E. Rampakakis

Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins

The Cdc6 replication licensing factor acts as a molecular switch at the E-cadherin locus, leading to E-cadherin transcriptional repression and local activation of replication.

Efficacy of BIO K+ CL1285® in the reduction of antibiotic-associated diarrhea – a placebo controlled double-blind randomized, multi-center study

Introduction Antibiotic associated diarrhea (AAD) is a frequently encountered adverse event following antibiotic administration. Evidence suggests that probiotics may be beneficial in preventing and decreasing the severity of AAD. Material and methods Adult patients who were prescribed antibiotics for 3-14 days were enrolled from eight Canadian centers. Study treatment was randomized at a 1 : 1 ratio of BIO-K+CL1285® or placebo and was administered within 24 h of initiation to 5 days after termination of antibiotherapy. Patients were followed for 21 days after last dose of study treatment. The primary outcome was severity and incidence of AAD. Severity was measured by the total number of days with diarrhea and incidence was defined as the number of patients with at least one day with diarrhea over the total number of patients enrolled in the study. Results 216 patients were randomized to BIO-K+ and 221 to placebo. The mean (SD) number of days with diarrhea was 1.19. (3.20) days for the placebo and 0.67 (2.05) days for BIO-K+CL1285® (p = 0.040). Adjusted multivariate linear regression results showed that the duration of diarrhea for BIO-K+CL1285 ® vs. placebo was reduced by 51.5% (b[SE] = 0.515 [0.256], p = 0.045). The incidence of diarrhea was 21.8% for the BIO-K+ and 29.4% for the placebo group (OR = 0.667, p = 0.067). Multivariate logistic regression, showed that the adjusted odds ratio of AAD in patients receiving BIO-K+ vs. placebo was 0.627 (p = 0.037). Study treatment was well tolerated. Conclusions BIO-K+ is effective for preventing and reducing the severity of AAD in patients receiving antibiotic therapy in a hospital setting.

Ku is involved in cell growth, DNA replication and G1-S transition

The Ku protein (Ku70-Ku80) is involved in various genome-maintenance processes such as DNA replication and repair, telomere maintenance, and chromosomal stability. We previously found that Ku80 is implicated in the loading of members of the pre-replicative complex (pre-RC) onto replication origins. Here, we report that acute reduction of Ku80 to 10% of its normal levels leads to impaired DNA replication and activation of a replication stress checkpoint. In the absence of Ku80, decreased levels of the initiator proteins Orc1 and Orc6 as well as reduced chromatin binding of Orc1, Orc4 and Cdc45 were observed, leading to decreased origin firing, whereas Orc2 and Orc3 were unaffected. Prolonged perturbation of DNA replication caused the block of cell-cycle progression in late G1 phase with low Cdk2 activity due to increased p21 expression and decreased Cdc25A and Cdk2 levels. The data suggest the interplay between the DNA-replication and cell-cycle machineries and shed light on a new role of Ku in G1-S transition.

Long‐term impact of adherence to oral bisphosphonates on osteoporotic fracture incidence

Adherence to osteoporosis treatments is a critical parameter resulting in suboptimal effectiveness in real‐life practice. The long‐term effect of adherence on fracture risk has not been assessed. This was a retrospective study using provincial health insurance claims databases to assess the association between adherence to oral bisphosphonates (OBP) and incidence of osteoporotic fractures in all Ontario patients with osteoporosis between April 1996 and December 2009. Multivariate logistic regression models were used to assess the association between OBP adherence and fracture risk. Treatment duration was classified into 2‐year intervals. Compliance was estimated with the medication possession ratio (MPR), and persistence was defined as the length of continuous therapy without a gap in refills >30 days. The study cohort was composed of 636,114 patients, among whom 36.1% were prescribed OBPs for 0 to 2 years, 19.7% for 2 to 4 years, 15.1% for 4 to 6 years, 12% for 6 to 8 years, 9.1% for 8 to 10 years, 6.1% for 10to 12 years, and 1.9% for 12 to 14 years. Overall, the mean (SD) compliance for the cohort was 0.72 (0.30) with 53.5% of the patients having compliance >80% and 24.6% being persistent with treatment during the 14‐year follow‐up period. Significant associations between high adherence and reduced fracture risk over the entire 14‐year period were observed; the overall odds ratio for categorical compliance (MPR >80% or MPR ≤80%), continuous compliance, and persistence were 0.909 (95% confidence interval [CI] 0.893–0.925), 0.918 (95% CI 0.893–0.944), and 0.804 (95% CI 0.787–0.821), respectively. In conclusion, adherence to OBP in osteoporosis management is suboptimal in a real‐life setting. A significant positive association exists between poor adherence and increased risk of osteoporotic fractures, which becomes augmented with longer treatment duration.

