Effects of recombinant human growth hormone on HIV-1-specific T-cell responses,thymic output and proviral DNA in patients on HAART: 48-week follow-up

Background  

Efficacious immune-based therapy in treated chronic HIV-1 infection requires the induction of virus-specific CD4⁺ T cells and subsequent maturation and maintenance of specific memory CD8⁺ T cells. Concomitant daily administration of recombinant human growth hormone (rhGH) with highly active antiretroviral therapy (HAART) was used in chronically infected patients with lipodystrophy in an attempt to reconstitute these virus-specific T-cell responses.     

A phase I, randomized study of combined IL-2 and therapeutic immunisation with antiretroviral therapy

Background  

Fully functional HIV-1-specific CD8 and CD4 effector T-cell responses are vital to the containment of viral activity and disease progression. These responses are lacking in HIV-1-infected patients with progressive disease. We attempted to augment fully functional HIV-1-specific CD8 and CD4 effector T-cell responses in patients with advanced chronic HIV-1 infection.     

Immunization with genetically attenuated P52-deficient Plasmodium berghei sporozoites induces a long-lasting effector memory CD8+ T cell response in the liver

Background

The induction of sterile immunity and long lasting protection against malaria has been effectively achieved by immunization with sporozoites attenuated by gamma-irradiation or through deletion of genes. For mice immunized with radiation attenuated sporozoites (RAS) it has been shown that intrahepatic effector memory CD8⁺ T cells are critical for protection. Recent studies have shown that immunization with genetically attenuated parasites (GAP) in mice is also conferred by liver effector memory CD8⁺ T cells.

Findings

In this study we analysed effector memory cell responses after immunization of GAP that lack the P52 protein. We demonstrate that immunization with p52 ^-GAP sporozoites also results in a strong increase of effector memory CD8⁺ T cells, even 6 months after immunization, whereas no specific CD4⁺ effector T cells response could be detected. In addition, we show that the increase of effector memory CD8⁺ T cells is specific for the liver and not for the spleen or lymph nodes.

Conclusions

These results indicate that immunization of mice with P. berghei p52 ^-GAP results in immune responses that are comparable to those induced by RAS or GAP lacking expression of UIS3 or UIS4, with an important role implicated for intrahepatic effector memory CD8⁺ T cells. The knowledge of the mediators of protective immunity after immunization with different GAP is important for the further development of vaccines consisting of genetically attenuated sporozoites.     

CpG increases vaccine antigen-specific cell-mediated immunity when administered with hepatitis B vaccine in HIV infection

Background  

Lack of adequate adjuvancy is a possible explanation for lack of vaccine immunogenecity. Immunostimulatory CpGs are potent vaccine adjuvants and may be an important component of the development vaccines, particularly those for which a cellular immune response is required for protection. We have previously demonstrated that CpG ODN co-administration with hepatitis B vaccine results in earlier, stronger and more sustained antibody responses to hepatitis B surface antigen in HIV infected individuals, and wished to determine if, in this population, helper T-cell responses were also enhanced.     

IMP321 (sLAG-3), an immunopotentiator for T cell responses against a HBsAg antigen in healthy adults: a single blind randomised controlled phase I study

Background  

LAG-3 (CD223) is a natural high affinity ligand for MHC class II. The soluble form (sLAG-3) induces maturation of monocyte-derived dendritic cells in vitro and is used as a potent Th1-like immune enhancer with many antigens in animal models. To extend this observation to human, a proof of concept study was conducted with a clinical-grade sLAG-3, termed IMP321, coinjected with alum-non-absorbed recombinant hepatitis B surface antigen.     

Synthesis of novel 4H-pyrimido[1,6-a]pyrimidines via a one-pot three-component condensation

Abstract  

Highly substituted novel 4H-pyrimido[1,6-a] pyrimidines were prepared by a trifluoromethanesulfonic acid catalyzed one-pot three-component condensation of 4-aminopyrimidines, aldehydes, and β-ketoesters. A preliminary feasibility study was undertaken on these compounds, to assess the potential production of a library of further diversified compounds by nucleophilic replacement of Cl (R¹) or by reaction of electrophiles with the NH₂ (R²) group.     

