Magnetic resonance imaging of Hoffa's fat pad and relevance for osteoarthritis research: a narrative review.

OBJECTIVE: To give an illustrative overview of Hoffa's fat pad pathology with a radiologic emphasis on the anatomy, on technical considerations, and on imaging differential diagnoses in the context of osteoarthritis (OA) imaging research. DESIGN: A PubMed database search including only English literature and covering a 20 year period was performed. The search was based on but no limited to the query terms "Hoffa", "Hoffa's fat pad" or "infrapatellar fat pad (IPFP)" in combination with "synovitis", "OA", and "magnetic resonance imaging (MRI)". The literature search yielded 289 publications that were screened for relevance; additional references were included when these were considered of importance. RESULTS: Several anatomic variants and pathologic conditions may be encountered when assessing Hoffa's fat pad including tumors and tumor-like lesions such as osteochondroma, tenosynovial giant cell tumor (TGCT) (and pigmented nodular synovitis) and arthrofibrosis, traumatic changes including contusions and anatomic variants such as recesses. The latter may be accountable for differences in cross-sectional area or volume changes over time. Signal changes are commonly used in OA research as surrogate markers for synovitis but are non-specific findings. CONCLUSIONS: Quantitative approaches to evaluate 3D parameters of Hoffa's fat pad are increasingly applied and their role in regard to structural progression and clinical manifestations of disease needs to be further elucidated. In applying such approaches, knowledge of the detailed anatomy and potential pitfalls that may be a result of anatomical variants, inflammatory disease manifestations and additional diverse pathologies encountered seems to be paramount.

Baseline radiographic osteoarthritis and semi-quantitatively assessed meniscal damage and extrusion and cartilage damage on MRI is related to quantitatively defined cartilage thickness loss in knee osteoarthritis: the Multicenter Osteoarthritis Study.

OBJECTIVES: To provide a comprehensive simultaneous relation of various semiquantitative knee OA MRI features as well as the presence of baseline radiographic osteoarthritis (OA) to quantitative longitudinal cartilage loss. METHODS: We studied Multicenter OA Study (MOST) participants from a longitudinal observational study that included quantitative MRI measurement of cartilage thickness. These subjects also had Whole Organ MRI Score (WORMS) scoring of cartilage damage, bone marrow lesions (BMLs), meniscal pathology, and synovitis, as well as baseline radiographic evaluation for Kellgren and Lawrence (KL) grading. Knee compartments were classified as progressors when exceeding thresholds of measurement variability in normal knees. All potential risk factors of cartilage loss were dichotomized into "present" (score ≥2 for cartilage, ≥1 for others) or "absent". Differences in baseline scores of ipsi-compartmental risk factors were compared between progressor and non-progressor knees by multivariable logistic regression, adjusting for age, sex, body mass index, alignment axis (degrees) and baseline KL grade. Odds ratios (OR) and 95% CIs were calculated for medial femorotibial compartment (MFTC) and lateral femorotibial compartment (LFTC) cartilage loss. Cartilage loss across both compartments was studied using Generalized Estimating Equations. RESULTS: 196 knees of 196 participants were included (age 59.8 ± 6.3 years [mean ± SD], BMI 29.5 ± 4.6, 62% women). For combined analyses of MFTC and LFTC, baseline factors related to cartilage loss were radiographic OA (KL grade ≥2: aOR 4.8 [2.4-9.5], cartilage damage (aOR 2.3 [1.2-4.4])), meniscal damage (aOR 3.9 [2.1-7.4]) and extrusion (aOR 2.9 [1.6-5.3]), all in the ipsilateral compartment, but not BMLs or synovitis. CONCLUSION: Baseline radiographic OA and semiquantitatively (SQ) assessed MRI-detected cartilage damage, meniscal damage and extrusion, but not BMLs or synovitis is related to quantitatively measured ipsi-compartmental cartilage thinning over 30 months.