Burden of illness, quality of life, and healthcare utilization among patients with herpes zoster in South Korea: a prospective clinical–epidemiological study

OBJECTIVES To assess the herpes zoster (HZ) disease burden, including the severity and duration of HZ-associated pain, its impact on quality of life (QoL), and healthcare resource utilization (HCRU) in a South Korean clinical setting. METHODS Patients aged ≥50 years were followed prospectively for ≤6 months. Based on the duration of their episode at enrollment, cases were classified as incident (<7 days) or prevalent (≥7 days). HZ pain and discomfort were measured with the HZ Severity of Illness (HZ-SOI) severity-by-duration composite score. RESULTS One hundred fifty-one patients (69.5% prevalent cases) were enrolled. Prodrome pain was experienced by 68.2% of patients, of whom 95.1% experienced moderate-to-severe pain; post-herpetic neuralgia was experienced by 38.4%. Prevalent disease, higher acute pain, and older age were significant predictors of greater HZ-SOI, while use of antivirals was associated with decreased HZ-SOI. HZ-associated pain was associated with reduced QoL and affected all daily living activities (particularly mood, life enjoyment, general activities, and sleep), resulting in significant HCRU, including primary care doctor, specialist, or physiotherapist consultations, hospitalizations, and emergency department visits. CONCLUSION Severe morbidity, impaired QoL, and significant HCRU are associated with HZ in South Korea, especially in older patients, supporting the need for early intervention and preventive strategies to reduce the HZ-associated disease burden.

Treating to a Target in Established Active Rheumatoid Arthritis Patients Receiving a Tumor Necrosis Factor Inhibitor: Results From a Real‐World Cluster‐Randomized Adalimumab Trial

In early rheumatoid arthritis (RA), treating to a target is more effective than routine care (RC). Our aim was to determine if treating to a target has better outcomes than RC in established active RA.

Predictors of postherpetic neuralgia in patients with herpes zoster: a pooled analysis of prospective cohort studies from North and Latin America and Asia

OBJECTIVES The most common complication of herpes zoster (HZ) is postherpetic neuralgia (PHN), a persistent pain that can substantially affect quality of life (QoL). This analysis aimed to evaluate predictors of PHN in HZ patients. METHODS A pooled analysis of prospective cohort studies of HZ patients aged ≥ 50 years from North America (Canada), Latin America (Brazil, Mexico, and Argentina), and Asia (Taiwan, South Korea, and Thailand) was performed. Patients within 14 days of rash onset were included. The incidence of PHN was defined as a worst pain score of ≥ 3, persisting/appearing at >90 days after rash onset. Socio-demographics, HZ disease characteristics, treatment, pain-related interference with activities of daily living, and health-related QoL were assessed. RESULTS Of 702 patients with HZ, 148 (21.1%) developed PHN. Similar risks of PHN were observed across geographic regions. On multivariate analysis, older age, greater severity of pain at rash onset, employment status, walking problems at enrollment, and pain interference affecting social relationships were significantly associated with the development of PHN. CONCLUSIONS In addition to older age and severe acute pain, this study suggests that impaired physical and social functioning from acute zoster pain may play a role in the development of PHN in this prospective cohort study of HZ patients from North and Latin America and Asia.