Radiosensitivity of CD3−CD8+CD56+ NK cells

The effect of lower doses (0.5–3.0 Gy) of gamma radiation on radiosensitivity of CD3?/CD8+ NK cells subpopulation isolated from the peripheral blood of healthy volunteers was studied 48 h after the irradiation. Only a subtle increase in terms of induction of apoptosis (A+ cells), was observed in Annexin positive CD3?/CD8+ NK cells. The assessment of the relative presence of CD3^?/CD8⁺ NK cells in Annexin negative populations of lymphocytes considerably contributes to the elimination of individual variability and could be useful in biodosimetry.Living CD3?/CD8+; Annexin negative NK cells were analyzed using five-color flow cytometry 16 h after irradiation by the doses of 1–10 Gy. The study was carried out on NK cells subsets CD3?/CD8? CD16+, CD56 (dim) and CD56 (bright). NK cells characterized with their low-density expression of CD56 (dim) are more cytotoxic and express CD16. Those with high-density expression of CD56 (bright) are known for their capacity to produce cytokines following activation of monocytes but their natural cytotoxicity is low; they are classified as CD16? or CD16 (dim). A dose-depending decrease in the relative presence of CD3?/CD8+ NK cells was observed 16 h after ionizing radiation (1–10 Gy). The decrease was highly pronounced in CD56 (bright) subset of NK cells and this subpopulation was considered as the most radiosensitive one. Unfortunately, the most radiosensitive subpopulation of NK cells – CD56bright cannot be used as a biodosimetric marker due to its insufficient amount in peripheral blood.     

Diffusion-weighted MRI in the characterization of cystic pancreatic lesions: usefulness of ADC values

Purpose

To evaluate the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI) in the differentiation of cystic pancreatic lesions.

Materials and Methods

Institutional review board approval was obtained, and written informed consent was taken from all enrolled subjects. Fifty-four patients with cystic pancreatic lesions of at least 1 cm in diameter (range:10–96 mm) at ultrasonography and/or computed tomography and 10 normal subjects underwent MRI at 1.5 T. These subjects included thirty-four patients with intraductal papillary mucinous tumors (IPMTs), 10 with pseudocysts, 5 with serous cystoadenoma and 5 with mucinous cystoadenoma. The MR protocol included axial T1w and T2w sequences and coronal MR cholangiopancreatography images. DW-MRI was performed using a breath-hold single-shot echo-planar sequence with a b gradient factor value of 500 s/mm² in the three orthogonal axes. Apparent diffusion coefficient (ADC) was calculated for cerebrospinal fluid, normal pancreatic parenchyma, and for each focal pancreatic lesion. Imaging results were correlated with endoscopic retrograde cholangiopancreatography, endoscopic ultrasound-guided fine needle aspiration, surgery and/or imaging follow-up.

Results

Mean ADC value was 4.1×10⁻³ mm²/s for cerebrospinal fluid, 1.73×10⁻³ mm²/s for normal pancreatic parenchyma, 4.09×10⁻³ mm²/s for IPMT, 3.89×10⁻³ mm²/s for mucinous cystoadenoma, 3.65×10⁻³ mm²/s for serous cystoadenoma and 2.83×10⁻³ mm²/s for pseudocyst. Mean ADC values of each of the different types of pancreatic lesions were statistically different (P<.05).

Conclusion

DW-MRI may be helpful in the differential diagnosis of cystic pancreatic lesions.     

Microglial responses around intrinsic CNS neurons are correlated with axonal regeneration

Background  

Microglia/macrophages and lymphocytes (T-cells) accumulate around motor and primary sensory neurons that are regenerating axons but there is little or no microglial activation or T-cell accumulation around axotomised intrinsic CNS neurons, which do not normally regenerate axons. We aimed to establish whether there was an inflammatory response around the perikarya of CNS neurons that were induced to regenerate axons through a peripheral nerve graft.     

Aging is associated with increased collagen type IV accumulation in the basal lamina of human cerebral microvessels

Background  

Microvascular alterations contribute to the development of stroke and vascular dementia. The goal of this study was to evaluate age and hypertension related changes of the basal lamina in cerebral microvessels of individuals, who died from non-cerebral causes.     

