COMT), the enzyme involved in O-methylation of catecholamines (CAT). Intriguingly, metanephrine, in contrast to epinephrine, is not remarkably secreted during a stress in hypertensive or normotensive subjects, whereas in PHEO patients CAT and MN are both raised to high levels. Because epinephrine and metanephrine are almost exclusively produced by the adrenal medulla, this suggests distinct CAT metabolism in chromaffin cells and pheochromocytes. OBJECTIVE: The objective of the study was to compare CAT metabolism between adrenal medulla and PHEO tissue regarding related enzyme expression including monoamine oxidases (MAO) and COMT. DESIGN: A multicenter comparative study was conducted. STUDY PARTICIPANTS: The study included 21 patients with a histologically confirmed PHEO and eight adrenal glands as control. MAIN OUTCOME MEASURES: CAT, dihydroxyphenol-glycol, 3,4-dihydroxyphenylacetic acid, and MN were measured in adrenal medulla and PHEO tissue. Western blot, quantitative RT-PCR and immunofluorescence studies for MAOA, MAOB, tyrosine hydroxylase, dopamine β-hydroxylase, L-amino acid decarboxylase, and COMT were applied on tissue homogenates and cell preparations. RESULTS: At both the protein and mRNA levels, MAOA and COMT are detected less often in PHEO compared with adrenal medulla, conversely to tyrosine hydroxylase, L-amino acid decarboxylase, and dopamine β-hydroxylase, much more expressed in tumor tissue. MAOB protein is detected less often in tumor but not differently expressed at the mRNA level. Dihydroxyphenol-glycol is virtually absent from tumor, whereas MN, produced by COMT, rises to 4.6-fold compared with adrenal medulla tissue. MAOA down-regulation was observed in 100% of tumors studied, irrespectively of genetic alteration identified; on the other hand, MAOA was strongly expressed in all adrenal medulla collected independently of age, gender, or late sympathetic activation of the deceased donor. CONCLUSION: High concentrations of MN in tumor do not only arise from CAT overproduction but also from low MAOA expression, resulting in higher substrate availability for COMT.

Biologics in rheumatoid arthritis - recommendations for Swiss practice.

The new paradigm of therapy in rheumatoid arthritis is to aim toward early and complete remission, using a larger use of conventional DMARDs and biologic agents. The present recommendations were established through a consensus to help practitioners in their daily use of those agents, to reflect the current "best practice" in Switzerland.

Description of the Occurrence of Canine Dirofilariasis in the State of Rio de Janeiro, Brazil

In order to evaluate the prevalence of canine heartworm in the State of Rio de Janeiro, a multicenter survey was carried out in two phases. The survey involved 1376 dogs from two cities: Rio de Janeiro and Niterói, and its surroundings, including the eastern shore and mountain resorts, which were further divided into sections. In the first phase, 795 dog blood samples were examined by the modified Knott test for the detection of microfilariae. A total of 134 samples (16.85%) were microfilaremic: 8.61% from Rio de Janeiro, 21.76% from Niterói and its surroundings, 33.33% from the eastern shore and 30.43% from the mountain resorts. In the second phase, 595 dog blood samples were examined first by the modified Knott test and the amicrofilaremic samples were subsequently examined by an immunoenzymatic test (ELISA) for antigen detection. In summary, 83 samples (13.95%) were microfilaremic and 44 (7.98%) of the amicrofilaremic samples were positive for heartworm antigen (occult infections). In Rio de Janeiro, 13.68% of the dogs were infected (i.e., antigen-and/or microfilaria-positive) and 8.51% of the dogs had microfilaremic infections. In comparison, Niterói and its surroundings showed values of 24.46% and 17.30% and the eastern shore showed values of 52.46% and 31.15%. In contrast the mountain resorts showed 20% microfilaremic only

Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer.

OBJECTIVE: To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. RESULTS: Twenty pretreated SCLC patients (median age, 60 years) with extensive (n=13) or limited-stage disease (n=7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1-2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase. CONCLUSION: This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m(2)) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC.

