Historical Lessons on Vaccine Hesitancy: Smallpox, Polio, and Measles, and Implications for COVID-19.

Vaccine hesitancy continues to pose a formidable obstacle to increasing national COVID-19 vaccination rates in the US, but this is not the first time that American vaccination efforts have confronted resistance and apathy. This study examines the history of US vaccination efforts against smallpox, polio, and measles, highlighting persistent drivers of vaccine hesitancy as well as factors that helped overcome it. The research reveals that logistical barriers, negative portrayals in the media, and fears about safety stymied inoculation efforts as early as the 18th century and continue to do so. However, vaccine hesitancy has been markedly diminished when trusted community leaders have guided efforts, when ordinary citizens have felt personally invested in the success of the vaccine, and when vaccination efforts have been tied to broader projects to improve public health and social cohesion. Deliberately cultivating such factors could be an effective strategy for lessening opposition today, when COVID-19's distinctive characteristics make addressing vaccine hesitancy more urgent than it has ever been.

[Spontaneous course of traumatic tympanic membrane perforations]. / Spontaner Heilungsverlauf traumatischer Trommelfellperforationen.

BACKGROUND: Traumatic eardrum perforation is a common presentation in otorhinolaryngologic practices and emergency clinics. A consistent management strategy (active intervention vs. watchful waiting) is, however, still lacking. OBJECTIVE: In the following study, the outcome of watchful waiting is analyzed and presented. MATERIALS AND METHODS: A collective of 272 patients presenting at two different specialist ENT practices within days of traumatic tympanic membrane perforation from June 2002 to March 2019 were analyzed. Treatment was non-surgical, with prospective monitoring. Whereas antibiotics were not given at all in one practice, they were given only upon signs of infection in the other practice. The outcome was evaluated retrospectively on the basis of patient files. RESULTS: The collective consisted of 185 males and 87 females. Mean age was 30 years (range: 7 months to 82 years). The perforations were most commonly located in the upper anterior and lower posterior quadrants. According to Griffin grading, the size was grade I in 97%. The three most common causes were impact to the ear, barotrauma, and foreign bodies. Under a watchful waiting regimen, 95% of the patients presenting for follow-up checks showed complete closure. CONCLUSION: Watchful waiting can be assessed as appropriate in traumatic eardrum perforation, provided otorhinolaryngologic follow-up is ensured. An exception is blast injury, which is now much less common in Central Europe, as this is associated with a risk of secondary cholesteatomas. In these rare cases, active treatment with surgical exploration of the middle ear including relining the perforation is indicated.

Association of sporadic and familial Barrett's esophagus with breast cancer.

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC). Based on striking aggregation of breast cancer and BE/EAC within families as well as shared risk factors and molecular mechanisms of carcinogenesis, we hypothesized that BE may be associated with breast cancer. Pedigree analysis of families identified prospectively at multiple academic centers as part of the Familial Barrett's Esophagus Consortium (FBEC) was reviewed and families with aggregation of BE/EAC and breast cancer are reported. Additionally, using a matched case-control study design, we compared newly diagnosed BE cases in Caucasian females with breast cancer (cases) to Caucasian females without breast cancer (controls) who had undergone upper endoscopy (EGD). Two familial pedigrees, meeting a stringent inclusion criterion, manifested familial aggregation of BE/EAC and breast cancer in an autosomal dominant inheritance pattern with incomplete penetrance. From January 2008 to October 2016, 2812 breast cancer patient charts were identified, of which 213 were Caucasian females who underwent EGD. Six of 213 (2.82%) patients with breast cancer had pathology-confirmed BE, compared to 1 of 241 (0.41%) controls (P-value < 0.05). Selected families with BE/EAC show segregation of breast cancer. A breast cancer diagnosis is marginally associated with BE. We postulate a common susceptibility between BE/EAC and breast cancer.

Impacts of Regulations on Air Quality and Emergency Department Visits in the Atlanta Metropolitan Area, 1999-2013.

