Radical radiotherapy remains the cornerstone of treatment for patients with unresectable locally advanced non small cell lung cancer (NSCLC) either as single modality treatment for poor performance status patients or with sequential or concomitant chemotherapy for good performance status patients. Advances in understanding of tumour molecular biology, targeted drug development and experiences of novel agents in the advanced disease setting have brought targeted agents into the NSCLC clinic. In parallel experience using modified accelerated fractionation schedules in locally advanced disease have demonstrated improved outcomes compared to conventional fractionation in the single modality and sequential chemo-radiotherapy settings. Early studies of targeted agents combined with (chemo-) radiotherapy in locally advanced disease in different clinical settings are discussed below and important areas for future studies are high-lighted.
Non small cell lung cancer (NSCLC); radical radiotherapy; modified fractionation; targeted agents
The optimal dose and schedule of thymoglobulin (ATG) for graft-versus-host disease prevention (GVHD) is unknown. We compared two doses of ATG (4.5 mg/kg and 7.5 mg/kg) in a Bayesian adaptively randomized fashion, and assessed whether ATG levels measured on days 0, 7, 14, and 28 were associated with clinical outcomes. Treatment success was defined as the patient being alive, engrafted, in remission, and without acute GVHD at day 100. Twenty patients received ATG 4.5 mg/kg (n=15) or 7.5 mg/kg (n=5) with reduced-intensity conditioning (RIC) followed by unrelated donor hematopoietic cell transplantation (HCT). The first 10 patients were randomized fairly. Then, based on data from the first 10 patients, the posterior probability that the 4.5 mg/kg dose is superior to the 7.5 mg/kg dose was found to be 0.94, and the next 10 patients were each assigned to the ATG 4.5 mg/kg arm. The posterior mean treatment success rates for the ATG 4.5 mg/kg and ATG 7.5 mg/kg arms were 0.73 and 0.45, respectively. The posterior probability that the success rate was greater in the 4.5 mg/kg arm than in the 7.5 mg/kg arm was 0.93. There was no difference in the overall survival (p=0.607), relapse-free survival (p=0.607), treatment-related mortality (p=0.131), or incidence of acute (p=0.303) or chronic GVHD (p=0.999) between the two doses. ATG levels were not associated with clinical outcomes. Thus, our results favor the use of ATG 4.5 mg/kg over ATG 7.5 mg/kg in patients undergoing unrelated donor HCT with RIC regimens.
ATG; Graft-Versus-Host Disease; hematopoietic cell transplantation
A total of 149 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with myeloablative (MAC; n=38) or reduced-intensity conditioning (RIC; n=110) regimens at MD Anderson Cancer Center were evaluated. Of the total, 120 (81%) patients had relapsed or had refractory disease. Median age of MM patients was 50 (28-70) years with a follow-up time of 28.5(3-164) months. The 100-day and 5-year treatment related mortality (TRM) rates were 17% and 47%, respectively. TRM was significantly lower with RIC regimens (13%) vs. 29% for MAC at 100 days (p=0.012). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 35% and chronic GVHD was 46%. PFS and OS at 5 years were 15% and 21%, respectively. In multivariate analysis, allo-HCT for primary remission consolidation was associated with longer PFS (HR 0.35; 95% CI, 0.18–0.67) and OS (HR 0.29; 95% CI 0.15–0.55), while absence of high-risk cytogenetics was associated with longer PFS only (HR 0.59; 95% CI 0.37–0.95). We observe that TRM has decreased with the use of RIC regimens and long-term disease control can be expected in a subset of MM patients undergoing allo-HCT. Further studies should be conducted in carefully designed clinical trials in this patient population.
Multiple Myeloma; Allogenic transplant; Survival
Pseudomonas aeruginosa, is an opportunistic, bacterial pathogen causing persistent and frequently fatal infections of the lung in patients with cystic fibrosis. Isolates from chronic infections differ from laboratory and environmental strains in a range of traits and this is widely interpreted as the result of adaptation to the lung environment. Typically, chronic strains carry mutations in global regulation factors that could effect reduced expression of social traits, raising the possibility that competitive dynamics between cooperative and selfish, cheating strains could also drive changes in P. aeruginosa infections. We compared the expression of cooperative traits - biofilm formation, secretion of exo-products and quorum sensing (QS) - in P. aeruginosa isolates that were estimated to have spent different lengths of time in the lung based on clinical information. All three exo-products involved in nutrient acquisition were produced in significantly smaller quantities with increased duration of infection, and patterns across four QS signal molecules were consistent with accumulation over time of mutations in lasR, which are known to disrupt the ability of cells to respond to QS signal. Pyocyanin production, and the proportion of cells in biofilm relative to motile, free-living cells in liquid culture, did not change. Overall, our results confirm that the loss of social behaviour is a consistent trend with time spent in the lung and suggest that social dynamics are potentially relevant to understanding the behaviour of P. aeruginosa in lung infections.
