Regulatory T cells and type 2 innate lymphoid cell-dependent asthma.

Group 2 innate lymphoid cells (ILC2s) are a recently identified group of cells with the potent capability to produce Th2-type cytokines such as interleukin (IL)-5 and IL-13. Several studies suggest that ILC2s play an important role in the development of allergic diseases and asthma. Activation of pulmonary ILC2s in murine models lacking T and B cells induces eosinophilia and airway hyper-reactivity (AHR), which are cardinal features of asthma. More importantly, numerous recent studies have highlighted the role of ILC2s in asthma persistence and exacerbation among human subjects, and thus, regulation of pulmonary ILC2s is a major area of investigation aimed at curbing allergic lung inflammation and exacerbation. Emerging evidence reveals that a group of regulatory T cells, induced Tregs (iTregs), effectively suppress the production of ILC2-driven, pro-inflammatory cytokines IL-5 and IL-13. The inhibitory effects of iTregs are blocked by preventing direct cellular contact or by inhibiting the ICOS-ICOS-ligand (ICOSL) pathway, suggesting that both direct contact and ICOS-ICOSL interaction are important in the regulation of ILC2 function. Also, cytokines such as IL-10 and TGF-ß1 significantly reduce cytokine secretion by ILC2s. Altogether, these new findings uncover iTregs as potent regulators of ILC2 activation and implicate their utility as a therapeutic approach for the treatment of ILC2-mediated allergic asthma and respiratory disease.

Multiple attractors in the response to a vaccination program.

Though it is well known that multiple attractors may co-exist in the SEIR (susceptible/exposed/infective/recovered) epidemic model with vital dynamics and seasonally forced oscillations in transmission, the epidemiological significance of multiple attractors has been a subject of debate. I show that the co-existence of attractors is relevant in using the model to study the dynamics of the introduction of a vaccination program into a stable epidemic cycle. Responses to the program may include more than one attractor. The exact timing of the introduction of the program relative to the original epidemic cycle is critical in determining which attractor appears in the response. Analysis of this simple model suggests that the role of multiple attractors in the response to vaccination should be examined in more realistic epidemiological models.

Field trial in Chiapas, Mexico, of a rapid detection method for malaria in anopheline vectors with low infection rates.

A method consisting of filtration of up to 100 macerated mosquitoes in a batch, followed by fixation with glutaraldehyde and concentration of filtrate by centrifugation has been developed to rapidly assess malaria infection in anopheline mosquitoes. Determination of the presence of sporozoites is made by observation of a sample of the final filtrate with a phase microscope. The method is simple and field adaptable, essential factors for the application of any technique to large scale field operations. Application of the technique in El Gancho, Chiapas, Mexico, in February 1984 yielded an infection rate for Anopheles albimanus of 0.9% for intradomicile-collected human bait mosquitoes and 0.1% for peridomicile-collected human bait mosquitoes.

An analysis of the mortality effect in a breast cancer screening study.

In order to better understand the effect of breast cancer screening on mortality, we use the theory of competing risks to analyse deaths from the long-term follow-up of the HIP breast cancer screening trial. We conclude that some, but not all, of the breast cancer cases detected early as a result of screening realized a benefit in terms of elimination of the risk of breast cancer mortality. Breast cancer screening appears not to affect the rate of mortality from causes of death other than breast cancer. Methodologically, we demonstrate the importance of analysing mortality separately for the breast cancer cases as well as for the entire population in a trial.

Inflammatory breast cancer: the experience of the surveillance, epidemiology, and end results (SEER) program.

