Particulate matter emissions of different brands of mentholated cigarettes.

Inhaling particulate matter (PM) in environmental tobacco smoke (ETS) endangers the health of nonsmokers. Menthol, an additive in cigarettes, attenuates respiratory irritation of tobacco smoke. It reduces perceptibility of smoke and therefore passive smokers may inhale ETS unnoticed. To investigate a possible effect of menthol on PM concentrations (PM10, PM2.5, and PM1), ETS of four mentholated cigarette brands (Elixyr Menthol, Winston Menthol, Reyno Classic, and Pall Mall Menthol Blast) with varying menthol content was analyzed. ETS was generated in a standardized way using an automatic environmental tobacco smoke emitter (AETSE), followed by laser aerosol spectrometry. This analysis shows that the tested cigarette brands, despite having different menthol concentrations, do not show differences with regard to PM emissions, with the exception of Reyno Classic, which shows an increased emission, although the menthol level ranged in the midfield. More than 90% of the emitted particles had a size smaller than or equal to 1 µm. Regardless of the menthol level, the count median diameter (CMD) and the mass median diameter (MMD) were found to be 0.3 µm and 0.5 µm, respectively. These results point out that there is no effect of menthol on PM emission and that other additives might influence the increased PM emission of Reyno Classic. IMPLICATIONS: Particulate matter (PM) in ETS endangers the health of nonsmokers and smokers. This study considers the effect of menthol, an additive in cigarettes, on PM emissions. Does menthol increase the amount of PM? Due to the exposure to secondhand smoke nearly 900,000 people die each year worldwide. The aim of the study is to measure the particle concentration (L-1), mass concentration (µg m-3), and dust mass fractions shown as PM10, PM2.5, and PM1 of five different cigarette brands, including four with different menthol concentrations and one menthol-free reference cigarette, in a well-established standardized system.

Modifiable determinants of attitude towards dengue vaccination among healthy inhabitants of Aceh, Indonesia: Findings from a community-based survey.

OBJECTIVE: To explore and understand the attitude towards dengue vaccination and its modifiable determinants among inhabitants of Aceh (northern Sumatra Island, Indonesia), the region that was most severely affected by the earthquake and tsunami of 26 December 2004. METHODS: A community-based, cross-sectional study was conducted among 535 healthy inhabitants in nine regencies (Kabupaten or Kotamadya) of Aceh that were selected randomly from November 2014 to March 2015. A set of validated, pre-tested, structured questionnaires was used to guide the interviews. The questionnaires covered a range of explanatory variables and one outcome variable (attitude to dengue vaccination). Multi-step logistic regression analysis and Spearman's rank correlation were used to test the role of explanatory variables for the outcome variable. RESULTS: More than 70% of the participants had a poor attitude towards dengue vaccination. Modifiable determinants associated with poor attitude to dengue vaccination were low education level, working as farmers and traditional market traders, low socioeconomic status and poor knowledge, attitude and practice regarding dengue fever (P < 0.05). The KAP domain scores were correlated strongly with attitude to dengue vaccination, rs = 0.25, rs = 0.67 and rs = 0.20, respectively (P < 0.001). Multivariate analysis found that independent predictors associated with attitude towards dengue vaccination among study participants were only sex and attitude towards dengue fever (P < 0.001). CONCLUSIONS: This study reveals that low KAP regarding dengue fever, low education level and low socioeconomic status are associated with a poor attitude towards dengue vaccination. Therefore, inhabitants of suburbs who are working as farmers or traditional market traders with low socioeconomic status are the most appropriate target group for a dengue vaccine introduction program.

Towards a sexual ethics of rights and responsibilities.

Sexual rights as human rights encompass individual freedoms and social entitlements. Both depend for their realisation on equally important social responsibilities on the part of individuals, couples, families, other social institutions, and the State. The principle that all persons must understand their own sexual rights and responsibilities and respect the equal rights of others - particularly those of their sexual partners - informs our interpretation of the ethical basis of sexual behaviours. We propose a conceptual framework for defining a sexual ethics of equal rights and responsibilities pertaining to five dimensions of sexual behaviour: 1) sexual relationships and the right to choose one's partner; 2) sexual expression and the right to seek pleasure; 3) sexual consequences and the right to cooperation from one's partner; 4) sexual harm and the right to protection; and 5) sexual health and the right to information, education and health services. We suggest that the ethical principles presented here pertaining to sexual partnerships should be incorporated into sexuality education, sexual and reproductive health services, and social policies aimed at promoting the health and rights of all persons regardless of gender, marital status, sexual orientation, religion, ethnicity and other personal or group identities.

