Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry

Purpose: The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controversial. The aim of this study was to explore features of breast cancers arising in Lynch syndrome families. Experimental Design: This observational study involved 107 cases of breast cancer identified from the Colorectal Cancer Family Registry (Colon CFR) from 90 families in which (a) both breast and colon cancer co-occurred, (b) families met either modified Amsterdam criteria, or had at least one early-onset (<50 years) colorectal cancer, and (c) breast tissue was available within the biospecimen repository for mismatch repair (MMR) testing. Eligibility criteria for enrollment in the Colon CFR are available online. Breast cancers were reviewed by one pathologist. Tumor sections were stained for MLH1, PMS2, MSH2, and MSH6, and underwent microsatellite instability testing. Results: Breast cancer arose in 35 mutation carriers, and of these, 18 (51%) showed immunohistochemical absence of MMR protein corresponding to the MMR gene mutation segregating the family. MMR-deficient breast cancers were more likely to be poorly differentiated (P = 0.005) with a high mitotic index (P = 0.002), steroid hormone receptor–negative (estrogen receptor, P = 0.031; progesterone receptor, P = 0.022), and to have peritumoral lymphocytes (P = 0.015), confluent necrosis (P = 0.002), and growth in solid sheets (P < 0.001) similar to their colorectal counterparts. No difference in age of onset was noted between the MMR-deficient and MMR-intact groups. Conclusions: MMR deficiency was identified in 51% of breast cancers arising in known mutation carriers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lacking

Reply to William B. Grant

THE UVI working group acknowledges the contribution of Vitamin D to bone health as stated in our paper. However, we concluded that an optimal level of Vitamin D for humans has not yet been established with any certainty...

Changes in Knee Biomechanics After a Hip-Abductor Strengthening Protocol for Runners With Patellofemoral Pain Syndrome

Context: Very few authors have investigated the relationship between hip-abductor muscle strength and frontal-plane knee mechanics during running. Objective: To investigate this relationship using a 3-week hip-abductor muscle-strengthening program to identify changes in strength, pain, and biomechanics in runners with patellofemoral pain syndrome (PFPS). Design: Cohort study. Setting: University-based clinical research laboratory. Patients or Other Participants: Fifteen individuals (5 men, 10 women) with PFPS and 10 individuals without PFPS (4 men, 6 women) participated. Intervention(s): The patients with PFPS completed a 3-week hip-abductor strengthening protocol; control participants did not. Main Outcome Measure(s): The dependent variables of interest were maximal isometric hip-abductor muscle strength, 2-dimensional peak knee genu valgum angle, and stride-to-stride knee-joint variability. All measures were recorded at baseline and 3 weeks later. Between-groups differences were compared using repeated-measures analyses of variance. Results: At baseline, the PFPS group exhibited reduced strength, no difference in peak genu valgum angle, and increased stride-to-stride knee-joint variability compared with the control group. After the 3-week protocol, the PFPS group demonstrated increased strength, less pain, no change in peak genu valgum angle, and reduced stride-to-stride knee-joint variability compared with baseline. Conclusions: A 3-week hip-abductor muscle-strengthening protocol was effective in increasing muscle strength and decreasing pain and stride-to-stride knee-joint variability in individuals with PFPS. However, concomitant changes in peak knee genu valgum angle were not observed.

Changing parental high risk behaviour in the reduction of SIDS : the imperative of translational research

Objectives To investigate the factors associated with sudden infant death syndrome (SIDS) from birth to age 2 years, whether recent advice has been followed, whether any new risk factors have emerged, and the specific circumstances in which SIDS occurs while cosleeping (infant sharing the same bed or sofa with an adult or child). Design Four year population based case-control study. Parents were interviewed shortly after the death or after the reference sleep (within 24 hours) of the two control groups. Setting South west region of England (population 4.9 million, 184 800 births). Participants 80 SIDS infants and two control groups weighted for age and time of reference sleep: 87 randomly selected controls and 82 controls at high risk of SIDS (young, socially deprived, multiparous mothers who smoked). Results The median age at death (66 days) was more than three weeks less than in a study in the same region a decade earlier. Of the SIDS infants, 54% died while cosleeping compared with 20% among both control groups. Much of this excess may be explained by a significant multivariable interaction between cosleeping and recent parental use of alcohol or drugs (31% v 3% random controls) and the increased proportion of SIDS infants who had coslept on a sofa (17% v 1%). One fifth of SIDS infants used a pillow for the last sleep (21% v 3%) and one quarter were swaddled (24% v 6%). More mothers of SIDS infants than random control infants smoked during pregnancy (60% v 14%), whereas one quarter of the SIDS infants were preterm (26% v 5%) or were in fair or poor health for the last sleep (28% v 6%). All of these differences were significant in the multivariable analysis regardless of which control group was used for comparison. The significance of covering the infant’s head, postnatal exposure to tobacco smoke, dummy use, and sleeping in the side position has diminished although a significant proportion of SIDS infants were still found prone (29% v 10%). Conclusions Many of the SIDS infants had coslept in a hazardous environment. The major influences on risk, regardless of markers for socioeconomic deprivation, are amenable to change and specific advice needs to be given, particularly on use of alcohol or drugs before cosleeping and cosleeping on a sofa.

