Pharmacosimulation of delays and interruptions during administration of tirofiban: a systematic comparison between EU and US dosage regimens

Journal of Thrombosis and Thrombolysis - Tirofiban is a glycoproteine (GP) IIb/IIIa receptor antagonist, which inhibits platelet-platelet aggregation and is a potential adjunctive antithrombotic...     

Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II

Cytogenetic abnormalities of chromosome 13 (CA 13) and those detected by fluorescence in situ hybridization (FISH 13) have both been associated with poor prognosis in multiple myeloma (MM) patients. The prognostic implications of CA, FISH 13 and other standard laboratory parameters were examined in the first 231 patients enrolled in Total Therapy II, an intensive cytotoxic chemotherapy programme with tandem autotransplants. Three-year projections of event-free survival (EFS) and overall survival (OS) were 71% and 77% respectively. CA 13 was detected in 14% and significantly correlated with FISH 13 (present in 51%), tumour burden, proliferative activity and lactic dehydrogenase (LDH). Both EFS and OS were significantly shorter in patients with CA 13, FISH 13, LDH >or= 190 U/l, beta2 microglobulin >or= 4 mg/l and C reactive protein >or= 4.0 mg/l; other CA was an additional risk factor for OS. Two-thirds of CA 13 patients were identified by FISH 13 and plasma-cell-labelling index (PCLI) >or= 0.4%; however, PCLI failed to identify additional risk groups in FISH subsets. Although present in considerably fewer patients, CA 13 imparted more rapid relapse (61% at 3 years) and death (43% at 3 years) than FISH 13 (38% and 35%; P = 0.02 and 0.1 respectively) and should be part of the initial work-up of patients with MM.     

Essential role of p21/waf1 in the mediation of the anti-proliferative effects of GHRH antagonist JMR-132

GHRH, besides its neuroendocrine action in controlling the release of GH from the pituitary, stimulates the growth of various cancers in vivo and in vitro by direct mechanism(s). However, the molecular mechanism that mediates these proliferative effects of GHRH in extrapituitary tissues remains poorly characterized. In the present study, we investigated whether the tumor suppressor p21/waf1 is involved in the mediation of the proliferative effects of GHRH in A549 human lung cancer epithelial cells. Exposure of A549 cells to the GHRH antagonist JMR-132 caused a significant inhibition in the rate of cell proliferation. In A549 cells, GHRH suppressed while JMR-132 increased the levels of p21 expression in a dose-dependent manner. This suggests that GHRH could regulate p21 levels. We then evaluated whether p21 is required in A549 cells for the regulation of cell proliferation by GHRH. To this end, we knocked-down p21 expression in A549 cells by siRNA and assessed the effects of antagonist JMR-132 on cell proliferation. We found that the loss of p21 expression abolished the anti-proliferative effects of JMR-132. Suppression of p21 expression by siRNA in human HT29 colon cancer cells and non-transformed mouse osteoblasts KS483 also blocked the anti-proliferative effects of JMR-132 suggesting that the regulation of cell proliferation by GHRH is p21 dependent. These results shed light on the molecular mechanism of action of GHRH antagonists in tumor tissues and suggest that the antineoplastic activity of GHRH antagonists could be considered for the treatment of cancers expressing p21.     

Peridevice Leak Following Amplatzer Left Atrial Appendage Occlusion: Cardiac Computed Tomography Classification and Clinical Outcomes

ObjectivesThis study aimed to investigate cardiac computed tomography (CT) and transesophageal echocardiography (TEE) peridevice leak (PDL) assessments, and the clinical relevance of PDL.BackgroundPDL assessment is integral during follow-up after left atrial appendage (LAA) occlusion. Comparative studies of TEE and cardiac CT are sparse, and the clinical relevance of PDL is uncertain.MethodsThis was a single-center observational study of consecutive patients undergoing LAA occlusion with Amplatzer devices (Amplatzer Cardiac Plug/Amulet) between 2010 and 2018 (N = 415). Patients with both 8-week CT and TEE were included for analysis (n = 346). Images were analyzed by blinded investigators (K.K. and A.S.). PDL on cardiac CT was classified from grade 1 to 3, based on PDL at the device disc, device lobe, and LAA contrast patency. Primary clinical outcome was a composite of ischemic stroke, transient ischemic attack, systemic embolism, or all-cause death.ResultsPDL was present in 110 patients (32%) by TEE, with 29 (8%) >3 mm. By cardiac CT, 210 patients (61%) had PDL at the disc, with contrast patency in 204 patients (59%). A grade 3 PDL (gap at disc, lobe, and LAA contrast patency) was present in 63 patients (18%). Bland-Altman analysis showed poor agreement between CT and TEE for leak sizing. CT and TEE detected PDL was not significantly associated with worse outcome, hazard ratio: 1.82 (95 % confidence interval: 0.95 to 3.50); p = 0.07 and hazard ratio: 1.43 (95% confidence interval: 0.74 to 2.76); p = 0.28, respectively.ConclusionsPDL occurrence is substantially higher with CT compared with TEE, with a large discrepancy between modalities in leak quantification. A novel CT-based classification is proposed, yet PDL was not associated with worse clinical outcome.     