Purpose: An efficient technique has been developed for microwave assisted synthesis of 1-[5-(substituted aryl)-1H-pyrazol-3-yl]-3,5-diphenyl-1H-1,2,4-triazole as antinociceptive and antimicrobial agents.
Methods: The desired compounds (S1-S10) were synthesized by the microwave irradiation via cyclization of formerly synthesized chalcones of 3,5-diphenyl-1H-1,2,4-triazole and hydrazine hydrate in mild acidic condition. All newly synthesized compounds were subjected to study their antinociceptive and antimicrobial activity. The analgesic potential of compounds was tested by acetic acid induced writhing response and hot plate method. The MIC values for antimicrobial activity were premeditated by liquid broth method.
Results: The compounds S1, S2, S4, S6 and S10 were found to be excellent peripherally acting analgesic agents when tested on mice by acetic acid induced writhing method and compounds S3, S6 and S1 at dose level of 100 mg/kg were exhibited superior centrally acting antinociceptive activity when tested by Eddy’s hot plate method. In antimicrobial activity compound S10 found to be broad spectrum antibacterial agent at MIC value of 15.62 µg/ml and compound S6 was exhibited antifungal potential at 15.62 µg/mL on both fungal strains.
Conclusion: Some novel pyrazoles clubbed with 1,2,4-triazole derivatives were synthesized and evaluated as possible antimicrobial, centrally and peripherally acting analgesics.
Microwave; Antinociceptive; Antimicrobial; Hot plate method; MIC; Chalcones
To assess the impact of spleen status on engraftment and early morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), we analyzed 9,683 myeloablative allograft recipients from 1990 to 2006; 472 had prior splenectomy (SP), 300 splenic irradiation (SI), 1,471 with splenomegaly (SM), and 7,440 with normal spleen (NS). Median times to neutrophil and platelet engraftment were 15 vs. 18 days and 22 vs. 24 days for the SP and NS groups, respectively (p<0.001). Hematopoietic recovery at day +100 was not different across all groups, however the odds of days +14 and +21 neutrophil and day +28 platelet engraftment were 3.26, 2.25, and 1.28 for splenectomy, and 0.56, 0.55, and 0.82 for splenomegaly groups compared to normal spleen (p<0.001), respectively. Among patients with splenomegaly, use of peripheral blood grafts improved neutrophil engraftment at day +21, and CD34+ cell dose >5.7x106/kg improved platelet engraftment at day+28. After adjusting variables by Cox regression, the incidence of graft-versus-host disease (GVHD) and overall survival were not different among groups. Splenomegaly is associated with delayed engraftment while splenectomy prior to HCT facilitates early engraftment without impact on survival.
Engraftment; splenectomy; spleen; stem cell transplantation; myeloproliferative disease
Evidence based, single-session, behavioral interventions that can be used in public health settings are urgently needed for preventing the spread of HIV and other sexually transmitted infections (STI). Brief interventions are particularly promising given the relatively low burden they place on financially limited service providers.
To estimate the efficacy of single-session, behavioral interventions for STI prevention.
MEDLINE (PubMed), PsycINFO, CINAHL, ERIC, Proquest, all international sub-databases in the WHO's Global Health Library were searched through May 2011.
Data from 29 single-session interventions (20 studies; N = 52,465) with an STI outcome were coded and analyzed.
The odds of participants being infected with an STI in the intervention group were reduced by 35% (OR = .65, 95% CI=.55–.77) relative to control group participants. Interventions were compared to active controls and follow-up periods averaged 58 weeks. As such, single-session interventions lead to considerable benefit in terms of disease prevention and create minimal burden for both the patient and the provider.
Single-session interventions were most often implemented during routine health care services by clinic staff. Use of these procedures make these interventions a reasonable option for currently existing health care infrastructure. Brief and effective STI prevention interventions are a valuable tool for disease prevention and can be readily adapted to bolster the benefits of partially effective biomedical STI/HIV prevention technologies.
