We compare percutaneous nephrolithotomy (PCNL) and open surgery in the treatment of staghorn stones in children.
We retrospectively reviewed the electronic records of children who underwent treatment for staghorn stones between September 2000 and August 2013. They were divided between Group 1 (patients who underwent PCNL) and Group 2 (patients who underwent open surgery). We compared stone-free and complications rates, need for multiple procedures, and hospital stay.
The study included 41 patients (35 boys and 6 girls), with mean age 7.4 ± 3.1 years (range: 2–15). Of these 41 patients, 26 had unilateral renal stone and 15 had bilateral renal stones. The total number of treated renal units was 56: 28 underwent PCNL and 28 underwent open surgery. The complication rate was comparable for both groups (32% for open surgery vs. 28.6%, p = 0.771). Multiple procedures were more needed in PCNL group (60.7% vs. 32% in open surgery, p = 0.032). The stone-free rate was 71.4% after PCNL and 78.6% after open surgery (p = 0.537). A significant difference was observed in shorter hospital stay after PCNL (5 vs. 8.8 days, p < 0.001). Our study’s limitations include its retrospective design and relatively small sample size.
For the treatment of staghorn stones in children, PCNL was comparable to open surgery in complication and stone-free rates. PCNL had the advantage of a shorter hospital stay and open surgery showed a decreased need for multiple procedures.
To assess the probability of spontaneous stone passage and its predictors after drainage of obstructed kidney by JJ stent, as insertion of an internal ureteric stent is often used for renal drainage in cases of calcular ureteric obstruction.
Patients and methods
Between January 2011 and June 2013, patients for whom emergent drainage by ureteric stents were identified. The patients’ demographics, presentation, and stone characteristics were reviewed. The primary endpoint for this study was stone-free status at the time of stent removal, where all patients underwent non-contrast spiral computed tomography (NCCT) before stent removal. Ureteroscopic stone extraction was performed for CT detectable ureteric stones at the time of stent removal. Potential factors affecting the need for ureteroscopic stone extraction at the time of stent removal were assessed using univariate and multivariate statistical analyses.
Emergent ureteric stents were undertaken in 196 patients (112 males, 84 females) with a mean (SD) age of 53.7 (16.2) years, for renal obstruction drainage. At the time of stent removal, 83 patients (42.3%) were stone free; with the remaining 113 patients (57.7%) undergoing ureteroscopic stone extraction. On multivariate analysis, stone width [odds ratio (OR) 15.849, 95% confidence interval (CI) 2.83; P = 0.002) and radio-opaque stones (OR 12.035, 95% CI 4.65; P < 0.001) were independent predictors of the need for ureteroscopic stone extraction at the time of stent removal.
Spontaneous ureteric stone passage is possible after emergent drainage of an obstructed kidney by ureteric stenting. Stone opacity, larger stone width, and positive preoperative urine culture are associated with a greater probability of requiring ureteroscopic stone extraction after emergent drainage by ureteric stenting.
BMI, body mass index; MSUC, midstream urine culture; NCCT, non-contrast spiral CT; OR, odds ratio; PCN, percutaneous nephrostomy; ROC, Receiver operating characteristic; SIRS, systemic inflammatory response syndrome; URS, ureteroscopy; Emergency; Drainage; Ureteroscopy; Ureteric calculi; Ureteric stent
Aim. To compare pars plana vitrectomy (PPV) with silicone tamponade or gas (Groups Ia and Ib) and a new modified Ando plombe equipped with a fiber optic light (Group II) for cases with macular hole retinal detachment (MHRD) in high myopic eyes (axial length > 26 mm). Methods. A prospective interventional randomized case series included 60 eyes (20 in each group). Successful outcome was considered if the retina was completely attached at the end of the follow-up period. Complications were identified for each group. Results. Visual acuity improved by 37.31%, 40.67%, and 49.40% in Groups Ia, Ib, and II, respectively. The success rate was 55%, 60%, and 100% in Groups Ia , Ib, and II, respectively, with a statistically significant difference between Groups Ia, Ib, and II (p < 0.001 in Ia, p: 0.002 in Ib). Complications rates were 60%, 45%, and 20% in Groups Ia, Ib, and II, respectively, with a statistically significant difference between Groups Ia and II (p: 0.01). Conclusion. Fiber optic illuminated Ando plombe allows better positioning under the macula and consequently improves the success rate of epimacular buckling in comparison to PPV with internal tamponade in MMHRD.