Severe radiographic knee osteoarthritis--does Kellgren and Lawrence grade 4 represent end stage disease?--the MOST study.

OBJECTIVE: To determine what MRI-detectable osteoarthritis features that are not visualized on radiography demonstrate progression longitudinally in Kellgren and Lawrence (KL) grade 4 knees. METHODS: We studied subjects from the Multicenter Osteoarthritis Study who had KL grade 4 knees at baseline and had baseline and 30-month MRI. Cartilage damage, bone marrow lesions (BMLs), meniscal damage, synovitis (signal changes in Hoffa fat pad), and effusion (fluid equivalent signal in the joint cavity) were semiquantitatively scored using the Whole Organ MRI Score (WORMS) system in five subregions of the medial and lateral tibiofemoral (TF) compartments. Analysis was performed for the compartment showing bone-on-bone appearance ("index") on radiograph and also for the other TF compartment of the same knee. Synovitis and effusion were assessed for the whole knee. Changes in scores at follow-up were noted for each feature. For cartilage and BML, within-grade changes were also recorded. RESULTS: 140 subjects (164 knees) were included (50% women, mean age 66.0 ± 8.6 years, mean BMI 30.4 ± 5.1 kg/m(2)). Longitudinally, 51 index compartments (34%) showed an increase in the sum of cartilage scores from all subregions. In the other compartment, 25% showed an increase in the sum score for cartilage damage. For BMLs in the index compartment, 50 knees (33%) showed an increase in maximum score and 32 (21%) showed a decrease. Meniscal status mostly remained stable. Effusion worsened in 36 knees (25%) and improved in 13 knees (9%). Synovitis worsened in 14 knees (10%) and improved in six knees (4%). CONCLUSION: In KL grade 4 knees, MRI-detected cartilage loss and fluctuation of BMLs, effusion, and synovitis occurred frequently over a 30-month period.

Smoking status and its relationship with exercise capacity, physical activity in daily life and quality of life in physically independent, elderly individuals.

OBJECTIVE: To investigate the relationship between smoking status and exercise capacity, physical activity in daily life and health-related quality of life in physically independent, elderly (≥60 years) individuals. DESIGN: Cross-sectional, observational study. SETTING: Community-dwelling, elderly individuals. PARTICIPANTS: One hundred and fifty-four elderly individuals were categorised into four groups according to their smoking status: never smokers (n=57), passive smokers (n=30), ex-smokers (n=45) and current smokers (n=22). MAIN OUTCOME MEASURES: Exercise capacity [6-minute walk test (6MWT)], physical activity in daily life (step counting) and health-related quality of life [36-Item Short Form Health Survey (SF-36) questionnaire] were assessed. RESULTS: Current and ex-smokers had lower mean exercise capacity compared with never smokers: 90 [standard deviation (SD) 10] % predicted, 91 (SD 12) % predicted and 100 (SD 13) % predicted distance on 6MWT, respectively [mean differences -9.8%, 95% confidence intervals (CI) -17.8 to -1.8 and -9.1%, 95% CI -15.4 to -2.7, respectively; P<0.05 for both]. The level of physical activity did not differ between the groups, but was found to correlate negatively with the level of nicotine dependence in current smokers (r=-0.47, P=0.03). The median score for the mental health dimension of SF-36 was worse in passive {72 [interquartile range (IQR) 56 to 96] points} and current [76 (IQR 55 to 80) points] smokers compared with ex-smokers [88 (IQR 70 to 100) points] (median differences -16 points, 95% CI -22.2 to -3.0 and -12 points, 95% CI -22.8 to -2.4, respectively; P<0.05 for both). CONCLUSIONS: Among elderly individuals, current smokers had lower exercise capacity than never smokers. Although the level of physical activity did not differ between the groups, an association was found with smoking. Tobacco exposure was associated with worse scores for the mental health dimension of SF-36 in physically independent, elderly individuals.

Susceptibility artifacts detected on 3T MRI of the knee: frequency, change over time and associations with radiographic findings: data from the joints on glucosamine study.

