Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved

The insulin receptor (IR) and the insulin-like growth factor I receptor (IGF-IR) have a highly homologous structure, but different biological effects. Insulin and IGF-I half-receptors can heterodimerize, leading to the formation of insulin/IGF-I hybrid receptors (Hybrid-Rs) that bind IGF-I with high affinity. As the IR exists in two isoforms (IR-A and IR-B), we evaluated whether the assembly of the IGF-IR with either IR-A or IR-B moieties may differently affect Hybrid-R signaling and biological role. Three different models were studied: (a) 3T3-like mouse fibroblasts with a disrupted IGF-IR gene (R(-) cells) cotransfected with the human IGF-IR and with either the IR-A or IR-B cDNA; (b) a panel of human cell lines variably expressing the two IR isoforms; and (c) HepG2 human hepatoblastoma cells predominantly expressing either IR-A or IR-B, depending on their differentiation state. We found that Hybrid-Rs containing IR-A (Hybrid-Rs(A)) bound to and were activated by IGF-I, IGF-II, and insulin. By binding to Hybrid-Rs(A), insulin activated the IGF-I half-receptor beta-subunit and the IGF-IR-specific substrate CrkII. In contrast, Hybrid-Rs(B) bound to and were activated with high affinity by IGF-I, with low affinity by IGF-II, and insignificantly by insulin. As a consequence, cell proliferation and migration in response to both insulin and IGFs were more effectively stimulated in Hybrid-R(A)-containing cells than in Hybrid-R(B)-containing cells. The relative abundance of IR isoforms therefore affects IGF system activation through Hybrid-Rs, with important consequences for tissue-specific responses to both insulin and IGFs.     

Receptor-isoform-selective insulin analogues give tissue-preferential effects

The relative expression patterns of the two IR (insulin receptor) isoforms, +/- exon 11 (IR-B/IR-A respectively), are tissue-dependent. Therefore we have developed insulin analogues with different binding affinities for the two isoforms to test whether tissue-preferential biological effects can be attained. In rats and mice, IR-B is the most prominent isoform in the liver (> 95%) and fat (> 90%), whereas in muscles IR-A is the dominant isoform (> 95%). As a consequence, the insulin analogue INS-A, which has a higher relative affinity for human IR-A, had a higher relative potency [compared with HI (human insulin)] for glycogen synthesis in rat muscle strips (26%) than for glycogen accumulation in rat hepatocytes (5%) and for lipogenesis in rat adipocytes (4%). In contrast, the INS-B analogue, which has an increased affinity for human IR-B, had higher relative potencies (compared with HI) for inducing glycogen accumulation (75%) and lipogenesis (130%) than for affecting muscle (45%). For the same blood-glucose-lowering effect upon acute intravenous dosing of mice, INS-B gave a significantly higher degree of IR phosphorylation in liver than HI. These in vitro and in vivo results indicate that insulin analogues with IR-isoform-preferential binding affinity are able to elicit tissue-selective biological responses, depending on IR-A/IR-B expression.     

Altered expression of insulin receptor isoforms in breast cancer

Purpose

Insulin-like growth factor (IGF) signaling through human insulin receptor isoform A (IR-A) contributes to tumorigenesis and intrinsic resistance to anti-IGF1R therapy. In the present study, we (a) developed quantitative TaqMan real time-PCR-based assays (qRT-PCR) to measure human insulin receptor isoforms with high specificity, (b) evaluated isoform expression levels in molecularly-defined breast cancer subtypes, and (c) identified the IR-A:IR-B mRNA ratio as a potential biomarker guiding patient stratification for anti-IGF therapies.

Experimental Design

mRNA expression levels of IR-A and IR-B were measured in 42 primary breast cancers and 19 matched adjacent normal tissues with TaqMan qRT-PCR assays. The results were further confirmed in 165 breast cancers. The tumor samples were profiled using whole genome microarrays and subsequently subtyped using the PAM50 breast cancer gene signature. The relationship between the IR-A:IR-B ratio and cancer subtype, as well as markers of proliferation were characterized.

Results

The mRNA expression levels of IR-A in the breast tumors were similar to those observed in the adjacent normal tissues, while the mRNA levels of IR-B were significantly decreased in tumors. The IR-A:IR-B ratio was significantly higher in luminal B breast cancer than in luminal A. Strong concordance between the IR-A:IR-B ratio and the composite Oncotype DX proliferation score was observed for stratifying the latter two breast cancer subtypes.

