Nasopharyngeal/nasal type T/NK lymphomas: analysis of 14 cases and review of the literature

AIMS AND BACKGROUND: Lymphoid malignancies expressing CD56 are rare and most occur in the nasal or nasopharyngeal region. They derive from natural killer cells or from a small subset of T cells that have granular cytoplasm containing molecules that mediate cytotoxic activity: TIA-1, granzyme B and perforin. Both types are closely associated with Epstein-Barr virus. METHODS: We report the pathologic, immunophenotypic and molecular findings in 14 cases of nasopharyngeal/nasal type T/NK lymphomas. RESULTS: Clinically, all patients had localized disease and also had symptoms limited to the nose. The neoplastic cells were frequently pleomorphic, and angiocentric growth was common. Combined immunophenotypic and gene rearrangement analyses demonstrated that most of the cases were true NK cell tumors and were either CD56+ and CD3- or CD56+ and CD3+. Immunohistochemical study showed TIA-1 and granzyme B expression in all cases. By in situ hybridization, most of the cases were associated to Epstein-Barr virus, harboring type 1 virus, and polymerase chain reaction amplification across the 30 bp deletion showed high frequency of latent membrane protein-1-deleted variants. CONCLUSIONS: The nasal type T/NK cell lymphoma shows distinctive clinicopathologic, immunophenotypic and molecular features. These results confirm the important role of Epstein-Barr virus as a local factor in their pathogenesis.     

Familial isolated unilateral large vestibular aqueduct syndrome

Large vestibular aqueduct syndrome (LVAS) is one of the most frequent inner ear malformations. It is associated with varying degrees of hearing loss, that may be progressive, sudden or fluctuant; nevertheless normal hearing in cases with LVAS has been described. Although unilateral LVAS has been described, all patients show clinical and radiological findings in both ears, in contrast to the family presented here, where 2 siblings are affected by unilateral sensorineural hearing loss associated with ipsilateral LVAS, with an autosomal recessive pattern. In order to search for the origin of this inner ear malformation, mutations in genes GJB2 (connexin-26 gene), PDS (Pendred's syndrome gene) and mitochondrial 12sRNA were studied, without positive results. In this paper we hypothesize the probable embryological origin for this malformation.     

Chronic benzylamine administration in the drinking water improves glucose tolerance,reduces body weight gain and circulating cholesterol in high-fat diet-fed mice

Benzylamine is found in Moringa oleifera, a plant used to treat diabetes in traditional medicine. In mammals, benzylamine is metabolized by semicarbazide-sensitive amine oxidase (SSAO) to benzaldehyde and hydrogen peroxide. This latter product has insulin-mimicking action, and is involved in the effects of benzylamine on human adipocytes: stimulation of glucose transport and inhibition of lipolysis. This study examined whether chronic, oral administration of benzylamine could improve glucose tolerance and the circulating lipid profile without increasing oxidative stress in overweight and pre-diabetic mice. The benzylamine diffusion across the intestine was verified using everted gut sacs. Then, glucose handling and metabolic markers were measured in mice rendered insulin-resistant when fed a high-fat diet (HFD) and receiving or not benzylamine in their drinking water (3600 μmol/(kg day)) for 17 weeks. HFD-benzylamine mice showed lower body weight gain, fasting blood glucose, total plasma cholesterol and hyperglycaemic response to glucose load when compared to HFD control. In adipocytes, insulin-induced activation of glucose transport and inhibition of lipolysis remained unchanged. In aorta, benzylamine treatment partially restored the nitrite levels that were reduced by HFD. In liver, lipid peroxidation markers were reduced. Resistin and uric acid, surrogate plasma markers of metabolic syndrome, were decreased. In spite of the putative deleterious nature of the hydrogen peroxide generated during amine oxidation, and in agreement with its in vitro insulin-like actions found on adipocytes, the SSAO-substrate benzylamine could be considered as a potential oral agent to treat metabolic syndrome.     

Bactericidal activity of amoxicillin against non-susceptible Streptococcus pneumoniae in an in vitro pharmacodynamic model simulating the concentrations obtained with the 2000/125 mg sustained-release co-amoxiclav formulation

OBJECTIVES: To investigate the bactericidal activity against Streptococcus pneumoniae of simulated amoxicillin serum concentrations obtained in humans after 2000/125 mg sustained-release (SR) and 875/125 mg co-amoxiclav administered twice and three times a day, respectively. METHODS: An in vitro computerized pharmacodynamic simulation was carried out and colony counts were determined over 24 h. Ten strains non-susceptible to amoxicillin (four of them exhibiting an MIC of 4 mg/L, five strains with an MIC of 8 mg/L and one strain with an MIC of 16 mg/L) were used. RESULTS: With amoxicillin 2000 mg, an initial inoculum reduction >99.99% was obtained for strains with an MIC of 4 mg/L, > or =99% for strains with an MIC of 8 mg/L and 70.6% for the strain with an MIC of 16 mg/L at 24 h sampling time. At this sampling time, no reduction of initial inocula was obtained with amoxicillin 875 mg/8 h for two of the four strains with an MIC of 4 mg/L, three of the five strains with an MIC of 8 mg/L or for the strain with an MIC of 16 mg/L. CONCLUSIONS: The new co-amoxiclav 2000/125 mg SR formulation appears to offer advantages versus previous formulations with respect to bactericidal activity against current amoxicillin non-susceptible strains.     

