Electrical coupling of neuro-ommatidial photoreceptor cells in the blowfly

A new method of microstimulation of the blowfly eye using corneal neutralization was applied to the 6 peripheral photoreceptor cells (R1-R6) connected to one neuro-ommatidium (and thus looking into the same direction), whilst the receptor potential of a dark-adapted photoreceptor cell was recorded by means of an intracellular microelectrode. Stimulation of the photoreceptor cells not impaled elicited responses in the recorded cell of about 20% of the response elicited when stimulating the recorded cell. This is probably caused by gap junctions recently found between the axon terminals of these cells. Stimulation of all 6 cells together yielded responses that were larger and longer than those obtained with stimulation of just the recorded cell, and intensity-response curves that deviated more strongly from linearity. Evidence is presented that the resistance of the axon terminal of the photoreceptor cells quickly drops in response to a light flash, depending on the light intensity. Incorporating the cable properties of the cell body and the axon, the resistance of the gap junctions, and the (adapting) terminal resistance, a theoretical model is presented that explains the measurements well. Finally, it is argued that the gap junctions between the photoreceptor cells may effectively uncouple the synaptic responses of the cells by counteracting the influence of field potentials.

Quantum and Semiclassical Calculations of Cold Atom Collisions in Light Fields

We derive and apply an optical Bloch equation (OBE) model for describing collisions of ground and excited laser cooled alkali atoms in the presence of near-resonant light. Typically these collisions lead to loss of atoms from traps. We compare the results obtained with a quantum mechanical complex potential treatment, semiclassical Landau-Zener models with decay, and a quantum time-dependent Monte-Carlo wave packet (MCWP) calculation. We formulate the OBE method in both adiabatic and diabatic representations. We calculate the laser intensity dependence of collision probabilities and find that the adiabatic OBE results agree quantitatively with those of the MCWP calculation, and qualitatively with the semiclassical Landau-Zener model with delayed decay, but that the complex potential method or the traditional Landau-Zener model fail in the saturation limit.Comment: 21 pages, RevTex, 7 eps figures embedded using psfig, see also http://www.physics.helsinki.fi/~kasuomin

Dynamics and Control of Oscillatory Bioreactors

Bioreactors are widely used in many industries to generate a range of products using various host cells e.g., yeast, insect, and mammalian cells. Depending on the process, product, and host cell, some bioreactors exhibit sustained periodic behavior in key process variables such as metabolite concentrations, biomass, and product titer. Such dynamical behavior can arise from different mechanisms, including predator-prey dynamics, substrate inhibition, and cell sub-population synchrony. Oscillatory dynamical behavior is undesirable as it can impact downstream processes, especially in a continuous operation, and can make process operations and product quality control more challenging. This article provides an overview of oscillatory dynamics. The mechanisms that give rise to the oscillations and process control strategies for suppressing the oscillations are discussed, while providing insights that go beyond past studies. Alternative process configurations are proposed for bypassing the mechanisms that generate oscillations.Comment: Submitted to Biotechnology Progress, ICB V Special Issue (invited). Pavan Inguva and Krystian Ganko contributed equally to this work. Corresponding author: Richard D. Braat

Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals

Objectives Darunavir is a protease inhibitor that is administered with low-dose ritonavir to enhance its bioavailability. It is prescribed at standard dosage regimens of 600/100 mg twice daily in treatment-experienced patients and 800/100 mg once daily in naive patients. A population pharmacokinetic approach was used to characterize the pharmacokinetics of both drugs and their interaction in a cohort of unselected patients and to compare darunavir exposure expected under alternative dosage regimens. Methods The study population included 105 HIV-infected individuals who provided darunavir and ritonavir plasma concentrations. Firstly, a population pharmacokinetic analysis for darunavir and ritonavir was conducted, with inclusion of patients' demographic, clinical and genetic characteristics as potential covariates (NONMEM®). Then, the interaction between darunavir and ritonavir was studied while incorporating levels of both drugs into different inhibitory models. Finally, model-based simulations were performed to compare trough concentrations (Cmin) between the recommended dosage regimen and alternative combinations of darunavir and ritonavir. Results A one-compartment model with first-order absorption adequately characterized darunavir and ritonavir pharmacokinetics. The between-subject variability in both compounds was important [coefficient of variation (CV%) 34% and 47% for darunavir and ritonavir clearance, respectively]. Lopinavir and ritonavir exposure (AUC) affected darunavir clearance, while body weight and darunavir AUC influenced ritonavir elimination. None of the tested genetic variants showed any influence on darunavir or ritonavir pharmacokinetics. The simulations predicted darunavir Cmin much higher than the IC50 thresholds for wild-type and protease inhibitor-resistant HIV-1 strains (55 and 550 ng/mL, respectively) under standard dosing in >98% of experienced and naive patients. Alternative regimens of darunavir/ritonavir 1200/100 or 1200/200 mg once daily also had predicted adequate Cmin (>550 ng/mL) in 84% and 93% of patients, respectively. Reduction of darunavir/ritonavir dosage to 600/50 mg twice daily led to a 23% reduction in average Cmin, still with only 3.8% of patients having concentrations below the IC50 for resistant strains. Conclusions The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be propose

Ageing with HIV: medication use and risk for potential drug-drug interactions

Objectives To compare the use of co-medication, the potential drug-drug interactions (PDDIs) and the effect on antiretroviral therapy (ART) tolerability and efficacy in HIV-infected individuals according to age, ≥50 years or <50 years. Methods All ART-treated participants were prospectively included once during a follow-up visit of the Swiss HIV Cohort Study. Information on any current medication was obtained by participant self-report and medical prescription history. The complete treatment was subsequently screened for PDDIs using a customized version of the Liverpool drug interaction database. Results Drug prescriptions were analysed for 1497 HIV-infected individuals: 477 age ≥50 and 1020 age <50. Older patients were more likely to receive one or more co-medications compared with younger patients (82% versus 61%; P < 0.001) and thus had more frequent PDDIs (51% versus 35%; P < 0.001). Furthermore, older patients tended to use a higher number of co-medications and certain therapeutic drug classes more often, such as cardiovascular drugs (53% versus 19%; P < 0.001), gastrointestinal medications (10% versus 6%; P = 0.004) and hormonal agents (6% versus 3%; P = 0.04). PDDIs with ART occurred mainly with cardiovascular drugs (27%), CNS agents (22%) and methadone (6%) in older patients and with CNS agents (27%), methadone (15%) and cardiovascular drugs (11%) in younger patients. The response to ART did not differ between the two groups. Conclusions The risk for PDDIs with ART increased in older patients who take more drugs than their younger HIV-infected counterparts. However, medication use in older and younger patients did not differ in terms of effect on antiretroviral tolerability and respons