Conclusions

The reduction in IR-B expression is the key to the altered IR-A:IR-B ratio observed in breast cancer. The IR-A:IR-B ratio may have biomarker utility in guiding a patient stratification strategy for an anti-IGF therapeutic.     

Phosphatidylinositol 3-Kinase (PI3K) Activity Bound to Insulin-like Growth Factor-I (IGF-I) Receptor, which Is Continuously Sustained by IGF-I Stimulation, Is Required for IGF-I-induced Cell Proliferation

Continuous stimulation of cells with insulin-like growth factors (IGFs) in G(1) phase is a well established requirement for IGF-induced cell proliferation; however, the molecular components of this prolonged signaling pathway that is essential for cell cycle progression from G(1) to S phase are unclear. IGF-I activates IGF-I receptor (IGF-IR) tyrosine kinase, followed by phosphorylation of substrates such as insulin receptor substrates (IRS) leading to binding of signaling molecules containing SH2 domains, including phosphatidylinositol 3-kinase (PI3K) to IRS and activation of the downstream signaling pathways. In this study, we found prolonged (>9 h) association of PI3K with IGF-IR induced by IGF-I stimulation. PI3K activity was present in this complex in thyrocytes and fibroblasts, although tyrosine phosphorylation of IRS was not yet evident after 9 h of IGF-I stimulation. IGF-I withdrawal in mid-G(1) phase impaired the association of PI3K with IGF-IR and suppressed DNA synthesis the same as when PI3K inhibitor was added. Furthermore, we demonstrated that Tyr(1316)-X-X-Met of IGF-IR functioned as a PI3K binding sequence when this tyrosine is phosphorylated. We then analyzed IGF signaling and proliferation of IGF-IR(-/-) fibroblasts expressing exogenous mutant IGF-IR in which Tyr(1316) was substituted with Phe (Y1316F). In these cells, IGF-I stimulation induced tyrosine phosphorylation of IGF-IR and IRS-1/2, but mutated IGF-IR failed to bind PI3K and to induce maximal phosphorylation of GSK3β and cell proliferation in response to IGF-I. Based on these results, we concluded that PI3K activity bound to IGF-IR, which is continuously sustained by IGF-I stimulation, is required for IGF-I-induced cell proliferation.     

Decorin differentially modulates the activity of insulin receptor isoform A ligands

The proteoglycan decorin, a key component of the tumor stroma, regulates the action of several tyrosine-kinase receptors, including the EGFR, Met and the IGF-IR. Notably, the action of decorin in regulating the IGF-I system differs between normal and transformed cells. In normal cells, decorin binds with high affinity to both the natural ligand IGF-I and the IGF-I receptor (IGF-IR) and positively regulates IGF-IR activation and downstream signaling. In contrast, in transformed cells, decorin negatively regulates ligand-induced IGF-IR activation, downstream signaling and IGF-IR-dependent biological responses. Whether decorin may bind another member of the IGF-I system, the insulin receptor A isoform (IR-A) and its cognate ligands, insulin, IGF-II and proinsulin, have not been established. Here we show that decorin bound with high affinity insulin and IGF-II and, to a lesser extent, proinsulin and IR-A. We utilized as a cell model system mouse embryonic fibroblasts homozygous for a targeted disruption of the Igf1r gene (designated R⁻ cells) which were stably transfected with a human construct harboring the IR-A isoform of the receptor. Using these R⁻/IR-A cells, we demonstrate that decorin did not affect ligand-induced phosphorylation of the IR-A but enhanced IR-A downregulation after prolonged IGF-II stimulation without affecting insulin and proinsulin-dependent effects on IR-A stability. In addition, decorin significantly inhibited IGF-II-mediated activation of the Akt pathways, without affecting insulin and proinsulin-dependent signaling. Notably, decorin significantly inhibited IGF-II-mediated cell proliferation of R⁻/IR-A cells but affected neither insulin- nor proinsulin-dependent mitogenesis. Collectively, these results suggest that decorin differentially regulates the action of IR-A ligands. Decorin preferentially inhibits IGF-II-mediated biological responses but does not affect insulin- or proinsulin-dependent signaling. Thus, decorin loss may contribute to tumor initiation and progression in malignant neoplasms which depend on an IGF-II/IR-A autocrine loop.     

