Immunization with the conjugate vaccine Vi-CRM(197) against Salmonella Typhi induces Vi-specific mucosal and systemic immune responses in mice

Typhoid fever is a public health problem, especially among young children in developing countries. To address this need, a glycoconjugate vaccine Vi-CRM(197), composed of the polysaccharide antigen Vi covalently conjugated to the non-toxic mutant of diphtheria toxin CRM(197), is under development. Here, we assessed the antibody and cellular responses, both local and systemic, following subcutaneous injection of Vi-CRM(197). The glycoconjugate elicited Vi-specific serum IgG titers significantly higher than unconjugated Vi, with prevalence of IgG1 that persisted for at least 60 days after immunization. Vi-specific IgG, but not IgA, were present in intestinal washes. Lymphocytes proliferation after restimulation with Vi-CRM(197) was observed in spleen and mesenteric lymph nodes. These data confirm the immunogenicity of Vi-CRM(197) and demonstrate that the vaccine-specific antibody and cellular immune responses are present also in the intestinal tract, thus strengthening the suitability of Vi-CRM(197) as a promising candidate vaccine against Salmonella Typhi.     

Lung anabolic activity in patients with chronic heart failure: Potential implications for clinical practice

ObjectiveThe proteins in the lungs are in constant flux, undergoing degradation and resynthesis. We investigated pulmonary protein and amino acid metabolism, the biochemical basis of the remodeling process, in individuals with chronic heart failure receiving or not receiving β-blocker therapy with bisoprolol (BIS).MethodsClinically stable rehabilitative patients with chronic heart failure, without metabolic diseases or liver/renal failure, and with a stable weight over the preceding 3 mo underwent right heart catheterization, and radial artery cannulation. Mixed central venous and arterial blood samples were drawn simultaneously to calculate the venous-arterial difference of amino acids (pulmonary uptake and release).ResultsTwenty-two patients on BIS therapy and eight not receiving BIS were analyzed. The two groups showed a net pulmonary protein synthesis (i.e., a positive value of phenylalanine [venous-arterial difference] × cardiac index product) and amino acid extraction, the rates of which were significantly lower in patients on BIS therapy. The two groups had pulmonary hypertension (mean pulmonary artery pressure >19 mmHg). Pulmonary vascular resistance was 57% higher in patients not receiving BIS than in those on BIS therapy (6.65 ± 2.90 versus 4.23 ± 1.49 mmHg/L · min^?1 · m^?2, P < 0.05). Pulmonary vascular resistance correlated positively with the pulmonary extraction of total essential amino acids (r = +0.4576, P = 0.01) and leucine (r = +0.5083, P = 0.004), the most important amino acid for protein synthesis.ConclusionPatients with chronic heart failure have increased rates of amino acid extraction and pulmonary protein synthesis, suggesting, at least in part, an increased rate of lung remodeling. Therapy with BIS attenuates lung metabolic abnormalities.     

A Chaperone Enhances Blood α-Glucosidase Activity in Pompe Disease Patients Treated With Enzyme Replacement Therapy

Enzyme replacement therapy is currently the only approved treatment for Pompe disease, due to acid α-glucosidase deficiency. Clinical efficacy of this approach is variable, and more effective therapies are needed. We showed in preclinical studies that chaperones stabilize the recombinant enzyme used for enzyme replacement therapy. Here, we evaluated the effects of a combination of enzyme therapy and a chaperone on α-glucosidase activity in Pompe disease patients. α-Glucosidase activity was analyzed by tandem-mass spectrometry in dried blood spots from patients treated with enzyme replacement therapy, either alone or in combination with the chaperone N-butyldeoxynojirimycin given at the time of the enzyme infusion. Thirteen patients with different presentations (3 infantile-onset, 10 late-onset) were enrolled. In 11 patients, the combination treatment resulted in α-glucosidase activities greater than 1.85-fold the activities with enzyme replacement therapy alone. In the whole patient population, α-glucosidase activity was significantly increased at 12 hours (2.19-fold, P = 0.002), 24 hours (6.07-fold, P = 0.001), and 36 hours (3.95-fold, P = 0.003). The areas under the curve were also significantly increased (6.78-fold, P = 0.002). These results suggest improved stability of recombinant α-glucosidase in blood in the presence of the chaperone.     

