Safety profile of morphine following surgery in neonates.

OBJECTIVE: To determine the effect of morphine on duration of mechanical ventilation, apnoea and hypotension among full-term neonates who underwent thoracic or abdominal surgery in a level III neonatal intensive care unit. METHOD: Medical records of 82 infants were reviewed retrospectively and data including patient demographics, clinical diagnosis, type of surgery, postoperative opioid administration, duration of mechanical ventilation, hypotension, apnoea and pain scores (premature infant pain profile (PIPP) score) were collected. RESULT: Sixty-two neonates (76%) received morphine following surgery as a continuous intravenous infusion during the postoperative period. Linear regression analysis showed that morphine dosage and duration were significantly associated with the duration of mechanical ventilation. An increase in morphine infusion rate by 10 microg kg(-1) h(-1) was associated with an increase in the duration of mechanical ventilation by 24 h (P<0.0001) and an increase in morphine duration of 1 hour was associated with a longer duration of mechanical ventilation by 38 min (P<0.0001). Logistic regression analysis showed no association between morphine infusion rate or duration and hypotension. Apnoea was not associated with morphine dosage or duration of infusion in neonates receiving morphine following extubation. Score on the PIPP correlated significantly with morphine infusion rate across time (r=0.47, P<0.01). CONCLUSION: Postoperative morphine dose and duration may prolong the duration of mechanical ventilation but there are no significant dose-dependent effects on other parameters including apnoea or hypotension following extubation in term neonates. More research is needed to determine the safety profile of morphine for management of pain in non-ventilated neonates.     

Clinical and pathological features of an Alzheimer's disease patient with the MAPT Delta K280 mutation

We identified a case of Alzheimer's disease with a deletion of the lysine residue at codon 280 (DeltaK280) in exon 10-encoded microtubule-binding repeat domain of the tau gene (MAPT). This mutation was originally identified in a sporadic case of frontotemporal dementia (FTD) with a family history of Parkinson's disease. In the original report, the authors were careful in their assessment of the pathogenicity and suggested one could not be sure whether the mutation was pathogenic or not. The mutation has always presented a conundrum because it is the only known mutation, of assumed pathogenicity, which increases the proportion of 3-repeat tau mRNA in in vitro assays. Here we present the clinical and pathological features of a new case with this mutation and discuss whether the mutation is indeed pathogenic.     

Polymorphisms in exons 1B and 1C of the type I interleukin-1 receptor gene in patients with endometriosis

To study possible correlation between the prevalence of polymorphisms in the type I interleukin-1 receptor gene and pelvic endometriosis. Genotypes of 223 women were analyzed: 109 women with surgically and histologically confirmed endometriosis and 114 healthy women. Distributions of two single-base polymorphisms of the human interleukin-1 receptor type I (IL-1RI) gene were evaluated: PstI, due to a C-->T transition in exon 1B and BsrBI a C-->A transition at position 52 in exon 1C. Polymorphisms were detected by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analysis (RFLP) resolved on 3% agarose gels stained with ethidium bromide. Genotypes for PstI polymorphisms did not differ significantly among control and endometriosis (P = 0.058). However, in relation to BsrBI polymorphism, protective risk was observed for the development of endometriosis [OR 0.39-IC 95% (0.2-0.9)]. BsrBI heterozygote genotype (C/A) showed protective effect against endometriosis development.     

Comparison of redox and D29 phage methods for detection of isoniazid and rifampicin resistance in Mycobacterium tuberculosis

Rapid, accurate and inexpensive methods are essential to detect drug-resistant Mycobacterium tuberculosis and allow timely application of effective treatment and precautions to prevent transmission. The proportion method, the MTT and Alamar Blue redox methods, and the D29 mycobacteriophage assay, were compared for their ability to detect resistance to isoniazid and rifampicin. When tested against a panel of known M. tuberculosis strains, the redox methods and the D29 assay showed good sensitivity and specificity compared to the proportion method, suggesting that they could be useful alternatives for identifying multidrug resistance in M. tuberculosis.     

