An information theory model of hydrophobic interactions

A molecular model of poorly understood hydrophobic effects is heuristically developed using the methods of information theory. Because primitive hydrophobic effects can be tied to the probability of observing a molecular-sized cavity in the solvent, the probability distribution of the number of solvent centers in a cavity volume is modeled on the basis of the two moments available from the density and radial distribution of oxygen atoms in liquid water. The modeled distribution then yields the probability that no solvent centers are found in the cavity volume. This model is shown to account quantitatively for the central hydrophobic phenomena of cavity formation and association of inert gas solutes. The connection of information theory to statistical thermodynamics provides a basis for clarification of hydrophobic effects. The simplicity and flexibility of the approach suggest that it should permit applications to conformational equilibria of nonpolar solutes and hydrophobic residues in biopolymers.     

Changes in newspaper coverage of cardiovascular health issues in conjunction with a community-based intervention

Numerous community-based prevention projects, with significant media components, have been conducted over the past decade. Multiple evaluation strategies have been used to document the effectiveness of these interventions, including intermediate measures of community impact such as assessment of media coverage. As part of the evaluation of a community-based intervention (the Bootheel Heart Health Project), dissemination of information on cardiovascular disease (CVD) was measured through a media content analysis of newspapers. Data were analyzed from 23 newspapers in six rural counties in southeastern Missouri for the period October 1988 through August 1993. An increase was observed in CVD-related coverage in the pre-intervention period (mean articles per month = 31.5) compared with the post-intervention period (mean articles per month = 50.7) (F = 10.2; P = 0.003). In supporting data from a separate randomized risk factor survey of 1510 residents in the same area, respondents reported hearing of heart health coalitions primarily through local newspapers. The current study documents increasing print media coverage of cardiovascular health issues in a high-risk, rural area and shows that media content analysis can be a useful evaluation tool in community-based interventions.     

Following in the right footsteps

An initiative which targets resources towards chiropody patients with the greatest needs has been taking place in Nottinghamshire during the past three years. Ian Morton and Peter Pratt describe its progress and outline its new goals.     

Cisplatin disposition in children and adolescents with cancer

Summary The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m² (11) or 90 mg/m² (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (±SE) elimination half-life of free cisplatin in serum was 1.3 (±0.4) h. Serial serum concentrations of total platinum following 90 mg/m² dosages were adequately described by a biexponential equation. The mean (±SE) serum T_1/2 of total platinum was 0.42 (±0.10) h and the mean (±SE) T_1/2 was 44.43 (±8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K₁₂) that is about six times the rate of transport out of tissues (K₂₁). The mean (±SE) renal clearance of total platinum from 0–3 h was 37.36 (±11.96) ml/min/m² and 35.8 (±13.6) ml/min/m² for the 30 mg/m² and 90 mg/m² groups, respectively. This value decreased to 3.25 (±0.94) and 2.16 (±0.4) ml/min/m² for the two groups by the 6–12 h interval, and remained between 1 and 3 ml/min/m² for the duration of the observation period. The ratio of total plantinum clearance to creatinine clearance decreased significantly(P<0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.     

Insights from semantic dementia on the relationship between episodic and semantic memory

An influential theory of long-term memory, in which new episodic learning is dependent upon the integrity of semantic memory, predicts that a double dissociation between episodic and semantic memory is not possible in new learning. Contrary to this view, we found, in two separate experiments, that patients with impaired semantic memory showed relatively preserved performance on tests of recognition memory if the stimuli were perceptually identical between learning and test. A significant effect of semantic memory was only seen when a perceptual manipulation was introduced in the episodic task. To account for these findings, we propose a revision to current models of long-term memory, in which sensory/perceptual information and semantic memory work in concert to support new learning.     

Clinical effects and pharmacokinetics of the fusion protein PIXY321 in children receiving myelosuppressive chemotherapy

A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m² per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 μg/m² per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m² (range 77–1804 ml/min per m²) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were <1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients. Received: 29 January 1997 / Accepted: 9 May 1997