Animal and human models for sepsis

Several preclinical models for sepsis have been used in the last decades to successfully unravel the pathophysiologic processes during sepsis. Furthermore, these models for sepsis revealed promising immunomodulating agents for the treatment of sepsis. Nevertheless, several clinical trials evaluating the efficacy of these new anti-inflammatory agents in septic patients showed disappointing results. In this article the advantages and disadvantages of different models for sepsis are discussed. Most models for sepsis lack an infectious focus. Importantly, investigations studying the effects of several immunomodulating strategies have demonstrated strikingly opposite results when using models for sepsis lacking an infectious focus and when using models for sepsis with a more natural route of infection. These differences will be discussed in this article. In general, it is advised to use a combination of models to test a new therapeutic agent, before starting a clinical study evaluating this new therapy.     

Reduced interferon-gamma release in patients recovered from Legionnaires' disease

BACKGROUND: Legionella pneumophila, a Gram negative intracellular pathogen, causes Legionnaires' disease (LD). Interferon (IFN)-gamma is important for host defence against L pneumophila so reduced IFN-gamma production capacity and/or responsiveness might render humans more susceptible to infection with L pneumophila. METHODS: Seventy seven patients who suffered from LD after a point source outbreak one year earlier participated in the study. Whole blood was incubated with non-specific stimuli (lipopolysaccharide (LPS) or interleukin (IL)-12) or specific stimuli (viable or heat killed L pneumophila) to evaluate IFN-gamma production, and with IFN-gamma to evaluate IFN-gamma responsiveness. Expression of complement receptor 3 on monocytes was determined by flow cytometry. Thirty seven companions who were also exposed but had not developed LD served as controls. RESULTS: Patients released less IFN-gamma than controls in response to stimulation with LPS (mean (SE) 393 (58) pg/ml v 914 (178) pg/ml; p=0.001) and IL-12 (96 (14) pg/ml v 177 (41) pg/ml; p=0.058). IFN-gamma responsiveness, measured by release of IFN-gamma inducible protein (IP)-10, tumour necrosis factor alpha, IL-12 production capacity, and monocyte expression of complement receptor 3, did not differ between patients and controls. IFN-gamma release after stimulation with LPS and IP-10 release after stimulation with IFN-gamma were weakly associated with severity of LD in the former patient group (rho=-0.3, p=0.011 and rho=-0.3, p=0.037, respectively). CONCLUSION: These results suggest that impaired IFN-gamma production may contribute to susceptibility to L pneumophila infection.     

Non-Hodgkin's lymphomas and occupation in Sweden

Objectives: To investigate whether there is a risk excess of non-Hodgkin's lymphoma among Swedish workers associated with particular occupations. Methods: The base population was made up of Swedish men (1,779,646) and women (1,101,669) who were gainfully employed at the time of the 1970 census, had also been present in the 1960 census and were still alive and older than 24 years as of 1 January, 1971. They were followed up for 19 years until the end of 1989. Age- period standardised incidence ratios were computed in a dataset linking cancer diagnoses from the Swedish national cancer register to occupational and demographic data obtained in the census of 1970. Log-linear Poisson models were fitted, allowing for geographical area. Risk estimators per occupation were also computed for workers reporting the same occupation in 1960 and 1970, a more specifically exposed group. Results: There were 7,610 non-Hodgkin's lymphomas reported in the study cohort, 5,391 cases in men and 2,219 in women. A relative risk of over 1.20 and statistically significant was observed in men among accountants and auditors, secretaries and typists, auctionists, non-specified rail and road transport workers, telecommunications traffic officers, telegraph and radio operators, photographic-laboratory workers and other production and related work. The risk excess was confirmed in men with the same occupation in both censuses. In women, only three occupations achieved statistical significance: metal platers and coaters, truck and conveyor operators and store and warehouse workers. Conclusions: The risk excess observed in telecommunication and transport workers could be explained by electromagnetic radiation exposure. We did not find a risk excess in agricultural occupations, that has been largely documented by other study groups. Received: 3 August 2000 / Accepted: 30 March 2001     

Dietary fat, body weight, and cancer: contributions of studies in rodents to understanding these cancer risk factors in humans