Interleukin-12 production by leukemia-derived dendritic cells counteracts the inhibitory effect of leukemic microenvironment on T cells

OBJECTIVE: Acute myeloid leukemia (AML) cells are poorly immunogenic and inhibit T-cell function. AML-derived dendritic cells (AML-DCs) have better antigen-presentation capacity than undifferentiated leukemic blasts, but may not be fully competent to stimulate T cells previously inhibited by leukemic cells. MATERIALS AND METHODS: AML-DCs were generated from AML cells and used to stimulate proliferation and cytokine production by T cells previously inhibited by AML cells. AML-DCs were also transfected with interleukin (IL)-12 gene by the nonviral method, nucleofection. RESULTS: Mature AML-DCs stimulated naive and, to a lesser extent, leukemic cell (LC)-cultured T cells more efficiently than their immature counterparts and their activity was mediated by IL-12. AML-DCs generated from CD14(-) AML samples (which represent 80% of total AML patients) were defective in IL-12 production and T-cell activation. Addition of exogenous IL-12 to LC-cultured T cells stimulated by CD14(-)-derived AML-DCs restored optimal interferon-gamma (IFN-gamma) production and Th1 skewing. IL-12 gene-nucleofected AML-DCs derived from CD14(-) cells produced significant amounts of IL-12, maintained leukemia-specific karyotype, DC-like phenotype, and function. When stimulated by IL-12-gene transduced CD14(-)-derived AML-DCs, LC-cultured T cells produced higher concentrations of IFN-gamma, thus maintaining a Th1 cytokine profile. CONCLUSION: IL-12 produced by AML-DCs plays a critical role in counteracting the inhibitory activity of LCs on T-cell function. IL-12 gene can be successfully expressed into AML-DCs defective in endogenous IL-12 production by using a novel nonviral method that does not modify their phenotypical, cytogenetic, and functional features. Genetically modified AML-DCs restore a near normal T-cell function.     

Alcohol consumption in elderly people across European countries: Results from the food in later life project

The aim of this paper is to identify social and cultural aspects of alcohol consumption in a sample of older people living in their own homes, in eight different European countries. We explore several aspects of alcohol consumption, establishing comparisons between genders, age groups and living circumstances. The phenomenon of alcohol consumption within these countries and cultures is compared in order to gain a better understanding of similarities and differences. Maria Daniel Vaz de Almeida PhD belongs to the Faculty of Nutrition and Food Sciences (FCNAUP), where she is the Head of the Faculty and Professor of Community Nutrition. She has been involved in several European research projects in nutrition and public health. Kate Davidson PhD is a co-director of the Centre for Research on Ageing and Gender (CRAG) at the Sociology Department at the University of Surrey. CRAG brings together social scientific expertise to conduct policy relevant research on gender and ageing. The principal aim is to advance understanding of how gender influences the experience of ageing, and how ageing influences gender roles and relationships across the life course.     

Improved thymopoietic potential in aviremic HIV infected individuals treated with HAART by intermittent IL-2 administration

OBJECTIVE: In HIV-positive individuals administration of intermittent interleukin (IL)-2 in addition to highly active antiretroviral therapy (HAART) induces expansion of the peripheral T cell pool with dilution of signal joint T cell receptor excision circles (sjTREC) that cannot be used to measure thymic output. We analysed whether in vitro thymopoiesis could be used to predict in vivo thymic output in IL-2 treated subjects. DESIGN AND METHODS: We correlated the relative variation of peripheral CD4 T cells over 12 months in HIV-positive subjects on HAART or HAART + IL-2 with the mean levels of both sjTREC and T cells developed in chimeric murine foetal thymic organ cultures (FTOC) reconstituted with circulating progenitors. RESULTS: In contrast with HAART treated individuals in which these values were directly correlated, in subjects receiving HAART + IL-2 the increase of CD4 T cells in vivo was correlated to neither sjTREC number nor to reconstitution of FTOC, probably reflecting a main effect of IL-2 in the expansion of the peripheral T cell pool. Nevertheless, addition of IL-2 to HAART determined a significant increase of in vitro thymopoietic potential in individuals with undetectable viraemia. CONCLUSIONS: The increased T cell development in vitro after addition of IL-2 to HAART suggests that intermittent IL-2 administration may exert a positive influence on lymphopoiesis. In two subjects with positive viraemia treated with IL-2 we observed reduced in vitro development of T cell precursors suggesting that the positive influence of IL-2 on thymopoiesis could be secondary to the control of viral replication by HAART. These observations provide novel evidence in support of the potential beneficial use of IL-2 in HAART treated individuals.     

