The Antiviral Protein Human Lactoferrin Is Distributed in the Body to Cytomegalovirus (CMV) Infection-Prone Cells and Tissues

Purpose. Lactoferrin has anti-Cytomegalovirus (CMV) and -HIV properties in vitro. However, the pharmacokinetic behavior of the 80-kD protein has not been well defined. We, therefore, assessed the plasma decay and body distribution of lactoferrin after intravenous administration to freely moving rats. Furthermore, the systemic availability of lactoferrin after intraperitoneal dosing was determined. Methods and Results. After intravenous injection, human lactoferrin (hLF) was rapidly cleared from the plasma, but higher doses resulted in prolonged plasma levels. Immunohistochemical analysis revealed a pronounced distribution of hLF to endothelial cells in the liver whereas diffuse staining in hepatocytes indicated the presence of considerable amounts in this large cell population. This endothelial association, which also was found in other organ/tissues, including blood vessels, was confirmed by in vitro cell-binding studies. In addition, leukocytes in plasma that were infiltrated in various organs showed binding of hLF. A small fraction of hLF was transported into the lymphatic system. Western blot analysis revealed that hLF, present in the various organs, mainly consisted of an 80-kD protein. After intraperitoneal administration, small amounts of 80-kD hLF distributed to the general circulation. The bioavailability was 0.6% but increased to 3.6% after multiple administrations. Conclusions. The affinity of hLF for endothelial cells and leukocytes, and its penetration into the lymphatic system, indicates that this protein reaches target cells and body compartments that are crucial for CMV and HIV replication. The ability to reach the blood compartment after intraperitoneal dosing offers opportunities for parenteral administration of the protein in future studies on its antiviral effects in vivo.     

Cancer of the brain and nervous system and occupational exposures in Finnish women

Occupational agents were evaluated for the risk of brain-nervous system cancer in a cohort of 413,877 Finnish women with blue-collar occupations in 1970. Observed and expected numbers of incident cases and the intensities of exposure to 25 agents were generated for 183 job titles from 1971 to 1995. Poisson regression models linked incidence and exposure data. Increased risks were found for medium/high intensities of iron (standardized incidence ratio [SIR], 2.15; 95% confidence interval [CI], 0.96 to 4.80), oil mist (1.95; 0.97 to 3.90), any chromium compounds (1.51; 0.85 to 2.67), electromagnetic fields (1.37; 0.98 to 2.10), aliphatic and alicyclic hydrocarbon compounds (1.34; 0.80 to 2.27), lead (1.27; 0.81 to 2.01), cadmium (1.26; 0.72 to 2.22), and aromatic hydrocarbon compounds (1.20; 0.71 to 2.03). Strengths of the study include fair number of cases, virtually complete case coverage, and a high-quality job exposure matrix. Ecological design and cross-sectional job assessment introduced exposure misclassification and tended to drive risk estimates toward unity.     

Occupational health in Central America

The 12.4 million economically active population (EAP) of the seven Central American countries includes a large informal sector. Social security covers only 14-60%. No surveillance of occupational safety and health (OSH) hazards or accidents exists. Extrapolating the incidence of occupational accidents among insured Costa Rican workers to the Central American EAP yields two million accidents yearly, still a gross underestimate. Occupational diseases are underreported, misdiagnosed, and not recognized as such. A number of regional OSH programs aim at modernization of the labor administrations and address the formal sector, in particular textile maquila, in connection with free trade agreements. The weak role of the ministries of health is expected to strengthen under the Pan American Health Organization OSH program. Employers largely influence new policies. Workers' influence on OSH policies has been weak, with only about 10% unionization rate and scarce resources and OSH knowledge. Informal workers, however, are getting organized. OSH research is underdeveloped and not linked to policy making. Construction, agriculture, and general un/underemployment are considered priorities for intervention. The informal sector needs to be included in national and regional OSH policies. Regional collaboration and international development support are of strategic importance to achieve sustainable improvement in OSH.     

The influence of charge clustering on the anti-HIV-1 activity and in vivo distribution of negatively charged albumins

The substitution of human serum albumin with negatively charged molecules, such as succinic acid (Suc-HSA) or aconitic acid (Aco-HSA), resulted in proteins with potent anti-HIV activities, by binding to viral gp120 (V3 loop). The aim of the present study was to investigate whether the distribution of negative charges on the albumin backbone influences the anti-HIV activity. Therefore, we prepared albumins with clusters of negatively charged groups by coupling of heparin. The effects of this substitution on anti-HIV activity, in vivo distribution and the protein structure as compared to random succinylation were assessed. In vitro studies indicated that HSA-modified with heparin 6 or 13 kD displayed anti-HIV activity (IC50=660 and 37 nM, respectively) and exhibited affinity for gp120-V3 loop, although the activity was lower than that of Suc-HSA. Combined derivatization of HSA with heparin 13 kD and aconitic acid groups resulted in significantly increased inhibitory actions (IC50=2.8 nM). Structural analysis showed that modification of HSA with heparin did not lead to extensive unfolding of the protein, meaning that these modified proteins were still globular in structure. In contrast, succinylation of HSA resulted in a highly randomly coiled conformation. Dynamic light scattering experiments revealed that, at neutral pH, the heparin fragments attached to the protein were wrapped around the molecule rather than sticking out into the solution. In conclusion, coupling of sufficient clustered negative charges, by coupling of Hep-fragments, on HSA resulted in a clear anti-HIV activity of the protein. Yet, random distribution of anionic groups in the albumin seemed more optimal for in vitro anti-HIV activity. The higher plasma and lymphatic concentrations of Hep-HSA compared to Suc-HSA seemed more favorable for an anti-HIV activity in vivo.     

