Control Series Research Articles

The chromosome 7q region association with rheumatoid arthritis in females in a british population is not replicated in a North American case–control series

The single-nucleotide polymorphism (SNP) rs11761231 on chromosome 7q has been reported to be sexually dimorphic marker for rheumatoid arthritis (RA) susceptibility in a British population. We sought to replicate this finding and to better characterize susceptibility alleles in the region in a North American population. DNA from 2 North American collections of RA patients and controls (1,605 cases and 2,640 controls) was genotyped for rs11761231 and 16 additional chromosome 7q tag SNPs using Sequenom iPlex assays. Association tests were performed for each collection and also separately, contrasting male cases with male controls and female cases with female controls. Principal components analysis (EigenStrat) was used to determine association with RA before and after adjusting for population stratification in the subset of the samples for which there were whole-genome SNP data (772 cases and 1,213 controls). We failed to replicate an association of the 7q region with RA. Initially, rs11761231 showed evidence for association with RA in the North American Rheumatoid Arthritis Consortium (NARAC) collection (P=0.0073), and rs11765576 showed association with RA in both the NARAC (P=0.038) and RA replication (P = 0.0013) collections. These markers also exhibited sex differentiation. However, in the whole-genome subset, neither SNP showed significant association with RA after correction for population stratification. While 2 SNPs on chromosome 7q appeared to be associated with RA in a North American cohort, the significance of this finding did not withstand correction for population substructure. Our results emphasize the need to carefully account for population structure to avoid false-positive disease associations.

A combined model predictive control and time series forecasting framework for production-inventory systems

Model Predictive Control (MPC) has been previously applied to supply chain problems with promising results; however most systems that have been proposed so far possess no information on future demand. The incorporation of a forecasting methodology in an MPC framework can promote the efficiency of control actions by providing insight in the future. In this paper this possibility is explored, by proposing a complete management framework for production-inventory systems that is based on MPC and on a neural network time series forecasting model. The proposed framework is tested on industrial data in order to assess the efficiency of the method and the impact of forecast accuracy on the overall control performance. To this end, the proposed method is compared with several alternative forecasting approaches that are implemented on the same industrial dataset. The results show that the proposed scheme can improve significantly the performance of the production-inventory system, due to the fact that more accurate predictions are provided to the formulation of the MPC optimization problem that is solved in real time.

Should California Reconsider Its Legal Drinking Age?

The recent call by 120 American college presidents for reassessment of the legal drinking age of 21 occurs as earlier studies prove to be increasingly limited and outdated. This study tests drinking age effects during the 1975-2005 period using Incidence Rate Ratio analysis of fatal traffic accident and violent death trends among persons ages 16-17, 18-20, and 21-24, as states with lower drinking ages at the time later raised their age limits to 21. Corresponding trends among ages 25-44 and in states that maintained constant drinking ages of 21 were used as control series. The 10 states that maintained “graduated drinking ages” of 18 for beer and/or wine displayed significantly lower violent death incidences among young people than did states with drinking ages for all alcoholic beverages of 18, 19, 20, or 21. This secondary data analysis suggests that California could reduce violent deaths, especially from homicides and motor vehicles, among 18-20-year-olds by approximately 9%, with similar benefits for 16-17- and 21-24-year-olds, if the legal drinking age for beer and wine was reduced to 18 and a controlled system of low-alcohol bars was initiated.

Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells.