IGF-IR Signal Transduction Protein Content and Its Activation by IGF-I in Human Placentas: Relationship with Gestational Age and Birth Weight

Introduction

The human placenta expresses the IGF-I and IGF-IR proteins and their intracellular signal components (IRS-1, AKT and mTOR). The aim of this study was to assess the IGF-IR content and activation of downstream signaling molecules in placentas from newborns who were classified by gestational age and birth weight. We studied placentas from 25 term appropriate (T-AGA), 26 term small (T-SGA), 22 preterm AGA (PT-AGA), and 20 preterm SGA (PT-SGA) newborns. The total and phosphorylated IGF-IR, IRS-1, AKT, and mTOR contents were determined by Western Blot and normalized by actin or with their respective total content. The effect of IGF-I was determined by stimulating placental explants with recombinant IGF-I 10^-8 mol/L for 15, 30, and 60 minutes.

Results

The IGF-IR content was higher in T-SGA compared to T-AGA placentas, and the IRS-1 content was higher in PT-placentas compared with their respective T-placentas. The effect of IGF-I on the phosphorylated forms of IGF-IR was increased in T-SGA (150%) and PT-SGA (300%) compared with their respective AGA placentas. In addition, AKT serine phosphorylation was higher in PT-SGA compared to PT-AGA and T-SGA placentas (90% and 390% respectively).

Conclusion

The higher protein content and response to IGF-I of IGF-IR, IRS-1, and AKT observed in SGA placentas may represent a compensatory mechanism in response to fetal growth restriction.     

A Description of Mortality Associated with IPT plus ART Compared to ART Alone among HIV-Infected Individuals in Addis Ababa,Ethiopia: A Cohort Study

Background

Tuberculosis (TB) is the most common human immunodeficiency virus (HIV) associated opportunistic infection. It is the leading cause of death in HIV-infected individuals in sub-Saharan Africa. Anti-retroviral therapy (ART) and isoniazid preventive therapy (IPT) are the two useful TB preventative strategies available to reduce TB among people living with HIV (PLHIV). Therefore, the aim of this study is to compare mortality associated with IPT taken together with ART, as well as ART alone, among PLHIV.

Methods

A retrospective cohort study was undertaken at Tikur Anbessa Specialized Hospital (TASH) and Zewditu Memorial Hospital (ZMH) on 185 patients receiving IPT (6 months) plus ART and 557 patients receiving ART alone. Mortality rates (MR) per 100 person-years (PYs) were used to compare mortality rates amongst the groups. Time-to-death and survival probabilities of the patients were determined using the Kaplan Meier Method. The Cox Proportional Hazard Model was employed to estimate the effect of IPT plus ART on survival of PLHIV.

Results

The mortality cases noted in patients treated by IPT plus ART versus ART alone were 18 (4.5 cases/100 PYs) and 116 (10 cases/100 PYs), respectively. In reference to the ART alone, the IPT plus ART reduced the likelihood of death significantly (aHR 0.48; 95% CI 0.38–0.69) and median time to death was about 26 months (IQR 19–34). Moreover, WHO stage IV (aHR 2.42: 95% CI 1.42–4.11), CD4 values ≥350cells/mm3 (aHR 0.52; 95% CI 0.28–0.94), adherence to ART (aHR 0.12; 95% CI 0.08–0.20), primary levels of education (aHR 2.20; 95% CI 1.07–4.52); and alcohol consumption (aHR 1.71; 95% CI 1.04–2.81) were factors strongly associated with mortality.

Conclusion

We found that PLHIV treated by the IPT plus ART had a lower likelihood of mortality and delayed time-to-death when compared to patients treated by ART alone.     

The role of insulin receptors and IGF-I receptors in cancer and other diseases

There is evidence, both in vitro and in vivo, that receptor tyrosine kinases play a key role in the formation and progression of human cancer. In particular, the insulin-like growth factor receptor (IGF-IR), a tyrosine kinase receptor for IGF-I and IGF-II, has been well documented in cell culture, animal studies, and humans to play a role in malignant transformation, progression, protection from apoptosis, and metastasis. In addition, the hormone insulin (which is very closely related to the IGFs) and its tyrosine kinase receptor (the IR, which is very closely related to the IGR-IR) have been documented both in vitro and in vivo to play a key role in cancer biology. Indeed, several epidemiological studies have shown that insulin resistance status, characterized by hyperinsulinaemia, is associated with an increased risk for a number of malignancies, including carcinomas of the breast, prostate, colon and kidney. Recent data have elucidated some molecular mechanisms by which IR is involved in cancer. IR is over-expressed in several human malignancies. Interestingly, one of the two IR isoform (IR-A) is especially over-expressed in cancer. IR-A is the IR foetal isoform and has the peculiar characteristic to bind not only insulin but also IGF-II. In addition, the IR contributes to formation of hybrid receptors with the IGF-IR (HR). By binding to hybrid receptors, insulin may stimulate specific IGF-IR signalling pathways. Over-expression of IR-A is, therefore, a major mechanism of IGF system over-activation in cancer. In this respect, IR-A isoform and hybrid receptors should be regarded as potential molecular targets, in addition to IGF-IR, for novel anti-cancer therapy. These findings may have important implications for both the prevention and treatment of common human malignancies. They underline the concept that hyperinsulinaemia, associated with insulin resistance and obesity, should be treated by changes in life style and/or pharmacological approaches to avoid an increased risk for cancer. Moreover, native insulin and insulin analogue administration should be carefully evaluated in terms of the possible increase in cancer risk.     