OBJECTIVE: To determine the prevalence of intraarticular susceptibility artifacts and to detect longitudinal changes in the artifacts, on 3T magnetic resonance imaging (MRI) of the knee in a cohort of patients with knee pain, and to assess the association of susceptibility artifacts with radiographic intraarticular calcifications. DESIGN: Three hundred and forty-six knees of 177 subjects aged 35-65 were included. 3T MRI was performed at baseline and at 6 months. Baseline radiographs were assessed for presence/absence of linear/punctate calcifications within the tibiofemoral joint (TFJ) space. Corresponding MRIs were assessed for susceptibility artifacts (i.e., linear/punctate hypointensities) in the TFJ space on coronal dual-echo steady-state (DESS) sequences. Kappa statistics were applied to determine agreement between findings on baseline DESS and radiography. Changes in artifacts over time were recorded. RESULTS: In the medial compartment, 13 (4%) of the knees showed susceptibility artifacts at baseline. Six knees had persistent artifacts and six knees had incident artifacts at follow-up. Agreement between DESS and radiography was κ = 0.18 (-0.15, 0.51) in the medial compartment. Frequency of artifacts in the lateral compartment was low (2%). CONCLUSION: Susceptibility artifacts detected on knee MRI are not frequent, and likely correspond to vacuum phenomena as they commonly change over time and are not associated with intraarticular calcifications. Radiologists should be aware of these artifacts as they can interfere with cartilage segmentation.

Knee malalignment is associated with an increased risk for incident and enlarging bone marrow lesions in the more loaded compartments: the MOST study.

OBJECTIVE: To examine the relationship of knee malalignment with occurrence of incident and enlarging bone marrow lesions (BMLs) and regression of BMLs. METHODS: Subjects from the Multicenter Osteoarthritis Study aged 50-79 years with or at high risk of knee osteoarthritis were studied. Full-limb radiographs were taken at baseline and hip-knee-ankle mechanical axis was measured. Baseline and 30-month magnetic resonance imaging (MRI) of knees (n = 1782) were semiquantitatively assessed for BMLs. Outcome was defined as a change in BML score in femoral/tibial condyle in medial/lateral compartments. Medial compartment in varus alignment and lateral compartment in valgus alignment were combined to form 'more loaded' compartment, while lateral compartment in valgus and medial compartment in varus were combined to form 'less loaded' compartment. Relative risk (RR) of BML score increase or decrease in relation to malalignment was estimated using a log linear regression model with the Poisson assumption, adjusting for age, gender, body mass index, physical activity scale for the elderly, race and clinic site. Further, results were stratified by ipsilateral meniscal and cartilage status at baseline. RESULTS: Baseline varus alignment was associated with higher risk of BML score increase from baseline to follow-up in the medial compartment [adjusted RRs (95%CI): 1.5 (1.2-1.9)] and valgus alignment in the lateral compartment [1.4 (1.0-2.1)]. Increase in BML score was more likely in the more loaded compartments [1.7 (1.4-2.0)] in malaligned knees. Regardless of ipsilateral cartilage or meniscus status, adjusted RR for BML score increase was higher in the more loaded compartments of malaligned knees than those with neutral alignment. Decrease in BML score was less likely in the more loaded compartments in malaligned knees [0.8 (0.7-1.0)]. CONCLUSION: Knee malalignment is associated with increased risk of incident and enlarging BMLs in the more loaded compartments of the tibiofemoral joint.

Osteoarthritis year 2011 in review: imaging in OA--a radiologists' perspective.

