Revascularization of the Posterior Circulation

The primary objective of revascularization procedures in the posterior circulation is the prevention of vertebrobasilar ischemic stroke. Specific anatomical and neurophysiologic characteristics such as posterior communicating artery size affect the susceptibility to ischemia. Current indications for revascularization include symptomatic vertebrobasilar ischemia refractory to medical therapy and ischemia caused by parent vessel occlusion as treatment for complex aneurysms. Treatment options include endovascular angioplasty and stenting, surgical endarterectomy, arterial reimplantation, extracranial-to-intracranial anastomosis, and indirect bypasses. Pretreatment studies including cerebral blood flow measurements with assessment of hemodynamic reserve can affect treatment decisions. Careful blood pressure regulation, neurophysiologic monitoring, and neuroprotective measures such as mild brain hypothermia can help minimize the risks of intervention. Microscope, microinstruments and intraoperative Doppler are routinely used. The superficial temporal artery, occipital artery, and external carotid artery can be used to augment blood flow to the superior cerebellar artery, posterior cerebral artery, posterior inferior cerebellar artery, or anterior inferior cerebellar artery. Interposition venous or arterial grafts can be used to increase length. Several published series report improvement or relief of symptoms in 60 to 100% of patients with a reduction of risk of future stroke and low complication rates.     

Scale-up of Adhesive Transdermal Drug Delivery Systems

Pharmaceutical Research -     

Reversible Adsorption of Soluble Hexameric Insulin onto the Surface of Insulin Crystals Cocrystallized with Protamine: An Electrostatic Interaction

Mixing pharmaceutical preparations of soluble neutral regular insulin solution (NRI) and neutral protamine Hagedorn (NPH) crystalline insulin suspension leads to a reduction in the measurable amount of soluble insulin in the formulation supernatant. However in spite of the loss in soluble insulin, the time-actions of these components have been shown, in clinical trials, to be unaffected. The interaction between these different physical forms of insulin has been studied using reversed-phase HPLC, isothermal titrating calorimetry, and Doppler electrophoretic light scattering analysis. Sorbent surface and solution perturbation studies revealed that the NRI adsorbs to the surface of the NPH crystal with an equilibrium constant ranging from 10⁴ M^–1 to 10⁷ M^–!, depending on the protamine concentration, pH, ionic strength, and temperature. This adsorption behavior suggests that the binding is mediated by electrostatic interactions arising between the positively-charged NPH crystal and the negatively-charged NRI hexamer. Doppler electrophoretic light scattering results, used to probe the pH-dependent surface charge of NPH and soluble insulin hexamer, support the conclusion that electrostatic interactions mediate the adsorption process. Adsorption studies under physiological conditions indicate that the elevated temperature and ionic strength, in a subcutaneous depot, are sufficient to lead to the dissociation of the NRI/NPH complex that exists in these NPH mixture formulations.     

Lateral Skull Base Surgery: The Otology Group Experience

Lateral skull base surgery has remained the surgical frontier of new developments in the treatment of lesions heretofore difficult to access. Examination of surgical results stimulates technical innovation and provides an intervention risk-benefit ratio assessment for particular lesions useful in management planning. With this in mind, we report the updated collective experience with lateral skull base surgery at the Otology Group over the past 20 years. Two hundred ninety-eight patients underwent surgical intervention for lateral skull base lesions. In 81 patients these lesions were malignant; in 217, benign. Of the benign lesions, 165 were glomus tumors: 139 glomus jugulare, 19 glomus vagale, and 7 glomus tympanicum. The remainder comprised 21 menigniomas, 14 neuromas, two neurofibromas, and a small group of much rarer entities. The philosophy of surgical approach, results, and follow-up are discussed.     

Mood state and cerebral metabolism in persons with age-associated memory impairment

People undergoing medical procedures sometimes experience feelings that may influence the results. In this study, we explore the relationship between changes in mood state self-ratings and cerebral glucose metabolism during positron emission tomography (PET) in persons with age-associated memory impairment (mean age 59.4±9.8 years). Brain regions of interest involved in both mood and memory were examined. Mood ratings of increased boredom correlated significantly with mesial temporal and parietal asymmetry and decreased parietal metabolism. Mood ratings of increased fatigue correlated with basal ganglia asymmetry and the right basal ganglia and left mesial temporal metabolism. These findings suggest that subjective mood state changes during PET may influence metabolism in brain regions implicated in emotion and memory function in people with age-related memory complaints.     

