Down-regulation of stathmin expression is required for megakaryocyte maturation and platelet production

The final stages of of megakaryocyte (MK) maturation involve a series of steps, including polyploidization and proplatelet formation. Although these processes are highly dependent on dynamic changes in the microtubule (MT) cytoskeleton, the mechanisms responsible for regulation of MTs in MKs remain poorly defined. Stathmin is a highly conserved MT-regulatory protein that has been suggested to play a role in MK differentiation of human leukemic cell lines. However, previous studies defining this relationship have reached contradictory conclusions. In this study, we addressed this controversy and investigated the role of stathmin in primary human MKs. To explore the importance of stathmin down-regulation during megakaryocytopoiesis, we used a lentiviral-mediated gene delivery system to prevent physiologic down-regulation of stathmin in primary MKs. We demonstrated that sustained expression of constitutively active stathmin delayed cytoplasmic maturation (ie, glycoprotein GPIb and platelet factor 4 expression) and reduced the ability of MKs to achieve high levels of ploidy. Moreover, platelet production was impaired in MKs in which down-regulation of stathmin expression was prevented. These studies indicate that suppression of stathmin is biologically important for MK maturation and platelet production and support the importance of MT regulation during the final stages of thrombopoiesis.     

NSAID-induced deleterious effects on the proximal and mid small bowel in seronegative spondyloarthropathy patients

AIM:To investigate the small bowel of seronegative spondyloarthropathy(SpA) patients in order to ascertain the presence of mucosal lesions.METHODS:Between January 2008 and June 2010,54 consecutive patients were enrolled and submitted to avideo capsule endoscopy(VCE) examination.Historyand demographic data were taken,as well as the history of non-steroidal anti-inflammatory drug(NSAID) consumption.After reading each VCE recording,a capsule endoscopy scoring index for small bowel mucosal inflammatory change(L...     

Increased liver stiffness in extrahepatic cholestasis caused by choledocholithiasis

Background

Extrahepatic cholestasis that is caused by benign and malignant diseases has been reported to increase liver stiffness (LS), as measured by transient elastography (TE).

Objectives

The aim of this study was to evaluate LS in patients with extrahepatic cholestasis due to choledocholithiasis before and after endoscopic sphincterotomy and stone removal.

Patients and Methods

LS was measured by TE (Fibroscan) in patients with extrahepatic cholestasis that was caused by choledocholithiasis before and 1 month after endoscopic sphincterotomy and successful stone removal.

Results

We studied 12 patients (7 females, 5 males), aged 36 to 76 years (mean age 57.1 ± 11.6 years), with extrahepatic cholestasis that was caused by choledocholithiasis. LS was increased in all patients (range: 6.2-18.4 kPa; mean: 8.9 ± 3.5 kPa) before endoscopic therapy. Successful biliary drainage was effected by sphincterotomy and stone removal in all patients, which led to a significant decline in LS to 3.9-8.1 kPa (Mean: 5.6 ± 1.2 kPa; p < 0.001) within a mean observation time of 29 days. The decrease in LS values correlated significantly with a decline in serum total bilirubin levels (r = 0.691; p < 0.0001).

Conclusions

Extrahepatic cholestasis due to choledocholithiasis increases LS and should be excluded before assesing liver fibrosis by transient elastography.     

Food-drug interactions: grapefruit juice

Food-drug interactions are increasingly recognized as important clinical events which may change significantly the bioavailability of oral administrated drugs. Grapefruit juice (GFJ) demonstrated multiple interactions with drugs leading to loss of the therapeutic effects or increased side-effects. GFJ decreases pre-systemic metabolism through a) competitive or mechanism-based inhibition of gut wall CYP3A4 isoenzymes and b) P-glycoprotein (P-gp), c) multidrug resistance protein-2 (MRP2) or d) organic anion-transporting polypeptide (OATP) inhibition. Although, GFJ presents high amounts of flavonoids (e.g. naringin, naringenin), furanocoumarins (e.g. 6',7'-dihydroxybergamottin, bergamottin) are the main chemicals involved in the pharmacokinetic interactions. As compounds of GFJ show additive or synergistic effects, all the major furanocoumarins are necessary for the maximal inhibitory effect. Also, related citrus fruits (sweeties, pummelo and sour orange) or various plants containing furanocoumarins may present pharmacological interactions, yet to be discovered.     