With major technological advances and application of magnetic resonance imaging (MRI) to large longitudinal osteoarthritis (OA) studies the role of imaging has become increasingly important for OA research over the last years. Currently, radiography, MRI and ultrasound are the most established imaging tools applied in a research setting. MRI assessment of OA features can be morphologic, compositional and can be applied in non-loaded and loaded conditions. Morphologic assessment includes semiquantitative and quantitative analyses. Novel semiquantitative scoring methods for knee, hip and hand OA using MRI were introduced. A series of key reports were published this year, reviewing the importance of radiography and MRI as a research tool. Although radiography is insensitive for the detection of OA-related structural pathology when compared to MRI, it still has been widely used for subject inclusion in observational and interventional studies due also to a straight forward disease definition that was established more than 50 years ago. In an attempt to generate an MRI-based definition of structural disease, a Delphi exercise was performed to develop a testable MRI definition of structural OA. This presentation reviews publications related to imaging of OA, published in English between September 2010 and October 2011, excluding animal studies or in vitro data. This is not a systematic or comprehensive review and the selection of papers included is based on the expert opinions of the presenter, from a musculoskeletal radiologist's perspective.

Osteoarthritis year 2010 in review: imaging.

Osteoarthritis (OA) is no longer viewed as a passive, degenerative disorder, but rather an active disease process driven primarily by mechanical factors. OA should also be conceptualized as a disease of a whole joint organ, and therefore imaging of OA requires techniques which enable us to visualize the whole joint organ. Although clinical decision making based on imaging findings remains controversial the importance of imaging-derived data in OA research cannot be overemphasized. Since mid-2009, numerous publications reporting on imaging-oriented studies on OA have been reported. These include magnetic resonance (MR) imaging of numerous features of the whole joint such as synovitis, subchondral bone, meniscus, cartilage and cyst-like lesions. Active research is also ongoing using conventional radiography with a focus on measurements of joint space width and alignment of the knee joint. Ultrasound is emerging as a useful imaging technique, particularly in the field of hand OA research. As the importance of imaging-derived data increases, all potential authors are advised that they should seek opinions from expert musculoskeletal radiologist to ascertain the application of correct imaging techniques, especially the MR pulse sequences and image interpretation. The peer-review process of OA imaging in any journal, therefore, should involve musculoskeletal radiologists experienced in OA research to ensure the publication of papers with scientifically sound contents.

Cyst-like lesions of the knee joint and their relation to incident knee pain and development of radiographic osteoarthritis: the MOST study.

OBJECTIVE: To determine whether intra- and periarticular cyst-like lesions of the knee are associated with incident knee pain and incident radiographic knee osteoarthritis (OA). DESIGN: The Multicenter Osteoarthritis (MOST) Study is a cohort of individuals who have or are at high risk for knee OA. Using a nested case-control study design, we investigated the associations of cyst-like lesions (Baker's, meniscal and proximal tibiofibular joint (PTFJ) cysts, and prepatellar and anserine bursitides) with (1) incident pain at 15- or 30-month follow-up and (2) incident radiographic OA at 30-month follow-up. Baseline cyst-like lesions were scored semiquantitatively using the Whole Organ Magnetic Resonance Imaging Score (WORMS). Conditional logistic regression models were used to assess the relation between these lesions and the outcomes, adjusting for potential confounding factors (i.e., cartilage loss, meniscal damage, bone marrow lesions, synovitis and joint effusion, which were also scored using WORMS). RESULTS: Incident knee pain study included 157 cases and 336 controls. Prevalence of meniscal and PTFJ cysts in the case group was twice that in the control group [9 (6%) vs 9 (3%) and 9 (6%) vs 10 (3%), respectively]. Incident radiographic OA study included 149 cases and 298 controls. Prevalence of grade 2 Baker's cysts and PTFJ cysts in the case group was approximately four times that in the control group [16(11%) vs 9 (3%) and 6 (4%) vs 3 (1%), respectively]. However, none of the cyst-like lesions was associated with incident pain or radiographic OA after fully adjusted logistic regression analyses and correction of P-values for multiple comparisons. CONCLUSION: None of the analyzed lesions was an independent predictor of incident knee pain or radiographic OA. Intra- and periarticular cyst-like lesions are likely to be a secondary phenomenon seen in painful or OA-affected knees, rather than a primary trigger for incident knee pain or radiographic OA.