The epidemiology of invasive group A streptococcal disease in Victoria, Australia

Objective To estimate the incidence and severity of invasive group A streptococcal infection in Victoria, Australia. Design Prospective active surveillance study. Setting Public and private laboratories, hospitals and general practitioners throughout Victoria. Patients eople in Victoria diagnosed with group A streptococcal disease notified to the surveillance system between 1 March 2002 and 31 August 2004. Main outcome measure Confirmed invasive group A streptococcal disease. Results We identified 333 confirmed cases: an average annualised incidence rate of 2.7 (95% CI, 2.3-3.2) per 100000 population per year. Rates were highest in people aged 65 years and older and those younger than 5 years. The case-fatality rate was 7.8%. Streptococcal toxic shock syndrome occurred in 48 patients (14.4%), with a case-fatality rate of 23%. Thirty cases of necrotising fasciitis were reported; five (17%) of these patients died. Type 1 (23%) was the most frequently identified emm sequence type in all, age groups. All tested isolates were susceptible to penicillin and clindamycin. Two isolates (4%) were resistant to erythromycin. Conclusion The incidence of invasive group A streptococcal disease in temperate Australia is greater than previously appreciated and warrants greater public health attention, including its designation as a notifiable disease.

A metastatic neuroendocrine anaplastic small cell tumor in a patient with multiple endocrine neoplasia type 1 syndrome : assessment of disease status and response to doxorubicin, cyclophosphamide, etoposide chemotherapy through scintigraphic imaging with 111In-pentetreotide

Extrapulmonary small cell and small cell neuroendocrine tumors of unknown primary site are, in general, aggressive neoplasms with a short median survival. Like small cell lung cancer (SCLC), they often are responsive to chemotherapy and radiotherapy. Small cell lung cancer and well differentiated neuroendocrine carcinomas of the gastrointestinal tract and pancreas tend to express somatostatin receptors. These tumors may be localized in patients by scintigraphic imaging using radiolabeled somatostatin analogues. A patient with an anaplastic neuroendocrine small cell tumor arising on a background of multiple endocrine neoplasia type 1 syndrome is reported. The patient had a known large pancreatic gastrinoma and previously treated parathyroid adenopathy. At presentation, there was small cell cancer throughout the liver and skeleton. Imaging with a radiolabeled somatostatin analogue, 111In- pentetreotide (Mallinckrodt Medical B. V., Petten, Holland), revealed all sites of disease detected by routine biochemical and radiologic methods. After six cycles of chemotherapy with doxorubicin, cyclophosphamide, and etoposide, there was almost complete clearance of the metastatic disease. 111In-pentetreotide scintigraphy revealed uptake consistent with small areas of residual disease in the liver, the abdomen (in mesenteric lymph nodes), and posterior thorax (in a rib). The primary gastrinoma present before the onset of the anaplastic small cell cancer showed no evidence of response to the treatment. The patient remained well for 1 year and then relapsed with brain, lung, liver, and skeletal metastases. Despite an initial response to salvage radiotherapy and chemotherapy with carboplatin and dacarbazine, the patient died 6 months later.

A preliminary study of the effects of Tai Chi and Qigong medical exercise on indicators of metabolic syndrome, glycaemic control, health-related quality of life, and psychological health in adults with elevated blood glucose