Double-oblique free-breathing high resolution three-dimensional coronary magnetic resonance angiography.

OBJECTIVES: The goal of the present study was to develop a strategy for three-dimensional (3D) volume acquisition along the major axes of the coronary arteries. BACKGROUND: For high-resolution 3D free-breathing coronary magnetic resonance angiography (MRA), coverage of the coronary artery tree may be limited due to excessive measurement times associated with large volume acquisitions. Planning the 3D volume along the major axis of the coronary vessels may help to overcome such limitations. METHODS: Fifteen healthy adult volunteers and seven patients with X-ray angiographically confirmed coronary artery disease underwent free-breathing navigator-gated and corrected 3D coronary MRA. For an accurate volume targeting of the high resolution scans, a three-point planscan software tool was applied. RESULTS: The average length of contiguously visualized left main and left anterior descending coronary artery was 81.8 +/- 13.9 mm in the healthy volunteers and 76.2 +/- 16.5 mm in the patients (p = NS). For the right coronary artery, a total length of 111.7 +/- 27.7 mm was found in the healthy volunteers and 79.3 +/- 4.6 mm in the patients (p = NS). Comparing coronary MRA and X-ray angiography, a good agreement of anatomy and pathology was found in the patients. CONCLUSIONS: Double-oblique submillimeter free-breathing coronary MRA allows depiction of extensive parts of the native coronary arteries. The results obtained in patients suggest that the method has the potential to be applied in broader prospective multicenter studies where coronary MRA is compared with X-ray angiography.

Clinical benefits of an adherence monitoring program in the management of secondary hyperparathyroidism with cinacalcet: results of a prospective randomized controlled study.

BACKGROUND/AIMS: One of the causes of uncontrolled secondary hyperparathyroidism (sHPT) is patient's poor drug adherence. We evaluated the clinical benefits of an integrated care approach on the control of sHPT by cinacalcet. METHODS: Prospective, randomized, controlled, multicenter, open-label study. Fifty hemodialysis patients on a stable dose of cinacalcet were randomized to an integrated care approach (IC) or usual care approach (UC). In the IC group, cinacalcet adherence was monitored using an electronic system. Results were discussed with the patients in motivational interviews, and drug prescription adapted accordingly. In the UC group, drug adherence was monitored, but results were not available. RESULTS: At six months, 84% of patients in the IC group achieved recommended iPTH targets versus 55% in the UC group (P = 0.04). The mean cinacalcet taking adherence improved by 10.8% in the IC group and declined by 5.3% in the UC group (P = 0.02). Concomitantly, the mean dose of cinacalcet was reduced by 7.2 mg/day in the IC group and increased by 6.4 mg/day in the UC group (P = 0.03). CONCLUSIONS: The use of a drug adherence monitoring program in the management of sHPT in hemodialysis patients receiving cinacalcet improves drug adherence and iPTH control and allows a reduction in the dose of cinacalcet.