IntroductionBasal-like carcinomas (BLCs) and human epidermal growth factor receptor 2 overexpressing (HER2+) carcinomas are the subgroups of breast cancers that have the most aggressive clinical behaviour. In contrast to HER2+ carcinomas, no targeted therapy is currently available for the treatment of patients with BLCs. In order to discover potential therapeutic targets, we aimed to discover deregulated signalling pathways in human BLCs.MethodsIn this study, we focused on the oncogenic phosphatidylinositol 3-kinase (PI3K) pathway in 13 BLCs, and compared it with a control series of 11 hormonal receptor negative- and grade III-matched HER2+ carcinomas. The two tumour populations were first characterised by immunohistochemistry and gene expression. The PI3K pathway was then investigated by gene copy-number analysis, gene expression profiling and at a proteomic level using reverse-phase protein array technology and tissue microarray. The effects of the PI3K inhibition pathway on proliferation and apoptosis was further analysed in three human basal-like cell lines.ResultsThe PI3K pathway was found to be activated in BLCs and up-regulated compared with HER2+ tumours as shown by a significantly increased activation of the downstream targets Akt and mTOR (mammalian target of rapamycin). BLCs expressed significantly lower levels of the tumour suppressor PTEN and PTEN levels were significantly negatively correlated with Akt activity within that population. PTEN protein expression correlated significantly with PTEN DNA copy number and more importantly, reduced PTEN DNA copy numbers were observed specifically in BLCs. Similar to human samples, basal-like cell lines exhibited an activation of PI3K/Akt pathway and low/lack PTEN expression. Both PI3K and mTOR inhibitors led to basal-like cell growth arrest. However, apoptosis was specifically observed after PI3K inhibition.ConclusionsThese data provide insight into the molecular pathogenesis of BLCs and implicate the PTEN-dependent activated Akt signalling pathway as a potential therapeutic target for the management of patients with poor prognosis BLCs.

Electrophysiological effects of short-term antihypertensive therapy

Evaluation of: Porthan K, Viitasalo M, Hiltunen TP et al. Short-term electrophysiological effects of losartan, bisoprolol, amlodipine, and hydrochlorothiazide in hypertensive men. Ann. Med. DOI: 10.1080/07853890802195211 (2008) (Epub ahead of print).Left ventricular hypertrophy (LVH) detected by ECG has been shown to be associated with a higher prevalence of ventricular arrhythmias in members of the general population, in a case–control series of hypertensive patients and in never-treated hypertensive patients. In-keeping with this, it has been observed that hypertension-induced LVH increases the risk of sudden cardiac death. Furthermore, a consistent bulk of data suggests antihypertensive therapy targeted at regression or prevention of electrocardiographic LVH may reduce the incidence of arrhythmias. In this regard, recent clinical trials showed that antihypertensive therapy may delay or prevent the occurrence of cardiac arrhythmias and sudden cardiac death in patients with hypertension. Porthan et al. hypothesized that an antihypertensive therapy might also rapidly affect ventricular repolarization and sought to investigate the short-term electrophysiological effects of four common antihypertensive drugs, represented by an angiotensin II receptor blocker (losartan), a β-blocker (bisoprolol), a calcium channel blocker (amlodipine) and a thiazide diuretic (hydrochlorothiazide) in hypertensive men. Porthan et al. showed that losartan and bisoprolol favorably affected ventricular repolarization, with beneficial effects on ECG parameters of ventricular repolarization duration and heterogeneity. On the contrary, hydrochlorothiazide significantly increased repolarization heterogeneity, while amlodipine administration did not affect ECG repolarization measures. Thus, the observed findings suggest an intriguing hypothesis on the possible role of antihypertensive therapy in favouring or preventing cardiac arrhythmias.

Evaluating new candidate SNPs as low penetrance risk factors in sporadic breast cancer: A two-stage Spanish case–control study

Objectives A polygenic model has been proposed in order to explain the genetic susceptibility to sporadic breast cancer. According to this model, common population variants would be responsible for low to modest effects on the risk of developing the disease. We have carried out a high-throughput SNP genotyping project in order to shed some light on the complex genetic aetiology of non-familial breast cancer. Methods Ninety-one genes have been selected because of their implications in several candidate cell pathways for breast cancer. A total of 640 SNPs in these genes were genotyped in a series of 450 consecutive cases and 448 controls from mainland Spain. Promising SNPs were then studied in an independent series of 294 cases and 299 controls from the Canary Islands. Results In the first case–control series we identified 25 SNPs with P-values below 0.05 (under a 1 df Chi-square test), five of them with P-values below 0.01 (best = 0.0008). In the stage 2 Canary Islands series, odd ratios (OR) for two SNPs in HUS1 were in a consistent direction. Conclusions SNPs located at the gene HUS1 are good candidates for further investigation in independent association studies and functional assays.