Binding of insulin-like growth factor-I (IGF-I) to primary cultures of chondrocytes from rat rib growth cartilage

Binding of insulin-like growth factor I (IGF-I) to cultured resting, proliferative and hypertrophic growth plate chondrocytes was investigated. The optimal binding conditions and the extent of degradation of the 125I-IGF-I at 20 degrees C were analyzed in a time-course study. The maximal binding without noticeable degradation was observed after 3 h. The binding of IGF-I to the proliferative cells was 2-fold higher than to the resting and the hypertrophic cells. On the proliferative chondrocytes two classes of receptors with different affinities were found. 125I-IGF-I could be displaced from the proliferative cells by unlabelled IGF-I, IGF-II and insulin, respectively. Half maximal binding was observed at 0.3 nmol/l (= 2.2 micrograms/l) of IGF-I, 4.3 nmol/l (= 32 micrograms/l) of IGF-II and 350 nmol/l (= 2000 micrograms/l) of insulin. No specific binding of human growth hormone (hGH) could be demonstrated. When binding of epidermal growth factor (EGF) to the proliferative cells was assessed, little, but specific binding was observed.     

Fluid shear stress synergizes with insulin-like growth factor-I (IGF-I) on osteoblast proliferation through integrin-dependent activation of IGF-I mitogenic signaling pathway

This study tested the hypothesis that shear stress interacts with the insulin-like growth factor-I (IGF-I) pathway to stimulate osteoblast proliferation. Human TE85 osteosarcoma cells were subjected to a steady shear stress of 20 dynes/cm(2) for 30 min followed by 24-h incubation with IGF-I (0-50 ng/ml). IGF-I increased proliferation dose-dependently (1.5-2.5-fold). Shear stress alone increased proliferation by 70%. The combination of shear stress and IGF-I stimulated proliferation (3.5- to 5.5-fold) much greater than the additive effects of each treatment alone, indicating a synergistic interaction. IGF-I dose-dependently increased the phosphorylation level of Erk1/2 by 1.2-5.3-fold and that of IGF-I receptor (IGF-IR) by 2-4-fold. Shear stress alone increased Erk1/2 and IGF-IR phosphorylation by 2-fold each. The combination treatment also resulted in synergistic enhancements in both Erk1/2 and IGF-IR phosphorylation (up to 12- and 8-fold, respectively). Shear stress altered IGF-IR binding only slightly, suggesting that the synergy occurred primarily at the post-ligand binding level. Recent studies have implicated a role for integrin in the regulation of IGF-IR phosphorylation and IGF-I signaling. To test whether the synergy involves integrin-dependent mechanisms, the effect of echistatin (a disintegrin) on proliferation in response to shear stress +/- IGF-I was measured. Echistatin reduced basal proliferation by approximately 60% and the shear stress-induced mitogenic response by approximately 20%. It completely abolished the mitogenic effect of IGF-I and that of the combination treatment. Shear stress also significantly reduced the amounts of co-immunoprecipitated SHP-2 and -1 with IGF-IR, suggesting that the synergy between shear stress and IGF-I in osteoblast proliferation involves integrin-dependent recruitment of SHP-2 and -1 away from IGF-IR.     