Poor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells.
We studied engraftment results in 31 adults with hematologic cancers who received transplants of 2 cord-blood units, 1 of which contained cord blood that was expanded ex vivo in cocultures with allogeneic mesenchymal stromal cells. The results in these patients were compared with those in 80 historical controls who received 2 units of unmanipulated cord blood.
Coculture with mesenchymal stromal cells led to an expansion of total nucleated cells by a median factor of 12.2 and of CD34+ cells by a median factor of 30.1. With transplantation of 1 unit each of expanded and unmanipulated cord blood, patients received a median of 8.34×107 total nucleated cells per kilogram of body weight and 1.81×106 CD34+ cells per kilogram — doses higher than in our previous transplantations of 2 units of unmanipulated cord blood. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 15 days in the recipients of expanded cord blood, as compared with 24 days in controls who received unmanipulated cord blood only (P<0.001); the median time to platelet engraftment was 42 days and 49 days, respectively (P = 0.03). On day 26, the cumulative incidence of neutrophil engraftment was 88% with expansion versus 53% without expansion (P<0.001); on day 60, the cumulative incidence of platelet engraftment was 71% and 31%, respectively (P<0.001).
Transplantation of cord-blood cells expanded with mesenchymal stromal cells appeared to be safe and effective. Expanded cord blood in combination with unmanipulated cord blood significantly improved engraftment, as compared with unmanipulated cord blood only. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00498316.)
Although hypodontia and supernumerary teeth are often considered as mutually exclusive conditions, this case report presents an unusual case of hypodontia and a supernumerary tooth occurring simultaneously. An adolescent male was referred to the local hospital department regarding upper arch crowding. Plain film radiographs confirmed the congenital absence of both lower lateral incisors in addition to an unerupted conical supernumerary tooth in the maxillary midline. This condition has been called hypo-hyperdontia and in this paper, we discuss the clinical findings and treatment planning considerations in relation to the limited number of previously reported cases. The case report raises awareness of concomitant hypo-hyperdontia and serves to highlight that concomitant anomalies should be excluded when hypodontia or supernumerary teeth are diagnosed.
Systemic lupus erythematosus is an autoimmune disease with a high morbidity and nephritis is a common manifestation. Previous studies in murine lupus models have suggest a role for Toll-like receptor 2 and 4. We examined the role of these molecules in MRL lpr mice which is one of the most established and robust murine models. We compared disease parameters in Toll-like receptor 2 or Toll-like receptor 4 deficient mice with their littermate controls. We found no difference in the severity of glomerulonephritis as assessed by histology, serum creatinine and albuminuria when Toll-like receptor 2 or Toll-like receptor 4 deficient MRLlpr mice were compared with Toll-like receptor sufficient controls. We also found similar levels of anti-dsDNA and anti-ssDNA antibodies. These results show that Toll-like receptor 2 and Toll-like receptor 4 do not play a significant role in MRLlpr mice, and therefore they may not be important in human lupus.
While a combination of IV busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for AML/MDS, recurrent leukemia post transplantation remains a problem. To enhance the conditioning regimen’s antileukemic effect we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Busulfan (Bu) in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT); Patients were adaptively randomized as follows: Arm I - Clo:Flu 10:30 mg/m2, Arm II - 20:20 mg/m2, Arm III - 30:10 mg/m2, and Arm IV - single-agent Clo at 40 mg/m2. The nucleoside analog(s) were/was infused over one hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily AUC of 6,000 μMol-min +/− 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females with a median age of 45 years (range: 6-59). Nine patients had CML (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first CP: 4). Forty two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second CR and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft vs host disease- (GVHD) prophylaxis was tacrolimus and mini-MTX, and those who had an unrelated or one Ag-mismmatched donor received low-dose rabbit-ATG (Thymoglobulin™). RESULTS: All patients engrafted. Forty-one patients had active leukemia at the time of transplant, and 35 achieved CR (85%). Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival of 23 months. Marrow and blood (T-cell) chimerism studies at day +100 revealed that both in the lower dose Clo groups (groups 1+2) and the higher dose Clo groups (groups 3+4) the patients had a median of 100% donor (T-cell)-derived DNA. There has been no secondary graft failure. In the first 100 days one patient died of pneumonia, and one of liver GVHD. We conclude that 1) Clo±Flu with IV Bu as pretranslant conditioning is safe in high-risk myeloid leukemia patients, 2) Clofarabine is sufficiently immunosuppressive to support allo-SCT in myeloid leukemia, and 3) the median overall survival (OS) of 23 months in this high-risk patient population is encouraging. Additional studies to evaluate the antileukemic efficacy of Clo±Flu with IV Bu as pretransplant conditioning therapy are warranted.
