bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Incidence of Perforated Appendicitis in Children With Obesity
Authors: Blanco Felix C. , Sandler Anthony D. , Nadler Evan P.
Published: April 2012

Based on their clinical impression, the authors hypothesized that children with obesity may more commonly present with perforated appendicitis. Therefore, the authors reviewed their experience from 2008 to 2010 to determine whether obesity affected the clinical presentation of appendicitis. Variables studied were height, weight, use of diagnostic imaging, and clinical findings of appendicitis at presentation. Outcomes assessed were length of stay and complication rate. The study identified 319 patients with appendicitis. Children with obesity were more likely ( P = .026) to present with perforation (28/62, 45%) than nonobese patients (78/257, 30%). Neither length of stay nor complication rate was affected by the presence of obesity. The data suggest that children with obesity are more likely to present with perforated appendicitis. This finding suggests that the diagnosis of appendicitis may be more difficult in obese patients or their presentation may be delayed. Practitioners should have heightened awareness in children with obesity and symptoms of abdominal pain.
Identifying Social Risk via a Clinical Social History Embedded in the Electronic Health Record
Authors: Beck Andrew F. , Klein Melissa D. , Kahn Robert S.
Published: April 2012

Although the link between social determinants and health outcomes is well established, the social history remains poorly integrated into clinical care processes. This study’s purpose was to determine social risk documentation rates among newborns using a new electronic template. A retrospective review of 639 well-infant visits was performed. The authors determined documentation rates for a standardized social history embedded in the clinic electronic health record. Social history completion rates and prevalence of risks were identified. More than 80% of clinicians documented asking at least 1 of 7 questions (mean = 4.5, SD = 2.9). The most commonly asked question was about “making ends meet,” and the least common was about personal safety (79% vs 57%, P < .01). Nearly 30% of caregivers reported at least 1 risk, 11% at least 2 risks. An electronic health record–embedded social history led to documented screening in more than 80% of visits, identifying 30% as having at least 1 social risk.
Proximity and Visibility of Fruits and Vegetables Influence Intake in a Kitchen Setting Among College Students
Authors: Privitera Gregory J. , Creary Heather E.
Published: April 2012

The hypothesis that participants will eat more fruits (apple slices) and vegetables (carrot cuts) if they are made more proximate and visible was tested using a 2 × 2 between-participants design. Proximity was manipulated by placing fruits and vegetables in a bowl at a table where participants sat (near) or 2 m from the table (far). Visibility was manipulated by placing fruits and vegetables in an opaque bowl that was covered (not visible) or in a clear bowl that was open (visible). The results showed that placing apple slices and carrot cuts in closer proximity to participants increased intake of these healthy foods. Making these foods more visible increased intake of apple slices but not carrot cuts, possibly because fruits taste sweet and so may be more motivationally salient than bitter-tasting carrots. Regardless, these data are the first to demonstrate experimentally that the proximity and visibility of fruits and vegetables can influence intake of these foods.
What I See, What I Do
Authors: Tang Yi , Li Jiatao , Yang Hongyan
Published: April 2012

This study explores the potential benefits of executive hubris to firm innovation. Grounded in the upper echelons theory and the firm innovation literature, hypotheses were developed and tested in two studies with different contexts and methods. Study 1 uses a set of cross-sectional survey data on a large sample of Chinese CEOs in manufacturing industries. Study 2 uses a set of longitudinal archival data on U.S. public firms in high-tech industries. Both studies render robust support to the authors’ main theoretical prediction—that executive hubris is positively related to firm innovation. The authors further found that the main effect varies under certain environmental conditions: The relationship between executive hubris and firm innovation becomes weaker when the environment is more munificent and complex.
Bipolar II disorder in rural New South Wales
Authors: Robertson Andrew , de Moore Greg , Boyce Philip
Published: April 2012

Objective:

To determine the frequency with which bipolar II disorder (BD II) was diagnosed in clinics held in four rural towns in New South Wales (NSW).

Method:

A retrospective case file audit was conducted for patients referred for psychiatric assessment and treatment in four towns in rural NSW over a period of two years and nine months.

Results:

Of 559 patients seen for the first time during the study period, 113 (20.2%) were diagnosed with BD II, and of these this diagnosis was made for the first time in 69 patients (61%). Associated clinical findings in BD II patients are presented and a comparison is made with patients with non-bipolar depression seen during the same period.

Conclusion:

BD II was commonly seen in these rural clinics, and appears to be often under-diagnosed in general practice, as has been found to be the case in urban centres. This is seen as a serious public health problem, which needs to be addressed by educational steps directed at general practitioners (GPs), mental health clinicians, and perhaps also the general public.
Training Counselors to Work Competently With Individuals and Families With Health and Mental Health Issues
Authors: Sperry Len
Published: April 2012

A paradigm shift is underway in the training of professional counselors. It involves a shift in orientation from an input-based or traditional model of training to an outcomes-based or competency-based model of training. This article provides a detailed description of both input-based and outcomes-based training and instructional methods. It illustrates these differences in how counselor trainees are taught to work with clients with health and mental health issues.
Personality and Interpersonal Characteristics Within Distressed Marriages
Authors: Kilmann Peter R.
Published: April 2012

