New biomarkers are needed to detect pleural mesothelioma at an earlier stage and to individualize treatment strategies. We investigated whether fibulin-3 in plasma and pleural effusions could meet sensitivity and specificity criteria for a robust biomarker.
We measured fibulin-3 levels in plasma (from 92 patients with mesothelioma, 136 asbestos-exposed persons without cancer, 93 patients with effusions not due to mesothelioma, and 43 healthy controls), effusions (from 74 patients with mesothelioma, 39 with benign effusions, and 54 with malignant effusions not due to mesothelioma), or both. A blinded validation was subsequently performed. Tumor tissue was examined for fibulin-3 by immunohistochemical analysis, and levels of fibulin-3 in plasma and effusions were measured with an enzyme-linked immunosorbent assay.
Plasma fibulin-3 levels did not vary according to age, sex, duration of asbestos exposure, or degree of radiographic changes and were significantly higher in patients with pleural mesothelioma (105±7 ng per milliliter in the Detroit cohort and 113±8 ng per milliliter in the New York cohort) than in asbestos-exposed persons without mesothelioma (14±1 ng per milliliter and 24±1 ng per milliliter, respectively; P<0.001). Effusion fibulin-3 levels were significantly higher in patients with pleural mesothelioma (694±37 ng per milliliter in the Detroit cohort and 636±92 ng per milliliter in the New York cohort) than in patients with effusions not due to mesothelioma (212±25 and 151±23 ng per milliliter, respectively; P<0.001). Fibulin-3 preferentially stained tumor cells in 26 of 26 samples. In an overall comparison of patients with and those without mesothelioma, the receiver-operating-characteristic curve for plasma fibulin-3 levels had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff value of 52.8 ng of fibulin-3 per milliliter. In a comparison of patients with early-stage mesothelioma with asbestos-exposed persons, the sensitivity was 100% and the specificity was 94.1% at a cutoff value of 46.0 ng of fibulin-3 per milliliter. Blinded validation revealed an area under the curve of 0.87 for plasma specimens from 96 asbestos-exposed persons as compared with 48 patients with mesothelioma.
Plasma fibulin-3 levels can distinguish healthy persons with exposure to asbestos from patients with mesothelioma. In conjunction with effusion fibulin-3 levels, plasma fibulin-3 levels can further differentiate mesothelioma effusions from other malignant and benign effusions. (Funded by the Early Detection Research Network, National Institutes of Health, and others.)
Objective. To evaluate the role of key enzymes in the methionine-homocysteine metabolism (MHM) in the physiopathology of preeclampsia (PE).
Methods. Plasma and placenta from pregnant women (32 controls and 16 PE patients) were analyzed after informed consent. Protein was quantified by western blot. RNA was obtained with RNA purification kit and was quantified by reverse transcritase followed by real-time PCR (RT-qPCR). Identification of the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and A2756G methionine synthase (MTR) SNP was performed using PCR followed by a high-resolution melting (HRM) analysis. S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH) were measured in plasma using high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). The SNP association analysis was carried out using Fisher's exact test. Statistical analysis was performed using a Mann-Whitney test. Results. RNA expression of MTHFR and MTR was significantly higher in patients with PE as compared with controls. Protein, SAM, and SAH levels showed no significant difference between preeclamptic patients and controls. No statistical differences between controls and PE patients were observed with the different SNPs studied. Conclusion. The RNA expression of MTHFR and MTR is elevated in placentas of PE patients, highlighting a potential compensation mechanism of the methionine-homocysteine metabolism in the physiopathology of this disease.
The breast cancer resistance protein, also known as ABCG2, is one of the most studied ATP-binding cassette (ABC) transporters, due to its ability to confer multidrug resistance1,2. The lack of information on the physiological roles of ABCG2 in humans severely limits cancer chemotherapeutic approaches targeting this transporter. We report here that ABCG2 comprises the molecular basis of a new blood group system (Junior, Jr), and that individuals of the Jr(a−) blood type have inherited two null alleles of ABCG2. We thus identified 5 frameshift and 3 nonsense mutations in ABCG2. Furthermore, we show that the prevalence of the Jr(a−) blood type in the Japanese and European Gypsy populations is related to the mutations p.Q126X and p.R236X, respectively. The identification of ABCG2−/− (Jr(a−)) individuals, who appear phenotypically normal, is an essential step towards targeting ABCG2 in cancer, but also understanding the physiological and pharmacological roles of this promiscuous transporter in humans.
