Birth length and weight as predictors of breast cancer prognosis

Background Birth size, and particularly birth length, is positively associated with breast cancer risk in adulthood. The objective of this study was to examine whether birth size is associated with survival among breast cancer patients. Methods Information on birth size (weight, length and ponderal index (kg/length (m3)) was collected from birth archives for 331 breast cancer patients who were diagnosed at two university hospitals in Norway (Bergen and Trondheim). The patients were followed from the time of diagnosis until death from breast cancer, death from another cause, or to the end of follow-up, and birth size was related to survival, using Cox regression analysis. Results Breast cancer patients with birth length ≥ 52 cm had nearly twice the risk of dying (hazard ratio, 1.92, 95% confidence interval, 1.09-3.41) from breast cancer compared to women with birth length less than 48 cm, after adjustment for place of birth and year of diagnosis. Similar analyses related to birth weight and ponderal index showed no clear association with breast cancer survival. Conclusions Poorer outcome of breast cancer patients with high birth length may reflect effects of factors that stimulate longitudinal growth and simultaneously increase the risk of metastases and fatal outcome. It is possible that the insulin-like growth factor (IGF) system is involved in the underlying mechanisms

Generation of Novel Bone Forming Cells (Monoosteophils) from the Cathelicidin-Derived Peptide LL-37 Treated Monocytes

Bone generation and maintenance involve osteoblasts, osteoclasts, and osteocytes which originate from unique precursors and rely on key growth factors for differentiation. However, an incomplete understanding of bone forming cells during wound healing has led to an unfilled clinical need such as nonunion of bone fractures. Since circulating monocytes are often recruited to sites of injury and may differentiate into various cell types including osteoclasts, we investigated the possibility that circulating monocytes in the context of tissue injury may also contribute to bone repair. In particular, we hypothesized that LL-37 (produced from hCAP-18, cathelicidin), which recruits circulating monocytes during injury, may play a role in bone repair.Treatment of monocytes from blood with LL-37 for 6 days resulted in their differentiation to large adherent cells. Growth of LL-37-differentiated monocytes on osteologic discs reveals bone-like nodule formation by scanning electron microscopy (SEM). In vivo transplantation studies in NOD/SCID mice show that LL-37-differentiated monocytes form bone-like structures similar to endochondral bone formation. Importantly, LL-37-differentiated monocytes are distinct from conventional monocyte-derived osteoclasts, macrophages, and dendritic cells and do not express markers of the mesenchymal stem cells (MSC) lineage, distinguishing them from the conventional precursors of osteoblasts. Furthermore, LL-37 differentiated monocytes express intracellular proteins of both the osteoblast and osteoclast lineage including osteocalcin (OC), osteonectin (ON), bone sialoprotein II (BSP II), osteopontin (OP), RANK, RANKL, MMP-9, tartrate resistant acid phosphatase (TRAP), and cathepsin K (CK).Blood derived monocytes treated with LL-37 can be differentiated into a novel bone forming cell that functions both in vitro and in vivo. We propose the name monoosteophil to indicate their monocyte derived lineage and their bone forming phenotype. These cells may have wide ranging implications in the clinic including repair of broken bones and treatment of osteoporosis

Human macrophage foam cells degrade atherosclerotic plaques through cathepsin K mediated processes