To compare the efficacy, safety and cost of extracorporeal shockwave lithotripsy (ESWL) and percutaneous nephrolithotomy (PNL) for treating a 20–30 mm single renal pelvic stone.
Patients and methods
The computerised records of patients who underwent PNL or ESWL for a 20–30 mm single renal pelvic stone between January 2006 and December 2012 were reviewed retrospectively. Patients aged <18 years who had a branched stone, advanced hydronephrosis, a solitary kidney, anatomical renal abnormality, or had a surgical intervention within the past 6 months were excluded. The study included 337 patients with a mean (SD, range) age of 49.3 (12.2, 20–81) years. The patients’ criteria (age, sex, body mass index) and the stone characteristics (side, stone length, surface area, attenuation value and skin-to-stone distance) were compared between the groups. The re-treatment rate, the need for secondary procedures, success rate, complications and the total costs were calculated and compared.
In all, 167 patients were treated by ESWL and 170 by PNL. The re-treatment rate (75% vs. 5%), the need for secondary procedures (25% vs. 4.7%) and total number of procedures (three vs. one) were significantly higher in the ESWL group (P < 0.001). The success rate was significantly higher in the PNL group (95% vs. 75%, P < 0.001), as was the complication rate (13% vs. 6.6%, P = 0.050). The total costs of primary and secondary procedures were significantly higher for PNL (US$ 1120 vs. 490; P < 0.001).
PNL was more effective than ESWL for treating a single renal pelvic stone of 20–30 mm. However, ESWL was associated with fewer complications and a lower cost.
PNL, Percutaneous nephrolithotomy; BMI, Body mass index; RIRS, Retrograde intrarenal surgery; SFR, Stone-free rate; Percutaneous nephrolithotomy; Extracorporeal shockwaves lithotripsy; Single renal stone; Cost
Voltage sags can be symmetrical or unsymmetrical depending on the causes of the sag. At the present time, one of the most common procedures for mitigating voltage sags is by the use of dynamic voltage restorers (DVRs). By definition, a DVR is a controlled voltage source inserted between the network and a sensitive load through a booster transformer injecting voltage into the network in order to correct any disturbance affecting a sensitive load voltage. In this paper, modelling of DVR for voltage correction using MatLab software is presented. The performance of the device under different voltage sag types is described, where the voltage sag types are introduced using the different types of short-circuit faults included in the environment of the MatLab/Simulink package. The robustness of the proposed device is evaluated using the common voltage sag indices, while taking into account voltage and current unbalance percentages, where maintaining the total harmonic distortion percentage of the load voltage within a specified range is desired. Finally, several simulation results are shown in order to highlight that the DVR is capable of effective correction of the voltage sag while minimizing the grid voltage unbalance and distortion, regardless of the fault type.
Dynamic voltage restorers; Faults; Power conditioners; Power quality; Power system harmonics; Unbalanced conditions
Host Defense Peptides (HDPs) are small cationic peptides found in several organisms. They play a vital role in innate immunity response and immunomodulatory stimulation. This investigation was designed to study the antimicrobial activities of β-defensin peptide-4 (sAvBD-4) and 10 (sAvBD-4) derived from chickens against pathogenic organisms including bacteria and fungi. Ten bacterial strains and three fungal species were used in investigation. The results showed that the sAvBD-10 displayed a higher bactericidal potency against all the tested bacterial strains than that of sAvBD-4. The exhibited bactericidal activity was significant against almost the different bacterial strains at different peptide concentrations except for that of Pseudomonas aeruginosa (P. aeruginosa) and Streptococcus bovis (Str. bovis) strains where a moderate effect was noted. Both peptides were effective in the inactivation of fungal species tested yielding a killing rate of up to 95%. The results revealed that the synthetic peptides were resistant to salt at a concentration of 50 mM NaCl. However, they lost antimicrobial potency when applied in the presence of high salt concentrations. Based on blood hemolysis studies, a little hemolytic effect was showed in the case of both peptides even when applied at high concentrations. The data obtained from this study indicated that synthetic avian peptides exhibit strong antibacterial and antifungal activity. In conclusion, future work and research should be tailored to a better understanding of the mechanisms of action of those peptides and their potential use in the pharmaceutical industry to help reduce the incidence and impact of infectious agent and be marketed as a naturally occurring antibiotic.