Transforming growth factor-β (TGF-β) is a pleiotropic growth factor with broad tissue distribution that plays critical roles during embryonic development, normal tissue homeostasis, and cancer. While its cytostatic activity on normal epithelial cells initially defined TGF-β signaling as a tumor suppressor pathway, there is ample evidence indicating that TGF-β is a potent pro-tumorigenic agent, acting via autocrine and paracrine mechanisms to promote peri-tumoral angiogenesis, together with tumor cell migration, immune escape, and dissemination to metastatic sites. This review summarizes the current knowledge on the implication of TGF-β signaling in melanoma.
Melanoma; Metastasis; TGF-beta signaling; Therapeutic-targets
Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN gene (encoding for gigaxonin), which is predicted to be an E3 ligase adaptor. In GAN, aggregates of intermediate filaments (IFs) represent the main pathological feature detected in neurons and other cell types, including patients’ dermal fibroblasts. The molecular mechanism by which these mutations cause IFs to aggregate is unknown. Using fibroblasts from patients and normal individuals, as well as Gan–/– mice, we demonstrated that gigaxonin was responsible for the degradation of vimentin IFs. Gigaxonin was similarly involved in the degradation of peripherin and neurofilament IF proteins in neurons. Furthermore, proteasome inhibition by MG-132 reversed the clearance of IF proteins in cells overexpressing gigaxonin, demonstrating the involvement of the proteasomal degradation pathway. Together, these findings identify gigaxonin as a major factor in the degradation of cytoskeletal IFs and provide an explanation for IF aggregate accumulation, the subcellular hallmark of this devastating human disease.
Ex vivo perfusion of human spleens revealed innate retention of numerous cultured Plasmodium falciparum ring-infected red blood cells (ring-iRBCs). Ring-iRBC retention was confirmed by a microsphiltration device, a microbead-based technology that mimics the mechanical filtering function of the human spleen. However, the cellular alterations underpinning this retention remain unclear. Here, we use ImageStream technology to analyze infected RBCs’ morphology and cell dimensions before and after fractionation with microsphiltration. Compared to fresh normal RBCs, the mean cell membrane surface area loss of trophozoite-iRBCs, ring-iRBCs and uninfected co-cultured RBCs (uRBCs) was 14.2% (range: 8.3–21.9%), 9.6% (7.3–12.2%) and 3.7% (0–8.4), respectively. Microsphilters retained 100%, ∼50% and 4% of trophozoite-iRBCs, ring-iRBCs and uRBCs, respectively. Retained ring-iRBCs display reduced surface area values (estimated mean, range: 17%, 15–18%), similar to the previously shown threshold of surface-deficient RBCs retention in the human spleen (surface area loss: >18%). By contrast, ring-iRBCs that successfully traversed microsphilters had minimal surface area loss and normal sphericity, suggesting that these parameters are determinants of their retention. To confirm this hypothesis, fresh normal RBCs were exposed to lysophosphatidylcholine to induce a controlled loss of surface area. This resulted in a dose-dependent retention in microsphilters, with complete retention occurring for RBCs displaying >14% surface area loss. Taken together, these data demonstrate that surface area loss and resultant increased sphericity drive ring-iRBC retention in microsphilters, and contribute to splenic entrapment of a subpopulation of ring-iRBCs. These findings trigger more interest in malaria research fields, including modeling of infection kinetics, estimation of parasite load, and analysis of risk factors for severe clinical forms. The determination of the threshold of splenic retention of ring-iRBCs has significant implications for diagnosis (spleen functionality) and drug treatment (screening of adjuvant therapy targeting ring-iRBCs).