Exogenous hydrogen sulfide produces hemodynamic effects by triggering central neuroregulatory mechanisms.

Recently, it was found that hydrogen sulfide (H2S) may serve as an important transmitter in peripheral organs as well as in the brain. The aim of the present study was to evaluate the possible function of H2S in the brain regulation of the circulatory system. Experiments were performed on conscious, male, Wistar-Kyoto rats. Mean arterial blood pressure (MABP) and heart rate (HR) were recorded continuously under baseline conditions and during infusions into the lateral cerebral ventricle (LCV) of the experimental animals. In control series LCV infusion of vehicle (Krebs-Henseleit bicarbonate-buffer) did not cause significant changes in MABP or HR. LCV infusion of H2S donor (NaHS) at the rate of 400 n/h resulted in an increase in MABP, whereas infusions at the rate of 100 n/h and 200 n/h failed to change MABP. On the other hand LCV infusion of H2S donor at the rate of 200 n/h caused a significant increase in HR while infusion at the rate of 400 n/h produced an increase in HR, which was smaller than this observed during infusion at the rate of 200 n/h. H2S donor administered at the rate of 100 n/h failed to affect HR. In conclusion, the present study demonstrates that exogenous hydrogen sulfide changes hemodynamic parameters by centrally mediated mechanisms. The hemodynamic effect seems to be dependent on H2S concentration in cerebrospinal fluid. It appears that the hypertensive response may occur at a concentration, which does not exceed twice the physiological level.

Homozygosity for DNASE2 single nucleotide polymorphisms in the 5′-regulatory region is associated with rheumatoid arthritis

Objectives:To analyse the distribution of single nucleotide polymorphisms (SNPs) in the 5′-regulatory region of the DNASE2 gene, in patients with rheumatoid arthritis (RA) and healthy controls.Methods:A total of 906 patients...

Reply to “Variation in KLK genes, prostate-specific antigen and risk of prostate cancer”

Reply to “Variation in KLK genes, prostate-specific antigen and risk of prostate cancer”

Dopamine β-hydroxylase −1021C>T association and Parkinson's disease

A single nucleotide polymorphism in the promoter region of the dopamine β-hydroxylase gene ( DBH −1021C > T; rs1611115) is reported to regulate plasma enzyme activity levels. This variant has also been the focus of two large association studies in Parkinson's disease yielding conflicting results. We examined this association in four Caucasian patient–control series ( n = 2696). A modest protective association was observed in the Norwegian series (OR = 0.81, p = 0.03; n = 1676), however, the effect was in the opposite direction in the Polish series (OR = 2.01, p = 0.01; n = 224). No association was observed for DBH −1021C > T with disease susceptibility in the US and Irish series, or combining all four series (OR = 0.91, p = 0.16, n = 2696). We observed a modest association between DBH −1021C > T and AAO in the combined series ( p = 0.01). Taken together, these findings indicate that DBH −1021C > T does not play a major role in the pathogenesis of Parkinson's disease.

Morphological criteria of egg quality in marine fishes: Activation and cleavage of eggs of Zebrasoma scopas (Acanthuridae)

