Relative Contributions of Lipooligosaccharide Inner and Outer Core Modifications to Nontypeable Haemophilus influenzae Pathogenesis

Nontypeable Haemophilus influenzae (NTHi) is a frequent commensal of the human nasopharynx that causes opportunistic infection in immunocompromised individuals. Existing evidence associates lipooligosaccharide (LOS) with disease, but the specific and relative contributions of NTHi LOS modifications to virulence properties of the bacterium have not been comprehensively addressed. Using NTHi strain 375, an isolate for which the detailed LOS structure has been determined, we compared systematically a set of isogenic mutant strains expressing sequentially truncated LOS. The relative contributions of 2-keto-3-deoxyoctulosonic acid, the triheptose inner core, oligosaccharide extensions on heptoses I and III, phosphorylcholine, digalactose, and sialic acid to NTHi resistance to antimicrobial peptides (AMP), self-aggregation, biofilm formation, cultured human respiratory epithelial infection, and murine pulmonary infection were assessed. We show that opsX, lgtF, lpsA, lic1, and lic2A contribute to bacterial resistance to AMP; lic1 is related to NTHi self-aggregation; lgtF, lic1, and siaB are involved in biofilm growth; opsX and lgtF participate in epithelial infection; and opsX, lgtF, and lpsA contribute to lung infection. Depending on the phenotype, the involvement of these LOS modifications occurs at different extents, independently or having an additive effect in combination. We discuss the relative contribution of LOS epitopes to NTHi virulence and frame a range of pathogenic traits in the context of infection.     

Primary palpebral localization of a trabecular Merkel cell carcinoma (1 case)

We report one case of Merkel cell carcinoma. They commonly arise on the eyelids of elderly patients. Others localisations are on the skin of the pelvis. Clinical aspects, histological study, associating morphological aspect, ultra-structural and immuno-histo-chemical studies are characteristics enough to differentiate this tumor others tumors of the skin like cutaneous malignant lymphoma. The origin of this tumor is still discussed, but sure neuro-endocrinal. Possibility of visceral metastases on a small number of cases (6 to 8%) must be consider when treated. Total surgical ablation should be obtained.     

Ameloblastoma de senos paranasales

Ameloblastomas usually arise from the odontogenic epithelium of maxilla or mandible. Primary sinonasal tract origin is extraordinarily uncommon. Ameloblastomas are locally invasive neoplams and rarelly metastatize. Surgical excision is the treatment of choice. Radiotherapy is indicated as complementary to surgery when the ressection has not been completed and in cases in which surgery is not feasible. Since 1966 to 2001, 36 cases of ameloblastoma of the paranasal sinus's have been published. A new case is reported and a comment on the treatment options is performed.     

Withdrawing and withholding life support in the intensive care unit: a Spanish prospective multi-centre observational study

OBJECTIVE: To determine how frequently life support is withheld or withdrawn from adult critically ill patients, and how physicians and patients families agree on the decision regarding the limitation of life support. DESIGN: Prospective multi-centre cohort study. SETTING: Six adult medical-surgical Spanish intensive care units (ICUs). PATIENTS AND PARTICIPANTS: Three thousand four hundred ninety-eight consecutive patients admitted to six ICUs were enrolled. MEASUREMENTS AND RESULTS: Data collected included age, sex, SAPS II score on admission and within 24 h of the decision to limit treatment, length of ICU stay, outcome at ICU discharge, cause and mode of death, time to death after the decision to withhold or withdraw life support, consultation and agreement with patient's family regarding withholding or withdrawal, and the modalities of therapies withdrawn or withheld. Two hundred twenty-six (6.6%) of 3,498 patients had therapy withheld or withdrawn and 221 of them died in the ICU. Age, SAPS II and length of ICU stay were significantly higher in patients dying patients who had therapy withheld or withdrawn than in patients dying despite active treatment. The proposal to withhold or withdraw life support was initiated by physicians in 210 (92.9%) of 226 patients and by the family in the remaining cases. The patient's family was not involved in the decision to withhold or withdraw life support therapy in 64 (28.3%) of 226 cases. Only 21 (9%) patients had expressed their wish to decline life-prolonging therapy prior to ICU admission. CONCLUSIONS: The withholding and withdrawing of treatment was frequent in critically ill patients and was initiated primarily by physicians.     