Desmoid tumors are benign, slow-growing mesenchymal tumors. Aggressiveness is local with no potential for metastasis or dedifferentiation. The treatment is challenging, particularly in the case of huge intra-abdominal locations. We, herein, report on a 21-year-old patient with a giant intra-abdominal desmoid tumor occupying substantially the entire abdominal cavity. After failure of a first-line combination of celecoxib and tamoxifen, the patient was given doxorubicin-dacarbazine chemotherapy. The treatment was well tolerated, and rapidly, the clinical digestive symptoms improved. After 6 cycles, the computed tomography scan showed a partial response (regression of tumor volume by 55%). During follow-up, the tumor continued to regress: 25 months after the end of chemotherapy, the tumor volume had regressed by 95% when compared to the start of computed tomography and by 90% when compared to the end of chemotherapy. Thirty-three months after the diagnosis, the patient is alive without any symptom. Our case provides further evidence of the remarkable efficacy of a doxorubicin-dacarbazine regimen, especially in function- or life-threatening situations where a rapid response is required. We review the literature and discuss the challenging issue regarding treatment of desmoid tumors.
Desmoid tumor; Chemotherapy; Doxorubicin; Dacarbazine
To emphasize the potentially harmful effects of high-intensity exercise on cardiac health and the fine line between physiologic and pathologic adaptation to chronic exercise in the elite athlete. This case also highlights the crucial need for regular evaluation of symptoms that suggest cardiac abnormality in athletes.
Sudden cardiac death (SCD) of young athletes is always a tragedy because they epitomize health. However, chronic, high-intensity exercise sometimes has harmful effects on cardiac health, and pathologic changes, such as myocardial fibrosis, have been observed in endurance athletes. In this case, a highly trained 30-year-old cyclist reported brief palpitations followed by presyncope feeling while exercising. Immediate investigations revealed nonsustained ventricular tachycardia originating from the left ventricle on a stress test associated with myocardial fibrosis of the left ventricle as shown with magnetic resonance imaging. Despite complete cessation of exercise, life-threatening arrhythmia and fibrosis persisted, leading to complete restriction from competition.
Hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, myocarditis, postmyocarditis, use of drugs and toxic agents, doping, and systemic disease.
The arrhythmia could not be treated with catheter ablation procedure or drug suppression. Therefore, the athlete was instructed to withdraw completely from sport participation and to have a medical follow-up twice each year.
To our knowledge, no other report of left ventricle exercise-induced fibrosis associated with life-threatening arrhythmia in a living young elite athlete exists. Only postmortem evidence supports such myocardial pathologic adaptation to exercise.
To prevent SCD in young athletes, careful attention must be paid to exercise-related symptoms that suggest a cardiac abnormality because they more often are linked to life-threatening cardiovascular disease.
myocardial fibrosis; high-intensity exercise; sudden death
Investigating long-term cardiac effects of low doses of ionizing radiation is highly relevant in the context of interventional cardiology and radiotherapy. Epidemiological data report that low doses of irradiation to the heart can result in significant increase in the cardiovascular mortality by yet unknown mechanisms. In addition co-morbidity factor such as hypertension or/and atherosclerosis can enhance cardiac complications. Therefore, we explored the mechanisms that lead to long-term cardiac remodelling and investigated the interaction of radiation-induced damage to heart and cardiovascular systems with atherosclerosis, using wild-type and ApoE-deficient mice.
Methods and Results
ApoE−/− and wild-type mice were locally irradiated to the heart at 0, 0.2 and 2 Gy (RX). Twenty, 40 and 60 weeks post-irradiation, echocardiography were performed and hearts were collected for cardiomyocyte isolation, histopathological analysis, study of inflammatory infiltration and fibrosis deposition. Common and strain-specific pathogenic pathways were found. Significant alteration of left ventricular function (eccentric hypertrophy) occurred in both strains of mice. Low dose irradiation (0.2 Gy) induced premature death in ApoE−/− mice (47% died at 20 weeks). Acute inflammatory infiltrate was observed in scarring areas with accumulation of M1-macrophages and secretion of IL-6. Increased expression of the fibrogenic factors (TGF-β1 and PAI-1) was measured earlier in cardiomyocytes isolated from ApoE−/− than in wt animals.
The present study shows that cardiac exposure to low dose of ionizing radiation induce significant physiological, histopathological, cellular and molecular alterations in irradiated heart with mild functional impairment. Atherosclerotic predisposition precipitated cardiac damage induced by low doses with an early pro-inflammatory polarization of macrophages.