Characterization of insulin/IGF hybrid receptors: contributions of the insulin receptor L2 and Fn1 domains and the alternatively spliced exon 11 sequence to ligand binding and receptor activation

The IR (insulin receptor) and IGFR (type I insulin-like growth factor receptor) are found as homodimers, but the respective pro-receptors can also heterodimerize to form insulin-IGF hybrid receptors. There are conflicting data on the ligand affinity of hybrids, and especially on the influence of different IR isoforms. To investigate further the contribution of individual ligand binding epitopes to affinity and specificity in the IR/IGFR family, we generated hybrids incorporating both IR isoforms (A and B) and IR/IGFR domain-swap chimaeras, by ectopic co-expression of receptor constructs in Chinese hamster ovary cells, and studied ligand binding using both radioligand competition and bioluminescence resonance energy transfer assays. We found that IR-A-IGFR and IR-B-IGFR hybrids bound insulin with similar relatively low affinity, which was intermediate between that of homodimeric IR and homodimeric IGFR. However, both IR-A-IGFR and IR-B-IGFR hybrids bound IGF-I and IGF-II with high affinity, at a level comparable with homodimeric IGFR. Incorporation of a significant fraction of either IR-A or IR-B into hybrids resulted in abrogation of insulin- but not IGF-I-stimulated autophosphorylation. We conclude that the sequence of 12 amino acids encoded by exon 11 of the IR gene has little or no effect on ligand binding and activation of IR-IGFR hybrids, and that hybrid receptors bind IGFs but not insulin at physiological concentrations regardless of the IR isoform they contained. To reconstitute high affinity insulin binding within a hybrid receptor, chimaeras in which the IGFR L1 or L2 domains had been replaced by equivalent IR domains were co-expressed with full-length IR-A or IR-B. In the context of an IR-A-IGFR hybrid, replacement of IR residues 325-524 (containing the L2 domain and part of the first fibronectin domain) with the corresponding IGFR sequence increased the affinity for insulin by 20-fold. We conclude that the L2 and/or first fibronectin domains of IR contribute in trans with the L1 domain to create a high affinity insulin-binding site within a dimeric receptor.     

Vitamin D Status among Young Children Aged 1–3 Years: A Cross-Sectional Study in Wuxi,China

Background

The increasingly recognized importance of vitamin D has been discussed and vitamin D status among young children has attracted widespread attention in recent years. However, study on vitamin D status in young children aged 1–3 y is limited in China.

Objective

To evaluate the nutritional vitamin D status of young children aged 1–3 y in Wuxi, southeastern China.

Methods

A large cohort of 5,571 young children aged 1–3 y were recruited in this study who visited the child health clinics at the Wuxi Maternity and Child Health Hospital (latitude 31.57°N) during January 2014 to January 2015. Wuxi was located in southeastern China at a latitude of 31.57°N. Finger-stick blood sampling was conducted in all the subjects and serum 25-Hydroxyvitamin D (25(OH)D) levels were measured to evaluate their vitamin D status.

Results

In this study, serum 25(OH)D levels of young children at the age of 1–3 years ranged from 20.6–132.9 nmol/L (Median: 71.5 nmol/L). 16.1% of the population had vitamin D deficiency (<50 nmol/L), while 38.8% of the subjects had a sufficient (50–74.9 nmol/L) vitamin D level. An optimal vitamin D status (≥75 nmol/L) was found in 45.1% of the young children. The prevalence of vitamin D deficiency was higher in autumn (19.5%) than in summer (12.1%). There was no significant difference in vitamin D status between genders. The binary logistic regression analysis revealed that child age was strongly associated with vitamin D deficiency (adjusted OR: 1.173; 95%CI: 1.053–1.308; P = 0.004).

Conclusions

The prevalence of vitamin D deficiency was 16.1% among young children aged 1–3 y in Wuxi. Season and child age were associated with their vitamin D status. It is implied that young children should receive adequate amounts of vitamin D supplementation and spend more time outdoors to prolong the sunlight exposure when they grow older.     

The Effects of Anti-Dementia and Nootropic Treatments on the Mortality of Patients with Dementia: A Population-Based Cohort Study in Taiwan

Background

Few studies have examined the contribution of treatment on the mortality of dementia based on a population-based study.

Objective

To investigate the effects of anti-dementia and nootropic treatments on the mortality of dementia using a population-based cohort study.

Methods

12,193 incident dementia patients were found from 2000 to 2010. Their data were compared with 12,193 age- and sex-matched non-dementia controls that were randomly selected from the same database. Dementia was classified into vascular (VaD) and degenerative dementia. Mortality incidence and hazard ratios (HRs) were calculated.