The current status of inflammatory breast cancer (IBC) among U.S. females was reviewed with the use of data abstracted from medical records of patients diagnosed with breast cancer between 1975 and 1981 in nine geographic areas covered by the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. Patients were selected on the basis of reported clinical and pathologic features of IBC and were divided into 3 groups: I) both clinical and pathologic features of IBC; II) clinical features without pathologic confirmation; and III) pathologic evidence only. The age distribution of pathologically defined IBC, in general, showed younger ages than those for other breast cancers in both the white and black populations. Further analysis was restricted to white females due to the relatively small numbers of black and other nonwhite patients with IBC. The disease presentations of both clinically and pathologically defined IBC were similar with regard to the likelihood of the presence of metastases at initial staging. Survival was evaluated by comparison of patients with nonmetastatic (MO) disease. Three years after diagnosis, the relative survival rates among patients in groups I, II, and III were observed to be 34, 60, and 52%, respectively. Survival of patients with all other types of breast cancer was 90% at 3 years. The management of IBC appeared to differ from the treatment of other forms of breast cancer; chemotherapy was given more frequently as the first course of cancer-directed therapy in white SEER females with evidence of MO IBC compared with the group with MO non-IBC. When all possible combinations of initial therapy were considered, the treatment for IBC was more variable than the treatment for non-IBC.

Seasonality and period-doubling bifurcations in an epidemic model.

The annual incidence rates of some endemic infectious diseases are steady while others fluctuate dramatically, often in a regular cycle. In order to investigate the role of seasonality in driving cycles of recurrent epidemics, we analyze numerically the susceptible/exposed/infective/recovered (SEIR) epidemic model with seasonal transmission. We show that small amplitude periodic solutions exhibit a sequence of period-doubling bifurcations as the amplitude of seasonal variation increases, predicting a transition to chaos of the kind studied in other biological contexts. The epidemiological implication is that the seasonal mechanism generating biennial epidemics may not be able to account for small-amplitude recurrent epidemics of arbitrary periodicity.

Some new directions for research in epidemic models.

Problems requiring further development of epidemic theory are discussed. One important area is the association between progressive disease and horizontally-transmitted agents, as in, e.g., the current epidemic of acquired immunodeficiency syndrome (AIDS) which has been linked to spread of a virus. Models of disease transmission must be combined with models of disease progression. More work is also needed to explain why the annual incidence of some diseases fluctuates dramatically, often in regular cycles, rather than stabilizing at a predictable level.

Possible immunological implications of an association between the stages of first and second independent breast cancers.

Concepts regarding cell-mediated immunity and breast cancer are reviewed. Patients having in situ breast cancers have been found by in vivo and in vitro measurements to have cell-mediated immunity to autologous and homologous in situ breast cancer tissue which may last for some time after diagnosis. These observations suggest that antigenically similar cancers arising subsequently in the contralateral breast should be less likely to progress beyond the in situ stage and, if they do become invasive, should exhibit prognostically favorable signs of cell-mediated immunity, e.g. sinus histiocytosis in the lymph nodes and/or lymphoid infiltrate and perivenous lymphoid infiltrate associated with the primary tumor. Cell-mediated immunity has also been shown to be negatively associated with the stage of disease at diagnosis for invasive cancers, i.e. the proportion of patients exhibiting cell-mediated immunity decreases as the stage at diagnosis increases. These observations suggest that the stages of independent breast cancers occurring in the same woman should be positively correlated. Data from the SEER Program of the National Cancer Institute were examined in this regard and a strong positive association between the stage of first and second independent primary breast cancers was found with the effect on the stage of a second breast cancer following a the first invasive breast cancer appearing to decrease with time subsequent to diagnosis. These observations are consistent with the immunogenicity of breast cancer.

Malaria epidemiology and detectability.

Conventional malaria surveys based on the microscopic examination of blood do not always detect chronic, low-grade infections caused by immunity. A model incorporating differences in detectability within the host population shows how the false negative tests caused by poor detectability confound measures of prevalence and the rates of infection and recovery. The model can also use multiple surveys on one group of individuals to estimate roughly the true prevalence. The form of data required is the number of times parasites are detected for each person; simply noting the cumulative proportion of individuals who show positive tests, as often reported in the literature, yields little information. Improved estimation of epidemiological variables awaits additional work on how best to analyse chronic malarial infection.