Is the Hygiene Hypothesis an Example of Hormesis?

The “hygiene hypothesis” has been suggested to explain the rising incidence of allergic disorders in developed countries. The postulated mechanism is that infectious and/or microbial agents stimulate the immune system toward Th1 (allergy fighting) rather than Th2 (allergy promoting) response. This paper reviews the evidence related to early life infectious/microbial exposures and subsequent atopic disorders and evaluates whether these data suggest a hormetic effect. Our review indicates an insufficient and contradictory association for bacterial/viral infections, with protective effects being either absent or specific to certain infections and/or populations. Chronic, heavy parasitic burdens appear to confer protection against atopic disorders, but are associated with considerable pathology. Moreover, light parasitic burden may increase allergic responses (i.e., no “low dose” beneficial effect). In contrast, there is consistent evidence that general microbial exposures, particularly gut commensals, may be protective against allergy development, which is consistent with a hormetic effect (i.e., potentially beneficial effects at low doses and detrimental effects at high levels). Conclusion: General microbial exposures in relation to the “hygiene hypothesis” may represent a hormetic effect, although further research with more rigorous study methods (i.e., prospective designs and measurement of exposure timing, dose, route, etc.) are needed

Onset of human preterm and term birth is related to unique inflammatory transcriptome profiles at the maternal fetal interface.

BackgroundPreterm birth is a main determinant of neonatal mortality and morbidity and a major contributor to the overall mortality and burden of disease. However, research of the preterm birth is hindered by the imprecise definition of the clinical phenotype and complexity of the molecular phenotype due to multiple pregnancy tissue types and molecular processes that may contribute to the preterm birth. Here we comprehensively evaluate the mRNA transcriptome that characterizes preterm and term labor in tissues comprising the pregnancy using precisely phenotyped samples. The four complementary phenotypes together provide comprehensive insight into preterm and term parturition.MethodsSamples of maternal blood, chorion, amnion, placenta, decidua, fetal blood, and myometrium from the uterine fundus and lower segment (n = 183) were obtained during cesarean delivery from women with four complementary phenotypes: delivering preterm with (PL) and without labor (PNL), term with (TL) and without labor (TNL). Enrolled were 35 pregnant women with four precisely and prospectively defined phenotypes: PL (n = 8), PNL (n = 10), TL (n = 7) and TNL (n = 10). Gene expression data were analyzed using shrunken centroid analysis to identify a minimal set of genes that uniquely characterizes each of the four phenotypes. Expression profiles of 73 genes and non-coding RNA sequences uniquely identified each of the four phenotypes. The shrunken centroid analysis and 10 times 10-fold cross-validation was also used to minimize false positive finings and overfitting. Identified were the pathways and molecular processes associated with and the cis-regulatory elements in gene's 5' promoter or 3'-UTR regions of the set of genes which expression uniquely characterized the four phenotypes.ResultsThe largest differences in gene expression among the four groups occurred at maternal fetal interface in decidua, chorion and amnion. The gene expression profiles showed suppression of chemokines expression in TNL, withdrawal of this suppression in TL, activation of multiple pathways of inflammation in PL, and an immune rejection profile in PNL. The genes constituting expression signatures showed over-representation of three putative regulatory elements in their 5'and 3' UTR regions.ConclusionsThe results suggest that pregnancy is maintained by downregulation of chemokines at the maternal-fetal interface. Withdrawal of this downregulation results in the term birth and its overriding by the activation of multiple pathways of the immune system in the preterm birth. Complications of the pregnancy associated with impairment of placental function, which necessitated premature delivery of the fetus in the absence of labor, show gene expression patterns associated with immune rejection

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber

Peer-Assessed Outcomes in the Multimodal Treatment Study of Children With Attention Deficit Hyperactivity Disorder

Peer-assessed outcomes were examined at the end of treatment (14 months after study entry) for 285 children (226 boys, 59 girls) with attention deficit hyperactivity disorder (ADHD) who were rated by their classmates (2,232 classmates total) using peer sociometric procedures. All children with ADHD were participants in the Multimodal Treatment Study of Children with ADHD (MTA). Treatment groups were compared using the orthogonal treatment contrasts that accounted for the largest amount of variance in prior MTA outcome analyses: Medication Management + Combined Treatment versus Behavior Therapy + Community Care; Medication Management versus Combined Treatment; Behavior Therapy versus Community Care. There was little evidence of superiority of any of the treatments for the peer-assessed outcomes studied, although the limited evidence that emerged favored treatments involving medication management. Post hoc analyses were used to examine whether any of the four treatment groups yielded normalized peer relationships relative to randomly selected- classmates. Results indicated that children from all groups remained significantly impaired in their peer relationships

Phase II evaluation of mitoxantrone in advanced pancreatic carcinoma: A Southwest Oncology Group study