Clofarabine; Fludarabine; IV Busulfan; CML; AML; MDS; Allogeneic Stem Cell Transplantation
Delayed recovery of platelet count post allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been associated with worse transplant outcomes. Thrombopoietic agents have been successfully used in immune mediated thrombocytopenia or thrombocytopenia from bone marrow failure syndromes; however, the experience regarding their use after allo-HSCT is limited. Here we report on the safety and efficacy of romiplostim used in 3 consecutive patients with thrombocytopenia post allogeneic transplantation. Two patients had prolonged platelet recovery due to poor graft function while one had secondary failure of platelet recovery, likely immune mediated, post transplantation. Successful use of such agents post-transplant may improve platelet recovery, decrease rates of complications and potentially improve outcomes.
Post-transplant thrombocytopenia; romiplostim; allogeneic hematopoietic stem cell transplantation
Early detection of oral premalignant lesions (OPL) and oral cancers (OC) is critical for improved survival. We evaluated if the addition of autofluorescence visualization (AFV) to conventional white-light examination (WLE) improved the ability to detect OPLs/OCs. Sixty high-risk patients, with suspicious oral lesions or recently diagnosed untreated OPLs/OCs, underwent sequential surveillance with WLE and AFV. Biopsies were obtained from all suspicious areas identified on both examinations (n = 189) and one normal-looking control area per person (n = 60). Sensitivity, specificity, and predictive values were calculated for WLE, AFV, and WLE + AFV. Estimates were calculated separately for lesions classified by histopathologic grades as low-grade lesions, high-grade lesions (HGL), and OCs. Sequential surveillance with WLE + AFV provided a greater sensitivity than WLE in detecting low-grade lesions (75% versus 44%), HGLs (100% versus 71%), and OCs (100% versus 80%). The specificity in detecting OPLs/OCs decreased from 70% with WLE to 38% with WLE + AFV. Thirteen of the 76 additional biopsies (17%) obtained based on AFV findings were HGLs/OCs. Five patients (8%) were diagnosed with a HGL/OC only because of the addition of AFV to WLE. In seven patients, additional HGL/OC foci or wider OC margins were detected on AFV. Additionally, AFV aided in the detection of metachronous HGL/OC in 6 of 26 patients (23%) with a history of previously treated head and neck cancer. Overall, the addition of AFV to WLE improved the ability to detect HGLs/OCs. In spite of the lower specificity, AFV + WLE can be a highly sensitive first-line surveillance tool for detecting OPLs/OCs in high-risk patients.
Objective assessments of lip movement can be beneficial in many disciplines including visual speech recognition, for surgical outcome assessment in patients with cleft lip and for the rehabilitation of patients with facial nerve impairments. The aim of this study was to develop an outcome measure for lip shape during speech using statistical shape analysis techniques. Lip movements during speech were captured from a sample of adult subjects considered as average using a three-dimensional motion capture system. Geometric Morphometrics was employed to extract three-dimensional coordinate data for lip shape during four spoken words decomposed into seven visemes (which included the resting lip shape). Canonical variate analysis was carried out in an attempt to statistically discriminate the seven visemes. The results showed that the second canonical variate discriminated the resting lip shape from articulation of the utterances and accounted for 17.2% of the total variance of the model. The first canonical variate was significant in discriminating between the utterances and accounted for 72.8% of the total variance of the model. The outcome measure was created using the 95% confidence intervals of the canonical variate scores for each subject plotted as ellipses for each viseme. The method and outcome model is proposed as reference to compare lip movement during speech in similar population groups.
In MPTP animal models of Parkinson’s disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association.
Parkinson’s Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression.
Two ADORA2A polymorphisms were inversely associated with PD risk – rs71651683, a 5’ variant (adjusted allelic OR= 0.51, 95% CI 0.33–0.80, permutation-adjusted p=0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wildtype genotype were 0.76 (95% CI 0.57–1.02) and 0.37 (95% CI 0.13–1.01), respectively (permutation-adjusted p for trend=0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (pinteraction=0.05) or rs2470890 (pinteraction=0.04).
