Factors governing late-recurrence of disease in a cohort of early-stage breast cancer survivors

Purpose. To determine the risk of late breast cancer recurrence (5 years after treatment) in a population of women diagnosed with early-stage breast cancer at The University of Texas M.D. Anderson Cancer Center (MDACC) between 1985-2000 and to examine the effect of this population’s BMI, smoking history, reproductive history, hormone use, and alcohol intake at the time of diagnosis on risk of late recurrence.^ Methods. Patients included 1,913 members of the Early Stage Breast Cancer Repository recruited at MDACC who had survived without a recurrence for at least five years after their initial diagnosis of early stage breast cancer. Clinical and epidemiological information was ascertained twice on participants during the study—first by medical record abstraction then by patient interview at least five years after receipt of adjuvant treatment. A total of 223 late breast cancer recurrences were captured, with an average follow-up of 10.6 years. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). ^

Epithelial antibiotic induced in states of disease

Epithelial defensins provide an active defense against the external microbial environment. We investigated the distribution and expression of this class of antimicrobial peptides in normal cattle and in animals in varying states of disease. β-defensin mRNA was found to be widely expressed in numerous exposed epithelia but was found at higher levels in tissues that are constantly exposed to and colonized by microorganisms. We observed induction in ileal mucosa during chronic infection with Mycobacterium paratuberculosis and in bronchial epithelium after acute infection with Pasteurella haemolytica. It has been proposed that expression of antimicrobial peptides is an integral component of the inflammatory response. The results reported here support this hypothesis and suggest that epithelial defensins provide a rapidly mobilized local defense against infectious organisms.

Frequency of HLA allele-specific peptide motifs in HIV-1 proteins correlates with the allele’s association with relative rates of disease progression after HIV-1 infection

An HLA allele-specific cytotoxic T lymphocyte response is thought to influence the rate of disease progression in HIV-1-infected individuals. In a prior study of 139 HIV-1-infected homosexual men, we identified HLA class I alleles and observed an association of specific alleles with different relative hazards for progression to AIDS. Seeking an explanation for this association, we searched HIV-1 protein sequences to determine the number of peptides matching motifs defined by combinations of specific amino acids reported to bind 16 class I alleles. Analyzing complete sequences of 12 clade B HIV isolates, we determined the number of allele motifs that were conserved (occurring in all 12 isolates) and nonconserved (occurring in only one isolate), as well as the average number of allele motifs per isolate. We found significant correlations with an allele’s association with disease progression for counts of conserved motifs in gag (R = 0.73; P = 0.002), pol (R = 0.58, P = 0.024), gp120 (R = 0.78, P = 0.00056), and total viral protein sequences (R = 0.67, P = 0.0058) and also for counts of nonconserved motifs in gag (R = 0.62, P = 0.013), pol (R = 0.74, P = 0.0017), gp41 (R = 0.52, P = 0.046), and total viral protein (R = 0.71, P = 0.0033). We also found significant correlations for the average number of motifs per isolate for gag, pol, gp120, and total viral protein. This study provides a plausible functional explanation for the observed association of different HLA alleles with variable rates of disease progression.

National burden of disease in India from indoor air pollution

In the last decade, a number of quantitative epidemiological studies of specific diseases have been done in developing countries that for the first time allow estimation of the total burden of disease (mortality and morbidity) attributable to use of solid fuels in adult women and young children, who jointly receive the highest exposures because of their household roles. Few such studies are available as yet for adult men or children over 5 years. This paper evaluates the existing epidemiological studies and applies the resulting risks to the more than three-quarters of all Indian households dependent on such fuels. Allowance is made for the existence of improved stoves with chimneys and other factors that may lower exposures. Attributable risks are calculated in reference to the demographic conditions and patterns of each disease in India. Sufficient evidence is available to estimate risks most confidently for acute respiratory infections (ARI), chronic obstructive pulmonary disease (COPD), and lung cancer. Estimates for tuberculosis (TB), asthma, and blindness are of intermediate confidence. Estimates for heart disease have the lowest confidence. Insufficient quantitative evidence is currently available to estimate the impact of adverse pregnancy outcomes (e.g., low birthweight and stillbirth). The resulting conservative estimates indicate that some 400–550 thousand premature deaths can be attributed annually to use of biomass fuels in these population groups. Using a disability-adjusted lost life-year approach, the total is 4–6% of the Indian national burden of disease, placing indoor air pollution as a major risk factor in the country.

Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users who are carriers of hereditary prothrombotic conditions

Objective: To investigate whether users of oral contraceptives who are carriers of a hereditary prothrombotic condition (factor V Leiden mutation, protein C, S, or antithrombin deficiency) have an increased risk of cerebral sinus thrombosis.