Objectives To evaluate the feasibility, acceptability and effects of a Tai Chi and Qigong exercise programme in adults with elevated blood glucose. Design, Setting, and Participants A single group pre–post feasibility trial with 11 participants (3 male and 8 female; aged 42–65 years) with elevated blood glucose. Intervention Participants attended Tai Chi and Qigong exercise training for 1 to 1.5 h, 3 times per week for 12 weeks, and were encouraged to practise the exercises at home. Main Outcome Measures Indicators of metabolic syndrome (body mass index (BMI), waist circumference, blood pressure, fasting blood glucose, triglycerides, HDL-cholesterol); glucose control (HbA1c, fasting insulin and insulin resistance (HOMA)); health-related quality of life; stress and depressive symptoms. Results There was good adherence and high acceptability. There were significant improvements in four of the seven indicators of metabolic syndrome including BMI (mean difference −1.05, p<0.001), waist circumference (−2.80 cm, p<0.05), and systolic (−11.64 mm Hg, p<0.01) and diastolic blood pressure (−9.73 mm Hg, p<0.001), as well as in HbA1c (−0.32%, p<0.01), insulin resistance (−0.53, p<0.05), stress (−2.27, p<0.05), depressive symptoms (−3.60, p<0.05), and the SF-36 mental health summary score (5.13, p<0.05) and subscales for general health (19.00, p<0.01), mental health (10.55, p<0.01) and vitality (23.18, p<0.05). Conclusions The programme was feasible and acceptable and participants showed improvements in metabolic and psychological variables. A larger controlled trial is now needed to confirm these promising preliminary results.

Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes

The aim of this study was to use lipidomics to determine if the lipid composition of apolipoprotein-B-containing lipoproteins is modified by dyslipidaemia in type 2 diabetes and if any of the identified changes potentially have biological relevance in the pathophysiology of type 2 diabetes. VLDL and LDL from normolipidaemic and dyslipidaemic type 2 diabetic women and controls were isolated and quantified with HPLC and mass spectrometry. A detailed molecular characterisation of VLDL triacylglycerols (TAG) was also performed using the novel ozone-induced dissociation method, which allowed us to distinguish vaccenic acid (C18:1 n-7) from oleic acid (C18:1 n-9) in specific TAG species. Lipid class composition was very similar in VLDL and LDL from normolipidaemic type 2 diabetic and control participants. By contrast, dyslipidaemia was associated with significant changes in both lipid classes (e.g. increased diacylglycerols) and lipid species (e.g. increased C16:1 and C20:3 in phosphatidylcholine and cholesteryl ester and increased C16:0 [palmitic acid] and vaccenic acid in TAG). Levels of palmitic acid in VLDL and LDL TAG correlated with insulin resistance, and VLDL TAG enriched in palmitic acid promoted increased secretion of proinflammatory mediators from human smooth muscle cells. We showed that dyslipidaemia is associated with major changes in both lipid class and lipid species composition in VLDL and LDL from women with type 2 diabetes. In addition, we identified specific molecular lipid species that both correlate with clinical variables and are proinflammatory. Our study thus shows the potential of advanced lipidomic methods to further understand the pathophysiology of type 2 diabetes.

Supernatants of acquired immunodeficiency syndrome-related Kaposi's sarcoma cells induce endothelial cell chemotaxis and invasiveness

Kaposi's sarcoma (KS) in general, and acquired immunodeficiency syndrome-related KS (AIDS-KS) in particular, is a highly invasive and intensely angiogenic neoplasm of unknown cellular origin. We have recently established AIDS-KS cells in long term culture and reported the development of KS-like lesions in nude mice inoculated with these cells. Here, we have examined the in vitro invasiveness of basement membrane by AIDS-KS cells, as well as the effect(s) of their supernatants on the migration and invasiveness of human vascular endothelial cells. AIDS-KS cells were highly invasive in the Boyden chamber invasion assay and formed invasive, branching colonies in a 3-dimensional gel (Matrigel). Normal endothelial cells form tube-like structures on Matrigel. AIDS-KS cell-conditioned media induced endothelial cells to form invasive clusters in addition to tubes. KS-cell-conditioned media, when placed in the lower compartment of the Boyden chamber, stimulated the migration of human and bovine vascular endothelial cells across filters coated with either small amounts of collagen IV (chemotaxis) or a Matrigel barrier (invasion). Basic fibroblast growth factor could also induce endothelial cell chemotaxis and invasion in these assays. However, when antibodies to basic fibroblast growth factor were used the invasive activity induced by the AIDS-KS-cell-conditioned media was only marginally inhibited, suggesting that the large quantities of basic fibroblast growth factor-like material released by the AIDS-KS cells are not the main mediators of this effect. Specific inhibitors of laminin and collagenase IV action, which represent critical determinants of basement membrane invasion, blocked the invasiveness of the AIDS-KS cell-activated endothelial cells in these assays. These data indicate that KS cells appear to be of smooth muscle origin but secrete a potent inducer of endothelial cell chemotaxis and invasiveness which could be responsible for angiogenesis and the resulting highly vascularized lesions. These assays appear to be a model to study the invasive spread and angiogenic capacity of human AIDS-related KS and should prove useful in the identification of molecular mediators and potential inhibitors of neoplastic neovascularization.

Mastery motivation in children with intellectual disability : Is there evidence for a Down syndrome behavioural phenotype?