Considerable research has established that particular partner characteristics have a negative impact upon marital quality and that marital distress often results from the failure of partners to resolve personality differences. This study assessed personality and interpersonal differences related to marital distress within 92 clinical couples. Husbands in marriages of 6 years or less reflected distant, apathetic, hostile, and domineering features, while their wives reflected a greater need for attention and stimulation. Husbands in marriages of 7 years or more reflected greater distant and apathetic, self-focused, hostile, and domineering characteristics, while their wives reported greater passive dependency. The shorter married wives’ and husbands’ marital distress was most strongly associated with their own avoidant and self-defeating characteristics. The longer married wives’ marital distress was associated with their husbands’ dominant and self-involved characteristics. The longer married husbands’ marital distress was most strongly associated with their own dominant and self-centered characteristics, but with none of their wives’ characteristics. Partner ratings supported interpersonal theory expectations that distressed couples would reflect noncomplementary interaction patterns. Marital therapists may increase the likelihood of remediating/preventing marital distress by helping couples to recognize that their own and their partner’s personality traits, and interpersonal styles can be linked to marital distress, that these links seemingly differ for males and females, and that these links are likely to change over the marital life cycle.
My Customers Are in My Blind Spot
Authors: Wägar Karolina , Roos Inger , Ravald Annika , Edvardsson Bo
Published: April 2012

It is clearly recognized that service providers often have an incomplete and fragmentary understanding of their customers' relationship behaviors. Although it is clear that this incomplete understanding has serious implications for customer relationship management, and might even constitute a strategic risk, there have been no explicit attempts to analyze the phenomenon. The authors therefore introduce and develop the concept of the blind spot as a metaphor referring to situations where a service provider’s visual field is obscured. The authors examine the phenomenon of blind spots in a temporal and a relational context, determine their consequences, and outline the implications for customer relationship management. A number of blind spot scenarios are presented in order to illustrate how blind spots obstruct the service provider’s ability to make correct interpretations of customer relationships, and thereby also correct estimations of relationship stability. The conceptualization of blind spots as outlined in this article sheds light on the underlying mechanisms that drive customer behavior in terms of relationship stability and hence offers a deeper understanding of the dynamic nature of customer relationships. From a managerial point of view, proper monitoring systems and routines for analyzing relevant customer information play essential roles in understanding and managing blind spots.
How Statins Could Be Evaluated Successfully in Clinical Trials for Alzheimer’s Disease?
Authors: Burgos Javier S. , Benavides Jesús , Douillet Patrice , Velasco Javier , Valdivieso Fernando
Published: April 2012

Over the last decade, a large number of experimental observations have suggested a relationship between alterations in cholesterol homeostasis and Alzheimer’s disease (AD). Moreover, epidemiological studies have pointed an association between statin treatment and a decrease in the risk of having AD. For these reasons, a large number of clinical trials have been carried out to determine whether the statins can prevent the progression of AD. However, these studies did not provide clear evidence for the therapeutic efficacy in AD. We consider that there are a number of explanations for this failure that may provide guidance for selecting and clinically developing statins with therapeutic efficacy in AD.
Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation
Authors: Gopal Ajay K. , Ramchandren Radhakrishnan , O'Connor Owen A. , Berryman Robert B. , Advani Ranjana H. , Chen Robert , Smith Scott E. , Cooper Maureen , Rothe Achim , Matous Jeffrey V. , Grove Laurie E. , Zain Jasmine
Published: April 2012

Hodgkin lymphoma (HL) relapsing after allogeneic stem cell transplantation (alloSCT) presents a major clinical challenge. In the present investigation, we evaluated brentuximab vedotin, a CD30-directed Ab-drug conjugate, in 25 HL patients (median age, 32 years; range, 20-56) with recurrent disease after alloSCT (11 unrelated donors). Patients were > 100 days after alloSCT, had no active GVHD, and received a median of 9 (range, 5-19) prior regimens. Nineteen (76%) had refractory disease immediately before enrollment. Patients received 1.2 or 1.8 mg/kg of brentuximab vedotin IV every 3 weeks (median, 8 cycles; range, 1-16). Overall and complete response rates were 50% and 38%, respectively, among 24 evaluable patients. Median time to response was 8.1 weeks, median progression-free survival was 7.8 months, and the median overall survival was not reached. Cough, fatigue, and pyrexia (52% each), nausea and peripheral sensory neuropathy (48% each), and dyspnea (40%) were the most frequent adverse events. The most common adverse events ≥ grade 3 were neutropenia (24%), anemia (20%), thrombocytopenia (16%), and hyperglycemia (12%). Cytomegalovirus was detected in 5 patients (potentially clinically significant in 1). These results support the potential utility of brentuximab vedotin for selected patients with HL relapsing after alloSCT. These trials are registered with www.clinicaltrials.gov as NCT01026233, NCT01026415, and NCT00947856.
Evidence for local dendritic cell activation in pulmonary sarcoidosis
Authors: Berge Bregje Ten , KleinJan Alex , Muskens Femke , Hammad Hamida , Hoogsteden Henk C , Hendriks Rudi W , Lambrecht Bart N , Van den Blink Bernt
Published: April 2012

Background

Sarcoidosis is a granulomatous disease characterized by a seemingly exaggerated immune response against a difficult to discern antigen. Dendritic cells (DCs) are pivotal antigen presenting cells thought to play an important role in the pathogenesis. Paradoxically, decreased DC immune reactivity was reported in blood samples from pulmonary sarcoidosis patients. However, functional data on lung DCs in sarcoidosis are lacking. We hypothesized that at the site of disease DCs are mature, immunocompetent and involved in granuloma formation.