Immunostimulatory effects of three classes of CpG oligodeoxynucleotides on PBMC from HCV chronic carriers

Background  

Chronic hepatitis C virus (HCV) infection results from weak or absent T cell responses. Pegylated-interferon-alpha (IFN-α) and ribavirin, the standard of care for chronic HCV, have numerous immune effects but are not potent T cell activators. A potent immune activator such as TLR9 agonist CpG oligodeoxynucleotide (CpG) may complement current treatment approaches.     

Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease

Background  

Predominantly, magnetic resonance imaging (MRI) studies in animal models of Parkinson's disease (PD) have focused on alterations in T₂ water ¹H relaxation or ¹H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan in vivo brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin.     

Paradoxical uptake of Gd-EOB-DTPA on the hepatobiliary phase in the evaluation of hepatic metastasis from breast cancer: is the “target sign” a common finding?

Purpose

The purpose was to describe magnetic resonance imaging (MRI) findings of breast cancer liver metastasis using gadoxetic acid (Gd-EOB-DTPA) with an emphasis on the added value of the hepatobiliary phase (HBP).

Material and methods

Nine patients with 13 liver metastases were included in the study after the medical records of 29 breast cancer patients who underwent Gd-EOB-DTPA-enhanced MRI between February 2008 and June 2010 were reviewed. The diagnoses of liver metastasis were established by percutaneous liver biopsy or surgery and on the basis of image findings. Two radiologists retrospectively evaluated signal intensity (SI) and sizes of metastases and patterns of enhancement in an HBP. The SI ratio was calculated as the SI of the central hyperintense portion in “target” lesions divided by the SI of nearby normal liver parenchyma on the HBP. We also measured apparent diffusion coefficient (ADC) values from Diffusion Weighted Image (DWI).

Results

Liver metastases were all hypointense [n=13/13 (100%)] on T1-weighted imaging (WI), and many lesions had a “target” appearance with a central high SI and a peripheral low SI rim (47%) on T2WI. Dynamic study showed rim enhancement on the arterial phase (85%) and a “target” appearance, consisting of a central enhancing portion with peripheral washout or hypointense rim, on the HBP (62%). The mean SI ratio was 0.7. The mean ADC value of “target” appearing metastases was 1.25 (×10⁻³ mm²/s; range 1.3–1.6) compared with a mean value of 0.8 (×10⁻³ mm²/s; range 0.8–1.4) in homogeneous defect on the HBP. There was statistically significant difference (P<.05).

Conclusion

Breast cancer liver metastases commonly demonstrated as a peripheral ring enhancement on arterial dominant phase and a target sign with a central round enhancing portion and a peripheral hypointense rim on the HBP.     

Multimodal investigations of trans-endothelial cell trafficking under condition of disrupted blood-brain barrier integrity

Background  

Stem cells or immune cells targeting the central nervous system (CNS) bear significant promises for patients affected by CNS disorders. Brain or spinal cord delivery of therapeutic cells is limited by the blood-brain barrier (BBB) which remains one of the recognized rate-limiting steps. Osmotic BBB disruption (BBBD) has been shown to improve small molecule chemotherapy for brain tumors, but successful delivery of cells in conjunction with BBBD has never been reported.     

Antiviral activity of Engystol<Superscript>®</Superscript> and Gripp-Heel<Superscript>®</Superscript>: an in-vitro assessment

Background  

Infections with respiratory viruses can activate the innate immune response - an important host defence mechanism in the early stage of viral infection. Interferon (IFN) release, triggered by virus infection, is an important factor in establishing an antiviral state, where IFN activation occurs prior to the onset of the adaptive immune response.     