INTRODUCTION: The United States and Western Europe have seen great improvements in air quality, presumably in response to various regulations curtailing emissions from the broad range of sources that have contributed to local, regional, and global pollution. Such regulations, and the ensuing controls, however, have not come without costs, which are estimated at tens of billions of dollars per year. These costs motivate accountability-related questions such as, to what extent do regulations lead to emissions changes? More important, to what degree have the regulations provided the expected human health benefits?Here, the impacts of specific regulations on both electricity generating unit (EGU) and on-road mobile sources are examined through the classical accountability process laid out in the 2003 Health Effects Institute report linking regulations to emissions to air quality to health effects, with a focus on the 1999-2013 period. This analysis centers on regulatory actions in the southeastern United States and their effects on health outcomes in the 5-county Atlanta metropolitan area. The regulations examined are largely driven by the 1990 Clean Air Act Amendments (C). This work investigates regulatory actions and controls promulgated on EGUs: the Acid Rain Program (ARP), the NOx Budget Trading Program (NBP), and the Clean Air Interstate Rule (CAIR) - and mobile sources: Tier 2 Gasoline Vehicle Standards and the 2007 Heavy Duty Diesel Rule. METHODS: Each step in the classic accountability process was addressed using one or more methods. Linking regulations to emissions was accomplished by identifying major federal regulations and the associated state regulations, along with analysis of individual facility emissions and control technologies and emissions modeling (e.g., using the U.S. Environmental Protection Agency's [U.S. EPA's] MOtor Vehicle Emissions Simulator [MOVES] mobile-source model). Regulators, including those from state environmental and transportation agencies, along with the public service commissions, play an important role in implementing federal rules and were involved along with other regional stakeholders in the study. We used trend analysis, air quality modeling, satellite data, and a ratio-of-ratios technique to investigate a critical current issue, a potential large bias in mobile-source oxides of nitrogen (NOx) emissions estimates.The second link, emissions-air quality relationships, was addressed using both empirical analyses as well as chemical transport modeling employing the Community Multiscale Air Quality (CMAQ) model. Kolmogorov-Zurbenko filtering accounting for day of the year was used to separate the air quality signal into long-term, seasonal, weekday-holiday, and short-term meteorological signals. Regression modeling was then used to link emissions and meteorology to ambient concentrations for each of the species examined (ozone [O3], particulate matter ≤ 2.5 µm in aerodynamic diameter [PM2.5], nitrogen dioxide [NO2], sulfur dioxide [SO2], carbon monoxide [CO], sulfate [SO4-2], nitrate [NO3-], ammonium [NH4+], organic carbon [OC], and elemental carbon [EC]). CMAQ modeling was likewise used to link emissions changes to air quality changes, as well as to further establish the relative roles of meteorology versus emissions change impacts on air quality trends. CMAQ and empirical modeling were used to investigate aerosol acidity trends, employing the ISORROPIA II thermodynamic equilibrium model to calculate pH based on aerosol composition. The relationships between emissions and meteorology were then used to construct estimated counterfactual air quality time series of daily pollutant concentrations that would have occurred in the absence of the regulations. Uncertainties in counterfactual air quality were captured by the construction of 5,000 pollutant time series using a Monte Carlo sampling technique, accounting for uncertainties in emissions and model parameters.Health impacts of the regulatory actions were assessed using data on cardiorespiratory emergency department (ED) visits, using patient-level data in the Atlanta area for the 1999-2013 period. Four outcome groups were chosen based on previous studies identifying associations with ambient air pollution: a combined respiratory disease (RD) category; the subgroup of RD presenting with asthma; a combined cardiovascular disease (CVD) category; and the subgroup of CVD presenting with congestive heart failure (CHF).Models were fit to estimate the joint effects of multiple pollutants on ED visits in a time-series framework, using Poisson generalized linear models accounting for overdispersion, with a priori model formulations for temporal and meteorological covariates and lag structures. Several parameterizations were considered for the joint-effects models, including different sets of pollutants and models with nonlinear pollutant terms