<p>Abstract</p> <p>Background</p> <p>Proteolytic degradation of Type I Collagen by proteases may play an important role in remodeling of atherosclerotic plaques, contributing to increased risk of plaque rupture.</p> <p>The aim of the current study was to investigate whether human macrophage foam cells degrade the extracellular matrix (ECM) of atherosclerotic plaques by cathepsin K mediated processes.</p> <p>Methods</p> <p>We 1) cultured human macrophages on ECM and measured cathepsin K generated fragments of type I collagen (C-terminal fragments of Type I collagen (CTX-I) 2) investigated the presence of CTX-I in human coronary arteries and 3) finally investigated the clinical potential by measuring circulating CTX-I in women with and without radiographic evidence of aortic calcified atherosclerosis.</p> <p>Results</p> <p>Immune-histochemistry of early and advanced lesions of coronary arteries demonstrated co-localization of Cathepsin-K and CTX-I in areas of intimal hyperplasia and in shoulder regions of advanced plaques. Treatment of human monocytes with M-CSF or M-CSF+LDL generated macrophages and foam cells producing CTX-I when cultured on type I collagen enriched matrix. Circulating levels of CTX-I were not significantly different in women with aortic calcifications compared to those without.</p> <p>Conclusions</p> <p>Human macrophage foam cells degrade the atherosclerotic plaques though cathepsin K mediated processes, resulting in increase in levels of CTX-I. Serum CTX-I was not elevated in women with aortic calcification, likely due to the contribution of CTX-I from osteoclastic bone resorption which involves Cathepsin-K. The human macrophage model system may be used to identify important pathway leading to excessive proteolytic plaque remodeling and plaque rupture.</p

Model for fitting longitudinal traits subject to threshold response applied to genetic evaluation for heat tolerance

A semi-parametric non-linear longitudinal hierarchical model is presented. The model assumes that individual variation exists both in the degree of the linear change of performance (slope) beyond a particular threshold of the independent variable scale and in the magnitude of the threshold itself; these individual variations are attributed to genetic and environmental components. During implementation via a Bayesian MCMC approach, threshold levels were sampled using a Metropolis step because their fully conditional posterior distributions do not have a closed form. The model was tested by simulation following designs similar to previous studies on genetics of heat stress. Posterior means of parameters of interest, under all simulation scenarios, were close to their true values with the latter always being included in the uncertain regions, indicating an absence of bias. The proposed models provide flexible tools for studying genotype by environmental interaction as well as for fitting other longitudinal traits subject to abrupt changes in the performance at particular points on the independent variable scale

Alterations in osteoclast function and phenotype induced by different inhibitors of bone resorption - implications for osteoclast quality

<p>Abstract</p> <p>Background</p> <p>Normal osteoclasts resorb bone by secretion of acid and proteases. Recent studies of patients with loss of function mutations affecting either of these processes have indicated a divergence in osteoclastic phenotypes. These difference in osteoclast phenotypes may directly or indirectly have secondary effects on bone remodeling, a process which is of importance for the pathogenesis of both osteoporosis and osteoarthritis. We treated human osteoclasts with different inhibitors and characterized their resulting function.</p> <p>Methods</p> <p>Human CD14 + monocytes were differentiated into mature osteoclasts using RANKL and M-CSF. The osteoclasts were cultured on bone in the presence or absence of various inhibitors: Inhibitors of acidification (bafilomycin A1, diphyllin, ethoxyzolamide), inhibitors of proteolysis (E64, GM6001), or a bisphosphonate (ibandronate). Osteoclast numbers and bone resorption were monitored by measurements of TRACP activity, the release of calcium, CTX-I and ICTP, as well as by counting resorption pits.</p> <p>Results</p> <p>All inhibitors of acidification were equally potent with respect to inhibition of both organic and inorganic resorption. In contrast, inhibition of proteolysis by E64 potently reduced organic resorption, but only modestly suppressed inorganic resorption. GM6001 alone did not greatly affect bone resorption. However, when GM6001 and E64 were combined, a complete abrogation of organic bone resorption was observed, without a great effect on inorganic resorption. Ibandronate abrogated both organic and inorganic resorption at all concentrations tested [0.3-100 μM], however, this treatment dramatically reduced TRACP activity.</p> <p>Conclusions</p> <p>We present evidence highlighting important differences with respect to osteoclast function, when comparing the different types of osteoclast inhibitors. Each class of osteoclast inhibitors will lead to different alterations in osteoclast quality, which secondarily may lead to different bone qualities.</p

A retrospective cohort study of stroke onset: implications for characterizing short term effects from ambient air pollution