Understanding diet and energy balance as risk factors for breast, colon, and other cancers requires information on the contribution of each factor and of interactions among factors to cancer risk. Rodent models for breast cancer provide extensive data on effects of dietary fat and calories, energy balance, body weight gain, and physical activity on tumor development. Analyses of the combined data from many studies have shown clearly that quality and quantity of dietary fat and energy balance contribute independently to increased mammary gland tumorigenesis. These findings were seen in female rats fed diets high in fat (35-40% of calories) compared to rats fed control diets, with approximately 10% of calories as fat (Fay and Freedman, 1997, Breast Cancer Res. Treat. 46, 215-223). The methods used permit comparison of experimental and epidemiological data, and they may be useful in extrapolating between species and developing public health recommendations. In addition to the contributions of lifetime-diet composition, intake, energy balance, and physical activity to cancer risk, there are questions about the timing and duration of alterations in these factors and about the "dose-response" characteristics of cancer risk to the factors. Endocrine mechanisms may be significant in mammary gland tumor risk, but experimental and epidemiological data indicate that cancers at other sites, such as colon and liver, also are influenced by the factors listed. Other diet and lifestyle factors that influence energy, or specifically fat, metabolism may also affect risk for cancers that are promoted by increased intake of fat and calories. Studies of separate and interactive effects of dietary fat, black tea, weight gain, and mammary gland tumorigenesis (Rogers, et al, 1998, Carcinogenesis 19, 1269-1273) have been analyzed. Using adjustment of carcinogenesis endpoints for body weight, tumor burden, and latency, they were found to be related to weight gain within treatment groups in 2 of 3 experiments.      

Leukemia, lymphomas, and myeloma mortality in the vicinity of nuclear power plants and nuclear fuel facilities in Spain.

Mortality due to hematological tumors in towns near Spain's seven nuclear power plants and five nuclear fuel facilities during the period 1975-1993 was ascertained. The study was based on 610 leukemia-, 198 lymphoma-, and 122 myeloma-induced deaths in 489 towns situated within a 30-km radius of such installations. As control areas, we used 477 towns lying within a 50- to 100-km radius of each installation, matched by population size and a series of sociodemographic characteristics (income level, proportion of active population engaged in farming, proportion of unemployed, percentage of illiteracy, and province). Relative risk (RR) for each area and the trends in risk with increasing proximity to an installation were analyzed using log-linear models. None of the nuclear power plants registered an excess risk of leukemia-induced mortality in any of the surrounding areas. Excess risk of leukemia mortality was, however, observed in the vicinity of the uranium-processing facilities in Andújar [RR, 1.30; 95% confidence interval, 1.03-1.64] and Ciudad Rodrigo (RR, 1.68; 95% confidence interval, 0.92-3.08). Excess risk of multiplemyeloma mortality was found in the area surrounding the Zorita nuclear power plant. Statistical testing revealed that, with the single exception of multiple myeloma, none of the tumors studied showed evidence of a rise in risk with proximity to an installation. No study area yielded evidence of a raised risk of leukemia mortality among persons under the age of 25 years. More specific studies are called for in areas near installations that have been fully operational for longer periods. In this connection, stress should be laid on the importance of using dosimetric information in all future studies.     

Histologic grade and CD44 are independent predictors of axillary lymph node invasion in early (T1) breast cancer.

Background: The detection rate of small, often subclinical breast cancers is increasing in affluent societies. Concomitantly, the demand for more conservative surgical approaches is also increasing among the women affected. Predictors of the absence of nodal invasion would spare many patients with early breast cancer the risks, costs and side effects of lymphadenectomy, and thus treatment with curative intent would be applied using really minimal surgery. Patients and Methods: We reviewed the records of 135 patients with unifocal invasive breast cancers, 2 cm or less in diameter, operated upon at 'Fundación Tejerina-Centro de Patología de la Mama', Madrid, Spain, between January 1993 and December 1997. Full clinical and pathological data were available for all of them, together with estrogen and progesterone receptor determinations, which had been routinely performed in 134 and 133 cases, respectively. Additionally, Ki67, c-erb-B2, p53, nm23, HSP27, HSP60 and CD44std expression was studied on archival, paraffin-embedded tumor material from these same patients by means of immunohistochemistry. Results: In the univariate analysis, only histologic grade 3 (p < 0.001), Ki67 expression in more than 10% of tumor cells (p = 0.005) and CD44std negativity (p = 0.004) were significantly associated with axillary node involvement. In multivariate analysis, histologic grade 3 and CD44std negativity retained statistical significance, and thus emerged as independent predictors of nodal invasion. The combination of both, furthermore, identified a subgroup in which the axillary nodes were invariably affected. Conclusion: Some pathological and molecular features of small breast cancers were able to predict nodal metastasis significantly. However, none, either alone nor combined, was able to exclude axillary node invasion completely. Copyright Copyright 1999 S. Karger AG, Basel     

Mammographic density and risk of breast cancer according to tumor characteristics and mode of detection: a Spanish population-based case-control study

Introduction

It is not clear whether high mammographic density (MD) is equally associated with all subtypes of breast cancer (BC). We investigated the association between MD and subsequent BC, considering invasiveness, means of detection, pathologic subtype, and the time elapsed since mammographic exploration and BC diagnosis.