antimicrobial activity; synthetic AvBD-4 and 10; bacteria; fungi; natural antibiotic
Little is known about the parasite/host factors that lead to Post Kala-azar Dermal Leishmaniasis (PKDL) in some visceral leishmaniasis (VL) patients after drug-cure. Studies in Sudan provide evidence for association between polymorphisms in the gene (IFNGR1) encoding the alpha chain of interferon-γ receptor type I and risk of PKDL. This study aimed to identify putative functional polymorphisms in the IFNGR1 gene, and to determine whether differences in expression of interferon-γ (IFNG) and IFNGR1 at the RNA level are associated with pathogenesis of VL and/or PKDL in Sudan.
Sanger sequencing was used to re-sequence 841 bp of upstream, exon1 and intron1 of the IFNGR1 gene in DNA from 30 PKDL patients. LAGAN and SYNPLOT bioinformatics tools were used to compare human, chimpanzee and dog sequences to identify conserved noncoding sequences carrying putative regulatory elements. The relative expression of IFNG and IFNGR1 in paired pre- and post-treatment RNA samples from the lymph nodes of 24 VL patients, and in RNA samples from skin biopsies of 19 PKDL patients, was measured using real time PCR. Pre- versus post-treatment expression was evaluated statistically using the nonparametric Wilcoxon matched pairs signed-rank test.
Ten variants were identified in the 841 bp of sequence, four of which are novel polymorphisms at -77A/G, +10 C/T, +18C/T and +91G/T relative to the IFNGR1 initiation site. A cluster of conserved non-coding sequences with putative regulatory variants was identified in the distal promoter of IFNGR1. Variable expression of IFNG was detected in lymph node aspirates of VL patients before treatment, with a marked reduction (P = 0.006) in expression following treatment. IFNGR1 expression was also variable in lymph node aspirates from VL patients, with no significant reduction in expression with treatment. IFNG expression was undetectable in the skin biopsies of PKDL cases, while IFNGR1 expression was also uniformly low.
Uniformly low expression of IFN and IFNGR1 in PKDL skin biopsies could explain parasite persistence and is consistent with prior demonstration of genetic association with IFNGR1 polymorphisms. Identification of novel potentially functional rare variants at IFNGR1 makes an important general contribution to knowledge of rare variants of potential relevance in this Sudanese population.
PKDL; Visceral leishmaniasis; Polymorphisms; RNA expression; IFNG; IFNGR1; Rare variants; Sudan
To determine the use of the prostate specific antigen (PSA) level and digital rectal examination (DRE) findings to estimate the resected tissue weight (RTW) before transurethral resection of the prostate (TURP).
Patients and methods
We retrospectively analysed 983 patients who underwent TURP between December 2006 and December 2012. The primary outcome was the RTW required for clinical improvement, and was not associated with re-intervention. Age, PSA level, body mass index (BMI) and DRE findings were correlated and modelled with the RTW. The DRE result was defined as DREa (small vs. large) or DREb (small vs. moderate vs. large) according to the surgeon’s report. Equations to calculate RTW were developed and tested using receiver operating characteristic (ROC) curve analyses.
There were significant correlations between PSA level (r = 0.4, P < 0.001) and RTW, whilst BMI and age showed weak correlations. The median (range) RTW was 45 (7–60) vs. 15 (6–60) g for small vs. large prostates (DREa) (P < 0.001), respectively. Similarly, the median (range) RTW was 11 (6–59) vs. 26.2 (6–60) vs. 42 (7–60) g in small vs. moderate vs. large prostates (DREb) (P < 0.001), respectively. Using PSA level and DREb (model 3) there was a significantly better ability to estimate RTW than using PSA and DREa (model 2) or PSA alone (model 1) based on ROC curve analyses. The equation developed by model 3 (RTW = 1.2 + (1.13 × PSA) + (DREb × 9.5)) had a sensitivity and specificity of 82% and 71% for estimating a RTW of >30 g, and 84% and 63% for estimating a RTW of >40 g, respectively.
The PSA level and DRE findings can be used to predict the RTW before TURP.