Role of receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1-alpha (MIP-1a) in monoclonal gammopathy of undetermined significance (MGUS)

The aim of this study was to evaluate the role of markers of bone remodelling, and osteoclast activation/function in patients with monoclonal gammopathy of undetermined significance (MGUS). We have measured serum levels of soluble RANKL (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein-1alpha (MIP-1alpha), markers of bone resorption [N-telopeptide of collagen type-I (NTX), and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)] and bone formation [bone-alkaline phosphatase (bALP)] in 40 MGUS patients. These parameters were compared with those of 42 newly diagnosed myeloma patients, and 45 healthy, gender- and age-matched controls. MGUS patients had elevated levels of NTX, sRANKL, and sRANKL/OPG ratio compared with controls (P < 0.0001). Furthermore, TRACP-5b, MIP-1alpha and NTX were decreased in patients with MGUS compared with myeloma patients (P < 0.001), while OPG and bALP were increased (P < 0.001). Serum levels of MIP-1alpha, as well as TRACP-5b, and sRANKL/OPG ratio were reduced, while bALP was increased in MGUS patients, even when compared with myeloma patients who had stage I/II disease. These results demonstrate that increased osteoclastogenesis leading to increased bone resorption is present in MGUS but seems to be compensated for by normal bone formation, which is absent in MM. Furthermore MIP-1alpha, bALP, and sRANKL/OPG may be useful tools for distinguishing between cases of MGUS and early myeloma.     

Enteric infection in relapse of inflammatory bowel disease: importance of microbiological examination of stool

OBJECTIVE: Previous reports have suggested that diarrhoeal relapses of inflammatory bowel disease (IBD) may be associated or confused with enteric infection, and that treatment of such infections with appropriate antibiotics may be beneficial. To re-evaluate the suggestion that enteric infection is rare and microbiological testing of stool not routinely necessary in patients presenting with relapse of IBD, we have reviewed the incidence of concurrent infection in patients presenting in relapse over a recent 5-year period. METHODS: Stool microbiology results relating to relapses of IBD during the period 1997-2001 were obtained retrospectively. Relapse was confirmed by standard clinical, sigmoidoscopic and laboratory criteria. RESULTS: During the period 1997-2001 there were 237 relapses in 213 patients. Enteric infection was found in 25 (10.5%) relapses in 24 patients; in seven patients, infection was associated with the initial presentation of their IBD. Clostridium difficile toxin was detected in 13 (5.5%) instances; the 12 other infections (5% relapses) were Campylobacter spp. (five), Entamoeba histolytica (three), Salmonella spp. (one), Plesiomonas shigelloides (one), Strongyloides stercoralis (one) and Blastocystis hominis (one). There was a significant association between infection and the need for hospital admission. Of the 13 relapses associated with C. difficile, ten were in outpatients, seven patients had undergone previous antibiotic treatment, and four patients were presenting with IBD for the first time. All relapses resolved satisfactorily after treatment with antibiotics with or without corticosteroids. CONCLUSIONS: The high prevalence of enteric infections, of which C. difficile was the most common, indicates that all patients presenting with relapse of IBD should have stool examined microbiologically.     

Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning

OBJECTIVES: The aim of this study was to identify prognostic factors for outcome of high-risk patients with multiple myeloma after allogeneic transplantation prepared by reduced intensity conditioning (RIC). MATERIALS AND METHODS: Data from 45 consecutive patients (median age 52 years, range 38-68), who received grafts from a sibling (n = 34) or unrelated donor (n = 11) were analyzed. Fourteen patients received an RIC allotransplant while chemosensitive (>/=partial remission [PR]), whereas 31 chemoresistant patients (相似文献   

Autologous hemopoietic stem cell transplantation for multiple sclerosis: Is it worthwile?

High-dose immunosuppressive chemotherapy or total body irradiation followed by autologous transplantation of hemopoietic stem cells (ASCT) was introduced in the treatment of active, progressing, and therapy-resistant multiple sclerosis (MS) in 1995. Since then, more than 300 patients have undergone this sort of treatment worldwide and the European Group for Blood and Marrow Transplantation (EBMT) published on two occasions, in 2002 and in 2006, the results of collective analyses performed in 85 and in 183 cases, respectively. In most communications the results were reported favorable with some cases showing spectacular recoveries and also probabilities of long-lasting disease stability, between 60 and 80% at three years after transplant. Of great interest was the fact that magnetic resonance imaging studies invariably showed that the inflammation in the central nervous system resolved and gadolinium-enhancing lesions were completely abolished or markedly reduced. These results appear superior to those yielded by standard therapies but this superiority needs to be demonstrated by comparative studies, such as the EBMT-launched ASTIMS trial. Moreover, ASCT is a rather toxic procedure associated with a mortality risk of 2–3%. Therefore, it is not a treatment for the general population of MS patients but only for selected cases that do not respond to standard therapies and worsen rapidly, i.e. in situations where benefits are expected to counterbalance morbidity and mortality risks. Nevertheless, certain issues seem to have cleared up: ASCT should be used early, during the inflammatory phase of the disease; very high-intensity pre-transplant conditioning regimens increase toxicity but do not seem to increase efficacy compared to intermediate-intensity regimens; the results are dramatic and life-saving in resistant, so-called “malignant” cases; ASCT does not only cause debulking of autoreactive clones but it also brings about qualitative immunological changes that might eventually establish immunologic self-tolerance; the progression of brain atrophy appears to slow down with time; with the implementation of proper patient-selection criteria, the risks of morbidity and mortality can be minimized.     

A Review on Joint Carotid Intima-Media Thickness and Plaque Area Measurement in Ultrasound for Cardiovascular/Stroke Risk Monitoring: Artificial Intelligence Framework

Journal of Digital Imaging - Cardiovascular diseases (CVDs) are the top ten leading causes of death worldwide. Atherosclerosis disease in the arteries is the main cause of the CVD, leading to...