and first-order interactions among pollutants. Use of different periods for parameter estimates was assessed, as associations between pollutant levels and ED visits varied over the study period. A 7-pollutant, nonlinear model with pollutant interaction terms was chosen as the baseline model and fitted using pollutant and outcome data from 1999-2005 before regulations might have substantially changed the toxicity of pollutant mixtures. In separate analyses, these models were fitted using pollutant and outcome data from the entire 1999-2013 study period. Daily counterfactual time series of pollutant concentrations were then input into the health models, and the differences between the observed and counterfactual concentrations were used to estimate the impacts of the regulations on daily counts of ED visits. To account for the uncertainty in both the estimation of the counterfactual time series of ambient pollutant levels and the estimation of the health model parameters, we simulated 5,000 sets of parameter estimates using a multivariate normal distribution based on the observed variance-covariance matrix, allowing for uncertainty at each step of the chain of accountability. Sensitivity tests were conducted to assess the robustness of the results. RESULTS: EGU NOx and SO2 emissions in the Southeast decreased by 82% and 83%, respectively, between 1999 and 2013, while mobile-source emissions controls led to estimated decreases in Atlanta-area pollutant emissions of between 61% and 93%, depending on pollutant. While EGU emissions were measured, mobile-source emissions were modeled. Our results are supportive of a potential high bias in mobile-source NOx and CO emissions estimates. Air quality benefits from regulatory actions have increased as programs have been fully implemented and have had varying impacts over different seasons. In a scenario that accounted for all emissions reductions across the period, observed Atlanta central monitoring site maximum daily 8-hour (MDA8h) O3 was estimated to have been reduced by controls in the summertime and increased in the wintertime, with a change in mean annual MDA8h O3 from 39.7 ppb (counterfactual) to 38.4 ppb (observed). PM2.5 reductions were observed year-round, with average 2013 values at 8.9 µg/m3 (observed) versus 19.1 µg/m3 (counterfactual). Empirical and CMAQ analyses found that long-term meteorological trends across the Southeast over the period examined played little role in the distribution of species concentrations, while emissions changes explained the decreases observed. Aerosol pH, which plays a key role in aerosol formation and dynamics and may have health implications, was typically very low (on the order of 1-2, but sometimes much lower), with little trend over time despite the stringent SO2 controls and SO42- reductions.Using health models fit from 1999-2005, emissions reductions from all selected pollution-control policies led to an estimated 55,794 cardiorespiratory disease ED visits prevented (i.e., fewer observed ED visits than would have been expected under counterfactual scenarios) - 52,717 RD visits, of which 38,038 were for asthma, and 3,057 CVD visits, of which 2,104 were for CHF - among the residents of the 5-county area over the 1999-2013 period, an area with approximately 3.5 million people in 2013. During the final two years of the study (2012-2013), when pollution-control policies were most fully implemented and the associated benefits realized, these policies were estimated to prevent 5.9% of the RD ED visits that would have occurred in the absence of the policies (95% interval estimate: -0.4% to 12.3%); 16.5% of the asthma ED visits (95% interval estimate: 7.5% to 25.1%); 2.3% of the CVD ED visits (95% interval estimate: -1.8% to 6.2%); and -.6% of the CHF ED visits (95% interval estimate: 26.3% to 10.4%). Estimates of ED visits prevented were generally lower when using health models fit for the entire 1999-2013 study period.Sensitivity analyses were conducted to show the impact of the choice of parameterization of the health models and to assess alternative definitions of the study area. When impacts were assessed for separate policy interventions, policies affecting emissions from EGUs, especially the ARP and the NBP, appeared to have had the greatest effect on prevention of RD and asthma ED visits. CONCLUSIONS: This study demonstrates the effectiveness of regulations on improving air quality and health in the southeastern United States. It also demonstrates the complexities of accountability assessments as uncertainties are introduced in each step of the classic accountability process. While accounting for uncertainties in emissions, air quality-emissions relationships, and health models does lead to relatively large uncertainties in the estimated outcomes due to specific regulations, overall the benefits of regulations have been substantial.

