DNA immunization circumvents deficient induction of T helper type 1 and cytotoxic T lymphocyte responses in neonates and during early life

The relative deficiency of T helper type 1 (Th1) and cytotoxic T lymphocyte (CTL) responses in early life is associated with an increased susceptibility to infections by intracellular microorganisms. This is likely to reflect a preferential polarization of immature CD4 T cells toward a Th2 rather than a Th1 pattern upon immunization with conventional vaccines. In this report, it is shown that a single immunization within the first week of life with DNA plasmids encoding viral (measles virus hemagglutinin, Sendai virus nucleoprotein) or bacterial (C fragment of tetanus toxin) vaccine antigens can induce adult-like Th1 or mixed Th1/Th2 responses indicated by production of IgG2a vaccine-specific antibodies and preferential secretion of interferon-γ (IFN-γ) compared with interleukin (IL)-5 by antigen-specific T cells, as well as significant CTL responses. However, in spite of this potent Th1-driving capacity, subsequent DNA immunization was not capable of reverting the Th2-biased responses induced after early priming with a recombinant measles canarypox vector. Thus, DNA vaccination represents a novel strategy capable of inducing Th1 or mixed Th1/Th2 and CTL responses in neonates and early life, providing it is performed prior to exposure to Th2-driving conventional vaccine antigens.     

3-dimensional functional imaging of human brain using echo-shifted FLASH MRI

A 3-dimensional MRI method has been developed for functional mapping of the human brain, based on blood oxygenation level dependent (BOLD) contrast mechanisms. The method uses recently introduced principles of echo-shifted FLASH to acquire a single 3D data set in 20 s. The technique was tested on a conventional 1.5 Tesla clinical scanner with a standard head coil using visual stimulation with a 8 Hz flashing white light, or a varying checkerboard pattern. Areas of increased signal intensity were identified in the visual cortex, consistent with the known functional organization.     

Candesartan: from left ventricular hypertrophy to heart failure, a global approach

Cardiovascular disease is a continuum, starting with risk factors resulting from physiological changes and extending to vascular pathology associated with adverse clinical outcomes. The overactivation of the renin-angiotensin-aldosterone system has been related to the development and worsening of risk factors associated with cardiovascular diseases such as hypertension and heart failure. Treatment at each stage along the continuum may prevent, or at least delay, the next one, and so it is crucial to initiate therapy as early as possible in such patients so as to provide optimal care. Candesartan, a long-acting angiotensin receptor antagonist, has been shown to be an effective, and well-tolerated therapy, in both the early and late phases of cardiovascular disease (prehypertension, hypertension, left ventricular hypertrophy and heart failure). This article reviews the data supporting the use of candesartan in cardiovascular medicine, with a focus on left ventricular hypertrophy and ultimately heart failure. Particular emphasis is given to the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program, which has shown a positive impact of candesartan in patients with chronic heart failure in terms of reducing the incidence of cardiovascular deaths and chronic heart failure hospitalizations.     

Outcomes of early parent‐child adrenocortical attunement in the high‐risk offspring of depressed parents

This study examined the impact of parent‐child attunement of morning cortisol on parenting and child outcomes in dyads with and without parental depression. Participants included 142 parent‐child dyads (3–5 years‐old) who provided morning cortisol samples at Wave 1, and 98 dyads returned for the 3‐year follow‐up at Wave 2. Results indicated that for parents with a history of depression and for female children, stronger attunement predicted increases in parental hostility from Wave 1 to Wave 2. For females only, stronger attunement was related to children's depressive symptoms at Wave 1 and Wave 2. Stronger attunement was also associated with increases in children's depressive symptoms from Wave 1 to Wave 2, poorer psychosocial functioning at Wave 1, and ADHD symptoms at Wave 2. Findings highlight attunement as an important biological process related to parenting and child outcomes and suggest it may play a role in the intergenerational transmission of depression risk.     