Results

The median survival time was 3.39 years (95% confidence interval [CI]: 2.88–3.79) for VaD without medication, 6.62 years (95% CI: 6.24–7.21) for VaD with nootropics, 3.01 years (95% CI: 2.85–3.21) for degenerative dementia without medication, 8.11 years (95% CI: 6.30–8.55) for degenerative dementia with anti-dementia medication, 6.00 years (95% CI: 5.73–6.17) for degenerative dementia with nootropics, and 9.03 years (95% CI: 8.02–9.87) for degenerative dementia with both anti-dementia and nootropic medications. Compared to the non-dementia group, the HRs among individuals with degenerative dementia were 2.69 (95% CI: 2.55–2.83) without medication, 1.46 (95% CI: 1.39–1.54) with nootropics, 1.05 (95% CI: 0.82–1.34) with anti-dementia medication, and 0.92 (95% CI: 0.80–1.05) with both nootropic and anti-dementia medications. VaD with nootropics had a lower mortality (HR: 1.25, 95% CI: 1.15–1.37) than VaD without medication (HR: 2.46, 95% CI: 2.22–2.72).

Conclusion

Pharmacological treatments have beneficial effects for patients with dementia in prolonging their survival.     

Survival Outcomes According to Adjuvant Treatment and Prognostic Factors Including Host Immune Markers in Patients with Curatively Resected Ampulla of Vater Cancer

Background

Ampulla of Vater cancer (AoV Ca) is a rare tumor, and its adjuvant treatment has not been established. The purpose of this study was to find out prognostic factors including host immunity and role of adjuvant treatment in AoV Ca.

Methods and Findings

We reviewed 227 AoV Ca patients with curative resection. Clinical characteristics, adjuvant treatment, disease-free survival (DFS) and overall survival (OS) were analyzed. Among all patients, 63.9, 36.1 and 33.9% had T1/T2, T3/T4 stage and lymph node-positive disease (LN+), respectively. OS of all patients was 90.9 months (95% CI: 52.9–129.0). OS was different according to neutrophil-to-lymphocyte ratio (HR 1.651, 95% CI: 1.11–2.47), platelet-to-lymphocyte ratio (HR 1.488, 95% CI: 1.00–2.21) and systemic inflammatory index (HR 1.669, 95% CI: 1.13–2.47). In multivariate analysis, adverse prognostic factors for OS included vascular invasion (HR 2.571, 95% CI: 1.20–5.53) and elevated CA 19–9 (HR 1.794, 95% CI: 1.07–3.05). A total of 104 patients (46.3%) received adjuvant treatment (25 out of 111of T1/T2 & LN (-), 79 out of 116 of T3/T4 or LN (+)). In T3/T4 or LN (+) stage, adjuvant CCRT with maintenance chemotherapy provided the longest OS (5-year OS rate: 47.0 vs. 41.4%).

Conclusions

Vascular invasion and elevated CA 19–9 were adverse prognostic factors in resected AoV Ca. In T3/T4 or LN (+) stage, adjuvant CCRT with maintenance chemotherapy provided the best survival outcome. Adjuvant treatment should be further defined in AoV Ca, especially with poor prognostic factors.     

Intimate Partner Violence Is Associated with Stress-Related Sleep Disturbance and Poor Sleep Quality during Early Pregnancy

Objectives

To examine the associations of Intimate partner violence (IPV) with stress-related sleep disturbance (measured using the Ford Insomnia Response to Stress Test [FIRST]) and poor sleep quality (measured using the Pittsburgh Sleep Quality Index [PSQI]) during early pregnancy.

Methods

This cross-sectional study included 634 pregnant Peruvian women. In-person interviews were conducted in early pregnancy to collect information regarding IPV history, and sleep traits. Adjusted odds ratios (aOR) and 95% confidence intervals (95%CIs) were calculated using logistic regression procedures.

Results

Lifetime IPV was associated with a 1.54-fold increased odds of stress-related sleep disturbance (95% CI: 1.08–2.17) and a 1.93-fold increased odds of poor sleep quality (95% CI: 1.33–2.81). Compared with women experiencing no IPV during lifetime, the aOR (95% CI) for stress-related sleep disturbance associated with each type of IPV were: physical abuse only 1.24 (95% CI: 0.84–1.83), sexual abuse only 3.44 (95%CI: 1.07–11.05), and physical and sexual abuse 2.51 (95% CI: 1.27–4.96). The corresponding aORs (95% CI) for poor sleep quality were: 1.72 (95% CI: 1.13–2.61), 2.82 (95% CI: 0.99–8.03), and 2.50 (95% CI: 1.30–4.81), respectively. Women reporting any IPV in the year prior to pregnancy had increased odds of stress-related sleep disturbance (aOR = 2.07; 95% CI: 1.17–3.67) and poor sleep quality (aOR = 2.27; 95% CI: 1.30–3.97) during pregnancy.