Methods

We analyzed myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in broncho-alveolar lavage (BAL) and blood from newly diagnosed, untreated pulmonary sarcoidosis patients and healthy controls using 9-color flowcytometry. DCs, isolated from BAL using flowcytometric sorting (mDCs) or cultured from monocytes (mo-DCs), were functionally assessed in a mixed leukocyte reaction with naïve allogeneic CD4+ T cells. Using Immunohistochemistry, location and activation status of CD11c+DCs was assessed in mucosal airway biopsies.

Results

mDCs in BAL, but not in blood, from sarcoidosis patients were increased in number when compared with mDCs from healthy controls. mDCs purified from BAL of sarcoidosis patients induced T cell proliferation and differentiation and did not show diminished immune reactivity. Mo-DCs from patients induced increased TNFα release in co-cultures with naïve allogeneic CD4+ T cells. Finally, immunohistochemical analyses revealed increased numbers of mature CD86+ DCs in granuloma-containing airway mucosal biopsies from sarcoidosis patients.

Conclusion

Taken together, these finding implicate increased local DC activation in granuloma formation or maintenance in pulmonary sarcoidosis.
Adjunctive naturopathic care for type 2 diabetes: patient-reported and clinical outcomes after one year
Authors: Bradley Ryan , Sherman Karen J , Catz Sheryl , Calabrese Carlo , Oberg Erica B , Jordan Luesa , Grothaus Lou , Cherkin Dan
Published: April 2012

Background

Several small, uncontrolled studies have found improvements in self-care behaviors and reductions in clinical risk in persons with type 2 diabetes who received care from licensed naturopathic physicians. To extend these findings and determine the feasibility and promise of a randomized clinical trial, we conducted a prospective study to measure the effects of adjunctive naturopathic care (ANC) in primary care patients with inadequately controlled type 2 diabetes.

Methods

Forty patients with type 2 diabetes were invited from a large integrated health care system to receive up to eight ANC visits for up to one year. Participants were required to have hemoglobin A1c (HbA1c) values between 7.5-9.5 % and at least one additional cardiovascular risk factor (i.e., hypertension, hyperlipidemia or overweight). Standardized instruments were administered by telephone to collect outcome data on self-care, self-efficacy, diabetes problem areas, perceived stress, motivation, and mood. Changes from baseline scores were calculated at 6- and 12-months after entry into the study. Six and 12-month changes in clinical risk factors (i.e., HbA1c, lipid and blood pressure) were calculated for the ANC cohort, and compared to changes in a cohort of 329 eligible, non-participating patients constructed using electronic medical records data. Between-cohort comparisons were adjusted for age, gender, baseline HbA1c, and diabetes medications. Six months was pre-specified as the primary endpoint for outcome assessment.

Results

Participants made 3.9 ANC visits on average during the year, 78 % of which occurred within six months of entry into the study. At 6-months, significant improvements were found in most patient-reported measures, including glucose testing (P = 0.001), diet (P = 0.001), physical activity (P = 0.02), mood (P = 0.001), self-efficacy (P = 0.0001) and motivation to change lifestyle (P = 0.003). Improvements in glucose testing, mood, self-efficacy and motivation to change lifestyle persisted at 12-months (all P < 0.005). For clinical outcomes, mean HbA1c decreased by −0.90 % (P = 0.02) in the ANC cohort at 6-months, a −0.51 % mean difference compared to usual care (P = 0.07). Reductions at 12-months were not statistically significant (−0.34 % in the ANC cohort, P = 0.14; -0.37 % difference compared to the usual care cohort, P = 0.12).

Conclusions

Improvements were noted in self-monitoring of glucose, diet, self-efficacy, motivation and mood following initiation of ANC for patients with inadequately controlled type 2 diabetes. Study participants also experienced reductions in blood glucose that exceeded those for similar patients who did not receive ANC. Randomized clinical trials will be necessary to determine if ANC was responsible for these benefits.
Artemisinin-based combination therapy does not measurably reduce human infectiousness to vectors in a setting of intense malaria transmission
Authors: Huho Bernadette J , Killeen Gerard F , Ferguson Heather M , Tami Adriana , Lengeler Christian , Charlwood J Derek , Kihonda Aniset , Kihonda Japhet , Kachur S Patrick , Smith Thomas A , Abdulla Salim MK
Published: April 2012

Background

Artemisinin-based combination therapy (ACT) for treating malaria has activity against immature gametocytes. In theory, this property may complement the effect of terminating otherwise lengthy malaria infections and reducing the parasite reservoir in the human population that can infect vector mosquitoes. However, this has never been verified at a population level in a setting with intense transmission, where chronically infectious asymptomatic carriers are common and cured patients are rapidly and repeatedly re-infected.

Methods

From 2001 to 2004, malaria vector densities were monitored using light traps in three Tanzanian districts. Mosquitoes were dissected to determine parous and oocyst rates. Plasmodium falciparum sporozoite rates were determined by ELISA. Sulphadoxine-pyrimethamine (SP) monotherapy was used for treatment of uncomplicated malaria in the contiguous districts of Kilombero and Ulanga throughout this period. In Rufiji district, the standard drug was changed to artesunate co-administered with SP (AS + SP) in March 2003. The effects of this change in case management on malaria parasite infection in the vectors were analysed.