Alternative splicing plays a major role in the adaptation of cardiac function exemplified by the isoform switch of titin, which adjusts ventricular filling. We previously identified a rat strain deficient in titin splicing. Using genetic mapping, we found a loss-of-function mutation in RBM20 as the underlying cause for the pathological titin isoform expression. Mutations in human RBM20 have previously been shown to cause dilated cardiomyopathy. We showed that the phenotype of Rbm20 deficient rats resembles the human pathology. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20 dependent regulation of alternative splicing. Additionally to titin we identified a set of 30 genes with conserved regulation between human and rat. This network is enriched for genes previously linked to cardiomyopathy, ion-homeostasis, and sarcomere biology. Our studies emphasize the importance of posttranscriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure.
The low-density lipoprotein receptor-related protein 1 (LRP-1) is a large endocytic receptor mediating the clearance of various molecules from the extracellular matrix. In the field of cancer, LRP-1-mediated endocytosis was first associated with antitumor properties. However, recent results suggested that LRP-1 may coordinate the adhesion-deadhesion balance in malignant cells to support tumor progression. Here, we observed that LRP-1 silencing or RAP (receptor-associated protein) treatment led to accumulation of CD44 at the tumor cell surface. Moreover, we evidenced a tight interaction between CD44 and LRP-1, not exclusively localized in lipid rafts. Overexpression of LRP-1-derived minireceptors indicated that the fourth ligand-binding cluster of LRP-1 is required to bind CD44. Labeling of CD44 with EEA1 and LAMP-1 showed that internalized CD44 is routed through early endosomes toward lysosomes in a LRP-1-dependent pathway. LRP-1-mediated internalization of CD44 was highly reduced under hyperosmotic conditions but poorly affected by membrane cholesterol depletion, revealing that it proceeds mostly via clathrin-coated pits. Finally, we demonstrated that CD44 silencing abolishes RAP-induced tumor cell attachment, revealing that cell surface accumulation of CD44 under LRP-1 blockade is mainly responsible for the stimulation of tumor cell adhesion. Altogether, our data shed light on the LRP-1-mediated internalization of CD44 that appeared critical to define the adhesive properties of tumor cells.
Cross-talk between NK cells and dendritic cells (DCs) is critical for the potent therapeutic response to dsRNA, but the receptors involved remained controversial. We show in this paper that two dsRNAs, polyadenylic-polyuridylic acid and polyinosinic-polycytidylic acid [poly(I:C)], similarly engaged human TLR3, whereas only poly(I:C) triggered human RIG-I and MDA5. Both dsRNA enhanced NK cell activation within PBMCs but only poly(I:C) induced IFN-γ. Although myeloid DCs (mDCs) were required for NK cell activation, induction of cytolytic potential and IFN-γ production did not require contact with mDCs but was dependent on type I IFN and IL-12, respectively. Poly(I:C) but not polyadenylic-polyuridylic acid synergized with mDC-derived IL-12 for IFN-γ production by acting directly on NK cells. Finally, the requirement of both TLR3 and Rig-like receptor (RLR) on mDCs and RLRs but not TLR3 on NK cells for IFN-γ production was demonstrated using TLR3- and Cardif-deficient mice and human RIG-I–specific activator. Thus, we report the requirement of cotriggering TLR3 and RLR on mDCs and RLRs on NK cells for a pathogen product to induce potent innate cell activation.
Fibromyalgia (FM) is a condition characterized by widespread pain and is estimated to affect 0.5-5% of the general population. Historically, it has been classified as a rheumatologic disorder, but patients consult physicians from a variety of specialties in seeking diagnosis and ultimately treatment. Patients report considerable delay in receiving a diagnosis after initial presentation, suggesting diagnosis and management of FM might be a challenge to physicians.
A questionnaire survey of 1622 physicians in six European countries, Mexico and South Korea was conducted. Specialties surveyed included primary care physicians (PCPs; n=809) and equal numbers of rheumatologists, neurologists, psychiatrists and pain specialists.
The sample included experienced doctors, with an expected clinical caseload for their specialty. Most (>80%) had seen a patient with FM in the last 2 years. Overall, 53% of physicians reported difficulty with diagnosing FM, 54% reported their training in FM was inadequate, and 32% considered themselves not knowledgeable about FM. Awareness of American College of Rheumatology classification criteria ranged from 32% for psychiatrists to 83% for rheumatologists. Sixty-four percent agreed patients found it difficult to communicate FM symptoms, and 79% said they needed to spend more time to identify FM. Thirty-eight percent were not confident in recognizing the symptoms of FM, and 48% were not confident in differentiating FM from conditions with similar symptoms. Thirty-seven percent were not confident developing an FM treatment plan, and 37% were not confident managing FM patients long-term. In general, rheumatologists reported least difficulties/greatest confidence, and PCPs and psychiatrists reported greatest difficulties/least confidence.