Starting young: sexual initiation and HIV prevention in early adolescence.

The rising numbers of new HIV infections among young people ages 15-24 in many developing countries, especially among young women, signal an urgent need to identify and respond programmatically to behaviors and situations that contribute to the spread of HIV and other sexually transmitted infections in early adolescence. Quantitative and qualitative studies of the sexual knowledge and practices of adolescents age 14 and younger reveal that substantial numbers of boys and girls in many countries engage in unprotected heterosexual vaginal intercourse--by choice or coercion--before their 15th birthdays. Early initiation into male-male or male-female oral and/or anal sex is also documented in some populations. Educational, health, and social programs must reach 10-14-year-olds as well as older adolescents with the information, skills, services, and supplies (condoms, contraceptives) they need to negotiate their own protection from unwanted and/or unsafe sexual practices and to respect the rights of others.

Back to basics: HIV/AIDS belongs with sexual and reproductive health.

The Programme of Action of the International Conference on Population and Development (ICPD) held in Cairo in 1994 offers a comprehensive framework for achieving sexual and reproductive health and rights, including the prevention and treatment of HIV/AIDS, and for advancing other development goals. The United Nations Millennium Development Goals now incorporate a target of universal access to sexual and reproductive health within the goal of improving maternal health, but combating HIV remains a separate project with malaria and tuberculosis. We present a brief history of key decisions made by WHO, other United Nations' agencies, the United Nations Millennium Project and major donors that have led to the separation of HIV/AIDS from its logical programmatic base in sexual and reproductive health and rights. This fragmentation does a disservice to the achievement of both sets of goals and objectives. In urging a return to the original ICPD construct as a framework for action, we call for renewed leadership commitment, investment in health systems to deliver comprehensive sexual and reproductive health services, including HIV/AIDS prevention and treatment, comprehensive youth programmes, streamlined country strategies and donor support. All investments in research, policies and programmes should build systematically on the natural synergies inherent in the ICPD model to maximize their effectiveness and efficiency and to strengthen the capacity of health systems to deliver universally accessible sexual and reproductive health information and services.

How young is "too young"? Comparative perspectives on adolescent sexual, marital, and reproductive transitions.

This study puts forth three criteria for assessing the extent to which the timing of sexual, marital, and reproductive transitions among male and female adolescents could be considered "too young": (1) the physiological maturation of the body; (2) the cognitive capacity for making safe, informed, and voluntary decisions; and (3) institutionalized concepts of "old enough" for consent to sexual intercourse and marriage as reflected in legal frameworks and international standards. Expansion of the age grouping of adolescence is proposed, from the customary 15-19 into three age categories--early adolescence (ages 10-14, or 10-11 and 12-14), middle adolescence (15-17), and late adolescence (18-19)--to better capture the age-specific variations in the trajectories of male and female sexual, marital, and reproductive events. An application of the three adolescent development criteria to the timing of transitions observed in Demographic and Health Surveys in 64 developing countries leads to the conclusion that boys and girls aged 14 and younger are universally "too young" to make safe and consensual transitions; that 15-17-year-olds may or may not be too young, depending on their circumstances; and that 18-year-olds are generally "old enough." Policies and programs should focus on capacity building and the creation of an enabling environment for making safe and voluntary transitions among all age groups, but particularly among 10-14-year-olds, whose sexual and reproductive health and rights are so clearly at stake.

Differential spatial expression and activation pattern of EGFR and HER2 in human breast cancer.