<p>Abstract</p> <p>Background</p> <p>Case-crossover studies used to investigate associations between an environmental exposure and an acute health response, such as stroke, will often use the day an individual presents to an emergency department (ED) or is admitted to hospital to infer when the stroke occurred. Similarly, they will use patient's place of residence to assign exposure. The validity of using these two data elements, typically extracted from administrative databases or patient charts, to define the time of stroke onset and to assign exposure are critical in this field of research as air pollutant concentrations are temporally and spatially variable. Our a priori hypotheses were that date of presentation differs from the date of stroke onset for a substantial number of patients, and that assigning exposure to ambient pollution using place of residence introduces an important source of exposure measurement error. The objective of this study was to improve our understanding on how these sources of errors influence risk estimates derived using a case-crossover study design.</p> <p>Methods</p> <p>We sought to collect survey data from stroke patients presenting to hospital EDs in Edmonton, Canada on the date, time, location and nature of activities at onset of stroke symptoms. The daily mean ambient concentrations of NO₂and PM_2.5on the self-reported day of stroke onset was estimated from continuous fixed-site monitoring stations.</p> <p>Results</p> <p>Of the 336 participating patients, 241 were able to recall when their stroke started and 72.6% (95% confidence interval [CI]: 66.9 - 78.3%) experienced stroke onset the same day they presented to the ED. For subjects whose day of stroke onset differed from the day of presentation to the ED, this difference ranged from 1 to 12 days (mean = 1.8; median = 1). In these subjects, there were no systematic differences in assigned pollution levels for either NO₂or PM_2.5when day of presentation rather than day of stroke onset was used. At the time of stroke onset, 89.9% (95% CI: 86.6 - 93.1%) reported that they were inside, while 84.5% (95% CI: 80.6 - 88.4%) reported that for most of the day they were within a 15 minute drive from home. We estimated that due to the mis-specification of the day of stroke onset, the risk of hospitalization for stroke would be understated by 15% and 20%, for NO₂and PM_2.5, respectively.</p> <p>Conclusions</p> <p>Our data suggest that day of presentation and residential location data obtained from administrative records reasonably captures the time and location of stroke onset for most patients. Under these conditions, any associated errors are unlikely to be an important source of bias when estimating air pollution risks in this population.</p

Protein C Inhibitor—A Novel Antimicrobial Agent

Protein C inhibitor (PCI) is a heparin-binding serine proteinase inhibitor belonging to the family of serpin proteins. Here we describe that PCI exerts broad antimicrobial activity against bacterial pathogens. This ability is mediated by the interaction of PCI with lipid membranes, which subsequently leads to their permeabilization. As shown by negative staining electron microscopy, treatment of Escherichia coli or Streptococcus pyogenes bacteria with PCI triggers membrane disruption followed by the efflux of bacterial cytosolic contents and bacterial killing. The antimicrobial activity of PCI is located to the heparin-binding site of the protein and a peptide spanning this region was found to mimic the antimicrobial activity of PCI, without causing lysis or membrane destruction of eukaryotic cells. Finally, we show that platelets can assemble PCI on their surface upon activation. As platelets are recruited to the site of a bacterial infection, these results may explain our finding that PCI levels are increased in tissue biopsies from patients suffering from necrotizing fasciitis caused by S. pyogenes. Taken together, our data describe a new function for PCI in innate immunity

Paratuberculosis sero-status and milk production, SCC and calving interval in Irish dairy herds

The objective of this study was to investigate the impact of paratuberculosis sero-status on milk yield, fat, protein, somatic cell count and calving interval in Irish dairy herds. Serum from all animals over 12 months of age (n = 2,602) in 34 dairy herds was tested for antibodies to Mycobacterium avium subsp. paratuberculosis using an ELISA. Herds were categorised by sero-status into positive, non-negative and negative, where a positive herd contained two or more positive cows, a non-negative herd contained only one positive cow and a negative herd contained no positive cows. Data at animal, parity and herd-level were analysed by multiple regression using general linear models. Positive herds (mean herd size = 129 cows) and non-negative herds (81 cows) were larger than negative herds (72 cows) (P < 0.01). Negative herds had the highest economic breeding index (EBI), while positive herds had the highest estimated breeding value (EBV) for milk yield. There was no significant effect of paratuberculosis sero-status at animal, parity or herd-level on milk yield, milk fat or protein production, somatic cell count score (SCCS) or calving interval. Negative herds tended to have a lower SCCS than positive and nonnegative herds (P = 0.087). This study only examined the effects of paratuberculosis sero-status but did not examine the clinical effects of Johne's disease at the farm or dairy industry levels