Diagnosis and managing FM is challenging for physicians, especially PCPs and psychiatrists, but other specialties, including rheumatologists, also express difficulties. Improved training in FM and initiatives to improve patient-doctor communication are needed and may help the management of this condition.
Waldenström's macroglobulinemia (WM) is a clonal B-cell lymphoproliferative disorder (LPD) of post-germinal center nature. Despite the fact that the precise molecular pathway(s) leading to WM remain(s) to be elucidated, a hallmark of the disease is the absence of the immunoglobulin heavy chain class switch recombination. Using two-dimensional gel electrophoresis, we compared proteomic profiles of WM cells with that of other LPDs. We were able to demonstrate that WM constitutes a unique proteomic entity as compared with chronic lymphocytic leukemia and marginal zone lymphoma. Statistical comparisons of protein expression levels revealed that a few proteins are distinctly expressed in WM in comparison with other LPDs. In particular we observed a major downregulation of the double strand repair protein Ku70 (XRCC6); confirmed at both the protein and RNA levels in an independent cohort of patients. Hence, we define a distinctive proteomic profile for WM where the downregulation of Ku70—a component of the non homologous end-joining pathway—might be relevant in disease pathophysiology.
Waldenström macroglobulinemia; proteomics; 2D-electrophoresis; XRCC6
Bacterial biofilms are complex cell communities found attached to surfaces and surrounded by an extracellular matrix composed of exopolysaccharides, DNA, and proteins. We investigated the whole-genome expression profile of Pseudomonas aeruginosa sessile cells (SCs) present in biofilms developed on a glass wool substratum. The transcriptome and proteome of SCs were compared with those of planktonic cell cultures. Principal component analysis revealed a biofilm-specific gene expression profile. Our study highlighted the overexpression of genes controlling the anthranilate degradation pathway in the SCs grown on glass wool for 24 h. In this condition, the metabolic pathway that uses anthranilate for Pseudomonas quinolone signal production was not activated, which suggested that anthranilate was primarily being consumed for energy metabolism. Transposon mutants defective for anthranilate degradation were analyzed in a simple assay of biofilm formation. The phenotypic analyses confirmed that P. aeruginosa biofilm formation partially depended on the activity of the anthranilate degradation pathway. This work points to a new feature concerning anthranilate metabolism in P. aeruginosa SCs.
Anthranilate degradation; biofilm; glass wool; Pseudomonas aeruginosa
Proteins exported by Plasmodium falciparum to the red blood cell (RBC) membrane modify the structural properties of the parasitized RBC (Pf-RBC). Although quasi-static single cell assays show reduced ring-stage Pf-RBCs deformability, the parameters influencing their microcirculatory behavior remain unexplored. Here, we study the dynamic properties of ring-stage Pf-RBCs and the role of the parasite protein Pf155/Ring-Infected Erythrocyte Surface Antigen (RESA). Diffraction phase microscopy revealed RESA-driven decreased Pf-RBCs membrane fluctuations. Microfluidic experiments showed a RESA-dependent reduction in the Pf-RBCs transit velocity, which was potentiated at febrile temperature. In a microspheres filtration system, incubation at febrile temperature impaired traversal of RESA-expressing Pf-RBCs. These results show that RESA influences ring-stage Pf-RBCs microcirculation, an effect that is fever-enhanced. This is the first identification of a parasite factor influencing the dynamic circulation of young asexual Pf-RBCs in physiologically relevant conditions, offering novel possibilities for interventions to reduce parasite survival and pathogenesis in its human host.