Cardiac resynchronization therapy improves heart rate profile and heart rate variability of patients with moderate to severe heart failure.

OBJECTIVES: This study sought to report long-term changes of cardiac autonomic control by continuous, device-based monitoring of the standard deviation of the averages of intrinsic intervals in the 288 five-min segments of a day (SDANN) and of heart rate (HR) profile in heart failure (HF) patients treated with cardiac resynchronization therapy (CRT). BACKGROUND: Data on long-term changes of time-domain parameters of heart rate variability (HRV) and of HR in highly symptomatic HF patients treated with CRT are lacking. METHODS: Stored data were retrieved for 113 HF patients (New York Heart Association functional class III to IV, left ventricular ejection fraction < or =35%, QRS >120 ms) receiving a CRT device capable of continuous assessment of HRV and HR profile. RESULTS: The CRT induced a reduction of minimum HR (from 63 +/- 9 beats/min to 58 +/- 7 beats/min, p < 0.001) and mean HR (from 76 +/- 10 beats/min to 72 +/- 8 beats/min, p < 0.01) and an increase of SDANN (from 69 +/- 23 ms to 93 +/- 27 ms, p < 0.001) at three-month follow-up, which were consistent with improvement of functional capacity and structural changes. Different kinetics were observed among these parameters. The SDANN reached the plateau before minimum HR, and mean HR was the slowest parameter to change. Suboptimal left ventricular lead position was associated with no significant functional and structural improvement as well as no change or even worsening of HRV. The two-year event-free survival rate was significantly lower (62% vs. 94%, p < 0.005) in patients without any SDANN change (Delta change < or =0%) compared with patients who showed an increase in SDANN (Delta change >0%) four weeks after CRT initiation. CONCLUSIONS: Cardiac resynchronization therapy is able to significantly modify the sympathetic-parasympathetic interaction to the heart, as defined by HR profile and HRV. Lack of HRV improvement four weeks after CRT identifies patients at higher risk for major cardiovascular events.     

Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias

S ummary . The relationship between body iron status, degree of anaemia, erythroid expansion, age and sex has been studied in eight patients with congenital dyserythropoietic anaemia (CDA) and two patients with congenital sideroblastic anaemia, who had received no or very few blood transfusions and no medicinal iron during the course of their illness. All patients had increased iron stores. Iron load was mild in three women in the reproductive age and severe in two men, in middle age, who had evidence of parenchymal organ dysfunction. Iron loading, as judged by the plasma ferritin concentration, was independent of the degree of anaemia while it was closely related to the patient's age and the degree of increase in the total erythropoietic activity. It is concluded that patients with CDA or congenital sideroblastic anaemia are at high risk of developing haemochromatosis in middle age. Prophylactic phlebotomy or iron chelation therapy should be considered for such patients.     

Effect of abutment angulation in the retention and durability of three overdenture attachment systems: An in vitro study

PURPOSE

This in vitro study investigated and compared the durability and retention of three types of attachments.

MATERIALS AND METHODS

Three commercially available attachments were investigated: Clix®, Dalbo-Plus® and Locator®. In total, 72 samples of these attachments were placed in the acrylic resin forms and subjected to mechanical testing (5400 cycles of insertion and removal) over the respective ball or Locator abutments immersed in artificial saliva at pH 7 and 37℃. The abutments were placed at angulations of 0°, 10° and 20°. The retention force was recorded at the beginning and after 540, 1080, 2160, 3240, 4320 and 5400 insertion-removal cycles.

RESULTS

The results revealed that there were significant differences in the average values of the insertion/removal force due to angulation (F _(2.48) = 343619, P<.05) and the type of attachment (F _(7.48) = 23.220, P<.05).

CONCLUSION

Greater angulation of the abutments was found to influence the retention capacity of the attachments, and the fatigue test simulating 5 years of denture insertion and removal did not produce wear in the metal abutments.