AUC, area under the curve; BMI, body mass index; ROC, receiver operating characteristic; RTW, resected tissue weight; PV, prostate volume; PSA; TURP; Prostate volume; Resected tissue weight; DRE
Date palm is a very important crop in western Asia and northern Africa, and it is the oldest domesticated fruit tree with archaeological records dating back 5000 years. The huge economic value of this crop has generated considerable interest in breeding programs to enhance production of dates. One of the major limitations of these efforts is the uncertainty regarding the number of date palm cultivars, which are currently based on fruit shape, size, color, and taste. Whole mitochondrial and plastid genome sequences were utilized to examine single nucleotide polymorphisms (SNPs) of date palms to evaluate the efficacy of this approach for molecular characterization of cultivars. Mitochondrial and plastid genomes of nine Saudi Arabian cultivars were sequenced. For each species about 60 million 100 bp paired-end reads were generated from total genomic DNA using the Illumina HiSeq 2000 platform. For each cultivar, sequences were aligned separately to the published date palm plastid and mitochondrial reference genomes, and SNPs were identified. The results identified cultivar-specific SNPs for eight of the nine cultivars. Two previous SNP analyses of mitochondrial and plastid genomes identified substantial intra-cultivar ( = intra-varietal) polymorphisms in organellar genomes but these studies did not properly take into account the fact that nearly half of the plastid genome has been integrated into the mitochondrial genome. Filtering all sequencing reads that mapped to both organellar genomes nearly eliminated mitochondrial heteroplasmy but all plastid SNPs remained heteroplasmic. This investigation provides valuable insights into how to deal with interorganellar DNA transfer in performing SNP analyses from total genomic DNA. The results confirm recent suggestions that plastid heteroplasmy is much more common than previously thought. Finally, low levels of sequence variation in plastid and mitochondrial genomes argue for using nuclear SNPs for molecular characterization of date palm cultivars.
Anti-leishmanial drug regimens that include a single dose AmBisome® could be suitable for eastern African patients with symptomatic visceral leishmaniasis (VL) but the appropriate single dose is unknown.
A multi-centre, open-label, non-inferiority, randomized controlled trial with an adaptive design, was conducted to compare the efficacy and safety of a single dose and multiple doses of AmBisome® for the treatment of VL in eastern Africa. The primary efficacy endpoint was definitive cure (DC) at 6 months. Symptomatic patients with parasitologically-confirmed, non-severe VL, received a single dose of AmBisome® 7.5 mg/kg body weight or multiple doses, 7 times 3 mg/kg on days 1–5, 14, and 21. If interim analyses, evaluated 30 days after the start of treatment following 40 or 80 patients, showed the single dose gave significantly poorer parasite clearance than multiple doses at the 5% significance level, the single dose was increased by 2·5 mg/kg. In a sub-set of patients, parasite clearance was measured by quantitative reverse transcriptase (qRT) PCR.
The trial was terminated after the third interim analysis because of low efficacy of both regimens. Based on the intention-to-treat population, DC was 85% (95%CI 73–93%), 40% (95%CI 19–64%), and 58% (95%CI 41–73%) in patients treated with multiple doses (n = 63), and single doses of 7·5 (n = 21) or 10 mg/kg (n = 40), respectively. qRT-PCR suggested superior parasite clearance with multiple doses as early as day 3. Safety data accorded with the drug label.
The tested AmBisome® regimens would not be suitable for VL treatment across eastern Africa. An optimal single dose regimen was not identified.
Visceral leishmaniasis is a potentially fatal disease which affects 0.2–0.4 million people every year, principally in South-East Asia, Latin America or Eastern Africa. Currently the safest drug in use is AmBisome®, which cures 90% of patients in India at 5 mg/kg, and is even more effective at higher doses (10 mg/kg) or in combination with miltefosine or paromomycin. These regimens have been shown to be equally cost-effective in India. However, the drug requires a cold chain for storage and reconstitution prior to injection. Although it is licensed for use in eastern Africa, in practice it is mainly used as a second-line treatment. A small study carried out in Kenya indicated that a higher dose is necessary in eastern Africa in contrast to Asia. This study aimed to determine the minimum single dose that is safe and effective for treatment of eastern African VL patients so as to be used in simplified treatment regimens. However, the tested regimens were found to be ineffective, and an optimal single dose that could potentially be used in simplified treatment regimens was not identified.