Results

Plasmodium falciparum entomological inoculation rates exceeded 300 infective bites per person per year at both sites over the whole period. The introduction of AS + SP in Rufiji was associated with increased oocyst prevalence (OR [95%CI] = 3.9 [2.9-5.3], p < 0.001), but had no consistent effect on sporozoite prevalence (OR [95%CI] = 0.9 [0.7-1.2], p = 0.5). The estimated infectiousness of the human population in Rufiji was very low prior to the change in drug policy. Emergence rates and parous rates of the vectors varied substantially throughout the study period, which affected estimates of infectiousness. The latter consequently cannot be explained by the change in drug policy.

Conclusions

In high perennial transmission settings, only a small proportion of infections in humans are symptomatic or treated, so case management with ACT may have little impact on overall infectiousness of the human population. Variations in infection levels in vectors largely depend on the age distribution of the mosquito population. Benefits of ACT in suppressing transmission are more likely to be evident where transmission is already low or effective vector control is widely implemented.
Comparison of molecular tests for the diagnosis of malaria in Honduras
Authors: Fontecha Gustavo A , Mendoza Meisy , Banegas Engels , Poorak Mitra , De Oliveira Alexandre M , Mancero Tamara , Udhayakumar Venkatachalam , Lucchi Naomi W , Mejia Rosa E
Published: April 2012

Background

Honduras is a tropical country with more than 70% of its population living at risk of being infected with either Plasmodium vivax or Plasmodium falciparum. Laboratory diagnosis is a very important factor for adequate treatment and management of malaria. In Honduras, malaria is diagnosed by both, microscopy and rapid diagnostic tests and to date, no molecular methods have been implemented for routine diagnosis. However, since mixed infections, and asymptomatic and low-parasitaemic cases are difficult to detect by light microscopy alone, identifying appropriate molecular tools for diagnostic applications in Honduras deserves further study. The present study investigated the utility of different molecular tests for the diagnosis of malaria in Honduras.

Methods

A total of 138 blood samples collected as part of a clinical trial to assess the efficacy of chloroquine were used: 69 microscopically confirmed P. falciparum positive samples obtained on the day of enrolment and 69 follow-up samples obtained 28 days after chloroquine treatment and shown to be malaria negative by microscopy. Sensitivity and specificity of microscopy was compared to an 18 s ribosomal RNA gene-based nested PCR, two single-PCR reactions designed to detect Plasmodium falciparum infections, one single-PCR to detect Plasmodium vivax infections, and one multiplex one-step PCR reaction to detect both parasite species.

Results

Of the 69 microscopically positive P. falciparum samples, 68 were confirmed to be P. falciparum-positive by two of the molecular tests used. The one sample not detected as P. falciparum by any of the molecular tests was shown to be P. vivax-positive by a reference molecular test indicating a misdiagnosis by microscopy. The reference molecular test detected five cases of P. vivax/P. falciparum mixed infections, which were not recognized by microscopy as mixed infections. Only two of these mixed infections were recognized by a multiplex test while a P. vivax-specific polymerase chain reaction (PCR) detected three of them. In addition, one of the day 28 samples, previously determined to be malaria negative by microscopy, was shown to be P. vivax-positive by three of the molecular tests specific for this parasite.

Conclusions

Molecular tests are valuable tools for the confirmation of Plasmodium species and in detecting mixed infections in malaria endemic regions.
Pedometer determined physical activity tracks in African American adults: The Jackson Heart Study
Authors: Newton Robert L , M Hongmei Han , Dubbert Patricia M , Johnson William D , Hickson DeMarc A , Ainsworth Barbara , Carithers Teresa , Taylor Herman , Wyatt Sharon , Tudor-Locke Catrine
Published: April 2012

Background

This study investigated the number of pedometer assessment occasions required to establish habitual physical activity in African American adults.

Methods

African American adults (mean age 59.9 ± 0.60 years; 59 % female) enrolled in the Diet and Physical Activity Substudy of the Jackson Heart Study wore Yamax pedometers during 3-day monitoring periods, assessed on two to three distinct occasions, each separated by approximately one month. The stability of pedometer measured PA was described as differences in mean steps/day across time, as intraclass correlation coefficients (ICC) by sex, age, and body mass index (BMI) category, and as percent of participants changing steps/day quartiles across time.

Results

Valid data were obtained for 270 participants on either two or three different assessment occasions. Mean steps/day were not significantly different across assessment occasions (p values > 0.456). The overall ICCs for steps/day assessed on either two or three occasions were 0.57 and 0.76, respectively. In addition, 85 % (two assessment occasions) and 76 % (three assessment occasions) of all participants remained in the same steps/day quartile or changed one quartile over time.

Conclusion

The current study shows that an overall mean steps/day estimate based on a 3-day monitoring period did not differ significantly over 4 – 6 months. The findings were robust to differences in sex, age, and BMI categories. A single 3-day monitoring period is sufficient to capture habitual physical activity in African American adults.
Competitive DNA transfection formulation via electroporation for human adipose stem cells and mesenchymal stem cells
Authors: Flanagan Michael , Gimble Jeffrey M , Yu Gang , Xia Xueqing , Bunnell Bruce A , Li Shulin
Published: April 2012

Background

Adipose stem cells have a strong potential for use in cell-based therapy, but the current nucleofection technique, which relies on unknown buffers, prevents their use.

