Line-1: Implications in the etiology of cancer, clinical applications, and pharmacologic targets.

Long interspersed nuclear elements-1 (Line-1 or L1) accounts for approximately 17% of the human genome. The majority of L1s are inactive, but ∼100 remain retrotransposon competent (RC-L1) and able to retrotranspose through RNA intermediates to different locations of the genome. L1 is involved in both disease initiation and progression via retrotransposition dependent and independent mechanisms. Retrotransposed L1 sequences disrupt genetic loci at sites of insertion, while the activities of L1 si/piRNAs, mRNAs, and ORF1 and ORF2 proteins, and have been implicated in the etiology and progression of several human diseases. Despite these relationships, little is known about the clinical utility of L1 as a biomarker of disease initiation and progression, or the utility of small molecules to inhibit and reverse the harmful effects of L1. In this review, we discuss the life cycle of L1, somatic and germline inhibitions, the mechanisms of L1 retrotransposition dependent and independent disease initiation and progression, clinical utilities, and potential of L1s as pharmacologic targets for the treatment of cancer.

Within-female plasticity in sex allocation is associated with a behavioural polyphenism in house wrens.

Sex allocation theory assumes individual plasticity in maternal strategies, but few studies have investigated within-individual changes across environments. In house wrens, differences between nests in the degree of hatching synchrony of eggs represent a behavioural polyphenism in females, and its expression varies with seasonal changes in the environment. Between-nest differences in hatching asynchrony also create different environments for offspring, and sons are more strongly affected than daughters by sibling competition when hatching occurs asynchronously over several days. Here, we examined variation in hatching asynchrony and sex allocation, and its consequences for offspring fitness. The number and condition of fledglings declined seasonally, and the frequency of asynchronous hatching increased. In broods hatched asynchronously, sons, which are over-represented in the earlier-laid eggs, were in better condition than daughters, which are over-represented in the later-laid eggs. Nonetheless, asynchronous broods were more productive later within seasons. The proportion of sons in asynchronous broods increased seasonally, whereas there was a seasonal increase in the production of daughters by mothers hatching their eggs synchronously, which was characterized by within-female changes in offspring sex and not by sex-biased mortality. As adults, sons from asynchronous broods were in better condition and produced more broods of their own than males from synchronous broods, and both males and females from asynchronous broods had higher lifetime reproductive success than those from synchronous broods. In conclusion, hatching patterns are under maternal control, representing distinct strategies for allocating offspring within broods, and are associated with offspring sex ratios and differences in offspring reproductive success.

The depression puzzle. Do the pieces fit?

BACKGROUND: Depression is a common problem in the Australian community. It results in considerable disability. Currently screening tools promoted for detection of depression are nonspecific. They are not diagnostic tools. While people identified by screening are, by definition, at higher risk of depression, the diagnosis still needs to be based on interview findings. Screening tools do not substitute for time spent with patients developing rapport and an understanding of the causes of the depression and formulating possible management steps. Screening alone has not been shown to improve outcomes for people with depression. OBJECTIVE: This article examines the current prevalence of depression in Australia and whether screening tools ultimately contribute to a reduction in morbidity. DISCUSSION: Screening instruments have arbitrary cut off points for identifying patients with depression and their findings regarding prevalence should be applied with caution. If the thresholds are low then 'prevalences' are raised. It is unclear whether all 'cases' detected using screening instruments require clinical intervention.

Differing functional recovery of donor-derived immune cells after purified haploidentical and fully mismatched hematopoietic stem cell transplantation in mice.

Functional recovery of the immune system is critical for long-term survival in hematopoietic stem cell transplant recipients. In this study, two donor-recipient allogeneic transplant settings (haploidentical and fully mismatched) are used to investigate the functional activity of donor-derived B and T cells in animals grafted with purified c-kit(+), Thy 1.1(lo), Lin(-/lo), and Sca-1(+) hematopoietic stem cells (KTLS HSC).Ovalbumin-specific immunoglobulin G, polyclonal immunoglobulin isotypes, and B- and T-cell proliferation were examined on the recipients who received haploidentical or fully mismatched HSC.A severe deficiency of antigen-specific immunoglobulin response occurs in fully engrafted mice that received KTLS HSC from fully mismatched, but not haploidentical, donors. This lack of B-cell-specific immunity is not due to a deficiency of polyclonal immunoglobulins in serum. B cells from both fully mismatched and haploidentical recipients proliferate normally after stimulation with anti-mu and the percentage of mature B cells is normal. The T-cell response to anti-CD3 in fully mismatched recipients was much weaker than that of their untransplanted controls. However, T cells from haploidentical recipients respond normally to anti-CD3. This study demonstrates that numerical recovery of donor-derived cells in the periphery of recipients does not represent a functional reconstitution, particularly in animals that receive fully mismatched transplants. Defects of specific B-cell immunity and T-cell proliferation are observed in fully mismatched, purified HSC transplant recipients with a quantitative recovery within the normal range of donor-derived lymphocytes.