Octacalcium Phosphate (OCP) Crystals Induce Synovial Inflammation and Cartilage

Introduction: The presence of intra-articular basic calcium phosphate (BCP) crystals, including OCP, carbonated-apatite, hydroxyapatite and tricalcium phosphate crystals, is associated with severe osteoarthritis and destructive arthropathies such as Milwaukee shoulder. Although BCP crystals displayed, in vitro, mitogenic, anabolic and catabolic responses, their intra-articular effect was never assessed.Objective: To determine the effects of OCP crystals in joints in vivo.Methods: OCP crystals (200 ug in 20 ml PBS) were injected into the right knee joint (the contra-lateral knee joint injected with 20 ul of PBS serving as a control) of wild-type mice treated or not by the IL1R antagonist Anakinra or mice deficient for the inflammasome proteins ASC and NALP3. 4 days and 17 days after crystal injection, mice were sacrificed and knee joints dissected. Histological scoring for synovial inflammation and characterisation of macrophages, neutrophils and T cells were performed. Technetium (Tc) uptake was measured at 6h, 1 and 4 days after OCP injection. Cartilage degradation was evaluated by Safranin O staining and VDIPEN immunohistochemistry. Intra-articular localisation of injected OCP crystals was evidenced by Von Kossa staining.Results: The intra-articular localisation of injected OCP crystals was evidenced by Von Kossa staining performed on non-decalcified samples embedded in methyl-metacrylate. Injection of OCP crystals into knee joints led at day 4 to an inflammatory response with intense macrophage staining and also some neutrophil recruitment in the synovial membrane. This synovitis was not accompanied by increased Tc uptake into the knee joint, Tc uptake being similar in OCP crystal injected knee or control knee at all time points investigated (6h, 1 day, 4 days). The histological modifications persisted over 17 days, with an additional fibrosis evidenced at this later time-point. The OCP crystal-induced synovitis was totally IL-1a and IL-1 independent as shown by the absence of inhibitory effects of anakinra injected into wild-type mice. Accordingly, OCP crystal-induced synovitis was similar in ASC-/- and NALP3-/- mice as no alterations of inflammation were demonstrated between these mice groups. Concerning cartilage matrix degradation, OCP crystals induced a strong breakdown of proteoglycans 4 and 17 days after injection, as measured by loss of red staining from Safranin O-stained sections of cartilage surfaces. In addition, we also measured advanced cartilage matrix destruction mediated by MMPs, as evidenced by VDIPEN staining of cartilage. OCP-mediated cartilage degradation was similar in all experimental conditions tested (WT+Anakinra, or ASC or NALP3 deficient mice).Conclusion: These data indicate in vivo that the intra-articular presence of OCP crystals is associated with cartilage destruction along with synovial inflammation. This is an interesting and new model of destructive arthropathy related to BCP crystals which will allow to assess new therapies in this disease.

Nasopharyngeal carriage of individual Streptococcus pneumoniae serotypes during pediatric radiologically confirmed community acquired pneumonia following PCV7 introduction in Switzerland.

BACKGROUND: Community-acquired pneumonia (CAP) is a serious cause of morbidity among children in developed countries. The real impact of 7-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal pneumonia is difficult to assess accurately. METHODS: Children aged ≤16 years with clinical and radiological pneumonia were enrolled in a multicenter prospective study. Children aged ≤16 years admitted for a minor elective surgery was recruited as controls. Nasopharyngeal samples for PCR serotyping of S. pneumoniae were obtained in both groups. Informations on age, gender, PCV7 vaccination status, day care/school attendance, siblings, tobacco exposure were collected. RESULTS: In children with CAP (n=236), 54% of the nasopharyngeal swabs were PCR-positive for S. pneumoniae compared to 32% in controls (n=105) (p=0.003). Serotype 19A was the most common pneumococcal serotype carried in children with CAP (13%) and in controls (15%). Most common serotypes were non-vaccine types (39.4% for CAP and 47.1% for controls) and serotypes included only in PCV13 (32.3% for CAP and 23.5% for controls). There was no significant difference in vaccine serotype distribution between the two groups. In fully vaccinated children with CAP, the proportion of serotypes carried only in PCV13 was higher (51.4%) than in partially vaccinated or non vaccinated children (27.6% and 28.6% respectively, p=0.037). CONCLUSIONS: Two to 4 years following introduction of PCV7, predominant S. pneumoniae serotypes carried in children with CAP were non PCV7 serotypes, and the 6 new serotypes included in PCV13 accounted for 51.4% of carried serotypes in fully vaccinated children.

Musculoskeletal Conditions Briefing

Musculoskeletal conditions (MSCs) are a group of diseases that affect the body’s bones, joints, muscles and the tissues that connect them. Common MSCs include back pain, rheumatoid arthritis, osteoarthritis, osteoporosis, and spinal disorders. MSCs are the most common cause of severe long term pain and physical disability in developed countries. They significantly affect the psychosocial wellbeing of individuals as well as their families and carers. They are responsible for substantial costs to the health and social care system and the economy. They are a leading cause of absence from work and lost productivity at work. MSCs comprise a diverse group of conditions. Some have a specific medical diagnosis (eg rheumatoid arthritis) but others have no clear medical diagnosis (eg back pain). Risk factors for the development and progression of MSCs include age, sex, family history, obesity, physical inactivity, injury and biomechanical occupational health issues.