Methods

BC cases occurring in the population of women who attended screening from 1997 through 2004 in Navarre, a Spanish region with a fully consolidated screening program, were identified via record linkage with the Navarre Cancer Registry (n = 1,172). Information was extracted from the records of their first attendance at screening in that period. For each case, we randomly selected four controls, matched by screening round, year of birth, and place of residence. Cases were classified according to invasiveness (ductal carcinoma in situ (DCIS) versus invasive tumors), pathologic subtype (considering hormonal receptors and HER2), and type of diagnosis (screen-detected versus interval cases). MD was evaluated by a single, experienced radiologist by using a semiquantitative scale. Data on BC risk factors were obtained by the screening program in the corresponding round. The association between MD and tumor subtype was assessed by using conditional logistic regression.

Results

MD was clearly associated with subsequent BC. The odds ratio (OR) for the highest MD category (MD >75%) compared with the reference category (MD <10%) was similar for DCIS (OR = 3.47; 95% CI = 1.46 to 8.27) and invasive tumors (OR = 2.95; 95% CI = 2.01 to 4.35). The excess risk was particularly high for interval cases (OR = 7.72; 95% CI = 4.02 to 14.81) in comparison with screened detected tumors (OR = 2.17; 95% CI = 1.40 to 3.36). Sensitivity analyses excluding interval cases diagnosed in the first year after MD assessment or immediately after an early recall to screening yielded similar results. No differences were seen regarding pathologic subtypes. The excess risk associated with MD persisted for at least 7 to 8 years after mammographic exploration.

Conclusions

Our results confirm that MD is an important risk factor for all types of breast cancer. High breast density strongly increases the risk of developing an interval tumor, and this excess risk is not completely explained by a possible masking effect.     

A model of corrective gene transfer in X-linked ichthyosis

Single gene recessive genetic skin disorders offer attractive prototypes for the development of therapeutic cutaneous gene delivery. We have utilized X-linked ichthyosis (XLI), characterized by loss of function of the steroid sulfatase arylsulfatase C (STS), to develop a model of corrective gene delivery to human skin in vivo. A new retroviral expression vector was produced and utilized to effect STS gene transfer to primary keratinocytes from XLI patients. Transduction was associated with restoration of full-length STS protein expression as well as steroid sulfatase enzymatic activity in proportion to the number of proviral integrations in XLI cells. Transduced and uncorrected XLI keratinocytes, along with normal controls, were then grafted onto immunodeficient mice to regenerate full thickness human epidermis. Unmodified XLI keratinocytes regenerated a hyperkeratotic epidermis lacking STS expression with defective skin barrier function, effectively recapitulating the human disease in vivo. Transduced XLI keratinocytes from the same patients, however, regenerated epidermis histologically indistinguishable from that formed by keratinocytes from patients with normal skin. Transduced XLI epidermis demonstrated STS expression in vivo by immunostaining as well as a normalization of histologic appearance at 5 weeks post-grafting. In addition, transduced XLI epidermis demonstrated a return of barrier function parameters to normal. These findings demonstrate corrective gene delivery in human XLI patient skin tissue at both molecular and functional levels and provide a model of human cutaneous gene therapy.      

A STD/HIV prevention trial among adolescents in managed care

OBJECTIVE: To determine if sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV) infection, risk assessment, and education tools provided as part of office-based primary care reduce adolescent risky sexual behaviors. DESIGN: A randomized intervention trial with 3- and 9-month follow-up. SETTING: Five staff-model managed care sites in Washington, DC (n = 19 pediatricians). PATIENTS: Consecutive 12- to 15-year-olds receiving a general health examination; 81% minority. Participation rate = 215/432 (50%). Nine-month follow-up rate = 197/215 (92%). INTERVENTION: Audiotaped STD risk assessment and education about staying safe (safer = condoms, safest = abstinence). MAIN OUTCOME MEASURES: Adolescent-reported sexual intercourse and condom use. RESULTS: More intervention adolescents reported pediatrician discussion on 11/13 sexual topics. Although more vaginal intercourse (odds ratio [OR] = 2.46, 95% confidence interval [CI] = 1.04-5.84) was reported in the intervention group at 3 months, this was not true of overall sexual intercourse (OR = 1.55, 95% CI =.73-3.32). More sexually active adolescents reported condom use in the intervention group at 3 months (OR = 18.05, 95% CI = 1.27-256.03). At 9 months, there were no group differences in sexual behaviors; however, more signs of STD were reported by the control (7/103) than the intervention group (0/94). CONCLUSIONS: STD risk assessment and education tools administered in a single office visit facilitated STD/HIV prevention education. Any impact on sexual activity and condom use was short-lived. Further research is needed to develop brief, office-based sexual risk reduction for young adolescents.