DNA methylation-associated inactivation of TGFbeta-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers

The transforming growth factor beta (TGFbeta)-signalling pathway is deregulated in many cancers. We examined the role of gene silencing via aberrant methylation of DRM/Gremlin and HPP1, which inhibit TGFbeta signalling, and RUNX3, which facilitates TGFbeta-signalling, of all genes that are thought to be tumour suppressors, are aberrantly expressed, and are thus thought to have important role in human cancers. We examined DRM/Gremlin mRNA expression in 44 cell lines and the promoter methylation status of DRM/Gremlin, HPP1, and RUNX3 in 44 cell lines and 511 primary tumours. The loss of DRM/Gremlin mRNA expression in human cancer cell lines is associated with DNA methylation, and treatment with the methylation inhibitor-reactivated mRNA expression (n=13). Methylation percentages of the three genes ranged from 0-83% in adult tumours and 0-50% in paediatric tumours. Methylation of DRM/Gremlin was more frequent in lung tumours in smokers, and methylation of all three genes was inversely correlated with prognosis in patients with bladder or prostate cancer. Our results provide strong evidence that these TGFbeta-related genes are frequently deregulated through aberrant methylation in many human malignancies.     

Disseminated intravascular coagulation (DIC): an approach

The etiology of disseminated intravascular coagulation (DIC) can be classified into three processes: (1) endothelial cell injury which activates Hageman factor and the intrinsic clotting system, (2) tissue injury which activates the extrinsic clotting system, or (3) red cell or platelet injury with the release of coagulant phospholipids. These initiating mechanisms result in a final common product, thrombin, which cleaves fibrinogen, activates factor XIII, aggregates platelets, releases platelet constituents and triggers secondary fibrinolysis. Plasmin produces fibrinogen degradation products which participate in the hemorrhagic diathesis. Detection of these fragments provides a sensitive method of diagnosing DIC. DIC usually presents with bleeding at multiple sites, and occasionally with thrombotic episodes or acrocyanosis. The diagnostic manifestations of DIC include a hemorrhagic-thrombotic diathesis, a specific coagulation test profile, the presence of fibrin thrombi and the response to heparin therapy. Analysis of our large series of patients finds the presence of three abnormal screening tests to be diagnostic (prothrombin time, fibrinogen and platelets). If only two of the three are abnormal, a test for fibrinolysis (thrombin time, euglobulin clot lysis time or fibrinogen degradation products) should be abnormal in order to establish the diagnosis. Treatment with heparin usually results in decreased bleeding. The prothrombin time, fibrinogen level and euglobulin lysis become normal within one to three days in those who stop bleeding. The titer of fibrinogen degradation products may respond rapidly but if greatly elevated remains abnormal for more than a week. Platelet levels do not respond uniformly to heparin therapy; when they do respond, it frequently requires several weeks. Even severe fibrinolysis responds to heparin therapy and is probably always secondary to DIC. Epsilon aminocaproic acid (EACA) therapy alone aggravates DIC and often results in thrombosis.     

Effect of probiotics and breastfeeding on the bifidobacterium and lactobacillus/enterococcus microbiota and humoral immune responses

OBJECTIVE: To assess impact of probiotics and breastfeeding on gut microecology. STUDY DESIGN: Mothers were randomized to receive placebo or Lactobacillus rhamnosus GG before delivery, with treatment of the infants after delivery. We assessed gut microbiota, humoral immune responses, and measured soluble cluster of differentiation 14 (sCD14) in colostrum in 96 infants. RESULTS: Fecal Bifidobacterium and Lactobacillus/Enterococcus counts were higher in breastfed than formula-fed infants at 6 months; P <.0001 and P=.01, respectively. At 3 months, total number of immunoglobulin (Ig)G-secreting cells in breastfed infants supplemented with probiotics exceeded those in breastfed infants receiving placebo; P=.05, and their number correlated with concentration of sCD14 in colostrum. Total numbers of IgM-, IgA-, and IgG-secreting cells at 12 months were higher in infants breastfed exclusively for at least for 3 months and supplemented with probiotics as compared with breastfed infants receiving placebo; P=.005, P=.03 and P=.04, respectively. Again, sCD14 in colostrum correlated with numbers of IgM and IgA cells; P=.05 in both. CONCLUSIONS: We found an interaction between probiotics and breastfeeding on number of Ig-secreting cells, suggesting that probiotics during breastfeeding may positively influence gut immunity.     