Practical considerations in the use of outpatient antimicrobial therapy for musculoskeletal infections

Successful treatment of many musculoskeletal infections often requires an extended course of outpatient antimicrobial therapy, much of which is administered parenterally outside the hospital under the guidance of an infectious disease specialist. Delivery of outpatient parenteral antimicrobial therapy (OPAT) may occur in physicians' offices, ambulatory infusion centers, or hospital clinics but most frequently is done in patients' homes, often by the patients themselves. In this article, we outline the essential elements of outpatient antimicrobial therapy for musculoskeletal infections with particular emphasis on OPAT, including patient selection and evaluation; antimicrobial administration, including the route, duration, and complications of central venous access; and clinical and laboratory monitoring of antimicrobial therapy. We believe that primary care physicians, orthopedists, and infectious disease specialists caring for patients with musculoskeletal infections should become familiar with the use of, indications for, and complications of OPAT.     

A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant pleural mesothelioma in which only staging is prognostic for survival. In this study of epithelioid diffuse malignant pleural mesothelioma, we investigate the prognostic utility of nuclear features. The slides of 232 epithelioid diffuse malignant pleural mesothelioma patients (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed for the following seven nuclear features: nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, intranuclear inclusions, prominence of nucleoli, mitotic count, and atypical mitoses. MIB-1 immunohistochemistry was performed using tissue microarray, and MIB-1 labeling index was recorded as the percentage of positive tumor cells. Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis. Multivariate analysis revealed nuclear atypia (P=0.012) and mitotic count (P<0.001) as independent prognostic factors, and these two factors were utilized to create a three-tier nuclear grade score. The resulting nuclear grade stratified patients into three distinct prognostic groups: grade I (n=107, median overall survival=28 months), grade II (n=91, 14 months), and grade III (n=34, 5 months). Not only was nuclear grade an independent predictor of overall survival (P<0.001), but it was also a stronger discriminator of survival than all currently available factors. Furthermore, nuclear grade was associated with time to recurrence (P=0.004) in patients who underwent complete surgical resection (n=159). MIB-1 labeling index correlated with mitotic count (P<0.001) and nuclear atypia (P=0.037) and stratified overall survival (P<0.001) and time to recurrence (P=0.048), confirming the prognostic value of the nuclear grade. Nuclear grading in epithelioid mesothelioma provides a simple, practical, and cost-effective prognostic tool that better stratifies clinical outcome and time to recurrence than currently available clinicopathologic factors.     

In vivo diode dosimetry vs. computerized tomography and digitally reconstructed radiographs for critical organ dose calculation in high-dose-rate brachytherapy of cervical cancer

Purpose

To investigate the correlation between the dose predicted by the treatment planning system using digitally reconstructed radiographs or three-dimensional (3D)-reconstructed CT images and the dose measured by semiconductor detectors, under clinical conditions of high-dose-rate brachytherapy of the cervix uteri.

Patients and methods

Thirty-two intracavitary brachytherapy applications were performed for 12 patients with cancer of the cervix uteri. The prescribed dose to Point A was 7 Gy. Dose was calculated for both International Commissioning on Radiation Units and Measurements (ICRU) bladder and rectal points based on digitally reconstructed radiographs and for 3D CT images-based volumetric calculation of the bladder and rectum. In vivo diode dosimetry was performed for the bladder and rectum.

Results

The ICRU reference point and the volumes of 1, 2, and 5 cm³ received 3.6 ± 0.9, 5.6 ± 2.0, 5.1 ± 1.7, 4.3 ± 1.4 and 5.0 ± 1.2, 5.3 ± 1.3, 4.9 ± 1.1, and 4.2 ± 0.9 Gy for the bladder and rectum, respectively. The ratio of the 1 cm³ and the ICRU reference point dose to the diode dose was 1.8 ± 0.7 and 1.2 ± 0.5 for the bladder and 1.9 ± 0.6 and 1.7 ± 0.5 for the rectum, respectively.

Conclusions

3D image-based dose calculation is the most accurate and reliable method to evaluate the dose given to critical organs. In vivo diode dosimetry is an important method of quality assurance, but clinical decisions should be made based on 3D-reconstructed CT image calculations.