Conclusion

Lifetime and prevalent IPV exposures are associated with stress-related sleep disturbance and poor sleep quality during pregnancy. Our findings suggest that sleep disturbances may be important mechanisms that underlie the lasting adverse effects of IPV on maternal and perinatal health.     

The Role of Digital Rectal Examination for Diagnosis of Acute Appendicitis: A Systematic Review and Meta-Analysis

Background

Digital rectal examination (DRE) has been traditionally recommended to evaluate acute appendicitis, although several reports indicate its lack of utility for this diagnosis. No meta-analysis has examined DRE for diagnosis of acute appendicitis.

Objectives

To assess the role of DRE for diagnosis of acute appendicitis.

Data Sources

Cochrane Library, PubMed, and SCOPUS from the earliest available date of indexing through November 23, 2014, with no language restrictions.

Study Selection

Clinical studies assessing DRE as an index test for diagnosis of acute appendicitis.

Data Extraction and Synthesis

Two independent reviewers extracted study data and assessed the quality, using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Bivariate random-effects models were used for the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (DOR) as point estimates with 95% confidence intervals (CI).

Main Outcomes and Measures

The main outcome measure was the diagnostic performance of DRE for diagnosis of acute appendicitis.

Results

We identified 19 studies with a total of 7511 patients. The pooled sensitivity and specificity were 0.49 (95% CI 0.42–0.56) and 0.61 (95% CI 0.53–0.67), respectively. The positive and negative likelihood ratios were 1.24 (95% CI 0.97–1.58) and 0.85 (95% CI 0.70–1.02), respectively. The DOR was 1.46 (0.95–2.26).

Conclusion and Relevance

Acute appendicitis cannot be ruled in or out through the result of DRE. Reconsideration is needed for the traditional teaching that rectal examination should be performed routinely in all patients with suspected appendicitis.     

Factors Associated with Ever Being HIV-Tested in Zimbabwe: An Extended Analysis of the Zimbabwe Demographic and Health Survey (2010–2011)

Introduction

Zimbabwe has a high human immunodeficiency virus (HIV) burden. It is therefore important to scale up HIV-testing and counseling (HTC) as a gateway to HIV prevention, treatment and care.

Objective

To determine factors associated with being HIV-tested among adult men and women in Zimbabwe.

Methods

Secondary analysis was done using data from 7,313 women and 6,584 men who completed interviewer-administered questionnaires and provided blood specimens for HIV testing during the Zimbabwe Demographic and Health Survey (ZDHS) 2010–11. Factors associated with ever being HIV-tested were determined using multivariate logistic regression.

Results

HIV-testing was higher among women compared to men (61% versus 39%). HIV-infected respondents were more likely to be tested compared to those who were HIV-negative for both men [adjusted odds ratio (AOR) = 1.53; 95% confidence interval (CI) (1.27–1.84)] and women [AOR = 1.42; 95% CI (1.20–1.69)]. However, only 55% and 74% of these HIV-infected men and women respectively had ever been tested. Among women, visiting antenatal care (ANC) [AOR = 5.48, 95% CI (4.08–7.36)] was the most significant predictor of being tested whilst a novel finding for men was higher odds of testing among those reporting a sexually transmitted infection (STI) in the past 12 months [AOR = 1.86, 95%CI (1.26–2.74)]. Among men, the odds of ever being tested increased with age ≥20 years, particularly those 45–49 years [AOR = 4.21; 95% CI (2.74–6.48)] whilst for women testing was highest among those aged 25–29 years [AOR = 2.01; 95% CI (1.63–2.48)]. Other significant factors for both sexes were increasing education level, higher wealth status and currently/formerly being in union.

Conclusions

There remains a high proportion of undiagnosed HIV-infected persons and hence there is a need for innovative strategies aimed at increasing HIV-testing, particularly for men and in lower-income and lower-educated populations. Promotion of STI services can be an important gateway for testing more men whilst ANC still remains an important option for HIV-testing among pregnant women.     

Prognostic Significance of Molecular Analysis of Peritoneal Fluid for Patients with Gastric Cancer: A Meta-Analysis

Background

Accurately distinguishing serosal invasion in patients with gastric cancer (GC) prior to surgery can be difficult. Molecular analysis of peritoneal fluid (MAPF) for free cancer cells with higher sensitivity than other methods; however, its prognostic value for GC remains controversial, precluding its application in clinical practice.