Variation by stage in the effects of prediagnosis weight loss on mortality in a prospective cohort of esophageal cancer patients.

Cancer cachexia is increasingly recognized as a poor prognostic marker for various tumor types. Weight loss in esophageal cancer is multifactorial, as patients with bulky tumors also have reduced ability to eat. We aimed to investigate the relationship between prediagnosis weight loss and mortality in esophageal cancer and to determine whether these associations vary with tumor stage. We conducted a prospective cohort study of esophageal cancer patients at two tertiary centers. We recorded baseline patient characteristics including medications, smoking, body mass index, and weight loss in the year prior to diagnosis, and collected data on treatment and outcomes. We used Cox regression modeling to determine the associations between percent weight loss and outcomes. The main outcome of interest was all-cause mortality; secondary endpoints were esophageal cancer-specific mortality and development of metastases. We enrolled 134 subjects, the majority of whom had adenocarcinoma (82.1%); median percent weight loss was 4.7% (IQR: 0%-10.9%). Increasing percent weight loss was not associated with all-cause mortality (ptrend = 0.36). However, there was evidence of significant interaction by tumor stage (p = 0.02). There was a strong and significant association between prediagnosis weight loss and mortality in patients with T stages 1 or 2 (adjusted HR 8.26 for highest versus lowest tertile, 95%CI 1.11-61.5, ptrend = 0.03) but not for T stages 3 or 4 (ptrend = 0.32). Body mass index one year prior to diagnosis was not associated with mortality. Prediagnosis weight loss was associated with increased all-cause mortality only in patients with early stage esophageal cancer. This suggests that tumor-related cachexia can occur early in esophageal cancer and represents a poor prognostic marker.

Safety and efficacy of endoscopic spray cryotherapy for esophageal cancer.

Although surgery is traditionally the standard of care for esophageal cancer, esophagectomy carries significant morbidity. Alternative endoscopic therapies are needed for patients who are not candidates for conventional treatment. The objective of this study is to assess the safety, efficacy, and tolerability of spray cryotherapy of esophageal adenocarcinoma. This study includes patients with esophageal adenocarcinoma who had failed or were not candidates for conventional therapy enrolled retrospectively and prospectively in an open-label registry and patients in a retrospective cohort from 11 academic and community practices. Endoscopic spray cryotherapy was performed until biopsy proven local tumor eradication or until treatment was halted due to progression of disease, patient withdrawal or comorbidities. Eighty-eight patients with esophageal adenocarcinoma (median age 76, 80.7% male, mean length 5.1 cm) underwent 359 treatments (mean 4.4 per patient). Tumor stages included 39 with T1a, 25 with T1b, 9 with unspecified T1, and 15 with T2. Eighty-six patients completed treatment with complete response of intraluminal disease in 55.8%, including complete response in 76.3% for T1a, 45.8% for T1b, 66.2% for all T1, and 6.7% for T2. Mean follow-up was 18.4 months. There were no deaths or perforations related to spray cryotherapy. Strictures developed in 12 of 88 patients (13.6%) but were present before spray cryotherapy in 3 of 12. This study suggests that endoscopic spray cryotherapy is a safe, well-tolerated, and effective treatment option for early esophageal adenocarcinoma.

Use of proton pump inhibitors is associated with fractures in young adults: a population-based study.