Pain is the most common reason patients seek medical attention and pain relief has been put forward as an ethical obligation of clinicians and a fundamental human right. However, pain management is challenging because the pathophysiology of pain is complex and not completely understood. Widely used analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen) have been associated with adverse events. Adverse event rates are of concern, especially in long-term treatment or at high doses. Paracetamol and NSAIDs are available by prescription, over the counter, and in combination preparations. Patients may be unaware of the risk associated with high dosages or long-term use of paracetamol and NSAIDs. Clinicians should encourage patients to disclose all medications they take in a “do ask, do tell” approach that includes patient education about the risks and benefits of common pain relievers. The ideal pain reliever would have few risks and enhanced analgesic efficacy. Fixed-dose combination analgesics with two or more agents may offer additive or synergistic benefits to treat the multiple mechanisms of pain. Therefore, pain may be effectively treated while toxicity is reduced due to lower doses. One recent fixed-dose combination analgesic product combines tramadol, a centrally acting weak opioid analgesic, with low-dose paracetamol. Evidence-based guidelines recognize the potential value of combination analgesics in specific situations. The current guideline-based paradigm for pain treatment recommends NSAIDs for ongoing use with analgesics such as opioids to manage flares. However, the treatment model should evolve how to use low-dose combination products to manage pain with occasional use of NSAIDs for flares to avoid long-term and high-dose treatment with these analgesics. A next step in pain management guidelines should be targeted therapy when possible, or low-dose combination therapy or both, to achieve maximal efficacy with minimal toxicity.
NSAIDs; opioids; combination analgesics; moderate pain; severe pain; analgesics; tramadol/paracetamol
The existence of multiple VEGF-A isoforms raised the possibility that they may have distinct functions in tumor growth. We have previously published that VEGF189 and VEGF165 contribute to breast cancer progression and angiogenesis, but VEGF165 induced the most rapid tumor uptake. Since VEGF165 has been described as a survival factor for breast tumor cells, we questioned here the effects of VEGF189 on the survival/apoptosis of MDA-MB-231 cells. We used clones that overexpress VEGF189 (V189) or VEGF165 (V165) isoforms and compared them to a control one (cV). Overexpression of VEGF189 resulted in increased cell apoptosis, as determined by Annexin-V apoptosis assay, under serum starvation and doxorubicin treatment, while VEGF 165 was confirmed to be a survival factor. Since MDA-MB-231 highly express NRP1 (a co-receptor for VEGF-A), we used short hairpin RNA (shRNA) to knock down NRP1 expression. V189shNRP1 clones were characterized by reduced apoptosis and higher necrosis, as compared with V189shCtl, under stress conditions. Unexpectedly, NRP1 knockdown had no effect on the survival or apoptosis of V165 cells. VEGF189 showed greater affinity toward NRP1 than VEGF165 using a BIAcore binding assay. Finally, since endogenously produced urokinase-type plasminogen (uPA) has been found to prevent apoptosis in breast cancers, we analyzed the level of uPA activity in our clones. An inhibition of uPA activity was observed in V189shNRP1 clones. Altogether, these results suggest a major role of NRP1 in apoptosis induced by VEGF189 in stress conditions and confirm VEGF165 as a survival factor.
VEGF isoforms; survival; apoptosis; NRP-1; breast cancer cells
Short accessory pathway (AP) effective refractory period (ERP) is one of the risk factors in Wolff-Parkinson-White syndrome (WPW). The purpose of study was to evaluate the reproducibility of APERP measurement during a same electrophysiological study (EPS).
EPS consisted of 2 APERP measurements performed prospectively in 77 patients for a WPW in control state (CS) at a cycle length of 400 ms (n=76) and after isoproterenol (n=56).
In CS, 18 patients (24 %) had the same APERP at both measurements; 41 (54.6 %) had differences from 10 to 40 ms, 17 (22.4 %) had differences > 40 ms. Among 45 patients with initial APERP > 240 ms, 7 had an APERP ≤ 240 ms at 2nd study. Among 31 patients with initial APERP ≤ 240 ms, 5 had an APERP > 240 ms at 2nd study. Pearson's product-moment correlation was 0.75. After isoproterenol, 5 patients (9 %) had the same APERPs; 37 (66 %) had differences from 10 to 40 ms and 14 had differences > 40 ms. Among 38 patients with initial APERP > 200 ms, 12 had an AP ERP ≤ 200 ms at 2nd study. Among 18 patients with initial APERP ≤ 200 ms, 10 had still APERP ≤ 200 ms at 2nd study. Pearson's product-moment correlation was 0.54.
There are important variations of APERPs during EPS mainly after isoproterenol infusion. Therefore the values of APERPs should be interpreted cautiously.