Results

We developed an optimal nucleofection formulation for human adipose stem cells by using a three-step method that we had developed previously. This method was designed to determine the optimal formulation for nucleofection that was capable of meeting or surpassing the established commercial buffer (Amaxa), in particular for murine adipose stem cells. By using this same buffer, we determined that the same formulation yields optimal transfection efficiency in human mesenchymal stem cells.

Conclusions

Our findings suggest that transfection efficiency in human stem cells can be boosted with proper formulation.
Roles of Polo-like kinase 3 in suppressing tumor angiogenesis
Authors: Xu Dazhong , Wang Qi , Jiang Yongping , Zhang Yanxi , Vega-SaenzdeMiera Eleazar , Osman Iman , Dai Wei
Published: April 2012

Angiogenesis is essential for promoting growth and metastasis of solid tumors by ensuring blood supply to the tumor mass. Targeting angiogenesis is therefore an attractive approach to therapeutic intervention of cancer. Tumor angiogenesis is a process that is controlled by a complex network of molecular components including sensors, signaling transducers, and effectors, leading to cellular responses under hypoxic conditions. Positioned at the center of this network are the hypoxia-inducible factors (HIFs). HIF-1 is a major transcription factor that consists of two subunits, HIF-1α and HIF-1β. It mediates transcription of a spectrum of gene targets whose products are essential for mounting hypoxic responses. HIF-1α protein level is very low in the normoxic condition but is rapidly elevated under hypoxia. This dramatic change in the cellular HIF-1α level is primarily regulated through the proteosome-mediated degradation process. In the past few years, scientific progress has clearly demonstrated that HIF-1α phosphorylation is mediated by several families of protein kinases including GSK3β and ERKs both of which play crucial roles in the regulation of HIF-1α stability. Recent research progress has identified that Polo-like kinase 3 (Plk3) phosphorylates HIF-1α at two previously unidentified serine residues and that the Plk3-mediated phosphorylation of these residues results in destabilization of HIF-1α. Plk3 has also recently been found to phosphorylate and stabilize PTEN phosphatase, a known regulator of HIF-1α and tumor angiogenesis. Given the success of targeting protein kinases and tumor angiogenesis in anti-cancer therapies, Plk3 could be a potential molecular target for the development of novel and effective therapeutic agents for cancer treatment.
Antagonist-mediated down-regulation of toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus
Authors: Yu Shui-Lian , Chan Paul KS , Wong Chun-Kwok , Szeto Cheuk-Chun , Ho Suzanne C , So Karine , Yu May MY , Yim So-Fan , Cheung Tak-Hong , Wong Martin CS , Cheung Jo LK , Yeung Apple CM , Li Edmund K , Tam Lai-Shan
Published: April 2012

Introduction

Prevalence of an abnormal Papanicolaou smear was significantly increased in lupus patients in cross-sectional studies, associated with a higher prevalence of high-risk human papillomavirus (HPV) infection. The nucleic acid-specific Toll-like receptors (TLRs) locate at the endolysosomal compartments and trigger the induction of cytokines for the innate immune response. This study evaluated whether abnormal host innate immune response in lupus patients may enhance HPV persistence.

Methods

Protein levels of TLRs 3, 7, 8 and 9 in cervical epithelial cells of lupus patients and controls with or without HPV infection were assessed using flow cytometry. Characteristics associated with the differential expression of TLRs in systemic lupus erythematosus (SLE) were elucidated. The effect and interferon-stimulated genes (ISGs) (ISG15 and Mx-1) gene expressions were then measured in oncogenic HeLa (HPV18), CaSki (HPV) and C33A (HPV negative) cell lines using flow cytometry and quantitative real-time PCR. Ex vivo productions of cytokines and interferon-gamma (IFN-γ) upon TLR ligands stimulations were subsequently measured using cytometric bead array and ELISA.

Results

For subjects with HPV infection, levels of TLR3 and TLR7 were significantly lower in lupus patients compared with controls. Significantly decreased TLRs 7, 8 and 9 levels were observed in HPV-negative SLE compared to healthy controls. For SLE with and without HPV infection, TLR7 and 9 levels were significantly lower in infected SLE than those in HPV-negative patients. Independent explanatory variables associated with down-regulation of TLR7 level included HPV infection and a higher cumulative dose of prednisolone; while a higher cumulative dose of hydroxychloroquine and HPV infection were associated with down-regulation of TLR9 level. In cervical cell lines, TLRs 3, 7, 8, 9 protein levels and antiviral ISG15 and Mx-1 gene expressions were inhibited in two oncogenic HPV types. Functional data showed that the induction of pro-inflammatory cytokines by TLR ligands (R837, ssRNA and ODN2395) was greatly impaired in CaSki and HeLa than C33A cells.