Haploinsufficiency of Activation-Induced Deaminase for Antibody Diversification and Chromosome Translocations both In Vitro and In Vivo

The humoral immune response critically relies on the secondary diversification of antibodies. This diversification takes places through somatic remodelling of the antibody genes by two molecular mechanisms, Class Switch Recombination (CSR) and Somatic Hypermutation (SHM). The enzyme Activation Induced Cytidine Deaminase (AID) initiates both SHM and CSR by deaminating cytosine residues on the DNA of immunoglobulin genes. While crucial for immunity, AID-catalysed deamination is also the triggering event for the generation of lymphomagenic chromosome translocations. To address whether restricting the levels of AID expression in vivo contributes to the regulation of its function, we analysed mice harbouring a single copy of the AID gene (AID^+/−). AID^+/− mice express roughly 50% of normal AID levels, and display a mild hyperplasia, reminiscent of AID deficient mice and humans. Moreover, we found that AID^+/− cells have an impaired competence for CSR and SHM, which indicates that AID gene dose is limiting for its physiologic function. We next evaluated the impact of AID reduction in AID^+/− mice on the generation of chromosome translocations. Our results show that the frequency of AID-promoted c-myc/IgH translocations is reduced in AID^+/− mice, both in vivo and in vitro. Therefore, AID is haploinsufficient for antibody diversification and chromosome translocations. These findings suggest that limiting the physiologic levels of AID expression can be a regulatory mechanism that ensures an optimal balance between immune proficiency and genome integrity.     

No major differences in the functional profile of HIV Gag and Nef-specific CD8+ responses between long-term nonprogressors and typical progressors

The mechanism explaining the failure of HIV-specific CD8(+) T cell responses to successfully control HIV replication remains elusive. A total of 83 drug-naive HIV-infected individuals, 27 of whom were long-term nonprogressors (LTNP), was examined. The ability of CD8(+) T lymphocytes to produce three different cytokines (MIP-1beta, TNF-alpha, IL-2) in response to HIV Gag and Nef peptides and to polyclonal stimuli and the ability of HIV-specific CD8(+) T cells to expand in vitro were evaluated by multiparameter flow cytometry. In response to polyclonal stimulation, LTNP presented significantly higher levels of several CD8(+) T cell subsets than progressors. While most patients presented detectable Gag and Nef-specific CD8(+) responses, no significant differences in any of the CD8(+) functional T cell subsets were recognized when comparing LTNP and progressors. HIV responses were dominated by cells producing only MIP-1beta or TNF-alpha, being similar in LTNP and progressors. However, expansion of HIV-specific CD8(+) T cells was more frequent in LTNP than progressors, especially for cells producing MIP-1beta. LTNP show higher levels of CD8(+) responses against polyclonal stimuli than progressors. However, HIV-specific CD8(+) responses do not differ between them except for a more preserved ability of cells from LTNP to expand in vitro.     

Prospective evaluation of a clinical guideline recommending early patients discharge in bleeding peptic ulcer

Background and Aim: To validate an early discharge policy in patients admitted with upper gastrointestinal bleeding (UGIB) due to ulcers. Methods: Patients with gastroduodenal ulcer or erosive gastritis/duodenitis were included in a previous study aiming to develop a practice guideline for early discharge of patients with UGIB. Variables associated with unfavorable evolution were analyzed in order to identify patients with low‐risk of re‐bleeding. After that, a one‐year prospective analysis of all UGIB episodes was carried out. Results: A total of 341 patients were identified in the retrospective study. Variables associated with unfavorable evolution were: systolic blood pressure ≤ 100 mmHg, heart rate ≥ 100 bpm, and a Forrest endoscopic classification of severe. 10% of patients were immediately discharged; however, if predictive variables obtained in the multivariate analysis had been used, hospitalization could have been prevented in 34% of patients. A total of 77 patients were included in the prospective analysis. Although only 19.5% of patients were immediately discharged without complications, 29 patients (37.7%) were theoretically suitable for early discharge. Conclusions: Patients with UGIB who have clean‐based ulcers and are stable on admission can be safely discharged immediately after endoscopy. Implementation of the clinical practice guideline safely reduced hospital admission for those patients.     

Surfactant protein A (SP-A)-tacrolimus complexes have a greater anti-inflammatory effect than either SP-A or tacrolimus alone on human macrophage-like U937 cells

Protamine has attracted much attention as DNA condenser and nuclear transfer enhancer although the excess of hydrophilicity and the strong DNA pack restrain its potentialities. In order to overcome this limitation, we added Protamine in the composition of solid lipid nanoparticles (SLN-Protamine) and we compared this carrier with the same kind of SLN containing Esterquat 1 instead of Protamine (SLN-EQ1). Carriers cytotoxicity was assessed on COS-I cells evaluating the cell cycle by propidium iodide test, while the transfection efficiency was studied using pEGFP as plasmid model. The cell penetrating activity of Protamine inside the lipid vectors was evaluated studying cell internalization by confocal microscopy using Red Nile-labeled carriers. SLN-Protamine:pDNA showed a mean diameter five-times smaller than the size of SLN-EQ1:pDNA and a remarkably lesser cytotoxicity. Transfection by SLN-Protamine:pDNA was seven-times more effective compared with the Protamine:pDNA polyplexes while no transfection capacity was observed for SLN-EQ1:pDNA complexes due to their inability to be internalized owing to their larger dimension. Red Nile-SLN-Protamine were localized in endocytic-like vesicles into the nuclear membrane suggesting the inclusion of Protamine in nano-lipophilic systems may enhance the reduction in the complex dimensions, the nuclear pDNA translocation and the pDNA release in the cells.