UNLABELLED: Proton pump inhibitors (PPIs) are associated with risk for fracture in osteoporotic adults. In this population-based study, we found a significant association between PPIs and fracture in young adults, with evidence of a dose-response effect. Young adults who use PPIs should be cautioned regarding risk for fracture. INTRODUCTION: Proton pump inhibitors (PPIs) are associated with fracture in adults with osteoporosis. Because PPI therapy may interfere with bone accrual and attainment of peak bone mineral density, we studied the association between use of PPIs and fracture in children and young adults. METHODS: We conducted a population-based, case-control study nested within records from general medical practices from 1994 to 2013. Participants were 4-29 years old with ≥ 1 year of follow-up who lacked chronic conditions associated with use of long-term acid suppression. Cases of fracture were defined as the first incident fracture at any site. Using incidence density sampling, cases were matched with up to five controls by age, sex, medical practice, and start of follow-up. PPI exposure was defined as 180 or more cumulative doses of PPIs. Conditional logistic regression was used to estimate the odds ratio and confidence interval for use of PPIs and fracture. RESULTS: We identified 124,799 cases and 605,643 controls. The adjusted odds ratio for the risk of fracture associated with PPI exposure was 1.13 (95% CI 0.92 to 1.39) among children aged < 18 years old and 1.39 (95% CI 1.26 to 1.53) among young adults aged 18-29 years old. In young adults but not children, we observed a dose-response effect with increased total exposure to PPIs (p for trend <0.001). CONCLUSIONS: PPI use was associated with fracture in young adults, but overall evidence did not support a PPI-fracture relationship in children. Young adults who use PPIs should be cautioned regarding potentially increased risk for fracture, even if they lack traditional fracture risk factors.

Real-time modelling used for outbreak management during a cholera epidemic, Haiti, 2010-2011.

The emergence of epidemic cholera in post-earthquake Haiti portended a public health disaster of uncertain magnitude. In order to coordinate relief efforts in an environment with limited healthcare infrastructure and stretched resources, timely and realistic projections of the extent of the cholera outbreak were crucial. Projections were shared with Government and partner organizations beginning 5 days after the first reported case and were updated using progressively more advanced methods as more surveillance data became available. The first projection estimated that 105 000 cholera cases would occur in the first year. Subsequent projections using different methods estimated up to 652 000 cases and 163 000-247 000 hospitalizations during the first year. Current surveillance data show these projections to have provided reasonable approximations of the observed epidemic. Providing the real-time projections allowed Haitian ministries and external aid organizations to better plan and implement response measures during the evolving epidemic.

Hypogonadism in patients with sickle cell disease: central or peripheral?

There is conflicting evidence in the literature on the etiology of hypogonadism in patients with sickle cell disease (SCD). A cross-sectional study was done to determine whether hypogonadism in male patients with SCD is due to primary testicular failure or secondary pituitary/hypothalamic dysfunction and assess the association between hypogonadism and serum ferritin levels. Hormonal assessment for serum concentrations of testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) was done for 34 men with SCD and their charts were reviewed for relevant clinical variables. Eight men (24%) were classified hypogonadal based on their serum testosterone levels. These men have significantly lower LH (p = 0.001) and FSH (p = 0.01) levels than normogonadal men, indicating a central etiology. There was no significant difference between hypogonadal and normogonadal men with respect to ferritin levels (p = 0.71). Our study indicates a central etiology of hypogonadism in patients with SCD. In this small study ferritin level was not significantly related to hypogonadism.

[Local use of tranexamic acid in ENT surgery]. / Die lokale Anwendung von Tranexamsäure in der HNO-Chirurgie.

Bleeding is a main complication in ENT surgery especially in oral and nasal interventions. Based on good results in local application of tranexamic acid after dental extraction, the different possibilities of local application of tranexamic acid in ENT surgery are discussed and the current literature is presented. In our experience, the rate of secondary hemorrhage after oral and nasal interventions can be reduced considerably by local application of tranexamic acid, which means risk reduction and better compliance especially in an increasingly aging patient population. Based on our experience, the local use of tranexamic acid in ENT surgery should be the focus of future studies.

Dark is a Drosophila homologue of Apaf-1/CED-4 and functions in an evolutionarily conserved death pathway.