Musculoskeletal Conditions Briefing: Technical Documentation

Musculoskeletal conditions (MSCs) are a group of diseases that affect the body’s bones, joints, muscles and the tissues that connect them. Common MSCs include back pain, rheumatoid arthritis, osteoarthritis, osteoporosis, and spinal disorders. MSCs are the most common cause of severe long term pain and physical disability in developed countries. They significantly affect the psychosocial wellbeing of individuals as well as their families and carers. They are responsible for substantial costs to the health and social care system and the economy. They are a leading cause of absence from work and lost productivity at work. MSCs comprise a diverse group of conditions. Some have a specific medical diagnosis (eg rheumatoid arthritis) but others have no clear medical diagnosis (eg back pain). Risk factors for the development and progression of MSCs include age, sex, family history, obesity, physical inactivity, injury and biomechanical occupational health issues. This document details the methods used to calculate the estimates and forecasts.

Potential exposure to hepatitis C virus through accidental blood contact in interventional radiology.

PURPOSE: To quantify the prevalence of accidental blood exposure (ABE) among interventional radiologists and contrast that with the prevalence of patients with hepatitis C virus (HCV) undergoing interventional radiology procedures. MATERIALS AND METHODS: A multicenter epidemiologic study was conducted in radiology wards in France. The risk of ABE to radiologists was assessed based on personal interviews that determined the frequency and type of ABE and the use of standard protective barriers. Patients who underwent invasive procedures underwent prospective sampling for HCV serologic analysis. HCV viremia was measured in patients who tested positive for HCV. RESULTS: Of the 77 radiologists who participated in 11 interventional radiology wards, 44% reported at least one incident of mucous membrane blood exposure and 52% reported at least one percutaneous injury since the beginning of their occupational activity. Compliance with standard precautions was poor, especially for the use of protective clothes and safety material. Overall, 91 of 944 treated patients (9.7%) tested positive for HCV during the study period, of whom 90.1% had positive viremia results, demonstrating a high potential for contamination through blood contacts. CONCLUSIONS: The probability of HCV transmission from contact with contaminated blood after percutaneous injury ranged from 0.013 to 0.030; the high frequency of accidental blood exposure and high percentage of patients with HCV could generate a risk of exposure to HCV for radiologists who perform invasive procedures with frequent blood contact. The need to reinforce compliance with standard hygiene precautions is becoming crucial for medical and technical personnel working in these wards.

Prevalence of chronic conditions – Musculoskeletal Conditions

IPH has estimated and forecast the number of adults with MSCs for the years 2010, 2015 and 2020. In the Republic of Ireland, the data are based on the Survey of Lifestyle, Attitudes and Nutrition (SLÁN) 2007 . The data describe the number of people who report that they have experienced doctor-diagnosed MSC in the previous 12 months:     Lower back pain or any other chronic back condition     Rheumatoid arthritis (inflammation of the joints)     Osteoarthritis (arthrosis, joint degradation) Data are  available by age and sex for each Local Health Office of the Health Service Executive (HSE) in the Republic of Ireland. In Northern Ireland, the data are based on the Health and Social Wellbeing Survey 2005/06 and Understanding Society 2009. The data describe the number of adults who:     Have ever consulted a doctor about back pain     Are currently receiving treatment for musculoskeletal problems (such as arthritis, rheumatism)     Have ever been told by a doctor or other health professional that they had have arthritis? Data are available by age and sex for each Local Government District in Northern Ireland. There are significant differences between the definitions used in RoI and NI and North-South comparisons are not valid. The RoI measures relate to specific MSCs in the previous 12 months that had been diagnosed by a doctor. The NI measures relate to doctor-consultations at any time in the past, doctor-diagnosis at any time in the past and current treatment. The IPH estimated prevalence per cents may be marginally different to estimated prevalence per cents taken directly from the reference study. There are two reasons for this: 1) The IPH prevalence estimates relate to 2010 while the reference studies relate to earlier years (Northern Ireland Health and Social Wellbeing Survey 2005/06, Survey of Lifestyle, Attitudes and Nutrition 2007, Understanding Society 2009). Although we assume that the risk of the condition in the risk groups do not change over time, the distribution of the number of people in the risk groups in the population changes over time (eg the population ages).  This new distribution of the risk groups in the population means that the risk of the condition is weighted differently to the reference study and this results in a different overall prevalence estimate. 2) The IPH prevalence estimates are based on a statistical model of the reference study. The model includes a number of explanatory variables to predict the risk of the condition. Therefore the model does not include records from the reference study that are missing data on these explanatory variables. A prevalence estimate for a condition taken directly from the reference study would include these records.