Methods

PubMed, EMBASE and other databases were systematically searched. Thirty-one studies were eligible for the meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled for overall survival (OS), disease-free survival (DFS) and peritoneal recurrence-free survival (PRF).

Results

The current meta-analysis focused on patients with GC and negative cytological diagnoses. The results showed that positive MAPF status (MAPF⁺) led to poorer prognoses for OS (HR 2.59, 95% CI 1.99–3.37), DFS (HR 4.92, 95% CI 3.28–7.37) and PRF (HR 2.81, 95% CI 2.12–3.72) compared with negative MAPF status (MAPF^-). Moreover, among the patients with GC who received curative treatment, the MAPF⁺ patients had poorer prognoses for OS (HR 3.27, 95% CI 2.49–4.29), DFS (HR 3.90, 95% CI 2.74–5.57) and PRF (HR 5.45, 95% CI 3.70–8.03). A meta-analysis of multivariate-adjusted HRs demonstrated that MAPF⁺ status was an independent prognostic factor for patients with GC who underwent curative treatment (OS: HR 2.19, 95% CI 1.47–3.28; PRF: HR 3.44, 95% CI 2.01–5.87). Using the identical target genes (CEA, CEA/CK20) as molecular markers, the patients with GC who were MAPF⁺ had significantly worse prognoses for OS (CEA: HR 3.03, 95% CI 2.29–4.01; CEA/CK20: HR 4.24, 95% CI 2.42–7.40), DFS (CEA: HR 3.99, 95% CI 2.24–7.12; CEA/CK20: HR 4.31, 95% CI 1.49–2.48) and PRF (CEA: HR 4.45, 95% CI 2.72–7.31; CEA/CK20: HR 6.46, 95% CI 3.62–11.55) than the patients who were MAPF^-.

Conclusion/Significance

The above results demonstrate that MAPF could be a prognostic indicator for patients with GC who have a negative cytological diagnosis and/or are receiving curative treatment. MAPF could provide clinicians with additional prognostic information that could aid in developing individualized treatment plans prior to surgery. The widely used target genes CEA, CEA/CK20 were confirmed to be valuable MAPF markers for predicting the prognosis of GC.     

Factors Associated to Prevalence and Incidence of Carbapenem-Resistant Enterobacteriaceae Fecal Carriage: A Cohort Study in a Mexican Tertiary Care Hospital

Background

Carbapenem-resistant Enterobacteriaceae (CRE) infections have emerged as a serious threat to health worldwide. They are associated with increased morbidity and mortality and are capable of silently colonizing the gastrointestinal tract. Because of this, there is great interest to characterize the epidemiology of CRE carriage and acquisition in healthcare facilities. The aim of this study was to determine the prevalence and factors associated with CRE fecal carriage (CRE-fc), and risk factors for incident cases.

Methods/Results

A cohort study was conducted at a tertiary care hospital from January 1^st to April 30^th, 2014 during a CRE outbreak. Weekly rectal swabs were performed in patients considered at risk until discharge. CRE-fc prevalence was 10.9% (CI 95% 7.7–14.7) among 330 patients. Treatment with carbapenems (OR 2.54, CI 95% 1.15–5.62); transfer from an institution (OR 2.16, CI 95% 1.02–4.59); multi-drug resistant infection within the previous six months (OR 2.81, CI 95% 1.47–5.36); intensive care unit admission (OR 0.42, CI 95% 0.20–0.88); hematologic malignancy (OR 4.02, CI 95% 1.88–8.06); invasive procedures (OR 2.18, CI 95% 1.10–4.32); and sharing a room with a known CRE carrier (OR 3.0, CI 95% 1.43–6.31) were independently associated factors for CRE-fc. Risk factors associated with CRE-fc incidence were determined for 87 patients initially negative and with subsequent screening; the incidence rate was 2.5 cases, per 1000 person-years (CI 95% 1.5–3.9). Independently associated risk factors were carbapenem treatment (HR 2.68, CI 95% 1.03–6.98), hematologic malignancy (HR 5.74, 95% CI 2.46–13.4) and a mean daily colonization pressure ≥10% (HR 5.03, IC 95% 1.77–14.28). OXA-48-like (OXA-232) and CTX-M-15 were the predominantly identified mechanisms of resistance.

Conclusions

We found an elevated incidence and prevalence of CRE-fc in our hospital. Hematologic patients need to be considered a population at risk, and antibiotic stewardship along with infection control programs need to be improved to avoid nosocomial spread.     

Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence

Objective

Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases.

Methods

We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts.

Results

Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R ² = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence.

Conclusion

Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I.