Here we identify a new gene, dark, which encodes a Drosophila homologue of mammalian Apaf-1 and Caenorhabditis elegans CED-4, cell-death proteins. Like Apaf-1, but in contrast to CED-4, Dark contains a carboxy-terminal WD-repeat domain necessary for interactions with the mitochondrial protein cytochrome c. Dark selectively associates with another protein involved in apoptosis, the fly apical caspase, Dredd. Dark-induced cell killing is suppressed by caspase-inhibitory peptides and by a dominant-negative mutant Dredd protein, and enhanced by removal of the WD domain. Loss-of-function mutations in dark attenuate programmed cell deaths during development, causing hyperplasia of the central nervous system, and other abnormalities including ectopic melanotic tumours and defective wings. Moreover, ectopic cell killing by the Drosophila cell-death activators, Reaper, Grim and Hid, is substantially suppressed in dark mutants. These findings establish dark as an important apoptosis effector in Drosophila and raise profound evolutionary considerations concerning the relationship between mitochondrial components and the apoptosis-promoting machinery.

[Sonographic differential diagnosis of thyroid nodule. Pharyngoesophageal diverticulum]. / Zur sonographischen Differenzialdiagnose des Schilddrüsenknotens. Das pharyngoösophageale Divertikel.

Esophagography is the standard diagnostic method for diverticulum of the pharyngoesophageal junction. Less known is detection of the diverticulum during thyroid gland ultrasonography. Thyroid nodules located near the left trachea with a hyperechogenic border, beneath which a hypoechogenic zone and an echogenic center are seen, are highly suspicious for diverticulum of the hypopharynx/esophagus and should be investigated further. Postoperative follow-up is facilitated by the rapid sonographic involution of the preoperatively described nodule.

Regulation of parasite-induced eosinophilia: selectively increased interleukin 5 production in helminth-infected patients.

Production of the eosinophilogenic cytokines interleukin 3 (IL-3), granulocyte/macrophage colony-stimulating factor (GM-CSF), and IL-5 by mitogen-stimulated peripheral blood mononuclear cells was compared between 11 noneosinophilic individuals and seven patients with helminth-induced eosinophilia. Both the kinetics and quantities of IL-3 and GM-CSF were similar in the two groups. In contrast, IL-5 production at both the protein and the mRNA level was markedly greater in the eosinophilic patients, an observation suggesting that IL-5 may be particularly important in mediating the selective eosinophilia seen in filarial and other helminth infections.

Induction of human IgE synthesis by CD4+ T cell clones. Requirement for interleukin 4 and low molecular weight B cell growth factor.

We have analyzed in detail the precise requirements for the induction of human IgE synthesis using several experimental approaches with purified B cells and well-characterized alloantigen-specific CD4+ T cell clones expressing different profiles of lymphokine secretion. Using these clones under cognate conditions in which the B cells expressed alloantigens recognized by the cloned T cells, we have confirmed that IL-4 is required for the induction of IgE synthesis, but we have clearly demonstrated that IL-4 by itself is not sufficient. With several cloned CD4+ T cell lines, including an IL-4-producing clone that could not induce IgE synthesis, and cloned T cells pretreated with cyclosporin A to inhibit lymphokine synthesis, we showed that Th cell-B cell interactions are necessary for IgE synthesis, and that low molecular weight B cell growth factor (LMW-BCGF) and IL-4, in combination, are lymphokines of major importance in the induction of IgE synthesis. Together our results indicate that optimal induction of an IgE-specific response requires the exposure of B cells to a particular complex of signals that include (a) a signal(s) involving Th-B cell interaction that primes B cells to receive additional signals from soluble lymphokines, (b) a specific B cell proliferative signal provided by LMW-BCGF, and (c) a specific B cell differentiation signal provided by IL-4.

Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes.

In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (IL-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. IL-10 was detectable 7 h after activation of the monocytes and maximal levels of IL-10 production were observed after 24-48 h. These kinetics indicated that the production of IL-10 by human monocytes was relatively late as compared to the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of IL-10 by LPS activated monocytes was, similar to that of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by IL-4. Furthermore we demonstrate here that IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level. Viral-IL-10, which has similar biological activities on human cells, also inhibited the production of TNF alpha and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-IL-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced IL-10 inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF. In addition, IL-10 had autoregulatory effects since it strongly inhibited IL-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced IL-10 was found to be responsible for the reduction in class II major histocompatibility complex (MHC) expression following activation of monocytes with LPS. Taken together our results indicate that IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to downregulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.