Conclusions

In conclusion, prednisolone and TLR antagonist (hydroxychloroquine) may down-regulate protein levels of TLR7 and TLR9 in lupus patients, thereby decreasing the innate immune response against HPV infection. Upon infection, HPV further down-regulate TLR7 and 9 levels for viral persistence. Furthermore, reduction of nucleic acid-sensing TLRs 7, 8 and 9 in carcinogenic HPVs ensures that the expression of inducible pro-inflammatory cytokines is minimized to prevent the expression of antiviral ISGs (ISG15 and Mx-1) on a biologically relevant antiviral response.
Interaction between smoking and functional polymorphism in the TGFB1 gene is associated with ischaemic heart disease and myocardial infarction in patients with rheumatoid arthritis: a cross-sectional study
Authors: Chen Ying , Dawes Peter T , Packham Jon C , Mattey Derek L
Published: April 2012

Introduction

Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine that plays important roles in immunity and inflammation. Some studies have suggested that polymorphism in the TGFB1 gene is associated with heart disease in the general population. The purpose of the present study was to determine whether common single-nucleotide polymorphisms (SNP) in the TGFB1 gene are associated with ischaemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and to investigate the influence of smoking on any association.

Methods

PCR-based assays were used to determine the genotypes of TGFB1 SNPs including TGFB1-509 C/T (rs1800469, in the promoter region), +868 T/C (rs1800470, in exon 1) and +913 G/C (rs1800471, in exon 1) in 414 subjects with established RA. Genotyping for the +868 SNP was also carried out on a second study population of RA patients (n = 259) with early disease. Serum levels of TGF-beta1 were measured using a commercial ELISA kit. Smoking history and IHD/MI status were obtained on each patient. Associations with IHD/MI were assessed using contingency tables and logistic regression analyses.

Results

The heterozygous genotype of TGFB+868 was associated with an increased risk of IHD (OR 2.14, 95% CI 1.30 - 3.55) and MI (OR 2.42, 95% CI 1.30-4.50), compared to the homozygous genotypes combined. Smoking was an independent risk for IHD and MI, and evidence of interaction between smoking and TGFB+868 was found. Multivariate analyses indicated that the strongest associations with IHD and MI were due to the combined effect of the TGFB1+868 TC genotype and smoking (OR 2.75, 95% CI 1.59-4.75; and OR 2.58 95% CI 1.33-4.99, respectively), independent of other cardiovascular risk factors. The association of the +868 TC genotype and evidence of +868 TC-smoking interaction with IHD were replicated in a second population of RA patients with early disease. Serum TGF-beta1 levels were not associated with TGFB1 genetic variations, smoking or IHD/MI status.

Conclusions

Interaction between smoking and polymorphism in the TGFB1 gene may influence the risk of IHD and MI in patients with RA.
Risk of end-stage renal disease associated with gout: a nationwide population study
Authors: Yu Kuang-Hui , Kuo Chang-Fu , Luo Shue-Fen , See Lai-Chu , Chou I-Jun , Chang Hsiao-Chun , Chiou Meng-Jiun
Published: April 2012

Introduction

We explored the risk of end-stage renal disease (ESRD) among gout patients in a representative cohort in Taiwan.

Methods

The primary database used was the Taiwan National Health Insurance Research Database. Subjects older than 20 years without ESRD, coronary heart disease, or stroke were included in the study. The case definition of gout in the present study was gout diagnosis and medical treatment for gout. An ESRD case was defined by the presence of chronic renal failure necessitating long-term renal replacement therapy. Multivariate Cox proportional hazards models were used to evaluate the risk of ESRD among gout patients.

Results

The analysis included data of 656,108 patients who were followed up for a mean of 8.0 years. Among them, 19,963 (3.0%) patients had gout. At the end of 2008, 2,377 individuals (gout, n = 276; non-gout, n = 2,101) had ESRD, and 861 individuals (gout, n = 77, 27.9%; non-gout, n = 521, 24.8%) died due to ESRD. The rates of incidence of ESRD were 1.73 and 0.41 cases per 1,000 patient-years in the gout and non-gout groups. After adjustment for age, sex, and history of diabetes mellitus and/or hypertension, gout was associated with a hazard ratio (HR) of 1.57 for ESRD (95% confidence interval [CI], 1.38-1.79; P < 0.001). In patients with ESRD, the adjusted HR for death in patients with gout was 0.95 (0.74-1.23, P = 0.71), which was similar to the HR obtained in patients without gout.

Conclusions

Gout is associated with an increased hazard for development of ESRD.
Identification of low-frequency TRAF3IP2 coding variants in psoriatic arthritis patients and functional characterization
Authors: Böhm Beate , Burkhardt Harald , Uebe Steffen , Apel Maria , Behrens Frank , Reis André , Hüffmeier Ulrike
Published: April 2012

Introduction

In recent genome-wide association studies for psoriatic arthritis (PsA) and psoriasis vulgaris, common coding variants in the TRAF3IP2 gene were identified to contribute to susceptibility to both disease entities. The risk allele of p.Asp10Asn (rs33980500) proved to be most significantly associated and to encode a mutant protein with an almost completely disrupted binding property to TRAF6, supporting its impact as a main disease-causing variant and modulator of IL-17 signaling.

Methods

To identify further variants, exons 2-4 encoding both known TNF-receptor-associated factor (TRAF) binding domains were sequenced in 871 PsA patients. Seven missense variants and one three-base-pair insertion were identified in 0.06% to 1.02% of alleles. Five of these variants were also present in 931 control individuals at comparable frequency. Constructs containing full-length wild-type or mutant TRAF3IP2 were generated and used to analyze functionally all variants for TRAF6-binding in a mammalian two-hybrid assay.