Choice of starting dose and escalation for phase I studies of antitumor agents

Summary The standard approaches to initial dose selection and dose escalation in phase I trials may be inappropriately conservative. These approaches mandate accrual of large numbers of patients, most of whom are treated at low and potentially ineffective doses. We compared the clinically determined maximum tolerable dose (MTD) with the starting dose of 45 drugs that had undergone phase I studies during the period 1977–1989. We also examined the number of dose-escalation steps required to achieve the MTD in relation to nonhematologic and hematologic dose-limiting toxicity. The median ratio of MTD to starting dose for all drugs was 20 (range, <1–433) and the median number of dose levels studied to reach the MTD was 8 (range, 0–23). For drugs with nonhematologic dose-limiting toxicity, the median ratio of MTD to starting dose was 30 (range, 3–385) as compared with 12.8 (range, <1–433) for those with hematologic dose-limiting toxicity (P=0.023). The median number of dose-escalation steps required to reach the MTD was 9 (range, 2–18) for drugs with nonhematologic dose-limiting toxicity as compared with 5.5 (range, 0–23) for those with hematologic dose-limiting toxicity (P=0.038). We also examined the response rate for 1,110 patients treated with 21 phase-I-study drugs for which response information was available. Responses were reported for 29 patients (2.6%). Among the 476 patients treated at the 3 highest dose steps, 17 responded (3.6%), which is double the response rate obtained at the lower doses (P=0.08). It is suggested that although the usual methods for choosing starting doses and dose-escalation schemes for phase I studies are safe, they are overly conservative and delay opportunities for therapeutic benefit in phase I and subsequent phase II trials.This research was supported in part by NCI grant 2P30-CA-14236-16     

Reversible reorganisation of the motor cortical representation of the hand in cervical dystonia.

Previous work has suggested that there may be a widespread disturbance of motor control mechanisms in patients with cervical dystonia. In the present study, we used transcranial magnetic stimulation to investigate the topography of the corticomotor projection to the abductor pollicis brevis (APB) muscle in 10 subjects with idiopathic torticollis. Threshold-adjusted stimuli were delivered at multiple scalp sites during a low-level voluntary contraction of the APB, and maps were generated of motor evoked potential amplitude versus scalp site. The cortical maps for the APB on the side opposite to the direction of head rotation were displaced laterally or posteriorly in all subjects and reverted to a more normal position after botulinum toxin injection of the cervical muscles in 5 subjects. The findings point to a reversible reorganisation of the corticomotor representation of the hand on the same side as the sternocleidomastoid (SCM) muscle that is involved in producing the dystonia. These results provide further evidence for the involvement of cortical centres and for a more widespread abnormality of motor control mechanisms in focal dystonia. The findings also support the notion that head turning is chiefly mediated by the hemisphere ipsilateral to the direction of the head rotation by means of a corticomotor projection to the contralateral SCM.     

The effects of pulse configuration on magnetic stimulation.

A study is presented in which the authors have examined the effects of pulse configuration, stimulation intensity, and coil current direction during magnetic stimulation. Using figure-8 and circular coils, the median nerve was stimulated at the cubital fossa and at the wrist of 10 healthy volunteers, and the response amplitude and site of stimulation were determined. The key findings of this study are in agreement with other researchers' findings and confirm that biphasic stimulating pulses produce significantly higher M-wave amplitudes than monophasic stimulating pulses for the same stimulus intensity. Mean response amplitudes for biphasic stimuli applied by both coils at the elbow and wrist are consistently higher for the normal current direction. Mean response amplitudes for monophasic pulses are almost always higher for reversed currents. The site for effective stimulation (the position of the virtual cathode) cannot be defined within a fixed distance from the center of the coil (3 to 4 cm), as has been suggested by other researchers, but was found to vary depending on the coil current amplitude and direction as well as the degree of inhomogeneity of the tissues surrounding the nerve. There is a statistically significant relationship between virtual cathode shift and stimulus intensity for biphasic and monophasic pulses. Reversing the coil current direction has no statistically significant effect on the virtual cathode position. Virtual cathode shifts can be measured for biphasic and monophasic stimulations using a figure-8 coil at the wrist and the elbow. However, such a shift is difficult to determine with a circular coil.