Peptide Delivery to Tissues via Reversibly Linked Protein Transduction Sequences

The development of peptide-based therapeutics has suffered from challenges associated with delivery to intact tissue. In skin, an array of protein targets resides only tens of micrometers below the surface; however, because of difficulties in traversing the cutaneous barrier, the potential for peptide-based therapeutics remains unrealized. We have developed a general approach for topical peptide delivery into skin using releasable protein transduction sequences to enable peptide transport across tissue boundaries. Upon entry into the cell, the disulfide linkage between the peptide transduction sequences and peptide cargo is cleaved, permitting the dissociation of the highly charged peptide transduction sequences from the active peptide. A prototype cargo peptide, the hemagglutinin (HA) epitope, was conjugated to a hepta-arginine protein transduction sequence via a releasable disulfide linkage. This construct penetrated the skin to deep dermis within 1 h after topical application. Consistent with the dissociation of the protein transduction and cargo sequences, absorbed protein transduction sequences and HA peptides displayed differential intracellular localization. Reversible protein transduction sequence linkage thus represents a noninvasive platform for tissue delivery of intact peptides with no requirement for viral vectors or parenteral injection and may be of broad utility in molecular therapy

Reduced serum hepcidin levels in patients with chronic hepatitis C

BACKGROUND/AIMS: Patients with chronic hepatitis C (CHC) often have increased liver iron, a condition associated with reduced sustained response to antiviral therapy, more rapid progression to cirrhosis, and development of hepatocellular carcinoma. The hepatic hormone hepcidin is the major regulator of iron metabolism and inhibits iron absorption and recycling from erythrophagocytosis. Hepcidin decrease is a possible pathophysiological mechanism of iron overload in CHC, but studies in humans have been hampered so far by the lack of reliable quantitative assays for the 25-amino acid bioactive peptide in serum (s-hepcidin). METHODS: Using a recently validated immunoassay, we measured s-hepcidin levels in 81 untreated CHC patients and 57 controls with rigorous definition of normal iron status. All CHC patients underwent liver biopsy with histological iron score. RESULTS: s-hepcidin was significantly lower in CHC patients than in controls (geometric means with 95\% confidence intervals: 33.7, 21.5-52.9 versus 90.9, 76.1-108.4 ng/mL, respectively; p<0.001). In CHC patients, s-hepcidin significantly correlated with serum ferritin and histological total iron score, but not with s-interleukin-6. After stratification for ferritin quartiles, s-hepcidin increased significantly across quartiles in both controls and CHC patients (chi for trend, p<0.001). However, in CHC patients, s-hepcidin was significantly lower than in controls for each corresponding quartile (analysis of variance, p<0.001). CONCLUSIONS: These results, together with very recent studies in animal and cellular models, indicate that although hepcidin regulation by iron stores is maintained in CHC, the suppression of this hormone by hepatitis C virus is likely an important factor in liver iron accumulation in this condition

POSIÇÃO CORPORAL E OXIGENAÇÃO PARTE I - PACIENTES COM DISFUNÇÃO PULMONAR UNILATERAL

Este estudo verificou o efeito das posições sentada, supina e laterais sobre os gases do sangue arterial, em pacientes com disfunção pulmonar unilateral, no pós-operatório recente de cirurgia cardíaca. Os gases sangüíneos foram mensurados após o paciente permanecer 15 minutos em cada posição. Concluiu-se que quando o paciente deitava-se sobre o lado do pulmão considerado sadio ou em supino, a Pa02 foi significativamente superior. No entanto, na posição deitada sobre o lado afetado, houve piora significativa da Pa02.The purpose of this study was to analyse the effects of sitting, supine and laterals positions on arterial oxygen tension (Pa02) and arterial carbon dioxide tension (PaC02), in 21 adults patients, carier of some pulmonary unilateral disfunction, in recent post-operative cardiac surgery. The diagnosis of the pulmonary disfunction was done through radiographic torax evaluation. The patients stayed during 15 minutes in each position and after this, the arterial blood gases were measured. Based on Friedman test and Multiple Comparation test (a = 0,05), it was found that the Pa02 was significantly higher when the patients were lying on the "healthy'' side or in supine position; the Pa02 was significantly lower when the patients where lying on the "sick" side. No significant changes in PaC02 were noted