Impaired fibrinolysis and postoperative thromboembolism in orthopedic patients.

The incidence of deep vein thrombosis (DVT) and pulmonary embolism was studied prospectively in patients undergoing elective total hip replacement. 96 patients were randomly allocated to receive either low molecular weight heparin (LMWH) or unfractionated heparin (UFH). All patients had bilateral phlebography and pulmonary perfusion/ventilation scintigraphy 10-12 days after surgery. The following fibrinolytic variables were analysed in plasma and related to thromboembolism: tissue plasminogen activator (t-PA) activity, t-PA antigen (t-PA Ag), plasminogen activator inhibitor (PAI-1) activity and PAI-1 antigen (PAI-1 Ag). No significant difference was found, regarding the fibrinolytic response to surgery, between patients treated with LMWH and UFH. The level of PAI-1 activity was significantly increased before operation in patients developing DVT as compared to non-DVT patients (p less than 0.03). Immediately after surgery and in the morning the first postoperative day the levels of PAI-1 activity, PAI-1 Ag and t-PA Ag were positively correlated to thromboembolism. PAI-1 activity was the only preoperative fibrinolytic variable correlated to thromboembolism.     

Performance of Turbuhaler® in Patients with Acute Airway Obstruction and COPD,and in Children with Asthma

The dry-powder inhaler (DPI) Turbuhaler((R)) has been on the market for nearly two decades. Products containing terbutaline, formoterol, budesonide, and the combination budesonide/formoterol are widely used by patients with asthma and COPD. Most patients and physicians find Turbuhaler((R)) easy to use, and local side effects are rare. This is thought to arise from the lack of additives or only small amounts in the formulation, in addition to minimal deposition of the drug in the oropharynx and on the vocal cords during inspiration.The function of Turbuhaler((R)) has frequently been questioned. This article aims to review and clarify some key issues that have been challenged in the literature (e.g. the effectiveness of Turbuhaler((R)) in patients with more restricting conditions), to discuss the importance of lung deposition, and to explain the low in vivo variability associated with Turbuhaler((R)) and the lack of correlation with the higher in vitro variability.Turbuhaler((R)), like other DPIs, is flow dependent to some degree. However, a peak inspiratory flow (PIF) through Turbuhaler((R)) of 30 L/min gives a good clinical effect. These PIF values can be obtained by patients with conditions thought to be difficult to manage with inhalational agents, such as asthmatic children and adult patients with acute severe airway obstruction and COPD. Excellent clinical results with Turbuhaler((R)) in large controlled studies in patients with COPD and acute severe airway obstruction provide indirect evidence that medication delivered via Turbuhaler((R)) reaches the target organ.Due to the large amount of small particles and the moderate inbuilt resistance in Turbuhaler((R)), which opens up the vocal cords during inhalation, Turbuhaler((R)) is associated with a high lung deposition (25-40% of the delivered dose) compared with pressurized metered-dose inhalers (pMDIs) and other DPIs. A good correlation has been found between lung deposition and clinical efficacy. A high lung deposition always results in the best ratio between clinical efficacy and risk of unwanted systemic activity. Studies with Turbuhaler((R)) also show that the in vivo variation in lung deposition is significantly lower compared with a pMDI or, for example, the Diskus((R)) inhaler, and much lower than the in vitro dose variability seen in laboratory tests. Turbuhaler((R)) appears to be a reliable DPI which can be used with confidence by patients with airway diseases, including those with clinical conditions believed to be difficult to manage with inhalational therapy.     

Detection of malignant epithelial cells in effusions using flow cytometric immunophenotyping: an analysis of 92 cases

We compared the efficiency of immunophenotyping using flow cytometry (FCM) and a combination of morphologic and immunocytochemical studies for detecting malignant cells in 92 effusions. Cytologic results were as follows: carcinoma cells, 43 specimens; benign, 42 specimens; suggestive of nonepithelial malignancy, 7 specimens. After immunocytochemical analysis, 5 benign specimens were reclassified as malignant and 4 malignant epithelial specimens as benign. With FCM, cells positive for Ber-EP4, B 72.3, AH6, and HB-TN were detected in 28 to 36 (64%-82%) of 44 carcinomas but only 2 to 12 (5%-29%) of 41 benign specimens. Significant association was seen for coexpression. Ber-EP4 and AH6 were the most sensitive; Ber-EP4 was the most specific. The presence of cells positive for 3 of 4 markers strongly suggested malignancy (34/44 carcinoma specimens [77%]; 3/41 reactive specimens [7%]). The presence of cells positive for all 4 markers was diagnostic of malignancy (17/44 malignant specimens [39%]; 0/41 reactive effusions [0%]). FCM and immunocytochemical resultsfor Ber-EP4 expression showed excellent association. FCM is a powerful tool for diagnosing difficult effusions and can quantify coexpression of various markers in fresh specimens. By using established cellular markers coupled with biological markers, FCM also has great promise for experimental purposes.     