Overexpression of HER family members is a well established prognostic factor and identifies potential targets for antibody-based receptor blocking strategies. While several studies have analyzed the expression of HER2 and other HER-family members in malignant tumors, considerably less is known about their expression and activation in non-involved breast tissue from breast cancer patients. We have therefore investigated the differential expression of EGFR, HER2, and their tyrosine-kinase activated forms (ptyr-1248 Her-2 and ptyr-845 EGFR) in 63 tumor specimen containing: a) malignant epithelium, b) in non-malignant tissue located at the peritumoral margin, and c) in uninvolved breast tissue obtained from tissue distant from the tumor. Using immunohistochemistry (IHC), we found significantly higher HER2 protein expression levels in malignant epithelium than in marginal and peripheral non-malignant epithelium (p=1.3 x 10(-10) Fisher's exact test). Epithelial EGFR expression did not differ between the three tissue types, but stromal EGFR protein was significantly more common in marginal and peripheral tissues when compared to tumor tissues (p=0.008, Fisher's exact test). When analyzing activated receptor forms, we found epithelial ptyr-1248 HER2 expression in one tumoral, one marginal and one peripheral sample. We did not observe ptyr-845 EGFR in any of the samples analyzed. We found a significant overall correlation between epithelial and stromal EGFR expression (r=0.442; p<0.0001; Spearman's Rho), and between stromal EGFR expression and normal tissue type (r=0.170; p<0.02; Spearman's Rho). Epithelial HER2 expression and normal tissue type (r=0.492; p<0.0001; Spearman's Rho) were inversely correlated. Taken together, we have observed a differential expression pattern of EGFR, HER2, and activated HER2 that is dependent on the spatial relation to a malignant tumor. Our findings of decreased intratumoral EGFR expression and the absence of activated EGFR suggests that, in contrast to HER2, EGFR inhibition might not be an ideal target for antibody therapy.

Fertility regulation and reproductive health in the Millennium Development Goals: the search for a perfect indicator.

Although several key elements of sexual and reproductive health are included in the United Nations Millennium Development Goals, a measure of women's capacity to regulate their fertility safely and effectively is missing. We considered the usefulness of 3 pairs of indicators in monitoring this component of reproductive health: contraceptive prevalence and total fertility; unmet need for contraception and unplanned births; and unsafe abortion and abortion mortality. A single measure of contraceptive use is insufficient. The risks women face from unplanned births and unsafe abortion should also be incorporated into the monitoring process, either directly within the Millennium Development Goals framework or as a parallel effort by reporting governments and other agencies.

The sexual ethics of HIV testing and the rights and responsibilities of partners.

The discourse of much of the international AIDS community champions the rights of individuals in low-income countries to "just say no" to routine HIV testing in health-care settings and, if tested and found positive, not to inform their sexual partner(s) if such disclosure could result in substantial personal harm. This study contends that the right of individuals to refuse testing ignores the right of their sexual partners--male or female, regular or casual--to be informed of the health risks to which they may be exposed on entering or continuing a sexual relationship or engaging in particular sexual acts. If, as the UN has declared, all persons have the right to decide freely and responsibly on matters relating to their sexuality, including their sexual and reproductive health, free from coercion, discrimination, and violence, then all persons have the right and the responsibility to know their own and their partner's serostatus and to protect themselves and their partner(s) from sexually transmitted infections (STIs). Support by AIDS activists for policies of routine STI/HIV testing, counseling, and disclosure between both partners in a sexual relationship would help to promote an ethic of equal rights and shared responsibility for sexual behavior and its consequences.

Selective spatial upregulation of intratumoral stromal aromatase in breast cancer patients: evidence for imbalance of local estrogen metabolism.

The suppression of local estrogens levels is of key importance in the treatment of ER-positive breast cancer. Essentially all endocrine strategies act by either suppressing estrogen formation or competitively inhibiting receptor-binding in tumor cells. Nevertheless, little is still known about the local expression of aromatase and sulfotransferase which are the key modulators of intra-tumoral estrogen levels. We have performed immunohistochemostry to investigate the expression of aromatase and sulfotransferase in 42 samples obtained directly from malignant breast tumors, and compared it to biopsies obtained from uninvolved tissue in the vicinity of the invasion front, and to distant breast tissue. We found that aromatase was equally detectable in both tumor epithelial and stroma, but was mostly epithelial in non-malignant tissues (P=0.00008, Fisher's exact test). Also, aromatase protein expression was significantly more common in tumoral stroma when compared with peritumoral and distant breast stroma (P=0.00005, and P<0.00001 respectively). With the notable exception of cystosarcoma phylloides, sulfotransferase protein was detectable only in epithelial tissues, regardless of the location within the diseased breast. However, epithelial sulfotransferase was correlated with epithelial aromatase (r=0.35461, P=0.0009, Spearman's rho test) and with the epithelial ER status (r=0.29313, P=0.005). We have demonstrated a differential aromatase and sulfotransferase protein expression pattern that is dependent on the spatial relation to a malignant breast tumor. Our results indicate a net increase in intratumoral active estrogen levels through increased stromal aromatization, while physiological local inactivation by sulfotransferase activity remains essentially unchanged.