Morphological changes of the eggs of Zebrasoma scopas obtained just after ovulation and after the storage of ovulated oocytes in the ovarian cavity of the female (in vivo) or in the external medium (in vitro) are described. The dynamics of cortical reaction is followed in noninseminated oocytes, as well as in inseminated oocytes of various quality. The average proportions of eggs exhibiting normal cleavage in the control series (comprised the eggs inseminated just after ovulation) and in the series stored in vivo for 2 and 4 h at 27 ° C are 83, 30, and 35%, respectively. The average proportions of eggs with normal cleavage in the control series and in the series stored in vitro for 2 and 4 h at 25 ° C are 88, 79, and 34%, respectively. The storage of oocytes in vitro at 7 ° C for 2 h leads to the abrupt decrease of their quality with the proportion of normally cleaved eggs reaching only 15%. The types of abnormal cleavage leading to subsequent degradation of cells of the blastodisc and total mortality of eggs are as follows: (1) mitotic cleavage of nuclei accompanied by incomplete cytotomy, (2) mitotic cleavage of nuclei without cytotomy, (3) a weak adhesion between cells, and (4) desynchronization of cell divisions. The methods for the assessment of egg quality just after ovulation and at initial developmental stages are suggested for marine teleost fishes.

Reply: 3B circumscribed masses: to assess or not to assess?

Reply: 3B circumscribed masses: to assess or not to assess?

Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition

There is substantial evidence that cerebrospinal fluid (CSF) levels of both Abeta42 and tau/ptau are promising biomarkers for Alzheimer's disease (AD). We show that both Abeta and tau exhibit more than 10-fold interindividual variation in CSF levels suggesting that these biomarkers may also be effectively used as endophenotypes for genetic studies of AD. To test the role of common variation in the gene encoding microtubule associated protein tau (MAPT) in influencing CSF tau/ptau levels, we genotyped 21 MAPT single nucleotide polymorphisms (SNPs) in 313 individuals and tested for association with CSF tau/ptau levels. We identified alleles of several SNPs that show association with increased CSF tau/ptau levels. When CSF Abeta42 levels were used to stratify the sample into those with and without likely Abeta deposition in the brain the association was only observed in individuals with evidence of Abeta deposition. This association was replicated in an independent CSF series. When these SNPs were evaluated in a late-onset AD case control series the alleles associated with higher CSF tau/ptau were associated with an earlier age at onset but had no effect on risk for AD. In vivo gene expression studies show that these alleles are associated with increased MAPT mRNA levels in individuals with evidence of brain Abeta deposition. This endophenotype-based approach provides evidence for a gene (MAPT SNPs)-physiological environment (Abeta deposition) interaction that places changes in CSF tau after Abeta deposition and suggest that this interaction predisposes for the development of tauopathy and accelerated disease progression.

Evolution of Bone Mineral Density After Percutaneous Kyphoplasty in Fresh Osteoporotic Vertebral Body Fractures and Adjacent Vertebrae Along With Sagittal Spine Alignment

Prospective controlled cohort study of 27 adult osteoporotic patients who underwent kyphoplasty for fresh osteoporotic spinal fractures. To define the evolution of vertebral bone mineral density (BMD) at kyphoplasty and adjacent levels along with sagittal spinal alignment to contribute to the etiology of adjacent vertebral fractures after augmentation. Osteoporotic compression fractures can be effectively treated with methylmethacrylate vertebral augmentation. However, to the authors' knowledge the effect of vertebral augmentation on the vertebral endplate BMD of the augmented and adjacent nonaugmented levels has not as yet been described. Twenty-seven consecutive selected patients (9 men, 18 women), with an average age of 72+/-9 years underwent 1, 2, or 3-level percutaneous kyphoplasty for painful fresh osteoporotic vertebral fractures at the thoracolumbar spine. All patients were radiologically examined with plain roentgenograms, computed tomography, and magnetic resonance imaging. Lateral dual energy x-ray absorptiometry in the augmented and on the adjacent vertebrae (1 level above and below kyphoplasty) was used to measure BMD preoperatively to the last postoperative observation in the subchondral bone of the vertebral endplates. Anthropometric data, sagittal global balance (plumbline), and segmental spine reconstruction (vertebral body height, Gardner kyphotic angle) were recorded and analyzed. The patients were followed for at least 2 years. Kyphoplasty was performed between T12 and L5. A total of 48 vertebral bodies were augmented. Thirteen patients received 1 level and the remaining 14 received 2 or 3-level kyphoplasty. No significant changes in the sagittal spinal balance were shown postoperatively. Gardner kyphotic angle and posterior vertebral body height improved postoperatively, however, insignificantly. Significant [analysis of variance (ANOVA), P=0.008] increase of anterior vertebral body height in the fractured vertebra was achieved postoperatively without subsequent loss of correction. BMD increased significantly in the lower endplate of the augmented vertebra (ANOVA, P=0.05). In 1-level augmentation, no BMD changes were shown at the adjacent vertebrae above and below kyphoplasty. On the contrary, in the multilevel augmentation, a statistically significant (ANOVA, P=0.05) decrease of the BMD was shown in the upper endplate of the adjacent level above kyphoplasty. During the 2-year follow-up, there were 5 (18%) new fractures at the T11-T12 area above the augmented vertebra. All of the fractures occurred in patients who received 2 and 3-level kyphoplasty. The observed 2-year evolution of vertebral endplate BMD, after kyphoplasty under stable global sagittal spinal balance, might contribute to the pathogenesis of new fractures in adjacent vertebra. However, other studies with control series and longer follow-up are necessary to show if these BMD changes are the result of vertebral augmentation or are merely natural history.