The dual role of p55 tumour necrosis factor-alpha receptor in Actinobacillus actinomycetemcomitans-induced experimental periodontitis: host protection and tissue destruction

Inflammatory immune reactions in response to periodontopathogens are thought to protect the host against infection, but may trigger periodontal destruction. Thus, we examined the mechanisms by which the proinflammatory cytokine tumour necrosis factor (TNF)-alpha modulates the outcome of Actinobacillus actinomycetemcomitans-induced periodontal disease in mice. Our results showed that TNF-alpha receptor p55-deficient mice [p55TNF-knock-out (KO)] developed a less severe periodontitis in response to A. actinomycetemcomitans infection, characterized by significantly less alveolar bone loss and inflammatory reaction. Real-time polymerase chain reaction (PCR) demonstrated that levels of chemokines (CXCL1, 3 and 10; CCL3 and 5) and their receptors (CXCR2 and 3, CCR5) were lower in p55TNF-KO mice, as were matrix metalloproteinase (MMP)-1, 2 and 9 and receptor activator of nuclear factor kB ligand (RANKL) mRNA levels. However, the absence of the TNF-alpha p55 results in an impairment of protective immunity to A. actinomycetemcomitans infection, characterized by increased bacterial load and higher levels of C-reactive protein during the course of disease. Such impaired host response may be the result of the reduced chemoattraction of lymphocytes, neutrophils and macrophages, and reduced inducible nitric oxide synthase expression (iNOS) and myeloperoxidase (MPO) production in periodontal tissues of p55 TNF-KO mice. Our results demonstrate the mechanisms involved determining periodontal disease severity by TNF-alpha receptor p55, and its role in providing immune protection to A. actinomycetemcomitans periodontal infection.     

Black Hispanics have a worse cardiovascular risk profile than mixed Hispanics in Venezuela

In order to characterize components of the metabolic syndrome (MS) in Venezuelan black Hispanics and compare these metabolic abnormalities with those found in the predominant mixed Hispanic population, 2336 mixed Hispanics (69% women) and 281 black Hispanics (60% women), aged 20-78 years, without prior history of diabetes and/or cardiovascular disease were evaluated in a population-based study in Zulia State, Venezuela. Blood pressure (BP), waist circumference, as well as fasting insulin, fasting blood glucose (FBG), triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) levels were measured. The criteria proposed by the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) to identify those with metabolic abnormalities were used. We found that black Hispanics showed higher frequency of age-adjusted elevated BP than mixed Hispanics in both men (66.9% vs. 52.3%, p < 0.01) and women (39.3% vs. 30.4%, p < 0.05). In men, elevated FBG was also more frequent in black Hispanics (32.7%) than in mixed Hispanics (22.3%), despite the lack of significant differences in fasting insulin, HOMA-insulin resistance and HOMA-beta cell function values. In women low HDL-C and higher abdominal obesity were more common in black Hispanics (71.8% and 54.1%, respectively) than in mixed Hispanics (56.2% and 44.5%, respectively), despite the greater frequency of high TG in mixed Hispanics (22.6%) when compared to black Hispanics (13.3%). Furthermore, in logistic regression analysis black Hispanic race was independently associated with higher risk for hypertension, fasting hyperglycemia, and low HDL-C. These results suggest that black Hispanics have worse cardiovascular risk profile than mixed Hispanics in Zulia State, with higher BP, higher FBG, more abdominal obesity, and lower HDL-C. Identification and intervention of these high-risk subjects are important strategies for diabetes and cardiovascular disease prevention in Venezuela.     

Conventional type 1 dendritic cells induce TH1, TH1-like follicular helper T cells and regulatory T cells after antigen boost via DEC205 receptor

Conventional dendritic cells (cDCs) are specialized in antigen presentation. In the mouse spleen, cDCs are classified in cDC1s and cDC2s, and express DEC205 and DCIR2 endocytic receptors, respectively. Monoclonal antibodies (mAbs) αDEC205 (αDEC) and αDCIR2 have been fused to different antigens to deliver them to cDC1s or cDC2s. We immunized mice with αDEC and αDCIR2 fused to an antigen using Poly(I:C) as adjuvant. The initial immune response was analyzed from days 3 to 6 after the immunization. We also studied the influence of a booster dose. Our results showed that antigen targeting to cDC1s promoted a pro-inflammatory T_H1 cell response. Antigen targeting to cDC2s induced T_FH cells, GCs, and plasma cell differentiation. After boost, antigen targeting to cDC1s improved the T_H1 cell response and induced T_H1-like T_FH cells that led to an increase in specific antibody titers and IgG class switch. Additionally, a population of regulatory T cells was also observed. Antigen targeting to cDC2s did not improve the specific antibody response after boost. Our results add new information on the immune response induced after the administration of a booster dose with αDEC and αDCIR2 fusion mAbs. These results may be useful for vaccine design using recombinant mAbs.     