Branched co-polymers of histidine and lysine are efficient carriers of plasmids

We previously determined that a linear co-polymer of histidine and lysine (HK) in combination with liposomes enhanced the transfection efficiency of cationic liposomes. In the current study, we designed a series of HK polymers with increased branching and/or histidine/lysine ratio to determine if either variable affects transfection efficiency. In the presence of liposomes, the branched polymer with the highest number of histidines, HHK4b, was the most effective at enhancing gene expression. Furthermore, when serum was added to the medium during transfection, the combination of HHK4b and liposomes as a gene-delivery vehicle increased luciferase expression 400-fold compared to liposomes alone. In contrast to linear HK polymers, the higher branched HHK polymers were effective carriers of plasmids in the absence of liposomes. Without liposomes, the HHK4b carrier enhanced luciferase expression 15-fold in comparison with the lesser branched HHK2b carrier and increased expression by 5-logs in comparison with the HHK or HK carrier. The interplay of several parameters including increased condensation of DNA, buffering of acidic endosomes and differential binding affinities of polymer with DNA have a role in the enhancement of transfection by the HK polymers. In addition to suggesting that branched HK polymers are promising gene-delivery vehicles, this study provides a framework for the development of more efficient peptide-bond-based polymers of histidine and lysine.

Von Willebrand factor propeptide as a marker of disease activity in systemic sclerosis (scleroderma)

In 44 consecutive patients with systemic sclerosis (SSc), plasma concentrations of von Willebrand factor (vWf) were higher than those of the vWf propeptide, but the propeptide showed less variability within patient subgroups. Higher values of the propeptide were observed in patients with early pulmonary involvement. A closer correlation of the propeptide than of vWf to biochemical markers of activity was also evident. Our results suggest that the propeptide, despite a shorter circulating half-time and lower plasma concentrations than vWf, is more useful in the assessment of disease activity in SSc.

Abrogation of disease development in plants expressing animal antiapoptotic genes

An emerging topic in plant biology is whether plants display analogous elements of mammalian programmed cell death during development and defense against pathogen attack. In many plant–pathogen interactions, plant cell death occurs in both susceptible and resistant host responses. For example, specific recognition responses in plants trigger formation of the hypersensitive response and activation of host defense mechanisms, resulting in restriction of pathogen growth and disease development. Several studies indicate that cell death during hypersensitive response involves activation of a plant-encoded pathway for cell death. Many susceptible interactions also result in host cell death, although it is not clear how or if the host participates in this response. We have generated transgenic tobacco plants to express animal genes that negatively regulate apoptosis. Plants expressing human Bcl-2 and Bcl-xl, nematode CED-9, or baculovirus Op-IAP transgenes conferred heritable resistance to several necrotrophic fungal pathogens, suggesting that disease development required host–cell death pathways. In addition, the transgenic tobacco plants displayed resistance to a necrogenic virus. Transgenic tobacco harboring Bcl-xl with a loss-of-function mutation did not protect against pathogen challenge. We also show that discrete DNA fragmentation (laddering) occurred in susceptible tobacco during fungal infection, but does not occur in transgenic-resistant plants. Our data indicate that in compatible plant–pathogen interactions apoptosis-like programmed cell death occurs. Further, these animal antiapoptotic genes function in plants and should be useful to delineate resistance pathways. These genes also have the potential to generate effective disease resistance in economically important crops.

The effect of cultivation on the size, shape, and persistence of disease patches in fields

Epidemics of soil-borne plant disease are characterized by patchiness because of restricted dispersal of inoculum. The density of inoculum within disease patches depends on a sequence comprising local amplification during the parasitic phase followed by dispersal of inoculum by cultivation during the intercrop period. The mechanisms that control size, shape, and persistence have received very little rigorous attention in epidemiological theory. Here we derive a model for dispersal of inoculum in soil by cultivation that takes account into the discrete stochastic nature of the system in time and space. Two parameters, probability of movement and mean dispersal distance, characterize lateral dispersal of inoculum by cultivation. The dispersal parameters are used in combination with the characteristic area and dimensions of host plants to identify criteria that control the shape and size of disease patches. We derive a critical value for the probability of movement for the formation of cross-shaped patches and show that this is independent of the amount of inoculum. We examine the interaction between local amplification of inoculum by parasitic activity and subsequent dilution by dispersal and identify criteria whereby asymptomatic patches may persist as inoculum falls below a threshold necessary for symptoms to appear in the subsequent crop. The model is motivated by the spread of rhizomania, an economically important soil-borne disease of sugar beet. However, the results have broad applicability to a very wide range of diseases that survive as discrete units of inoculum. The application of the model to patch dynamics of weed seeds and local introductions of genetically modified seeds is also discussed.

T-cell receptor (TCR) usage in Lewis rat experimental autoimmune encephalomyelitis: TCR beta-chain-variable-region V beta 8.2-positive T cells are not essential for induction and course of disease.