Granulocyte/macrophage colony-stimulating factor and interleukin 3 release from human peripheral blood eosinophils and neutrophils.

Human peripheral blood eosinophils released eosinophil survival-enhancing activity when stimulated with the calcium ionophore, ionomycin. The release of activity was detected as early as 3 h after stimulation and was inhibited by an immunomodulating agent, cyclosporin A. The survival-enhancing activity was completely abolished by treatment with anti-interleukin 3 (IL-3) and anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) monoclonal antibodies. Moreover, IL-3 and GM-CSF were measurable in ionomycin-stimulated eosinophil supernatants by immunoassay. Eosinophils produced approximately one-half as much IL-3 and one-fifth as much GM-CSF as ionomycin-stimulated mononuclear cells. Neutrophils also produced IL-3 and GM-CSF, but the amounts were less than those produced by eosinophils. These observations suggest a novel role for eosinophils in pathophysiology of allergic inflammation and host defense mechanisms.

Role of interleukin 6 (IL-6) in protection from lethal irradiation and in endocrine responses to IL-1 and tumor necrosis factor.

Primary responsibility for the induction of various acute phase reactions has been ascribed to interleukin 1 (IL-1), tumor necrosis factor (TNF), or IL-6, suggesting that these cytokines may have many overlapping activities. Thus, it is difficult to identify the cytokine primarily responsible for a particular biologic effect, since IL-1 and TNF stimulate one another, and both IL-1 and TNF stimulate IL-6. In this work, the contribution of IL-6 in radioprotection, induction of adrenocorticotropic hormone (ACTH), and induction of hypoglycemia was assessed by blocking IL-6 activity. Administration of anti-IL-6 antibody to otherwise untreated mice greatly enhanced the incidence of radiation-induced mortality, indicating that like IL-1 and TNF, IL-6 also contributes to innate resistance to radiation. Anti-IL-6 antibody given to IL-1-treated or TNF-treated mice reduced survival from lethal irradiation, demonstrating that IL-6 is also an important mediator of both IL-1- and TNF-induced hemopoietic recovery. A similar IL-1/IL-6 interaction was observed in the case of ACTH induction. Anti-IL-6 antibody blocked the IL-1-induced increase in plasma ACTH, whereas recombinant IL-6 by itself did not induce such an increase. Anti-IL-6 antibody also mitigated TNF-induced hypoglycemia, but did not reverse IL-1-induced hypoglycemia. It is, therefore, likely that TNF and IL-1 differ in their mode of induction of hypoglycemia. Our results suggest that an interaction of IL-6 with IL-1 and TNF is a prerequisite for protection from radiation lethality, and its interaction with IL-1 for induction of ACTH.

A role for stem cell factor (SCF): c-kit interaction(s) in the intestinal tract response to Salmonella typhimurium infection.

Cholera toxin (CT) has been shown to induce stem cell factor (SCF) production in mouse ligated intestinal loops. Further, SCF interaction(s) with its receptor (c-kit) was shown to be important for the intestinal tract secretory response after CT exposure. In this study, we have investigated whether SCF production is induced in the intestinal tract after exposure to Salmonella typhimurium and whether this production could be an important intestinal tract response to Salmonella infection. Using a mouse ligated intestinal loop model, increased levels of SCF mRNA were detected at 2-4 h post-Salmonella challenge. Intestinal fluid obtained from Salmonella-challenged loops contained high levels of SCF by ELISA. Human and murine intestinal epithelial cell lines were also shown to have increased levels of SCF mRNA after exposure to Salmonella. Inhibition of Salmonella invasion of epithelial cells was shown to be one potentially important role for SCF:c-kit interactions in host defense to Salmonella infection. Pretreatment of human or murine intestinal cell lines with SCF resulted in a cellular state that was resistant to Salmonella invasion. Finally, mice having mutations in the white spotting (W) locus, which encodes the SCF-receptor (c-kit), were significantly more susceptible to oral Salmonella challenge than their control littermates. Taken together, the above results suggest that an important intestinal tract response to Salmonella infection is an enhanced production of SCF and its subsequent interactions with c-kit.