Obesity Impact on the Attentional Cost for Controlling Posture

International audienceBACKGROUND: This study investigated the effects of obesity on attentional resources allocated to postural control in seating and unipedal standing. METHODS: Ten non obese adults (BMI = 22.4±1.3, age = 42.4±15.1) and 10 obese adult patients (BMI = 35.2±2.8, age = 46.2±19.6) maintained postural stability on a force platform in two postural tasks (seated and unipedal). The two postural tasks were performed (1) alone and (2) in a dual-task paradigm in combination with an auditory reaction time task (RT). Performing the RT task together with the postural one was supposed to require some attentional resources that allowed estimating the attentional cost of postural control. 4 trials were performed in each condition for a total of 16 trials. FINDINGS: (1) Whereas seated non obese and obese patients exhibited similar centre of foot pressure oscillations (CoP), in the unipedal stance only obese patients strongly increased their CoP sway in comparison to controls. (2) Whatever the postural task, the additional RT task did not affect postural stability. (3) Seated, RT did not differ between the two groups. (4) RT strongly increased between the two postural conditions in the obese patients only, suggesting that body schema and the use of internal models was altered with obesity. INTERPRETATION: Obese patients needed more attentional resources to control postural stability during unipedal stance than non obese participants. This was not the case in a more simple posture such as seating. To reduce the risk of fall as indicated by the critical values of CoP displacement, obese patients must dedicate a strong large part of their attentional resources to postural control, to the detriment of non-postural events. Obese patients were not able to easily perform multitasking as healthy adults do, reflecting weakened psycho-motor abilities

Renal function at the time of a myocardial infarction maintains prognostic value for more than 10 years

<p>Abstract</p> <p>Background</p> <p>Renal function is an important predictor of mortality in patients with myocardial infarction (MI), but changes in the impact over time have not been well described.</p> <p>We examined the importance of renal function by estimated GFR (eGFR) and se-creatinine as an independent long-term prognostic factor.</p> <p>Methods</p> <p>Prospective follow-up of 6653 consecutive MI patients screened for entry in the Trandolapril Cardiac Evaluation (TRACE) study. The patients were analysed by Kaplan-Meier survival analysis, landmark analysis and Cox proportional hazard models. Outcome measure was all-cause mortality.</p> <p>Results</p> <p>An eGFR below 60 ml per minute per 1.73 m², consistent with chronic renal disease, was present in 42% of the patients. We divided the patients into 4 groups according to eGFR. Overall, Cox proportional-hazards models showed that eGFR was a significant prognostic factor in the two groups with the lowest eGFR, hazard ratio 1,72 (confidence interval (CI) 1,56-1,91) in the group with the lowest eGFR. Using the eGFR group with normal renal function as reference, we observed an incremental rise in hazard ratio. We divided the follow-up period in 2-year intervals. Landmark analysis showed that eGFR at the time of screening continued to show prognostic effect until 16 years of follow-up. By multivariable Cox regression analysis, the prognostic effect of eGFR persisted for 12 years and of se-creatinine for 10 years. When comparing the lowest group of eGFR with the group with normal eGFR, prognostic significance was present in the entire period of follow-up with a hazard ratio between 1,97 (CI 1,65-2,35) and 1,35 (CI 0,99-1,84) in the 2-year periods.</p> <p>Conclusions</p> <p>One estimate of renal function is a strong and independent long-term prognostic factor for 10-12 years following a MI.</p