Results

None of the newly found alleles, though, encoded proteins with different binding properties to TRAF6, or to the cytoplasmic tail of the IL-17-receptor α-chain, suggesting that they do not contribute to susceptibility.

Conclusions

Thus, the TRAF3IP2-variant p.Asp10Asn is the only susceptibility allele with functional impact on TRAF6 binding, at least in the German population.
Novel Genes of Visceral Adiposity: Identification of Mouse and Human Mesenteric Estrogen-Dependent Adipose (MEDA)-4 Gene and Its Adipogenic Function
Authors: Zhang H. , Chen X. , Sairam M. R.
Published: April 2012

Visceral adiposity represents a high risk factor for type 2 diabetes, metabolic syndrome, and cardiovascular disease as well as various cancers. While studying sex hormone imbalance-induced early obesity and late onset of insulin resistance in FSH receptor knock out female mice, we identified a novel mesenteric estrogen-dependent adipose gene (MEDA-4) selectively up-regulated in a depot-specific manner in mesenteric adipose tissue. Meda-4 cloned from both mouse and human adipose tissue codes for a 34-kDa cytosolic protein with 91% homology. Mouse Meda-4 mRNA is expressed highest in visceral adipose tissue and localizes predominantly in the adipocyte fraction. Human MEDA-4 is also more abundant in omental fat than sc depot in obese patients. In 3T3-L1 cells endogenous Meda-4 expression increases early during differentiation, and its overexpression promotes differentiation of preadipocytes into adipocytes and enhances glucose uptake. Conversely, short hairpin RNA-mediated knockdown of Meda-4 reduces both adipogenic and glucose uptake potential. In promoting adipogenesis, Meda-4 up-regulates transcription factor peroxisome proliferator-activated receptor-γ2. Meda-4 promotes lipid accumulation in adipocytes, regulating adipocyte fatty acid-binding protein 2, CD36, lipoprotein lipase, hormone-sensitive lipase, acyl-Coenzyme A oxidase-1, perilipin-1, and fatty acid synthase expression. 17β-Estradiol reduced Meda-4 expression in mesenteric adipose tissue of ovariectomized mice and in 3T3-L1 adipocytes. Thus our study identifies Meda-4 as a novel adipogenic gene, capable of promoting differentiation of preadipocytes into adipocytes, increasing lipid content and glucose uptake in adipocytes. Therefore it might play an important role in adipose tissue expansion in normal and aberrant hormonal conditions and pathophysiological states.
Drug-Drug Interactions with Glucagon-Like Peptide-1 Receptor Agonists
Authors: Hurren Kathryn M , Pinelli Nicole R
Published: April 2012

Objective:

To review drug interaction studies of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and concurrent oral medications.

Data Sources:

PubMed was searched (to December 5, 2011) using the terms exenatide, liraglutide, albiglutide, and lixisenatide. The search was limited to studies published in English and conducted in adults. Abstracts from the American Diabetes Association Scientific Sessions from 2004 through 2011 were also searched.

Study Selection and Data Extraction:

All abstracts were screened for eligibility, which consisted of studies reporting the effects of GLP-1 RA administration on the pharmacokinetics and pharmacodynamics of concurrent oral medications. Data extracted from eligible trials included study and population characteristics; pharmacokinetic parameters including maximum concentration (Cmax,), time to maximum concentration (tmax), and area under the concentration-time curve (AUC); and pharmacodynamic properties.

Data Synthesis:

Our search identified 254 potentially relevant articles; of those, 11 articles evaluating 15 drug interactions were reviewed. Only 1 study was conducted in patients with type 2 diabetes. Equivalence in AUC was demonstrated in the majority of drug interactions studied (11 of 15). The AUCs of acetaminophen and lovastatin were decreased after exenatide administration and those of lisinopril and digoxin were decreased after liraglutide administration. In 10 studies, GLP-1 RAs decreased the Cmax and, in 14 studies, prolonged the tmax of study drug. Pharmacokinetic properties of drugs and differences in study design can explain differences in interaction potential.

Conclusions:

GLP-IRAs may produce clinically significant interactions with drugs that require achievement of target peak concentrations or a rapid onset of action. Studies in patients with type 2 diabetes are needed to further assess and allow comparison of several GLP-1 RA agents’ impact on steady-state pharmacokinetics and pharmacodynamics of concomitant oral medications.
Willingness to Wait and Altered Encoding of Time-Discounted Reward in the Orbitofrontal Cortex with Normal Aging
Authors: Roesch Matthew R. , Bryden Daniel W. , Cerri Domenic H. , Haney Zachary R. , Schoenbaum Geoffrey
Published: April 2012