Visceral leishmaniasis (VL) is a serious parasitic disease for which control measures are limited and drug resistance is increasing. First and second generation vaccine candidates have not been successful. The goal of the present study was to select possibly immunogenic L. donovani donovani GP63 peptides using immunoinformatics tools and to test their immunogenicity in vitro. The amino acid sequence of L. donovani donovani GP63 [GenBank accession: ACT31401] was screened using the EpiMatrix algorithm for putative T cell epitopes that would bind to the most common HLA class II alleles (DRB1*1101 and DRB1*0804) among at–risk populations. Four T cell epitopes were selected from nine potential candidates. Stimulation of whole blood from healthy volunteers using the peptides separately produced mean IFN-γ and IL-4 levels that were not significantly different from negative controls, while the pooled peptides produced a moderate IFN-γ increase in some volunteers. However, mean IL-10 levels were significantly reduced for all individuals compared with controls. The immunogenicity of these epitopes may be harnessed most effectively in a vaccine delivered in combination with immune-modulating adjuvants.
visceral leishmaniasis; vaccine; T cell epitopes; EpiMatrix
Tuberculosis is a major health problem in developing countries. The distinction between tuberculous lymphadenitis, non-specific lymphadenitis and malignant lymph node enlargement has to be made at primary health care levels using easy, simple and cheap methods.
To develop a reliable clinical algorithm for primary care settings to triage cases of non-specific, tuberculous and malignant lymphadenopathies.
Calculation of the odd ratios (OR) of the chosen predictor variables was carried out using logistic regression. The numerical score values of the predictor variables were weighed against their respective OR. The performance of the score was evaluated by the ROC (Receiver Operator Characteristic) curve.
Four predictor variables; Mantoux reading, erythrocytes sedimentation rate (ESR), nocturnal fever and discharging sinuses correlated significantly with TB diagnosis and were included in the reduced model to establish score A. For score B, the reduced model included Mantoux reading, ESR, lymph-node size and lymph-node number as predictor variables for malignant lymph nodes. Score A ranged 0 to 12 and a cut-off point of 6 gave a best sensitivity and specificity of 91% and 90% respectively, whilst score B ranged -3 to 8 and a cut-off point of 3 gave a best sensitivity and specificity of 83% and 76% respectively. The calculated area under the ROC curve was 0.964 (95% CI, 0.949 – 0.980) and -0.856 (95% CI, 0.787 - 0.925) for scores A and B respectively, indicating good performance.
The developed algorithm can efficiently triage cases with tuberculous and malignant lymphadenopathies for treatment or referral to specialised centres for further work-up.
In the title compound, C23H20BrNO4, the pyran ring has a flattened boat conformation with the O and methine C atoms lying to one side of the plane [0.160 (5) and 0.256 (6) Å, respectively] defined by the remaining atoms. Nevertheless, the 4H-benzo[h]chromene ring system approximates a plane (r.m.s. deviation = 0.116 Å) with the bromobenzene ring almost perpendicular [dihedral angle = 83.27 (16)°] and the ester group coplanar [C—C—C—O = 3.4 (5)°]; the methoxy substituent is also coplanar [C—O—C—C = 174.5 (3)°]. In addition to an intramolecular N—H⋯O(ester carbonyl) hydrogen bond, the ester carbonyl O atom also forms an intermolecular N—H⋯O hydrogen bond with the second amine H atom, generating a zigzag supramolecular chain along the c axis in the crystal packing. The chains are linked into layers in the bc plane by N—H⋯Br hydrogen bonds, and these layers are consolidated into a three-dimensional architecture by C—H⋯π interactions.
To present the results of percutaneous nephrolithotomy (PCNL) for treating staghorn stones.
Patients and methods
A database was compiled from the computerised files of patients who underwent PCNL for staghorn stones between 1999 and 2009. The study included 238 patients (128 males and 110 females) with a mean (SD) age of 48.9 (14) years, who underwent 242 PCNLs, and included staghorn stones that were present in the renal pelvis and branched into two or more major calyces. PCNL was performed or supervised by an experienced endourologist. All perioperative complications were recorded. The stone-free status was evaluated after PCNL and again after 3 months.
Multiple tracts were needed in 35.5% of the procedures, and several sessions of PCNL were needed in 30% of patients. There were perioperative complications in 54 procedures (22%); blood transfusion was needed in 34 patients (14%). The stone-free rate for PCNL monotherapy was 56.6% (137 patients). Secondary procedures were required for 51 patients (21%), and included shock-wave lithotripsy for 49 and ureteroscopy for two. The 3-month stone-free rate was 72.7% (176 patients). Multiple tracts resulted in an insignificantly higher overall complication rate than with a single tract (P = 0.219), but the reduction in the haemoglobin level was statistically significant with multiple tracts (P = 0.001).