In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms.
Parkinson's disease; caffeine; adenosine receptor A2A; polymorphisms; CYP1A2; case-control; epidemiology
In the present study in vivo analgesic activity of some previously synthesized 1,2,4-triazole derivatives containing pyrazole, tetrazole, isoxazole and pyrimidine ring have been evaluated.
Acetic acid induced writhing method and Hot plate method has been described to study analgesic activity of some 1,2,4-triazole derivatives containing pyrazole, tetrazole, isoxazole and pyrimidine as a pharmacological active lead.
Thirty six different derivatives containing 1,2,4-triazole ring were subjected to study their in vivo analgesic activity. Chloro, nitro and methoxy, hydroxy and bromo substituted derivatives showed excellent analgesic activity and dimethylamino, furan and phenyl substituted derivatives showed moderate analgesic activity in both of the methods. Compounds IIIa, IIId, IIIf, IIIi, IIIj, IVa, IVb, IVd, IVf, IVh, IVj IV3a and IIj were found to be superior analgesic agents after screening by Acetic acid induced writhing method. Compounds IIIb, IIId, IIIf, IIIh, IIIj, IVa, IVb, IVd, IVf, IVh, IVi, IV3c, IV3e and IIj were showed analgesic potential after screening of Hot plate method.
All tested compounds containing 1,2,4-triazole were found to be promising analgesic agents, for this activity pyrazole, tetrazole, isoxazole and pyrimidine leads might be supported.
Triazole; Analgesic Activity; Pyrazole; Tetrazole; Isoxazole; Pyrimidine
Eperisone Hydrochloride (EPE) is a potent new generation antispasmodic drug which is used in the treatment of moderate to severe pain in combination with Paracetamol (PAR). Both drugs are available in tablet dosage form in combination with a dose of 50 mg for EPE and 325 mg PAR respectively.
The method is based upon Q-absorption ratio method for the simultaneous determination of the EPE and PAR. Absorption ratio method is used for the ratio of the absorption at two selected wavelength one of which is the iso-absorptive point and other being the λmax of one of the two components. EPE and PAR shows their iso-absorptive point at 260 nm in methanol, the second wavelength used is 249 nm which is the λmax of PAR in methanol.
Results: The linearity was obtained in the concentration range of 5-25 μg/mL for EPE and 2-10 μg/mL for PAR. The proposed method was effectively applied to tablet dosage form for estimation of both drugs. The accuracy and reproducibility results are close to 100% with 2% RSD. Results of the analysis were validated statistically and found to be satisfactory. The results of proposed method have been validated as per ICH guidelines.
A simple, precise and economical spectrophotometric method has been developed for the estimation of EPE and PAR in pharmaceutical formulation.
Eperisone Hydrochloride; Paracetamol; Iso-absorptive point; Absorption ratio method; Spectrophotometric method; ICH
The goal of this study is to demonstrate a practical magnetic resonance imaging technique for quantifying a wide range of hepatic iron concentration (HIC) for hematologic oncology patients with transfusion iron overload in a routine clinical setting. To cover a wide range of T2* values from hematologic patients, we used a dual-acquisition method with two clinically available acquisition protocols on a 1.5T MRI scanner with different ΔTEs to acquire data in two breath-holds. An in-house image postprocessing software tool was developed to generate T2*, iron maps, and water and fat images, when fat is presented in the liver. The resulting iron maps in DICOM format are transferred to the institutional electronic medical record system for review by radiologists. The measured liver T2* values for 28 patients ranged from 0.56 ± 0.13 to 25.0 ± 2.1 milliseconds. These T2* values corresponded to HIC values ranging from 1.2 ± 0.1 mg/g to 45.0 ± 10.0 mg/g (dry weight). A moderate correlation between overall serum ferritin levels and R2* was found with a correlation coefficient of 0.83. Repeated phantom scans confirmed that the precision of this method is better than 4% for T2* measurements. The dual- acquisition method also improved the ability to quantify HIC of the patients with hepatic steatosis.