Volumetric and semiquantitative assessment of MRI-detected subchondral bone marrow lesions in knee osteoarthritis: a comparison of contrast-enhanced and non-enhanced imaging.

OBJECTIVE: Aim was to compare volumetric and semi-quantitative (SQ) measurements of subchondral bone marrow lesions (BMLs) on non-fat-suppressed (FS) T1-weighted (w), T1-w FS contrast enhanced (CE) and proton density (PD)-w FS images in order to define which sequence depicts the lesions to their maximum extent and if T1-w FS CE images and PD-w FS images may be used interchangeably to assess BMLs in a volumetric or SQ fashion. DESIGN: Thirty-two patients with clinical knee osteoarthritis (OA) were scanned on a standard 1.5 T MRI system. A total of 47 BMLs were identified and were manually segmented on all three sequences. BMLs were also assessed semiquantitatively using the Whole Organ Magnetic Resonance Imaging Score (WORMS). The volumetric and SQ results were compared across the three imaging sequences using paired t-tests. RESULTS: Eighty-three percent of the lesions appeared largest on the PD-w FS sequence. Significant differences were observed for volumetric measurements between all three sequences (P < 0.001), however the mean volume difference between PD-w FS and T1-w FS CE (38%) was much smaller than for non-FS T1-w and PD-w FS/T1-w FS CE sequences (195% and 114%, respectively). Significant differences in WORMS scores were noted between PD-w FS and non-FS T1-w images and between T1-w FS CE and non-FS T1-w images (P < 0.001), but no significant difference was observed between PD-w FS and T1-w FS CE images. CONCLUSION: Our findings suggest that the T1-w FS CE and PD-w FS sequences may be interchangeably used for quantitative volumetric and SQ assessment of BMLs.

Follicular non-Hodgkin's lymphoma.

Follicular non-Hodgkin's lymphoma (NHL) is a unique subtype of NHL, which is indolent, incurable with a high prevalence of residual mass after treatment, and may transform to more aggressive NHL. The aim of this review is to (1) describe the histological and flow cytometry characteristics of follicular NHL; (2) introduce the Follicular Lymphoma International Prognostic Index 2 (FLIPI-2), which allows better treatment selection and patient stratification for clinical trials; (3) illustrate the classic and atypical ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET)/CT appearance of follicular NHL; and (4) characterize the appearance of nodal and extranodal follicular NHL with pathological correlation. Imaging is essential in every step of the management of patients with follicular lymphoma. Overall survival is improved with better predictive tools and new targeted biological therapies. Radiologists should be aware of possible active residual mass, indolent recurrence, transformation, and association with other primary cancers in patients treated for follicular lymphoma.

Cow's milk increases the activities of human nuclear receptors peroxisome proliferator-activated receptors alpha and delta and retinoid X receptor alpha involved in the regulation of energy homeostasis, obesity, and inflammation.

The nuclear peroxisome proliferator-activated receptors (PPAR) have been shown to play crucial roles in regulating energy homeostasis including lipid and carbohydrate metabolism, inflammatory responses, and cell proliferation, differentiation, and survival. Because PPAR agonists have the potential to prevent or ameliorate diseases such as hyperlipidemia, diabetes, atherosclerosis, and obesity, we have explored new natural agonists for PPAR. For this purpose, cow's milk was tested for agonistic activity toward human PPAR subtypes using a reporter gene assay. Milk increased human PPARalpha activity in a dose-dependent manner with a 3.2-fold increase at 0.5% (vol/vol). It also enhanced human PPARdelta activity in a dose-dependent manner with an 11.5-fold increase at 0.5%. However, it only slightly affected human PPARgamma activity. Ice cream, butter, and yogurt also increased the activities of PPARalpha and PPARdelta, whereas vegetable cream affected activity of PPARdelta but not PPARalpha. Skim milk enhanced the activity of PPAR to a lesser degree than regular milk. Milk and fresh cream increased the activity of human retinoid X receptor (RXR)alpha as well as PPARalpha and PPARdelta, whereas neither affected vitamin D3 receptor, estrogen receptors alpha and beta, or thyroid receptors alpha and beta. Both milk and fresh cream were shown by quantitative real-time PCR to increase the quantity of mRNA for uncoupling protein 2 (UCP2), an energy expenditure gene, in a dose-dependent manner. The increase in UCP2 mRNA was found to be reduced by treatment with PPARdelta-short interfering (si)RNA. This study unambiguously clarified at the cellular level that cow's milk increased the activities of human PPARalpha, PPARdelta, and RXRalpha. The possible role in enhancing the activities of PPARalpha, PPARdelta, and RXRalpha, and the health benefits of cow's milk were discussed.

