Enteral Bioavailability of Human Granulocyte Colony Stimulating Factor Conjugated with Poly(ethylene glycol)

Purpose. The focus of this paper is to demonstrate that pegylation of a therapeutic protein, recombinant human granulocyte colony stimulating factor (PEG-G-CSF), results in an increase in stability and in retention of in vivo bioactivity when administered by the intraduodenal route and may, therefore, be a suitable form of the protein for inclusion in an oral delivery formulation. Methods. The ability of PEG-G-CSF to elicit a therapeutic response from the enteral route was investigated by two methods of intraduodenal dosing in an in vivo model to determine the optimal dosing method: by slow, constant infusion, or by a single bolus administration. Results. Circulating levels of the proteins confirmed that PEG-G-CSF was delivered into the systemic circulation from the enteral route and that biological activity was retained. Bioavailability from the enteral route by the constant infusion method was calculated from the intravenous administration of the proteins to be between 1.8 and 3.5% while un-modified G-CSF failed to elicit a quantifiable response by this method. Bolus administration of PEG-G-CSF also resulted in biological activity although responses were short lived and significantly lower than with the pegylated formulation. Conclusions. The possible mechanisms of enteral delivery of PEG-G-CSF are discussed. Our results indicate that oral delivery of pegylated G-CSF may be possible and in fact, preferable to using the un-modified form of the therapeutic.     

Tolerance to the reinforcing effects of cocaine

This study tested the hypothesis that prolonged exposure to high doses of cocaine would produce tolerance to the reinforcing effects of cocaine. We determined the rate of administration of low doses of cocaine in rats and then exposed these subjects to high doses of cocaine (5mg) three-times a day for 1 week. This treatment caused a 2-fold faster intake of cocaine, and the lowest dose of cocaine that would maintain self-administration was double the previous threshold dose. To our knowledge this is the first controlled demonstration of tolerance to the reinforcing effects of cocaine produced by chronic exposure to the drug, and we suggest that this tolerance may be a key marker for the development of drug dependence.     

Parental knowledge of school backpack weight and contents.

Parental knowledge of their students' backpack weight and contents was assessed by identifying 188 students who carried backpacks weighing at least 10% of their body weights through a survey of 745 students in three elementary schools. Most parents (96%) had never checked their child's backpack weight; 34% had never checked the backpack contents.     

Synthesis and physico‐chemical properties of peptides in soil humic substances

Abstract: Soil humic substances (HS) are heterologous, polydispersive, and multi‐functional organometallic macromolecules ubiquitous in soils and sediments. They are key players in the maintenance of the belowground ecosystems and in the bioavailability of both organic and inorganic contaminants. It is widely assumed that the peptidic substructures of HS are readily degraded and therefore do not contribute significantly to interactions with contaminants such as toxic metals. To investigate the turnover of humified peptides, laboratory soil aging experiments were conducted with ¹³C‐glucose or ¹⁵N‐nitrate for 8.5 months. Evidence for random‐coil peptidic structures in the labeled HS was obtained from 2‐D nuclear magnetic resonance (NMR), pyrolysis gas chromatography‐mass spectrometry (pyro‐GC‐MS), and circular dichroism data. Interaction of metals with the peptidic carbonyls of labeled HS was rationalized from the solid‐state NMR data. Detailed ¹³C and ¹⁵N labeling patterns of amino acid residues in the acid hydrolysates of HS acquired from NMR and GC‐MS revealed two pools of peptides, i.e. one extant (unlabeled) and the other, newly humified with little isotopic scrambling (fully labeled). The persistence of pre‐existing peptidic structures indicates their resistance to degradation while the presence of fully labeled peptidic amino acids suggests wholesale incorporation of newly synthesized peptides into HS. These findings are contrary to the general notion that humified peptides are readily degraded.     

Transforming growth factor beta(2) (TGF beta(2)) produces effective pleurodesis in sheep with no systemic complications

BACKGROUND: We have recently shown that transforming growth factor (TGF)beta(2) induces effective pleurodesis in rabbits. However, rabbits have a thin pleura while humans have a thick visceral pleura. The effect of intrapleural administration of TGF beta(2) in animals with a thick pleura and its associated systemic effects have not been investigated. This study was undertaken (1) to develop a new animal model for the study of pleurodesis using sheep which have a thick pleura resembling that of humans; (2) to study the efficacy of TGF beta(2) as a pleurodesis agent in the sheep model; and (3) to assess whether histological changes occur in extrapulmonary organs after intrapleural administration of TGF beta(2). METHODS: Twelve sheep were divided into four groups and were given a single intrapleural injection of TGF beta(2) in a concentration of 1.0 microg/kg, 0.5 microg/kg, 0.25 microg/kg or 0.125 microg/kg to the right pleural cavity via a chest tube. The left pleural cavity served as the control. Any pleural fluid that accumulated after the intrapleural TGF beta(2) injection was collected and analysed. The degree of pleurodesis was graded from 1 (no adhesions) to 8 (complete symphysis >50% of chest wall) at day 14 when the sheep were killed. Biopsy specimens were taken from the lungs and extrapulmonary organs. RESULTS: All sheep that received > or = 0.25 microg/kg TGF beta(2) developed excellent pleurodesis (score = 8) while those that received 0.125 microg/kg had a median score of 6. The pleurodesis score did not exceed 2 in the control (left) side of any sheep. Sheep receiving > or = 0.50 microg/kg TGF beta(2) developed large exudative pleural effusions while those receiving a lower dose did not. The production of effusions neither hindered nor was necessary for inducing pleurodesis. There were no significant fibrotic changes in any of the extrapulmonary organs. CONCLUSION: Intrapleural injection of 0.25-1.0 microg/kg TGF beta(2) produces excellent pleurodesis in a new sheep model with no evidence of extrapulmonary fibrosis.     

Long-term adaptive life functioning in relation to initiation of treatment with antipsychotics over the lifetime trajectory of schizophrenia.

BACKGROUND: There is evidence that the stage of illness at which antipsychotic treatment is initiated in schizophrenia may have consequences for its subsequent course. How this might relate to impaired adaptive life functioning in the long-term is poorly understood. METHODS: Thirty-eight inpatients, many of whom had been admitted in the preneuroleptic era, were assessed using the Social-Adaptive Functioning Evaluation (SAFE); constituent clinical and medication phases of the lifetime trajectory of their illnesses were then analyzed to identify predictors of SAFE score using multiple regression modeling. RESULTS: The primary, independent predictor of SAFE score was duration of initially unmedicated psychosis, which accounted for 22% of variance (p<.001) therein. Conversely, duration of subsequently treated illness, although decades longer, failed to predict SAFE score. CONCLUSIONS: These findings are consistent with some form of "progressive" process, particularly over the first several years following the emergence of psychosis, which is associated with accrual of deficits in adaptive life functioning.