Molecular mechanisms of the adaptive, innate and regulatory immune responses in the intestinal mucosa of celiac disease patients

Celiac disease is a complex genetic disorder that affects the small intestine of genetically predisposed individuals when they ingest gluten, a dietary protein. Although several genome screens have been successful in identifying susceptibility loci in celiac disease, the only genetic contributors identified so far are the human leukocyte antigen (HLA)-DQ2/DQ8 molecules. One of the most important aspects in the pathogenesis of celiac disease is the activation of a T-helper 1 immune response, when the antigen-presenting cells that express HLA-DQ2/DQ8 molecules present the toxic gluten peptides to reactive CD4(+) T-cells. Recently, new insights into the activation of an innate immune response have also been described. It is generally accepted that the immune response triggers destruction of the mucosa in the small intestine of celiac disease patients. Hence, the activation of a detrimental immune response in the intestine of celiac disease patients appears to be key in the initiation and progression of the disease. This review summarizes the immunologic pathways that have been studied in celiac disease thus far, and will point to new potential candidate genes and pathways involved in the etiopathogenesis of celiac disease, which should lead to novel alternatives for diagnosis and treatment.     

A European multicentre, placebo-controlled supplementation study with alpha-tocopherol, carotene-rich palm oil, lutein or lycopene: analysis of serum responses

Increased levels of oxidative stress have been implicated in tissue damage and the development of chronic diseases, and dietary antioxidants may reduce the risk of oxidative tissue damage. As part of a European multicentre project, several studies were undertaken with the aim of testing whether the consumption of foods rich in carotenoids reduces oxidative damage to human tissue components. We describe here the serum response of carotenoids and tocopherols upon supplementation with carotenoids from natural extracts (alpha-carotene+beta-carotene, lutein or lycopene; 15 mg/day) and/or with alpha-tocopherol (100 mg/day) in a multicentre, placebo-controlled intervention study in 400 healthy male and female volunteers, aged 25-45 years, from five European regions (France, Northern Ireland, Republic of Ireland, The Netherlands and Spain). Supplementation with alpha-tocopherol increased serum alpha-tocopherol levels, while producing a marked decrease in serum gamma-tocopherol. Supplementation with alpha- + beta-carotene (carotene-rich palm oil) resulted in 14-fold and 5-fold increases respectively in serum levels of these carotenoids. Supplementation with lutein (from marigold extracts) elevated serum lutein (approx. 5-fold), zeaxanthin (approx. doubled) and ketocarotenoids (although these were not present in the supplement), whereas lycopene supplementation (from tomato paste) resulted in a 2-fold increase in serum lycopene. The isomer distributions of beta-carotene and lycopene in serum remained constant regardless of the isomer composition in the capsules. In Spanish volunteers, additional data showed that the serum response to carotenoid supplementation reached a plateau after 4 weeks, and no significant side effects (except carotenodermia) or changes in biochemical or haematological indices were observed throughout the study. This part of the study describes dose-time responses, isomer distribution, subject variability and side effects during supplementation with the major dietary carotenoids in healthy subjects.     

