Translational Modeling of Drug-Induced Myelosuppression and Effect of Pretreatment Myelosuppression for AZD5153, a Selective BRD4 Inhibitor.

In this work, we evaluate the potential risk of thrombocytopenia in man for a BRD4 inhibitor, AZD5153, based on the platelet count decreases from a Han Wistar rat study. The effects in rat were modeled and used to make clinical predictions for human populations with healthy baseline blood counts. At doses >10 mg, a dose-dependent effect on circulating platelets is expected, with similar predicted changes for both q.d. and b.i.d. dose schedules. These results suggest that at predicted efficacious doses, AZD5153 is likely to have some reductions in the clinical platelet counts, but within the normal range at projected efficacious doses. The model was then extended to incorporate preexisting myelosuppression where bone marrow function is inhibited by acute myeloid leukemia. Under these conditions, duration of platelet count recovery has the potential to be prolonged due to drug-induced myelosuppression.

Modeling and Simulation Approaches for Cardiovascular Function and Their Role in Safety Assessment.

Systems pharmacology modeling and pharmacokinetic-pharmacodynamic (PK/PD) analysis of drug-induced effects on cardiovascular (CV) function plays a crucial role in understanding the safety risk of new drugs. The aim of this review is to outline the current modeling and simulation (M&S) approaches to describe and translate drug-induced CV effects, with an emphasis on how this impacts drug safety assessment. Current limitations are highlighted and recommendations are made for future effort in this vital area of drug research.

Manipulation of ultracold Rb atoms using a single linearly chirped laser pulse.

At ultracold temperatures, atoms are free from thermal motion, which makes them ideal objects of investigations aiming to advance high-precision spectroscopy, metrology, quantum computation, producing Bose condensates, etc. The quantum state of ultracold atoms may be created and manipulated by making use of quantum control methods employing low-intensity pulses. We theoretically investigate population dynamics of ultracold Rb vapor induced by nanosecond linearly chirped pulses having kW/cm2 beam intensity and show a possibility of controllable population transfer between hyperfine (HpF) levels of 5(2)/S(1/2) state through Raman transitions. Satisfying the one-photon resonance condition with the lowest of the HpF states of 5(2)/P(1/2) or 5(2)/P(3/2) state allows us to enter the adiabatic region of population transfer at very low field intensities, such that corresponding Rabi frequencies are less than or equal to the HpF splitting. This methodology provides a robust way to create a specifically designed superposition state in Rb in the basis of HpF levels and perform state manipulation controllable on the picosecond-to-nanosecond time scale.

Simplified guide for precise implant placement: a technical note.

Ideal implant placement is ultimately determined by the requirements of the final restoration. For the surgeon placing implants, proper angulation, parallelism, and spacing are critical to the final restoration. The use of a stainless-steel drill guide sleeve in an acrylic resin surgical template can make it possible to achieve optimal placement. Communication between the restoring dentist, surgeon, and laboratory technician is enhanced by this system since dowel pins fit precisely into the sleeves and determine sleeve and, ultimately, implant position. This system allows the surgeon to negotiate bony irregularities and ramping defects with ease while preparing a more concentric implant site.

The reverse-torque test: a clinical report.

Reverse torque to failure on implants has been studied in animals. Three implants were reverse torqued to failure in a human volunteer, with failure rates between 45 and 58 Ncm. Clinical data are presented on 404 implants examined after reverse-torque testing and loading, with no increase in failure rates. Reverse-torque testing at 20 Ncm appears to be a safe, reliable method for verifying osseointegration with pure titanium screw-shaped implants.

Laser Doppler study of porcine cauda equina blood flow. The effect of electrical stimulation of the rootlets during single and double site, low pressure compression of the cauda equina.

STUDY DESIGN: This study involved a model of spinal claudication to assess the effect of single and double site compressions on blood flow in porcine cauda equina. Real-time monitoring of blood flow was achieved by using laser Doppler probes. OBJECTIVES: To ascertain the difference between single and double site compressions on blood flow and nerve conduction in the cauda equina. Also, to provide possible explanations for the mechanisms underlying the pathophysiology of neurogenic claudication. SUMMARY OF BACKGROUND DATA: The model used was based on that of K. Olmarker. Double as compared with single site compression of cauda equina showed impaired nerve impulse propagation and decreased blood flow. METHOD: Pigs weighing 22-27 kg were anesthesized and the cauda equina was exposed by dorsal laminectomy of the sacral and first three coccygeal vertebrae. Polyethylene balloons were placed over the rootlets at the first and third coccygeal segments, and stimulating electrodes were positioned on the rootlets proximally to evoke motor activity. Electromyographic activity was monitored from tail musculature. Laser Doppler probes monitored blood flow in the cauda equina both between and distal to the two compression sites. RESULTS: Single site, low level compression did not affect blood flow whereas double site compression decreased it profoundly. Proximal stimulation caused a marked increase in blood flow, which was not sustained during prolonged compression. Electromyographic activity diminished concomitantly during this compression. CONCLUSIONS: Low pressure, double site compression significantly reduces cauda equina blood flow and prevents the sustained increase in blood flow required to maintain normal neurologic rootlet function. Local blood flow failure may therefore be responsible for claudication symptoms.

Team management of atrophic edentulism with autogenous inlay, veneer, and split grafts and endosseous implants: case reports.

Predictable success of autogenous graft and implant reconstructions is critically dependent on preoperative alignment and prosthetic considerations planned by the surgeon and the restorative dentist in a team approach. In such cases the surgeon has an opportunity to place accurate bone grafts that allow implants to be secured in both the correct position and correct axis for good prosthetic restoration. With careful thought, the restorative dentist and surgeon can plan the location, shape, and volume of an implant-graft reconstruction. Nine requirements for successful onlay grating with implants and five case reports illustrating the team approach are presented.

Use of collagen tubes containing particulate hydroxylapatite for augmentation of the edentulous atrophic maxilla: a preliminary report.

Collagen tubes of specific configuration containing particulate hydroxylapatite were placed by a palatal approach to augment edentulous atrophic maxillas. Both the ability to chew and comfort of the denture were improved in the 12 reported cases. Eleven cases showed solidification of the implant between 8 and 16 weeks. There was no problem with particle migration or loss of vestibular height.