This study quantified the antibiotic release kinetics and subsequent bactericidal efficacy of rifampicin (RIF) against Gram-positive and Gram-negative bacteria under in vitro static conditions. Antibiotic-loaded scaffolds were fabricated by electrospinning poly(caprolactone) (PCL) with 10% or 20% (w/w) RIF. Scaffold fiber diameter and RIF loading were characterized, and RIF release kinetics were measured. RIF-releasing and RIF-free scaffolds were inoculated with Pseudomonas aeruginosa and Staphylococcus epidermidis, and the suspended concentration live and dead bacteria were determined by fluorescent microscopy. Adherent bacteria and biofilm formation were examined using scanning electron microscopy. Mean fiber diameters were 557 ± 399 nm for RIF-free, 402 ± 225 nm for 10% RIF, and 665 ± 402 nm for 20% RIF scaffolds. RIF release kinetics exhibited a short-burst release during the first hour, followed by a 7 h, zero-order release during which both RIF scaffolds released ~50% of their initial RIF mass loading. P. aeruginosa and S. epidermidis suspended cell populations proliferated in accordance with logarithmic growth models when exposed to control scaffolds; however both RIF-containing scaffolds completely inhibited bacterial growth in suspension and, subsequently, prevented biofilm formation within the scaffolds through the first 6 h.
The idea from human societies that self-interest can lead to a breakdown of cooperation at the group level is sometimes termed the public goods dilemma. We tested this idea in the opportunistic bacterial pathogen, Pseudomonas aeruginosa, by examining the influence of putative cheats that do not cooperate via cell-to-cell signalling (quorum-sensing, QS). We found that: (i) QS cheating occurs in biofilm populations owing to exploitation of QS-regulated public goods; (ii) the thickness and density of biofilms was reduced by the presence of non-cooperative cheats; (iii) population growth was reduced by the presence of cheats, and this reduction was greater in biofilms than in planktonic populations; (iv) the susceptibility of biofilms to antibiotics was increased by the presence of cheats; and (v) coercing cooperator cells to increase their level of cooperation decreases the extent to which the presence of cheats reduces population productivity. Our results provide clear support that conflict over public goods reduces population fitness in bacterial biofilms, and that this effect is greater than in planktonic populations. Finally, we discuss the clinical implications that arise from altering the susceptibility to antibiotics.
quorum-sensing; biofilms; public goods; spatial structure; cooperation; cheating
To examine genetic associations of polymorphisms in the dopamine receptor D2 (DRD2) and D3 (DRD3) genes with risk of Parkinson’s disease (PD).
The study included 1325 newly diagnosed patients with PD and 1735 controls from a consortium of five North American case-control studies. We collected risk factor information by in-person or telephone interview. Six DRD2 and two DRD3 polymorphisms were genotyped using a common laboratory. Odds ratios were estimated using logistic regression.
Among non-Hispanic whites, homozygous carriers of Taq1A DRD2 (rs1800497) polymorphism had an increased risk of PD compared to homozygous wildtype carriers (OR=1.5, 95% CI 1.0–2.3). In contrast, the direction of association for Taq1A polymorphism was opposite for African Americans, showing an inverse association with PD risk (OR=0.10, 95% CI 0.2–0.7). Among white Hispanics who carried two alleles, the Ser9Gly DRD3 (rs6280) polymorphism was associated with a decreased risk of PD (OR=0.4, 95%CI 0.2–0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms.
DRD2 polymorphisms are unlikely to be true disease-causing variants; however, three DRD2 polymorphisms (including Taq1A) may be in linkage disequilibrium with possible disease associated variants in the DRD2-ANKK1-NCAM1-TTC12 gene cluster.
Parkinson's disease; dopamine receptor genes; case-control studies; epidemiology
Despite recent advances, multiple myeloma remains incurable and most patients eventually develop progressive disease. Allogeneic hematopoietic stem cell transplantation (allo HCT) offers a potentially curative option in 10–20% of patients with relapsed or refractory disease. We evaluated the outcome of patients undergoing allo HCT with reduced-intensity conditioning (RIC) for relapsed and/or refractory myeloma at our institution.
Fifty-one patients with heavily pretreated, relapsed myeloma, who received RIC allo HCT between 1996 and 2006, were included in this analysis.
Median time from diagnosis to allo HCT was 34 months. Median follow-up in surviving patients was 27 months (3–98). Cumulative transplant-related mortality (TRM) at 1 year was 25%. Progression-free survival (PFS) and overall survival (OS) at 2 years were 19% and 32%, respectively. The incidence of grade II-IV acute or chronic graft-vs-host disease (GVHD) was 27% and 47%, respectively. At the time of this analysis, 12 patients (24%) were alive 7 of whom (14%) were in remission for up to 6 years after allo SCT. A lower β2 microglobulin (<3.3) and a prior autotransplant predicted a lower NRM, longer PFS and OS.