Nigral and striatal regulation of angiotensin receptor expression by dopamine and angiotensin in rodents: implications for progression of Parkinson's disease

The basal ganglia have a local renin–angiotensin system and it has been shown that the loss of dopaminergic neurons induced by neurotoxins is amplified by local angiotensin II (AII) via angiotensin type 1 receptors (AT1) and nicotinamide adenine dinucleotide phosphate (NADPH) complex activation. Recent studies have revealed a high degree of counter‐regulatory interactions between dopamine and AII receptors in non‐neural cells such as renal proximal tubule cells. However, it is not known if this occurs in the basal ganglia. In the striatum and nigra, depletion of dopamine with reserpine induced a significant increase in the expression of AT1, angiotensin type 2 receptors (AT2) and the NADPH subunit p47^phox, which decreased as dopamine function was restored. Similarly, 6‐hydroxydopamine‐induced chronic dopaminergic denervation induced a significant increase in expression of AT1, AT2 and p47^phox, which decreased with L‐dopa administration. A significant reduction in expression of AT1 mRNA was also observed after administration of dopamine to cultures of microglial cells. Transgenic rats with very low levels of brain AII showed increased AT1, decreased p47 ^phox and no changes in AT2 expression, whereas mice deficient in AT1 exhibited a decrease in the expression of p47 ^phox and AT2. The administration of relatively high doses of AII (100 nm ) decreased the expression of AT1, and the increased expression of AT2 and p47^phox in primary mesencephalic cultures. The results reveal an important interaction between the dopaminergic and local renin–angiotensin system in the basal ganglia, which may be a major factor in the progression of Parkinson’s disease.     

Erythrocyte deformability in morbid obesity before bariatric surgery. Influence of abdominal obesity

Although there are several studies dealing with erythrocyte deformability (ED) in obese patients, research on this topic in morbidly obese subjects is scarce. In these studies ED seems to be decreased, although the cause remains unknown. A case-control study in 76 morbid obese subjects (23 women and 53 men, aged 44 ± 13 years) and in 79 normal-weight controls (30 women and 49 men, aged 43 ± 13 years) was undertaken. ED has been determined by ektacytometric techniques in a Rheodyn SSD, by means of the elongation index (EI) at 12, 30 and 60 Pascals, along with anthropometric, lipidic, metabolic and inflammatory parameters. EI was statistically lower in morbidly obese subjects than in controls at all the shear stresses tested (EI12: 47.3 ± 2.14 vs. 47.9 ± 2.07; p = 0.047, EI30: 52.16 ± 2.1 vs. 53.12 ± 1.4; p = 0.007, EI60: 53.9 ± 2.4 vs. 55.2 ± 2.50; p = 0.001) as were anthropometric lipidic and inflammatory parameters (p < 0.001). In the bivariate correlation EI60 correlated negatively with most anthropometric, lipidic and inflammatory parameters. However, in the multivariate analysis, the case-control status was not significantly associated with EI60 and only triglycerides, glucose, hs-CRP and waist circumference were independently associated with EI60, constituting independent predictors of altered ED although, waist circumference, showed the highest statistical significance (p = 0.007). ED is decreased in morbidly obese subjects associated with insulin resistance and inflammation parameters although abdominal obesity seems to be of paramount importance in altering this rheological parameter.     

Iontophoretic drug delivery across the nail

INTRODUCTION: Topical drug delivery to treat nail diseases such as onychomycosis and psoriasis is receiving increasing attention. Topical nail delivery is challenged by the complicated structure of the nail and the low permeability of most drugs across the nail plate. Considerable effort has been directed at developing methods to promote drug permeation across the nail plate. Iontophoresis efficiently enhances molecular transport across the skin and the eye and is now being tested for its potential in ungual delivery. AREAS COVERED: This review covers the basic mechanisms of transport (electro-osmosis and -migration) and their relative contribution to nail iontophoresis as well as the key factors governing nail permselectivity and ionic transport numbers. Methodological issues concerning research in this area are summarized. The data available in vivo on nail iontophoresis of terbinafine specifically are reviewed in separate sections. EXPERT OPINION: Our understanding of nail iontophoresis has improved considerably since 2007; most decisively, the feasibility of nail iontophoresis in vivo has been clearly demonstrated. Future work is required to establish the adequate implementation of the technique so that its clinical efficacy to treat onychomycosis and nail psoriasis can be unequivocally determined.