Genome profiles of bilateral dysgerminomas, a unilateral gonadoblastoma, and a metastasis from a 46, XY phenotypic female

We present a case report of a 16-year-old, phenotypic female with bilateral dysgerminomas, a unilateral gonadoblastoma, and a peritoneal metastasis. The patient's constitutional karyotype was 46,XY. The chromosomal copy number, examined by the comparative genomic hybridization technique, showed 3 gains in the dysgerminoma of the right ovary, 6 gains in the dysgerminoma of the left ovary, and 2 gains and 1 loss in the gonadoblastoma of the left ovary. The metastasis showed 5 gains of which 4 were also observed in the dysgerminoma of the left ovary. The DNA ploidy classifications of the gonadoblastoma and the dysgerminoma in the right ovary were tetraploid, whereas the dysgerminoma in the left ovary and the metastasis were aneuploid. We therefore propose that the metastasis most probably developed from the dysgerminoma of the left ovary.     

The p75 neurotrophin receptor is widely expressed in conventional papillary thyroid carcinoma

Papillary thyroid carcinomas (PTCs) are associated with alterations in several proto-oncogenes related with nervous system development and function, such as TrkA and RET, which are commonly rearranged in these carcinomas. The other oncogenic event recently identified in PTC is the BRAF V600E mutation. Because the role of TrkA was not completely elucidated in thyroid cancer ethiopathogenesis, we decided to study the expression of active, phosphorylated TrkA and of its coreceptor p75 neurotrophin receptor (p75 NTR) in a series of 92 PTC (37 lesions of conventional PTC, 28 of follicular variant of PTC [FVPTC], and 27 of other variants of PTC) as well as in 21 samples of normal thyroid and nonneoplastic thyroid lesions used as a controls. We observed neoexpression of p75 NTR in PTC, particularly in conventional PTC and in other variants of PTC displaying a papillary growth pattern, rather than in FVPTC. No immunoexpression of p75 NTR was observed in normal thyroid nor in nonneoplastic thyroid lesions. The cellular localization of p75 NTR immunoexpression was also significantly associated with the growth pattern of PTC, being much more frequently detected in an apical localization in PTC with papillary architecture than in PTC with a follicular or solid growth pattern. This apical localization of p75 NTR was significantly associated with the presence of BRAF V600E. No significant differences were detected between normal thyroid, nonneoplastic lesions, and PTC (or any PTC variant) regarding expression/activation of TrkA, thus suggesting that by itself and in contrast to p75 NTR, TrkA is not altered during PTC development.     

Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK): Co-expression in metastatic serous ovarian carcinoma

Activation or suppression of intracellular signaling via the mitogen-activated protein kinase (MAPK) family has been linked to expression of matrix metalloproteinases (MMP) in experimental models, but this association has not been demonstrated in clinical material. The objective of this study was to investigate the possible association between expression and activity of MMP, expression of the MMP inducer EMMPRIN, and the expression (level) and phosphorylation status (activity) of the extracellular-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK) and high osmolarity glycerol response kinase (p38) in effusions from patients diagnosed with serous ovarian carcinoma. MAPK level and activity were studied in 55 effusions using immunoblotting. MMP-1, MMP-2, MMP-9 and EMMPRIN expression was studied using immunocytochemistry (ICC) and mRNA in situ hybridization (ISH). The gelatinolytic activity of MMP-2 and MMP-9 was measured by zymography. ERK and phospho-ERK (p-ERK) were detected in 54/55 (98%) and 50/55 (91%) specimens, respectively. JNK and p-JNK were detected in 53/55 (96%) and 38/55 (69%) specimens, respectively. p38 was expressed in 54/55 (98%) specimens, and its phosphorylated form was found in 51/55 (92%). MMP-2 mRNA expression (P=0.048), protein expression (P=0.046) and gelatinolytic activity (P=0.039) correlated with ERK phosphorylative activity. MMP-2 activity also correlated with p38 activity (P=0.017). MMP-9 protein expression correlated with phosphorylation of p38 (P=0.046), but enzyme activity showed inverse relationship with both p-ERK (P=0.05) and p-p38 (P=0.033) expression. EMMPRIN expression correlated with MMP-1 (P<0.001), MMP-2 (P=0.042) and MMP-9 (P=0.029) expression, as well as with ERK activity (P=0.001). Our results present the first evidence of a possible link between MAPK signaling and MMP expression and activity in vivo. These data may expand our understanding regarding the mechanisms by which MMP synthesis is regulated in effusions and possibly affect treatment strategies for this form of malignancy. This revised version was published online in July 2006 with corrections to the Cover Date.