The main purpose of the current study was to provide empirical evidence to support or refute assumptions of phenotypic deficits in motivation for children with Down syndrome. Children with moderate intellectual disability associated with etiologies other than Down syndrome were recruited in an extension of a previous study that involved children with Down syndrome and typically developing children. The participants were 29 children with moderate intellectual disability and 33 children with Down syndrome who were matched on mental age to 33 typically developing children, aged 3 to 8 years. Mastery motivation was assessed on task measures of curiosity, preference for challenge, and persistence, as well as parental reports. There were no significant group differences on the mastery motivation tasks. Parental ratings of mastery motivation differed, with typically developing children generally being rated more highly than each of the disability groups. The view that motivational deficits are part of the Down syndrome behavioural phenotype was not supported.

A biomarker panel to discriminate between systemic inflammatory response syndrome and sepsis and sepsis severity

Introduction: In this study, we report on initial efforts to discover putative biomarkers for differential diagnosis of a systemic inflammatory response syndrome (SIRS) versus sepsis; and different stages of sepsis. In addition, we also investigated whether there are proteins that can discriminate between patients who survived sepsis from those who did not. Materials and Methods: Our study group consisted of 16 patients, of which 6 died and 10 survived. We daily measured 28 plasma proteins, for the whole stay of the patients in the ICU. Results: We observed that metalloproteinases and sE-selectin play a role in the distinction between SIRS and sepsis, and that IL-1, IP-10, sTNF-R2 and sFas appear to be indicative for the progression from sepsis to septic shock. A combined measurement of MMP-3, -10, IL-1, IP-10, sIL-2R, sFas, sTNF-R1, sRAGE, GM-CSF, IL-1 and Eotaxin allows for a good separation of patients that survived from those that died (mortality prediction with a sensitivity of 79% and specificity of 86%). Correlation analysis suggests a novel interaction between IL-1a and IP-10. Conclusion: The marker panel is ready to be verified in a validation study with or without therapeutic intervention.

A review of pedestrian group dynamics and methodologies in modelling pedestrian group behaviours

Observations conducted by researchers revealed that the group interaction within crowds is a common phenomenon and has great influence on pedestrian behaviour. However, most research currently undertaken by various researchers failed to consider the group dynamics when developing pedestrian flow models. This paper presented a critical review of pedestrian models that incorporates group behaviour. Models reviewed in this paper are mainly created by microscopic modelling approaches such as social force, cellular automata, and agent-based method. The purpose of this literature review is to improve the understanding of group dynamics among pedestrians and highlight the need for considering group dynamics when developing pedestrian simulation models.

Clinical trials in pediatrics

“Children are not little adults.” Almost all aspects of children's health including clinical trials and drug development are poor cousins of adult health. Over the years, pediatricians worldwide caution against blind extrapolation of adult data to children as it may result in considerable harm [1,2]. Also, it is increasingly recognized that the roots of many chronic diseases in adulthood stem from childhood and tackling health issues in children lead to improved health in adults [3,4]. Furthermore, investment in early childhood has long-term benefits in adults not only in health but also in other aspects of life such as education and crime reduction [4,5]. Arguably, health at birth is the single most important predictor of health in adulthood as the inequality of an infant at birth has intergenerational effects [5]. The Carolina Abecedarian Project showed that early childhood programs that are of high quality result in substantial societal benefits (e.g., reduction of crime, increased earnings, better education) [4,5]. A recent publication from this project found that this benefit also translated into improved adult health outcomes [4]. In a randomized trial, Campbell and colleagues described that disadvantaged children who were randomized to the intervention group (early education, health screenings and nutrition program) had significantly lower rates of metabolic syndrome, obesity and hypertension, when aged in their mid-30s, compared with the control group [4]...

Analysis of passenger group behaviour and its impact on passenger flow using an agent-based model

Group interaction within crowds is a common phenomenon and has great influence on pedestrian behaviour. This paper investigates the impact of passenger group dynamics using an agent-based simulation method for the outbound passenger process at airports. Unlike most passenger-flow models that treat passengers as individual agents, the proposed model additionally incorporates their group dynamics as well. The simulation compares passenger behaviour at airport processes and discretionary services under different group formations. Results from experiments (both qualitative and quantitative) show that incorporating group attributes, in particular, the interactions with fellow travellers and wavers can have significant influence on passengers activity preference as well as the performance and utilisation of services in airport terminals. The model also provides a convenient way to investigate the effectiveness of airport space design and service allocations, which can contribute to positive passenger experiences. The model was created using AnyLogic software and its parameters were initialised using recent research data published in the literature.