PCNL for staghorn stones must be done by an experienced endourologist in a specialised centre with all the facilities for stone management and treatment of possible complications. The patients must be informed about the range of stone-free and complication rates, and the possibility of multiple sessions or secondary procedures.
NCCT, non-contrast CT; PCNL, percutaneous nephrolithotomy; Percutaneous nephrolithotomy; Staghorn; Stones; Kidney
Water hyacinth, Eichhornia crassipes (Mart) Solms, originating in the amazonian basin, is a warm water aquatic plant. Water hyacinth is considered one of the most productive plants on earth and, accordingly, is considered one of the top ten world's worst weeds. Water hyacinth spread to other tropical and subtropical regions by humans. It invaded about 62 countries in Africa, Asia and North America, and propagated extremely serious ecological, economical and social problems in the region between 40 degrees north and 45 degrees south. The dense weed of water hyacinth forms dense monocultures that can threaten local native species diversity and change the physical and chemical aquatic environment, thus altering ecosystem structure and function by disrupting food chains and nutrient cycling. We have separated and identified nine active fractions from water hyacinth and showed their promising therapeutic activities. Several compounds (alkaloid, phthalate derivatives, propanoid and phenyl derivatives) were identified in the extract of water hyacinth.
water hyacinth; antimicrobial; anticancer; active compounds
Post kala-azar dermal leishmanaisis (PKDL) in Sudan is associated with elevated interferon-γ. To study interferon-γ pathways in PKDL, we genotyped 80 trios from the Masalit ethnic group for polymorphisms at −470 ins/delTT, -270T/C, -56T/C and +95T/C in IFNGR1, and at −179G/A and +874T/A in IFNG. No associations occurred at IFNG. Global association with haplotypes comprising all 4 markers at IFNGR1 (χ210df = 21.97, P=0.015) was observed, associated with a significant (χ21df=4.54, P=0.033) bias in transmission of the haplotype insTT T T T, and less (χ21df=5.59, P=0.018) than expected transmission of insTT C C C. When compared with data on malaria associations from The Gambia, the results suggest a complex pattern of haplotypic variation at the IFNGR1 promoter locus associated with different infectious disease in African populations that reflect the complex roles of IFN-γ in parasite killing versus inflammation and pathogenesis.
PKDL; leishmaniasis; association; IFNGR1
With advances in anisotropic particle synthesis, particle shape is now a feasible parameter for tuning suspension properties. However, there is a need to determine how these newly synthesized particles with prescribed shapes affect suspension properties and to solve the inverse problem of inferring the shape of particles from property measurements. Either way, accurate suspension property predictions are required. Towards this end, we calculated a set of dilute suspension properties for a family of cube-like shapes that smoothly interpolate between spheres and cubes. Using three conceptually different methods, we numerically computed the electrical properties of particle suspensions, including the intrinsic conductivity of perfect conductors and insulators. We also considered hydrodynamic properties relevant to particle solutions including the hydrodynamic radius, the intrinsic viscosity and the intrinsic solvent diffusivity. Additionally, we determined the second osmotic virial coefficient using analytic expressions along with numerical integration. As the particles became more cube-like, we found that all of the properties investigated become more sensitive to particle shape.
Bupropion was tested for efficacy to achieve methamphetamine (MA) abstinence in dependent, non-daily users.
A randomized, double-blind, placebo-controlled trial, with 12-week treatment and 4-week follow-up, was conducted with 204 treatment-seeking participants having MA dependence per DSM-IV, who used MA on a less-than-daily basis. 104 were randomized to matched placebo and 100 to bupropion, sustained-release 150mg, twice daily. Participants were seen three times weekly to obtain urine for MA and bupropion assays, study assessments, and thrice weekly, 90-minute, group psychotherapy. There was no biomarker for placebo adherence. The primary outcome was achievement of abstinence throughout the last two weeks of treatment; ‘success’ requiring at least two urine samples during each of Weeks 11 and 12, and all samples MA-negative (<300ng/mL).