Low frequency epithelial cells in bone marrow aspirates from prostate carcinoma patients are cytogenetically aberrant.

BACKGROUND: Low frequency epithelial cells occur in bone marrow aspirates of 25-50% of patients with locally confined prostate carcinoma. It is assumed that bone marrow epithelial cells derive from the primary tumor; however, it has not been established unequivocally that they are tumor cells. Immunofluorescence approaches were used to quantify the frequency of epithelial cells in bone marrow aspirates from prostate carcinoma patients and genotypic analyses were used to determine whether they contained numeric aberrations of chromosomes 1, 7, and 8. METHODS: Epithelial cells in bone marrow aspirates collected after radical prostatectomy were visualized using fluorescence microscopy and fluorophore-linked antibodies against cytokeratin 8,18 (CK) and prostate specific antigen (PSA). Antibodies specific for proliferating nuclear cell antigen (PCNA) were used to evaluate the cycling status of discriminated cells. Copies of chromosomes 1, 7, and 8 in the discriminated epithelial cells were quantified using fluorescence in situ hybridization. RESULTS: CK+ cells were present in bone marrow aspirates from 30 of 66 patients (approximately 45%) at a median frequency of 1.4 CK+ cells/10(5) mononuclear cells. Few CK+ epithelial cells in the bone marrow aspirates coexpressed PSA and none of the CK+ cells expressed PCNA. Approximately 70-75% of the CK+ cells contained 7 and 8 aneusomies. Gains of chromosome 1 occurred in 42% of the CK+ cells. CONCLUSIONS: The majority of CK+ cells in bone marrow aspirates collected after surgery are cytogenetically aberrant, which is consistent with a primary tumor origin. The prevalence and frequency of CK+ cells is independent of tumor stage/grade and androgen treatment.

Ultrastructural studies on the tegument of the metacercariae of Meiogymnophallus minutus and Meiogymnophallus fossarum (Digenea: Gymnophallidae) in Cerastoderma edule (Bivalvia) from Portugal.

Unencysted metacercariae of Meiogymnophallus minutus (Cobbold, 1859) and the sibling species Meiogymnophallus fossarum (Bartoli, 1965) infect the edible cockle, Cerastoderma edule (L.), with free metacercariae occurring simultaneously in the same host specimens in Portugal. Observations on the tegument of both species show that changes in the morphology of the body surface occurs in the intermediate host. Scanning and transmission electron microscopy revealed an alveoli-like tegument with palmate, digitated spines protruding from each individual alveolus. Uniciliated papillate receptors, which may or not may be recessed, were abundant, surrounding the suckers as well as being distributed on the body surface. Transmission electron microscopy revealed a significant number of 3 types of densely packed secretory vesicles, thin cysternae, and mitochondria in the surface tegument of the body, oral cavity, and esophagus. No distinguishing differences were observed in the surface ultrastructure of M. minutus and M. fossarum metacercariae.

Evaluation of the MUREX*ICE HIV-1.O.2 capture enzyme immunoassay for early identification of HIV-1 seroreverting infants in a developing country.

BACKGROUND: A simple, inexpensive serological assay is required for the early determination of HIV infection status among infants born to HIV-1-seropositive women in developing countries. OBJECTIVES: To evaluate the use of a commercially available capture enzyme immunoassay (EIA), the MUREX*ICE HIV-1.O.2, for the early identification of seroreverting, uninfected infants. STUDY DESIGN: Infants with a clearly defined HIV-1 infection status, as determined by polymerase chain reaction results and/or seroreactivity at 18 months, were tested for antibodies to HIV. The time to seroreversion using the capture EIA was compared with the results obtained using an indirect assay, the GENELAVIA MIXT EIA. RESULTS: Seroreverting infants were identified earlier with the capture than the indirect EIA; all of the uninfected infants were seronegative at 12 months with the capture EIA while 100% seroreversion was only seen at 18 months with the indirect EIA. CONCLUSIONS: In general, the capture EIA identified seroreverting infants 3-6 months earlier than the indirect EIA. However, caution must be exercised in interpreting seroreactivity in a breast-fed population where HIV infection may occur in a child who has previously seroreverted.

Pyogenic liver abscess.