Patient with advanced adenocarcinoma of the pancreas and no prior chemotherapy were treated on a Phase II trial of mitoxantrone. Doses were adjusted for hepatic dysfunction as defined by bilirubin. Twenty-four patients with a bilirubin ⩽ 1.5 mg% received mitoxantrone 12 mg/m 2 i.v. repeated every three weeks. Myelosuppression in the form of leukopenia was the major toxicity. There were no responses in twenty-four evaluable patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45319/1/10637_2004_Article_BF00216928.pd

The phenotype of spontaneous preterm birth: application of a clinical phenotyping tool

Spontaneous preterm birth (SPTB) is a complex condition that is likely a final common pathway with multiple possible etiologies. We hypothesized that a comprehensive classification system could appropriately group women with similar STPB etiologies, and provide an explanation, at least in part, for the disparities in SPTB associated with race and gestational age at delivery

Exploiting antitumor immunity to overcome relapse and improve remission duration

Cancer survivors often relapse due to evolving drug-resistant clones and repopulating tumor stem cells. Our preclinical study demonstrated that terminal cancer patient’s lymphocytes can be converted from tolerant bystanders in vivo into effective cytotoxic T-lymphocytes in vitro killing patient’s own tumor cells containing drug-resistant clones and tumor stem cells. We designed a clinical trial combining peginterferon α-2b with imatinib for treatment of stage III/IV gastrointestinal stromal tumor (GIST) with the rational that peginterferon α-2b serves as danger signals to promote antitumor immunity while imatinib’s effective tumor killing undermines tumor-induced tolerance and supply tumor-specific antigens in vivo without leukopenia, thus allowing for proper dendritic cell and cytotoxic T-lymphocyte differentiation toward Th1 response. Interim analysis of eight patients demonstrated significant induction of IFN-γ-producing-CD8+, -CD4+, -NK cell, and IFN-γ-producing-tumor-infiltrating-lymphocytes, signifying significant Th1 response and NK cell activation. After a median follow-up of 3.6 years, complete response (CR) + partial response (PR) = 100%, overall survival = 100%, one patient died of unrelated illness while in remission, six of seven evaluable patients are either in continuing PR/CR (5 patients) or have progression-free survival (PFS, 1 patient) exceeding the upper limit of the 95% confidence level of the genotype-specific-PFS of the phase III imatinib-monotherapy (CALGB150105/SWOGS0033), demonstrating highly promising clinical outcomes. The current trial is closed in preparation for a larger future trial. We conclude that combination of targeted therapy and immunotherapy is safe and induced significant Th1 response and NK cell activation and demonstrated highly promising clinical efficacy in GIST, thus warranting development in other tumor types

Is the Hygiene Hypothesis an Example of Hormesis?

The “hygiene hypothesis” has been suggested to explain the rising incidence of allergic disorders in developed countries. The postulated mechanism is that infectious and/or microbial agents stimulate the immune system toward Th1 (allergy fighting) rather than Th2 (allergy promoting) response. This paper reviews the evidence related to early life infectious/microbial exposures and subsequent atopic disorders and evaluates whether these data suggest a hormetic effect. Our review indicates an insufficient and contradictory association for bacterial/viral infections, with protective effects being either absent or specific to certain infections and/or populations. Chronic, heavy parasitic burdens appear to confer protection against atopic disorders, but are associated with considerable pathology. Moreover, light parasitic burden may increase allergic responses (i.e., no “low dose” beneficial effect). In contrast, there is consistent evidence that general microbial exposures, particularly gut commensals, may be protective against allergy development, which is consistent with a hormetic effect (i.e., potentially beneficial effects at low doses and detrimental effects at high levels). Conclusion: General microbial exposures in relation to the “hygiene hypothesis” may represent a hormetic effect, although further research with more rigorous study methods (i.e., prospective designs and measurement of exposure timing, dose, route, etc.) are needed

Is the Hygiene Hypothesis an Example of Hormesis?

The “hygiene hypothesis” has been suggested to explain the rising incidence of allergic disorders in developed countries. The postulated mechanism is that infectious and/or microbial agents stimulate the immune system toward Th1 (allergy fighting) rather than Th2 (allergy promoting) response. This paper reviews the evidence related to early life infectious/microbial exposures and subsequent atopic disorders and evaluates whether these data suggest a hormetic effect. Our review indicates an insufficient and contradictory association for bacterial/viral infections, with protective effects being either absent or specific to certain infections and/or populations. Chronic, heavy parasitic burdens appear to confer protection against atopic disorders, but are associated with considerable pathology. Moreover, light parasitic burden may increase allergic responses (i.e., no “low dose” beneficial effect). In contrast, there is consistent evidence that general microbial exposures, particularly gut commensals, may be protective against allergy development, which is consistent with a hormetic effect (i.e., potentially beneficial effects at low doses and detrimental effects at high levels). Conclusion: General microbial exposures in relation to the “hygiene hypothesis” may represent a hormetic effect, although further research with more rigorous study methods (i.e., prospective designs and measurement of exposure timing, dose, route, etc.) are needed