Bilateral hemodynamic responses to auditory stimulation in newborn infants

We studied hemodynamic auditory evoked responses of 20 healthy full-term neonates with near-infrared spectroscopy. The instrument used allows the measurements to be performed simultaneously above both auditory cortices. The stimulation consisted of 5-s trains of sound (700-ms interstimulus interval) with a 25-s silent interval. In response to the stimulation, a significant increase in concentration of oxygenated hemoglobin was detected in 14 out of 21 measurements. The mean latency of the largest response was 9.63+/-2.20 s (mean+/-SD) and the mean amplitude was 1.02+/-0.53 microM. The response amplitude was significantly larger in active (1.28+/-0.59 microM) than in quiet sleep (0.76+/-0.32 microM). The latency of the oxygenated hemoglobin concentration response was significantly shorter (r=-0.70 and p=0.0023) for infants with higher gestational age.     

Breast milk fatty acid composition is associated with development of atopic dermatitis in the infant

OBJECTIVE: Breast milk fatty acids may have immunomodulatory properties related to the development of atopic disease. The aim of this study was to assess the impact of the breast milk fatty acid composition on the development of atopic dermatitis (AD) in high-risk infants. METHODS: Mothers with atopic disease were recruited at the end of gestation. Maternal food records and breast milk samples were collected at the infants' age of one month. Infants were clinically examined and AD diagnosed at one, three, six, and 12 months. RESULTS: Altogether 13 of 34 (38%) infants were diagnosed with AD during the first year of life. Infants developing AD had consumed breast milk with a higher ratio of saturated to polyunsaturated fatty acids and less n-3 fatty acids compared to infants not developing AD. Specifically, breast milk consumed by infants with AD contained more stearic acid, 8.9% of total fatty acids (95% confidence interval 7.9-10.0) in comparison to those without AD, 7.1% (95% CI 6.6-7.7). CONCLUSION: Breast milk rich in saturated and low in n-3 fatty acids may be a risk factor for atopic dermatitis in the infant.     

Somatic factors at 8 years of age in children with recurrent use of antibiotics in early infancy

Aim: To examine the influence of recurrent therapy with antibiotics (RTA) in infancy on children's somatic factors at 8 y of age. Methods: Subject selection was based on stratified randomized cluster sampling. Altogether 1287 infants were potential participants in the follow-up study. Children with ≥6 courses of antibiotics (100 children) during their first 18 mo of life and children with no (62%) or ≤2 courses (38%) of antibiotics participated in a clinical examination in a case-control setting (100 matched controls) at the age of 8 y. Results: The children with RTA continued to have more infections and had had more courses of antibiotics compared to controls during the follow-up. There was no clinically significant difference in the somatic and dental status at the age of 8 between the two groups. The parents of the children with RTA reported significantly more often recurrent infections than the parents of the controls.

Conclusions: The children with recurrent therapy with antibiotics in early childhood also continue to be prescribed more antibiotics in later childhood when compared to those who received no or few antibiotics in infancy. However, recurrent infections and medications do not seem to have a marked effect on the somatic and dental status of these children at 8 y of age.     

The discrimination of and orienting to speech and non-speech sounds in children with autism

The present study aimed to find out how different stages of cortical auditory processing (sound encoding, discrimination, and orienting) are affected in children with autism. To this end, auditory event-related potentials (ERP) were studied in 15 children with autism and their controls. Their responses were recorded for pitch, duration, and vowel changes in speech stimuli, and for corresponding changes in the non-speech counterparts of the stimuli, while the children watched silent videos and ignored the stimuli. The responses to sound repetition were diminished in amplitude in the children with autism, reflecting impaired sound encoding. The mismatch negativity (MMN), an ERP indexing sound discrimination, was enhanced in the children with autism as far as pitch changes were concerned. This is consistent with earlier studies reporting auditory hypersensitivity and good pitch-processing abilities, as well as with theories proposing enhanced perception of local stimulus features in individuals with autism. The discrimination of duration changes was impaired in these children, however. Finally, involuntary orienting to sound changes, as reflected by the P3a ERP, was more impaired for speech than non-speech sounds in the children with autism, suggesting deficits particularly in social orienting. This has been proposed to be one of the earliest symptoms to emerge, with pervasive effects on later development.     

Decreased in vitro cellular response to tetanus toxoid and tuberculin in patients using topical corticosteroids

Topical corticosteroids are the mainstay of treatment in inflammatory skin diseases. Corticosteroids penetrate human skin, especially when the penetration barrier is damaged. Whether long-term application of topical corticosteroids can lead to alteration of immune responses is not clear. We sought to examine the impact of topical corticosteroids on immune responses in patients using long-term topical corticosteroids. Peripheral blood mononuclear cell proliferation in response to tetanus toxoid and tuberculin stimulation was studied, and tetanus toxoid-specific antibodies were examined with ELISA. The results showed that, compared with the control group, the stimulation indices of patients' peripheral blood mononuclear cell to tetanus toxoid and tuberculin stimulations were lowered, which was especially significant in the tetanus toxoid group. No significant decrease was found in serum levels of tetanus toxoid-specific antibody. The results suggest that topical corticosteroids can suppress cell-mediated immune response in patients using long-term topical corticosteroids.