Bupropion and placebo groups did not differ significantly in the percentage achieving abstinence for the last 2 weeks of treatment (chi-square, p=0.32). Subgroup analysis of participants with lower baseline MA use (≤18 of last 30 days before consent) also revealed no difference in success between groups (p=0.73). Medication adherence per protocol (detectable bupropion, >5ng/mL, in ≥50% of urine samples from Study Weeks 1–10 and ≥66% of urine samples from Weeks 11–12) was achieved by 47% of participants taking bupropion.
These data indicate that bupropion did not increase abstinence in dependent participants who were using MA less-than-daily. Medication non-adherence was a limitation in this trial. Psychosocial therapy remains the mainstay of treatment for MA dependence. Further research on subgroups who may respond to bupropion may be warranted.
www.ClinicalTrials.gov : NCT00687713.
Bupropion; Methamphetamine; Substance-related disorders; Drug therapy; Medication adherence; Patient acuity
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In this study, a series of novel furo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine based-derivatives were designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The synthesized compounds were evaluated for their ability to in vitro inhibit VEGFR-2 kinase enzyme. Seven compounds (15b, 16c, 16e, 21a, 21b, 21c and 21e) demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range, of which the thieno[2,3-d]pyrimidine based-derivatives (21b, 21c and 21e) exhibited IC50 values of 33.4, 47.0 and 21 nM respectively. Moreover, furo[2,3-d]pyrimidine-based derivative (15b) showed the strongest inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 99.5% inhibition at 10 μM concentration. Consistent with our in vitro findings, compounds (21b and 21e) orally administered at 5 and 10 mg/kg/day for 8 consecutive days demonstrated potent anticancer activity in Erhlich ascites carcinoma (EAC) solid tumor murine model. Such compounds blunted angiogenesis in EAC as evidenced by reduced percent microvessel via decreasing VEGFR-2 phosphorylation with subsequent induction of apoptotic machinery. Furthermore, Miles vascular permeability assay confirmed their antiangiogenic effects in vivo. Intriguingly, such compounds showed no obvious toxicity.
L-DOPA therapy in Parkinson’s disease often results in side effects such as L-DOPA-induced dyskinesia (LID). Our previous studies demonstrated that defective desensitization of dopamine receptors caused by decreased expression of G protein-coupled receptor kinases (GRKs) plays a role. Overexpression of GRK6, the isoform regulating dopamine receptors, in parkinsonian rats and monkeys alleviated LID and reduced LID-associated changes in gene expression. Here we show that 2-fold lentivirus-mediated overexpression of GRK6 in the dopamine-depleted striatum in rats unilaterally lesioned with 6-hydroxydopamine ameliorated supersensitive ERK response to L-DOPA challenge caused by loss of dopamine. A somewhat stronger effect of GRK6 was observed in drug-naïve than in chronically L-DOPA-treated animals. GRK6 reduced the responsiveness of p38 MAP kinase to L-DOPA challenge rendered supersensitive by dopamine depletion. The JNK MAP kinase was unaffected by loss of dopamine, chronic or acute L-DOPA, or GRK6. Overexpressed GRK6 suppressed enhanced activity of Akt in the lesioned striatum by reducing elevated phosphorylation at its major activating residue Thr308. Finally, GRK6 reduced accumulation of ΔFosB in the lesioned striatum, the effect that paralleled a decrease in locomotor sensitization to L-DOPA in GRK6-expressing rats. The results suggest that elevated GRK6 facilitate desensitization of DA receptors, thereby normalizing of the activity of multiple signaling pathways implicated in LID. Thus, improving the regulation of dopamine receptor function via the desensitization mechanism could be an effective way of managing LID.
Parkinson’s disease; L-DOPA-induced dyskinesia; GRK6; lentivirus; ERK1/2; p38; Akt; JNK; ΔFosB
AIM: To explore the approaches exerted by mesenchymal stem cells (MSCs) to improve Parkinson’s disease (PD) pathophysiology.