Experience with 34 patients with pyogenic liver abscess is reviewed to evaluate the impact of percutaneous drainage and duration of antibiotic therapy on results of treatment. Patients with shock, adult respiratory distress syndrome, disseminated intravascular coagulation, jaundice, severe hypoalbuminemia, and diabetes had a poor prognosis. Percutaneous drainage was used successfully in 4 of 6 patients, but its use did not affect mortality rate or length of hospital stay. Percutaneous drainage may be the procedure of choice for selected patients. Half of our patients received antibiotics for 2 weeks or less with no abscess recurrences in this group. Long-term antibiotics may not be necessary after adequate surgical or percutaneous abscess drainage.

Depression and diethylstilbestrol exposure in women.

Fifty women exposed to diethylstilbestrol (DES) in utero, 50 of their unexposed sisters (sister controls) and 43 women with abnormal Papanicolaou smears (population controls) were tested using the Diagnostic Interview Schedule to assess differences in depression and other kinds of psychologic impairment possibly associated with DES exposure. There were significant differences between DES-exposed women and their sisters in major depression and major recurrent depression. Papanicolaou controls were more depressed in comparison to sister controls. However, there were no significant differences in depression between Papanicolaou controls and the DES exposed, suggesting that major and recurrent depressions are more likely to result from concern about reproductive and other gynecologic problems than from the hormonal effects of intrauterine exposure to DES. Differences in amphetamine abuse/dependence were also noted between the DES exposed and the sister controls.

General body growth in children with clefts of the lip, palate, and craniofacial structure.

This paper discusses general body growth in children with craniofacial clefts. Body growth is important in such patients because morphology reflects the cumulation of metabolism over time. The same hormones that direct general body growth also govern the ontogeny of the head and face. Body growth varies in children with different types of clefts. We found no average differences from US norms for those with isolated clefts of the lip alone or those with bilateral clefts of the lip and palate. Children with unilateral clefts of the lip and palate and with isolated cleft palate were significantly shorter than their unaffected peers. Males with these defects were also thinner than normal based on average standard deviation scores for body mass indices. Both unilateral and bilateral clefts of the lip and palate predominated in males, while isolated cleft lip was more frequent in females. Our results indicate that congenital metabolic variation contributes to the development of orofacial clefting and influences postnatal development in certain types of cleft. Accordingly, cleft type is important to growth prognosis, and growth status is relevant to optimization of therapy in orofacial cleft patients.

Radiation hormesis, public health, and public policy: a commentary.

Public policy affecting public health regarding effects of low-level ionizing radiations has been, and is being, determined by effects estimates based on linear or other monotonic extrapolation from high-level radiation dose-response data to presumed ecologically realistic low-level exposure effects. Such predictive, unmeasured estimates are very possibly in serious error; they are incompatible with observed low-level dose-response data that indicate a negative correlation between low-level radiation data and health effects, such as cancer mortality rates. Observed negative correlations with low-level radiation data are to be expected on the basis of evidence supporting the validity of the hormesis phenomenon. Hormesis theory, derived in part from evolutionary biology, asserts that while high levels of exposure to an agent such as ionizing radiation are indeed hazardous, ecologically realistic low levels can be stimulatory and largely beneficial. Stimulation of activities of DNA and other repair mechanisms may be involved. Although evidence of the reality of radiation hormesis has been reported in about 1000 scientific publications over the last century, this effect has been largely unrecognized. Moreover, this widespread non-acceptance of hormesis as a real-world phenomenon is usually but not always present in the case of chemical hormesis; the oversight appears systematic. The ignoring of the hormesis phenomenon seems to constitute a very serious error in modern biomedical science and in preventive medicine. A mathematical model is offered that describes the general shape of certain dose-response functions when radiation hormesis at low-level exposure is taken into consideration along with the well-known detrimental effects of high-level radiation.

An invasive microwave antenna for locally-induced hyperthermia for cancer therapy.

A microwave system has been developed and characterized for delivering heat directly into tumors. This system employs a microwave power source (3-10W) operating in the 500 MHz to 1.3 GHz frequency range, coaxial transmission line, and a monopole antenna. Absorbed power was measured in saline, in tissue equivalent phantoms, and in tumors in live and dead mice. Antennas were designed to operate at 500 MHz and 1 GHz, and the critical design parameters have been identified for this system. Analytical and experimental results obtained in our laboratory suggest that this system is capable of providing controlled temperature distributions appropriate for hyperthermia in animal tumors. Theoretical results predict that 3 GHz may be an optimum choice for this system in animal tumors of approximately 1 cm diameter; the microwave antenna system provides a heat distribution superior to that obtained using a resistance heater of similar dimensions. We propose that further development of this approach may overcome some of the problems associated with other systems which use external radiation sources, and implications for clinical application of this system are discussed.