Metazoan origins of DNA replication: Regulation through dynamic chromatin structure

DNA replication in eukaryotes is initiated at multiple replication origins distributed over the entire genome, which are normally activated once per cell cycle. Due to the complexity of the metazoan genome, the study of metazoan replication origins and their activity profiles has been less advanced than in simpler genome systems. DNA replication in eukaryotes involves many protein–protein and protein–DNA interactions, occurring in multiple stages. As in prokaryotes, control over the timing and frequency of initiation is exerted at the initiation site. A prerequisite for understanding the regulatory mechanisms of eukaryotic DNA replication is the identification and characterization of the cis‐acting sequences that serve as replication origins and the trans‐acting factors (proteins) that interact with them. Furthermore, in order to understand how DNA replication may become deregulated in malignant cells, the distinguishing features between normal and malignant origins of DNA replication as well as the proteins that interact with them must be determined. Based on advances that were made using simple genome model systems, several proteins involved in DNA replication have been identified. This review summarizes the current findings about metazoan origins of DNA replication and their interacting proteins as well as the role of chromatin structure in their regulation. Furthermore, progress in origin identification and isolation procedures as well as potential mechanisms to inhibit their activation in cancer development and progression are discussed. J. Cell. Biochem. 106: 512–520, 2009.

The Association of Socioeconomic Status and Symptom Severity in Persons with Fibromyalgia

Objective. Although persons with lower socioeconomic status (SES) generally have poorer health status for many medical conditions, the association of SES with symptom severity in fibromyalgia (FM) is unknown. The subjective symptoms of FM may be influenced by personal perceptions, and environmental and psychosocial factors. Therefore SES may influence symptom expression and severity. Methods. Data for this cross-sectional analysis were obtained from a real-life prospective cohort of 246 patients with FM categorized according to level of education: high school graduates or less (Group 1; n = 99), college graduates (Group 2; n = 84), and university graduates (Group 3; n = 63). The association between level of education, a well-validated measure of SES, and disease severity, functional status, and quality of life were examined. Results. Lower education was significantly associated with older age (p = 0.039), current unemployment (p < 0.001), and more severe disease, as measured by patient global assessment disease activity (p = 0.019), McGill Pain Questionnaire (p = 0.026), Pain Disability Index (p = 0.031), Pain Catastrophizing Scale (p = 0.015), Health Assessment Questionnaire (p = 0.001), and Fibromyalgia Impact Questionnaire (p = 0.002), but not pain level, anxiety, or depression. These associations remained significant even upon adjusting for age and sex differences. Conclusion. Patients with FM and lower SES, as assessed by education level, reported greater symptom severity and functional impairment, despite reporting similar levels of pain, depression, and anxiety. Although FM spans all socioeconomic groups, factors other than specific disease characteristics or mental status, appear to play an important role in patients’ perception of illness.

High prevalence of psoriatic arthritis in a cohort of patients with psoriasis seen in a dermatology practice.

Background/Objectives: The prevalence of psoriatic arthritis (PsA) is expected to range from 5 to 40% in individuals with psoriasis. The objective of this study was to quantify the prevalence of PsA in psoriasis patients seen in a dermatology practice and to define their characteristics using the validated Psoriatic Arthritis Screening Questionnaire (PASQ). Methods: Patients with definite plaque psoriasis (as determined by a dermatologist) completed the self-administered PASQ tool, and patients with a score ≥ 7 or ≥ 9 were assessed by a rheumatologist to ascertain the diagnosis of PsA according to the CASPAR (Classification Criteria for Psoriatic Arthritis) criteria. Results: Using a PASQ cutoff of 7, the estimated prevalence (95% CI) of PsA was 40.9% (29.0–52.8%), whereas a prevalence (95% CI) of 36.4% (24.8–48.0%) was estimated when a PASQ cutoff of 9 was used. Conclusion: Our estimated prevalence of PsA in psoriasis patients from a population of patients drawn from a dermatology practice is greater than most previous estimates. This finding illustrates the importance of screening for PsA in psoriasis patients as this comorbidity may affect the course of treatment and, if left untreated, may have a profound effect on the disability and quality of life of a large number of psoriasis patients.