Sebaceous lymphadenoma of the parotid gland: report of two cases and review of the literature.

Sebaceous lymphadenoma is an unusual salivary gland neoplasm which is rarely correctly diagnosed pre-operatively in the parotid gland. Two cases of sebaceous lymphadenoma are presented in which, in common with most cases reported in the literature, the correct pre-operative diagnosis was not made. Sebaceous lymphadenoma rarely transforms into a malignant tumour. Fine needle aspiration cytology identifies a benign process in the majority of patients who receive appropriate treatment on this basis. Although an uncommon tumour, it should be taken into consideration in the differential diagnosis of a solitary parotid mass.

Growth hormone signalling and apoptosis in neonatal rat cardiomyocytes.

Growth hormone (GH) has been reported to be useful to treat heart failure. To elucidate whether GH has direct beneficial effects on the heart, we examined effects of GH on oxidative stress-induced apoptosis in cardiac myocytes. TUNEL staining and DNA ladder analysis revealed that hydrogen peroxide (H2O2)-induced apoptosis of cardiomyocytes was significantly suppressed by the pretreatment with GH. GH strongly activated extracellular signal-regulated kinases (ERKs) in cardiac myocytes and the cardioprotective effect of GH was abolished by inhibition of ERKs. Overexpression of dominant negative mutant Ras suppressed GH-stimulated ERK activation. Overexpression of Csk that inactivates Src family tyrosine kinases also inhibited ERK activation evoked by GH. A broad-spectrum inhibitor of protein tyrosine kinases (PTKs), genistein, strongly suppressed GH-induced ERK activation and the cardioprotective effect of GH against apoptotic cell death. GH induced tyrosine phosphorylation of EGF receptor and JAK2 in cardiac myocytes, and an EGF receptor inhibitor tyrphostin AG1478 and a JAK2 inhibitor tyrphostin B42 completely inhibited GH-induced ERK activation. Tyrphostin B42 also suppressed the phosphorylation of EGF receptor stimulated by GH. These findings suggest that GH has a direct protective effect on cardiac myocytes against apoptosis and that the effect of GH is attributed at least in part to the activation of ERKs through Ras and PTKs including JAK2, Src, and EGF receptor tyrosine kinase.

Delayed onset of systemic lupus erythematosus in a child with endothelial tubuloreticular inclusion.

We report here on an 11-year-old Japanese girl who was found to have proteinuria by routine mass screening urinalysis for school children, and who developed systemic lupus erythematosus (SLE) 21 months later. The initial renal biopsy, performed 3 months after the first visit to Tokyo Medical University Kasumigaura Hospital (TMUKH), revealed membranous glomerulonephritis. In an immunofluorescent study, IgG was the only positive immunoglobulin found. A "full-house" immunofluorescence glomerulopathy, well known as a predictive finding for lupus nephritis, was not detected. Endothelial tubuloreticular inclusions (ETI) were found by electron microscopy. Because the diagnosis of SLE was not established clinically and serologically, the patient was followed every 3 months without drugs. Her urinary findings returned to normal within 18 months. Three months after the last visit, she was sent to Tsukuba University Hospital (TUH) for fever, arthralgia, dyspnea and butterfly rash. She was diagnosed as having SLE, pleuritis, and pericarditis. Although she was treated with methylpredonisolone and oral prednisolone, she developed cardiac tamponade on the 12th day of admission during the course of pneumococcal septicemia. Finally, she was treated successfully with surgical procedures, antibiotics and oral prednisolone and was discharged. We conclude that ETI is a more significant early sign of SLE than "full-house" immmunofluorescence glomerulopathy, especially in pediatric cases.

Calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy.

BACKGROUND: Cardiac hypertrophy is a fundamental adaptive response to hemodynamic overload; how mechanical load induces cardiac hypertrophy, however, remains elusive. It was recently reported that activation of a calcium-dependent phosphatase, calcineurin, induces cardiac hypertrophy. In the present study, we examined whether calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: Pressure overload produced by constriction of the abdominal aorta increased the activity of calcineurin in the rat heart and induced cardiac hypertrophy, including reprogramming of gene expression. Treatment of rats with a calcineurin inhibitor, FK506, inhibited the activation of calcineurin and prevented the pressure overload-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Load-induced expression of immediate-early-response genes and fetal genes was also suppressed by the FK506 treatment. CONCLUSIONS: The present results suggest that the calcineurin signaling pathway plays a pivotal role in load-induced cardiac hypertrophy and may pave the way for a novel pharmacological approach to prevent cardiac hypertrophy.

MAPK superfamily plays an important role in daunomycin-induced apoptosis of cardiac myocytes.

BACKGROUND: Although anthracyclines, such as daunomycin (DM) and adriamycin, are potent chemotherapeutic agents, they have serious adverse effects, including cardiac toxicity. In the present study, we investigated the molecular mechanisms of DM-induced cardiomyocyte impairment. METHODS AND RESULTS: When cultured cardiac myocytes of neonatal rats were exposed to 1 micromol/L DM for 24 hours, many cells became positive for TUNEL staining, with morphological changes characteristic of apoptosis. Fragmentation of DNA into oligonucleosome-size fragments was recognized by agarose gel electrophoresis in DM-treated myocytes. DM activated 3 members of the mitogen-activated protein kinase (MAPK) family dose-dependently, such as extracellular signal-regulated protein kinases (ERKs), c-Jun NH(2)-terminal kinases, and p38 MAPK in cardiac myocytes. Oxyradical scavengers or Ca(2+) chelators inhibited DM-induced activation of ERKs and p38 MAPK. DM-induced activation of ERKs was also inhibited by overexpression of dominant negative mutants of Ras (D.N.Ras), and the p38 MAPK activation was attenuated by D.N.Rho. The number of DM-induced apoptotic cells was markedly increased when the ERK signaling pathway was selectively blocked by a specific MAPK/ERK kinase inhibitor, PD98059, whereas pretreatment with a specific inhibitor of p38 MAPK, SB203580, significantly reduced the amount of apoptosis. CONCLUSIONS: These results suggest that DM activates MAPKs through reactive oxygen species and Ca(2+) and that the MAPK family plays important roles in DM-induced apoptosis in cardiac myocytes. ERKs protect cardiomyocytes from apoptosis, whereas p38 MAPK is involved in the induction of cardiomyocyte apoptosis.

Bone morphogenetic proteins induce cardiomyocyte differentiation through the mitogen-activated protein kinase kinase kinase TAK1 and cardiac transcription factors Csx/Nkx-2.5 and GATA-4.

