Efficient systemic and mucosal responses against the HIV-1 Tat protein by prime/boost vaccination using the lipopeptide MALP-2 as adjuvant

A major goal of HIV-1 vaccine development is the induction of mucosal immune responses able to stop or reduce viral infection directly at the portal of entry. We established a heterologous prime/boost vaccination protocol based on intradermal priming with the HIV-1 Tat protein and intranasal boosting with the Tat protein co-administered with the mucosal adjuvant MALP-2. Strong Tat-specific humoral responses were elicited in vaccinated mice at both systemic and mucosal levels. The cellular responses were characterized by a Th1 dominant helper pattern. The heterologous prime/boost regimen was also able to induce Tat-specific CTL, which were absent in animals receiving the homologous prime boost scheme. Thus, the heterologous prime/boost protocol was the only regimen able to evoke both CTL and sIgA responses. This suggests that a similar approach can be exploited to develop multi-component vaccines against HIV-1 infections able to induce both systemic and mucosal immune responses.     

Escitalopram-induced uveal effusions and bilateral angle closure glaucoma

PURPOSE: To report the onset of bilateral angle closure glaucoma resulting from ciliochoroidal effusions noted after taking escitalopram. DESIGN: Case report. METHODS: A 41-year-old woman with a medical history of depression was placed on escitalopram and presented with acute bilateral angle closure glaucoma. A medical history and ophthalmic examination (including slit-lamp photography and high-frequency ultrasonography) were performed at the time of diagnosis and at resolution of her symptoms. RESULTS: High-frequency ultrasonography revealed bilateral choroidal effusions with ciliary body detachments and angle closure. Attempts to reduce intraocular pressure with topical ocular antihypertensive drugs and subsequent laser peripheral iridotomy were unsuccessful. Over the course of four days, the use of topical cycloplegics, corticosteroids, and discontinuation of escitalopram resulted in normalization of intraocular pressures, deepening of anterior chamber depths, and resolution of her uveal effusions. CONCLUSIONS: The use of escitalopram resulted in uveal effusions, angle rotation, and acute bilateral angle closure glaucoma. Discontinuation of escitalopram and corticosteroid therapy resulted in normalization of the patient's eyes.     

A polymorphism in the delta-aminolevulinic acid dehydratase gene modifies plasma/whole blood lead ratio

Delta aminolevulinic acid dehydratase (ALAD) plays an important role in lead poisoning. This study was carried out to examine the effects of ALAD gene polymorphism (G177C) on %Pb-P(plasma lead)/Pb-B(whole blood) ratio in 142 subjects environmentally exposed to lead. Genotypes for the ALAD G177C polymorphism were determined by PCR and restriction fragment length digestion. Pb-P and Pb-B were determined by inductively coupled plasma mass spectrometry and by graphite furnace atomic absorption spectrometry, respectively. The allele frequencies for ALAD1 and ALAD2 alleles were 0.897 and 0.103, respectively. We combined both ALAD 1-2 and ALAD 2-2 genotypes together (ALAD 1-2/2-2 group) and compared with the ALAD 1-1 genotype group. While no significant differences were found in Pb-B, subjects from the ALAD 1-2/2-2 genotype group presented significantly higher Pb-P concentrations and %Pb-P/Pb-B ratios (0.89±0.07 μg/l, and 1.45±0.10%, respectively) when compared with subjects from the ALAD 1-1 genotype group (0.44±0.05 μg/l, and 0.48±0.02, respectively; both P<0.0001). The higher %Pb-P/Pb-B ratios in carriers of the ALAD-2 allele compared with noncarriers indicate that ALAD 1-2/2-2 subjects are probably at increased health risks associated with lead exposure.     

Toxicological evaluation of an ethanolic extract from Chiococca alba roots

The roots of Chiococca alba have been employed to treat rheumatic disorders and for other therapeutic purposes in Brazil and elsewhere. This study was undertaken to evaluate the toxicological properties of an ethanolic extract from Chiococca alba roots (EE), including mutagenicity in the Salmonella assay and acute and subacute toxicity to mice. Single oral doses of EE caused hypoactivity, but no deaths were noted up to the highest dose tested (2000 mg/kg). EE (500 mg/kg p.o.) reduced mouse locomotion in the open field test. EE was markedly more toxic when given by intraperitoneal (i.p.) and subcutaneous (s.c.) routes. Acute approximate lethal doses (ALD) were 125 mg/kg (males) and 250 mg/kg (females) and 250 mg/kg (both sexes) by i.p. and s.c. routes, respectively. Deaths after single doses were preceded by hypoactivity, ataxia and lethargy. Repeated administration of EE by gavage for 14 days caused no deaths. Activity of liver monooxygenases (pentoxy- and ethoxyresorufin-O-dealkylases) was not altered by repeated treatment with EE (2000 mg/kg/day p.o.). Administration of EE by the i.p. route for 14 days decreased weight gain and caused anemia, neutrophilia and deaths. The no-observed-adverse-effect level (NOAEL) for subacute treatment by the i.p. route was as low as 15.6 mg of EE/kg body weight (wt)/day. EE was not mutagenic in the Salmonella/microsome assay with TA100, TA98, TA97a and TA1535 strains. In summary, EE was not mutagenic and presented a low acute and subacute toxicity by the oral route. Toxicities by parenteral routes, however, were more pronounced.     

In vivo activity of the cleaved form of soluble urokinase receptor: a new hematopoietic stem/progenitor cell mobilizer

Cleaved forms of soluble urokinase receptor (c-suPAR) have been detected in body fluids from patients affected by various tumors. We recently reported increased c-suPAR levels in sera of healthy donors during granulocyte colony-stimulating factor (G-CSF)-induced mobilization of CD34(+) hematopoietic stem cells (HSC). In vitro, c-suPAR or its derived chemotactic peptide (uPAR(84-95)) stimulated migration of human CD34(+) HSCs and inactivated CXCR4, the chemokine receptor primarily responsible for HSC retention in bone marrow. These results suggested that c-suPAR could potentially contribute to regulate HSC trafficking from and to bone marrow. Therefore, we investigated uPAR(84-95) effects on mobilization of mouse CD34(+) hematopoietic stem/progenitor cells (HSC/HPC). We first showed that uPAR(84-95) stimulated in vitro dose-dependent migration of mouse CD34(+) M1 leukemia cells and inactivated murine CXCR4. uPAR(84-95) capability to induce mouse HSC/HPC release from bone marrow and migration into the circulation was then investigated in vivo. uPAR(84-95) i.p. administration induced rapid leukocytosis, which was associated with an increase in peripheral blood CD34(+) HSCs/HPCs. In vitro colony assays confirmed that uPAR(84-95) mobilized hematopoietic progenitors, showing an absolute increase in circulating colony-forming cells. uPAR(84-95) mobilizing activity was comparable to that of G-CSF; however, neither synergistic nor additive effect was observed in combining the two molecules. These findings show for the first time in vivo biological effects of c-suPAR. Its capability to mobilize HSCs suggests potential clinical applications in HSC transplantation.     

Synthesis and antimicrobial activity of new bromine-rich pyrrole derivatives related to monodeoxypyoluteorin

The synthesis and antimicrobial activity of new pyrrole derivatives structurally related to monodeoxypyoluteorin are described. The insertion of a keto or methylene spacer between the phenol group and the pyrroloyl moiety of brominated 2-(2'-hydroxybenzoyl)pyrroles leads to a decrease of the antibacterial activity.