Human placental cytotrophoblasts produce the immunosuppressive cytokine interleukin 10.

The mechanism by which the mammalian mother accepts the implanting fetus as an allograft remains unexplained, but is likely to be the result of a combination of factors. Mononuclear cytotrophoblasts, the specialized fetal cells of the placenta that invade the uterus, play an important role. These cells express HLA-G, an unusual major histocompatibility complex class I-B molecule, and secrete cytokines and pregnancy-specific proteins that can regulate immune function. We investigated whether cytotrophoblasts secrete interleukin 10 (IL-10), a cytokine that potently inhibits alloresponses in mixed lymphocyte reactions. Cytotrophoblasts from all stages of pregnancy produced IL-10 in vitro, but neither placental fibroblasts nor choriocarcinoma (malignant trophoblast) cell lines did so. Spontaneous IL-10 production averaged 650, 853, and 992 pg/10(6) cells in the first, second, and third trimesters of pregnancy, respectively. IL-10 secretion dropped approximately 10-fold after the first 24 h of culture, and was paralleled by a decrease in messenger RNA. IL-10 messenger RNA was detected in biopsies of the placenta and the portion of the uterus that contains invasive cytotrophoblasts, suggesting that this cytokine is also produced in vivo. IL-10 secreted by cytotrophoblasts in vitro is bioactive, as determined by its ability to suppress interferon gamma production in an allogeneic mixed lymphocyte reaction. We conclude that human cytotrophoblast IL-10 may be an important factor that contributes to maternal tolerance of the allogeneic fetus.

High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells.

Transplantation of HLA mismatched hematopoietic stem cells in patients with severe combined immunodeficiency (SCID) can result in a selective engraftment of T cells of donor origin with complete immunologic reconstitution and in vivo tolerance. The latter may occur in the absence of clonal deletion of donor T lymphocytes able to recognize the host HLA antigens. The activity of these host-reactive T cells is suppressed in vivo, since no graft-vs. -host disease is observed in these human chimeras. Here it is shown that the CD4+ host-reactive T cell clones isolated from a SCID patient transplanted with fetal liver stem cells produce unusually high quantities of interleukin 10 (IL-10) and very low amounts of IL-2 after antigen-specific stimulation in vitro. The specific proliferative responses of the host-reactive T cell clones were considerably enhanced in the presence of neutralizing concentrations of an anti-IL-10 monoclonal antibody, suggesting that high levels of endogenous IL-10 suppress the activity of these cells. These in vitro data correlate with observations made in vivo. Semi-quantitative polymerase chain reaction analysis carried out on freshly isolated peripheral blood mononuclear cells (PBMC) of the patient indicated that the levels of IL-10 messenger RNA (mRNA) expression were strongly enhanced, whereas IL-2 mRNA expression was much lower than that in PBMC of healthy donors. In vivo IL-10 mRNA expression was not only high in the T cells, but also in the non-T cell fraction, indicating that host cells also contributed to the high levels of IL-10 in vivo. Patient-derived monocytes were found to be major IL-10 producers. Although no circulating IL-10 could be detected, freshly isolated monocytes of the patient showed a reduced expression of class II HLA antigens. However, their capacity to stimulate T cells of normal donors in primary mixed lymphocyte cultures was within the normal range. Interestingly, similar high in vivo IL-10 mRNA expressions in the T and non-T cell compartment were also observed in three SCID patients transplanted with fetal liver stem cells and in four SCID patients transplanted with T cell-depleted haploidentical bone marrow stem cells. Taken together, these data indicate that high endogenous IL-10 production is a general phenomenon in SCID patients in whom allogenic stem cell transplantation results in immunologic reconstitution and induction of tolerance. Both donor T cells and host accessory cells contribute to these high levels of IL-10, which would suppress the activity of host-reactive T cell in vivo.