Active (p)CrkL is overexpressed in human malignancies: potential role as a surrogate parameter for therapeutic tyrosine kinase inhibition.

CrkL is a nuclear adaptor and transcriptional activator in Bcr-Abl expressing cells and constitutes the major tyrosine phosphorylated protein in CML, but the expression and biological function of CrkL in other malignancies is largely unknown. Using immunohistochemistry, we have analyzed the protein expression of activated (p)CrkL in normal and malignant tissues. We then treated K562 leukemia cells with imatinib to analyze the effect of tyrosine kinase inhibition on CrkL activation. pCrkL expression was predominantly epithelial and detected in the majority of non-malignant prostate (79%), 49% of colon biopsies, 36% of skin biopsies, and 41% of samples obtained from normal brain. Protein expression was, however, considerably less frequent in normal breast (18%), lung (16%) and ovarian (12%) tissues. In contrast to their corresponding benign tissues, pCrkL expression was significantly more common in breast cancer samples (49%, p<0.0001; Fisher's exact test), lung carcinomas (55%, p=0.0002), lymphatic tissues (80% vs. 10%, p=0.012), skin cancer (67%, p=0.020), ovarian malignomas (50%, p<0.0001) and colon carcinomas (63%, p<0.03). By contrast, activated CrkL was significantly less frequent in prostate carcinoma samples when compared to corresponding non-malignant prostatic tissues (14% vs. 79%, p<0.0001). pCrkL expression was abrogated in K562 cells with the addition of the tyrosine kinase inhibitor imatinib, which indicates that phosphorylation of CrkL is mediated through targets of therapeutic TK inhibition. We hypothesize that pCrkL is selectively up-regulated in a number of malignant tumor entities and involved in malignant transformation. We further suggest that pCrkL might serve as a potential surrogate parameter for the efficacy of therapeutic TK inhibition.

Detection and identification of significant ANAs in previously determined ANA negative samples.

BACKGROUND: An antinuclear antibody (ANA) substrate transfected with the cDNA to hyperexpress the 60 kD SS-A/Ro antigen (HEp-2000) has been shown to detect anti-SS-A/Ro antibodies missed by standard HEp-2 and other immunoassays. Despite this evidence, many laboratories remain convinced that with experienced technicians, standard HEp-2 is acceptable for ANA detection. AIM: To challenge the ability of HEp-2000 to detect anti-SS-A/Ro antibodies in samples previously determined to be ANA negative using standard HEp-2. METHODS: Three hundred and seventy-one pre-screened "negative" ANA samples were provided by a university hospital laboratory in Germany. These samples were tested on the HEp-2000 substrate at a dilution of 1:40 by indirect immunofluorescence (IIF). Samples that screened positive for a nuclear pattern were titered (range of 1:40-1:640) and all ANA-positive patterns were identified. Samples containing at least one positive ANA pattern at a dilution greater than or equal to 1:160 were further tested. Samples that produced a speckled pattern were tested for antibodies to the extractable nuclear antigens (ENA) and samples that showed homogeneous staining were tested for antibodies to dsDNA, and if negative, were then tested for anti-histone antibodies. RESULTS: Ninety-one patient samples were positive with titers > or =1:160. Speckled patterns were the most common finding (30 samples) followed by speckled/homogeneous mixed patterns (19 samples) and samples demonstrating the SS-A/Ro pattern (16 samples) either alone or in combination with other ANA patterns. The remaining 26 positive samples consisted of various other ANA patterns. The most commonly identified ENAs were SS-A/Ro (14 samples), Scl-70 (11 samples) and SSB (6 samples). No antibodies to dsDNA were identified in 23 positive samples with homogeneous staining patterns, though 17 of these samples tested positive for antibodies to histone. CONCLUSIONS: HEp-2000 detected anti-SS-A/Ro antibodies in 16 (4%) of the "ANA negative" samples. In addition to improved sensitivity for anti-SS-A antibodies, HEp-2000 demonstrated improved sensitivity over standard HEp-2 substrate for other significant ANAs including anti-Scl-70, anti-histone, and anti-SS-B antibodies.