Bone morphogenetic proteins (BMPs) have been shown to induce ectopic expression of cardiac transcription factors and beating cardiomyocytes in nonprecardiac mesodermal cells in chicks, suggesting that BMPs are inductive signaling molecules that participate in the development of the heart. However, the precise molecular mechanisms by which BMPs regulate cardiac development are largely unknown. In the present study, we examined the molecular mechanisms by which BMPs induce cardiac differentiation by using the P19CL6 in vitro cardiomyocyte differentiation system, a clonal derivative of P19 embryonic teratocarcinoma cells. We established a permanent P19CL6 cell line, P19CL6noggin, which constitutively overexpresses the BMP antagonist noggin. Although almost all parental P19CL6 cells differentiate into beating cardiomyocytes when treated with 1% dimethyl sulfoxide, P19CL6noggin cells did not differentiate into beating cardiomyocytes nor did they express cardiac transcription factors or contractile protein genes. The failure of differentiation was rescued by overexpression of BMP-2 or addition of BMP protein to the culture media, indicating that BMPs were indispensable for cardiomyocyte differentiation in this system. Overexpression of TAK1, a member of the mitogen-activated protein kinase kinase kinase superfamily which transduces BMP signaling, restored the ability of P19CL6noggin cells to differentiate into cardiomyocytes and concomitantly express cardiac genes, whereas overexpression of the dominant negative form of TAK1 in parental P19CL6 cells inhibited cardiomyocyte differentiation. Overexpression of both cardiac transcription factors Csx/Nkx-2.5 and GATA-4 but not of Csx/Nkx-2.5 or GATA-4 alone also induced differentiation of P19CL6noggin cells into cardiomyocytes. These results suggest that TAK1, Csx/Nkx-2.5, and GATA-4 play a pivotal role in the cardiogenic BMP signaling pathway.

Combined right hepatic and retrohepatic caval resection with reconstruction using a polytetrafluoroethylene graft for primary leiomyosarcoma of the liver: report of case.

We present herein the case of a 53-year-old woman who underwent successful surgical treatment for a leiomyosarcoma of the liver that originated from the posterior hepatic segment and involved the retrohepatic inferior vena cava (IVC). A computed tomographic scan and magnetic resonance imaging demonstrated a large tumor, with rich vascularity, in the liver. The IVC was found to be occluded on these scans, which was confirmed by venacavography. The patient underwent a combined right hepatic and caval resection with reconstruction using an expanded polytetrafluoroethylene graft. The tumor consisted of spindle-shaped cells with cigar-shaped nuclei. It also had a moderate degree of cellularity and ten mitotic figures per ten high-power fields. Immunohistologically, desmin and alpha-smooth muscle actin were stained positive in the tumor cells, implying that the tumor was derived from smooth muscle cells. The patient is alive and well 15 months after her operation.

Elevated B-type natriuretic peptide levels after anthracycline administration.

BACKGROUND: Cardiotoxicity leading to congestive heart failure is a complication of the anthracyclines. Biochemical methods to diagnose and monitor cardiac function after anthracycline administration would be most useful. We examined the diagnostic role of B-type natriuretic peptide (BNP), a potent biochemical marker of left ventricular dysfunction, in patients administered anthracyclines. METHODS: Twenty-seven consecutive patients receiving anthracyclines were investigated by serial measurements of BNP levels and other cardiac neurohormones (A-type natriuretic peptide, renin, aldosterone, angiotensin II, norepinephrine, and epinephrine) and myocardial markers (creatine kinase-MB and myosin light chain). Echocardiography was done to assess systolic (ejection fraction) and diastolic (mitral inflow A/E ratio) functions. RESULTS: Of the examined cardiac biochemical markers, BNP levels alone showed marked elevations to abnormal levels after anthracycline administration. Most patients showed transient increases (peak at 3 to 7 days). Patients with persistent elevations showed a poor prognosis. A/E ratio also correlated with increases in BNP levels in selected patients, which may suggest that raised BNP levels are reflective of induced diastolic dysfunction. CONCLUSIONS: Our studies suggest the possible use of BNP levels to assess the cardiac state after anthracycline administration. BNP levels most likely reflect cardiac tolerance to the cardiotoxic agent. Serial BNP profiles also suggest persistent elevations to be associated with potentially decompensatory states in contrast to tolerable transient increases. Diagnosis of degree of cardiac tolerance by response to drug administration may be analogous to use of stress testing (exercise) to help define underlying left ventricular dysfunction.