Wolff-Parkinson-White syndrome; accessory pathway; electrophysiology
Solitary fibrous tumors (SFTs) are mesenchymal neoplasms of fibroblastic origin, most commonly found in the pleura. Numerous extrathoracic locations have been reported during the last 2 decades. Herein, we report the first case of an SFT in the round ligament of the liver. A 46-year-old Caucasian man presented with a 12-month history of abdominal pain. An ultrasonography-guided microbiopsy first revealed a desmoid tumor. After failure of first- and second-line medical treatments (celecoxib and tamoxifen, then imatinib), histological reexamination was suspicious for a low-grade sarcoma. MRI was also suspicious for a malignant process. Hence, surgery was decided. Laparotomy found a huge and well-limited tumor that, unexpectedly, was appended to the round ligament of the liver and free from any other intra-abdominal contact. The tumor was easily removed. Excision was monobloc and macroscopically complete. Histological analysis diagnosed an SFT arising from the round ligament of the liver. No adjuvant treatment was given. Ten months after surgery, the patient is alive without any signs or symptoms of relapse. This is the first report of SFT arising from the round ligament of the liver. It illustrates the difficulty in diagnosing such tumors. Whilst diagnosis of SFT is rare, it should be kept in mind to allow early diagnosis and complete surgical resection, which provide the best chance for recovery.
Solitary fibrous tumors; Liver; Round ligament
The contribution of savannas to global carbon storage is poorly understood, in part due to lack of knowledge of the amount of belowground biomass. In these ecosystems, the coexistence of woody and herbaceous life forms is often explained on the basis of belowground interactions among roots. However, the distribution of root biomass in savannas has seldom been investigated, and the dependence of root biomass on rainfall regime remains unclear, particularly for woody plants. Here we investigate patterns of belowground woody biomass along a rainfall gradient in the Kalahari of southern Africa, a region with consistent sandy soils. We test the hypotheses that (1) the root depth increases with mean annual precipitation (root optimality and plant hydrotropism hypothesis), and (2) the root-to-shoot ratio increases with decreasing mean annual rainfall (functional equilibrium hypothesis). Both hypotheses have been previously assessed for herbaceous vegetation using global root data sets. Our data do not support these hypotheses for the case of woody plants in savannas. We find that in the Kalahari, the root profiles of woody plants do not become deeper with increasing mean annual precipitation, whereas the root-to-shoot ratios decrease along a gradient of increasing aridity.
Patients with fibromyalgia (FM) report widespread pain, fatigue, and other functional limitations. This study aimed to provide an assessment of the burden of illness associated with FM in France and its association with disease severity and core domains as defined by Outcome Measures in Rheumatology Clinical Trials (OMERACT) for FM.
This cross-sectional, observational study recruited patients with a prior diagnosis of FM from 18 community-based physician offices in France. Patients completed questions about FM impact (Fibromyalgia-Impact Questionnaire [FIQ]), core symptoms (defined by OMERACT), health-related quality of life (EQ-5D), current overall health status (rated on a scale from 0 to 100), productivity, treatment satisfaction, and out-of-pocket expenses related to FM. Site staff recorded patients' treatment and health resource use based on medical record review. Costs were extrapolated from 4-week patient-reported data and 3-month clinical case report form data and calculated in 2008 Euros using a societal perspective. Tests of significance used the Kruskal-Wallis test or Fisher's Exact test where P < 0.05 was considered significant.
Eighty-eight patients (mean 55.2 y; female:male 74:14) were recruited. The majority of patients (84.1%) were prescribed medications for FM. Patients mainly described medications as a little/not at all effective (40.0%) or somewhat effective (52.9%). Current Overall Health rating was 52.9 (± 17.8) and FIQ total score was 54.8 (± 17.3). FIQ total score was used to define FM severity, and 17 patients scored 0- < 39 (mild FM), 33 patients 39- < 59 (moderate FM), and 38 scored 59-100 (severe FM). As FM severity level worsened, patients had poorer overall health status and perceived their prescription medications to be less effective. Average cost/FM patient was higher for severe (€10,087) vs. moderate (€6,633) or mild FM (€5,473); however, the difference was not significant.
In a sample of 88 patients with FM from France, we found that FM poses a substantial economic and human burden on patients and society. FM severity level was significantly associated with patients' health status and core symptom domains.
Burden of illness; Fibromyalgia; France; Quality of life; Healthcare costs; Outcome Measures in Rheumatology Clinical Trials (OMERACT)