METHODS: MSCs were harvested from bone marrow of femoral bones of male rats, grown and propagated in culture. Twenty four ovariectomized animals were classified into 3 groups: Group (1) was control, Groups (2) and (3) were subcutaneously administered with rotenone for 14 d after one month of ovariectomy for induction of PD. Then, Group (2) was left untreated, while Group (3) was treated with single intravenous dose of bone marrow derived MSCs (BM-MSCs). SRY gene was assessed by PCR in brain tissue of the female rats. Serum transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1) and brain derived neurotrophic factor (BDNF) levels were assayed by ELISA. Brain dopamine DA level was assayed fluorometrically, while brain tyrosine hydroxylase (TH) and nestin gene expression were detected by semi-quantitative real time PCR. Brain survivin expression was determined by immunohistochemical procedure. Histopathological investigation of brain tissues was also done.
RESULTS: BM-MSCs were able to home at the injured brains and elicited significant decrease in serum TGF-β1 (489.7 ± 13.0 vs 691.2 ± 8.0, P < 0.05) and MCP-1 (89.6 ± 2.0 vs 112.1 ± 1.9, P < 0.05) levels associated with significant increase in serum BDNF (3663 ± 17.8 vs 2905 ± 72.9, P < 0.05) and brain DA (874 ± 15.0 vs 599 ± 9.8, P < 0.05) levels as well as brain TH (1.18 ± 0.004 vs 0.54 ± 0.009, P < 0.05) and nestin (1.29 ± 0.005 vs 0.67 ± 0.006, P < 0.05) genes expression levels. In addition to, producing insignificant increase in the number of positive cells for survivin (293.2 ± 15.9 vs 271.5 ± 15.9, P > 0.05) expression. Finally, the brain sections showed intact histological structure of the striatum as a result of treatment with BM-MSCs.
CONCLUSION: The current study sheds light on the therapeutic potential of BM-MSCs against PD pathophysiology via multi-mechanistic actions.
Parkinson’s disease; Pathophysiology; Bone marrow derived mesenchymal stem cells; Rotenone; Anti-inflammatory action; Ovariectomy; Anti-apoptotic effect; Neurogenic potential
The integration of ion mobility spectrometry (IMS) with mass spectrometry (MS) and the ability to trap ions in IMS-MS measurements is of great importance for performing reactions, accumulating ions, and increasing analytical measurement sensitivity. The development of Structures for Lossless Ion Manipulations (SLIM) offers the potential for ion manipulations in an extended and more effective manner, while opening opportunities for many more complex sequences of manipulations. Here, we demonstrate an ion separation and trapping module and a method based upon SLIM that consists of a linear mobility ion drift region, a switch/tee and a trapping region that allows the isolation and accumulation of mobility-separated species. The operation and optimization of the SLIM switch/tee and trap are described and demonstrated for the enrichment of the low abundance ions. A linear improvement in ion intensity was observed with the number of trapping/accumulation events using the SLIM trap, illustrating its potential for enhancing the sensitivity of low abundance or targeted species.
The merging of high-throughput gene expression techniques, such as microarray, in the screening of natural products as anticancer agents, is considered the optimal solution for gaining a better understanding of the intervention mechanism. Red yeast rice (RYR), a Chinese dietary product, contains a mixture of hypocholesterolemia agents such as statins. Typically, statins have this effect via the inhibition of HMG-CoA reductase, the key enzyme in the biosynthesis of cholesterol. Recently, statins have been shown to exhibit various beneficial antineoplastic properties through the disruption of tumor angiogenesis and metastatic processes. Mevinolin (MVN) is a member of statins and is abundantly present in RYR. Early experimental trials suggested that the mixed apoptotic/necrotic cell death pathway is activated in response to MVN exposure. In the current study, the cytotoxic profile of MVN was evaluated against MCF-7, a breast cancer-derived cell line. The obtained results indicated that MVN-induced cytotoxicity is multi-factorial involving several regulatory pathways in the cytotoxic effects of MVN on breast cancer cell lines. In addition, MVN-induced transcript abundance profiles inferred from microarrays showed significant changes in some key cell processes. The changes were predicted to induce cell cycle arrest and reactive oxygen species generation but inhibit DNA repair and cell proliferation. This MVN-mediated multi-factorial stress triggered specific programmed cell death (apoptosis) and DNA degradation responses in breast cancer cells. Taken together, the observed MVN-induced effects underscore the potential of this ubiquitous natural compound as a selective anticancer activity, with broad safety margins and low cost compared to benchmarked traditional synthetic chemotherapeutic agents. Additionally, the data support further pre-clinical and clinical evaluations of MVN as a novel strategy to combat breast cancer and overcome drug resistance.
mevinolin; microarray; MCF-7; natural products; p53