The role of more intense conditioning for second transplant was evaluated in myeloma patients achieving at least partial remission (PR) after first transplant with melphalan at 200 mg/m2. Forty-three ...patients received more intensive conditioning for the second transplant. Nineteen patients received cyclophosphamide 120 mg/kg along with melphalan 200 g/m2 (MEL-CY; group 1) while 24 patients received total body irradiation (1125 cGy) in conjunction with melphalan 140 mg/m2 (MEL-TBI; group 2). Forty-three matched control patients were identified from 450 patients receiving melphalan alone for second transplant (MEL200; group 3). Engraftment and toxicities were comparable among the groups with the exception of increased treatment-related mortality of 8% in group 2 compared to none in groups 1 and 3 (P = 0.07). Despite identical CR rates of 74, 71 and 70%, respectively, in groups 1, 2 and 3 (P = 1.0), event-free survival (median: 27, 15 and 61; P < 0.0001) and overall survival (median: 39, 25 and 76 months; P = 0.003) were significantly decreased in patients receiving more intensive conditioning (groups 1 and 2). Lymphocyte recovery, evaluated as a surrogate for immune recovery, was inferior in more intensively treated patients (groups 1 and 2 compared to group 3). Our findings suggest that more intense conditioning appears to have no benefit in patients responding to their first cycle of high-dose therapy and may even be detrimental in this setting. Bone Marrow Transplantation (2000) 25, 483-487.
Three cases of multiple myeloma treated with thalidomide are presented which highlight therapeutic dilemmas presented by therapy with this new agent. The difficulty of stem cell collection during ...thalidomide therapy is illustrated. The question of continuation of thalidomide after attainment of a plateau or remission is discussed and the management of neuropathy considered. Thalidomide, being a novel drug, presents a number of therapeutic issues that have yet to be resolved.
Hydrogen peroxide (H
2O
2) is now recognised as a key signalling molecule in eukaryotes. In plants, H
2O
2 is involved in regulating stomatal closure, gravitropic responses, gene expression and ...programmed cell death. Although several kinases, such as oxidative signal-inducible 1 (OXI1) kinase and mitogen-activated protein kinases are known to be activated by exogenous H
2O
2, little is known about the proteins that directly react with H
2O
2. Here, we utilised a proteomic approach, using iodoacetamide-based fluorescence tagging of proteins in conjunction with mass spectrometric analysis, to identify several proteins that might be potential targets of H
2O
2 in the cytosolic fraction of
Arabidopsis thaliana, the most prominent of which was cytosolic glyceraldehyde 3-phosphate dehydrogenase (cGAPDH; EC 1.2.1.12). cGAPDH from
Arabidopsis is inactivated by H
2O
2 in vitro, and this inhibition is reversible by the subsequent addition of reductants such as reduced glutathione (GSH). It has been suggested recently that
Arabidopsis GAPDH has roles outside of its catalysis as part of glycolysis, while in other systems this includes that of mediating reactive oxygen species (ROS) signalling. Here, we suggest that cGAPDH in
Arabidopsis might also have such a role in mediating ROS signalling in plants.
Standard doses of alkylating agents or purine analogues effect response rates of up to 50% in Waldenström's macroglobulinaemia (WM); however, complete responses are infrequent and there are no cures. ...We have evaluated the feasibility, safety and efficacy of high‐dose chemotherapy with peripheral blood stem cell support in six patients aged 45–69 years (median 51.5) with WM; four patients relapsed after prior therapy inclusive of purine analogues and two patients proceeded with transplant after minimal therapy. Four patients mobilized adequate numbers of stem cells; however, two patients with more extensive fludarabine therapy failed to mobilize and required a second attempt at stem cell collection. Five patients were treated with melphalan 200 mg/m2, including one patient who received tandem transplants and one patient who received melphalan 140 mg/m2 with added total body irradiation (TBI). There was no treatment‐related mortality and non‐haematological toxicities were manageable. Engraftment was prompt except in one patient with extensive prior use of fludarabine. All the six patients achieved at least partial response (PR), including one who achieved complete response (CR). Five patients are alive and four are event‐free at 52+, 15+, 12+ and 2+ months post transplant. This pilot study suggests safety and efficacy of high‐dose therapy in WM and suggests that the peripheral blood stem cells should preferably be procured prior to extensive use of purine analogues.
Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated ...whether this phenotypic association arises from a shared genetic basis.
Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05-1.11; P=2.86×10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38×10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains.
We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.
Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated ...loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.
Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal.
We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Power is a major problem for scaling the hardware needed to support memory disambiguation in future out-of-order architectures. In current machines, the traditional detection of memory ordering ...violations requires frequent associative searches of state proportional to the instruction window size. A new class of solutions yields an order-of-magnitude reduction in the energy required to properly order loads and stores for windows of hundreds to thousands of in-flight instructions
Tumour lysis syndrome (TLS), because of its low proliferative activity, is thought to only rarely complicate the treatment of patients with multiple myeloma. However, as more aggressive therapeutic ...approaches are increasingly used in the management of this disease, it is conceivable that clinicians will encounter this complication more frequently.
A retrospective analysis of > 800 patients with multiple myeloma treated at the University of Arkansas identified nine patients who developed a marked tumour lysis syndrome following intermediate‐ or high‐dose chemotherapy. Evaluation of disease characteristics revealed association with high tumour mass, high proliferative activity, increased lactic dehydrogenase levels, plasmablastic morphology, and unfavourable cytogenetic abnormalities.
Recognition of multiple myeloma patients at high risk for the development of tumour lysis syndrome and prompt intervention are required especially in the presence of abnormal baseline renal function frequently complicating the clinical course of these patients.
Dental caries is the irreversible microbial disease of teeth causing demineralization of inorganic and destruction of organic. It is of serious concern as it can lead to pain due to various pulpal ...and periapical pathologies. It is a tedious job to prevent this dental caries which is very common dental problem with each and everyone. With new concepts emerging in prevention and management of caries, Ozone therapy is tool to prevent and manage dental caries. The use of ozone (O3) gas as a therapy is skeptical due to unstable structure. The main beneficial effect of ozone is its antibacterial effect against various bacteria. These antibacterial effects are even attributed to the prevention and management of caries. This therapy is of controversy as some prove this to be less or no effective or some prove to be more effective. This article reviews various benefits of ozone therapy in prevention and management of caries and also discussion on controversies to it.
PDF