Monitoring gp43 antigenemia in Paracoccidioidomycosis patients during therapy

Paracoccidioidomycosis (PCM) is a systemic fungal disease that is particularly important among individuals living and working in rural areas of endemicity in Latin America. Detection of anti-Paracoccidioides brasiliensis antibodies is of limited value due to false-negative results. Detection of P. brasiliensis-gp43 circulating antigen is a practical approach for a specific diagnosis of the disease. In a previous study we described an inhibition enzyme-linked immunosorbent assay able to detect the 43-kDa P. brasiliensis antigen in sera of 100% of patients with the acute form of PCM and in 95.31 and 100% of patients with the chronic multifocal and unifocal forms of PCM. To investigate its potential application for the follow-up of PCM patients during treatment, antigen levels were monitored at regular intervals for up 8 to 12 months in serum samples from 23 patients. The results showed that treatment with itraconazole resulted in decreasing levels of circulating gp43 that were correlated with the reduction of anti-gp43 antibodies. It was also observed that by the end of 12 months of treatment gp43 levels were <5 microg/ml in all patients.     

Overexpression of immunomodulatory mediators in oral precancerous lesions

Human leukocyte antigen (HLA) G and E, programmed cell death 1 ligand 1 (PD-L1), IL-10 and TGF-β are proteins involved in failure of the antitumor immune response. We investigated the expression of these immunomodulatory mediators in oral precancerous lesions (oral leukoplakia-OL; n = 80) and whether these molecules were related to the risk of malignant transformation. Samples of normal mucosa (n = 20) and oral squamous cells carcinoma (OSCC, n = 20) were included as controls. Tissue and saliva samples were analyzed by immunohistochemistry and ELISA respectively. Fifteen OL samples showed severe dysplasia (18.7%) and 40 samples (50%) presented combined high Ki-67/p53. Irrespective of the degree of epithelial dysplasia and the proliferation/apoptosis index of OL, the expression of HLA-G, -E, PD-L1, IL-10, TGF-β2 and -β3 was higher to control (P < 0.05) and similar to OSCC (P > 0.05). The number of granzyme B⁺ cells in OL was similar to control (P = 0.28) and lower compared to OSCC (P < 0.01). Salivary concentrations of sHLA-G, IL-10 and TGF-β did not allow for a distinction between OL and healthy individuals. Overexpression of immunosuppressive mediators in the OL reflects the immune evasion potential of this lesion, which is apparently independent of at cytological and proliferation/apoptosis status.     

Obesity promotes prolonged ovalbumin‐induced airway inflammation modulating T helper type 1 (Th1), Th2 and Th17 immune responses in BALB/c mice

Clinical and epidemiological studies indicate that obesity affects the development and phenotype of asthma by inducing inflammatory mechanisms in addition to eosinophilic inflammation. The aim of this study was to assess the effect of obesity on allergic airway inflammation and T helper type 2 (Th2) immune responses using an experimental model of asthma in BALB/c mice. Mice fed a high‐fat diet (HFD) for 10 weeks were sensitized and challenged with ovalbumin (OVA), and analyses were performed at 24 and 48 h after the last OVA challenge. Obesity induced an increase of inducible nitric oxide synthase (iNOS)‐expressing macrophages and neutrophils which peaked at 48 h after the last OVA challenge, and was associated with higher levels of interleukin (IL)‐4, IL‐9, IL‐17A, leptin and interferon (IFN)‐γ in the lungs. Higher goblet cell hyperplasia was associated with elevated mast cell influx into the lungs and trachea in the obese allergic mice. In contrast, early eosinophil influx and lower levels of IL‐25, thymic stromal lymphopoietin (TSLP), CCL11 and OVA‐specific immunoglobulin (IgE) were observed in the obese allergic mice in comparison to non‐obese allergic mice. Moreover, obese mice showed higher numbers of mast cells regardless of OVA challenge. These results indicate that obesity affects allergic airway inflammation through mechanisms involving mast cell influx and the release of TSLP and IL‐25, which favoured a delayed immune response with an exacerbated Th1, Th2 and Th17 profile. In this scenario, an intense mixed inflammatory granulocyte influx, classically activated macrophage accumulation and intense mucus production may contribute to a refractory therapeutic response and exacerbate asthma severity.