EGFR activity in HER-2 over-expressing metastatic breast cancer: evidence for simultaneous phosphorylation of Her-2/neu and EGFR.

Her-2/neu overexpression is an important prognostic parameter in breast cancer patients and has become a response predictor for trastuzumab treatment. Nevertheless, while trastuzumab is highly effective in many Her-2/neu overexpressing tumors, some do not respond. The reason for the differential effect is unknown, but it has been hypothesized that the complex interactions between Her-2/neu and other members of the EGFR family are involved in trastuzumab resistance. We have analyzed the protein expression of Her-2/neu, EGFR, and their activated forms, ptyr-1248 Her-2/neu, ptyr-845 EGFR and ptyr-1173 EGFR, in 57 Her-2/neu overexpressing breast tumors and investigated potential correlations between the receptors. By performing immunohistochemistry on paraffin-embedded tissue sections, we found that ptyr-845 EGFR was significantly co-expressed with Her-2/neu and ptyr-1248 Her-2/neu (p=0.043 and p=0.040, respectively), while ptyr-1173 EGFR was only correlated to Her-2/neu expression (p=0.042). Interestingly, EGFR and its activated forms were all significantly inversely correlated with PgR expression (p=0.011, p=0.033 and p=0.032, respectively), and ptyr-845 EGFR was also inversely correlated with ER expression (p=0.008). While we have previously shown that serum levels of the extracellular component of Her-2/neu are associated with tumoral ptyr-1248 Her-2/neu expression, we did not find a similar relationship between serum EGFR and intratumoral total/activated EGFR. We did, however, observe significantly higher levels of serum EGFR in women with 3+ overexpression of HER-2/neu (p=0.047). Taken together, we have demonstrated the activation pattern of EGFR and Her-2/neu in Her-2/neu overexpressing breast cancer. We suggest that EGFR inhibition might enhance the efficacy of trastuzumab by preventing cross-phosphorylation.

Expression of tyrosine kinases in human malignancies as potential targets for kinase-specific inhibitors.

Tyrosine kinase (TK) inhibition has been identified as a promising strategy in the treatment of human malignancies and several synthetic inhibitors have been developed. While the selective blockage of specific TKs is highly effective in vitro, clinical results have been less impressive. It has been suggested that the simultaneous inhibition of multiple TKs might lead to more favorable therapeutic results in vivo. We have therefore performed a systematic analysis of intratumoral TK expression in order to identify potential targets for a simultaneous kinase inhibition. To this end, we have analyzed the protein expression of membrane-associated epidermal growth factor receptor (EGF-R), Her-2/neu, platelet-derived growth factor receptor (PDGF-R), insulin-like growth factor receptor (IGF-R), c-Kit and of cytoplasmatic c-Abl in 500 human tumors of epithelial, stromal and mesenchymal origin by immunohistochemistry, and found a distinct pattern of kinase expression: EGF-R, PDGF-R and c-Abl were expressed in the majority of malignant tumors, whereas c-Kit, Her-2/neu and IGF-R protein expression was considerably less frequent. Overall, the EGF-R protein expression was correlated with PDGF-R, c-Kit and c-Abl immunoreactivity (P = 0.003, P = 0.001 and P < 0.001, respectively). c-Abl was co-expressed with IGF-R and PDGF-R (P = 0.003 and P < 0.001, respectively). Kinase co-expression was also seen in tumor subgroups and was particularly significant in breast cancer where IGF-R protein was expressed together with PDGF-R and c-Abl (P = 0.003 and P = 0.004, respectively), and in colon cancer where PDGF-R was correlated with EGF-R (P < 0.001). With the exception of Her-2/neu expression and age, intra-tumoral TK expression was not associated with parameters such as grading or histological subtypes. Taken together, we have found a specific pattern of kinase co-expression and have identified several potential targets for a tumor-specific multimodal TK inhibition.