Robust damping control system design for TCSC using particle swarm optimization

PurposeModern power systems suffer from a well‐known problem of low‐frequency oscillations. Flexible AC transmission systems devices are used to overcome this problem. The aim of this paper is to develop a particle swarm optimization (PSO) based supplementary damping control system design for thyristor control series compensator (TCSC).Design/methodology/approachThe problem is formulated as an optimization problem with an eigenvalue‐based multi‐objective function. PSO is then used to find optimal set of controller parameters by minimizing the objective function.FindingsThe performance and robustness of the proposed approach is validated through small signal and large signal for different loading conditions of a multi‐machine power system.Originality/valueThe paper presents a novel PSO‐based control system design that exhibits robustness and excellent damping performance.

Effect of Prior Authorization of Second-Generation Antipsychotic Agents on Pharmacy Utilization and Reimbursements

Effect of Prior Authorization of Second-Generation Antipsychotic Agents on Pharmacy Utilization and Reimbursements

A Model Predictive Control and Time Series Forecasting Framework for Supply Chain Management

A Model Predictive Control and Time Series Forecasting Framework for Supply Chain Management

Lymphatic Vascular Invasion in Ovarian Serous Tumors of Low Malignant Potential With Stromal Microinvasion

Stromal microinvasion in ovarian serous tumors of low malignant potential (S-LMP) stratifies patients at long-term risk for disease progression independent of stage and primary ovarian histology. Despite the histologic impression and often-quoted incidence of lymphatic vascular invasion (LVI) in S-LMP with stromal microinvasion, there has been no formal evaluation in a case control series of S-LMP. The presence and extent of (LVI) was assessed in 20 S-LMP with stromal microinvasion and 20 S-LMP case controls without stromal microinvasion and compared with a series of low-grade and high-grade serous carcinomas using D2-40 monoclonal antibody recognizing podoplanin, a novel lymphatic endothelial marker. S-LMP case controls were matched for primary ovarian histology (usual vs. micropapillary), International Federation of Gynecology and Obstetrics (FIGO) stage, and age (best possible match). The patterns of stromal microinvasion included individual eosinophilic cells and cell clusters, cribriform, simple and noncomplex branching papillae, and inverted macropapillae. Immunohistologic staining with D2-40 monoclonal antibody clearly identified intratumoral LVI in 12/20 (60%) S-LMP with stromal microinvasion and 0/20 S-LMP without stromal microinvasion. Although only 4/13 (31%) low-grade serous carcinomas and 7/20 (35%) high-grade serous carcinomas had intratumoral LVI, hilar LVI was more common in the carcinomas (15% low-grade; 69% high-grade). Intratumoral LVI in S-LMP ranged from focal (6 cases) to multifocal (6 cases, maximum of 5 discrete foci) in any 1 section and included isolated single cells, simple papillae, and in 1 case, cribriform glands. Multifocal LVI was identified in 1 study patient who was pregnant. One of the 12 S-LMP patients with LVI had an intra-abdominal recurrence with high-grade disease at 16 months; whereas all other patients with follow-up were free of disease. LVI in ovarian S-LMP was significantly associated with the presence of stromal microinvasion (P<0.0001) and is independent of age, stage, primary ovarian histology, and pattern or extent of microinvasion. The presence of LVI in microinvasive S-LMP corroborates the view that microinvasion represents an early, but very low risk, invasive process that morphologically links S-LMP and low-grade serous carcinoma.