Traitement de la coxarthrose par des prothèses totales de hanche sur mesure [Treatment of coxarthrosis with fitted total hip prostheses replacement]

The treatment of hip osteoarthritis with total hip arthroplasty has continuously evolved since it was first introduced in the sixties. The problem of aseptic loosening of the cemented prostheses, mainly in young active patients, has stimulated two different types of research: on one side the improvement of cementing techniques and on the other side the development of cementless osteoinegrable implants. We discuss the problems of these cementless hip prostheses. Recently published anatomic and biomechanic studies have led to the development of personalized custom femoral stems for each patient. The conception technique and first clinical results are described.

Multi-segment foot kinematics after total ankle replacement and ankle arthrodesis during relatively long-distance gait.

This study aimed to investigate the influence of ankle osteoarthritis (AOA) treatments, i.e., ankle arthrodesis (AA) and total ankle replacement (TAR), on the kinematics of multi-segment foot and ankle complex during relatively long-distance gait. Forty-five subjects in four groups (AOA, AA, TAR, and control) were equipped with a wearable system consisting of inertial sensors installed on the tibia, calcaneus, and medial metatarsals. The subjects walked 50-m twice while the system measured the kinematic parameters of their multi-segment foot: the range of motion of joints between tibia, calcaneus, and medial metatarsals in three anatomical planes, and the peaks of angular velocity of these segments in the sagittal plane. These parameters were then compared among the four groups. It was observed that the range of motion and peak of angular velocities generally improved after TAR and were similar to the control subjects. However, unlike AOA and TAR, AA imposed impairments in the range of motion in the coronal plane for both the tibia-calcaneus and tibia-metatarsals joints. In general, the kinematic parameters showed significant correlation with established clinical scales (FFI and AOFAS), which shows their convergent validity. Based on the kinematic parameters of multi-segment foot during 50-m gait, this study showed significant improvements in foot mobility after TAR, but several significant impairments remained after AA.

Ambulatory measurement of ankle kinetics for clinical applications.

This study aimed to design and validate the measurement of ankle kinetics (force, moment, and power) during consecutive gait cycles and in the field using an ambulatory system. An ambulatory system consisting of plantar pressure insole and inertial sensors (3D gyroscopes and 3D accelerometers) on foot and shank was used. To test this system, 12 patients and 10 healthy elderly subjects wore shoes embedding this system and walked many times across a gait lab including a force-plate surrounded by seven cameras considered as the reference system. Then, the participants walked two 50-meter trials where only the ambulatory system was used. Ankle force components and sagittal moment of ankle measured by ambulatory system showed correlation coefficient (R) and normalized RMS error (NRMSE) of more than 0.94 and less than 13% in comparison with the references system for both patients and healthy subjects. Transverse moment of ankle and ankle power showed R>0.85 and NRMSE<23%. These parameters also showed high repeatability (CMC>0.7). In contrast, the ankle coronal moment of ankle demonstrated high error and lower repeatability. Except for ankle coronal moment, the kinetic features obtained by the ambulatory system could distinguish the patients with ankle osteoarthritis from healthy subjects when measured in 50-meter trials. The proposed ambulatory system can be easily accessible in most clinics and could assess main ankle kinetics quantities with acceptable error and repeatability for clinical evaluations. This system is therefore suggested for field measurement in clinical applications.