Cancer therapy with localized hyperthermia using an invasive microwave system.

A system has been developed for producing local hyperthermia in small animal tumors by means of an invasive needle microwave antenna. Thermal distributions produced by this system using 1 GHz microwaves have been characterized in mammary adenocarcinomas (MTG-B) implanted in thighs of C3H mice. Therapeutic efficacy by hyperthermia was demonstrated by comparing MTG-B diameters in mice following control, sham or hyperthermia treatment. It is proposed that this system could be employed clinically to provide very local hyperthermia in deep-seated tumors.

Essential hormones as carcinogenic hazards.

Recently, the Occupational Safety and Health Administration (OSHA) proposed regulations regarding lists of environmental substances that allegedly pose potential occupational carcinogenic risk. Known carcinogens such as bis(chloromethyl) ether, along with natural substances such as estradiol, estriol, estrone, progesterone, tannic acid, maltose, and lactose, were included in the general OSHA list. Clear distinction between true hazards and essential endogenously formed biochemicals was not made. A major reappraisal of the OSHA list is essential. The revised document should indicate the conditions under which various classes of substances constitute human health hazards -- including dosage levels and routes of entry.

PIP: The OSHA (Occupational Safety and Health Administration) considers certain substances to be carcinogenic including such hazardous chemicals as benzo(a)pyrene, asbestos, bis(chloromethyl) ether, 2-naphthylamine, and aflatchines B2 and G1 as well as natural substances such as estradiol, estriol, estrone, progesterone, tannic acid, maltose, and lactose. The results of the carcinogenic effects of these natural substances is in question because of administered dosage levels, chemical structure of the substances, the route the hormones entered the biological system, and testing done in animals and in vitro. Citing lactose, found in milk, and nitrite, found in saliva, as carcinogenics shows a lack of discrimination between authentic carcinogenic hazards and evolved natural chemicals endogenously produced which are essential to survival. It is suggested that OSHA reappraise the substances to indicate the conditions under which substances may be considered a human health hazard including dosages and routes of entry.

Maternal smoking, birth weight, infant death, and the self-selection problem.

Several aspects of the relationship between maternal smoking and birth weights of infants are discussed. No satisfactory explanation for Yerushalmy's results has been given other than that low birth weight appears to relate more to the smoker than to the smoking. Recent studies by Silverman support this position. The possibility that nicotine may induce a physiologic response that serves to alleviate bioenergetic deficiency in some individuals should not be overlooked. In this view, both smoking and low birth weight are symptoms of deficient maternal bioenergetic systems.

PIP: The literature is reviewed in terms of 4 questions of importance to the issue of maternal smoking--infant birth weight and health studies: 1) inference of causality from correlation; 2) the constitutional hypothesis; 3) maternal and fetal constitutional factors associated with low birth weight and perinatal death; and 4) environmental factors associated with low birth weight and perinatal death. Only a few maternal smoking-infant health studies used the invalid method of inference of causality from correlation. There is an underlying biological rationale supporting the constitutional hypothesis that appears to explain lower mean birth weights of children of women who smoke, compared with birth weights of children of nonsmokers. Examination of the National Institute of Neurological Diseases and Stroke findings shows the following maternal constitutional factors, on the average, among those delivered of infants with low birth weights: low prepregnant weight, shortness of stature, and, tentatively, hyperthyroidism. Maternal factors associated with elevated perinatal mortality rates include diabetes mellitus, higher prepregnant weight ranges and taller maternal heights, advanced maternal age, low maternal age, birth weight of less than 2501 grams for last prior child, and male sex of infant. Environmental factors associated with low birth weight and detrimental health characteristics include elevated levels of carbon monoxide and ionization radiation, low socioeconomic index of the family, alcohol consumption, and high altitude. As yet there has not been a definitive analysis of the relationship between maternal smoking and low birth weight and perinatal death that simultaneously considers constitutional factors such as maternal height and weight and other factors such as parity and birthweight of less than 2500 grams for a preceding child.

Health effects of atmospheric sulfur dioxide and dietary sulfites. The fallacy of typology.

Some animal studies have shown that exposure to low levels of sulfur dioxide and dietary bisulfite is relatively harmless. To the contrary, sulfite oxidase deficiency is known in man, bisulfite is mutagenic for several test organisms, and the atmospheric SO2 level is positively correlated with death rates for several chronic diseases among some human populations. The studies reporting harmlessness for animals may be misleading because of the fallacy of typology.