Steroid-free, tacrolimus-basiliximab immunosuppression in pediatric liver transplantation: Clinical and pharmacoeconomic study in 50 children

Corticosteroid-free immunosuppression (IS) may be potentially beneficial for transplanted patients, particularly children. The purpose of this study was to evaluate the efficacy and cost of such strategy in primary pediatric liver transplantation (LT). Fifty pediatric LT recipients were prospectively treated with a steroid-free, tacrolimus-basiliximab-based IS (group TB). A group of 34 children transplanted under a conventional tacrolimus-steroids regimen served as control series (group TS). Groups TB and TS were compared regarding patient and graft survival, rejection incidence, infectious complications, and growth, as well as cost of the transplant procedure. Patient and graft survivals at 3 years were 96% and 94% in group TB, versus 91% and 88% in group TS (P = 0.380 and P = 0.370, respectively). Rejection-free graft survival at 3 years was 72% in group TB, versus 41% in group TS (P = 0.007). Patients in group TB had significantly less viral infections than patients in group TS (P = 0.045). Height standard deviation score was significantly enhanced in children from group TB, when compared to group TS. Medical care costs were similar in both groups. Steroid avoidance together with basiliximab immunoprophylaxis was not harmful in terms of allograft acceptance, and even seemed to be beneficial in the long term.

Macular Carotenoid Levels of Normal Subjects and Age-Related Maculopathy Patients in a Japanese Population

Macular carotenoid pigments composed of lutein and zeaxanthin are thought to affect the development of age-related maculopathy (ARM). Macular carotenoid levels were measured in normal Japanese subjects and Japanese patients with ARM. Observational case-control series. One hundred normal eyes of 100 normal subjects and 187 eyes of 97 patients with ARM; all were Japanese. The definitions of early ARM and late ARM (exudative age-related macular degeneration [AMD] and dry AMD) were used according to an accepted international classification system. Macular carotenoid levels were measured using resonance Raman spectroscopy. Raman signal intensity generated from carbon-carbon double bond vibrations of lutein and zeaxanthin. The mean (+/-standard deviation [SD]) macular carotenoid level in normal subjects was 1471+/-540 Raman counts. The macular carotenoid levels in normal subjects declined with age. The mean macular carotenoid level was 620+/-204 (+/-SD) in eyes with early ARM and 427+/-283 (+/-SD) in eyes with late ARM (equal to AMD). The macular carotenoid levels of early ARM and AMD were significantly lower than those in normal subjects older than 60 years (1100+/-340 [+/-SD]). No difference was revealed in carotenoid levels by the severity for ARM, type of AMD (exudative, atrophic, and disciform scar), or types of choroidal neovascularization (classic, minimally classic, occult, polypoidal choroidal vasculopathy), although small numbers in some groups weakened statistical power. Macular carotenoid levels were affected by the severity of macular disease in the opposing eye. The average for normal eyes where AMD was found in the opposite eye was significantly lower than that of normal eyes in the absence of AMD in the opposite eye (i.e., healthy volunteers older than 60 years). Macular carotenoids decreased even in older healthy individuals. The ARM patients showed lower macular carotenoid levels than healthy people. Low macular carotenoid levels may be one of the risk factors of progression in ARM.