Predominant usage of V beta 8.2 gene segments, encoding a T-cell receptor (TCR) beta chain variable region, has been reported for pathogenic Lewis rat T cells reactive to myelin basic protein (MBP). However, up to 75% of the alpha/beta T cells in a panel of MBP-specific T-cell lines did not display TCR V beta 8.2, V beta 8.5, V beta 10, or V beta 16 elements. To further investigate TCR usage, we sorted the T-cell lines for V beta 8.2- and V beta 10-positive T cells or depleted the lines of cells with these TCRs. V beta 8.2-positive T cells and one of the depleted T-cell lines strongly reacted against the MBP peptide MBP-(68-88). The depleted T-cell line caused marked experimental autoimmune encephalomyelitis (EAE) even in Lewis rats in which endogenous V beta 8.2-positive T cells had been eliminated by neonatal treatment with anti-V beta 8.2 monoclonal antibodies. T-cell hybridomas generated from this line predominantly used V beta 3 TCR genes coexpressed with TCR V alpha 2 transcripts, which were also used by V beta 8.2-positive T cells. Furthermore, V beta 10-positive T cells reactive to MBP-(44-67) were encephalitogenic when injected immediately after positive selection. After induction of EAE by sorted V beta 8.2- or V beta 10-positive T-cell lines, immunocytochemical analysis of the spinal cord tissue showed a predominance of the injected TCR or of nontypable alpha/beta T cells after injection of the depleted line. Our results demonstrate heterogeneity of TCR beta-chain usage even for a single autoantigen in an inbred strain. Moreover, V beta 8.2-positive T cells are not essential for the induction and progression of adoptive-transfer EAE.

Catheter-related bloodstream infection: burden of disease in a tertiary hospital

Background: Surveillance programmes have become the most effective tool for controlling catheter-related bloodstream infections (CRBSI). However, few studies have investigated programmes covering all hospital settings. Aim: To describe the results of a control and prevention programme for CRBSI based on compliance with recommendations for insertion and maintenance, using annual burden of disease in a tertiary level hospital. Methods: A CRBSI control and prevention programme involving all hospital settings was implemented. The programme consisted of CRBSI surveillance, direct observation of insertion and maintenance of catheters to determine performance, and education for healthcare workers. Findings: In total, 2043 short-term catheters were inserted in 1546 patients for 18,570 catheter-days, and 279 long-term catheters were inserted in 243 patients for 40,440 catheter-days. The annual incidence density was 5.98 (first semester 6.40, second semester 5.64) CRBSI per 1000 catheter-days for short-term catheters, and 0.57 (first semester 0.66, second semester 0.43) CRBSI per 1000 catheter-days for long-term catheters. One hundred and forty insertion procedures were observed, with an average insertion time of 13 (standard deviation 7) min. Compliance with recommendations was as follows: hand hygiene, 86.8%; use of alcoholic chlorhexidine solution for skin disinfection, 35.5%; use of mask, 93.4%; use of gloves, 98.7%; use of gown, 75.0%; use of sterile cloth, 93.8%; use of cap, 92.2%; bandage application, 62.7%; and use of aseptic technique, 89.5%. Forty-five maintenance procedures were observed, and compliance rates were as follows: hand hygiene, 42.1%; use of gloves, 78.1%; and port disinfection with alcoholic chlorhexidine solution, 32.5%. Conclusion: The CRBSI control and prevention programme implemented at the study hospital has decreased the rate of CRBSI, provided important information about the total burden of disease, and revealed possible ways to improve interventions in the future.

Electrocardiographic features of disease progression in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is considered a progressive cardiomyopathy. However, data on the clinical features of disease progression are limited. The aim of this study was to assess 12-lead surface electrocardiographic (ECG) changes during long-term follow-up, and to compare these findings with echocardiographic data in our large cohort of patients with ARVC/D. METHODS Baseline and follow-up ECGs of 111 patients from three tertiary care centers in Switzerland were systematically analyzed with digital calipers by two blinded observers, and correlated with findings from transthoracic echocardiography. RESULTS The median follow-up was 4 years (IQR 1.9-9.2 years). ECG progression was significant for epsilon waves (baseline 14% vs. follow-up 31%, p = 0.01) and QRS duration (111 ms vs. 114 ms, p = 0.04). Six patients with repolarization abnormalities according to the 2010 Task Force Criteria at baseline did not display these criteria at follow-up, whereas in all patients with epsilon waves at baseline these depolarization abnormalities also remained at follow-up. T wave inversions in inferior leads were common (36% of patients at baseline), and were significantly associated with major repolarization abnormalities (p = 0.02), extensive echocardiographic right ventricular involvement (p = 0.04), T wave inversions in lateral precordial leads (p = 0.05), and definite ARVC/D (p = 0.05). CONCLUSIONS Our data supports the concept that ARVC/D is generally progressive, which can be detected by 12-lead surface ECG. Repolarization abnormalities may disappear during the course of the disease. Furthermore, the presence of T wave inversions in inferior leads is common in ARVC/D.

A guide to the work-relatedness of disease /

Includes bibliographical references.