Assessment of feasibility of workplace health promotion

BACKGROUND: A simple empirically based method for assessment of the feasibility of workplace health promotion programs is described, focusing on cancer hazards (lifestyles, workplace hazards, deficient early detection). The basic components of feasibility are addressed: extent of hazards; needs of employees for hazard reduction and acceptability of WHP; and social context. METHODS: The procedure consists of six modules: guidelines on feasibility assessment; employee questionnaire; interview checklists for probing attitudes of management and partners (social context); data form; debriefing; and assessment of feasibility. Pretesting was completed in 16 workplace communities representing industry, construction, transport, telecommunications, health care, lodging and catering, teaching, and municipality jobs in five countries; a total of 1,085 subjects completed the employee questionnaire on health hazards, needs, and acceptability. RESULTS: The method demonstrated its utility in obtaining and summarizing the necessary data. Feasibility was assessed for the 16 test communities. CONCLUSION: The procedure can be customized; it has a high degree of face validity or understandability, and it is applicable in a wide variety of settings.     

Selective loss of chromosome 11 in pheochromocytomas associated with the VHL syndrome

By using comparative genomic hybridization (CGH), we characterized the genetic profiles of 36 VHL-related pheochromocytomas. We then compared the results with those of sporadic and MEN 2-related pheochromocytomas. In 36 VHL-related tumors, loss of chromosome 3 and chromosome 11 were found in 34 tumors (94%) and 31 tumors (86%), respectively. There was significant concordance of deletions in chromosomes 3 and 11 (Kappa=0.64, P=0.0095), suggesting that they are involved in two different but necessary and complementary genetic pathways. The loss of chromosome 11 appeared to be specific for VHL-related pheochromocytoma as it was not present in any of the 10 VHL-related CNS hemangioblastomas studied and was significantly less common when compared with (a) sporadic pheochromocytomas from previously published results (13%; P=<0.0001), and (b) MEN 2-related pheochromocytomas from this and previously published studies (30%; P=0.0012). In summary, this is the first report of a novel consistent genetic alteration that is selected and specific for VHL-related pheochromocytoma, besides the two hits of the VHL gene.     

Chromosomal aberrations in benign and malignant Bilharzia-associated bladder lesions analyzed by comparative genomic hybridization

Background

Bilharzia-associated bladder cancer (BAC) is a major health problem in countries where urinary schistosomiasis is endemic. Characterization of the genetic alterations in this cancer might enhance our understanding of the pathogenic mechanisms of the disease but, in contrast to nonbilharzia bladder cancer, BAC has rarely been the object of such scrutiny. In the present study, we aimed to characterize chromosomal imbalances in benign and malignant post-bilharzial lesions, and to determine whether their unique etiology yields a distinct cytogenetic profile as compared to chemically induced bladder tumors.

Methods

DNAs from 20 archival paraffin-embedded post-bilharzial bladder lesions (6 benign and 14 malignant) obtained from Sudanese patients (12 males and 8 females) with a history of urinary bilharziasis were investigated for chromosomal imbalances using comparative genomic hybridization (CGH). Subsequent FISH analysis with pericentromeric probes was performed on paraffin sections of the same cases to confirm the CGH results.

Results

Seven of the 20 lesions (6 carcinomas and one granuloma) showed chromosomal imbalances varying from 1 to 6 changes. The most common chromosomal imbalances detected were losses of 1p21-31, 8p21-pter, and 9p and gain of 19p material, seen in three cases each, including the benign lesion.

Conclusion

Most of the detected imbalances have been repeatedly reported in non-bilharzial bladder carcinomas, suggesting that the cytogenetic profiles of chemical- and bilharzia-induced carcinomas are largely similar. However, loss of 9p seems to be more ubiquitous in BAC than in bladder cancer in industrialized countries.

     

Breast cancer screening, outside the population-screening program, of women from breast cancer families without proven BRCA1/BRCA2 mutations: a simulation study.

PURPOSE: We assessed the cost-effectiveness of mammography screening for women under the age of 50, from breast cancer families without proven BRCA1/BRCA2 mutations, because current criteria for screening healthy women from breast cancer families are not evidence-based. METHODS: We did simulation studies with mathematical models on the cost-effectiveness of mammography screening of women under the age of 50 with breast cancer family histories. Breast cancer screening was simulated with varying screening intervals (6, 12, 18, and 24 months) and screening cohorts (starting at ages 30, 35, 40, and 45, and continuing to age 50). Incremental costs of screening were compared with those of women ages 50 to 52 years, the youngest age group currently routinely screened in the nationwide screening program of the Netherlands, to determine cost-effectiveness. Sensitivity analyses were done to explore the effects of model assumptions. The cost-effectiveness of breast cancer screening for women over the age of 50 was not debated. RESULTS: The most effective screening interval was found to be 12 months, which, however, seems only to be cost-effective in a small group of women under the age of 50 with at least two affected relatives, including at least one affected in the first degree diagnosed under the age of 50. Significantly, early breast cancer screening never seemed to be cost-effective in women with only one affected first-degree or second-degree relative. CONCLUSION: Annual breast cancer screening with mammography for women under the age of 50 seems to be cost-effective in women with strong family histories of breast cancer, even when no BRCA1/BRCA2 mutation was found in affected family members.