Simplification therapy with once-daily didanosine, tenofovir and efavirenz in HIV-1-infected adults with viral suppression receiving a more complex antiretroviral regimen: final results of the EFADITE trial

BACKGROUND: High pill burden and side effects often impact on the long-term success of highly active antiretroviral therapy (HAART), which has led clinicians to search for more convenient regimens. Patients and methods: A prospective, multicentre, open, comparative study in which HIV-1-infected patients on HAART and with plasma HIV-1 RNA <50 copies/ml for longer than 6 months were switched to tenofovir, didanosine and efavirenz (QD arm) or remained on the same treatment regimen (control arm). Patients with grade 4 toxicities or plasma HIV-1 RNA values repeatedly >1000 copies/ml discontinued the study. RESULTS: A total of 390 patients were included in the trial (309 in the QD arm and 81 in the control arm). The main baseline characteristics were well balanced between groups. In the QD arm, 41% of patients received high (standard) didanosine doses and 59% received reduced doses. At 12 months, plasma HIV-1 RNA <400 copies/ml was attained in 66% of QD patients and 73% of controls in the intent-to-treat (ITT) analysis (P=NS). However, the number of individuals with HIV-1 RNA <400 copies/ml in the QD arm was 56% versus 71% when comparing the use of high versus low didanosine doses (P=0.007). Treatment discontinuation occurred in 87 QD cases (28%) and 17 controls (21%). Twenty QD individuals (6.5%) and 2 controls (2.5%) discontinued because of virological failure (P=NS). The median CD4+ cell count change at 12 months was -26 and +27 cells/microl in QD patients and controls, respectively (P=0.001). In individuals who attained HIV-1 RNA <400 copies/ml, CD4+ cell changes were -25 and +15 cells/microl in QD patients and controls, respectively (P=0.001). Moreover, CD4+ cell declines in the QD arm were significantly greater in patients taking high versus low didanosine doses (-59 versus -15 cells/microl; P=0.04). The lipid profile improved significantly in the QD arm, particularly in patients who were on protease inhibitors prior to simplification. CONCLUSIONS: Simplification to didanosine-tenofovir-efavirenz provides a virological suppression rate at 12 months similar to that seen in patients who do not change therapy, as long as low didanosine doses are administered. Decreases in CD4+ cell levels in patients in the QD arm (especially decreases seen with high didanosine doses) and dyslipidaemias along with less convenient pill burden and schedules in controls were the main long-term concerns for each option.     

Intravascular carcinomatosis of central nervous system due to metastatic inflammatory breast cancer: A case report

Central nervous system (CNS) involvement by metastatic cancer is well‐recognized and typically presents with multifocal solid tumors within the brain parenchyma or leptomeningeal dissemination. We describe herein a histologically very rare case of CNS metastasis in a 52‐year‐old woman who presented with mental status changes. Post mortem examination revealed extensive CNS involvement by metastatic inflammatory breast carcinoma, characterized by the presence of single tumor cells diffusely present within capillaries without parenchymal or perivascular invasion, and acute ischemic changes/infarcts bilaterally involving multiple areas. The cancer cells were found predominantly in the cerebral cortices and deep gray matter structures. Pre‐mortem magnetic resonance and CT imaging of the brain did not identify metastatic cancer; however, widespread ischemic changes (i.e. brain infarcts) were identified. Inflammatory breast carcinoma is well‐known to have a predilection for spread through lymphovascular spaces. Post mortem examination revealed tumor involvement of bilateral lungs, heart and bladder, with sinusoidal spread in the liver and lymph nodes and prominent involvement of the splenic red pulp in addition to extensive vascular involvement of the brain and spinal cord without a discrete mass, despite the presence of widely metastatic disease. The tumor cells in the CNS were strongly immunoreactive for pancytokeratin, E‐cadherin, cytokeratin‐7, epithelial membrane antigen and CAM 5.2. This unique histologic pattern of tumor spread is considered to represent “intravascular carcinomatosis” in the CNS, and most likely the cause of the patient's widespread ischemic injuries.