Allo HCT with RIC regimens is associated with acceptable toxicity and durable remission and survival in relapsed or refractory myeloma. Use of RIC allo HCT earlier in the course of the disease may offer greater benefit.
Stem cells still remain one of the most exciting and lucrative options for treatment of variety of nervous system disorders and diseases. Although there are neural stem cells present in adults, the ability of both the peripheral and central nervous system for self-repair is limited at best. As such, there is a great need for a tissue engineering approach to solve nervous system disorders and diseases. In this study, we have developed electrically conductive surfaces with controlled arrays of high aspect ratio nanowires for the growth and maintenance of neural stem cells. The nanowire surfaces were fabricated from polycaprolactone using a novelnanotemplating technique, and were coated with an electrically conductive polymer, polypyrrole. The polypyrrole coated nanowire surfaces were characterized using scanning electron microscopy and X-ray photoelectron spectroscopy. Additionally, the surface resistance of polypyrrole coated nanowire surfaces was measured. C17.2 neural stem cells were used to evaluate the efficacy of the polypyrrole coated nanowire surfaces to promote cell adhesion, proliferation, and differentiation. The results presented here indicate significantly higher cellular adhesion and proliferation on polypyrrole coated nanowire surfaces as compared to control surfaces. The differentiation potential of polypyrrole nanowire surfaces was also evaluated by immunostaining key neuronal markers that are expressed when NSCs differentiate into their respective neural lineages.
Nanowire surfaces; polycaprolactone; polypyrrole; C17.2 neural stem cells; neural tissue engineering
In India, Adenanthera pavonina is traditionally used in the treatment of diabetes mellitus and lipid disorders. In the present study, the antihyperglycaemic and lipid lowering effect of Adenanthera pavonina seed aqueous extract (APSAE) was evaluated using streptozotocin induced diabetes in rats. Streptozotocin was given at the dose of 55 mg/kg, i.p. After induction of diabetes, APSAE was administered for 30 days p. o. and simultaneously different biochemical parameters like plasma glucose, HbA1c, serum triglyceride, cholesterol, LDL-cholesterol and HDL-cholesterol were estimated. Diabetic control showed significant increase (P < 0.01) in plasma glucose, serum triglyceride, cholesterol, LDL-cholesterol and significant decrease (P < 0.01) in serum HDL-cholesterol and HbA1c. Treatment with APSAE showed significant reduction (P < 0.01) in plasma glucose when compared with diabetic control. The elevated levels of serum triglyceride and cholesterol levels were significantly reduced (P < 0.01) by APSAE. APSAE treatment for 30 days showed significant decrease in serum LDL-cholesterol (P < 0.01) and significant increase in serum HDL cholesterol level (P < 0.01). Moreover, diabetic control there was significant decrease in HbA1c which was significantly increased (P < 0.05) by treatment with APSAE. Hence, from the result obtained in the present study it can be confirmed that Adenanthera pavonina has the potential to treat diabetes condition and associated lipid disorders.
Adenanthera pavonina; Streptozotocin; antihyperglycaemic; Lipid lowering; HbA1c
We analysed the results of haematopoietic cell transplantation (HCT) in 30 patients aged 60–78 (median 65) years, with primary myelofibrosis or myelofibrosis evolving from antecedent polycythaemia vera or essential thrombocythaemia. Donors were human leucocyte antigen (HLA)-identical siblings (N = 15) or unrelated individuals (N = 15). Various conditioning regimens were used, ranging from very low intensity (fludarabine plus 2 Gy total body irradiation) to high dose (busulfan plus cyclophosphamide). Stem cell sources were granulocyte colony-stimulating factor mobilized peripheral blood progenitor cells in 29 patients and marrow in one patient. Sustained engraftment was documented in 27 of 30 patients. Day -100 mortality was 13%. With a median follow-up of 22 (range 0.5–69) months, 3-year overall survival and progression-free survival were 45% and 40%, respectively. Currently, 13 patients are surviving. Seven patients died with disease progression at 0.5–22 months, and 10 patients died from other causes at 1.5–37.5 months after HCT. While the selection of older patients for transplantation was probably biased, the present results are encouraging. Motivated older patients with myelofibrosis without substantial comorbid conditions should be offered the option of allogeneic HCT.
myelofibrosis, older patients; haematopoietic cell transplantation