An adeno-associated viral vector transduces the rat hypothalamus and amygdala more efficient than a lentiviral vector

Background  

This study compared the transduction efficiencies of an adeno-associated viral (AAV) vector, which was pseudotyped with an AAV1 capsid and encoded the green fluorescent protein (GFP), with a lentiviral (LV) vector, which was pseudotyped with a VSV-G envelop and encoded the discosoma red fluorescent protein (dsRed), to investigate which viral vector transduced the lateral hypothalamus or the amygdala more efficiently. The LV-dsRed and AAV1-GFP vector were mixed and injected into the lateral hypothalamus or into the amygdala of adult rats. The titers that were injected were 1 × 10⁸ or 1 × 10⁹ genomic copies of AAV1-GFP and 1 × 10⁵ transducing units of LV-dsRed.     

Serotonin-mediated modulation of Na<Superscript>+</Superscript>/K<Superscript>+</Superscript> pump current in rat hippocampal CA1 pyramidal neurons

Background  

The aim of this study was to investigate whether serotonin (5-hydroxytryptamine, 5-HT) can modulate Na⁺/K⁺ pump in rat hippocampal CA1 pyramidal neurons.     

Detection of bone metastases using diffusion weighted magnetic resonance imaging: comparison with C-methionine PET and bone scintigraphy

Purpose

We evaluated the ability of diffusion-weighted imaging (DWI) to detect bone metastasis by comparing the results obtained using this modality with those obtained using ¹¹C-methionine (MET) positron emission tomography (PET) and bone scintigraphy.

Materials and methods

This retrospective study involved 29 patients with bone metastasis. DWI was obtained using a single-shot echo planar imaging (EPI) sequence with fat suppression using a short inversion time inversion recovery sequence. The detection capabilities of DWI for bone metastases were compared with those of whole body MET PET (in 19 patients) and 99mTc-methylene diphosphonate bone scintigraphy (in 15 patients).

Results

Among the 19 patients who were diagnosed using DWI and PET, the PET identified 39 bone metastases, while the DWI identified 60 metastases out of 69 metastases revealed with conventional magnetic resonance imaging (MRI). Among the 15 patients who were diagnosed using DWI and bone scintigraphy, the bone scintigraphy identified 18 bone metastases, while the DWI identified 72 metastases out of 78 metastases revealed with conventional MRI. The overall bone metastasis detection rates were 56.5% for PET, 23.1% for bone scintigraphy and 92.3% for DWI.

Conclusion

DWI is a very sensitive method for detecting bone metastasis and is superior to MET PET and bone scintigraphy in terms of its detection capabilities.     

Diagnostic performance of apparent diffusion coefficient and quantitative kinetic parameters for predicting additional malignancy in patients with newly diagnosed breast cancer

Purpose

To evaluate the diagnostic performance of an apparent diffusion coefficient (ADC) and quantitative kinetic parameters in patients with newly diagnosed breast cancer.

Materials and Methods

We enrolled 169 lesions in 89 patients with breast cancer who underwent dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI). Comparisons between benign and malignant lesions were performed for lesion type (mass or nonmass-like enhancement), size (≥ 1 cm or < 1 cm), ADC, kinetic parameters and the presence of a US correlate.

Results

There were 63 benign and 106 malignant lesions. The mean size and initial peak enhancement of the benign lesions were significantly lower than those of malignant lesions (P < 0.001 for both). The ADC of the benign lesions was significantly higher than that of malignant lesions (1.42 × 10^− 3 mm²/sec vs. 1.04 × 10^− 3 mm²/sec; P < 0.001). The area under the receiver operating characteristic curve (AUC) for predicting malignancy was 0.87 for the combined parameters of size, ADC, and initial peak enhancement, which was higher than those of each parameter.

Conclusions

Combination of quantitative kinetic parameters and ADC showed higher diagnostic performance for predicting malignancy than each parameter alone for the evaluation of patients with breast cancer.     

Prior exposure to an attenuated <Emphasis Type="Italic">Listeria</Emphasis> vaccine does not reduce immunogenicity: pre-clinical assessment of the efficacy of a <Emphasis Type="Italic">Listeria</Emphasis>vaccine in the induction of immune responses against HIV

Background  

We have evaluated an attenuated Listeria monocytogenes (Lm) candidate vaccine vector in nonhuman primates using a delivery regimen relying solely on oral vaccination. We sought to determine the impact of prior Lm vector exposure on the development of new immune responses against HIV antigens.