Normal aging has been associated with cognitive changes, including shifts in responding for time-discounted rewards. The orbitofrontal cortex, an area previously associated with aging-related cognitive changes, is critical for normal discounting. Previously we have shown in a choice task that rats prefer immediate over delayed reward and that neural representations of delayed reward in orbitofrontal cortex were attenuated, whereas immediate reward elicited strong responses. Changes in choice performance were correlated with changes in firing rate in orbitofrontal neurons, suggesting that these reward representations were critical to the rats' ability to wait for reward. Here we asked whether age-dependent changes in discounting behavior were related to changes in the representation of delayed reward in the orbitofrontal cortex. Young (3–6 months) and aged (22–26 months) rats were trained on the same discounting paradigm used previously. We found that aged rats showed less sensitivity to increasing delay preceding reward delivery, shifting behavior away from the delayed reward more slowly than younger rats. This sensitivity was specific to delay, since choice performance did not differ between the two groups when delay was held constant and reward size varied. Aged rats exhibited a corresponding increase in the prevalence of neurons that fired more strongly for delayed reward. Again this change was specific to delay; there was no change in encoding of different-sized rewards. These results suggest that natural aging results in altered representations of reward in orbitofrontal cortex. These changes may relate to the increased ability to delay gratification and reduced impulsivity associated with aging.
Peroxynitrite Donor SIN-1 Alters High-Affinity Choline Transporter Activity by Modifying Its Intracellular Trafficking
Authors: Cuddy Leah K. , Gordon Alexis C. , Black Stefanie A. G. , Jaworski Ewa , Ferguson Stephen S. G. , Rylett R. Jane
Published: April 2012

Sodium-coupled, high-affinity choline transporters (CHTs) are inhibited by 3-morpholinosydnonimine (SIN-1) [peroxynitrite (ONOO−) donor]; ONOO−can be produced from nitric oxide and reactive oxygen species during neurodegeneration. SIN-1 rapidly increases CHT internalization from the cell surface, and this correlates with decreased choline uptake. This study addresses mechanisms by which SIN-1 inhibits CHT function in human neuronal SH-SY5Y cells. Thus, mutant L531A-CHT, which does not constitutively internalize into cells by a clathrin-mediated process, is resistant to SIN-1 effects. This suggests that CHT inhibition is not due to oxidative–nitrosative inactivation of the protein and that decreased levels of cell surface CHT in SIN-1-treated cells is related to alterations in its trafficking and subcellular disposition. Dominant-negative proteins AP180C and dynamin-K44A, which interfere with clathrin-mediated and dynamin-dependent endocytosis, respectively, attenuate CHT inhibition by SIN-1. CHT in both vehicle- and SIN-1-treated cells colocalizes with Rab7, Rab9, and Lamp-1 in late endosomes and lysosomes to a similar extent. Lysosome inhibitors increase choline uptake, suggesting that CHT proteins are normally degraded by lysosomes, and this is not altered by oxidative stress. Unexpectedly, inhibitors of proteasomes, but not lysosomes, attenuate SIN-1-mediated inhibition of choline uptake, indicating that proteasomal degradation plays a role in regulating CHT disposition in SIN-1-treated cells. SIN-1 treatment also enhances CHT ubiquitination. Thus, CHT inhibition in SIN-1-treated cells is mediated by proteasomal degradation, which differs from inhibitory mechanisms for some neurotransmitter transporters under similar conditions. Increased oxidative–nitrosative stress in the microenvironment of cholinergic nerve terminals would diminish cholinergic transmission by reducing choline availability for ACh synthesis.
Neural Circuit Reconfiguration by Social Status
Authors: Issa Fadi A. , Drummond Joanne , Cattaert Daniel , Edwards Donald H.
Published: April 2012

The social rank of an animal is distinguished by its behavior relative to others in its community. Although social-status-dependent differences in behavior must arise because of differences in neural function, status-dependent differences in the underlying neural circuitry have only begun to be described. We report that dominant and subordinate crayfish differ in their behavioral orienting response to an unexpected unilateral touch, and that these differences correlate with functional differences in local neural circuits that mediate the responses. The behavioral differences correlate with simultaneously recorded differences in leg depressor muscle EMGs and with differences in the responses of depressor motor neurons recorded in reduced,in vitropreparations from the same animals. The responses of local serotonergic interneurons to unilateral stimuli displayed the same status-dependent differences as the depressor motor neurons. These results indicate that the circuits and their intrinsic serotonergic modulatory components are configured differently according to social status, and that these differences do not depend on a continuous descending signal from higher centers.
Physicochemical Study of Bile Salt-Polymer Micellar Aggregates
Authors: Dey Tania , Das Akhil R.
Published: April 2012

The micellar behavior of Sodium Deoxycholate (NaDC), a bile salt in presence of a neutral water soluble polymer Poly(vinylpyrrolidone) (PVP) has been investigated at four different temperatures (10–40 ºC) using conductometric, tensiometric, viscometric and fluorometric methods. NaDC is found to associate co-operatively with the polymer beyond a critical concentration, saturate the polymer completely and then undergo micellization at a higher concentration. The counter-ion binding capacity to the micelles is considerably reduced in presence of PVP. The thermodynamic properties of micellization and interfacial adsorption depend on the polymer concentration and the entropic contributions are observed to control the complexation process. The NaDC-PVP aggregate exhibits polyelectrolytic behavior. The aggregation number (N) and polarity index (I1/I3) of the NaDC-PVP mixed entities have been explored by pyrene fluorescence probing technique. The values of N and I1/I3 are found to be affected by [PVP] and temperature: the N values decrease with temperature while those of I1/I3 show increasing trend. The dependence of N and I1/I3 values on [PVP] and temperature reveal interesting insights into the NaDC-PVP complexation phenomenon.